EP1315698A1 - Pyrrolidines as inhibitors of neuraminidases - Google Patents

Pyrrolidines as inhibitors of neuraminidases

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Publication number
EP1315698A1
EP1315698A1 EP99917414A EP99917414A EP1315698A1 EP 1315698 A1 EP1315698 A1 EP 1315698A1 EP 99917414 A EP99917414 A EP 99917414A EP 99917414 A EP99917414 A EP 99917414A EP 1315698 A1 EP1315698 A1 EP 1315698A1
Authority
EP
European Patent Office
Prior art keywords
pyrrolidine
acetamido
carboxylic acid
hydrogen
propen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99917414A
Other languages
German (de)
French (fr)
Inventor
Clarence J. Maring
Yu-Gui Gu
Hui-Ju Chen
Yuanwei Chen
David A. Degoey
William J. Flosi
Vincent L. Giranda
David J. Grampovnik
Warren M. Kati
Dale J. Kempf
Larry L. Klein
Allan C. Krueger
Zhen Lin
Darold L. Madigan
Keith F. Mcdaniel
Steven W. Muchmore
Hing L. Sham
Kent D. Stewart
Vincent S. Stoll
Minghua Sun
Gary T. Wang
Sheldon Wang
Yibo Xu
Ming C. Yeung
Chen Zhao
April Kennedy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
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Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1315698A1 publication Critical patent/EP1315698A1/en
Withdrawn legal-status Critical Current

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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase.
  • the invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
  • neuraminidase also known as sialidase
  • viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase.
  • Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1).
  • Some ofthe more important disease- causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus,
  • influenza virus There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
  • Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains.
  • a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus.
  • Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.
  • siastatin B analogs which are useful as neuraminidase inhibitors: Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and
  • An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.
  • An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.
  • Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.
  • Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
  • Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
  • Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
  • the present invention discloses compounds having Formula I:
  • R 1 is selected from the group consisting of
  • R 11 is selected from the group consisting of
  • R 12 and R 36 are independently selected from the group consisting of (i) hydrogen, (ii) C ⁇ -C ⁇ 2 alkyl, (iii) C 2 -C ⁇ 2 alkenyl, (iv) cycloalkyl, (v) (cycioalkyl)alkyl, (vi) (cycloalkyi)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl and (xv) (heterocyclic)alkyl
  • X is selected from the group consisting of
  • R 2 is selected from the group consisting of
  • C1-C3 loweralkyi hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
  • R 3 and R 4 are independently selected from the group consisting of
  • R 3 7 a ⁇ R 3 7 R 47 ⁇ and R 4 8 at eacn occurrence are independently selected from the group consisting of
  • R 37c at each occurrence is independently selected from the group consisting of
  • N(R 37c ) and R 14 when taken together are an azido group
  • N(O)(R 37c ) and R 14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
  • R 15 is selected from the group consisting of
  • R 5 is selected from the group consisting of
  • Q 1 is O, S, or N(R 18 );
  • R 17 and R 18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
  • R 19 , R 38 , and R 40 are independently selected, at each occurrence, from the group consisting of
  • Y is selected from the group consisting of
  • n 0, 1, or 2;
  • Q 2 is O, S, NR 25 , or CHR 26 ; and
  • Q 3 is NR 41 , or CHR 42 ;
  • R 20 at each occurrence is independently
  • R 21 is hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
  • R 23 and R 39 are independently hydrogen or methyl
  • R 41 and R 42 are independently hydrogen, methyl, or ethyl
  • R 24 is selected from the group consisting of
  • Q 4 is O, S, or N(R 33 );
  • R 25 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO 2 ;
  • R 26 group is hydrogen, methyl or ethyl ;
  • R 28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH 3 , -N(CH 3 )2, methoxy, ethoxy, or -CN;
  • R 28b is hydrogen, methyl or ethyl
  • R 28a , R 28b and the nitrogen to which they are bonded taken together represent azetidinyl
  • R 29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
  • R 30 group is hydrogen, methyl, ethyl, -OR 34 , -SR 34 , -N(R 35 ) 2 , -NHOH, -NHNH 2 , -N(CH 3 )NH 2 , or -N(CH 2 CH 3 )NH 2 ;
  • R 31 and R 32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl
  • R 33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO 2 ;
  • R 34 group is methyl or ethyl
  • R 35 group is independently hydrogen, methyl or ethyl
  • R 22 is selected from the group consisting of hydrogen, -CH 3 , -C 2 H 5l -C 3 H 7 , -OCH 3> -SCH 3 , -O-C 2 H 5 , and -S-C 2 H 5 ,
  • R 6 and R 7 are independently selected from the group consisting of
  • R 8 , R 9 , and R 10 are independently selected from the group consisting of
  • -17- Preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula II:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined above and wherein R 3 and R 4 are not both the same.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined above and wherein R 3 and R 4 are not both the same.
  • C- ⁇ -C 3 loweralkyi hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • R 5 is hydrogen or loweralkyi
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are independently hydrogen, fluoro or loweralkyi
  • R 10 is hydrogen, fluoro or loweralkyi
  • More preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R 1 is defined as above;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • R 5 is hydrogen or loweralkyi
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are independently hydrogen or loweralkyi
  • R 10 is hydrogen or loweralkyi
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • R 5 is hydrogen or loweralkyi
  • R 6 and R 7 are independently hydrogen or loweralkyi
  • R 8 and R 9 are independently hydrogen or loweralkyi
  • R 10 is hydrogen or loweralkyi
  • -21- Y is C 2 -C 5 alkenyl, C 2 .C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • More highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R 1 is -CO 2 H;
  • R 3 and R 4 are independently selected from hydrogen, heterocyclic and
  • R ⁇ is hydrogen or loweralkyi
  • R 6 and R 7 are hydrogen independently hydrogen or loweralkyi
  • R 8 and R 9 are hydrogen independently hydrogen or loweralkyi
  • R 10 is hydrogen or loweralkyi
  • Y is C 2 -C 5 alkenyl, C 2 -C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen or loweralkyi and R 3 is heterocyclic or -Z-R 14 wherein Z and R 14 are defined as above;
  • R >5 is hydrogen
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen or loweralkyi and R 3 is (a) heterocyclic, (b) alkyl,
  • R 37a and R 37b are independently selected from the group consisting of
  • -23- R 5 is hydrogen
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • Most highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R 1 is -CO 2 H;
  • R 4 is hydrogen and R 3 is (a) heterocyclic, (b) alkyl or (c) -C(R 37a )(OR 37c )- R 14 wherein R 14 is
  • R 37a and R 37b are independently selected from the group consisting of
  • R 5 is hydrogen
  • R 8 and R 9 are hydrogen ;
  • R 10 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2 -C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen and R 3 is (a) heterocyclic, (b) alkyl or (c) -C(R 37a )(OR 37c )- R 14 wherein R 14 is
  • R 5 is hydrogen
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 10 is hydrogen
  • -25- Y is C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • R 4 is hydrogen and R 3 is -C(R 37a )(OR 37c )-R 14 wherein R 14 is
  • R 5 is hydrogen
  • R 6 and R 7 are hydrogen
  • R 8 and R 9 are hydrogen
  • R 0 is hydrogen
  • Y is C 2 -C 5 alkenyl, C 2- C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • Preferred substituents R 1 include -CO 2 H or esters or prodrugs thereof.
  • Preferred esters include C 2 -C 6 loweralkyi esters or substituted or unsubstituted
  • R 1 include -CO 2 H or esters or prodrugs thereof.
  • Most highly preferred esters include C 2 -C 6 loweralkyi esters or substituted or unsubstituted benzyl esters.
  • C ⁇ -C 3 loweralkyi hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
  • R 3 and R 4 are independently selected from the group consisting of hydrogen, heterocyclic and -Z-R 14 wherein Z and R 14 are defined as most broadly defined previously herein and wherein one of R 3 and R 4 is other than hydrogen.
  • substituent R 4 is hydrogen or loweralkyi and R 3 includes heterocyclic or -Z-R 14 wherein Z and R 14 are defined as most broadly defined previously herein.
  • substituent R 4 is hydrogen or loweralkyi and R 3 includes
  • R 37a and R 37b are independently selected from the group consisting of
  • R 37c is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl.
  • substituent R 4 is hydrogen and R 3 includes
  • R 37a and R 37b are independently selected from the group consisting of
  • R 37c is (i) hydrogen, (ii) C C 3 loweralkyi or (iii) allyl.
  • substituent R 4 is hydrogen and R 3 includes
  • R 37a is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl
  • R 37c is. (i) hydrogen, (ii) C 1 -C 3 loweralkyi or (iii) allyl.
  • substituent R 4 is hydrogen and R 3 includes
  • R 14 is loweralkyi or loweralkenyl
  • R 37a is loweralkyi or loweralkenyl
  • R 37c is hydrogen, C 1 -C 3 loweralkyi or allyl, and especially, wherein R 37c is hydrogen or methyl.
  • R 5 include hydrogen or loweralkyi. Most highly preferred, R 5 is hydrogen.
  • R 6 and R 7 include independently hydrogen and loweralkyi. Most highly preferred, R 6 and R 7 are hydrogen.
  • R 8 , R 9 and R 10 incude independently hydrogen, fluoro and loweralkyi. Most highly preferred, R 8 , R 9 and R 10 are hydrogen.
  • Preferred substituent Y includes C 2 -C 5 alkenyl, C 2 .C 5 haloalkenyl,
  • More preferred substituent Y includes C 2 -C 5 alkenyl
  • substituent Y includes C 2 -C 5 alkenyl, C 2 -C 5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
  • Representative alkenyl and haloalkenyl substituents Y include:
  • -CF CCIBr
  • -C(CH 3 ) CH 2
  • -C(CH 3 ) CHF
  • -C(CH 3 ) CH-CH 3
  • -C(CH 3 ) CH-CF 3
  • Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
  • substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
  • substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
  • Preferred compounds of the invention include compounds selected from the group consisting of:
  • More preferred compounds of the invention include compounds selected from the group consisting of:
  • acid protecting group refers to groups used to protect acid groups (for example, -CO 2 H, -SO 3 H, -SO 2 H, -PO 3 H 2 , -PO 2 H groups and the like) against undesirable reactions during synthetic procedures.
  • acid protecting groups are disclosed in T.H. Greene and P.G.M. uts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991). Most frequently, such acid protecting groups are esters.
  • esters include:
  • alkyl esters especially loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
  • arylalkyl esters including, but not limited to, benzyl, phenethyl, 3- phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part ofthe arylalkyl group is unsubstituted or substituted as previously defined herein;
  • silylesters especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.
  • Preferred acid protecting groups are loweralkyi esters.
  • activated carboxylic acid group refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazoie derived esters, N-hydroxy-5-norbomene-2,3-dicarboximide derived esters, 2,4,5- trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
  • acylamino refers to groups having the formula -NHR 89 wherein R 89 is an acyl group.
  • Representative examples of acylamino include acetylamino, propionylamino, and the like.
  • alkenyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • lower alkenyl refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms.
  • Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1 -propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
  • alkenylene refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond.
  • lower alkenylene refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms.
  • alkenyloxy refers to groups having the formula -OR 81 where R 81 is an alkenyl group.
  • alkoxy refers to groups having the formula -OR 99 wherein R 99 is an alkyl group. Preferred R 99 groups are loweralkyi groups.
  • alkoxy groups include groups such as, for example, methoxy, ethoxy, ferf-butoxy, and the like.
  • alkoxyalkoxy refers to groups having the formula -O-R 96 -O-R 97 wherein R 97 is loweralkyi, as defined herein, and R 96 is a lower alkylene group.
  • Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, £-butoxymethoxy and the like.
  • alkoxyalkyl refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
  • alkyl refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms.
  • loweralkyi refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms.
  • Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, /so-propyl, n-butyl, / ' so-butyl, sec-butyl, f-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl- propyl, n-hexyl, and the like.
  • hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R 27 )- and sulfur wherein R 27 at each occurrence is independently hydrogen, loweralkyi, cylcoalkyl, cycloalkylalkyl or arylalkyl and
  • alkylamino refers to groups having the formula -NHR 91 wherein R 91 is an alkyl group. Preferred R 9 groups are loweralkyi groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
  • alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon.
  • lower alkylene refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms.
  • alkylene groups include groups such as, for example, methylene (-CH2-), 1,2-ethylene (-CH 2 CH 2 -), 1 ,1-ethylene (-CH(CH 3 )-), 1 ,3-propylene (-CH 2 CH 2 CH 2 -), 2,2-dimethylpropylene (-CH 2 C(CH 3 ) 2 CH 2 -), and the like.
  • hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R 27 )- and sulfur wherein R 27 at each occurrence is independently hydrogen, loweralkyi, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
  • alkylsulfonyl refers to the group having the formula, -SO 2 -R 78 , where R 78 is an alkyl group. Preferred groups R 78 are loweralkyi groups.
  • alkylsulfonylamino refers to the group having the formula, -SO 2 -R 77 , appended to the parent molecular moiety through an amino linkage (-NH-), where R 77 is an alkyl group.
  • Preferred groups R 77 are loweralkyi groups.
  • alkynyl refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
  • lower alkynyl refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms.
  • Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
  • alkynylene refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond.
  • lower alkynylene refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms.
  • Representative examples of alkynylene groups include groups such as, for example, -C ⁇ C-, -CH 2 -C ⁇ C-, -C ⁇ C-CH 2 -, -CH(CH 3 )-C ⁇ C-, and the like.
  • aminoalkyl refers to an alkyl radical to which is appended an amino (-NH 2 ) group.
  • aryl refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings.
  • Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyi and the like.
  • aryl substituents are each independently selected from the group consisting of loweralkyi, halo, haloalkyl, hydroxy, hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro.
  • substituted aryl examples include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methyisulfonylphenyl, and the like.
  • (aryl)alkenyl refers to a lower alkenyl group having appended thereto an aryl group.
  • Representative examples of (aryl)alkenyi groups include groups such as, for example phenylethylenyl, phenyipropenyl, and the like.
  • (aryl)alkyl refers to a loweralkyi group having appended thereto an aryl group.
  • Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
  • arylalkoxy refers to the group having the formula, -O-R 76 where R 76 is an arylalkyl group.
  • (aryl)alkynyl refers to an alkynylene group having appended thereto an aryl group.
  • Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
  • aryloxy refers to the group having the formula, -O-R 72 , where R 72 is an aryl group.
  • carboxyalkyl refers to the group having the formula, -R ⁇ -COOH, where R 64 is a lower alkylene group.
  • cyanoalkyi refers to an alkyl radical to which is appended a cyano group (-CN).
  • cycloalkenyl refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure.
  • Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
  • Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyi.
  • Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
  • (cycloalkenyl)alkenyl refers to a cycloalkenyl group appended to a lower alkenyl radical.
  • Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
  • (cycloalkenyl)alkyl refers to a cycloalkenyl group appended to a lower alkyl radical.
  • Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
  • (cycloalkenyl)alkynyl refers to a cycloalkenyl group appended to a lower alkynyl radical.
  • Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
  • cycloalkyl refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings.
  • Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomane, bicyclo[2.2.2]octane and the like.
  • Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyi.
  • Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
  • (cycloalkyl)alkyl refers to a cycloalkyl group appended to a loweralkyi radical.
  • Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
  • (cycloalkyl)alkenyl refers to a cycloalkyl group appended to a lower alkenyl radical.
  • Representative examples of (cycloalkyl)- alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.
  • (cycloalkyl)alkynyl refers to a cycloalkyl group appended to a lower alkynyl radical.
  • Representative examples of (cycloalkyl)- alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
  • dialkylamino refers to groups having the formula -N(R 90 ) 2 wherein each R 90 is independently a lower alkyl group.
  • Representative examples of dialkylamino include dimethylamino, diethylamino, N- methyl-N-isopropylamino and the like.
  • halo refers to F, CI, Br or I.
  • haloalkenyl refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen.
  • haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1 ,2- difluoroethylene, trifluoroethylene, 1 ,1 ,1-trifluoro-2-propylene and the like.
  • haloalkoxy refers to the group having the formula, -OR 69 , where R 69 is a haloalkyl group as defined herein.
  • examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
  • haloalkyl refers to a loweralkyi group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, pentafluoroethyl and the like.
  • heterocyclic ring or “heterocyclic” or “heterocycle” as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions.
  • heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
  • Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl,
  • X * is -CH 2 or -O- and Y * is -C(O)- or [-C(R 92 ) 2 -] V
  • R 92 is hydrogen or C 1 -C 4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like.
  • Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
  • Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyi, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen.
  • nitrogen containing heterocyclic rings can be N-protected.
  • (heterocyclic)alkenyl refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
  • (heterocyclic)alkoxy refers to the group having the formula, -OR 68 , where R 68 is a (heterocyclic)alkyl group.
  • heterocyclicalkyl refers to a heterocyclic group appended to a loweralkyi radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
  • heterocyclicalkynyl refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
  • heterocyclicoxy refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-O-).
  • hydroxy protecting group refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Such hydroxy protecting groups include:
  • substituted methyl ethers including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t- butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
  • substituted ethyl ethers including, but not limited to, 1-ethoxyethyl, 1- methyl-1-methoxyethyl, 1 -methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
  • substituted benzyl ethers including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
  • silyl ethers including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
  • esters including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichioroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
  • Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
  • hydroxyalkyi refers to the group having the formula, -R 65 -OH, where R 65 is an alkylene group
  • leaving group refers to a group which is easily displaced from the compound by a nucleophile.
  • leaving groups include a halide (for example, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,
  • N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
  • thioalkoxy refers to groups having the formula -SR 98 wherein R 98 is an alkyl group. Preferred groups R 98 are loweralkyi groups.
  • thio-substituted alkyl refers to an alkyl radical to which is appended a thiol group (-SH).
  • the compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention
  • -53- are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers.
  • substantially free is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
  • Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
  • Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
  • Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
  • Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries.
  • the resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries.
  • Enzymes such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
  • soivates and hydrates of the compounds of Formula I and II and III are meant to be included in this invention.
  • any variable for example R 1 , R 2 , R 3 , m, n, etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • combinations of substituents are permissible only if such combinations result in stable compounds.
  • Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
  • This invention is intended to encompass compounds having Formula I and II and III when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
  • R 1 is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R 1 substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
  • R 4 , R 8 , R 7 , R 8 , R 9 and R 10 are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
  • reaction of acrolein with an N-protected ⁇ -amino acid ester 1 (P 1 is an N-protecting group, preferably a benzyl group or the like and P 2 is a carboxylic acid protecting group, preferably a t-butyl group or the like) in an inert solvent (for example, toluene and the like) in the presence of an acid catalyst (for example, acetic acid and the like), followed by equilibration with a base (for example, with triethylamine or the like) and separation of the isomers by chromatography, provides substituted pyrrolidine 2.
  • P 1 is an N-protecting group, preferably a benzyl group or the like and P 2 is a carboxylic acid protecting group, preferably a t-butyl group or the like
  • an inert solvent for example, toluene and the like
  • an acid catalyst for example, acetic acid and the like
  • Alcohol 3 can be protected with an hydroxy protecting group P 3 (preferably with a silyl protecting group, for example, t-butyldimethylsilyl or the like) using standard alcohol protection methods to provide 4.
  • Oxidation of the vinyl group of compound 4 to an aldehyde is accomplished by reacting compound 4 with OsO 4 and N-methylmorpholine N-oxide to give the corresponding diol. The diol is then treated with sodium periodate to provide aldehyde 5.
  • Substituents R 3 can be introduced via reaction of aldehyde 5 with a Grignard reagent (for example, R 3 MgBr or the like) to give alcohol 6.
  • Oxidation of alcohol 6 for example, Swern
  • ketone 7 Reductive amination of ketone 7 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 8.
  • Amine 8 can be further functionalized to complete the introduction of the R 2 -X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 9a.
  • the other diastereomeric amine (9b) can also be isolated and further transformed according to Scheme 1.
  • hydroxy protecting group P 3 for example, by reaction with a fluoride ion source, such as tetrabutylammonium fluoride or the like, when P 3 is a silyl protecting group
  • a fluoride ion source such as tetrabutylammonium fluoride or the like
  • Transformation of the hydroxy group of alcohol 10 allows introduction of various substituents Y.
  • alkylation of the hydroxy group provides ethers H.
  • N- deprotection for example, where P 1 is a benzyl group, by hydrogenation
  • ester hydrolysis for example, with acid such as HCl
  • Oxidation of the hydroxy group of 0 (for example, Swern oxidation or the like) provides aldehyde 13.
  • Oxidation of aldehyde 13 (for example, with NaCIO 2 or the like) provides carboxylic acid 14.
  • the carboxylic acid substituent of 14 can be used to introduce a variety of other functional groups in substituent Y.
  • N-deprotection (for example, where P 1 is a benzyl group, by hydrogenation) gives 16 ⁇ , followed by ester hydrolysis (for example, with acid such as HCl), provides compound IjT of the invention.
  • aldehyde group of 13 or the carboxylic acid group of 14 can be used to introduce substituents Y which are -CN or various heterocycles, according to methods known to those skilled in the art and according to the specific methods exemplified herein.
  • aldehyde 13 for example, with Ph 3 PCH 2 or the like
  • hydrogenation causing N-deprotection (for example, where P 1 is a benzyl group) and olefin saturation
  • ester hydrolysis for example,
  • Olefination of 26a (for example, with Ph 3 PCH 2 , or triphenylphosine/methylene chloride/n-BuLi, or l " Ph 3 P + CH 2 CH3/KOtBu, or the like) provides 27 wherein Y is an olefinic substituent.
  • N-deprotection of the P 5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 28 wherein Y is an olefinic substituent.
  • the hydroxy group of alcohol 3 is protected with a base-labile hydroxy protecting group P 6 (for example, acetyl or the like) to give compound 29.
  • a base-labile hydroxy protecting group P 6 for example, acetyl or the like
  • Oxidation of the vinyl group of 29 with OsO 4 and N-methylmorpholine N-oxide provides diol 30.
  • Removal of the P 1 protecting group (for example, by hydrogenation or the like) provides pyrrolidine 3 .
  • Reprotection with an acid-labile N-protecting group P 5 (for example, t-butoxycarbonyl or the like) provides 32.
  • a hydroxy protecting group P 7 for example, a silyl protecting group such as triisopropylsilyl or the like
  • a hydroxy protecting group P 7 for example, a silyl protecting group such as triisopropylsilyl or the like
  • Oxidation of 33 for example, Swern oxidation or the like
  • ketone 34- Reductive amination of ketone 34 for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like gives amine 35.
  • -60- Amine 35 can be further functionalized to complete the introduction of the R 2 -X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 36a.
  • the other diastereomeric amine (36b) can also be isolated and further transformed according this scheme.
  • the alcohol can serve as a precursor for a variety of R 3 substituents in the compounds of the invention.
  • the alcohol of 40 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 4 . .
  • Aldehyde 4_1 can be reacted with Grignard reagents (R 14 MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R 14 Li or the like) to provide 42 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 42a and the other isomer 42b.
  • Grignard reagents R 14 MgBr or the like
  • organometallic reagents for example, organolithium reagents such as R 14 Li or the like
  • Isomer 42a or the mixture of isomers 42 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 43.
  • Reduction of ketone 43 (for example, with sodium borohydride in ethanol or the like) provides alcohol 42b as the major isomer, which can be isolated by chromatography.
  • reaction of ketone 43 with with Grignard reagents (R 37a MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R 37a Li or the like) provides alcohols 46a and 46b as a mixture of alcohol diastereomers which can be separated chromatographically.
  • organolithium reagents such as R 37a Li or the like
  • Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
  • R 22 ⁇ )- is an ester or amide
  • R 22 is loweralkyi or loweralkenyl o
  • Y is an alkene
  • Y is an alkene 40 or haloalkene
  • P 1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P 2 is a carboxylic acid protecting group (preferrably, a loweralkyi group, especially t-butyl); preferrably, P 1 and P 2 can be selectively deprotected/removed; or a salt thereof;
  • P 1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P 2 is a carboxylic acid protecting group (preferably, a
  • P , P 2 and P 3 can be selectively deprotected/removed; or a salt thereof;
  • P 1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P 2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P 4 is hydrogen or an N-protecting group (preferably, a carbamate N-protecting group, for example, benzyloxycarbonyl and the like); preferrably, P 1 , P 2 and P 4 can be selectively deprotected/removed; or a salt thereof;
  • P 5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P 2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P 6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P 7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); preferrably, P 2 , P 5 , P 6 and P 7 can be selectively deprotected/removed; or a salt thereof; and
  • P 5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P 2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P 6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P 7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); and R 2 is defined as herein (preferably, loweralkyi or haloloweralkyl; most preferably, methyl or trifluoromethyl); preferrably, P 2 , P 5 , P 6 and P 7 can be selectively deprotected/removed; or a salt thereof.
  • N-protecting group preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like
  • the reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
  • Acrolein (8 mL, 120 mmole) was added to a solution of f-butyl N-benzyl- glycinate (4.34 g, 19.6 mmole) and acetic acid (5 drops) in toluene (100 mL). The solution was heated at reflux. After 1 hour, the reaction was cooled to about 50 °C and an additional 3 mL of acrolein were added. The reaction was heated at reflux for an additional 2 hours and concentrated in vacuo.
  • the residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide a mixture of ( ⁇ )-(2S,3R,5R)- and ( ⁇ )-(2S,3S,5R)-1-benzyl-2-vinyl-3- formyl-pyrrolidine-5-carboxylic acid -butyl esters as an oil (yield: 2.78 g, 45%).
  • the mixture of aldehydes was equilibrated to an 8:1 ratio by stirring the crude product with triethylamine (0.5 mL) in ethyl acetate at room temperature followed by evaporation of the solvents.
  • the crude diol was dissolved in 6:1 tetrahydrofuran (THF)/water (50 mL) and treated with sodium periodate (3.0 g, 14.0 mmole). The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate, washed with water, dried over MgSO , filtered, and concentrated in vacuo.
  • the crude aldehyde was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 1.6 g, 46%).
  • reaction mixture was cooled to -30 °C and ( ⁇ )-(2R,3R,5R)-1-benzyl-2-formyl- 3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (0.5 g, 1.15 mmole) in of THF (6 mL) was added, dropwise.
  • the reaction was slowly warmed to -10 °C, over a period of about 2 hours, and quenched with aqueous ammonium chloride.
  • the resultant slurry was diluted with ethyl acetate and washed with water, brine, and dried over MgSO 4 and concentrated.
  • DiazaldTM (0.5 g, 2.33 mmole) in 5 mL of ether was added slowly to a solution of aqueous KOH (0.5 g in 1 mL of water) and 1 mL of ethanol maintained at 65 °C.
  • Diazomethane was distilled into a receiving flask charged with a solution of ( ⁇ )-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (30 mg, 0.065 mmole) in 3 mL of THF.
  • the receiving flask was cooled to 0 °C in an ice/water bath.
  • the condenser was cooled with dry ice/acetone and 3 mL of ether was added the distilling flask until the distillate was colorless.
  • the reaction was stirred for an additional 0.5 hours at 0 °C.
  • the yellowish reaction mixture was quenched with acetic acid (0.1 mL ) and diluted with ethyl acetate.
  • the organic layer was washed with 10% NaHCO 3 and brine, dried with MgSO and concentrated in vacuo.
  • the residue was purified by chromatography on silica gel using 50 % ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 20 mg, 65%).
  • the title compound is prepared by reacting a solution of ( ⁇ )- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester with hydroxylamine hydrochloride and 10% aqueous potassium carbonate in methanol according to the procedure described by Chelucci et al., Tetrahedron: Asymmetry 5:1973 (1994).
  • the title compound is prepared by reacting a solution of ( ⁇ )- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxyiminoformyl)- pyrrolidine-5-carboxyiic acid f-butyl ester with 1 ,1'-carbonyldiimidazole in dichloromethane according to the procedure described by Cheiucci et al., Tetrahedron: Asymmetry 5:1973 (1994).
  • the title compound is prepared according to the method described in Example U, substituting ( ⁇ )-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of ( ⁇ )- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxyiic acid f-butyl ester.
  • the title compound is prepared according to the method described in Example 1 K, substituting ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of ( ⁇ )-(2R,3R,5R,1'S)-2- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrroiidine-5-carboxylic acid f- butyl ester.
  • the title compound was prepared according to the method described in Example 1 K, substituting ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3- ethyl)pentyl-3-(N-methylcarbamoyl)pyrroiidine-5-carboxylic acid f-butyl ester in place of ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.
  • the title compound was prepared according to the method described in Example 1 K, substituting ( ⁇ )-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(N- (t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of ( ⁇ )-(2R,3R,5R,1 'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.

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Abstract

Disclosed are compounds of formula (I) which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

Description

PYRROLIDINES AS INHIBITORS OF NEURAMINIDASES
Technical Field
The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
Background of the Invention
Many disease-causing microorganisms possess a neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some ofthe more important disease- causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus,
-1- Newcastle disease virus, fowl plague virus, equine influenza virus and Sendai virus.
Mortality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains. Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus. Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von Itzstein, et al., European Patent Application No. EP539204, published April 28, 1993 (antiviral agent);
T. Honda, et al., European Patent Application No. EP823428, published February 11 , 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. WO98/06712, published February 19, 1998 (sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. WO95/20583, published August 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. WO95/18800, published July 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. WO92/06691 , published April 30, 1992 (viral neuraminidase inhibitor);
L Von Itzstein, et al., U.S. Patent No. 5,648,379, issued July 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. WO97/32214, published September 4, 1997 (bind to influenza virus neuraminidase active site); and
P. Reece, et al., International Patent Application No. WO98/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility listed after each reference:
-3- Y. Ohira, et al., International Patent Application No. WO98/11083, published March 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721 , published December 9, 1998 (antiviral agent); and
B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Patent No. 5,602,277, issued February 11 , 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Patent No. 5,453,533, issued September 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. WO96/30329, published October 3, 1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Patent No. 5,763,483, issued June 9, 1998 (neuraminidase inhibitor); and
K. Kent, et al., International Patent Application No. 98/07685, published February 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. WO98/17647, published April 30, 1998 discloses piperidine derivatives which are useful as neuraminidase inhibitors.
N. Bischofberger, et al., International Patent Application No. WO96/26933, published September 6, 1996 discloses various substituted 6-membered ring compounds which are useful as neuraminidase inhibitors. The following references disclose dihydropyran derivatives which are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. WO97/06157, published February 20, 1997; and
P. Cherry, et al., International Patent Application No. WO96/36628, published November 21 , 1996.
C. Kim, et al., U.S. Patent No. 5,512,596, issued April 30, 1996 discloses 6-membered aromatic ring derivatives which are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No. WO98/03487, published January 29, 1998 discloses substituted pyridazines which are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No. WO99/06369, published February 11 , 1999 discloses piperazine derivatives which are useful as neuraminidase inhibitors.
Y. Babu, et al., International Patent Application No. WO97/47194, published December 18, 1997 discloses substituted cyclopentanes which are useful as neuraminidase inhibitors and treatments for influenza.
L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid which are useful as Vibrio cholerae sialidase inhibitors.
The following references disclose siastatin B analogs which are useful as neuraminidase inhibitors: Y. Nishimura, et al., Natural Product Letters 1 39-44 (1992); and
Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).
-5- C. Penn, UK Patent Application No. GB2292081 , published February 14, 1996 discloses the use of a neuraminidase inhibitor in combination with an influenza vaccine.
An object of the invention is to provide compounds which inhibit neuraminidase of disease-causing microorganisms; especially, viral neuraminidase; and, most especially, influenza neuraminidase.
An object of the invention is also to provide compounds which inhibit neuraminidase from both A and B strains of influenza.
Another object of the invention is to provide prohylaxis of influenza infection in humans and other mammals.
Another object of the invention is to provide treatment of influenza infection in humans and other mammals.
Another object of the invention is to provide compounds which exhibit activity against influenza A virus and and influenza B virus by virtue of inhibiting influenza neuraminidase when such compounds are administered orally.
Another object of the invention is to provide a compound which can be effectively transported from the plasma into the lung bronchoaveolar fluid of humans and other mammals in order to block the replication of influenza virus in that tissue.
-6- Disclosure of the Invention
The present invention discloses compounds having Formula I:
I or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1 is selected from the group consisting of
(a) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO H,
(f) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2) (i) -PO2H, 0) -CH2PO2H,
(k) tetrazoiyl, (I) -CH -tetrazolyl, (m) -C(=O)-NH-S(O)2-R11,
(n) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 and
(p) -CH2SO2N(T-R11)R12 wherein T is selected from the group consisting of
(i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR36-
(vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR36-,
R11 is selected from the group consisting of
(i) C1-C12 alkyl, (ii) C2-C-ι2 alkenyl, (iii) cycloalkyl, (iv) (cyclo- alkyl)alkyl,
(v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl,
(viii) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl,
(xii) heterocyclic, (xiii) (heterocyclic)alkyl and (xiii) (xiv) (heterocyciic)alkenyl; and R12 and R36 are independently selected from the group consisting of (i) hydrogen, (ii) Cι-Cι2 alkyl, (iii) C2-Cι2 alkenyl, (iv) cycloalkyl, (v) (cycioalkyl)alkyl, (vi) (cycloalkyi)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of
(a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-,
(e) -N(R*)-SO2-, and (f) -SO2-N(R*)- wherein R* is hydrogen, C1-C3 loweralkyi or cyclopropyl;
R2 is selected from the group consisting of
(a) hydrogen, (b) d-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl,
(e) C5-C6 cycloalkenyl, (f) halo CrC6 alkyl and (g) halo C2-C6 alkenyl; or R2-X- is
vA °
Ύ2 wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)(Rbb)- wherein Raa and Rbb are indepedently selected from the group consisting of hydrogen,
C1-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from the group consisting of
(a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and
(f) -Z-R14
-8- wherein Z is
(i) -C(R37a)(R37 )-, (ii) -C(R47)=C(R48)-, (iii) -OC-, (iv) -C(=O)-,
(v) -C(=S)-, (vi) -C(=NR15)-, (vii) -C(R37a)(OR37c)-, (viii) - C(R37a)(SR37c)-,
(ix) -C(R37a)(N(R37b)(R37c))-, (x) -C(R37a)(R37b)-O-,
(xi) -C(R37a)(R37b)-N(R370)-, (xii) -C(R37a)(R37b)-N(O)(R37c)-,
(xiii) -C(R37a)(R37b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-,
(xv) -C(R37a)(R37b)-S(O)-, (xvi) -C(R37a)(R37b)-S(O)2-,
(xvii) -C(R37a)(R37b)-C(=O)-, (xviii) -C(R37a)(R37b)-C(=S)-,
(xix) -C(R37a)(R37b)-C(=NR15)-, (xx) -C(R37a)(OR37c)-C(=O)-,
(xxi) -C(R37a)(SR37c)-C(=O)-, (xxii) -C(R37a)(OR37c)-C(=S)-,
(xxiii) -C(R37a)(SR37c)-C(=S)-, (xxiv) -C(=O)-C(R37a)(OR37c)-,
(xxv) -C(=O)-C(R37a)(SR37c)-, (xxvi) -C(=S)-C(R37a)(OR37c)-,
(xxvii) -C(=S)-C(R37a)(SR37c)-, (xxviii) -C(R37a)(OR37c)-C(R37a)(OR37c)-,
(xxix) -C(R37a)(SR37c)-C(R37a)(OR37c)-,
(xxx) -C(R37a)(OR37c)-C(R37a)(SR37c)-,
(xxxi) -C(R37a)(SR37c)-C(R37a)(SR37c)-, (xxxii) -C(=O)-C(=O)-,
(xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-, (xxxv) -C(=O)-S-,
(xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R37a)-,
(xxxix) _C(=S)-N(R37a)-, (xl) -C(R37a)(R37b)-C(=O)-N(R37a)-,
(xli) -C(R37a)(R37b)-C(=S)-N(R37a)-, (xiii) -C(R37a)(R37b)-C(=O)-O-,
-9- (xliii) -C(R37a)(R37b)-C(=O)-S-, (xliv) -C(R37a)(R37b)-C(=S)-O-,
(xiv) -C(R37a)(R37 )-C(=S)-S-, (xlvi) -C(R37a)(R37b)-N(R37b)-C(=O)-,
(xlvii) -C(R37a)(R37b)-N(R37b)-C(=S)-, (xlviii) -C(R37a)(R37b)-O-C(=O)-,
(xiix) -C(R37a)(R37 )-S-C(=O)-, (I) -C(R37a)(R37b)-O-C(=S)-,
(Ii) -C(R37a)(R37b)-S-C(=S)-, (Iii) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-,
(liii) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-,
(liv) -C(R37a)(R37b)-N(R37b)-C(=O)-O-,
(lv) -C(R37a)(R37b)-N(R37b)-C(=O)-S-,
(lvi) -C(R37a)(R37b)-N(R37b)-C(=S)-O-,
(lvii) -C(R37a)(R37b)-N(R37b)-C(=S)-S-,
(lviii) -C(R37a)(R37b)-O-C(=O)-N(R37a)-,
(lix) -C(R37a)(R37b)-S-C(=O)-N(R37a)-,
(lx) -C(R37a)(R37b)-O-C(=S)-N(R37a)-,
(Ixi) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (Ixii) -C(R37a)(R37b)-O-C(=O)-O-,
(Ixiii) -C(R37a)(R37b)-S-C(=O)-O-, (Ixiv) -C(R37a)(R37b)-O-C(=O)-S-,
(Ixv) -C(R37a)(R37b)-S-C(=O)-S-, (Ixvi) -C(R37a)(R37b)-O-C(=S)-O-,
(Ixvii) -C(R37a)(R37b)-S-C(=S)-O-, (Ixviii) -C(R37a)(R37b)-O-C(=S)-S-,
(Ixix) -C(R37a)(R37b)-S-C(=S)-S- or (Ixx) -C(R37a)(R37b)-C(R37a)(OR37c)-;
is
(i) hydrogen, (ii) Cι-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) thiol-substituted alkyl, (vi) R37cO-substituted alkyl,
-10- (vii) R37cS-substituted alkyl, (viii) aminoalkyl,
(ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl,
(xi) R37aO-(O=)C-substituted alkyl, (xii) R37aS-(O=)C-substituted alkyl, (xiii) R37aO-(S=)C-substituted alkyl,
(xiv) R37aS-(S=)C-substituted alkyl,
(xv) (R37aO)2-P(=O)-substituted alkyl, (xvi) cyanoalkyl,
(xvi) C2-Cι2 alkenyl, (xviii) haloalkenyl, (xix) C2-C12 alkynyl,
(xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,
(xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,
(xxv) (cycloalkenyl)alkyl,
(xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl,
(xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,
(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,
(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,
with the proviso that R14 is other than hydrogen when Z is
-C(R37a)(R37b)-N(R37b)-C(=O)-O-, -C(R37a)(R37b)-N(R37b)-C(=S)-O-,
-C(R37a)(R37 )-N(R37b)-C(=O)-S-, -C(R37a)(R37b)-N(R37b)-C(=S)-S-,
-C(R37a)(R37b)-O-C(=O)-O-, -C(R37a)(R37b)-O-C(=S)-O-,
-C(R37a)(R37b)-S-C(=O)-O-, -C(R37a)(R37b)-S-C(=S)-O-,
-C(R37a)(R37b)-O-C(=O)-S-, -C(R37a)(R37b)-O-C(=S)-S-,
-11- -C(R37a)(R37b)-S-C(=O)-S- or -C(R37a)(R37b)-S-C(=S)-S-;
• R37a^ R37 R 47 ^ and R 48 at eacn occurrence are independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,
(v) alkoxyalkyl, (vi) C2-C12 alkenyl, (vii) haloalkenyl,
(viii) C2-C12 alkynyl, (ix) cycloalkyl,
(x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl,
(xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)- alkenyl,
(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,
(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,
(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and
(xxiv) (heterocyclic)alkynyl;
R37c at each occurrence is independently selected from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl,
(v) haloalkenyl, (vi) C2-C12 alkynyl, (vii) cycloalkyl,
(viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl,
(xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl,
(xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl,
-12- (xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic,
(xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,
(xxii) (heterocyclic)alkynyl, (xxiii) -C(=O)-R14, (xxiv) -C(=S)-R14,
(xxv) -S(O)2-R14 and (xxvi) hydroxyalkyl;
or when Z is -C(R37a)(R37b)-N(R37c)-, then N(R37c) and R14 when taken together are an azido group;
or when Z is -C(R37a)(R37b)-N(O)(R37c)-, then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R37a)(OR37c)-, -C(R37a)(SR37c)- or
-C(R37a)(N(R37b)(R37c))-, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;
R15 is selected from the group consisting of
(i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C-ι-C12 alkyl, (v) haloalkyl,
(vi) C2-C12 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl,
(ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl,
(xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl,
(xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic,
(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
-13- or R3 and R4 taken together, with the atom to which they are attached, form a carbocyciic or heterocyclic ring having from 3 to 8 ring atoms;
R5 is selected from the group consisting of
(a) hydrogen, (b) -CH(R38)2, (c) -O-R40, (d) C2-C4 alkynyl, (e) cyclopropyl,
(f) cyclobutyl, (g) -C(=Q1)-R17, and (h) -N(R19)2
wherein Q1 is O, S, or N(R18);
R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C 2 alkenyl,
(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,
(viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloaikenyl)alkyl,
(xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl,
(xv) heterocyclic, (xvi) (heterocyclic)alkyl and
(xvii) (heterocyclic)alkenyl;
Y is selected from the group consisting of
(a) hydrogen, (b) C C5 alkyl, (c) C C5 haloalkyl, (d) C2-C5 alkenyl,
(e) C2-C5 haloalkenyl, (f) C2-C5 alkynyl, (g) C3-C5 cycloalkyl,
(h) C3-C5 cycloalkyl-Cι-to-C3-alkyl, (i) C5 cycloalkenyl, (j) C5 cycloalkenyl-Cι-to- Cs-alkyl, (k) C5 cycloalkenyl-C2-to-C3-alkenyl, (I) -(CHR39)nOR20, (m) -CH(OR20)- CH2(OR20), (n) -(CHR39)nSR21, (o) -(CHR39)nCN, (p) -(CHR39)πN3, (q) phenyl,
-14- (r) halo-substituted phenyl, (s) -(CHR39)nC(=Q2)R22, (t) -(CHR39)nN(=Q3), (u) -N(O)=CHCH3, (v) -(CHR39)nNR23R24, (w) halo and (x) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1, or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42; R20 at each occurrence is independently
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) C1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl,
(x) allyl, (xi) C2-C3 haloalkenyl, (xii) amino, (xiii) -NHCH3l (xiv) -N(CH3)2,
(xv) -NHCH2CH3, (xvi) -N(CH3)(CH2CH3), (xvii) -N(CH2CH3)2 or
(xviii) -N(=CH2);
R21 is hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) CrC3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
R22 is
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,
(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio,
(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl,
(xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R28a)(R28b),
(xxiii) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl,
-15- (xxvi) thiolmethyl, (xxvii) -NHNH2, (xxviii) -N(CH3)NH2 or
(xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of
(i) hydrogen, (ii) Cι-C4 alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl,
(v) cyclopropyl, (vi) -C(=Q4)-R30, (v) -OR31, and (vi) -N(R32)2,
wherein Q4 is O, S, or N(R33);
R25 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R26 group is hydrogen, methyl or ethyl ;
R28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, -OR34, -SR34, -N(R35)2, -NHOH, -NHNH2, -N(CH3)NH2, or -N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
-16- R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, -CH3, -C2H5l -C3H7, -OCH3> -SCH3, -O-C2H5, and -S-C2H5,
and with the proviso that when R3 and R4 are each hydrogen, then Y is other than hydrogen;
R6 and R7 are independently selected from the group consisting of
(a) hydrogen, (b) C1-C12 alkyl, (c) C2-Cι2 alkenyl, (d) cycloalkyl,
(e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cycloalkenyl)alkyl,
(i) (cycloalkenyl)alkenyl, G) aryl, (k) (aryl)alkyl, (I) (aryl)alkenyl, (m) heterocyclic,
(n) (heterocyclic)alkyl and (0) (heterocyclic)alkenyl; and
R8, R9, and R10 are independently selected from the group consisting of
(a) hydrogen, (b) Cι-C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl,
(e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
-17- Preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 and R4 are not both the same.
Other preferred compounds of the invention are compounds having the relative sterochemistry depicted by Formula III:
III
-18- or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined above and wherein R3 and R4 are not both the same.
Other preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is Cι-C3 loweralkyi, halo C C3 loweralkyi, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is
γ1_^
Y2 wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
C-ι-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are independently hydrogen or loweralkyi;
R8 and R9 are independently hydrogen, fluoro or loweralkyi;
-19- R10 is hydrogen, fluoro or loweralkyi; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as above.
More preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is defined as above;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi, halo C1-C3 loweralkyi, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is
γ2 wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
C1-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are independently hydrogen or loweralkyi;
R8 and R9 are independently hydrogen or loweralkyi;
R10 is hydrogen or loweralkyi; and
-20- Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
Even more preferred compounds of the invention are compounds having Formula I or II or Hi or a salt, ester or prodrug thereof wherein R1 is defined as above;
-X-R2 is R -C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi, halo C1-C3 loweralkyi, C2-C3 alkenyl or halo C1-C3 alkenyl or -X-R2 is
Ύ2 < wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rb )- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
C1-C3 loweralkyi, hydroxy methyl, 1 -hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are independently hydrogen or loweralkyi;
R8 and R9 are independently hydrogen or loweralkyi;
R10 is hydrogen or loweralkyi; and
-21- Y is C2-C5 alkenyl, C2.C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
More highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo- C1-C3 loweralkyi;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are defined as above and wherein one of R3 and R4 is other than hydrogen;
Rδ is hydrogen or loweralkyi;
R6 and R7 are hydrogen independently hydrogen or loweralkyi;
R8 and R9 are hydrogen independently hydrogen or loweralkyi;
R10 is hydrogen or loweralkyi; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Even more highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is - CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is CTC3 loweralkyi or halo- C1-C3 loweralkyi;
R4 is hydrogen or loweralkyi and R3 is heterocyclic or -Z-R14 wherein Z and R14 are defined as above;
R >5 : is hydrogen;
-22- R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other even more highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo C1-C3 loweralkyi;
R4 is hydrogen or loweralkyi and R3 is (a) heterocyclic, (b) alkyl,
(b) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R14,
(h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyi, (xii) alkoxyalkyl, (xiii) cyanoalkyi, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) loweralkyi or (iii) loweralkenyl;
-23- R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Most highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo C-ι-C3 loweralkyi;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)- R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyi, (xii) alkoxyalkyl, (xiii) cyanoalkyi, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) Cι-C3 loweralkyi or (iii) allyl;
R5 is hydrogen;
-24- R6 and R7 are hydrogen;
R8 and R9 are hydrogen ;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is - CO2H;
-X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo d- C3 loweralkyi;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)- R14 wherein R14 is
(i) loweralkyi, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyi or
(iv) alkoxy-substituted loweralkyi;
R37a is
(i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl; and
R37c is
(i) hydrogen, (ii) Cι-C3 loweralkyi or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
-25- Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Other most highly preferred compounds of the invention are compounds having Formula I or II or III or a salt, ester or prodrug thereof wherein R1 is - CO2H;
-X-R2 is R -C(=O)-NH- or R2-SO2-NH- wherein R2 is C C3 loweralkyi or halo Cr C3 loweralkyi;
R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is
loweralkyi or loweralkenyl;
R37a is
loweralkyi or loweralkenyl; and
R37c is
hydrogen, C C3 loweralkyi or allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R 0 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
Preferred substituents R1 include -CO2H or esters or prodrugs thereof. Preferred esters include C2-C6 loweralkyi esters or substituted or unsubstituted
-26- benzyl esters. Preferred substituents R1 also include -S(O)2NHC(=O)R11 wherein R11 is defined as above.
Most highly preferred substituents R1 include -CO2H or esters or prodrugs thereof. Most highly preferred esters include C2-C6 loweralkyi esters or substituted or unsubstituted benzyl esters.
Preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C C3 loweralkyi, halo C C3 loweralkyi, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is
y ,A
Y2 wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
Cι-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl.
More preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is d-C3 loweralkyi, halo d-C3 loweralkyi, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is
γ2 wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
-27- C1-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl and 2-hydroxyethyl.
Even more preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is d-C3 loweralkyi, halo d-C3 loweralkyi, C -C3 alkenyl or halo C2-C3 alkenyl.
More highly preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is d-C3 loweralkyi or halo- Cι-C3 loweralkyi.
Even more highly preferred substituents -X-R2 include R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is d-C2 loweralkyi or halo d-C2 loweralkyi, and especially, CH3-C(=O)-NH-, CF3-C(=O)-NH-, CH3-SO2-NH- or CF3-SO2-NH-.
Preferred substituents R3 and R4 are independently selected from the group consisting of hydrogen, heterocyclic and -Z-R14 wherein Z and R14 are defined as most broadly defined previously herein and wherein one of R3 and R4 is other than hydrogen.
More highly preferred, substituent R4 is hydrogen or loweralkyi and R3 includes heterocyclic or -Z-R14 wherein Z and R14 are defined as most broadly defined previously herein.
Even more highly preferred, substituent R4 is hydrogen or loweralkyi and R3 includes
(a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R14, (h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
-28- (x) (heterocyclic)alkyl, (xi) hydroxyalkyi, (xii) alkoxyalkyl, (xiii) cyanoalkyi, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl.
Most highly preferred, substituent R4 is hydrogen and R3 includes
(a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-R14 wherein R14 is
(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyi, (xii) alkoxyalkyl, (xiii) cyanoalkyi, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and
R37c is (i) hydrogen, (ii) C C3 loweralkyi or (iii) allyl.
Also most highly preferred, substituent R4 is hydrogen and R3 includes
(a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)-R14 wherein R14 is
(i) loweralkyi, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyi or
(iv) alkoxy-substituted loweralkyi;
R37a is (i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl; and
R37c is. (i) hydrogen, (ii) C1-C3 loweralkyi or (iii) allyl.
-29- Also most highly preferred, substituent R4 is hydrogen and R3 includes
-C(R37a)(OR37c)-R14 wherein R14 is loweralkyi or loweralkenyl;
R37a is loweralkyi or loweralkenyl; and
R37c is hydrogen, C1-C3 loweralkyi or allyl, and especially, wherein R37c is hydrogen or methyl.
Preferred substituents R5 include hydrogen or loweralkyi. Most highly preferred, R5 is hydrogen.
Preferred substituents R6 and R7 include independently hydrogen and loweralkyi. Most highly preferred, R6 and R7 are hydrogen.
Preferred substituents R8, R9 and R10 incude independently hydrogen, fluoro and loweralkyi. Most highly preferred, R8, R9 and R10 are hydrogen.
Preferred substituent Y includes C2-C5 alkenyl, C2.C5 haloalkenyl,
-C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are defined as above.
More preferred substituent Y includes C2-C5 alkenyl,
C2.C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are defined as above.
Even more preferred substituent Y includes C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds. Representative alkenyl and haloalkenyl substituents Y include:
-CH=CH2, -CH=CHF, -CH=CH-CH3, -CH=CH-CF3, -CH=CHCI, -CH=CHBr,
-CH=CF2, -CH=CF(CH3), -CH=CF(CF3), -CH=CFCI, -CH=CFBr, -CH=C(CH3)2,
-30- -CH=C(CH3)(CF3), -CH=CCI(CH3), -CH=CBr(CH3), -CH=C(CF3)2, -CH=CCI(CF3),
-CH=CBr(CF3), -CH=CCI2, -CH=CCIBr, -CF=CH2, -CF=CHF, -CF=CH-CH3,
-CF=CH-CF3, -CF=CHCI, -CF=CHBr, -CF=CF2, -CF=CF(CH3), -CF=CF(CF3),
-CF=CFCI, -CF=CFBr, -CF=C(CH3)2, -CF=C(CH3)(CF3), -CF=CCI(CH3),
-CF=CBr(CH3), -CF=C(CF3)2, -CF=CCI(CF3), -CF=CBr(CF3), -CF=CCI2,
-CF=CCIBr, -C(CH3)=CH2, -C(CH3)=CHF, -C(CH3)=CH-CH3, -C(CH3)=CH-CF3,
-C(CH3)=CHCI, -C(CH3)=CHBr,-C(CH3)=CF2, -C(CH3)=CF(CH3),
-C(CH3)=CF(CF3), -C(CH3)=CFCI,
-C(CH3)=CFBr, -C(CH3)=C(CH3)2, -C(CH3)=C(CH3)(CF3), -C(CH3)=CCI(CH3),
-C(CH3)=CBr(CH3), -C(CH3)=C(CF3)2, -C(CH3)=CCI(CF3), -C(CH3)=CBr(CF3),
-C(CH3)=CCI2, -C(CH3)=CCIBr,
-C(CF3)=CH2, -C(CF3)=CHF, -C(CF3)=CH-CH3, -C(CF3)=CH-CF3, -C(CF3)=CHCI,
-C(CF3)=CHBr, -C(CF3)=CF2, -C(CF3)=CF(CH3), -C(CF3)=CF(CF3), - C(CF3)=CFCI, -C(CF3)=CFBr, -C(CF3)=C(CH3)2, -C(CF3)=C(CH3)(CF3), - C(CF3)=CCI(CH3),
-C(CF3)=CBr(CH3), -C(CF3)=C(CF3)2, -C(CF3)=CCI(CF3), -C(CF3)=CBr(CF3),
-C(CF3)=CCI2, -C(CF3)=CCIBr,
-CCI=CH2, -CCI=CHF, -CCI=CH-CH3, -CCI=CH-CF3, -CCI=CHCI, -CCI=CHBr,
-CCI=CF2, -CCI=CF(CH3), -CCI=CF(CF3), -CCI=CFCI, -CCI=CFBr, -CCI=C(CH3)2,
-CCI=C(CH3)(CF3), -CCI=CCI(CH3), -CCI=CBr(CH3), -CCI=C(CF3)2,
-CCI=CCI(CF3), -CCI=CBr(CF3), -CCI=CCI2, -CCI=CCIBr,
-31- -CH=CH-CH2CH3, -CH=CF-CH2CH3, -CF=CH-CH2CH3, -CF=CF-CH2CH3,
-CH=C(CH3)(CH2CH3), -CF=C(CH3)(CH2CH3), -CH=CCI(CH2CH3),
-CF=CCI(CH2CH3), -C(CH3)=CH-CH2CH3, -C(CH3)=CF-CH2CH3,
-CCI=CH-CH CH3, -CCI=CF-CH2CH3, -C(CH2CH3)=CH2, -C(CH2CH3)=CHF,
-C(CH2CH3)=CF2, -C(CH2CH3)=CH-CH3, -C(CH2CH3)=CF-CH3,
-C(CH2CH3)=CH-CI, -C(CH2CH3)=CFCI.
Representative Y substituents which are heterocyclic rings having 5 ring atoms and also containing one or two double bonds include:
furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl, imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl, oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl, pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinyl, thiadiazolyl, thiadiazolinyl, thiazolyl, thiazolinyl, thienyl, dihydrothienyl, triazolyl, triazolinyl.
More highly preferred substituents Y include cis-propenyl, trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
Most highly preferred substituents Y include cis-propenyl, cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl.
Preferred compounds of the invention include compounds selected from the group consisting of:
-32- (±)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cs-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ;
(±)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ; .
(-)-(2R,3S,5R, 1 'S)-2-(1 -Acetamido-2-ethyl)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5- carboxylate Ammonium Salt;
(±)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
-33- (±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid ;
-34- (±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,rR,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±H2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;.
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-hydroxy-3-cyano)propyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid ;
(±H2R,3S,5R,1'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2,3-dimethoxy)propyi-3-(c/s-propen-1 -yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(c/s-propen- 1-y|)-pyrrolidine-5-carboxylic Acid ;
-35- (±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(c s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine- 5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,rR,2'R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,rR,2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy)ethyl-3- c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
-36- (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(c/s-2-chloro-vin-1-yl)- pyrrolidine-5-carboxyiic Acid ;
(±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,1'S,3'R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3R,5R, 1 'S)-2-(1 -Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3R,5R,1'S)-1- f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol- 2-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'S)-2-(1 -acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1 -yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3R,5R, 1 'S)-2-(1 -acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3R,5R, 1 'S)-2-(1 -acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5- Carboxylic Acid ;
-37- (±)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5- carboxylic Acid ; and
(±)-(2S,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5- carboxylic Acid; or a pharmaceutically acceptable salt, ester or prodrug thereof.
More preferred compounds of the invention include compounds selected from the group consisting of:
(±)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxyiic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(c/s-propen-1- yl)-pyrroIidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ;
(±)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ; .
(-)-(2R,3S,5R, 1 'S)-2-(1 -Acetamido-2-ethyl)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5- carboxylate Ammonium Salt;
(±)-(2R,3S,5R,rR,2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cs-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
-38- (±)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic Acid ;
(±)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cs-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3R,5R, 1 'R,2'S)-2-(1 -Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cs-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(±H2R,3S,5R,1'R,2,S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-hydroxy-3-cyano)propyl-3-(c/s-propen- 1-y|)-pyrrolidine-5-carboxylic Acid ;
-39- (±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido- 1 -(3,6-dihydro-2-H-pyran-2-yl))methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-ethoxy)pentyl-3-(c/s-propen-1 -yl)- pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(c/s-propen- 1-y|)-pyrrolidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-ethoxy-3-vinyl)propyl-3-(c/s-propen-1 - yl)-pyrroiidine-5-carboxylic Acid ;
(±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ; and
(±)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
The term "acid protecting group" as used herein refers to groups used to protect acid groups (for example, -CO2H, -SO3H, -SO2H, -PO3H2, -PO2H groups and the like) against undesirable reactions during synthetic procedures. Commonly used acid protecting groups are disclosed in T.H. Greene and P.G.M. uts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991). Most frequently, such acid protecting groups are esters.
-40- Such esters include:
alkyl esters, especially loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
arylalkyl esters including, but not limited to, benzyl, phenethyl, 3- phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part ofthe arylalkyl group is unsubstituted or substituted as previously defined herein;
silylesters, especially, (tri-loweralkyl)silyl esters, (di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters, including, but not limited to, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl esters and the like; and the like.
Preferred acid protecting groups are loweralkyi esters.
The term "activated carboxylic acid group" as used herein refers to acid halides such as acid chlorides and also refers to activated ester derivatives including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, anhydrides derived from reaction of the carboxylic acid with N,N'-carbonyldiimidazole and the like, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N-hydroxybenzotriazoie derived esters, N-hydroxy-5-norbomene-2,3-dicarboximide derived esters, 2,4,5- trichlorophenol derived esters, p-nitrophenol derived esters, phenol derived esters, pentachlorophenol derived esters, 8-hydroxyquinoline derived esters and the like.
-41- The term "acyl" as used herein, refers to groups having the formula -C(=O)-R95 wherein R95 is hydrogen or an alkyl group. Preferred alkyl groups as R95 are loweralkyi groups. Representative examples of acyl groups include groups such as, for example, formyl, acetyl, propionyl, and the like.
The term "acylamino" as used herein, refers to groups having the formula -NHR89 wherein R89 is an acyl group. Representative examples of acylamino include acetylamino, propionylamino, and the like.
The term "alkenyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenyl" refers to straight or branched chain alkenyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkenyl groups include groups such as, for example, vinyl, 2-propenyl, 2-methyl-1 -propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.
The term "alkenylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon double bond. The term "lower alkenylene" refers to a divalent group derived from a straight or branched chain alkene group having from 2 to 6 carbon atoms. Representative examples of alkenylene groups include groups such as, for example, -CH=CH-, -CH2CH=CH-, -C(CH3)=CH-, -CH2CH=CHCH2-, and the like.
The term "alkenyloxy" as used herein, refers to groups having the formula -OR81 where R81 is an alkenyl group.
The term "alkoxy" as used herein, refers to groups having the formula -OR99 wherein R99 is an alkyl group. Preferred R99 groups are loweralkyi groups.
-42- Representative examples of alkoxy groups include groups such as, for example, methoxy, ethoxy, ferf-butoxy, and the like.
The term "alkoxyalkoxy" as used herein, refers to groups having the formula -O-R96-O-R97 wherein R97 is loweralkyi, as defined herein, and R96 is a lower alkylene group. Representative examples of alkoxyalkoxy groups include groups such as, for example, methoxymethoxy, ethoxymethoxy, £-butoxymethoxy and the like.
The term "alkoxyalkyl" as used herein refers to an alkyl radical to which is appended an alkoxy group, for example, methoxymethyl, methoxylpropyl and the like.
The term "alkoxycarbonyl" as used herein, refers to groups having the formula, -C(=O)- R80, where R80 is an alkoxy group.
The term "alkoxycarbonylalkyl" as used herein, refers to groups having the formula, -C(=O)- R79, appended to the parent molecular moiety through an alkylene linkage, where R79 is an alkoxy group.
As used herein, the term "alkyl" refers to straight or branched chain hydrocarbon radicals containing from 1 to 12 carbon atoms. The term "loweralkyi" refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms. Representative examples of alkyl groups include groups such as, for example, methyl, ethyl, n-propyl, /so-propyl, n-butyl, /'so-butyl, sec-butyl, f-butyl n-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethyl- propyl, n-hexyl, and the like. The hydrocarbon chains in alkyl groups or the alkyl portion of an alkyl-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R27)- and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyi, cylcoalkyl, cycloalkylalkyl or arylalkyl and
-43- wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term "alkylamino" as used herein, refers to groups having the formula -NHR91 wherein R91 is an alkyl group. Preferred R9 groups are loweralkyi groups. Representative examples of alkylamino include methylamino, ethylamino, and the like.
The term "alkylene" as used herein, refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 15 carbon. The term "lower alkylene" refers to a divalent group derived from a straight or branched chain saturated hydrocarbon group having from 1 to 6 carbon atoms. Representative examples of alkylene groups include groups such as, for example, methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1 ,1-ethylene (-CH(CH3)-), 1 ,3-propylene (-CH2CH2CH2-), 2,2-dimethylpropylene (-CH2C(CH3)2CH2-), and the like. The hydrocarbon chains in alkylene groups or the alkylene portion of an alkylene-containing substituent can be optionally interrupted by one or two heteroatoms or heterogroups independently selected from the group consisting of oxygen, -N(R27)- and sulfur wherein R27 at each occurrence is independently hydrogen, loweralkyi, cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two such heteroatoms or heterogroups are separated by at least one carbon atom.
The term "alkylsulfonyl" as used herein refers to the group having the formula, -SO2-R78, where R78 is an alkyl group. Preferred groups R78 are loweralkyi groups.
The term "alkylsulfonylamino" as used herein refers to the group having the formula, -SO2-R77, appended to the parent molecular moiety through an amino linkage (-NH-), where R77 is an alkyl group. Preferred groups R77 are loweralkyi groups.
-44- The term "alkynyl" as used herein, refers to a straight or branched chain hydrocarbon radical containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynyl" refers to straight or branched chain alkynyl radicals containing from 2 to 6 carbon atoms. Representative examples of alkynyl groups include groups such as, for example, acetylenyl, 1-propynyl, 2- propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.
The term "alkynylene" as used herein, refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 15 carbon atoms and also containing at least one carbon-carbon triple bond. The term "lower alkynylene" refers to a divalent group derived from a straight or branched chain alkynylene group from 2 to 6 carbon atoms. Representative examples of alkynylene groups include groups such as, for example, -C≡C-, -CH2-C≡C-, -C≡C-CH2-, -CH(CH3)-C≡C-, and the like.
The term "aminoalkyl" as used herein refers to an alkyl radical to which is appended an amino (-NH2) group.
The term "aryl" as used herein refers to a carbocyclic ring system having 6-10 ring atoms and one or two aromatic rings. Representative examples of aryl groups include groups such as, for example, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyi and the like.
The aryl groups can be unsubstituted or substituted with one, two or three substituents, each independently selected from loweralkyi, halo, haloalkyl, haloalkoxy, hydroxy, oxo (=O), hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy, amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstituted aryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstituted aryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, NH2C(=O)-, cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstituted heterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted
-45- (heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and -SO3H. Preferred aryl substituents are each independently selected from the group consisting of loweralkyi, halo, haloalkyl, hydroxy, hydroxyalkyi, alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino, dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples of substituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl, 4-methyisulfonylphenyl, and the like.
The term "(aryl)alkenyl" refers to a lower alkenyl group having appended thereto an aryl group. Representative examples of (aryl)alkenyi groups include groups such as, for example phenylethylenyl, phenyipropenyl, and the like.
The term "(aryl)alkyl" refers to a loweralkyi group having appended thereto an aryl group. Representative examples of (aryl)alkyl groups include groups such as, for example benzyl and phenylethyl.
The term "arylalkoxy" as used herein refers to the group having the formula, -O-R76 where R76 is an arylalkyl group.
The term "(aryl)alkynyl" refers to an alkynylene group having appended thereto an aryl group. Representative examples of (aryl)alkynyl groups include groups such as, for example phenylacetylenyl, phenylpropynyl, and the like.
The term "aryloxy" as used herein refers to the group having the formula, -O-R72, where R72 is an aryl group.
The term "carbamoyl" as used herein refers to the group having the formula, -C(=O)-NH2.
The term "carboxyalkyl" as used herein, refers to the group having the formula, -R^-COOH, where R64 is a lower alkylene group.
The term "cyanoalkyi" as used herein refers to an alkyl radical to which is appended a cyano group (-CN).
-46- The term "cycloalkenyl" as used herein refers to an aliphatic ring system having 5 to 10 carbon atoms and 1 or 2 rings containing at least one double bond in the ring structure. Representative examples of cycloalkenyl groups include groups such as, for example, cyclohexene, cyclopentene, norbornene and the like.
Cycloalkenyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyi. Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term "(cycloalkenyl)alkenyl" as used herein refers to a cycloalkenyl group appended to a lower alkenyl radical. Representative examples of (cycloalkenyl)alkenyl groups include groups such as, for example, cyclohexenylethylene, cyclopentenylethylene, and the like.
The term "(cycloalkenyl)alkyl" as used herein refers to a cycloalkenyl group appended to a lower alkyl radical. Representative examples of (cycloalkenyl)alkyl groups include groups such as, for example, cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl, cyclopentenylethyl, and the like.
The term "(cycloalkenyl)alkynyl" as used herein refers to a cycloalkenyl group appended to a lower alkynyl radical. Representative examples of (cycloalkenyl)alkynyl groups include groups such as, for example, cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.
The term "cycloalkyl" as used herein refers to an aliphatic ring system having 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomane, bicyclo[2.2.2]octane and the like.
-47- Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected hydroxy, halo, amino, alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl, mercapto, loweralkenyl and loweralkyi. Preferred substitutents are independently selected from loweralkyi, loweralkenyl, haloalkyl, halo, hydroxy and alkoxy.
The term "(cycloalkyl)alkyl" as used herein refers to a cycloalkyl group appended to a loweralkyi radical. Representative examples of (cycloalkyl)alkyl groups include groups such as, for example, cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl, and the like.
The term "(cycloalkyl)alkenyl" as used herein refers to a cycloalkyl group appended to a lower alkenyl radical. Representative examples of (cycloalkyl)- alkenyl groups include groups such as, for example, cyclohexylethylene, cyclopentylethylene, and the like.
The term "(cycloalkyl)alkynyl" as used herein refers to a cycloalkyl group appended to a lower alkynyl radical. Representative examples of (cycloalkyl)- alkynyl groups include groups such as, for example, cyclohexylacetylenyl, cyclopentylpropynyl, and the like.
The term "dialkylamino" as used herein, refers to groups having the formula -N(R90)2 wherein each R90 is independently a lower alkyl group. Representative examples of dialkylamino include dimethylamino, diethylamino, N- methyl-N-isopropylamino and the like.
The term "halo" as used herein refers to F, CI, Br or I.
The term "haloalkenyl" as used herein refers to a loweralkenyl group in which one or more hydrogen atoms is replaced with a halogen. Examples of haloalkenyl groups include 2-fluoroethylene, 1-chloroethylene, 1 ,2- difluoroethylene, trifluoroethylene, 1 ,1 ,1-trifluoro-2-propylene and the like.
-48- The term "haloalkoxy" as used herein refers to the group having the formula, -OR69, where R69 is a haloalkyl group as defined herein. Examples of haloalkoxy include chloromethoxy, fluoromethoxy, dichloromethoxy, trifluoromethoxy and the like.
The term "haloalkyl" as used herein, refers to a loweralkyi group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl, pentafluoroethyl and the like.
The term "heterocyclic ring" or "heterocyclic" or "heterocycle" as used herein, refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-membered ring containing one, two, three, or four nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen atom and one sulfur atom; two nitrogen atoms and one sulfur atom; one nitrogen atom and one oxygen atom; two nitrogen atoms and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen atom and one sulfur atom in non-adjacent positions; or two sulfur atoms in non-adjacent positions. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The nitrogen heteroatoms can be optionally quatemized. The term "heterocyclic" also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring, such as, for example, indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, benzofuryl, dihydrobenzofuryl or benzothienyl and the like.
Heterocyclic groups include, but are not limited to groups such as, for example, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl, piperidinyl, homopiperidinyl, pyrazinyl,
-49- piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorphoiinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl, tetrazolyl, tetrazolinyl, isoxazolyl, 1 ,2,3-oxadiazolyl, 1 ,2,4- oxadiazolyl, 1 ,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl, , 1 ,2,3- thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, thiadiazolinyl, 1 ,3-dithiolinyl, 1 ,2-dithiolyl, 1 ,3-dithioiyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1 ,3-oxathiolinyl, oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groups also include compounds of the formula
where X* is -CH2 or -O- and Y* is -C(O)- or [-C(R92)2-]V where R92 is hydrogen or C1-C4 alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl, 1 ,4-benzodioxanyl and the like. Heterocyclic groups also include bicyclic rings such as quinuclidinyl and the like.
Heterocyclic groups can be unsubstituted or substituted with from one to three substituents, each independently selected from loweralkyi, hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino and halogen. In addition, nitrogen containing heterocyclic rings can be N-protected.
The term "(heterocyclic)alkenyl" as used herein refers to a heterocyclic group appended to a lower alkenyl radical including, but not limited to, pyrrolidinylethenyl, morpholinylethenyl and the like.
-50- The term "(heterocyclic)alkoxy" as used herein refers to the group having the formula, -OR68, where R68 is a (heterocyclic)alkyl group.
The term "(heterocyclic)alkyl" as used herein refers to a heterocyclic group appended to a loweralkyi radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
The term "(heterocyclic)alkynyl" as used herein refers to a heterocyclic group appended to a lower alkynyl radical including, but not limited to, pyrrolidinylacetylenyl, morpholinylpropynyl and the like.
The term "(heterocyclic)oxy" as used herein refers to a heterocyclic group appended to the parent molecular moiety through an oxygen atom (-O-).
The term "hydroxy protecting group", "hydroxyl protecting group" or "-OH protecting group" as used herein refers to refers to groups used to hydroxy groups against undesirable reactions during synthetic procedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). Such hydroxy protecting groups include:
methyl ether;
substituted methyl ethers, including, but not limited to, methoxymethyl, methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl, t- butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl)ethoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl ether and the like;
substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl, 1- methyl-1-methoxyethyl, 1 -methyl-1-benzyloxyethyl, 2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;
-51- benzyl ether;
substituted benzyl ethers, including, but not limited to, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl, p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;
silyl ethers, including, but not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl, diphenylmethylsilyl ether and the like;
esters, including, but not limited to, formate, acetate, chloroacetate, dichloroacetate, trichioroacetate, trifluoroacetate, methoxyacetate, phenoxyacetate, pivaloate, benzoate ester and the like; and the like.
Preferred hydroxy protecting groups include substituted methyl ethers, benzyl ether, substituted benzyl ethers, silyl ethers and esters.
The term "hydroxyalkyi" as used herein refers to the group having the formula, -R65-OH, where R65 is an alkylene group
The term "leaving group" as used herein refers to a group which is easily displaced from the compound by a nucleophile. Examples of leaving groups include a halide (for example, CI, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like) and the like.
The term "N-protecting group" or "N-protected" as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991). N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,
-52- trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-meth- oxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxy- benzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycar- bonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycar- bonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxy- benzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropyi- methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyl- oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phen- oxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyl- oxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term "thioalkoxy" as used herein refers to groups having the formula -SR98 wherein R98 is an alkyl group. Preferred groups R98 are loweralkyi groups.
The term "thio-substituted alkyl" as used herein refers to an alkyl radical to which is appended a thiol group (-SH).
As used herein, the terms "S" and "R" configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention
-53- are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as individual optical isomers, including, enantiomers and single diastereomers of the compounds of the invention substantially free from their enantiomers or other diastereomers. By "substantially free" is meant greater than about 80% free of other enantiomers or diastereomers of the compound, more preferably greater than about 90% free of other enantiomers or diastereomers of the compound, even more preferably greater than about 95% free of other enantiomers or diastereomers of the compound, even more highly preferably greater than about 98% free of other enantiomers or diastereomers of the compound and most preferably greater than about 99% free of other enantiomers or diastereomers of the compound.
In addition, compounds comprising the possible geometric isomers of carbon-carbon double bonds and carbon-nitrogen double are also meant to be included in this invention.
Individual stereoisomers of the compounds of this invention can be prepared by any one of a number of methods which are within the knowledge of one of ordinary skill in the art. These methods include stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers and then chromatographically separating the diastereomers and regeneration of the individual enantiomers, enzymatic resolution and the like.
Stereospecific synthesis involves the use of appropriate chiral starting materials and synthetic reactions which do not cause racemization or inversion of stereochemistry at the chiral centers.
-54- Diastereomeric mixtures of compounds resulting from a synthetic reaction can often be separated by chromatographic techniques which are well-known to those of ordinary skill in the art.
Chromatographic resolution of enantiomers can be accomplished on chiral chromatography resins. Chromatography columns containing chiral resins are commercially available. In practice, the racemate is placed in solution and loaded onto the column containing the chiral stationary phase. The enantiomers are then separated by HPLC.
Resolution of enantiomers can also be accomplished by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliaries. The resulting diastereomers can then be separated by column chromatography. This technique is especially useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group that will form a salt or covalent bond with the chiral auxiliary. Chirally pure amino acids, organic carboxylic acids or organosulfonic acids are especially useful as chiral auxiliaries. Once the diastereomers have been separated by chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be recovered and used again.
Enzymes, such as esterases, phosphatases and lipases, can be useful for resolution of derivatives of the enantiomers in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be prepared. Certain enzymes will selectively hydrolyze only one of the enantiomers in the mixture. Then the resulting enantiomerically pure acid can be separated from the unhydrolyzed ester.
In addition, soivates and hydrates of the compounds of Formula I and II and III are meant to be included in this invention.
-55- When any variable (for example R1, R2, R3, m, n, etc.) occurs more than one time in any substituent or in the compound of Formula I or II or III or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. In addition, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds which can be isolated in a useful degree of purity from a reaction mixture.
This invention is intended to encompass compounds having Formula I and II and III when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
Compounds of the invention can be prepared according to the methods described in Schemes 1-5 as shown below.
Throughout the schemes, methods will be illustrated wherein R1 is a carboxylic acid or carboxylic acid ester substituent. It will be understood by those skilled in the art that other R1 substituents can (a) be obtained either from the carboxylic acid or carboxylic acid ester group, (b) can be introduced by similar methods to those used to introduce the carboxylic acid or carboxylic acid ester group or (c) can be introduced by other methods generally known in the art.
In adddition, throughout the schemes, methods will be illustrated wherein R4, R8, R7, R8, R9 and R10 are hydrogen. It will be understood by those skilled in the art that compounds wherein one or more of these substituents is other than hydrogen can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
-56- In addition, throughout the schemes, methods will be illustrated for obtaining compounds of the invention having the preferred relative stereochemistry. It will be understood by those skilled in the art that compounds of the invention having other relative stereochemistry can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
In addition, throughout the schemes, methods will be illustrated wherein X is -C(=O)-NH-. It will be understood by those skilled in the art that other X groups can be prepared by methods analogous to those disclosed in the schemes or by other methods generally known in the art.
As shown in Scheme 1 , reaction of acrolein with an N-protected α-amino acid ester 1 (P1 is an N-protecting group, preferably a benzyl group or the like and P2 is a carboxylic acid protecting group, preferably a t-butyl group or the like) in an inert solvent (for example, toluene and the like) in the presence of an acid catalyst (for example, acetic acid and the like), followed by equilibration with a base (for example, with triethylamine or the like) and separation of the isomers by chromatography, provides substituted pyrrolidine 2. Reduction of the aldehyde group to an alcohol with an aldehyde to alcohol reducing agent (for example, sodium borohydride or the like) in an inert solvent (for example, methanol or the like), followed by chromatographic separation of the isomers provides alcohol 3. Alcohol 3 can be protected with an hydroxy protecting group P3 (preferably with a silyl protecting group, for example, t-butyldimethylsilyl or the like) using standard alcohol protection methods to provide 4. Oxidation of the vinyl group of compound 4 to an aldehyde is accomplished by reacting compound 4 with OsO4 and N-methylmorpholine N-oxide to give the corresponding diol. The diol is then treated with sodium periodate to provide aldehyde 5. Substituents R3 can be introduced via reaction of aldehyde 5 with a Grignard reagent (for example, R3MgBr or the like) to give alcohol 6. Oxidation of alcohol 6 (for example, Swern
-57- oxidation or the like) provides ketone 7. Reductive amination of ketone 7 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 8. Amine 8 can be further functionalized to complete the introduction of the R2-X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 9a. The other diastereomeric amine (9b) can also be isolated and further transformed according to Scheme 1.
Removal of hydroxy protecting group P3 (for example, by reaction with a fluoride ion source, such as tetrabutylammonium fluoride or the like, when P3 is a silyl protecting group) provides alcohol 10. Transformation of the hydroxy group of alcohol 10 allows introduction of various substituents Y.
For example, alkylation of the hydroxy group provides ethers H. N- deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 12'. followed by ester hydrolysis (for example, with acid such as HCl), provides compound 12.1 of the invention.
Oxidation of the hydroxy group of 0 (for example, Swern oxidation or the like) provides aldehyde 13. Oxidation of aldehyde 13 (for example, with NaCIO2 or the like) provides carboxylic acid 14. The carboxylic acid substituent of 14 can be used to introduce a variety of other functional groups in substituent Y. For example, the carboxylic acid can be esterified (for example, by reaction with diazomethane or with ethanol and DCC or the like) or the carboxylic acid or an activated derivative thereof can be reacted with amines to provide 15 (wherein -C(=O)-R22 represents an ester or an amide). N-deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 16^, followed by ester hydrolysis (for example, with acid such as HCl), provides compound IjT of the invention.
-58- Derivatives of the aldehyde group of 13 or the carboxylic acid group of 14 can be used to introduce substituents Y which are -CN or various heterocycles, according to methods known to those skilled in the art and according to the specific methods exemplified herein.
Reaction of aldehyde 13 with loweralkyi- or loweraikenyl-Grignard reagents, followed by oxidation (for example, Swern oxidation or the like), provides ketones 17 wherein R22 is loweralkyi or loweralkenyl. N-deprotection (for example, where P1 is a benzyl group, by hydrogenation) gives 181, followed by ester hydrolysis (for example, with acid such as HCl), provides compound HT of the invention.
Compounds wherein substituent Y is an amino group or a derivative of an amino group can be prepared as shown in Scheme 2. Oxidation of aldehyde 2 (for example, with AgO or NaCIO2 or the like) provides carboxylic acid 19. Curtius rearrangement of carboxylic acid 19 (for example, reaction with DPPA, Et3N and benzyl alcohol or the like), followed by chromatographic separation of the diastereomers, provides amide 20 wherein P4 is an N-protecting group (for example, benzyloxycarbonyl or the like). Transformations analogous to those which converted compound 4 to compound 9a and 9b in Scheme 1 , enable the conversion of 20 to 21a and 21b, which can be separated by chromatography. Removal of protecting group P4 (for example, by selective hydrogenation) provides 22. Further derivatization of the amino group allows for introduction of substituents Y which are amine derivatives. N-deprotection (for example, where P1 is a benzyl group, by hydrogenation), followed by ester hydrolysis (for example, with acid such as HCl), provides compounds of the invention wherein Y is amino or an amine derivative.
Olefination of aldehyde 13 (for example, with Ph3PCH2 or the like), followed by hydrogenation (causing N-deprotection (for example, where P1 is a benzyl group) and olefin saturation, followed by ester hydrolysis (for example,
-59- with acid such as HCl), provides compounds of the invention wherein Y is loweralkyi.
As shown in Scheme 3, oxidation of the vinyl group of compound 4 to a diol (for example, with OsO4 and N-methylmorpholine N-oxide or the like) gives diol 23. Removal of N-protecting group P1 (for example, where P1 is a benzyl group, by hydrogenation) provides pyrrolidine 24. Reprotection with an acid- labile N-protecting group P5 (for example, t-butoxycarbonyl or the like) provides 25. Transformation of compound 25 to aldehyde 26a and 26b can be accomplished in a manner analogous to conversion of compound 4a to compound 10 and compound 10 to compound 13 as shown in Scheme 1. 26a and 26b can be separated by chromatography.
Olefination of 26a (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or l"Ph3P+CH2CH3/KOtBu, or the like) provides 27 wherein Y is an olefinic substituent. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 28 wherein Y is an olefinic substituent.
In yet another alternative method shown in Scheme 4, the hydroxy group of alcohol 3 is protected with a base-labile hydroxy protecting group P6 (for example, acetyl or the like) to give compound 29. Oxidation of the vinyl group of 29 with OsO4 and N-methylmorpholine N-oxide provides diol 30. Removal of the P1 protecting group (for example, by hydrogenation or the like) provides pyrrolidine 3 .. Reprotection with an acid-labile N-protecting group P5 (for example, t-butoxycarbonyl or the like) provides 32. Selective protection of the primary alcohol of 32 with a hydroxy protecting group P7 (for example, a silyl protecting group such as triisopropylsilyl or the like) provides compound 33. Oxidation of 33 (for example, Swern oxidation or the like) provides ketone 34- Reductive amination of ketone 34 (for example, by reaction with ammonium acetate and sodium cyanoborohydride in methanol or the like) gives amine 35.
-60- Amine 35 can be further functionalized to complete the introduction of the R2-X- substituent (for example, by reaction of the amine with an acylating agent such as acetic anhydride or the like or by other acylation methods), followed by chromatographic separation of the diastereomers to give 36a. The other diastereomeric amine (36b) can also be isolated and further transformed according this scheme.
Selective removal of the P6 hydroxy protecting group in 36a (for example, with K2CO3 in methanol or the like) provides alcohol 37. Oxidation of the alcohol to an aldehyde (for example, Swern oxidation or the like) provides 38. The aldehyde can serve as a precursor for various substituents Y in the compounds of the invention. For example, olefination of 38 (for example, with Ph3PCH2, or triphenylphosine/methylene chloride/n-BuLi, or l"Ph3P+CH2CH3/KOtBu, or the like) provides 39 wherein Y is an olefinic substituent. Removal of the P7 hydroxy protecting group (for example, with a fluoride ion source such as tetrabutylammonium fluoride or the like) gives alcohol 40.
The alcohol can serve as a precursor for a variety of R3 substituents in the compounds of the invention. For example, the alcohol of 40 can be oxidized to an aldehyde (for example, by Dess-Martin oxidation or the like) to give 4 .. Aldehyde 4_1 can be reacted with Grignard reagents (R14MgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R14Li or the like) to provide 42 as a mixture of alcohol diastereomers which can be separated chromatographically to provide the major isomer 42a and the other isomer 42b. Isomer 42a or the mixture of isomers 42 can be oxidized (for example, by Dess-Martin oxidation or the like) to give ketone 43. Reduction of ketone 43 (for example, with sodium borohydride in ethanol or the like) provides alcohol 42b as the major isomer, which can be isolated by chromatography. N- deprotection of the P5 protecting group and ester hydrolysis, under acidic
-61- conditions, provides compounds of the invention 44a or 44b, respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 42a or 42b provides ethers 45a or 45b, respectively. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 48a or 48b. respectively, wherein Y is an olefinic substituent.
As shown in Scheme 5, reaction of ketone 43 with with Grignard reagents (R37aMgBr or the like) or other organometallic reagents (for example, organolithium reagents such as R37aLi or the like) provides alcohols 46a and 46b as a mixture of alcohol diastereomers which can be separated chromatographically. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 47a or 47b. respectively, wherein Y is an olefinic substituent.
Alkylation of alcohol 46a or 46b provides ethers 49a or 49b, respectively. N-deprotection of the P5 protecting group and ester hydrolysis, under acidic conditions, provides compounds of the invention 50a or 50b. respectively, wherein Y is an olefinic substituent.
Esters or prodrugs of the compounds of the invention can be prepared by methods known in the art.
-62-
SCHEME 1
H
HO-
OP"
HN OP"
OF
P1
O
p3o- P30— >,
OP" H -. OP^ o o Y o 5 p3o— « p3o- P30— *
HO OP" o. H2N OP If N
H
RJ O R R 3°H Y o
8
p3o- p3o-
FTC(0)HN,, OP* OP"
8
RJ n P 11 ] OC> R0 O
9a 9b
-63- SCHEME 1 (cont'd.)
HO—-, R20O-
RzC(0)HN , / \ op: a OP" R2C(0)HN„ Y R p1 O
10 11
R∞O- R20O-
R2C(0)HN , / \ \ 00PP22 RR'CC((00))HHNN / I \ \ O c H 1
H Y O — - rV-ir
121 12"
O o
*4 HO Λ
R^C(0)HN,, .OP 32" D R2",C(0)HN/
10 .OP"
R°z P1 " όi R° if 13 14 o
R2 o
R=
R2C(0)HN , J~\ op2 R'!C(0)HN/
14 ,OP" ?, i
R R3 H ' r O,
15 16'
R22^)- is an ester or amide
-64-
SCHEME 1 (cont'd.)
o
R22-
R"C(0)HN, / \ OH le: r RY H Y O 16"
o
?22_J/
R ,'22 A/
■ r rc(o)HN"- ,/op2 R2C(°)HN- J \ OP2
R-> '1 l N 'if
R P1 o R3 H o
1Z 181
R22 is loweralkyi or loweralkenyl o
R22- R2C(0)HN//, j ~\ OH
18'
R H o
18"
-65- SCHEME 2
P4HN„
OP^ Y
P o 20
P4HN„ P HM
R^OJHN,, 0P2 R2C(0)HN / \ op2
R° Y O R° ^ P1 " of
21a 21b
H?N,
Hj>M
R"C(0)HN
R^OJHN,, OP" OP^
RJ y P1Y O
0
22a 22b
-66- SCHEME 3
p3o- p3o— >,
HO, OP" HO, OP^ ""
HO y 1 o iiff
HO y H O
23 24
P-Ό-
,OP^
R° Y
25
O
H -J{ H-4 -Z{0)W /tι 0P2 R2C(0)HN O λ -
R P5 O R p5Y o
26a 26b
*?
R2C(0)HN/y 0P2 R2C(0)HN/ OP^ a 6c — - rS p5 Y O 27 28
Y is an alkene
-67- SCHEME 4
P60— ;. p6o-
OP" HO O, o? "if
O HO y i
29 30 p6o— . PbO— -,
HO O OP" HO OP"
'if N
HO y H O HO y o
31 32 p6o- P60-
HO.
OP" OP2 o - p70 °^Y? P>Y O
33 34 p6o-
- ^ - OP2
If p70^ P5 O
35
-68- SCHEME 4 (cont'd.)
PbO— <.
R"C(0)HN OP" - Y P70' o
36a 36b
HO-, H→Γ OP< OP2 a Ύ
P70 O P70
37 ϊ
38
0P2 OP2 8 Ύ — - i
P70 O of
HO
39 Y is an alkene 40 or haloalkene
40
-69- SCHEME 4 (cont'd.)
41
45b
0H
Ύ O
48a
-70-
SCHEME 4 (cont'd.)
a
43
R"C(0)HN OH
N R ?1'4A ΛI M O
OH 44b
-71- SCHEME 5
OP"
Y o
R2C(0)HN^ OH
J | Υ
R1 K H 0 R37a H 47b
-72- SCHEME 5 (cont'd.)
Y,.
X
-73- The other compounds of the invention can be readily prepared from the compounds described herein using techniques known in the chemical literature. The methods required are known and can be readily practiced by those having ordinary skill in the art.
Key intermediates for the preparation of compounds of the invention include the following:
(1 )
wherein P1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferrably, a loweralkyi group, especially t-butyl); preferrably, P1 and P2 can be selectively deprotected/removed; or a salt thereof;
(2)
p3o-
OP"
P O wherein P1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferably, a
-74- loweralkyi group, especially t-butyl); and P }3 ; i,s hydrogen or a hydroxy protecting group (preferably, an acyl protecting group, for example, acetyl and the like, or a silyl protecting group, for example, t-butyldimethylsilyl and the like); preferrably, P , P2 and P3 can be selectively deprotected/removed; or a salt thereof;
(3)
P4HN
OP" '•',
N
O
wherein P1 is an N-protecting group (preferably, a benzyl group or a substituted benzyl group) and P2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P4 is hydrogen or an N-protecting group (preferably, a carbamate N-protecting group, for example, benzyloxycarbonyl and the like); preferrably, P1, P2 and P4 can be selectively deprotected/removed; or a salt thereof;
(4) p°o-
OP"
N p7o' O
-75- p6o- o OP"
^
N
O
P70'
or
p6o- ''.
H2 OP'
^ X I P70 o
wherein P5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); preferrably, P2, P5, P6 and P7 can be selectively deprotected/removed; or a salt thereof; and
-76- (5) p°o —
R2C(0)HN/ OP"
0
P70" or
A
R2C(0)HN/ OP2
V "ii
P70^ o
wherein P5 is an N-protecting group (preferably, an acid labile N-protecting group, such as t-butyloxycarbonyl and the like) and P2 is a carboxylic acid protecting group (preferably, a loweralkyi group, especially t-butyl); and P6 is hydrogen or a hydroxy protecting group (preferably, a base labile hydroxy protecting group, such as acetyl and the like); and P7 is hydroxy protecting group (preferably, a silyl protecting group, such as triisopropylsilyl and the like); and R2 is defined as herein (preferably, loweralkyi or haloloweralkyl; most preferably, methyl or trifluoromethyl); preferrably, P2, P5, P6 and P7 can be selectively deprotected/removed; or a salt thereof.
-77- All patents, patent applications, and literature references cited in this specification are hereby incorporated by reference in their entirety. In the case of inconsistencies, the present disclosure, including definitions, will prevail.
The reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
The following examples will serve to further illustrate the preparation of the compounds of the invention, without limitation.
-78- Examplel
(±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine- 5-carboxylic Acid Hydrochloride. o
O'Bu
1A. (±H2S.3R.5R)- and (±H2S.3S.5R)-1-Benzyl-2-vinyl-3-formyl-pyrrolidine- 5-carboxylic Acid f-Butyl Ester (8:1 ratio).
Acrolein (8 mL, 120 mmole) was added to a solution of f-butyl N-benzyl- glycinate (4.34 g, 19.6 mmole) and acetic acid (5 drops) in toluene (100 mL). The solution was heated at reflux. After 1 hour, the reaction was cooled to about 50 °C and an additional 3 mL of acrolein were added. The reaction was heated at reflux for an additional 2 hours and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide a mixture of (±)-(2S,3R,5R)- and (±)-(2S,3S,5R)-1-benzyl-2-vinyl-3- formyl-pyrrolidine-5-carboxylic acid -butyl esters as an oil (yield: 2.78 g, 45%). The mixture of aldehydes was equilibrated to an 8:1 ratio by stirring the crude product with triethylamine (0.5 mL) in ethyl acetate at room temperature followed by evaporation of the solvents.
1H NMR (CDCl3)(major isomer only): 51.45 (s, 9H), 2.26 (m, 1H), 2.69 (m, 1 H), 3.49 (dd, J=7.8, 3.0 Hz, 1H), 3.61 (d, J=13.5 Hz, 1 H), 3.93 (m, 1 H), 3.94 (d, J=13.5 Hz, 1 H), 5.22-5.33 (two dd, 2H), 5.7 (ddd, J=17.7, 10.2, 7.8 Hz, 1H), 7.21-7.35 (m, 5H), 9.71 (d, J=1.2 Hz, 1H).
MS (M+H)+ = 316.
-79- HO—-,
O'Bu
Ph
1B. (± -(2S.3R,5R)-1-Benzyl-2-vinyl-3-(hvdroxymethvπ-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of the 8:1 mixture of (±)-(2S,3R,5R)- and (±)-(2S,3S,5R)-1- benzyl-2-vinyl-3-formylpyrrolidine-5-carboxylic acid f-butyl ester (6.0 g, 19.0 mmole), prepared according to the method described in Example 1A, in 100 mL of methanol was cooled to 0 °C and treated with sodium borohydride (0.72 g, 19.0 mmole). The mixture was stirred for 0.5 hour, warmed to room temperature, and stirred for an additional 1 hour. The reaction was quenched with aqueous ammonium chloride, and the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was dried over MgSO , filtered and concentrated in vacuo. The residual oil was purified by chromatography on silica gel using a gradient of 20-30% ethyl acetate/hexanes to furnish the title compound as a colorless oil (yield: 4.0 g, 66%).
1H NMR (CDCI3): δ1.46 (s, 9H), 1.80 (m, 1 H), 2.16 (m, 1 H), 2.39 (m, 1H), 2.54 (m, 1H), 3.48-3.53 (m, 2H), 3.08 (d, 2H), 3.91 (d, 2H), 5.17-5.22 (m, 2H), 5.70 (m, 1H), 7.23-7.34 (m, 5H).
MS (M+H)+ = 318.
-80- TBDMSO— *
OlBu o Ph
1C. (±H2S.3R.5R)-1-Benzyl-2-vinyl-3-(f-butyldimethylsilyloxymethvh- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(hydroxymethyl)- pyrrolidine-5-carboxylic acid t-butyl ester (3.6 g, 11.4 mmole), ferf-butyldimethylsilyl chloride (3.7 g, 24.5 mmole) and imidazole (2.8 g, 41.2 mmole) in 80 mL of DMF was stirred at room temperature for 1.5 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 3.5 g, 71%).
1 H NMR (CDCI3): 60.02 (d, 6H), 0.86 (s, 9H), 1.43 (s, 9H), 1.67(ddd, 1H), 2.11 (m, 1 H), 2.28 (m, 1H), 3.40-3.70 (m, 6H), 3.90 (d, 2H), 5.11-5.19 (m, 2H), 5.69 (ddd, 1H), 7.20-7.30 (m, 5H).
MS (M+H)+ = 432.
TBDMSO— >, \ O'BU
O k Y o Ph
1D. (±H2R.3R.5R)-1-Benzyl-2-formyl-3-(f-butyldimethylsilyloxymethvn- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
Osmium tetroxide (20 mg) was added to a room temperature solution of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-( -butyldimethylsilyloxymethyl)-pyrrolidine-5-
-81- carboxylic acid £-butyl ester (3.5 g, 8. 2 mmole) in 60 mL of 8:1 acetone/water and N-methylmorpholine N-oxide (3.0 g, 25.6 mmole). The reaction mixture was stirred at room temperature for 6 hours and quenched with saturated aqueous Na2S2O3. The mixture was stirred for an additional 10 minutes and the solvent removed. The brownish residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO and concentrated in vacuo to provide the intermediate diol as an oil (~3.8g ) which was used without additional purification.
MS (crude): (M+H)+ = 466
The crude diol was dissolved in 6:1 tetrahydrofuran (THF)/water (50 mL) and treated with sodium periodate (3.0 g, 14.0 mmole). The mixture was stirred at room temperature for 1 hour and diluted with ethyl acetate, washed with water, dried over MgSO , filtered, and concentrated in vacuo. The crude aldehyde was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 1.6 g, 46%).
1H NMR (CDCI3): 60.03 (d, 6H), 0.86 (s, 9H), 1.46 (s, 9H), 1.72 (m, 1 H), 2.26-2.45 (m, 2H), 3.53-3.71 (m, 5H), 3.84 (d, 1 H), 3.93 (d, 1H), 7.27-7.31 (m, 5H), 9.32 (d, 1H).
MS (M+H)+ = 434.
-82- OlBu
1E. (±)-(2R.3R.5R)-1-Benzyl-2-(1-oxo-3-ethyl)pentyl-3-(f-butyldimethylsilyloxy- methyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A dry flask containing magnesium (0.14 g, 5.83 mmole), under argon, was charged with 10 mL of dry THF and 3 drops of dibromoethane. This was followed by addition of 1-bromo-2-ethylbutane (0.95 g, 5.83 mmole). The reaction mixture was heated at reflux for 45 minutes, until most of the magnesium had reacted. The reaction mixture was cooled to -30 °C and (±)-(2R,3R,5R)-1-benzyl-2-formyl- 3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester (0.5 g, 1.15 mmole) in of THF (6 mL) was added, dropwise. The reaction was slowly warmed to -10 °C, over a period of about 2 hours, and quenched with aqueous ammonium chloride. The resultant slurry was diluted with ethyl acetate and washed with water, brine, and dried over MgSO4 and concentrated. The crude alcohol product, an oil (~0.85 g), was used without further purification.
MS (M+H)+ = 520.
A solution of oxalyl chloride (2.5 mL, 2M in CH2CI2) in 10 mL of anhydrous dichloromethane was prepared and maintained under a nitrogen atmosphere, at -78 °C. DMSO (0.77 mL, 9.83 mmole) was added slowly to the solution. The mixture was stirred for 15 minutes and treated with the crude alcohol prepared above, about 0.85 g, in 5 mL of anhydrous dichloromethane. The solution was stirred for 1 hour and triethylamine (2.3 mL, 16.4 mmole) was added slowly to the reaction mixture. The solution was then allowed to slowly warmed to room temperature and diluted with dichloromethane. The organic layer was washed with water, dried over MgSO4, and concentrated. The residue was purified by
-83- chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 0.35 g, 66%).
MS (M+H)+ = 518.
TBDMSO- o'Bu
1 F. (±W2R.3R.5R.1'R)- and (±W2R.3R.5R.rSV1-Benzyl-2-(1-amino-3-ethylV pentyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-(f-butyl- dimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (0.20 g, 0.39 mmole), ammonium acetate (30 equiv.) and sodium cyanoborohydride (10 equiv.) in 5 mL of methanol was heated at reflux for 24 hours with occasional addition of an additional 60 equivalents of ammonium acetate and 20 equivalents of sodium cyanoborohydride. The solvent was evaporated. The resultant residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO , filtered, and concentrated. The product was purified by chromatography on silica gel using 30-50% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 130 mg, 64%).
1H NMR (CDCI3) δ 7.30 (m, 5H), 4.91 (s, 1H), 3.53(m, 2H), 3.08 (m, 1 H), 2.88 (m, 1H), 2.35 (m, 1H), 1.85 (m, 1 H), 1.44 (s, 9H), 1.20-1.40 (m, 7H), 0.88 (s, 9H), 0.85 (m, 6H), 0.03 (s, 6H)
MS (M+H)+ = 519.
-84- TBDMSO— *
1G. (±)-(2R.3R.5R.1'SV1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3- -butyl- dimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'R)- and (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1- amino-3-ethyl)pentyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid -butyl ester (110 mg, 0.21 mmole) and acetic anhydride (214 mg, 2.1 mmole) in 10 mL of dichloromethane was stirred for 1 hour. The solvent and excess acetic anhydride were removed in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound as a white solid (yield: 85 mg, 72%).
1H NMR (CDCI3) δ 7.28 (m, 5H), 5.14 (d, J=14Hz, 1 H), 4.36 (m, 1H), 3.95 (m, 2H), 3.62 (m, 1H), 3.52 (m, 1 H), 3.45 (m, 1H), 2.98 (m, 1H), 1.98 (s, 3H), 1.60 (m, 2H), 1.43 (s, 9H), 1.20-1.40 (m, 7H), 0.88 (s, 9H), 0.80 (m, 6H), 0.04 (s, 6H)
MS (M+H)+ = 561.
1H. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hvdroxy- methvD-pyrrolidine-5-carboxylic Acid -Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-( butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (85 mg,
-85- 0.15 mmole) in dry THF (5 mL) was prepared and maintained at room temperature under a nitrogen atmosphere. Tetrabutylammonium fluoride (1 M in THF, 0.23 mL) was added slowly to the solution. The reaction mixture was stirred for 1 hour. The solvent was removed in vacuo and the residue purified by chromatography on silica gel using 30-50% ethyl acetate/hexanes to provide the title compound as a white foam (yield: 41 mg, 61%).
1H NMR (CDCI3) δ 7.20-7.35 (m, 5H), 5.20 (d, J=14Hz, 1 H), 4.28 (m 1H), 4.93 (m, 2H), 3.65 (m, 2H), 3.50 (m, 1 H), 3.23 (m, 2H), 2.22 (m, 2H), 1.98 (s, 3H), 1.62 (m, 1H), 1.43 (s, 9H), 1.15-1.40 (m, 7H), 0.80 (m, 6H)
MS (M+H)+ = 447.
O'Bu
11. (±)-(2R.3R,5R.1'SV1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(methoxy- methvh-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A mixture of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (hydroxymethyl)-pyrrolidine-5-carboxyiic acid f-butyl ester (40 mg, 0.09 mmole) and silver oxide (200 mg, 0.90 mmole) in 3 mL of iodomethane was heated at reflux for three hours. The reaction was cooled, filtered, and the solvent was removed in vacuo, to provide the title product as a crude oil.
MS (M+H)+ = 461.
-86-
U. (±)-(2R.3R.5R.1 'SV2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethvh- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A mixture of the crude (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (32 mg, 0.07 mmole), prepared according to the method described in Example 11, and ammonium formate (130 mg, 2.1 mmole) in ethanol (5 mL) was heated at reflux in the presence of a catalytic amount of 10% palladium, on activated carbon, for 1.5 hours. The reaction was filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes followed by 10% methanol/dichloromethane to provide the title compound as a colorless oil (yield: 16 mg, 47%).
MS (M+H)+ = 371.
1K. (±H2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethylV pyrrolidine-5-carboxylic Acid Hydrochloride.
A solution of the (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- (methoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (15 mg) was dissolved
-87- in 6 N HCl in water (1 mL) and stirred at room temperature for 3 hours. The solvent was removed under high vacuum to provide the title compound as a white solid.
1H NMR(de-DMSO) δ 8.10 (d, J=14Hz, 1 H), 4.28 (m, 1 H), 4.18 (m,1 H), 3.45 (m, 1 H), 3.22 (s, 3H), 2.47 (m, 1 H), 2.38(m, 1 H), 1.90 (m, 1 H), 1.88 (s, 3H), 1.15-1.42 (m, 7H), 0.82 (t, J=12.5Hz, 3H), 0.79 (t, J=12.5Hz, 3H)
MS (M+H)+ = 315, (M-H)' = 313.
Example 2
(±H2R.3R.5R.1 'SV2-π-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine- 5-carboxylic Acid Hydrochloride.
2A. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvπpentyl-3-formyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of oxalyl chloride (0.11 mL, 2M in CH2CI2) in 5 mL of anhydrous dichloromethane was prepared and maintained, under a nitrogen atmosphere, at -78 °C. DMSO (32 mg, 0.42 mmole) was added slowly to the solution. The mixture was stirred for 15 minutes and treated with (±)-(2R,3R,5R,1'S)-1-benzyl- 2-(1 -acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f- butyl ester (38 mg, 0.085 mmole) in 5 mL of dichloromethane. The solution was stirred for 1 hour and triethylamine (86 mg, 0.85 mmole) was added slowly to the reaction mixture. The solution was allowed to warm to room temperature and
-88- diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgSO , filtered and concentrated. The residue was purified by chromatography on silica gel using 3% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 39 mg, 97%).
1H NMR (CDCI3) δ 9.68 (d,J=1.0Hz, 1 H), 7.28 (m,5H), 5.06 (d, J=14Hz, 1H), 4.38 (m, 1 H), 4.10 (m, 1H), 3.75 (m, 2H), 3.45 (m, 1 H), 2.62 (m, 1 H), 2.20 (m, 2H), 1.98 (s, 3H), 1.42 (s, 9H), 1.25-1.40 (m, 7H), 0.82 (m, 6H)
MS (M+H)+ = 445.
OlBu
2B. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
A solution of NaCIO2 (0.16 g) and NaH2PO4.H2O (0.17g) in water (1 mL) was added to a solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-formyl-pyrrolidine-5-carboxyiic acid t-butyl ester (35 mg, 0.079 mmole) and 2-methyl-2-butene (0.5 mL) dissolved in t-BuOH (1.5 mL) and acetonitrile (1.5 mL) at 0 °C. After 1 hour the reaction was quenched with 10% aqueous Na2S2O3 and extracted with dichloromethane. The organic layer was washed with water and brine, dried (MgSO4) and concentrated to provide the title product (yield: -30 mg).
MS (M+H)+ = 461.
-89-
2C. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3- methoxycarbonyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
A solution of Diazald™ (0.5 g, 2.33 mmole) in 5 mL of ether was added slowly to a solution of aqueous KOH (0.5 g in 1 mL of water) and 1 mL of ethanol maintained at 65 °C. Diazomethane was distilled into a receiving flask charged with a solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (30 mg, 0.065 mmole) in 3 mL of THF. The receiving flask was cooled to 0 °C in an ice/water bath. The condenser was cooled with dry ice/acetone and 3 mL of ether was added the distilling flask until the distillate was colorless. The reaction was stirred for an additional 0.5 hours at 0 °C. The yellowish reaction mixture was quenched with acetic acid (0.1 mL ) and diluted with ethyl acetate. The organic layer was washed with 10% NaHCO3 and brine, dried with MgSO and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50 % ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 20 mg, 65%).
1H NMR (CDCI3) δ 7.25 (m, 5H), 5.10 (d, J=14Hz, 1H), 4.23 (m, 1H), 4.08 (m,1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.69 (s, 3H), 3.40 (m, 1H), 2.75 (m, 1H), 2.33 (m, 1 H), 2.15 (m, 1 H), 1.98 (s, 3H), 1.42 (s, 9H), 1.20-1.40 (m, 7H), 0.83 (m, 6H)
MS (M+H)+ = 475.
-90-
2D. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A mixture of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- methoxycarbonyl-pyrrolidine-5-carboxylic acid f-butyl ester (14 mg, 0.03 mmole) and ammonium formate (0.3 g) in ethanol (1.5 mL) with a catalytic amount of 10% palladium on activated carbon was heated at about 75 °C, for 1 hour. After filtration to remove the catalyst, the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to provide the title compound as a colorless oil (yield: 8.5 mg, 73%).
MS (M+H)+ = 385.
2E. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
A solution of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxy- carbonylpyrrolidine-5-carboxylic acid f-butyl ester (8.5 mg, 0.022 mmole) in 4 N HCl in dioxane (1 mL) was stirred at room temperature for 24 hours. The solvent
-91- was removed in vacuo to provide the title compound as an off-white solid (yield 8 mg, 100%).
1H NMR (de-DMSO) δ 8.02 (d, J=14Hz, 1 H), 4.40 (m, 1 H), 4.22 (m, 1H), 3.85 (t, J=13Hz, 1 H), 3.70 (m, 1 H), 3.65 (s, 3H), 3.15 (m, 1 H), 2.55 (m, 1 H), 2.20 (m, 1 H), 1.84 (s, 3H), 1.12-1.42 (m, 7H), 0.82 (t, J=12.5Hz, 3H), 0.68 (t, 3H)
MS (M+H)+ = 329, (M-H)" = 327.
Example 3
(± 2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnPentyl-3-cvano-pyrrolidine-5- carboxylic Acid Hydrochloride.
„NOH
3A. (±)-(2R.3R.5R.1'SV1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (hvdroxyiminoformyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared by reacting a solution of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester with hydroxylamine hydrochloride and 10% aqueous potassium carbonate in methanol according to the procedure described by Chelucci et al., Tetrahedron: Asymmetry 5:1973 (1994).
-92-
3B. (±)-(2R.3R.5R.1'S -1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cvano- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared by reacting a solution of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxyiminoformyl)- pyrrolidine-5-carboxyiic acid f-butyl ester with 1 ,1'-carbonyldiimidazole in dichloromethane according to the procedure described by Cheiucci et al., Tetrahedron: Asymmetry 5:1973 (1994).
3C. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvhpentyl-3-cvano-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxyiic acid f-butyl ester.
-93-
3D. (±V(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-cvano-pyrrolidine-5- carboxylic Acid Hydrochloride.
The title compound is prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrroiidine-5-carboxylic acid f- butyl ester.
Example 4
(±)-(2R.3R.5R.1'S.')-2-(1-Acetamido-3-ethvhpentyl-3-propionyl-pyrrolidine-5- carboxylic Acid Hydrochloride.
\ OH
AcHN/, A \. O'Bu
Ph
4A. (±)-(2R.3R.5R.1'S.1"R)- and (±)-(2R.3R.5R.1'S.1"S)-1-Benzyl-2-(1- acetamido-3-ethyl)pentyl-3-(1-hvdroxy)propyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
Ethyl magnesium bromide (0.070mL, 3M in ether) was added to a solution of (±)-(2R,3R,5R,rS)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-
-94- pyrrolidine-5-carboxylic acid f-butyl ester (18 mg, 0.041 mmole) in 3 mL of tetrahydrofuran. The reaction mixture was maintained at 0 °C, and stirred for 1hour. The reaction was quenched with aqueous ammonium chloride and partitioned between ethyl acetate and water. The organic layer was dried over MgSO , filtered and concentrated to provide the title product (crude yield: 20mg, 100%).
MS (M+H)+ = 475.
4B. (±H2R.3R.5R.1'S.)-1-Benzyl-2-(1-acetamido-3-ethvhpentyl-3-propionyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 2A, substituting (±)-(2R,3R,5R,1'S,1"R)- and (±)-(2R,3R,5R,1'S,1"S)-1- benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-hydroxy)propyl-pyrrolidine-5-carboxylic acid f-butyl ester, 20 mg 0.041 mmole), in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2- (1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 11 mg, 56%).
MS (M+H)+ = 473.
-95- ?
4C. (±)-(2R.3R.5R.1'S.')-2-(1-Acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine- 5-carboxylic Acid f-Butyl Ester.
A mixture of (±)-(2R,3R,5R,1'S,)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- propionyl-pyrrolidine-5-carboxyiic acid f-butyl ester (11 mg, 0.023 mmole), ammonium formate (250 mg) and palladium (15 mg, 10% on carbon) in ethanol (1.5 mL) was heated at 70 °C for 20 minutes. The reaction was filtered, to remove the catalyst and concentrated. The residue was purified by chromatography on silica gel using 5% methanol/chloroform to provide the title compound (yield: 8.5 mg, 95%).
MS (M+H)+ = 383.
f OH
4D. (±)-(2R.3R.5R.1 'S.)-2-(1 -Acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine- 5-carboxylic Acid Hydrochloride.
A solution of (±)-(2R,3R,5R,1'S,)-2-(1-acetamido-3-ethyl)pentyl-3- propionyl-pyrrolidine-5-carboxylic acid f-butyl ester (8 mg) was dissolved in 4 N HCl in dioxane (1 mL) and stirred at room temperature for 24 hours. The reaction
-96- was concentrated in vacuo to provide the title compound as an off white solid (yield: 8 mg, 100%).
1H NMR (DMSO-d6) δ 8.03 (d, J=14Hz, 1H), 4.41 (m, 1 H), 4.20 (m, 1 H), 3.92 (m, 1H), 3.68 (m, 1 H), 3.46 (m, 1 H), 2.65 (m, 2H), 2.00 (m, 1 H)1.84 (s, 3H), 1.10-1.35 (m, 9H), 0.95 (t, J=Hz,3H), 0.81 (t, J=12.5Hz, 3H), 0.75 (t, J=12.5Hz, 3H)
MS: (M-H)' = 325, (M+35)+ = 361 , (2M-H) " = 651 ; (M+H)+ = 327, (2M+1 ) + = 653, (2M+Na) + = 675.
Example 5 (±)-(2R.3R.5R.1 'S)-2-(1-Acetamido-3-ethvnpentyl-3-(N-methylcarbamoylV pyrrolidine-5-carboxylic Acid Hydrochloride. o
CH3HN ~
5A. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-methyl- carbamoyl)pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (0.175 mmole) and triethylamine (18 mg, 0.175 mmole) in 10 mL THF was cooled in an ice-bath. Isobutylchloroformate (24 mg, 0.175 mmole) was added and stirred for 30 min. Then methylamine (2.0 M in THF, 0.35 mL, 0.70 mmole) was added. The mixture was stirred while allowed to warm up to room temperature overnight. The reaction was then diluted with ethyl acetate. The organic layer was washed with
-97- water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol / methylene chloride to provide the title compound, as an oil (yield: 17.2 mg, 21%).
MS: (M+H)+= 474
,0
CH3HN _//
5B. (±)-(2R.3R.5R.1'S)-2-π-Acetamido-3-ethvhpentyl-3-(N-methylcarbamovn- Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(N-methylcarbamoyl)pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxy- methyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 13 mg, 94%).
MS: (M+H)+= 384
.0
CH3HN _//
-98- 5C. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(N-methylcarbamovn- pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3- ethyl)pentyl-3-(N-methylcarbamoyl)pyrroiidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (D2O): δ 4.43 (t, J=10Hz, 1 H), 4.36 (m, 1H), 4.09 (dd, 1H), 3.08 (q, J=10Hz, 1 H), 2.75 (m, 4H), 2.25 (m, 4H), 2.02 (s, 3H), 1.5-1.15 (br, 7H), 0.80 (m, 6H).
MS: (M+H)+ = 328.
Example 6
(±H2R.3R.5R.1 'S)-2-(1 -Acetamido-3-ethyl)pentyl-3-f N-aminocarbamovh- pyrrolidine-5-carboxylic Acid Hydrochloride.
O BocHNHN-^C
OlBu
6A. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-(t- butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (60 mg, 0.13 mmole), t-butyl carbazate (21 mg, 0.16 mmole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 31 mg, 0.16 mmole) and 1-hydroxybenzotriazole (9 mg,
-99- 0.065 mmole) in 3 mL anhydrous THF was stirred at room temperature for 6 hours. The reaction was then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanol/methylene chloride to provide the title compound, as an oil (yield: 45.6 mg, 61%).
MS: (M+H)+= 575
.0
BOC-HNHN -//
AcHN,, Y ΛHi
6B. (±)-(2R.3R.5R.1'SV2-(1-Acetamido-3-ethyl)pentyl-3-(N-(t- butoxycarbonv0aminocarbamoyl)pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 1 J, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1- acetamido-3-ethyl)pentyl-3-(N-(t-butoxycarbonyl)aminocarbamoyl)pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S))-1-benzyl-2-(1- acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 28 mg, 75%).
MS: (M+H)+= 484
-100- O
NH2HN-A
6C. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(N-aminocarbamovh- pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(N- (t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3R,5R,1 'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (D2O): δ 4.32 (m, 2H), 4.18 (dd, 1H), 3.14 (q, J=8.4Hz, 1H), 2.75 (m, 1H), 2.26 (m, 1H), 2.01 (s, 3H), 1.50-1.15 (m, 7H), 0.80 (q, J=7.5Hz, 6H)
MS: (M+H)+= 329
-101- Example 7
(± ^R.SR.δR.I'S ^-d-Acetamido-S-ethvnpentyl-S-ethoxycarbonyl-pyrrolidine-δ- carboxylic Acid Hydrochloride.
7A. (±)-(2R.3R.5R.1'SV1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3- ethoxycarbonyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (42 mg, 0.091 mmole), ethanol (0.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 36 mg, 0.188 mmole) and 1 -hydroxybenzotriazole (7 mg, 0.05 mmole) in 2 mL anhydrous THF was stirred at room temperature overnight. The reaction was then diluted with ethyl acetate. The organic layer was washed with water,and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 2% methanol/methylene chloride to provide the title compound, as an oil (yield: 36 mg, 33%).
1H NMR (CDCI3): δ 7.50-7.20 (br, 5H), 5.12 (d, J=9Hz, 1H), 4.60-4.30 (br, 2H), 4.14 (q, J=6Hz, 2H), 4.08 (m, 1H), 3.85 (br, 1 H), 3.72 (m, 1 H), 3.40 (m, 1H), 2.75 (m, 1 H), 2.32 (m, 1 H), 1.97 (s, 3H), 1.40 (s, 9H), 1.37 (t, J=6Hz, 3H), 1.20- 1.50 (m, 7H), 0.83 (m, 6H).
Mass spectrum: (M+H)+ = 489
-102-
7B. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-ethoxycarbonyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)- pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
Mass spectrum: (M+H)+ = 399.
7C. (±)-(2R.3R.5R.1'S)-2-π-Acetamido-3-ethvnpentyl-3-ethoxycarbonyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 2E, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3- ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine- 5-carboxylic acid f-butyl ester.
-103- 1H NMR (D2O): δ 4.35 (m, 1 H), 4.20 (q, J=7.5Hz, 2H), 3.87-3.55 (m, 2H), 3.20 (q, J=7.5Hz, 1 H), 2.67 (m, 1H), 2.42 (m, 1 H), 2.02 (s, 3H), 1.24 (t, J=7.5Hz, 3H), 1.54-1.15 (m, 7H), 0.82 (m, 6 H).
Mass spectrum: (M+H)+ = 343, (M-H)' = 341.
Example 8
(±)-(2R.3R.5R.1'S -2-(1-Acetamido-3-ethvπpentyl-3-acetyl-pyrrolidine-5- carboxylic Acid Hydrochloride.
OH
O'Bu
8A. (±H2R.3R.5R.1'S.1"R)- and (±)-(2R.3R.5R.1'S.1"S)-1-Benzyl-2-(1- acetamido-3-ethyl)pentyl-3-(1-hvdroxy)ethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.
The title compound was prepared according to the method described in Example 4A substituting methyl magnesium bromide in place of ethyl magnesium bromide.
-104- .0
M
8B (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetyl - pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 2A, substituting (±)-(2R,3R,5R,1'S,1"R)- and (±)-(2R,3R,5R,1'S,1"S)-1- benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-hydroxy)ethyl-pyrrolidine-5-carboxylic acid f-butyl ester, prepared according to the procedure described in Example 8A, in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxy- methyl-pyrrolidine-5-carboxyiic acid f-butyl ester.
1H NMR(CDCI3) δ 5.00(d, J=9.7Hz, 1 H), 3.94(m, 2H), 3.68(m, 1H), 3.55(m, 1H), 2.64(m, 1H), 2.32(m, 1 H), 2.29(s, 3H),2.20(m, 1H), 1.94(s, 3H), 1.43(s, 9H), 1.15- 11.35(m, 7H), 0.80(m, 6H).
MS: (M+H)+=459
-105-
8C. (±V 2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetyl-Pyrrolidine-5- carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 4C, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-acetyl -pyrrolidine-5-carboxyiic Acid f-butyl ester., prepared according to the procedure described in Example 8B, in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-propionyl -pyrrolidine-5- carboxylic acid f-butyl ester.
MS: (M+H)+=369
_// ) OH H H "{ O
HCl
8D. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-acetyl -pyrrolidine-5- carboxylic Acid Hydrochloride.
The title compound is prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- acetyl-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-
-106- acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR(DMSO-d6) δ 8.20(m, 1 H), 4.35(m, 1 H), 4.15(m, 1 H), 4.03(m, 1H), 2.43(m, 1 H), 2.03(m, 1 H), 1.91(s, 3H), 1.77(s, 3H), 1.55(m, 1 H), 1.46(m, 1 H), 1.35(m, 2H), 1.12(m, 4H), 0.84(m, 3H), 0.79(m, 3H)
MS: (M+H)+=314, (M-H)" =312
Example 9
(±W2S.3R.5R.1 'S)-2-(1-Acetamido-3-ethvnpentyl-3-amino-pyrrolidine-5- carboxylic Acid Dihvdrochloride.
O
9A. (±)-(2S.3R.5RV and (±H2S.3S.5R)-1-Benzyl-2-vinyl-3-carboxyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R)- and (±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-formyl- pyrrolidine-5-carboxylic acid f-butyl ester (10 g, 31.7 mmole) (8:1 ratio), in 39 mL of ethanol was prepared. The solution was treated with a suspension of silver oxide (8.83 g, 38.1 mmole) and potassium hydroxide (10.86 g, 194 mmole) in 65 mL of water. The reaction was stirred at room temperature for 1 hour and filtered through a pad of Celite®. The ethanol was removed in vacuo. The aqueous solution was acidified with acetic acid to about pH 4. The acidic solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide the title compound as a brownish oil
-107- (crude yield: 8.2 g, 77%). The crude acid was used for the next step without further purification.
MS (M+H)+ = 332, (M-H)' = 330.
CbzHN
OlBu o Ph
9B. (±)-(2S.3R.5R)-1-Benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
A mixture of (±)-(2S,3R,5R)- and (±)-(2S,3S,5R)-1-benzyl-2-vinyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (1.0 g, 3.02 mmole), diphenylphosphoryl azide (0.83 g, 3.32 mmole), benzyl alcohol (0.36 g, 4.53 mmole) and triethylamine (0.32 g, 3.32 mmole) in 30 mL of toluene was heated at reflux for 16 hours. The solvent was evaporated and the residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 0.86 g, 65%).
1H NMR (CDCI3) δ 7.20-7.40(m, 10H), 5.70(m, 2H), 5.10-5.23(m, 3H), 4.10(m, 1H), 3.85(m, 1 H), 3.62(m, 1 H), 3.45(m, 2H), 2.50(m, 1 H), 1.70(m, 1 H), 1.41 (s, 9H).
MS (M+H)+ = 437.
-108- CbzHM O'Bu V o o
Ph
9C. (±)-(2R.3R.5R)-1-Benzyl-2-formyl-3-benzyloxycarbonylamino-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
Osmium tetroxide (3 crystals) was added to a stirred solution of the (±)- (2S,3R,5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid f-butyl ester (1.10 g, 2.52 mmole), N-methylmorpholine N-oxide (0.95 g, 8.07 mmole), in 27 mL of acetone/water (8:1), maintained at room temperature. After 6 hours, 10% aqueous Na2S2O3 was added and stirring continued for an additional 15 minutes. The reaction was extracted with dichloromethane and the organic layer was concentrated to provide the crude diol intermediate. The diol product was used in the next step without additional purification.
MS (M+H)+ = 471.
Sodium periodate (1.0 g, 4.52 mmole) was added in portions to a stirred solution of the crude diol (-1.25 g, 2.66 mmole) in 21 mL of THF/water (6:1). The reaction was stirred for 1 hour then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO , filtered and concentrated. The residue was purified by chromatography on silica gel using 15% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 0.66 g, 60%).
1H NMR (CDCI3) δ 9.44(d, J=1.2Hz, 1 H), 7.20-7.40(m, 10H), 5.98(d, J=14Hz, 1H), 5.10(m, 2H), 4.45(m, 1H), 3.90(m, 2H), 3.70(m, 1 H), 3.60(m, 1H), 2.43(m, 1 H), 1.70(m, 1 H), 1.45(s, 9H),
MS (M+H)+ = 439.
-109- 9D. (±H2R.3R.5R.1'R and (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-hvdroxy-3- ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
1-Bromo-2-ethylbutane (1.7 g, 10.3 mmole) was added a solution of dibromoethane (3 drops) in 15 mL of dry THF, under argon, in a flask charged with magnesium (0.25 g, 10.3 mmole). The reaction mixture was heated at reflux for 45 minutes, until most of the magnesium reacted. The solution was allowed to cool to room temperature and transferred via cannula to a suspension of
CuBr-SMe2 (2.12 g, 10.3 mmole) in 15 mL of dry THF, maintained under argon, at -10 °C. The mixture was stirred for 0.5 hours until the solution turned dark. A solution of (±)-(2R,3R,5R)-1-benzyl-2-formyl-3-benzyloxycarbonylamino- pyrrolidine-5-carboxylic acid f-butyl ester (0.45 g, 1.03 mmole) in 10 mL of THF was added dropwise and stirred for 1.5 hours, while maintaining the temperature at 0 °C. The reaction was quenched with aqueous ammonium chloride, diluted with ethyl acetate, washed with water and brine, dried over MgSO , filtered and concentrated. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide alcohol adducts as a pale yellow oil (yield: 160 mg, 30%).
1H NMR (CDCI3) δ 7.20-7.40(m, 10H), 6.10(d, J=14Hz, 1H), 5.10(m, 2H), 4.22(m, 1H), 4.01 (m, 1H), 3.71 (m, 1 H), 3.65(m, 2H), 3.55(m, 1 H), 3.20(m, 1 H), 2.00-2.30(m, 2H), 1.45(s, 9H), 1.15-1.40(m, 7H), 0.84(m, 6H)
MS (M+H)+ = 525.
-110-
9E. (±H2R.3R.5R)-1-Benzyl-2-(1-oxo-3-ethvnpentyl-3- benzyloxycarbonylamino-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of oxalyl chloride (0.29 ml, 2 M in CH2CI2) in 5 mL of dry dichloromethane was prepared and maintained under a nitrogen atmosphere at - 78 °C. DMSO (90 mg, 1.14 mmole) was added to the solution. The mixture was stirred for 15 minutes. The alcohol adduct, prepared above, (150 mg, 0.286 mmole), in 5 mL of dichloromethane, was added dropwise to the cold (-78 °C) reaction mixture. The solution was stirred, at -78 °C, for 1 hour. Triethylamine (250 mg, 2.29 mmole) was added slowly. The reaction was allowed to slowly warm to room temperature and then diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgSO , filtered and concentrated. The residue was purified by chromatography on silica gel using 5% ethyl acetate/hexanes to provide the title compound (yield: 100 mg, 67%).
1H NMR (CDCI3) δ7.35(m, 10H), 5.10(m, 2H), 4.28(m, 1 H), 3.95(m, 2H), 2.60(m, 1H), 2.40(m, 1H), 2.03(m, 1 H), 1.70(m, 2H), 1.45(s, 9H), 1.10-1.30(m, 7H), 0.70(m, 6H)
MS (M+H)+ = 523.
-111-
9F. (±H2S.3R.5R.1'R)- and (±W2S.3R.5R.1'S)-1-Benzyl-2-(1-amino-3- ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A mixture of (±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-benzyloxy- carbonylamino-pyrrolidine-5-carboxylic acid f-butyl ester (90 mg, 0.172 mmole), ammonium acetate (400 mg, 5.17 mmole) and sodium cyanoborohydride (65 mg, 1.03 mmole) in 5 mL in methanol was heated at reflux for 18 hours. Additional portions of ammonium acetate and sodium cyanoborohydride were added and heating continued for an additional 2 hours. The reaction was quenched with 1 N sodium hydroxide, and diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgSO , filtered and concentrated. The residue was purified by chromatography on silica gel using 1:1 ethyl acetate/hexanes followed by 5% methanol/dichloromethane to provide the title compounds, (yield: 58 mg, 64%)
MS (M+H)+ = 524.
-112- CbzHN,
9G. (±)-(2S.3R.5R.1'R and (±)-(2S.3R.5R.1'SV1-Benzyl-2-(1-acetamido-3- ethvDpentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'R)- and (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1- amino-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid f- butyl ester (50 mg, 0.096 mmole) and acetic anhydride (117 mg, 1.15 mmole) in 5 mL of dichloromethane was stirred for 1 hour at room temperature. The solvent was evaporated in vacuo and the residue purified by chromatography on silica gel using 30-50% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 51 mg, 97%).
1H NMR (CDCI3) δ 7.72-7.35(m, 10H), 5.82(d, J=14Hz, 1 H), 5.10(m, 2H), 4.38(m, 1H), 4.15(m, 2H), 3.63(m, 1 H), 3.38(m, 1 H), 3.10(m, 1H),2.15(m, 1H), 2.00(s, 3H), 1.65(m, 1H), 1.42(s, 9H), 1.20-1.35(m, 7H), 0.80(m, 6H)
MS (M+H)+ = 567.
-113- O'Bu
9H. (±)-(2S.3R,5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'R)- and (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1- acetamido-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid f-butyl ester (49 mg, 0.087 mmole), ammonium formate (150 mg, 0.22 mmole) and 10% palladium on activated carbon in ethanol (5 mL) was heated at 80 °C for 45 minutes. After filtration to remove the catalyst, the solvent was removed. The residue was purified by chromatography on silica gel using 5-10% methanol/dichloromethane to furnish the diastereomers, (±)-(2S,3R,5R,1'S) (19 mg) and (±)-(2S,3R,5R,1'R) (8.6 mg) of 2-(1-acetamido-3-ethyl)pentyl-3-amino- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (CDCI3) δ 6.00(d, J=14Hz, 1H), 3.90(m, 1H), 3.73(m, 1 H), 3.49(m, 1H), 3.10(m, 1 H), 2.48(m, 1 H), 2.03(s, 3H), 1.82(m, 1 H), 1.48(s, 9H), 1.15- 1.42(m, 7H), 0.85(m, 6H)
MS (M+H)+ = 342.
-114-
91. (±)-(2S.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5- carboxylic Acid Dihvdrochloride.
A solution of (±)-(2S,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-amino- pyrrolidine-5-carboxylic acid f-butyl ester (17 mg, 0.050 mmole) in 1 mL of 6 N HCl was stirred at room temperature for 3 hours. The solvent was removed under high vacuum to provide the title compound as a white solid (yield: 15 mg, 100%)
1H NMR (ds-DMSO) δ 8.28(bs, 1H), 7.90 (d, J=Hz,1 H), 4.71 (d, J=14Hz, 1H), 4.39(m, 1 H), 4.10(m, 1H), 3.92(m, 1H), 3.08(m, 1H), 2.64(m, 1H), 2.31(m, 1H), 1.95(m, 1 H), 1.88(s, 3H), 1.50(m, 1H), 1.10-1.40(m, 7H), 0.72-0.90(m,6H).
MS (M+H)+ = 286.
-115- Example 10
(±)-(2S.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5- carboxylic Acid Hydrochloride.
10A. (±H2S.3R.5R.1 'S)-1 -Benzyl-2-(1 -acetamido-3-ethvDpentyl-3-amino- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- benzyioxycarbonylamino-pyrrolidine-5-carboxylic acid f-butyl ester (50 mg, 0.88 mmole) was stirred with 10% palladium on carbon (5 mg) in 50 mL of ethyl acetate under 1 atmosphere of hydrogen for 45 minutes. The reaction was filtered and concentrated to provide the title compound as an oil (crude yield: 35 mg, 92%).
MS (M+H)+ = 431.
AcHN.
10B. (±H2S.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetamido- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- amino-pyrrolidine-5-carboxylic acid f-butyl ester (35 mg, 0.080 mmole) was
-116- reacted with acetic anhydride (0.05 mL) in 8 mL of dichloromethane for 1 hour. The reaction was concentrated and the residue purified by chromatography on silica gel using 50% ethyl acetate/hexanes followed by 3% methanol/dichloromethane to provide the title compound (yield: 30 mg, 80%).
1H NMR (CDCI3) δ7.20-7.35(m, 5H), 6.62(d, J=14Hz, 1 H), 5.34(d, J=14Hz, 1 H), 4.42(m, 2H), 4.20(m, 1H), 3.68(m, 1 H), 3.42(m, 1H), 3.10(m, 1 H), 2.18(m, 2H), 2.02(s, 3H), 1.96(s, 3H), 1.45(s, 9H), 1.25-1.42(m, 7H), 0.85(m, 6H).
MS (M + H)+ = 474.
AcHN ,0'Bu O
10C. (±)-(2S.3R.5R.1 'S)-2-(1 -Acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine- 5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester. The residue was purified by chromatography on silica gel using 5% methanol/dichloromethane to provide the title compound (yield: 11.5 mg, 50%).
1H NMR (CDCI3) δ 6.20(d, J=14Hz, 1 H), 5.94(d, J=14Hz, 1 H), 4.24(m, 1H), 4.08(m, 1H), 3.95(m, 1H), 3.75(m, 1 H), 3.18(m, 1 H), 2.45(m, 1 H), 2.02(s, 3H), 1.96(s, 3H), 1.82(m, 1 H), 1.49(s, 9H), 1.20-1.42(m, 7H), 0.85(m, 6H).
-117- MS (M + H)+ = 384.
10D (±)-(2S.3R.5R.1'S)-2-(1-Acetamido-3-ethvπpentyl-3-acetamido-pyrrolidine- 5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2S,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- acetamido-pyrrolidine-5-carboxylic acid f-butyl ester (11.0 mg, 0.029 mmole) in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 11.0 mg, 100%).
1H NMR(d6-DMSO) δ 8.15(d, J=14Hz, 1 H), 8.05(d, J=14Hz, 1H), 4.35(m, 1H), 4.28(m, 1 H), 4.19(m, 1H), 3.59(m, 1 H), 1.90(s, 3H), 1.81(s, 3H), 1.15- 1.40(m, 7H), 0.80(m, 6H).
MS: (M-H)' = 326, (M+35)+ = 362; (M+H) + = 328, (M+23) + = 350.
-118- Example 11
(±)-(2S.3R.5R.1 'S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonylamino- pyrrolidine-5-carboxylic Acid Hydrochloride.
MeOjCHPi,
AcHN-,
11 A. (± 2S.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxy- carbonylamino-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- amino-pyrrolidine-5-carboxylic acid f-butyl ester is reacted with methyl chloroformate and triethylamine in dichloromethane. The reaction is partitioned between dichloromethane and water. The organic layer is concentrated to provide the title compound.
11 B. (±)-(2S.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3- methoxycarbonylamino-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 1 J, substituting (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)- pentyl-3-methoxycarbonylaminopyrrolidine-5-carboxylic acid f-butyl ester in place
-119- of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
11C. (±H2S.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3- methoxycarbonylamino-pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound is prepared according to the method described in Example 1 K, substituting (±)-(2S,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- methoxycarbonylamino-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester.
-120- Example 12
(±)-f2R.3R,5R,1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(imidazoi-4-yl)-5-carboxylic Acid Dihvdrochloride.
12A. (±)-(2R.3R.5R.1'SV1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3-diazoacetyl- 5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester (405.3 mg, 0.88 mmol) and N- methylmorpholine (106 μl, 0.96 mmol) in THF (20 ml) was reacted with isobutyl chloroformate (96 μl, 0.93 mmole) at -10 °C for 30 minutes. To the reaction flask was cannulated a distilled diazomethane solution in ether prepared from the reaction of diazald (2.4 g) in ether (60 mi) with a solution of potassium hydroxide (2.4 g) in ethanol (15 ml) and water (15 ml). The reaction was stirred for 3 hours at room temperature then diluted with ether. The organic layer was washed with brine, dried (Na2SO ) and concentrated to give the title compound as a thick oil (430.4 mg).
-121-
12B. (±W2R.3R.5R.1'S)-1-Benzyl-2-(1-Acetamido-3-ethyl)pentyl-3-bromoacetyl- 5-carboxyiic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- diazoacetyl-5-carboxylic acid f-butyl ester (427.4 mg, 0.88 mmol) in dioxane (50 ml) was reacted with hydrobromic acid (0.25 ml, 2.2 mmol) at 0 °C for 0.5 hours. The reaction was quenched with saturated aqueous sodium bicarbonate (25 ml) and concentrated in vacuo. The residual aqueous layer was extracted with dichloromethane (3x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound as a white foamy solid (379.3 mg, 80.2 %).
MS: (M+H)+= 539.
-122-
12C. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3-(imidazol-4- yl)-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-bromoacetyl- 5-carboxylic acid f-butyl ester (60 mg, 0.112 mmol) was treated with formamidine acetate (120 mg, 1.15 mmol) in liquid ammonia and heated at 45 °C in a sealed tube for 20 h. The reaction was concentrated in vacuo. The residue was treated with aqueous NaHCO3 and extracted with dichloromethane (5x20 ml). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound as a white solid (21.2 mg, 39.4 %).
MS: (M+H)+= 483.
12D. (±)-(2R.3R.5R.1'S) -2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-4-vn-5- carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)
-123- pentyl-3-(imidazol-4-yl)-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxy-methyl- pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 12.9 mg, 66.2%).
1H NMR (CDCI3): δ 0.75 - 0.81 (m, 6H), 1.17 - 1.42 (m, 7H), 1.47 (s, 9H),
2.03 (s, 3H), 2.66 (m, 1 H), 3.50 (m, 1H), 3.73 (m, 1 H), 3.86 (m, 1 H),4.06 (m, 1H),
7.04 (br s, 1H), 7.86 (br s, 1H).
MS: (M+H)+= 393.
12E. (±W2R.3R.5R.1'S) -2-(1-Acetamido-3-ethvnpentyl-3-(imidazol-4-ylV5- carboxylic Acid Dihvdrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- (imidazoi-4-yl)-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1- acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester to provide the title compound solid (yield: 12.0 mg, 96.0%).
1H NMR (DMSO-d6): δ 0.67 (t, J = 7 Hz, 3H), 0.75 (t, J = 7 Hz, 3H), 1.11
(m, 3H), 1.23 (m, 4H), 1.78 (s, 3H), 2.33 (m, 1 H), 2.70 (m, 1H), 3.69 (dt, 1H), 3.95 (dd, 1H), 4.29 (m, 1H), 4.48 (dd, 1 H), 7.63 (s, 1 H), 8.28 (d, J = 9 Hz, 1 H), 9.06 (s, 1 H).
MS: (M+H)+= 337.
-124- Example13
(±)-(2R.3R.5R,1 'S)-2-(1-Acetamido-3-ethvnpentyl-3-(oxazol-2-yl)-pyrrolidine-5- carboxylic Acid Dihvdrochloride.
13A. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvπpentyl-3-(N-(2- hvdroxyethyl)carbamoyl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound is prepared according to the method described in Example 5A, substituting ethanolamine for N-methylamine hydrochloride.
o
OΕu
13B. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3-(oxazolin-2- yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (N-(2-hydroxyethyl)carbamoyi)-pyrrolidine-5-carboxylic acid t-butyl ester, triethylamine (4 eq.), carbon tetrachloride (3.5 eq.) in acetonitrile is reacted with triphenylphosphine (3.15 eq.) for 16h at room temperature. The reaction is concentrated in vacuo. The residue is partitioned between ethyl acetate and
-125- water. The organic layer is washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography on silica gel using ethyl acetate/hexanes to provide the title compound.
13C. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3-(oxazol-2-vn- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (oxazolin-2-yl)-pyrrolidine-5-carboxylic acid f-butyl ester is reacted with nickel peroxide in cyclohexane according to the method described by Meyer in J. Org. Chem. 1979, 497-501 to provide the title compound.
13D. (± 2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(oxazol-2-yl)- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)- pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-
-126- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
OH
Y O
13E. (±H2R.3R.5R.1'S)-2-f1-Acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)- pyrrolidine-5-carboxylic Acid Dihydrochloride.
The title compound is prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- (oxazol-2-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R, 1 'S)-2-(1 -acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester.
-127- Example14
(±H2S.3R.5R.1 'S)-2-(1 -Acetamido-3-methyl)butyl-3-(N-methylamino)pyrrolidine- 5-carboxylic Acid Dihydrochloride.
CH3 CbzN,
O-t-Bu o
Ph
14A. (±)-(2S.3R.5RV1-Benzyl-2-vinyl-3-(N-methyl-N-benzyloxycarbonylamino)- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino- pyrrolidine-5-carboxylic acid f-butyl ester (2.08 g, 4.77 mmole) was dissolved in 50 mL of anhydrous DMF and maintained under a nitrogen atmosphere. The solution was treated with sodium hydride (0.32 g, 8 mmole), and stirred at room temperature for 30 minutes. The solution was treated with iodomethane (0.8 ml, 12.85 mmole) and stirred for an additional 1 hour. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were concentrated to provide the crude product which was purified by chromatography on silica gel to provide the title compound as an oil (yield: 1.75 g, 81%).
1H NMR (CDCI3) δ 7.36-7.20 (m, 10H), 5.75-5.50 (br, 1 H), 5.25-5.07 (m, 4H), 4.75-4.50 (br, 1 H), 3.97 (d, J=13.5Hz, 1 H), 3.75 (m, 1 H), 3.61 (d, J=13.5Hz, 1H), 3.50 (m, 1 H), 2.93 (s, 3H), 2.45 (m, 1 H), 1.75 (m, 1 H), 1.46 (s, 9H).
MS (M+H)+ = 451.
-128- CH CbzNr
H o γ o°-Bu
Ph
14B. (±)-(2R.3R.5R)-1-Benzyl-2-formyl-3-(N-methyl-N-benzyloxycarbonyl- amino)pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 9C, substituting (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(N-methyl-N-benzyl- oxycarbonylamino)pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2S,3R,5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid f-butyl ester. (Yield: 747 mg, 42%.)
MS (M+H)+ = 453.
14C. (±)-(2R.3R.5R)-1-Benzyl-2-(1-oxo-3-methyl)butyl-3-(N-methyl-N- benzyloxycarbonylamino)pyrrolidine-5-carboxylic Acid f-Butyl Ester.
Isobutyl magnesium chloride (2.0 M in ether, 0.68 ml) was added dropwise over about 12 minutes to a solution of (±)-(2R,3R,5R)-1-benzyl-2-formyl-3-(N- methyl-N-benzyloxycarbonylamino)pyrrolidine-5-carboxylic acid f-butyl ester (196 mg, 0.43 mmole) in 5 mL of anhydrous THF, maintained at -78 °C. The resulting yellow solution was stirred at -78 °C for 1 hour. The solution was quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate. The
-129- organic layer was concentrated and the crude product was oxidized according to the procedure described in Example 9D. Purification by column chromatography on silica gel, with 10-25% ethyl acetate/hexanes, provided the title compound (yield: 78 mg, 36%).
1H NMR (CDCI3) δ 7.46-7.25 (m, 10H), 5.09 (br, 2H), 4.90-4.60 (m, 1H), 3.97-3.65 (m, 4H), 3.00 (s, 3H), 2.60 (br, 1 H), 2.20-1.80 (m, 3H), 1.46 (s, 9H), 0.80-0.67 (m, 7H).
MS (M+H)+ = 509.
14D. (±)-(2S.3R.5R.1'R and (±H2S.3R.5R.1'S)-1-Benzyl-2-π-amino-3- methvπbutyl-3-(N-methyl-N-benzyloxycarbonylamino)pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 9F, substituting (±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-methyl)butyl-3-(N- methyl-N-benzyloxycarbonylamino)pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R)-1-benzyl-2-formyl-3-benzyioxycarbonylamino-pyrrolidine- 5-carboxylic acid f-butyl ester. (Yield: 97 mg, 65%.)
MS (M+H)+ = 510.
-130-
14E. (±)-(2S.3R.5R.1 'R)- and (±H2S.3R.5R.1 'S)-1 -Benzyl-2-(1 -acetamido-3- methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'R)- and (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1- amino-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)pyrrolidine-5- carboxylic acid f-butyl ester (47 mg, 0.094 mmole) was reacted with acetic anhydride (0.15 mL) in 4 mL of dichloromethane at room temperature for 2 hours. The reaction was concentrated in vacuo to provide the title compound.
MS (M+H)+ = 552.
14F. (±)-(2S.3R.5R.1'S)-2-(1-Acetamido-3-methvnbutyl-3-(N-methylamino)- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3R,5R,1'R)- and (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1- acetamido-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)pyrrolidine-5- carboxylic acid f-butyl ester (0.094 mmole), palladium (40 mg , 10% on carbon) and ammonium formate (160 mg) in 3 mL of ethanol was heated at reflux for 30 minutes. Additional palladium on carbon (15 mg) and ammonium formate (50
-131- mg) were added. The solution was stirred for an additional 15 minutes and the mixture was then filtered to remove the solids and catalyst. The filtrate was evaporated and the residue purified by chromatography on silica gel 5% methanol/dichloromethane and 1 % NH OH to provide (±)-(2S,3R,5R,1'S) (15.4 mg, lower Rf) and (±)-(2S,3R,5R,1'R) (5.4 mg, higher Rf)- 2-(1-acetamido-3- methyl)butyl-3-(N-methylamino)pyrrolidine-5-carboxylic acid t-butyl esters (yield: 20.8 mg, 68%).
14G. (±)-(2S.3R.5R.1'S)-2-n-Acetamido-3-methvnbutyl-3-(N-methylamino)- pyrrolidine-5-carboxylic Acid Dihvdrochloride.
A solution of (±)-(2S,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(N- methylamino)pyrrolidine-5-carboxylic acid t-butyl ester (9.4 mg) was stirred with 4 N aqueous HCl (~1.5 mL) for 2 hours. The reaction was concentrated in vacuo to provide the title compound (yield: 10 mg, 100%).
1H NMR (major peaks) (DMSO-d6) δ2.57 (s, 3H), 1.90 (s, 3H), 1.47 (m, 3H), 0.91 (d, J=7.5Hz, 3H), 0.83 (d, J=7.5Hz, 3H)
MS:(M+H)+ = 272.
-132- Example15
(±)-(2R.3R.5R.1'S -2-(1-Acetamido-3-ethvnpentyl-3-(imidazol-2-vn-pyrrolidine-5- Carboxylic Acid Dihydrochloride.
^NH
AcHN,, \. O-t-Bu
J( Ph"i
15A. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-π-acetamido-3-ethyl)pentyl-3-πmidazol-2- yl)-Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
Ammonia gas was bubbled slowly through a solution of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester (20 mg, 0.045 mmole) and glyoxal (6.2 uL, 0.054 mmole, 1.2 equiv.) in 5 mL of methanol, maintained at 0 °C, for 5 minutes. After 7 hours at 0 °C, additional glyoxal (10 uL) was added and ammonia was bubbled through the solution for 5 minutes. The reaction was allowed to stir at room temperature for 16 hours. A final addition of glyoxal (10 uL) and ammonia as, described above, followed by reaction at room temperature for an additional 4 hours effected a complete reaction. The reaction was concentrated in vacuo and purified by chromatography on silica gel using 50% ethyl acetate/hexanes, followed by 10% methanol/chloroform to provide the title compound as a solid (yield: 19.9 mg, 91%).
1H NMR (CDCI3): d 0.67 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H), 1.09- 1.32 (m, 7H), 1.41 (s, 9H), 2.00 (m, 1 H), 2.09 (s, 3H), 2.79 (m, 1 H), 3.29 (m, 1H), 3.66 (dd, J=9.6, 2.7 Hz, 1 H), 3.77 (m, 1H), 3.92 (d, J=13.4 Hz, 1 H), 4.04 (d,
-133- J=13.4 Hz, 1H), 4.22 (dd, 1H), 4.49 (m, 1 H), 6.08 (br s, 1H), 7.00 (s, 2H), 7.21- 7.34 (m, 5H).
MS (M+H)+ = 483.
15B. (±H2R.3R.5R.1 'S)-2-(1 -Acetamido-3-ethyl)pentyl-3-(imidazol-2-vn- pyrrolidine-5-carboxylic Acid f-Butyl Ester
A mixture of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (imidazol-2-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (17 mg, 0.035 mmole), ammonium formate (250 mg) and 10% palladium on carbon (20 mg), in 5 mL of ethanol, was heated at reflux for 15 minutes The reaction was concentrated in vacuo and the residue was purified by chromatography on silica gel using 5% methanol/dichlormethane and 0.25% ammonium hydroxide to provide the title compound as a white solid (yield: 11.3mg, 81.9%).
MS (M+H)+ = 393.
-134-
15C. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(imidazol-2-yl)- pyrrolidine-5-Carboxylic Acid Dihvdrochloride.
(±)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)- pyrrolidine-5-carboxylic acid f-butyl ester (11 mg, 0.028 mmole) was dissolved in 2 mL of 6N HCl and stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to provide the title compound, as an off white solid (yield: 11.3 mg, 100%).
1 H NMR (DMSO-d6): d 0.71 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H), 1.09-
1.28 (m, 7H), 1.74 (s, 3H), 2.43 (m, 1H), 2.80 (m, 1 H), 3.85 (m, 1H), 4.04 (m, 1H),
4.29 (m, 1H), 4.52 (m, 1H), 7.64 (s, 2H), 8.07 (br d, J=9 Hz, 1H).
MS (M+H)+ = 337 and (M-H)' = 335.
-135- Example 16
(±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N.N-dimethylcarbamovn- pyrrolidine-5-carboxylic Acid Hydrochloride.
3 ,0 H3c-N^f
16A. (± 2R.3R.5R.1'S 1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N.N- dimethylcarbamovDpyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 5A substituting N,N-dimethylamine in place of N-methylamine (yield: 10 mg, 23%).
Mass spectrum: (M+H)+ = 488.
H,c ,0
H3C- -
16B. (±H2R.3R.5R.1 'S)-2-(1 -Acetamido-3-ethvnpentyl-3-(N-methylcarbamov - pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(N,N-dimethylcarbamoyl)pyrrolidine-5-carboxylic acid f-butyl ester
-136- in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxy- methyl-pyrrolidine-5-carboxylic acid f-butyl ester to provide the title compound (yield: 5.5 mg , 67%).
Mass spectrum: (M+H)+ = 398.
16C. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(N.N-dimethyl- carbamoyl)pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- (N,N-dimethylcarbamoyl)pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine- 5-carboxyiic acid f-butyl ester.
1H NMR (major peaks) (D20) d 3.15 (s, 3H), 2.94 (s, 3H), 1.98 (s, 3H), 0.80 (m, 6H)
MS (M+H)+ = 342, (M-H)' = 340.
-137- Example 17
(±H2R.3R.5R.1'S)-2-(1-Acetamido-3-Ethyl)pentyl-3-cvano-pyrrolidine-5- carboxylic Acid Hydrochloride.
NO o-t-Bu
Ph
17A. (±)(2S.3R.5R)-1 -Benzyl-2-vinyl-3-cvano-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester (8:1 ratio) (5g, 15.9 mmole) with hydroxylamine hydrochloride (1.28g, 18.5 mmole) and 10% aqueous potassium carbonate (8 mL) in 20 mL of methanol, according to the procedure described by Chelucci et al., Tetrahedron: Asymmetry 5:1973 (1994) provided an the intermediate oxime product.
The crude oxime, prepared above, was reacted with 1 ,1'- carbonyldiimidazole (3.9 , 23.9 mmole) in 50 mL of dichloromethane for 3 hours, at room temperature. The reaction was concentrated in vacuo and chromatographed on silica gel with 2-10% ethyl acetate/hexanes to provide the title compound (yield: 2.5g, 50%).
MS (M+H)+= 313
-138- NO
H^ 7 \ O-t-Bu n 0 ^ '"0 Ph
17B. (±)-(2R.3R.5R)-1-Benzyl-2-formyl-3-cvano-pyrrolidine-5-carboxylic Acid f- Butyl Ester.
The title compound is prepared according to the method described in Example 1D, substituting (±)(2S,3R,5R)-1-benzyl-2-vinyl-3-cyano-pyrrolidine-5- carboxylic acid f-butyl esterjn place of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(f- butyldimethylsilyioxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.2 g, 80%).
MS (M+H)+= 315
17C. (±)-(2R.3R.5R)-1-Benzyl-2-(1-oxo-3-ethyl)pentyl-3-cvano-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 1E, substituting (±)(2S,3R,5R)-1-benzyl-2-formyl-3-cyano-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R)-1-benzyl-2-formyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxyiic acid t-butyl ester (yield 0.4 g , 27%).
MS (M+H)+= 399
-139-
17D. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-amino-3-ethvnpentyl-3-cvano-pyrrolidine- 5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 1F, substituting (±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3- cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R)-1- benzyl-2-(1-oxo-3-ethyl)pentyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield 0.215 g , 50%).
MS (M+H)+= 400
17E. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3-cvano- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 1G, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-amino-3-ethyl)pentyl- 3-cyano-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3R,5R,1'R)- and (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield 0.210 g , 90%).
-140- 1H NMR (CDCI3) δ 7.25 (m, 5H), 5.08 (m, 1 H), 4.40 (m, 1 H), 4.15 (m, 1H), 3.78 (m,1 H), 3.48(m, 1 H), 2.93 (m, 1 H), 2.32 (m, 1 H), 2.12 (m, 1 H), 2.02 (s, 3H),1.52 (s, 9H), 1.35 (m, 7H), 0.85 (m, 6H)
MS: (M+H)+ = 442.
17F. (±)-(2R.3R.5R.1 'S)-2-(1 -Acetamido-3-ethyl)pentyl-3-cvano-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (CDCI3) δ 5.35 (bs, 1 H),4.00 (m, 1 H), 3.83 (m, 1 H), 3.39 (m, 1H), 3.08 (m, 1 H), 2.63 (m, 1 H), 2.15 (m, 1 H), 2.05 (s, 3H), 1.48 (s, 9H), 1.20-1.45 (m, 7H), 0.85 (m, 6H)
MS: (M+H)+=352
-141-
17G. (±H2R.3R.5R.1'SV2-(1-Acetamido-3-ethyl)pentyl-3-cvano-pyrrolidine-5- carboxyiic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- cyano-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid t- butyl ester.
1H NMR (de-DMSO) δ 9.12 (bs, 1 H), 8.05 (m, 1H), 4.38 (m, 1 H), 4.23 (m, 1H), 3.88 (m, 1H), 3.68 (m, 1H), 3.00 (m, 1H), 2.55 (m, 1H), 2.05 (m, 1H), 1.88 (s, 3H), 1.10-1.40 (m, 7H), 0.80 (m, 6H)
MS: (M+H)+= 296, (M-H)'= 294,
-142- Example 18
(±)-f2R.3S.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-ethyl-pyrrolidine-5-carboxylic Acid Hydrochloride.
18A. (±)-(2R.3S.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethvnpentyl-3-vinyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To an ice-cold suspension of methyl triphenylphosphonium bromide (240 mg, 0.67 mmol) in 5 mL THF was added potassium t-butoxide (60 mg, 0.54 mmol) under nitrogen. The color changed immediately to bright yellow. After stirring at room temperature for 1 h, (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido- 3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (100 mg, 0.225 mmol) in 5 mL THF was added and stirred at room temperature overnight. Reaction was then quenched with saturated ammonium chloride and extracted with ethyl acetate to give the crude product which was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 55 mg, 55%).
1H NMR (CDCI3): δ 7.45-7.20 (m, 5H), 5.94 (ddd, 1 H), 5.24 (d, J=12Hz, 1H), 4.98 (d, J=18Hz, 1H), 4.93 (d, J=10.5HZ, 1H), 4.37 (m, 1 H), 4.06 (d, J=13.5Hz, 1 H), 3.80 (d, J=13.5Hz, 1H), 3.41 (dd, J=9 Hz, J=3Hz, 1 H), 3.31 (q, J=13.5Hz, 1H), 2.60 (m, 1H), 2.26 (m, 1 H), 2.00 (s, 3H), 1.45 (s, 9H), 1.40-1.25 (m, 7H), 0.82 (m, 6H).
MS: (M+H)+= 443
-143- O'Bu
18B. (±)-(2R.3S.5R.1'S)-2-(1-acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3S,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (CDC ): δ 5.71 (br, 1 H), 4.00 (br, 1 H), 3.68 (t, J=8Hz, 1H), 3.10 (m, 1 H), 2.38 (m, 1H), 1.98 (s, 3H), 1.87 (m, 1 H), 1.47 (s, 9H), 1.55-1.20 (m, 10H), 0.93 (t, J=7.5Hz, 3H), 0.83 (m, 6H).
MS: (M+H)+= 355
18C. (±)-(2R.3S.5R.1'S)-2-(1-acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5- carboxylic Acid Hydrochloride
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- ethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-
-144- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid f- butyl ester.
1H NMR (D2O): δ 4.30 (br, 1 H), 4.25 (t, J=7.5Hz, 2H), 3.58 (br, 1 H), 2.61 (m, 1 H), 2.23 (br, 1 H), 2.05 (s, 3H), 1.90 (m, 1H), 1.70-1.20 (m, 9H), 0.92 (t, J=7.5Hz, 3H), 0.81 (m, 6H).
MS: (M+H)+= 299
Example 19
(±)-(2R.3S.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-propyl-pyrrolidine-5- carboxylic Acid Hydrochloride.
19A. (±W2R.3S.5R.1'S)-1-Benzyl-2-f1-acetamido-3-ethyl)pentyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester and (±H2R,3S.5R.1'S)-1-Benzyl- 2-(1 -acetamido-3-ethyl)pentyl-3-(fraπs-propen-1 -vP-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according the method described in Example 18A substituting ethyl triphenylphosphonium bromide for methyl triphenylphosphonium bromide.
1H NMR (CDCI3) δ 7.24 (m, 5H), 5.59 (m, 1 H), 5.36 (dd, J= 11 , 7Hz, 1 H), 5.28 (bs, 1H), 4.32 (m, 1 H), 4.06 (d, J= 12.9Hz, 1H), 3.80 (d, J= 12.9Hz, 1H), 3.42 (dd, J= 8.5, 2.0Hz, 1 H), 3.30 (dd, J= 6.1 , 3.1 Hz, 1 H), 2.88 (m, 1H), 2.29 (m, 2H), 2.01 (s, 3H), 1.64 (dd, J= 6.8, 1.7Hz, 3H), 1.44 (s, 9H), 1.30 (m, 7H), 0.81 (m, 6H).
-145- MS: (M+H)+= 457, (M+Na)+= 479, (M-H)- = 455.
CH 1 33 / \ t
AC .^J /O'BU
19B. (±)-(2R.3S.5R.1'S)-2-(1-acetamido-3-ethvnpentyl-3-propyl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3S,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyi)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester and (±)- (2R,3S,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(fraπs-propen-1-yl)- pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl- 2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyi-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 3.5 mg, 54%).
MS: (M+H)+= 369, (M+Na)+= 391 , (M-H)' = 367.
19C. (±H2R.3S.5R.1'S)-2-n-acetamido-3-ethyl)pentyl-3-propyl-pyrrolidine-5- carboxylic Acid Hydrochloride
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- ethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-
-146- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 3.5 mg, 100%).
1H NMR (DMSO-d6) δ 8.10 (d, J= 8.3Hz, 1 H), 4.24 (m, 1 H), 4.17 (m, 1H), 2.43 (m, 1 H), 2.19 (m, 1 H), 1.89 (s, 3H), 1.70 (m, 1 H), 1.50-1.20 (m, 12H), 0.87 (t, J= 6.8Hz, 3H), 0.84 (t, J= 7.0Hz, 3H), 0.79 (t, J= 7.3Hz, 3H).
MS: (M+H)+ = 313, (M+Na)+ = 335, (M-H)' = 311.
Example 20
(± 2R.3S.5R.1'S)-2-π-Acetamido-3-methvπbutyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride.
20A. (±W2R.3R.5R.1'RS)-1-Benzyl-2-(1.2-dihvdroxy)ethyl-3-(f- butyldimethylsilyloxymethvD-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
Osmium tetroxide was added to a room temperature solution of (±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(f-butyidimethylsilyloxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester (3.5 g, 8.12 mmol) in 60 mL of 8:1 acetone/water and N-methylmorpholine N-oxide (3.0 g, 25.6 mmol). The reaction mixture was stirred at room temperature for 6 hours and quenched with saturated aqueous Na2S2O3. The mixture was stirred for an additional 10 minutes and the solvent removed. The brownish residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO and concentrated in vacuo to provide the intermediate diol as an oil (~3.8g ) which was used without additional purification.
-147- MS: (M+H)+ = 466.
20B. (±H2R.3R.5R.1'RS)-2-(1.2-Dihvdroxy)ethyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'RS)-1-benzyl-2-(1 ,2-dihydroxy)ethyl-3- (f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (21.5g, 46.2 mmol). in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester.
MS: (M+H)+= 367.
20C. (±W2R.3R.5R.1'RS)-1-f-Butoxycarbonyl-2-(1.2-dihvdroxy)-ethyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'RS)-2-(1,2-Dihydroxy)ethyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (crude from previous step) was dissolved in 160 mL of 3:1 methanol/water and di-tert-butyl- dicarbonate (14.0 g, 64 mmol) was added. The mixture was stirred at room temperature for 72 h. Then solvent was removed and the residue was purified by
-148- chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound as light yellow solid (yield: 15.4 g, 70 %).
1H NMR (CDCI3): δ 0.03 (s, 3H), 0.05 (s, 3H), 1.37 (s, 9H), .42 (s, 9H), 1.47 (s, 9H) , 1.93 (d, 1 H), 2.30-2.50 (m, 2H), 3.28 (d, 1 H) , 3.66-3.43 (m, 4H), 3.85 (dd, 1H), 4.02-4.52 (m, 1H).
MS: (M+H)+= 476.
TBDMSO— s
H^ O H? Boc o°'BU
20D. (±)-(2R.3R.5R)-1-f-Butoxycarbonyl-2-formyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R,1'RS)-1-f-butoxycarbonyl-2-(1 ,2- dihydroxy)ethyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxyiic acid f- butyl ester (6.0 g, 12.6 mmol) was dissolved in 6:1 tetrahydrofuran (THF)/water (110 mL) and treated with sodium periodate (4.4 g, 20.6 mmol). The mixture was stirred at room temperature for 3 hour and diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetate/hexanes to provide the title compound as a white waxy solid (yield: 4.4 g, 78.6%).
1H NMR (CDCI3) (mixture of two rotamers): δ 0.05 and 0.06 (two s, 6H), 0.88 and 0.90 (two s, 9H), 1.42 and 1.44 (two s, 9H), 1.47 and 1.48 (two s, 9H), 1.89 -1.99 (m, 1 H), 2.37 - 2.43 (m, 2H), 3.54 - 3.67 (m, 2H), 4.02 - 4.34 (m, 2H), 9.43 and 9.53 ( two d, 1H).
MS: (M+H)+= 444.
-149- OlBu
20E. (±)-(2R.3R.5R.1'RSV1-f-Butoxycarbonyl-2-π-hvdroxy-3-methvnbutyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of (±)-(2R,3R,5R)-1-f-butoxycarbonyl-2-formyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (7.1 g, 16.03 mmol) in diethyl ether (75 mL) was reacted with isobutyl magnesium chloride (24 mL, 2.0 M in ether, 48 mmol) at 0°C for 2.5 hours. The reaction was quenched with saturated ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was used in next step without further purification.
MS: (M+H)+= 502
20F. (± 2R.3R.5R) 1-f-Butoxycarbonyl-2-f1-oxo-3-methvnbutyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
A solution of oxalyl chloride (16 mL, 2M in CH2CI2) in 100 mL of anhydrous dichloromethane was prepared and maintained under a nitrogen atmosphere, at -78 °C. DMSO (4.26 mL, 64.1 mmol) was added slowly to the solution. The mixture was stirred for 15 minutes and reacted with (±)-(2R,3R,5R,1'RS)-1-f- butoxycarbonyl-2-(1-hydroxy-3-methyl)butyl-3-(f-butyldimethylsilyloxymethyl)-
-150- pyrrolidine-5-carboxylic acid f-butyl in 30 mL of anhydrous dichloromethane. The solution was stirred for 1 hour and triethylamine (17 mL, 128 mmol) was added slowly to the reaction mixture. The solution was allowed to warm slowly to room temperature, quenched with saturated sodium bicarbonate and diluted with dichloromethane. The organic layer was washed with water and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5-10% ethyl acetate/hexanes to provide the title compound (yield: 6.3 g, 78.8 %).
H NMR (CDCI3): δ 0.07 (m, 6H), 0.81 - 0.96 (m, 15H), 1.40 and 1.42 (two s, 9H), 1.46 and 1.47 (two s, 9H), 1.72-1.82 (m, 1 H), 2.15-2.45 (m, 4H), 3.47 - 3.69 (m, 1H), 4.28 - 4.46 (m, 2H).
MS: (M+H)+= 500
20G. (±)-(2R.3R.5R.1'RS)-1-f-Butoxycarbonyl-2-π-amino-3-methv)butyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 1F, substituting (±)-(2R,3R,5R) 1-f-butoxycarbonyl-2-(1-oxo-3- methyl)butyl-3-(f-butyldimethylsiiyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-(f-butyl- dimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.54 g, 34.1%).
MS: (M+H)+= 501.
-151-
20H. (±)-(2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methv)butyl-3-(f- butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 1G, substituting (±)-(2R,3R,5R,1'RS)-1-f-butoxycarbonyl-2-(1-amino-3- methy)butyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'R)- and (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1- amino-3-ethyl)pentyl-3-(f-butyldimethylsilyloxymethyl)-pyrroiidine-5-carboxylic acid f-butyl ester (yield: 462 mg, 79.0 %).
(±)-(2R,3R,5R,1'S) 1H NMR (CDC ): δ 0.03 and 0.04 (two s, 6H), 0.86 (s, 9H), 0.89 and 0.95 (two d, 6H), 1.04 (m, 1H), 1.17 -1.25 (m, 2H), 1.44 (s, 9H), 1.46 (s, 9H), 1.86 (m, 1H), 1.99 (s, 3H), 2.07 (m, 1 H), 2.30 (m, 1 H), 3.48 (m, 1H), 3.61 (m, 1H), 3.67 (m, 1 H), 4.16 (m, 1H), 4.27 (m, 1H), 7.35 (br d, 1H).
MS: (M+H)+= 543.
OΈU
20I. (± 2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methv)butyl-3- (hvdroxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 1 H, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methy)butyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-
-152- butyl ester in place (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)butyl-3-t- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester.
MS: (M+H)+= 429.
20J. (± 2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methv)butyl-3- formyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 2A, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1.5 g, 91 %).
1H NMR (CDC ): δ 0.92 and 0.94 (two d, 6H), 1.07 (m, 1 H), 1.23-1.33 (m, 2H), 1.43 (s, 9H), 1.44 (s, 9H), 1.64 (m, 1 H), 2.03 (s, 3H), 2.39 (m, 1 H), 2.46 (m, 1 H), 3.18 (m, 1 H), 4.19 (m, 1 H), 4.32 (m, 1H), 4.39 (m, 1 H), 7.12 (br d, 1H).
MS: (M+H)+= 427
-153-
20K. (±W2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methv)butyl-3- vinyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
To a suspension of methyl triphenylphosphonium bromide (125.6 mg, 0.35 mmol) in 3 ml of anhydrous toluene was added potassium t-butoxide (1.0 M in THF, 0.31 mmol) dropwise at room temperature. After stirring for 16 hours, (±)- (2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl- pyrrolidine-5-carboxylic acid f-butyl ester (30 mg, 0.070 mmol) in 3 ml of toluene was added dropwise and stirred for 0.5 hour. The reaction was quenched with saturated ammonium chloride and diluted with methylene chloride. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compound, as an white foamy solid (yield: 23.7 mg, 79.4%).
1H NMR (CDCI3): δ 0.92 (m, 6H), 1.26 (m, 2H), 1.44 (s, 9H), 1.47 (s, 9H), 1.65 (m, 1H), 1.97 (s, 3H), 2.43 (m, 2H), 3.56 (m, 1 H), 4.15 (m, 2H), 4.32 (m, 1H), 5.11 (m, 1 H), 5.15 (m, 1 H), 5.75 (m, 1 H), 7.35 (br, 1H).
MS: (M+H)+= 425.
-154-
20L (±)-(2R.3S.5R.1'S)-2-(1-Acetamido-3-methvnbutyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methy)butyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 16.0 mg, 99.1%).
1H NMR (DMSO-dβ): δ 0.82 (d, 3H), 0.88 (d, 3H), 1.29 (m, 1H), 1.42 (m,
1H), 1.57 (m, 1 H), 1.87 (s, 3H), 1.91 (m, 1H), 2.40 (m, 1 H), 2.90 (m, 1 H), 4.20 (m, 1H), 4.32 (m, 1 H), 5.08 (dd, 1H), 5.17 (dd, 1 H), 5.72 (ddd, 1 H), 8.09 (d, 1H), 9.16 (br s, 1H), 9.28 (br s, 1H).
MS: (M+H)+= 269.
-155- Example 21
(±)-(2R.3R.5R.1 'S)-2-π-Acetamido-3-ethyl)pentyl-3-hvdroxymethyl-pyrrolidine-5- carboxylic Acid Hydrochloride.
21A. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-hvdroxymethyl- Pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R, 1 'S)-1 -benzyl-2-(1 -acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
MS: (M+H)+= 471
HO—. AcHN,, 7 V OH
21 B. (±H2R.3R.5R.1 'S)-2-(1-Acetamido-3-ethyl)pentyl-3-hvdroxymethyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1 'S)-2-(1-acetamido-3-ethyl)pentyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-
-156- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester
1H NMR (DMSO-de): δ 8.15 (d, J=9Hz, 1 H), 4.28-4.15 (m, 2H), 3.95-3.45 (m, 4H), 2.35 (m, 1 H), 1.98 (m, 1 H), 1.89 (s, 3H), 1.50-1.45 (m, 7H), 0.81 (t, J=7.4Hz, 3H), 0.77 (t, J=7.5Hz, 3H).
MS: (M+H)+= 301 , (M-H)"= 299
Example 22
(±H2R.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-Pyrrolidine-5- carboxylic Acid Hydrochloride.
22A. (±H2S.3R.5R.1'S)-1-Benzyl-2-(1-Acetamido-3-ethvnpentyl-3-(2- trimethylsilylethoxycarbonyiamino)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl- pyrrolidine-5-carboxylic acid t-butyl ester (80 mg, 0.18 mmol) prepared according to the procedure of Example 2B was reacted with diphenylphosphoryl azide (0.047 mL, 0.216 mmol), 2-trimethylsilylethanol (0.034 mL, 0.234 mmol), and triethylamine (0.030 mL, 0.216 mmol) in toluene (2 mL) at 75°C for 15 hours. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 25% ethyl acetate/hexanes to provide the title compound, as a light yellow oil (yield: 46 mg, 45%).
MS: (M+H)+= 576, (M+Na)+ = 598, (M-H)' = 574.
-157-
22B. (±)-(2S.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound is prepared according to the method described in Example 1H, substituting (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(2-trimethylsilylethoxycarbonylamino)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(f- butyldimethylsilyloxmethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.
MS: (M+H)+= 432, (M-H)' = 430.
22C. (±)-(2S.3R.5R.1'S)-1-Benzyl-2-(1-Acetamido-3-ethvnpentyl-3-(pyrrol-1-v - pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2S,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino- pyrrolidine-5-carboxylic acid t-butyl ester (34 mg, 0.078 mmol) was reacted with 40% succinic dialdehyde in water (50 mg, 0.234 mmol), acetic acid (0.00044 mL, 0.0078 mmol), and 4A molecular sieves (200 mg) in toluene (2 mL) at RT for 3 hours. The reaction was concentrated in vacuo and the resulting residue purified
-158- by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 7.1 mg, 19%).
MS: (M+H)+= 482, (M+Na)+ = 504, (M-H)' = 480.
22D. (±)-(2S.3R.5R.1'S)-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)- pyrrolidine-5-carboxylic Acid f-Butyl ester.
The title compound is prepared according to the method described in Example U, substituting (±)-(2S,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 3.5 mg, 61%).
MS: (M+H)+= 392, (M-H)' = 390.
-159- V , OH
22E. (± 2S.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-(pyrrol-1-vn- pyrroiidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2S,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- (pyrrol-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 3.5 mg, 100%).
1H NMR (D2O) δ 7.48 (bs, 1 H), 6.77 (bs, 2H), 5.97 (bs, 2H), 4.33 (m, 1H), 3.70 (m, 1H), 3.07 (m, 1H), 2.43 (m, 1H), 1.92 (m, 1H), 1.75 (s, 3H), 1.55 (m, 1H), 1.35-1.10 (m, 7H), 0.81 (m, 3H), 0.75 (m, 3H).
MS: (M+H)+= 336, (M-H)' = 334.
-160- Example 23
(±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-ethvnpentyl-3-π-c/s-N-hvdroxyimino)ethyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
NOH
H,CAt
OxBu
23A. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-π-acetamido-3-ethyl)pentyl-3-π-c/s-N- hvdroxyimino)ethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R,1'S) 1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetyl- pyrrolidine-5-carboxylic acid t-butyl ester (45 mg, 0.1 mmol) prepared according to the method of Example 8B in methanol/methylene chloride (3/1 ) was reacted with a solution of hydroxylamine hydrochloride ( 21 mg, 0.3 mmol) and sodium hydroxide (12 mg, 0.3 mmol) in methanol (2 mL) for 2h. The reaction was diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 40% ethyl acetate/hexanes to provide the cis- oxime title compound (lower Rf spot on TLC), as an oil (yield: 35 mg, 75%), as well as the fraπs-oxime title compound (higher Rf spot on TLC), as an oil (yield: 13 mg, 25%).
MS: (M+H)+= 474
-161- NOH
H,CAT
O'Bu
23B (±)-(2R.3R.5R.1'S)-2-(1-acetamido-3-ethvnpentyl-3π-c/s-N- hvdroxyimino)ethyl pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound is prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(1-c/s-N-hydroxyimino)ethyl-pyrroiidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (CDCI3): δ 3.92 (br, 1 H), 3.70 (m, 2H), 2.82 (m, 1 H), 2.38 (m, 1H), 1.88 (s, 3H), 1.78 (s, 3H), 1.39 (s, 9H), 1.40-1.20 (m, 7H), 0.76 (m, 6H).
MS: (M+H)+= 384
NOH
H3C-
AcHN,, JJ) OH
Jj J HCl ϊ
23C. (±W2R.3R.5R.rS -2-(1-acetamido-3-ethvl)oentvl-3-π-c/s- -N- hvdroxvimino)ethvl-ovrrolidine -5-carboxviic Acid Hydrochloride
The title compound is prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(1- c/s-N-hydroxyimino)ethyl-5-carboxylic acid f-butyl ester in place of (±)-
-162- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester.
1H NMR (D2O): δ 4.35 (m, 1 H), 4.00 (m, 1 H), 3.80 (m, 1 H), 3.71 (m, 1H), 3.63 (m, 1 H), 3.13 (q, J=8.4Hz„ 1H), 2.64 (m, 1 H), 2.18 (m, 1H), 1.97 (s, 3H), 1.85 (s, 3H), 1.50-1.10 (m, 7H), 0.77 (m, 6H).
MS: (M+H)+= 328
Example 24
(±)-(2R.3R.5R.1'S)-2-π-Acetamido-3-ethvnpentyl-3-(N-hvdroxyimino)methyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
24A. (±H2R.3R.5R.1'SV2-(1-Acetamido-3-ethvnpentyl-3-(N- hydroxyimino)methyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl- pyrrolidine-5-carboxylic acid t-butyl ester (18 mg, 0.051 mmol) prepared according to the method of Example 2A was reacted with hydroxylamine hydrochloride (7 mg, 0.11 mmol) in 1 N NaOH in methanol (3 mL) at 25°C for 1.5 hours. The reaction was quenched with aqueous ammonium chlororide (3ml) and water (3ml)and taken by dichloromethane (2x 10 ml). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound, as an oil (yield: 6 mg, 32%).
-163- MS: (M+H)+=370
NOH
OH
24B (±)-(2R.3R.5R.1'S)-2-π-Acetamido-3-ethvnpentyl-3-(N- hvdroxyimino)methyl-pyrrolidine-5-carboxylic Acid Hydrochloride
The title compound is prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(N- hydroxyimino)methyl-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester.
Example 25
(±W2R.3R.5R.1'SV2-π-Acetamido-3-ethyl)pentyl-3-(methoxyimino)methyl- pyrrolidine-5-carboxylic Acid .
NH2
CH30-
25A. (±H2R.3R.5R.1'S) 1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3- (methoxyimino)methyl-pyrrolidine-5-carboxylic Acid
(±)-(2R,3R,5R,1'S) 1-Benzyl-2-(1-acetamido-3-ethyl)ρentyl-3-cyano- pyrrolidine-5-carboxylic acid t-butyl ester (20 mg, 0.045 mmol) prepared according to the method of Example 17E was reacted with hydrogen chloride
-164- (0.45 mmol) in ether (2 mL) and methanol (0.1 mL) at 0°C for 5 hours. The reaction was neutralized with aqueous ammonium hydroxide and purified on silica gel with 3% methanol in dichloromethane to provide the title compound, as a white solid (yield: 5 mg, 26%).
MS: (M+H)+=418
NH
0H,O-^
25B. (±H2R.3R.5R.1'S)-2-π-Acetamido-3-ethvnpentyl-3- (methoxyimino)methyl-pyrrolidine-5-carboxylic Acid.
The title compound is prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S) 1-Benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(imino-methoxymethyl)-pyrrolidine-5-carboxylic acid t-butyl ester, in place of (±)-(2R,3R,5R, 1 'S)-1 -benzyl-2-(1 -acetamido-3-ethyl)pentyl-3- methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 3.9 mg, 96%).
1H NMR (DMSO-de) δ 7.52(d, J=8.7 HZ, 1H), 7.15(s, 1 H),6.77(s, 1H), 3.68(m, 1H),3.61(s, 3H), 3.22(m, 1 H), 2.51(m, 1H), 2.23(m, 1H), 1.82(m, 1H), 1.78(s, 3H), 1.40(m, 1H), 1.26(m, 3H), 1.13(m, 3H), 0.78(t, J=6.5HZ, 3H), 0.72(t, J=6.5HZ, 3H)
MS: (M+H)+=328
-165- Example 26
(±H2R.3R.5R.1 'S)-2-(1 -Acetamido-3-methyl)butyl-3-(hvdroxyacetv0-pyrrolidine- 5-carboxylic Acid Hydrochloride.
26A. (±H2R.3R.5R.1'S.1"RS)-1-f-Butoxycarbonyl-2-(1-acetamido-3- methy)butyl-3-(1,2-dihvdroxy)ethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 20A substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methy)butyl-3-vinyl-pyrroiidine-5-carboxyiic acid f-butyl ester for (±)-(2S,3R,5R)- 1-benzyl-2-vinyl-3-(f-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.
26B. (± 2R.3R.5R.1'SV1-f-Butoxycarbonyl-2-(1-acetamido-3-methv)butyl-3- (hvdroxyacetvπ-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R, 1'S,1 "RS)-1 -f-Butoxycarbonyl-2-(1 -acetamido-3- methy)butyl-3-(1 ,2-dihydroxy)ethyl-pyrrolidine-5-carboxylic acid f-butyl ester is reacted with dibutyltin oxide in methanol according to the procedure of Kong in J. Carbohydrate Chem. 1993, p. 557. The reaction is concentrated and the residue
-166- is redissolved in dichloromethane and reacted with bromine as described in the above reference to give the title compound.
26C. (±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-methv butyl-3-(hvdroxyacetvn- pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound is prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methy)butyl-3-hydroxyacetyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester.
-167- Example 27
(±)-(2S.3R.5R.1 'S)-2-( 1 -Acetamido-3-methv0butyl-3-amino-pyrrolidine-5- carboxylic Acid Dihvdrochloride.
CbzHN,
27A. (±W2S.3R.5R.1'RS)-1-Benzyl-2-(1-hvdroxy-3-methyl)butyl-3- benzyloxycarbonylamino-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 9D, substituting isobutylmagnesium bromide in place of 3- pentylmagnesium bromide.
CbzHN,
27B. (±H2S.3R.5R.1'SV1-Benzyl-2-(1-acetamido-3-methyl)butyl-3- benzyloxycarbonylamino-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Examples 9E-H substituting (±)-(2R,3R,5R,1'RS)-1-benzyl-2-(1-hydroxy-3- methyl)butyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester for (±)-(2R,3R,5R,1'RS)-1-benzyl-2-(1-hydroxy-3-ethyl)pentyl-3- benzyloxycarbonylamino-pyrrolidine-5-carboxylic acid t-butyl ester as the starting material of the sequence in Example 9E.
-168-
27C. (±)-(2S.3R.5R.1'S)-2-(1-acetamido-3-methvnbutyl-3-amino-pyrrolidine-5- carboxylic Acid Dihvdrochloride
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3- amino-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2- (1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylic acid f- butyl ester.
1H NMR (d6-DMSO) δ 8.64( bs, 1 H), 8.32 (bs, 1H), 8.23 (bs, 1H), 8.18 (d, J=6Hz, 1 H), 4.79 (d, J=7Hz, 1 H), 4.42 (m, 1 H), 4.33 (m, 1 H), 4.21 (m, 1 H), 4.07 (m, 1 H), 3.76 (m, 2H), 2.73 (m, 2H), 1.92 (m, 3H), 0.80-0.97 (m, 7H).
MS (M+H)+ = 258
-169- Example 28
(±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-methvnbutyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
28A. (±)-(2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methvhbutyl-3- carboxyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 2B, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyi)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3R,5R, 1 'S)-1 -benzyl-2-(1 -acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester.
28B. (± 2R.3R.5R.1'SV1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- methoxycarbonyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in Example 2C, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5- carboxylic acid f-butyl ester.
-170-
28C. (±W2R.3R.5R.1'S)-2-(1-Acetamido-3-methyl)butyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 2E, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1 'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-d6): δ 8.24, 8.08 (d, J=9Hz, 1H), 4.44, 4.36 (m, 1H), 4.25, 4.15 (m, 1H), 3.98, 3.88 (m, 1 H), 3.65, 3.64 (s, 3H), 3.18, 3.10 (m, 1H), 2.57, 2.20 (m, 2H), 1.87, 1.83 (s, 3H), 1.57 (m, 2H), 1.36 (m, 1H), 0.88 (d, J=7.5Hz, 3H), 0.82 (d, J=7.5Hz, 3H).
MS: (M+H)+= 301
-171- Example 29
(±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-methvnbutyl-3-(imidazol-2-yl)-pyrrolidine-5- Carboxylic Acid Dihvdrochloride.
29A. (±)-(2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-2- yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 15A, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 27.4 mg, 83. %).
MS: (M+H)+= 455.
29B. (±)-(2R.3R.5R.1 'S)-2-(1 -Acetamido-3-methvhbutyl-3-f imidazol-2-vn- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 15B, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of
-172- (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)- pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 19.1 mg, 95.5%).
MS: (M+H)+= 365.
OH
29C (±)-(2R.3R.5R.1'SV2-(1-Acetamido-3-methvnbutyl-3-(imidazol-2-vn- pyrrolidine-5-Carboxylic Acid Dihvdrochloride.
The title compound was prepared according to the method described in Example 15B, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)- pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-dβ): δ 0.76 (d, J = 6.6 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H),
1.18 (t, 2H), 1.44 (m, 1 H), 1.71 (s, 3H), 2.43-2.47 (m, 1H), 2.80 (m, 1 H), 3.83 (m, 1H), 4.05 (m, 1 H), 4.28 (m, 1H), 4.55 (t, 1 H), 7.65 (s, 2H), 8.03 (d, J = 8.4 Hz, 1H).
MS: (M+H)+= 326.
-173- Example 30
(±H2R.3R.5R.1 'S)-2-(1-Acetamido-3-methvnbutyl-3-(imidazol-4-yl)-pyrrolidine-5- carboxylic Acid Dihvdrochloride.
30A. (±)-(2R.3R.5R,1'SV1-f-Butoxycarbonyl-2-(1-acetamido-3-methv)butyl-3- carboxyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 2B, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methy)butyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester prepared according to the method described in Example 20J in place (±)-(2R,3R,5R,1'S)-1- benzyl-2-(1 -acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 129.5 mg, >100 %).
MS: (M+H)+= 443.
30B. (±H2R.3R.5R.1'S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-diazoacetyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 12A, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-
-174- methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 218.8 mg, 100%).
MS: (M+H)+= 458.
O
Br, v . ,θ'Bu
30C. (±W2R.3R.5R.1 'S)-1 -Benzyl-2-(1 -acetamido-3-methvnbutyl-3- bromoacetyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 12B, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- methyl)butyl-3-diazoacetyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-diazoacetyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 107.2 mg, 45.5 %).
1H NMR (CDCI3): δ 0.90 (d, 6H), 1.26 - 1.35 (m, 3H), 1.42 (s, 9H), 1.95 (s, 3H), 2.25 (m, 2H), 3.11 (m, 1H), 3.54 (dd, 1 H), 3.69 (m, 1 H), 3.93 (dd, 2H), 4.11 (d, 1 H), 4.27 (m, 1H), 4.35 (d, 1H), 5.05 (br d, 1 H), 7.25-7.32 (m, 5H).
MS: (M+H)+= 509.
-175- • N
HN
N* . OlBu
Ph
30D. (±)-(2R.3R.5R.1'SV1-Benzyl-2-π-acetamido-3-methyl)butyl-3-(imidazol-4- yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 12C, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- methyl)butyl-3-bromoacetyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3R,5R, 1 'S)-1 -benzyl-2-(1 -acetamido-3-ethyl)pentyl-3-bromoacetyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 32.3 mg, 60.4%).
MS: (M+H)+= 455.
30E. (± 2R.3R.5R.1'S)-2-n-Acetamido-3-methyl)butyl-3-(imidazol-4-vn- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example U, substituting (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 23.9 mg, 96.2%).
-176- 1H NMR (CDCI3): δ 0.87 (d, 3H), 0.89 (d, 3H), 1.26 (m, 1 H), 1.41 (m, 2H), 1.46 (s, 9H), 1.59 (m, 1H), 1.93 (s, 3H), 2.62 (m, 1H), 3.30 (m, 1 H), 3.54 (m, 1H), 3.79 (m, 1H), 4.01 (m, 1 H), 6.11 (br d, 1 H), 6.89 (s, 1H), 7.63 (s, 1 H).
MS: (M+H)+= 365.
/^N
H
30F. (±W2R.3R.5R.1'S)-2-(1-Acetamido-3-methvnbutyl-3-(imidazol-4-yl)- pyrrolidine-5-carboxylic Acid Dihvdrochloride.
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3- (imidazol-4-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)- (2R,3R,5R, 1 'S)-2-(1 -acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester to provide the title compound solid (yield: 24.4mg, 100%).
1H NMR (DMSO-d6): δ 0.76 (d, J = 3.6 Hz, 3H), 0.88 (d, J = 3.6 Hz, 3H),
1.22 (m, 1 H), 1.28 (m, 1 H), 1.48 (m, 1 H), 1.79 (s, 3H), 2.32 (dt, 1 H), 2.71 (dt, 1 H), 3.68 (m, 1H), 3.96 (m, 1 H), 4.28 (m, 1 H), 4.51 (t, 1H), 7.63 (s, 1 H), 8.23 (d, J = 5.1 Hz, 1H), 9.10 ( s, 1H), 9.67 (br s, 1H), 14.51 (br s, 1 H).
MS: (M+H)+= 309.
-177- Example 31
(±)-(2R.3R.5R.1 'S)-2-(1-Acetamido-3-methvnbutyl-3-rthiazol-4-vn-pyrrolidine-5- carboxylic Acid Dihvdrochloride.
31A. (±)-(2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methvhbutyl-3- (thiazol-4-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- bromoacetyl-pyrrolidine-5-carboxylic acid f-butyl ester (36.5 mg, 0.07 mmol) was reacted with thioformamide (21.4 mg, 0.35 mmol) in ethanol (5 ml) at reflux for 4 hours. The reaction was concentrated in vacuo. The residue was treated with 5 ml of aqueous NaHCO3 and extracted with dichloromethane (4 x 5 ml). The organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compound, as a white solid (yield: 23.8 mg, 70.4%).
MS: (M+H)+= 482.
-178-
31 B. (±)-(2R.3R.5R.1'S -2-(1-Acetamido-3-methvnbutyl-3-(thiazol-4-vn- pyrrolidine-5-carboxylic Acid Dihvdrochloride.
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 18.5 mg, 100%).
1H NMR (DMSO-d6): δ 0.62 (d, J = 4.2 Hz, 3H), 0.72 (d, J = 4.2 Hz, 3H),
1.05 (m, 1 H), 1.12 (m, 1 H), 1.30 (m, 1H), 1.72 (s, 3H), 2.14 (dt, 1 H), 2.59 (dt, 1H), 3.69 (m, 1 H), 3.92 (br m, 1 H), 4.21 (m, 1 H), 4.38 (br m, 1 H), 7.46 (d, J = 1.2 Hz, 1 H), 8.02 (d, J = 5.1 Hz, 1 H), 9.04 (d, J = 1.2 Hz, 1 H), 9.39 (br s, 1 H), 9.48 (br s, 1H).
.MS: (M+H)+= 326.
-179- Example 32
(±)-(2R.3R.5R.1'S)-2-(1-Acetamido-3-methvπbutyl-3-(thiazol-2-yl)-pyrrolidine-5- carboxylic Acid Dihydrochloride.
32A. (±)-(2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-π-acetamido-3-methvnbutyl-3- carbamoyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- carboxyl-pyrrolidine-5-carboxylic acid f-butyl ester (0.258g , 0.584 mmol) was reacted with isobutyl chloroformate (80 mg, 0.84 mmol) and N-methylmorpholine (59 mg, 0.584 mmol) in THF (10 mL) at 0°C for 0.25 hours. Aqueous ammonium hydroxide (.39 mL) was added and the reaction was stirred at 0°C for 0.5 hours . The reaction was diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% ethyl acetate to 5 % methanol-ethyl acetate to provide the title compound, as a glass (yield: 182 mg, 70.7 %).
1H NMR (CD3OD) δ 4.70(m,1 H), 4.36 (q, J=3 Hz,1 H), 4.05 (m,1H),2.87( q of t, J=9 and 3 Hz, 1 H), 2.52 (m, 1 H), 2.36 (m, 1H) 1.94 (d, 3H),1.63 (m, 1H), 1.41-1.53 (m, 18H), 1.3 (m, 2H), 0.9-0.18 (m, 6H)
MS: (M+H)+= 442
-180-
32B. (± 2R.3R.5R.1'S)- 1-f-Butoxycarbonyl-2-(1-acetamido-3-methvnbutyl-3- thiocarbamoyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methy)butyl-3- carbamoyl-pyrrolidine-5-carboxylic acid f-butyl ester (70 mg, 0.159 mmol) was reacted with P2Sι0 (8.5 mg, 0.019 mmol) in 4 mi tetrahydrofuran and 1 ml of methylene chloride at room temperature. After 1.25 hrs, 9.6 mg of P2Sι0 was added. The starting material had been consumed after 2 hrs. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgsO4, filtered and concentrated. Tic analysis showed two spots and the mass spectrum indicated it was a mixture of mono-thio and di-thio compounds. The material was used in the next reaction without further purification.
MS: (M+H)+= 458, 474
Bu
32C. (±)-(2R.3R.5R.1'SV1-f-Butoxycarbonyl-2-π-acetamido-3-methvhbutyl-3- (thiazol-2-vP-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methy)butyl-3- thiocarbamoyl-pyrrolidine-5-carboxyiic acid f-butyl ester (73 mg, o.16 mmol) was reacted with chloroacetaldehyde (50% in water) (0.02 ml, 0.16 mmol) in 5 ml of
-181- acetone at 75°C. Magnesium sulfate (0.9 g) and additional chloroacetaldehyde was added at intervals over the next 5 hr when till complete conversion of starting material. The reaction was diluted with ethyl acetate, washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo The residue was purified by chromatography on silica gel using 100% ethyl acetate to provide the title compound, as a glass (yield: 12.6 mg, 16.3%).
1H NMR (CDCI3) δ 7.69(m, 1H), 7.45(m, 1 H), 4.44 (m, 1 H), 4.28 (m, 2H), 3.52(m, !H), 2. 7 (m, 1H), 2.5 (m, 1 H), 1.99 (s, 3H), 1.44 (s, 9H), 1.37 (s, 9H), 1.27 (m, 3 H), 0.95 (m, 6 H).
MS: (M+H)+= 482
OH o
32D. (±W2R.3R.5R.1'S)-1- f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- (thiazol-2-yl)-pyrrolidine-5-carboxylic Acid Dihvdrochloride
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyi-3-(thiazol-2-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R, 1 'S)-2-(1 -acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 10.1 mg, 82%).
1H NMR (DMSO-de) δ 8.1 (d, J=10Hz, 1 H), 7.79 (d, J=4Hz, 1H), 7.69 (d=4 Hz, 1H), 4.49 (t, J=7.5, 1H), 4.22 (m, 1 H), 4.14 (t, J=9Hz, 1 H), 4.01 (q, J=10Hz, 1 H), 2.80 (m, 1 H), 2.25 (m, 1 H), 1.78 (s, 3H), 1.47 (m, 1 H), 1.25 (m, 2H), 0.83 (d, J=6.2Hz, 3H), 0.75 (d, J=6.2Hz, 3H)
-182- MS: (M-H)- = 324, (2M-1)'= 649, (M+35)"= 360
Example 33
(±)-(2R.3S.5R.1 'S)--2-(1-acetamido-3-methvnbutyl-3-(c/s-2-chloro-vin-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/OlBu o
33A. (±^^R.SS.δR.I'S^-l-f-Butoxycarbonyl^-d-acetamido-S-methvnbutyl-S- (c/s-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester and (±)- (2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(frar7S-2- chloro-vin-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 20K substituting (chloromethyl)triphenylphosphonium chloride in place of methyitriphenylphosphonium bromide. The higher Rf 0.73 (ethyl acetate) new spot was identified to be the cis- isomer (yield: 38.4 mg, 40 %) and the lower Rf 0.57 (ethyl acetate) spot trans- isomer (yield: 42 mg, 43 %).
cis- isomer 1 H NMR (CDCI3): δ 7.44 (br, 1 H), 6.13 (d, J=7.5Hz, 1 H), 5.32 (dd, J=9Hz, J=7.5Hz, 1H), 4.31-4.16 (m, 2H), 3.65 (m, 1 H), 3.12 (m, 1 H), 2.50 (m, 1 H), 1.98 (s, 3H), 1.62 (m, 1H), 1.47 (s, 9H), 1.45 (s, 9H), 1.30-1.07 (m, 2H), 0.82 (m, 6H)
MS: (M+H)+= 459
-183- trans- isomer 1H NMR (CDCI3): δ 6.12-5.90 (m, 2H), 4.30-4.07 (m,
2H), 3.64 (m, 1 H), 2.62-2.37 (m, 2H), 1.98 (s, 3H), 1.69 (m, 1 H), 1.48 (s, 9H), 1.45 (s, 9H), 1.26 (m, 2H), 0.91 (m, 6H).
MS: (M+H)+= 459
33B. (±)-(2R.3S.5R.1'SV2-(1-acetamido-3-methvnbutyl-3-(c s-2-chloro-vin-1-vn- PVrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- (c/'s-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (10 mg, 0.022 mmol) was reacted with trifluoroacetic acid (1.8 mL) in dichloromethane (0.4 mL) at room temperature for 7 hours. The reaction was concentrated in vacuo. The residue was dried on high vacuum to provide the title compound.
1H NMR (DMSO-de): δ 8.015 (d, J=7.63Hz, 1H), 6.42 (d, J=7.02Hz, 1H), 5.89 (dd, J=7.02Hz, J=8.7Hz, 1 H), 4.42 (m, 1H), 4.17 (m, 1 H), 3.59 (m, 1 H), 3.31 (m, 1 H), 2.47 (m, 1 H), 1.88 (s, 3H), 1.84 (m, 1 H), 1.58 (m, 1 H), 1.39 (m, 1 H), 1.29 (m, 2H), 0.885 (d, J=6.71Hz, 3H), 0.83 (d, J=6.41 , 3H).
MS: (M+H)+= 303
-184- Example 34
(± (2R.3S.5R.1'S)-2-(1-acetamido-3-methvnbutyl-3-(frans-2-chloro-vin-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
34B. (±)-(2R.3S.5R.1 'SV2-(1-acetamido-3-methvnbutyl-3-(frans-2-chloro-vinvn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-(frans-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl- 3-(c/s-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-d6): δ 8.04 (d, J=7.93Hz, 1 H), 6.355 (d, J=13.1 Hz, 1H), 5.93 (dd, J=13.1 Hz, J=9.32 Hz, 1 H), 4.33 (m, 1 H), 4.19 (m, 1H), 2.95 (m, 1H), 2.40 (m, 1H), 1.94 (m, 1 H), 1.88 (s, 3H), 1.58 (m, 1 H), 1.39 (m,1H), 1.29 (m, 1H), 0.89 (d, J=6.7 Hz, 3H), 0.825 (d, J=6.7 Hz, 3H).
MS: (M+H)+= 303
Example 35
(±)-(2R.3S.5R,1'S)-2-(1-acetamido-3-methvnbutyl-3-(c/s-propen-1-yl)-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt
-185-
35A. (±)-(2R.3R,5R.1'SV1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-( c s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
To a suspension of ethyl triphenylphosphonium bromide (479 mg, 1.29 mmol) in 3 mL anhydrous toluene was added potassium t-butoxide (1.0 M in THF, 0.94 mmol) dropwise at room temperature. After stirring for 2.5 hours, (±)- (2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl- pyrrolidine-5-carboxylic acid f-butyl ester (90 mg, 0.211 mmol) in 5 mL toluene was added dropwise and stirred for 1 hour. The reaction was quenched with saturated aqueous ammonium chloride and diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 70.6 mg, 76%).
MS: (M+H)+= 439
35B. (±)-(2R.3S.5R.1'S)-2-(1-acetamido-3-methyl)butyl-3-(c/s-propen-1-ylV pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in
-186- place of (±)-(2R,3S,5R,1 'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- (c/s-2-chloro-vinyl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-de): δ 8.04 (d, J=7.5Hz, 1 H), 5.51 (m, 1 H), 5.26 (m, 1H), 4.32 (m, 1H), 4.18 (m, 1H), 3.45 (m, 1H), 3.18 (m, 1H), 2.39 (m, 1H), 1.88 (s, 3H), 1.73 (m, 1 H), 1.63 (dd, 3H), 1.58 (m, 1 H), 1.38 (m, 1H), 1.28 (m, 1 H), 0.88 (d, J=6Hz, 3H), 0.81 (dd, J=6Hz, 3H).
MS: (M+H)+= 283
Example 36
(±)-(2R.3S.5R.1'S)-2-(1-acetamido-3-methvnbutyl-3-(2.2-dimethyl-vin-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
36A. (±V(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methvnbutyl-3- (2.2-dimethyl-vin-1-vh-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 20K substituting isopropyl triphenylphosphonium iodide in place of methyltriphenylphosphonium bromide (yield: 22.6 mg, 33 %).
1H NMR (CDCI3): δ 7.77 (d, 1H), 5.06 (d, J=10Hz, 1H), 4.18 (m, 2H), 3.50 (m, 1 H), 2.69 (m, 1 H), 2.32 (m, 1H), 1.97 (s, 3H), 1.70 (s, 3H), 1.64 (s, 3H), 1.65
-187- (m, 1 H), 1.47 (s, 9H), 1.44 (s, 9H), 1.30-1.00 (m, 3H), 0.93 (d, J=6Hz, 3H), 0.88 (d, J=6Hz, 3H).
MS: (M+H)+= 453
CH3
κOH
36B. (±)-(2R.3S.5R.1 'S)-2-π-acetamido-3-methyl)butyl-3-(2.2-dimethyl-vin-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-(2,2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1 'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl- 3-(c/'s-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-d6): δ 8.01 (d, J=7.5HZ, 1 H), 4.99 (d, J=10Hz, 1 H), 4.30 (m, 1 H), 4.14 (m, 1 H), 3.40 (m, 1 H), 3.06 (m, 1 H), 2.36 (m, 1 H), 1.86 (s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.57 (m, 1 H), 1.39-1.20 (m, 3H), 0.88 (d, J=6Hz, 3H), 0.81 (d, J=6Hz, 3H).
MS: (M+H)+= 297
Example 37
(±H2R.3S.5R.1 'S)-2-(1 -acetamido-3-methvnbutyl-3-(2.2-difluoro-vin-1 -yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
-188-
37A. (±)-(2R.3S.5R.1'SV1-f-Butoxycarbonyl-2-π-acetamido-3-methvnbutyl-3- (2,2-difluoro-vin-1-vπ-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
n-Butyllithium (1.6M in hexanes, 0.61 mL, 0.97 mmol) was added to diisopropylamine (136 μL, 0.97 mmol) in 4 mL THF at -78 °C and stirred for 30 min. diethyl difluoromethylphosphonate (182 mg, 0.97 mmol) was added, the colorless solution changed slowly to yellow after stirring at -78 °C for 2 hours. (±)-(2R,3R,5R, 1 'S)-1 -f-Butoxycarbonyl-2-(1 -acetamido-3-methyl)butyl-3-formyl- pyrrolidine-5-carboxylic acid f-butyl ester (59 mg, 0.138 mmol) in 3 mL THF was added, stirred at "78 °C for 30 min, then warm up to room temperature. The mixture was then heated at reflux for 1.5 hour, and stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, and diluted with ethyl acetate. The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as a light yellow oil (23.4 mg, 37%).
1H NMR (CDCI3): δ 7.44 (d, 1 H), 5.92 (ddd, 1H), 4.30-4.00 (m, 2H), 3.55 (m, 1H), 2.69 (m, 1 H), 2.45 (m, 1 H), 2.00 (s, 3H), 1.47 (s, 9H), 1.43 (s, 9H), 1.45- 1.00 (m, 4H), 0.91 (m, 6H).
MS: (M+H)+= 461
-189-
37B. (±)-(2R.3S.5R.1'SV2-π-acetamido-3-methyl)butyl-3-(2.2-difluoro-vin-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1 'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- (c/s-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-de): δ 8.04 (d, J=7.5Hz, 1H), 4.59 (ddd, 1H), 4.23 (m, 1H), 4.14 (m, 1 H), 3.48 (m, 1 H), 3.39 (m, 1H), 2.91 (m, 1H), 2.43 (m, 1 H), 1.85 (s, 3H), 1.58 (m, 1H), 1.40 (m, 1H), 1.31 (m, 1H), 1.22 (m, 1H), 0.89 (d, J=7.5Hz, 3H), 0.83 (d, J=7.5Hz, 3H).
MS: (M+H)+= 305
Example 38
(±)-(2R.3R.5R.1'S)-2-(1-acetamido-3-methvnbutyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
-190-
38A. (±W2R.3R.5R.1'S.1"RS)-1-f-Butoxycarbonyl-2-(1-acetamido-3- methvπbutyl-3-(1-hvdroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 4A substituting 2-propynyl magnesium bromide in place of ethyl magnesium bromide and substituting (±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1- acetamido-3-methyl)butyl-3-formyi-pyrrolidine-5-carboxylic acid f-butyl ester (250 mg, 0.587 mmol) in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester the crude product was used directly in the next reaction.
MS: (M+H)+=453
38B. (±W2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1- oxo-2-propyn-1-yl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1- hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester was reacted with Jones reagent (3.0 M in acetone, 0.33 mL) in acetone (90 mL) at 0 °C to room temperature for 1 hour. The reaction was diluted with ethyl acetate. The organic
-191- layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as a white solid (yield: 143 mg, 54%).
MS: (M+H)+= 451
HN^
N=
AcHN. X^ βlBu Boc I
38C. (±V(2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methvnbutyl-3- (pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1- oxo-1-ethynyl)methyl-pyrrolidine-5-carboxyiic acid f-butyl ester (140 mg, 0.311 mmol) was reacted with hydrazine monohydrate (0.24 mL, 4.944 mmol) in ethanol (12 mL) at room temperature for 4 hours. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compound, as a white solid (yield: 131 mg, 91%).
MS: (M+H)+= 465
-192-
38D. (±)-(2R.3R.5R.1'S)-2-(1-acetamido-3-methvhbutyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyi-2-(1-acetamido- 3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(c/s-2- chloro-vinyl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-d6): δ8.13 (d, J=7.5Hz, 1H), 7.65 (d, J=2.2Hz, 1 H), 6.20 (d, J=2.2Hz, 1H), 4.39 (m, 1H), 4.25 (m, 1 H), 3.94 (m, 1H), 3.56 (q, J=7.5Hz, 1H), 2.62(m, 1H), 2.17 (m, 1H), 1.87 (s, 3H), 1.42 (m, 1 H), 1.21 (m, 1 H), 1.11 (m, 1H), 0.80 (d, J=6.6Hz, 3H), 0.71 (d, J=6.6Hz, 3H).
MS: (M+H)+=309
-193- Example 39
(±)-(2R.3R.5R.1 'S)-2-(1-acetamido-3-methvnbutyl-3-(isoxazol-3-yl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt and (±H2R.3R.5R.1'S)-2-(1-acetamido- 3-methvDbutyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
39A. (± ^R.SR.δR.I'SVI-f-Butoxycarbonyl^-d-acetamido-S-methvnbutyl-S- (isoxazol-3-vD-pyrrolidine-5-carboxylic Acid f-Butyl Ester and (±)-(2R.3R.5R.1'SV 1-f-Butoxycarbonyl-2-π-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5- carboxylic Acid f-Butyl Ester
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1- oxo-1-ethynyl)methyl-pyrrolidine-5-carboxylic acid f-butyl ester (31 mg, 0.07 mmol) was reacted with hydroxyamine hydrochloride (4.9 mg, 0.07 mmol) and sodium carbonate (3.7 mg, 0.035 mmol) in ethanol (3 mL) at reflux for 30 hours. The reaction was concentrated in vacuo. The residue was purified by chromatography on silica gel using 3% methanol/dichloromethane to provide the title compound, as an oil (yield: 11.5 mg, 36%).
MS: (M+H)+= 466
-194-
39B. fcH2R.3R.5R.1 'SV2-M -acetamido-3-methvnbutyl-3-(isoxazol-3-vπ- pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt and (±)-(2R.3R.5R.1'S)-2- (1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylic acid f-butyl ester and (±)- (2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5- yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f- butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(c/s-2-chloro-vinyl)-pyrrolidine-5- carboxylic acid f-butyl ester.
1H NMR (DMSO-d6): δ 8.91 , 8.54 (d, 1H), 8.12, 8.05 (d, J=7.5Hz, 1H), 6.64, 6.43 (d, 1 H), 4.48, 4.51 (m, 1H), 4.28 (m, 1 H), 3.97, 3.89 (m, 1H), 3.70, 3.81 (m, 1H), 2.72 (m, 1H), 2.20, 2.25 (m, 1H), 1.83, 1.80 (s, 3H), 1.48 (m, 1H), 1.34- 1.10 (m, 2H), 0.83, 0.84 (d, J=6Hz, 3H), 0.77, 0.78 (d, J=6Hz, 3H).
MS: (M+H)+=310
Example 40
-195- (±)-(2R.3S.5R.1 'R)-2-(1-Acetamido-2-hvdroxy)ethyl-3-fc/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
AcO--
40A. (±)-(2R.3R.5R)-1-Benzyl-2-vinyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxyiic acid f-butyl ester (54.2 g, 0.17 mol) and 4-(dimethylamino)pyridine (0.5 g, 4.1 mmol), in anhydrous pyridine (400 mL) was reacted with acetic anhydride (30 mL, 0.32 mol) at 0°C for 1 hour then allowed to warm to room temperature. The reaction was stirred an additional 16 hours. The pyridine was removed in vacuo at 30°C. The residue was partitioned between ethyl acetate (100 mL) and of water (400 mL). The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined ethyl acetate layers were washed with brine, dried with MgSO4, filtered, and concentrated. The crude product was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 49.6 g, 81%).
1H NMR (CDCI3) δ 7.28 (m, 4H), 7.21 (m,1H), 5.68 (m,1H), 5.21 (m, 2H), 4.16 (dd, J=6.3, 10.7 Hz, 1 H), 4.10 (dd, J=7.3, 10.7 Hz, 1H), 3.92 (d, J=13.7 Hz, 1H), 3.64 (d, J=13.7 Hz, 1 H), 3.52 (m, 1H), 3.50 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 2.02 (s, 3H), 1.62 (m, 1H), 1.45 (s, 9H).
MS (M+H)+ = 360.
-196-
40B. (±W2R.3R.5R.1'RWand fcW2R.3R.5R.1'S)-1-Benzyl-2-(1.2- dihvdroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R)-1-benzyl-2-vinyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.(52.5 g, 0.15 mol) and 4-methylmorpholine N-oxide (54.7 g, 0.47 mol) in acetone (540 mL) and water (60 mL) was reacted with osmium tetroxide (200 mg, 0.8 mmol). After 24 hours, the reaction was quenched with 10% sodium thiosulfate (250 mL) concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (3 x 300 mL) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel using a gradient elution of ethyl acetate and dichloromethane to provide the title compound as a viscous oil (yield: 41.2 g, 72%).
1H NMR (DMSO) δ 7.32 (m, 3H), 7.30 (m, 1H), 7.22 (m, 1 H), 4.48 (t, J=5.4 Hz, 1H), 4.42 (d, J=5.4 Hz, 1H), 4.04 (m, 1H), 4.01 (m, 1H), 3.97 (m, 1H), 3.80 (d, J=13.2 Hz, 1 H), 3.78 (m, 1 H), 3.43 (m, 1 H), 3.39 (m, 1H), 3.32 (m, 1 H), 3.07 (t, J=4.9 Hz,1H), 2.48 (m,1 H), 2.19 (m, 1 H), 1.99 (s, 3H), 1.57 (dt, J=13.7, 2.0 Hz, 1H), 1.38 (s, 9H).
MS (M+H)+ = 394.
-197-
4QC. (±W2R.3R.5R.1'R) and fcW2R.3R.5R.1'S)-2-(1.2-Dihvdroxy)ethyl-3- (acetoxymethvD-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'R) and (±)-(2R,3R,5R,1'S)-1-Benzyl-2-(1 ,2- dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (24 g, 61 mmol) in ethanol (300 mL) was reacted with ammonium formate (38.5 g, 0.61 mol) and 10% Pd/C (2g) for 2 hours at reflux. The reaction was cooled and the catalyst removed by filtration through Celite. The filtrate was concentrated in vacuo to provide the title compound (yield: 16.7 g, 90%).
1H NMR (DMSO) δ 4.56 (m, 1 H), 4.30 (m, 1H), 4.06 (dd, J=5.8, 10.9 Hz, 2H), 3.79 (dd, J=8.8, 10.5 Hz, 2H ), 3.49 (m, 4H), 3.00 (m, 1 H), 2.35 (m, 1H), 2.16 (dt, J=12.6, 8.5 Hz, 1 H), 2.01 (s, 3H), 1.52 (m, 1 H), 1.40 (s, 9H).
MS (M+H)+ = 304.
HO
40D. (±W2R.3R.5R.1'R) and fcW2R.3R.5R.1,S)-1-f-Butoxycarbonyl 2-H.2- dihvdroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'R) and (±)-(2R,3R,5R,rS)-2-(1,2-Dihydroxy)ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxyiic acid f-butyl ester (33.4 g, 0.11 mol) in methanol (250 mL) and water (50 mL) was reacted with di-f-butyl dicarbonate (33.6 g, 0.15 mol) for 48 hours at room temperature. The methanol was removed in vacuo and the residue diluted with water ( 500 mL), and extracted with ethyl acetate (3 x 200 mL). The combined ethyl acetate layers were washed with brine,
-198- dried with MgSO , filtered and concentrated. The residue was chromatographed on silica gel using methanol/dichloromethane to provide the title compound as a white solid (yield: 32.8 g, 78%)
1H NMR (DMSO) δ 4.80 (m, 1 H), 4.45 (m, 1 H), 4.08 (m, 1H), 3.91 (m, 2H), 3.82 (m, 1 H), 3.71 (m, 1H), 3.28 (m, 2H), 2.48 (m, 1 H), 2.07 (m, 2H), 2.01 (m, 3H), 1.39 (m, 18H).
MS (M+H)+ = 404.
O'Bu 1 '
TIPSO O
40E (±W2R.3R.5R.1'R and (±W2R.3R.5R.1'S)-1-f-Butoxycarbonyl 2-(1- hvdroxy-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'R) and (±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl 2-(1 ,2- dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.(26.5 g, 66 mmol) in anhydrous dimethylformamide (200 mL ) was reacted with imidazole (8.9 g, 0.13 mol) and triisopropylsilyl chloride (19.0 g, 99 mmol) for 4 hours at room temperature. The solvent was removed under vacuum and the residue partitioned between 300 mL of water and 150 mL of ethyl acetate. The aqueous layer was extracted with ethyl acetate (2 x 100 mL), and the combined ethyl acetate layers extracted with brine, dried with MgSO , filtered and concentrated. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil (yield: 28.9 g, 79%).
-199- H NMR (CDCb) δ 4.22 (m, 1 H), 4.04 (m, 3H), 3.87 (t, J=2.0 Hz, 1H), 3.74 (dd, J=4.9, 9.8 Hz, 1H), 3.58 (dd, J=7.8, 10.2 Hz, 1 H), 3.39 (bs, 1H), 2.61 (m, 2H). 2.03 (s, 3H), 1.75 (m, 1 H), 1.46 (m, 18H), 1.07 (m ,18H).
MS (M+H)+ = 560.
40F fc)-(2R.3R.5R)-1-f-Butoxycarbonyl-2-(1-oxo-2-triisopropylsilyloxy ethyl-3- (acetoxymethvπ-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
Dimethylsulfoxide (6 mL, 85 mmol) was added slowly to a solution of oxalyl chloride (2 M) (19.3 mL, 38.6 mmol) in dry dichloromethane (70 mL) at -78°C. After 10 minutes, a solution of (±)-(2R,3R,5R,1'R) and (±)-(2R,3R,5R,1'S)-1-f- butoxycarbonyl 2-(1-hydroxy-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)- pyrrolidine-5-carboxylic acid f-butyl ester (14.4 g, 26 mmol) in dry dichloromethane (75 mL) was added at a rate such that the temperature did not exceed -70°C. After 1.5 hours, triethylamine (18 mL, 0.13 mol) was added and the temperature allowed to rise to 0°C. The reaction was quenched with a solution of ammonium chloride, diluted with water, and extracted with dichloromethane (3 x 100 mL). The combined dichloromethane layers were extracted with brine, dried with MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound as a colorless oil: (yield: 11 g, 77%).
1H NMR (CDCI3) δ 4.32 (m, 6H), 2.43 (m, 2H), 2.04 (s. 3H), 1.78 (m, 1H), 1.48 (s, 9H), 1.41 (s, 9H), 1.1 (m, 21 H).
MS (M+H)+ = 558.
-200-
40G fcW2R.3R.5R.1'R) and fcW2R.3R.5R.rS)-1-f-Butoxycarbonyl 2-M-amino- 2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxyiic Acid f-Butyl Ester.
(±)-(2R,3R,5R)-1-f-Butoxycarbonyi 2-(1-oxo-2-triisopropylsilyloxy)ethyl-3- (acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.(22 g, 39 mmol) in methanol (1 L) was reacted with ammonium acetate (77 g, 1.0 mol) and sodium cyanoborohydride (24.8 g, 0.39 mol) at reflux for 2 hours. The solvent was removed under in vacuo, and the residue was partitioned between water (300 mL) and dichloromethane (300 mL). The aqueous layer was extracted with dichloromethane (2 x 100 mL) and the combined organic layers were washed with brine, dried with MgSO4, filtered and concentrated to provide the title compound (crude yield: 22.0g, 100%).
TIPSO
40H (±W2R.3R.5R.1'R) and fcW2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-(1- acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±H2R,3R,5R,1'R) and (±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-amino- 2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (approx 39 mmol) in dichloromethane (500 mL) was reacted with acetic anhydride (18 mL, 0.19 mol), triethylamine (27.5 mL, 0.20 mol) and
-201- dimethylaminopyridine (50 mg, 0.39 mmol) for 18 hours at room temperature. The reaction was quenched with a solution of ammonium chloride. The aqueous layer was extracted with dichloromethane (3 x 100 mL) and the combined organic layers extracted with brine, dried with MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel using ethyl acetate/hexanes to provide the title compound (±)-(2R,3R,5R,1'R)-1-f-butoxycarbonyl 2-(1- acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (9.14 g, 39%) and (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl 2-(1- acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester (9.75 g, 41 % ) as white solids.
(±)-(2R,3R,5R,1'R) 1H NMR (CDCI3) δ 7.38 (d, J=8.3 Hz, 1 H), 4.34 (m, 1H), 4.20 (dd, J=2.4, 10.3 Hz, 1H), 4.09 (dd, J=8.8, 10.2 Hz. 1H), 4.02 (dd, J=7.3, 10.1 Hz, 1H), 3.88 (m, 1H), 3.71 (dd, J=4.4, 10.3 Hz, 1H), 3.65 (dd, J=7.9, 10,3 Hz, 1H), 2.74 (m, 1H), 2.60 (m, 1 H), 2.04 (s, 3H), 1.98 (s, 3H), 1.69 (dt, J=14.1 , 2.5 Hz, 1H), 1.46 (s, 9H), 1.42 (s, 9H), 1.07 (m, 21 H).
MS (M+H)+ = 601
(±)-(2R,3R,5R,1'S) 1H NMR (CDCI3) δ 6.82 (d, 1 H), 4.10 (m, 4H), 3.81 (m, 3H), 2.55 (m, 2H), 1.98 (m, 7H), 1.46 (s, 9H), 1.42 (s, 9H), 1.07 (m, 21 H).
MS (M+H)+ = 601.
-202-
401 (±W2R.3R.5R.1'RV1-f-Butoxycarbonyl 2-(1-acetamido-2- triisopropylsilyloxy)ethyl-3-hvdroxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3R,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-2- triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acid f-butyl ester.(8.2 g, 13.66 mmol) in methanol (200 mL) and water (50 mL) was reacted with potassium carbonate (19 g, 136 mmol) at room temperature for 2 hr. The solvent was then removed in vacuo and the residue was partitioned between water (100 mL) and dichloromethane (3 x 100 mL). The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a colorless oil.
40J fcW2R.3R.5R.1'RV1-f-Butoxycarbonyl 2-(1-acetamido-2- triisopropylsilyloxy)ethyl-3-formyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 2A substituting (±)-(2R,3R,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido- (2-triisopropylsilyloxy)ethyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5.9 g, 78%).
-203- 1H NMR (CDCI3) δ 1.04 -1.07 (m, 21H), 1.42 (s, 9H), 1.43 (s, 9H), 1.99 (s, 3H), 2.42 (m, 1 H), 2.62 (m, 1H), 3.04 (m, 1 H), 3.69 (m, 1 H), 3.82 (m, 1 H), 4.08 (m, 1 H), 4.38 (m, 1 H), 4.57 (t, 1 H), 7.33 (br d, 1 H), 9.65 (s, 1 H).
MS: (M+H)+= 557.
40K fcW2R.3S,5R.1'RV1-f-Butoxycarbonyl 2-(1-acetamido-2- triisopropylsilyloxy)ethyl-3-tc/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 35A substituting (±)-(2R,3R,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido- 2-triisopropylsilyloxy-)ethyl-3-formyl-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- formyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5.9 g, 78%).
1H NMR (CDCI3) δ 1.03 -1.10 (m, 21 H), 1.44 (s, 9H), 1.47 (s, 9H), 1.55 (m,1H), 1.64 (dd, 3H), 1.96 (s, 3H), 2.55 (m, 1 H), 3.42 (m, 1 H), 3.62 - 3.71 (m, 3H), 4.20 (dd, 1 H), 4.30 (m, 1H), 5.39 (m, 1H), 5.48 (m,1 H), 7.73 (br d, 1 H).
MS: (M+H)+= 569
-204-
40L (±W2R.3S.5R.1'RV1-f-Butoxycarbonyl 2-π-acetamido-2-hvdroxy-)ethyl-3- fc/s-propen-1-vO-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R, 1 'R)-1 -f-Butoxycarbonyl 2-(1 -acetamido-2- triisopropylsilyloxy)ethyl-3- c/s-propeπ-7-y/j-pyrrolidine-5-carboxylic acid f-butyl ester (4.85 g, 8.54 mmol) in THF (100 mL) was reacted with tetrabutyl ammonium fluoride (1M in THF) (12.8 mL, 12.8 mmol) for 30 minutes at room temperature. Water (100 mL) was added followed by extraction using dichloromethane (2 x 100 mL). This organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1 : ethyl acetate/hexane to provide the title compound as a colorless solid (yield: 3.1g , 89%) .
1H NMR (CDCI3): d 1.44 (s, 9H), 1.47 (s, 9H), 1.56 (dd, 3H), 1.80 (m, 1H), 2.02 (s, 3H), 2.67 (m, 1 H), 3.11 (t, 3H), 3.44 (dd, 1H), 3.59 (dd, 1 H), 3.74-3.84 (m, 2H), 4.15 (dd, 1 H) 5.39 (m, 1 H), 5.58 (m, 1 H), 6.42 (br d, 1H).
MS: (M+H)+= 413.
TFA
40M fcW2R.3S.5R.1'R)-2-π-Acetamido-2-hvdroxy)ethyl-3-r'c/s-propen-1-vπ- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 33B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido-
-205- 2-hydroxy)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1 'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- (frans-2-chloro-vinyl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 18.0 mg, 100%).
1H NMR (DMSO-de): d 1.66 (dd, 3H), 1.71 (dt, 1 H), 1.87 (s, 3H), 2.41 (dt, 1 H), 3.18 (m, 1 H), 3.43 (dd, 1 H), 3.61 (m, 1 H), 4.13 (m, 1 H), 4.35 (m, 1 H), 5.25 (m, 1 H), 5.51 (m, 1 H), 8.05 (d, 1 H), 9.16 (br s, 2H).
MS: (M+H)+= 257.
Example 41
(±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)butyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3 AcH O'Bu
- BNo-c ±
0- ^H °
41 A (±W2R.3S.5R.1 'RV1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3- (c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1 'R)-1-f-Butoxycarbonyl 2-(1-acetamido-2-hydroxy)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.(600 mg, 1.46 mmol) in dichloromethane (50 mL) was reacted with Dess-Martin Periodinane (928 mg, 2.18 mmol) for 1 hour at room temperature. The reaction was quenched with 1M aqueous sodium thiosulfate (50 mL), stirred for 20 minutes then extracted with dichloromethane (3 x 100 mL). The organic layer was dried over magnesium sulfate, concentrated in vacuo. The residue was purified by column
-206- chromatography on silica gel using 2/1 : ethyl acetate/hexane to provide the title compound (yield: 547 mg, 92%).
1H NMR (CDCI3) d 9.40 (d, J= 1 Hz, 1 H), 7.88 (bd), 5.69 (m, 1 H), 5.27 (m, 1H), 4.78 (dd, J= 9.5, 1. Hz, 1 H), 4.21 (t, J= 8. Hz, 1H), 3.45 (m, 2H), 2.41 (m, 1 H), 2.09 (s, 3H), 1.69 (dd, J= 7.0, 1. Hz, 3H), 1.55 (m, 1 H), 1.46 (s, 9H), 1.40 (s, 9H).
MS: (M+H)+= 411 , (M-H)- = 409.
H C
41B (±W2R.3S.5R.1'R.2'R) and fcW2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f- Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3- (cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (780 mg, 1.90 mmol) in THF (20 mL) was added dropwise to a solution of ethylmagnesium bromide (3M in ether) (3.17 mL, 9.51 mmol) in THF (15 mL) at room temperature and reacted for 40 minutes. The reaction was quenched with water (20 mL) and saturated aqueous ammonium chloride (20 mL) followed by extraction using dichloromethane (3 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1 : ethyl acetate/hexane to provide the title compounds (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl 2-(1-acetamido-2- hydroxy)butyi-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 472 mg, 56%) and (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl 2-(1-acetamido-2-
-207- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester(yield: 82 mg, 10%) as a colorless oils.
(±)-(2R,3S,5R,1'R,2'R) = MS: (M+H)+= 441 , (M+Na)+= 463, (M-H)- = 439.
(±)-(2R,3S,5R,1'R,2'S) = MS: (M+H)+= 441, (M+Na)+= 463, (M-H)- = 439.
41 C fcW2R.3S.5R.rR.2'S 2-(1-Acetamido-2-hvdroxy)butyl-3-(c s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
(±)-(2R,3S,5R, 1 'R,2'S)-1 -f-Butoxycarbonyl-2-(1 -acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (300 mg, 0.68 mmol) was reacted with trifluoroacetic acid (8 mL) in dichloromethane (2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight to provide the title compound (yield: 311 mg) as a colorless solid.
1H NMR (500 MHz, DMSO-d6) δ: 7.89 (d, J = 8.7 Hz, 1 H), 5.48 (m, 1 H), 5.29 (m, 1 H), 4.30 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1 H), 3.43 (m, 1 H), 3.15 (m, 1 H), 2.41 (m, 1 H), 1.82 (s, 3H), 1.63 (m, 1 H), 1.59 (dd, J = 6.8, 1.9 Hz, 3H), 1.55 (m, 1 H), 1.27 (m, 1 H), 0.85 (t, J = 7.3 Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)' = 283.
-208- Example 42
fcW2R.3S.5R.1'R.2,S)-2-f1-Acetamido-2-hvdroxy)butyl-3-(c/s-proDen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
42A (±)-(2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R,2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester. (460 mg, 1.05 mmol) was reacted with Dess-Martin Periodinane (666 mg, 1.57 mmol) in dichloromethane (30 mL) at room temperature for 17 hours. The reaction was quenched with 1M aqueous sodium thiosulfate (50 mL and stirred for 20 minutes. The reaction was was extracted with dichloromethane (3 x 100 mL). The organic layer was dried over magnesium sulfate.filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2:1 : ethyl acetate/hexane to provide the title compound as a colorless semi-solid (yield: 440 mg, 96%).
MS: (M+H)+= 439, (M+Na)+= 461 , (M-H)- = 437.
-209- ϊ /0'Bu
O
42B fcW2R.3S.5R.1'R.2'R) and fcW2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2- (1 -acetamido-2-hvdroxy)butyl-3-(c/s-propen-1 -vD-pyrrolidine-5-carboxylic Acid f- Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (435 mg, 0.99 mmol) in methanol (30 mL) was reacted with sodium borohydride (188 mg, 4.97 mmol) at room temperature for 0.5 hours. The solvent was removed in vacuo and water (30 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 50 mL). This organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2:1 ethyl acetate/hexane to provide the title compounds (±)- (2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.(yield: 305 mg, 70%) and compounds (±)-(2R,3S,5R,1 'R,2'R)-1 -f-butoxycarbonyl-2-(1 -acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 17 mg, 4%).
-210-
TFA
42C fcV(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
(±)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (300 mg, 0.68 mmol) was reacted with trifluoroacetic acid (8 mL) in dichloromethane (2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight and triturated with acetonitrile (2 x 5 mL) to provide the title compound (yield: 311 mg) as a colorless solid.
1H NMR (500 MHz, DMSO-d6) δ: 7.89 (d, J = 8.7 Hz, 1H), 5.48 (m, 1H), 5.29 (m, 1 H), 4.30 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1H), 3.43 (m, 1H), 3.15 (m, 1 H), 2.41 (m, 1 H), 1.82 (s, 3H), 1.63 (m, 1 H), 1.59 (dd, J = 6.8, 1.9 Hz, 3H), 1.55 (m, 1 H), 1.27 (m, 1 H), 0.85 (t, J = 7.3 Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)- = 283.
-211- Example 43
fc)-(2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-hvdroxy)butyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TFA
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: .0065 g, 100%).
1H NMR (DMSO-d6) δ 7.90 (d, J=8.8Hz, 1 H), 5.47 (m, 1H), 5.29 (t, J=9.8 Hz, 1H), 4.29 (t, J=8.8Hz, 1H), 4.02 (q, J=6.8Hz, 1H), 3.71 (bt, J=8Hz, 1H), 3.43 (m, 1H), 3.15 (quint, J=8.8Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.82 (s, 3H), 1.64 (m, 1H), 1.58 (dd, J=6.8,1.5Hz, 3H), 1.53 (m, 1 H), 0.85 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 285, (M+Na)+ = 307, (M-H)' = 283, (M+CF3COOH)' = 397, (2M-1)' = 563
Example 44
-212- fc)-(2R.3S.5R.1 'R.2'SV2-(1-Acetamido-2-hvdroxy-3-cvano)propyl-3-(c/'s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
N≡≡C
44A fcW2R.3S.5R.1 'R.2'R) and (±W2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-3-cvano)propyl-3-(c s-propen-1-yl)-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3- (c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (150 mg, 0.37 mmol) in THF (10 mL) was added dropwise to a solution of the lithium enolate of acetonitrile (1.83 mmol, 5 equivalents) in THF (15 mL) at -78 °C and reacted for 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10mL) followed by extraction using dichloromethane (2 X 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1 : ethyl acetate/hexane to provide the title compounds (±)- (2R,3S,5R,1 'R,2'R)-1-f-butoxycarbonyl 2-(1-acetamido-2-hydroxy-3-cyano)propyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 95mg, 58%) and (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl 2-(1-acetamido-2-hydroxy-3- cyano)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester(yield: 30 mg, 18%) as a colorless oils.
(±W2R,3S,5R,1'R,2'R) = MS: (M+H)+=452, (M-H)' =450
(±)-(2R,3S,5R,1 'R,2'S) =1H NMR (CDCI3) δ 8.14 (d, J=8.9Hz, 1 H), 5.51 (m, 1 H), 5.38 (m, 1 H), 4.25 (m, 1 H), 4.19 (m, 1 H), 3.94 (m, 1 H), 3.74 (m, 1 H), 3.22
-213- (m, 1 H), 2.54 (m, 1 H), 2.47 (m, 2H), 2.04 (s, 3H), 1.69 (m, 1H),1.65 (dd, J=6.5, 1.8Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H)
MS: (M+H)+=452, (M-H)" =450
44B fc)-f2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-3-cvano)propyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-cyano)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4.5 mg, 95%%).
1H NMR (DMSO-d6) δ 7.98 (d, J=10.0 Hz, 1 H), 5.49 (m, 1 H), 5.27 ( m, 1H), 4.30 (m, 1 H), 4.15 (m, 1H), 3.75(m, 1H), 3.18 (m, 1H), 2.72-2.58 (m, 2H), 2.41 (m, 1 H), 1.85 (s, 3H), 1.65 (m, 1H), 1.61 (dd, J=6.70, 1.80 Hz, 3H)
MS: (M+H)+ =296, (M-H)' =294
Example 45
-214- fcW2R.3S.5R.1'R.2'RV2-f1-Acetamido-2-hvdroxy-3-cvano)propyl-3-(c/'s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TFA
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-cyano)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 8 mg, 95%).
1H NMR (DMSO-d6) δ 7.75(d, J=9.0 Hz, 1H), 5.47(m, 1H), 5.25(m, 1H), 4.46(m, 1H), 4.20(m, 1 H), 4.13(m, 1H), 3.56(m, 1 H), 3.15(m, 1 H), 2.55(m, 2H), 2.42(m, 1H), 1.82(s, 3H), 1.72(m, 1 H), 1.55(dd, J=6.71 , 1.83, 3H)
MS: (M+H)+ =296, (M+23)+ =318, (M-H)' =294
Example 46
-215- fc)-(2R.3S.5R.1'R.2'RV2-π-Acetamido-2-hvdroxy-3-ethoxycarbonvπpropyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
βlQu lϊ
O
EtO EtO
46A fcW2R.3S.5R.1'R.2'R) and fcW2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-3-ethoxycarbonyl)propyl-3-(c/s-propen-1-vπ-pyrrolidine- 5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (900 mg, 2.187 mmol) in THF (40 mL) was added dropwise to a solution of the lithium enolate of ethyl acetate (8.75 mmol, 4 equivalents) in THF (40 mL) at -78 °C and reacted for 15 minutes. The reaction was quenched with saturated aqueous ammonium chloride followed by extraction using dichloromethane (3 X). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1 :1 ethyl acetate/hexane to provide the title compounds (±)-(2R,3S,5R,1'R,2'R)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 690 mg, 63%) and (±)- (2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3- ethoxycarbonyl)propyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 246 mg, 22.5%).
(±)-(2R,3S,5R,1'R,2'R) 1H NMR (CDCI3): δ 5.99 (d, 1H), 5.60 (m, 1H), 5.36 (m, 1H), 4.81 (m, 1 H), 4.15 (m, 4H), 3.74 (m, 1H), 3.07 (m, 1 H), 2.68 (m,
-216- 1 H), 2.48 (m 1 H), 2.33 (m, 1 H), 2.03 (s, 3H), 1.54 (dd, 3H), 1.47 (s, 9H), 1.46 (s, 9H), 1.24 (t, J=7.5Hz, 3H).
MS: (M+H)+=499
(±)-(2R,3S,5R,1'R,2'S) 1H NMR (CDCI3): δ 7.93 (d, 1H), 5.44 (m, 2H), 4.19 (m, 4H), 4.03 (m, 1H), 3.72 (m, 1 H), 3.37 (m, 1 H), 2.63 (m. 1 H), 2.48 (m, 2H), 2.01 (s, 3H), 1.65 (dd, 3H), 1.48 (s, 9H), 1.46 (s, 9H), 1.26 (t, J=7.5Hz, 3H).
MS: (M+H)+=499
46B fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-3- ethoxycarbonv0propyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1 -acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester.
1H NMR (DMSO-de): δ 7.74 (d, J=9Hz, 1 H), 5.48 (m, 1 H), 5.25 (m, 1H), 4.43 (m, 1 H), 4.24 (m, 1 H), 4.14 (m, 1H), 4.06 (q, J=7.5Hz, 2H), 3.54 (m, 1H), 3.16 (m, 1 H), 2.41 (m, 1 H), 2.36 (m, 2H), 1.82 (s, 3H), 1.77 (m, 1H), 1.56 (dd, 3H), 1.18 (t, J=7.5Hz, 3H).
-217- MS: (M+H)+= 343
Example 47
(±)-(2R.3S.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxy-3-ethoxycarbonyl)propyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester.
1H NMR (DMSO-de): δ 7.93 (d, J=9Hz, 1 H), 5.48 (m, 1 H), 5.30 (m, 1H), 4.19 (m, 1H), 4.09 (m, 1 H), 4.06 (q, J=7.5Hz, 2H), 3.94 (m, 1 H), 3.73 (m, 1H), 3.18 (m, 1H), 2.54 (dd, 1H), 2.40 (m, 1H), 2.27 (m, 1 H), 1.82 (s, 3H), 1.65 (m, 1 H), 1.60 (dd, 3H), 1.19 (t, J=7.5Hz, 3H).
MS: (M+H)+=343
-218- Example 48
TFA
(±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)propyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)propyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0030 g, 100%).
1H NMR (DMSO-de) d 8.97 (bs, 1H), 7.88 (d, J=8.5 Hz, 1 H), 5.45 (m, 1H), 5.28 (t, J = 9.1Hz, 1H), 4.30 (t, J=8.6Hz, 1H), 3.94 (q, J=7.3Hz, 1 H), 3.71 (t, J=8.0Hz, 1H), 3.62 (m, 1 H), 3.15 (quint., J=9.0Hz, 1H), 2.40 (dt, J=12.8, 7.6Hz, 1 H), 1.83 (s, 3H), 1.65 (m, 1H), 1.59 (dd, J=7.0, 1.5Hz, 3H), 1.08 (d, J=5.5Hz, 3H).
MS: (M+H)+ = 271 , (M+Na)+ = 293, (M-H)" = 269.
-219- Example 49
TFA
fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy)propyl-3-(cs-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0143 g, 100%).
1H NMR (DMSO-de) δ 7.70 (d, J=9.1 Hz, 1H), 5.49 (m, 1H), 5.25 (t, J = 9.1Hz, 1H), 4.43 (t, J=8.6Hz, 1H), 4.03 (m, 1H), 3.92 (m, 1H), 3.55 (t, J=8.5Hz, 1H), 3.17 (quint, J=8.5Hz, 1 H), 2.42 (dt, J=12.8,7.3Hz, 1H), 1.85 (s, 3H), 1.72 (dt, J=12.8,10.0Hz, 1 H), 1.57 (dd, J=6.7,1.8Hz, 3H), 1.04 (d, J=6.1Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)" = 269
-220- Example 50
fc)-(2R.3S.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxy-2-vinyl)ethyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
50A (±W2R.3S.5R.1'R.2'S) and fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-2-vinyl)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting vinyl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy-2-vinyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.5 mg, 18%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 22 mg, 59%).
(±)-(2R,3S,5R, 1 'R,2'S) MS: (M+H)+=439, (M-H)" = 437
(±)-(2R,3S,5R,rR,2'R) MS: (M+H)+=439, (M-H)" = 437
-221-
50B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-vinyl)ethyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1 'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-vinyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5 mg, 96%).
1H NMR (DMSO-de) δ7.85 (d, J=9.1Hz, 1H), 5.76 (m, 1H), 5.47(m, 1H), 5.25 (m, 2H), 5.14 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 3.96 (m, 1 H), 3.71 (m,1 H), 3.18 (m, 1H), 2.41 (m, 1H), 1.78 (s, 3H), 1.64 (m, 1H), 1.59 (dd, J=6.71 , 1.21 Hz, 3H)
MS: (M+H)+ =283, (M+23)+ =305, (M-H)" =281
-222- Example 51
(±W2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-hvdroxy-2-vinyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,rR,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-vinyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6 mg, 95%).
1H NMR (DMSO-de) δ 7.84 (d, J=9.7Hz, 1H), 5.78 (m, 1 H), 5.48 (m, 1H), 5.23 (m, 34.43 (m, 1H), 4.26 (m, 1 H), 4.20 (m, 1H), 3.55 (m, 1 H), 3.18 (m, 1H), 2.43 (m, 1 H), 1.81 (s, 3H), 1.73 (m, 1 H), 1.57 (dd, J=6.72, 1.83 HZ, 3H)
MS: (M+H)+ =283, (M+23)" =305, (M-H)" =281 , (2M-H)" =563
-223- Example 52
fc (2R.3S.5R.1 'R.2'SV2-π-Acetamido-2-hvdroxy-2-vinvπpropyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
/ CH3
AcHN. JL I. lBu
' N
H R Bnorc ϋ
O ιT
OH
52A (±W2R.3S.5R.1'R.2'S) and fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-3-vinyl)propyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting allyl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1 'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy- 2-vinyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 2.0 mg, 5%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)propyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 9.0 mg, 22%).
(±)-(2R,3S,5R, 1 'R,2'S) MS: (M+H)+ = 453; (M-H)" = 451.
(±)-(2R,3S,5R,1'R,2'R) 1H NMR (DMSO-d6) δ 7.70 (d, J=9.3Hz, 1H), 5.80 (m, 1 H), 5.51 (m, 1 H), 5.30 (m, 1 H), 5.00 (m, 2H), 4.58 (br d, 1 H), 3.93 (m, 2H), 3.50 (m, 1 H), 3.22 (br t, 1H), 2.02 (m, 3H), 1.88 (s, 3H), 1.56 (m, 4H), 1.41 (s, 9H), 1.36 (s, 9H)
MS: (M-H)" = 451 ; (M+H)+ = 452, (M+Na)+ = 475.
-224-
52B (±W2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-3-vinvπpropyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-vinyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2 mg, 100%).
H NMR (DMSO-d6) δ 7.85 (d, J=9.3Hz, 1 H), 5.81 (m, 1H), 5.42 (m, 1H), 5.28 (t, J=7.3Hz, 1H), 5.01 (br d, 2H), 3.99 (m, 2H), 3.57 (m, 2H), 3.08 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1 H), 1.81 (s, 3H),
1.57 (dd, J=1.4, 5.4Hz, 4H)
MS: (M-H)" = 295; (M+H)+ = 297, (M+Na)+ = 319.
-225- Example 53
(±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-3-vinyl)propyl-3-fc/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-vinyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6 mg, 100%).
1H NMR (DMSO-d6) δ 7.68 (d, J=9.2Hz, 1H), 5.78 (m, 1 H), 5.48 (m, 1H), 5.24 (t, J=7.8Hz, 1H), 5.04 (m, 2H), 4.38 (t, J=7.0, 1 H), 4.09 (t, J=7.0, 1 H), 3.81 (t, J=4.7, 1 H), 3.53 (t, J=8.5, 1H), 3.16 (m, 1H), 2.40 (m, 1 H), 2.11 (m, 2H), 1.83 (s, 3H), 1.70 (m, 1 H), 1.55 (dd, J=5.4, 1.4Hz, 3H)
MS: (M-H)" = 295; (M+H)+ = 297, (M+Na)+ = 319.
-226- Example 54
(±)-(2R.3S.5R.1 'R.2'S)-2-(1-Acetamido-2-hvdroxy)pentyl-3-(c/s-propen-1-ylV pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
CH3 AcHN..^i Y ,0'Bu n Ot'Bu M N Boc if )H
54A fcW2R.3S.5R.1'R.2'S) and fc)-(2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy)pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f- Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting propyl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1 mg, 1%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)pentyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 32 mg, 39%).
(±)-(2R,3S,5R,1'R,2'S) 1HNMR (CDCI3) δ 7.51 (d, J=8.2Hz, 1 H), 5.46 (m, 2H), 4.17 (dd, J=3.1 , 6.8Hz, 1 H), 4.05 (m, 1 H) 3.81 (t, J=3.4Hz, 1 H), 3.54 (m, 1H), 3.21 (m, 1 H), 2.60 (m, 1H), 2.02 (s, 3H), 1.70 (dt, J=3.0, 7.4Hz, 1H), 1.61 (d, J=5.4Hz, 3H), 1.54 (m, 1H), 1.47 (s, 9H), 1.44 (s, 9H), 1.32 (m, 4H), 0.90 (t, J=7.1Hz, 3H)
MS: (M+H)+ = 455, (M+Na)+ = 477; (M-H)" = 453.
(±)-(2R,3S,5R,1'R,2'R) 1H NMR (CDCI3) δ 5.98 (d, J=9.5Hz, 1 H), 5.60 (t, J=9.8Hz, 1 H), 5.36 (m, 1 H), 4.16 (m, 1 H), 3.75 (d, J=10.1Hz, 1H), 3.64 (m, 1H), 3.51 (m, 1 H), 3.09 (br t, 1 H), 2.68 (m, 1 H), 2.02 (s, 3H), 1.81 (d, J=13.9Hz,
-227- 1 H), 1.57 (m, 4H), 1.54 (dd, J=1.7, 5.1Hz, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 0.88 (t, J=6.8Hz, 3H)
MS: (M-H)" = 453; (M+H)+ = 455.
54B fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1 mg, 100%).
1H NMR (DMSO-de) δ 7.83 (d, J=9.2Hz, 1H), 5.43 (m, 1H), 5.23 (m, 1H), 3.98 (m, 1H), 3.56 (br t, 1H), 3.46 (m, 1 H), 3.08 (m, 2H), 2.32 (m, 1 H), 1.80 (s, 3H), 1.57 (dd, J=1.4, 5.4Hz, 4H), 1.43 (m, 2H), 1.23 (m, 2H), 0.85 (br t, 3H)
MS: (M+H)+ = 299, (M+Na)+ = 321.
-228- Example 55
TFA
fcW2R.3S.5R.1 'R.2'R)-2-(1-Acetamido-2-hvdroxy)pentyl-3-(c/s-ρropen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0190 g, 100%).
1H NMR (DMSO-de) δ 7.64 (d, J=9.3Hz, 1H), 5.48 (m, 1H), 5.24 (m, 1H), 4.38 (t, J=8.8Hz, 1H), 4.06 (m, 1H), 3.75 (m, 1 H), 3.53 (t, J=8.5Hz, 1H), 3.16 (quint, J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 1.82 (s, 3H), 1.70 (dt, 12.8,9.9Hz, 1 H), 1.55 (dd, J=7.0,1.6Hz, 3H), 1.35 (m, 2H), 1.26 (m 2H), 0.86 (t, J=6.7Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321 , (M-H)" = 297.
-229- Example 56
fcW2R.3S.5R.1 ,R.2'S)-2-(1-Acetamido-2-hvdroxy-3-methvnbutyl-3-(c s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
κO •>tl cBu o if
56A fcW2R.3S.5R.1'R.2'S) and fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-3-methv0buWI-3-(c/'s-propen-1-yl)-pyrrolidine-5- carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting isopropyl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy-3-methyl)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0092 g, 10%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0385 g, 40%).
(±)-(2R,3S,5R,1'R,2'S) MS: (M+H)+= 455, (M+Na)+= 477, (2M+Na)+=931 , (M-H)"=453.
(±)-(2R,3S,5R, 1 'R,2'R) MS: (M+H)+= 455, (M+Na)+= 477, (2M+Na)+= 931 , (M-H)"= 453.
-230-
56B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-3-methyl)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.010 g, 100%).
1H NMR (DMSO-ds) d 7.63 (d, J=9.2Hz, 1 H), 5.48 (m, 1H), 5.23 (m, 1H), 4.44 (m, 1H), 4.24 (m, 1H), 3.57 (t, J=8.7Hz, 1H), 3.33 (dd, J=8.5,2.5Hz, 1H), 3.21 (quint, J=9.1Hz, 1 H), 2.43 (dt, J=12.8,7.6Hz, 1H), 1.81 (s, 3H), 1.73 (dt, J=12.8,10.4Hz, 1 H), 1.56 (dd, J=6.7,1.9Hz, 3H), 1.55 (m, 1 H), 0.94 (d, J=6.7Hz, 3H), 0.78 (d, J=6.7Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321 , (M-H)" = 297, (M+CF3COOH)" = 411 , (2M-H)" = 595.
-231- Example 57
fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-3-methyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0433 g, 100%).
1H NMR (DMSO-de) d 7.88 (d, J=9.2Hz, 1H), 5.46 (m, 1H), 5.29 (m, 1H), 4.26 (t, J=8.5Hz, 1 H), 4.11 (m, 1H), 3.67 (m, 1H), 3.39 (dd, J=9.8,1.8Hz, 1H), 3.15 (quint, J=9.1 Hz, 1 H), 2.42 (dt, J=12.8,7.9Hz, 1H), 1.81 (s, 3H), 1.73 (m, 1 H), 1.62 (m, 1 H), 1.57 (dd, J=7.0,1.6Hz, 3H), 0.88 (d, J=6.7Hz, 3H), 0.75 (d, J=6.7Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321 , (M-H2O)+ = 281 , (M-H)" = 297, (M+CF3COOH)" = 411 , (2M-H)" = 595.
-232- Example 58
(±W2R.3S.5R.1 'R.2'S)-2-M -Acetamido-2-hvdroxy hexyl-3-(c/s-propen-1 -yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
°lBu /O'Bu i o if
58A (±W2R.3S.5R.1'R.2'S) and fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy)hexyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f- Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting butyl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)hexyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.0 mg, 8%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)hexyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.0 mg, 24%).
58B fcW2R,3S.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxy)hexyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)hexyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-
-233- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.0 mg, 100%).
1H NMR (DMSO-de) δ 8.34 (d, J=9.3Hz, 1 H), 5.24 (m, 1H), 5.12 (m, 1H), 3.90 (m, 1 H), 3.78 (m, 1 H), 3.23 (m, 1 H), 2.90 (m, 1 H), 2.14 (m, 1 H), 1.80 (m, 1 H), 1.75 (s, 3H), 1.52 (m, 3H), 1.45 (m, 1 H), 1.08 (br s, 6H), 0.83 (br t, 3H).
MS: (M-H)" = 311 ; (M+H)+ = 313.
Example 59
TFA
(±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy)hexyl-3-(c/'s-propen-1-ylV pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)hexyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.0 mg, 100%).
1H NMR (DMSO-de) δ 7.60 (d, J=9.3 Hz, 1 H), 5.46 (m, 1H), 5.24 (t, J=9.2 Hz, 1 H), 4.21 (t, J=8.3 Hz, 1H), 4.02 (t, J=7.9Hz, 1H), 3.74 (m, 1H), 3.47 (t, J=8.8, 1 H), 3.12 (m, 1 H), 2.37 (m, 1 H), 1.81 (s, 3H), 1.64 (m, 1 H), 1.55 (dd, J=1.5, 5.4 Hz, 3H), 1.29 (m, 6H), 0.86 (t, J=6.9, 3H)
-234- MS: (M-H)" = 311 ; (M+H)+ = 313, (M+Na)+ = 335.
Example 60
(±W2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-methyl)pentyl-3-(c s-propen- 1-yl)-pyrroiidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
60A (±W2R.3S.5R.1'R.2'RV1-f-Butoxycarbonyl-2-π-acetamido-2-hvdroxy-4- methyl)pentyl-3-(c s-propen-1-vπ-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting isobutyl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy-4-methyl)pentyl-3-(cs-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 31 mg, 51%).
(±)-(2R,3S,5R,1'R,2'R) 1H NMR (CDCI3) δ 5.98 (d, J=9.5Hz, 1H), 5.61 (t, J=8.2Hz, 1H), 5.35 (m, 1 H), 4.51 (dd, J=1.3, 3.1Hz, 1 H), 4.15 (m, 1H), 3.74 (d, J=10.5Hz, 1 H), 3.61 (m, 2H), 3.09 (t, J=7.5Hz, 1 H), 2.71 (m, 1 H), 2.02 (s, 3H), 1.81 (d, J=13.9Hz, 1H), 1.58 (br s, 1 H), 1.54 (dd, J=1.7, 5.1 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), 1.42 (m, 1 H), 0.87 (dd, J=2.4, 6.7Hz, 6H)
MS: (M-H)" = 467; (M+H)+ = 469, (M+Na)+ = 491.
-235-
60B fcW2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-4-methyl-2- oxo)pentyl-3-(c/s-propen-1-vD-Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R,2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4- methyl)butyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester (8.0 mg, 0.02 mmol) was reacted with Dess-Martin Periodinane (10 mg, 0.03 mmol) in dichloromethane (0.1 mL) at room temperature for 1 hour. The reaction was quenched with 1M aqueous sodium thiosulfate 1 mL and stirred for 20 minutes. The reaction was extracted with dichloromethane (3 x 1 mL). The organic layer was dried over magnesium sulfate.filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1 :1: ethyl acetate/hexane to provide the title compound as a colorless semi-solid (yield: 4.8 mg, 61%).
60C fcW2R.3S.5R.1'R.2'SV1-f-Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-4- methyl)pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-4-methyl-2- oxo)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (4.8 mg, 0.01 mmol) in methanol (0.1 mL) was reacted with sodium borohydride (2.0 mg,
-236- 0.05 mmol) at room temperature for 0.5 hours. The solvent was removed in vacuo and water (1 mL) was added. The aqueous layer was extracted with dichloromethane (3 x 1 mL). This organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1 :1 ethyl acetate/hexane to provide the title compound (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy- 4-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.4 mg, 51%).
60B fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4.4 mg, 100%).
1H NMR (D2O) δ 5.45 (m, 1H), 5.15 (t, J=11.0Hz, 1 H), 3.88 (m, 1H), 3.62 (t, J=8.0Hz, 1 H), 3.43 (br t, 1 H), 2.98 (m, 1 H), 2.36 (m, 1 H), 1.81 (s, 3H), 1.60 (m, 1 H), 1.51 (m, 1 H), 1.45 (dd, J=1.3, 5.4Hz, 3H), 1.17 (m, 3H), 0.74 (dd, J=6.7, 14Hz, 6H)
MS: (M-H)" = 311; (M+H)+ = 313, (M+Na)+ = 335.
-237- Example 61
(±W2R.3S.5R.1'R.2'R)-2-f1-Acetamido-2-hvdroxy-4-methyl)pentyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1.7 mg, 85%).
1H NMR (DMSO-de) δ 7.61 (d, J=9.8Hz, 1 H), 5.45 (m, 1H), 5.24 (t, J=7.4Hz, 1 H), 4.29 (br t, 1 H), 4.0 (br t, 1H), 3.83 (m, 1 H), 3.49 (t, J=8.8Hz, 1H), 3.13 (m, 1 H), 2.39 (m, 1 H), 1.82 (s, 3H), 1.68 (m, 2H), 1.55 (dd, J=1.4, 5.4Hz, 3H), 1.31 (m, 1 H), 1.04 (m, 1 H), 0.86 (dd, J=6.4, 8.3Hz, 6H)
MS: (M-H)" = 311 ; (M+H)+ = 313, (M+Na)+ = 335.
-238- Example 62
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)pent-3-vnyl)-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
62A fcW2R.3S.5R.1'R.2'S) and fcW2R.S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1- Acetamido-2-hvdroxy)pent-3-vnyl)-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting propyn-1-yl zinc for ethyl magnesium bromide to provide (±)-(2R,3S,5R, 1 'R,2'S)-1 -f-butoxycarbonyl-2-(1 -acetamido-2- hydroxy)pent-3-ynyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0073 g, 16%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pent-3-ynyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0349 g, 77%).
(±)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=451, (M+Na)+=473, (2M+Na)+=923,.(M-H)"=449.
(±)-(2R,3S,5R,1'R,2'R) MS: (M+H)+= 451, (M+Na)+=473, (2M+Na)+=923, (M-H)"=449.
-239-
62B fc)-(2R.3S.5R.1'R.2'SV2-π-Acetamido-2-hvdroxy)pent-3-vnvn-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pent-3-ynyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0052 g, 100%).
1H NMR (DMSO-de) d 7.97 (d, J=8.3 Hz, 1H), 5.48 (m, 1H), 5.25 (m, 1H), 4.35-4.20 (m, 3H), 3.67 (m, 1 H), 3.18 (quint, 8.8Hz, 1H), 2.41 (dt, J=12.7,7.8Hz, 1 H), 1.84 (s, 3H), 1.81 (d, J=1.9Hz, 3H), 1.63 (m, 1 H), 1.59 (dd, J=6.9,2.0Hz, 3H).
MS: (M+H)+ = 295, (M+Na)+ = 317, (M-H)" = 293, (M+CF3COO")"=407, (2M- H)*=587.
-240- Example 63
(±W2R.3S.5R.1'R.2'RV2-(1-Acetamido-2-hvdroxy)pent-3-vnvn -3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pent-3-ynyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(cs-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 0.0540 g, 100%).
1H NMR (DMSO-de) d 7.90 (d, J=8.8 Hz, 1 H), 5.50 (m, 1 H), 5.25 (m, 1H), 4.40-4.35 (m, 2H), 4.28 (m, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.18 (quint, 8.3Hz, 1H), 2.42 (dt, J=13.2,7.4Hz, 1H), 1.87 (s, 3H), 1.82 (d, J=1.9Hz, 3H), 1.71 (dt, J=12.7,10.0Hz, 1 H), 1.57 (dd, J=6.9,1.5Hz, 3H).
MS: (M+H)+ = 295, (M+Na)+ = 317, (M-H)" = 293, (M+CF3COO")"=407.
Example 64
-241- fc)-(2R.3S.5R.rR.2'R)-2-(1-Acetamido-2-hvdroxy-2-heptafluoropropyl)ethyl-3- (c/s-propen-1-v0-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3 \— , AcHN. JL .OH
A BOC CF3CF2CF2 QH
64A (±)-(2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-π-acetamido-2-hvdroxy-2- heptafluoropropyl)ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (41 mg, 0.10 mmol) and heptafluoropropyl iodide (0.144 mL, 1.0 mmol, 10 equivalents) in THF (2 mL) were reacted with 1M phenylmagnesium bromide (0.90 mL, 0.90 mmol, 9 equivalents) at -78 °C for 5 minutes. The reaction mixture was allowed to warm to room temperature over 1 h. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10 mL) followed by extraction using ethyl acetate (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/2: ethyl acetate/hexane to provide the title compound (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl 2-(1-acetamido-2-hydroxy- 2-heptafluoropropyl)ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 12.6 mg, 22%).
(±)-(2R,3S,5R,1'R,2'R) MS: (M+H)+=581 , (M+Na)+=603, (2M+Na)+=1183, (M-H)"=579.
-242- ,OH ^OH
TFA
64B fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-2- heptafluoropropyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-heptafluoropropyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyi-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 0.003 g, 100%).
1H NMR (DMSO-de) d 7.84 (d, J=9.3 Hz, 1H), 5.45 (m, 1H), 5.26 (m, 1H), 4.71 (t, J=9.7 Hz, 1H), 4.63 (d, J=22.0 Hz, 1H), 4.51 (m, 1H), 3.59 (t, J=9.3 Hz, 1H), 3.19 (quint, 8.3Hz, 1 H), 2.43 (dt, J=12.7,7.3Hz, 1H), 1.76 (s, 3H), 1.74 (m, 1H), 1.53 (dd, J=6.8,1.4Hz, 3H).
MS: (M+H)+ = 425, (M+Na)+ = 447, (M-H)" = 423, (2M-1)" = 847.
Example 65
-243- (±)-(2R,3S.5R.1'R.2'S)-2-(1-Acetamido-2.4-dihvdroxy)butyl-3-fc/s-propen-1-vh- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
65A fcW2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-π-acetamido-2.4- dihvdroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3- ethoxycarbonyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (35 mg, 0.07 mmol) was reacted with lithium borohydride (8 mg, 0.35 mmol) in THF (5 mL) at 25°C and reacted for 3 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (2 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane to provide the title compound (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl 2-(1- acetamido-2,4-dihydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 14 mg, 44%).
(±)-(2R,3S,5R,1'R,2'S) =MS: (M+H)+=457, (M-H)" =455
-244-
65B fcW2R.3S.5R.1'R.2'SV2-(1-Acetamido-2.4-dihvdroxy)butyl-3-fc/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2,4-dihydroxy)butyl 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-de) δ 7.93 (d, J=9.0Hz, 1 H), 5.56(m, 1H), 5.31 (m, 1H), 4.43 (m, 1H), 4.14 (m, 1 H), 3.69 (m, 1H), 3.63 (m, 1H), 3.23 (m, 2H), 3.07 (m, 1H), 2.43 (m, 1 H), 2.06 (s, 3H), 1.83 (m, 2H), 1.79 (m, 1H), 1.62 (dd, J=6.71 , 1.22 Hz, 3H)
MS: (M+H)+=301 , (M-H)" =299.
Example 66
-245- fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2.4-dihvdroxy')butyl-3-(c/'s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
OlBu
66A (2R.3S.5R.1 'R.2'R)-1 -f-Butoxycarbonyl-2-(1 -acetamido-2.4- dihvdroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 65A substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethoxycarbonyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxyiic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine- 5-carboxylic acid f-butyl ester, (yield: 11 mg, 70%).
H NMR (CDCI3) δ 5.58(m, 1H), 5.38(m, 1 H),4.16(m, 1 H), 4.05(m, 1H), 3.97(m, 1H), 3.78(m, 2H), 3.20(m, 1 H), 2.66(m, 1H) 2.54(m, 1H), 2.04(s, 3H), 1.80(m, 1H), 1.55(m, 2H), 1.47(s, 9H), 1.44(s, 9H)
MS: (M+H)+=457, (M-H)" =455
-246-
66B (±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2.4-dihvdroxy)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2,4-dihydroxy)butyl 3-(c s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f- butyl ester in place of (±)-(2R,3S>5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 8 mg, 96%).
1H NMR (DMSO-de) δ 7.91 (d, J=9.1 Hz, 1 H), 5.50 (m, 1H), 5.25 (m, 1H), 4.43 (m, 1H), 4.30 (m, 1H), 4.22 (m, 1H), 3.94 (m, 1H), 3.86 (m, 1H), 3.62 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1 H), 1.85 (s, 3H), 1.75 (m, 1H), 1.65 (m, 2H), 1.58 (dd, J=6.70, 1.81 Hz, 3H).
MS: (M+H)+ =301, (M-H)" =299.
-247- Example 67
fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-(phenylacetylen-1-vn)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
67A (±W2R.3S.5R.1'R.2'R and fcW2R.3S.5R.1'R.2'S) -1-f-Butoxycarbonyl-2- (1 -acetamido-2-hvdroxy-2-(phenylacetylen-1 -yl))ethyl-3-(c/'s-propen-1 -yl)- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting lithium phenylacetylide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1 'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy- 2-(phenylacetylen-1-yl))ethyl -3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 0.0010 g, 4%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl -3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0050 g, 21%).
(±)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=513, (M+Na)+=535, (2M+Na)+=1047, (M-H)"=511.
(±)-(2R,3S,5R,1'R,2'R) MS: (M+H)+=513, (M+Na)+=535, (2M+Na)+=1047, (M-H)"=511.
-248-
67B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-(phenylacetylen-1- yl))ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(c s-propen-1-yl)-pyrrolidine- 5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester.
Example 68
fcW2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-hvdroxy-2-(phenylacetylen-1-yl))ethyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
68A fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-2-(phenylacetylen-1- yl))ethyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1 'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(c/s-propen-1-yl)-pyrrolidine-
-249- 5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 0.0034 g, 100%).
1H NMR (DMSO-de) δ 9.2 (bs, 1H), 8.04 (d, J=9.2 Hz, 1 H), 7.45-7.35 (m, 5H), 5.50 (m, 1 H), 5.29 (m, 1 H), 4.64 (d, J=4.9, 1H), 4.5-4.4 (m, 2H), 3.81 (m, 1 H), 3.22 (quint, J=8.5Hz, 1H), 2.45 (dt, J=12.8,7.3Hz, 1 H), 1.89 (s, 3H), 1.74 (dt, J=12.7, 10.0Hz, 1H), 1.58 (dd, J=7.3,1.8Hz, 3H).
MS: (M+H)+ = 357, (M+Na)+ = 379, (M-H)" = 355.
Example 69
fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-3-ethvnpentyl-3-(c s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
.OtBu J
69A fcW2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-π-Acetamido-2-oxo-3- ethv0pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2',R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 8 mg, 81%).
MS: (M+H)+=481 , (M-H)" =479
-250-
69B (±W2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-π-Acetamido-2-hvdroxy-3- ethyl)pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-oxo-3-ethyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5 mg, 63%).
MS: (M+H)+=483, (M-H)- =481
69C fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-3-ethyl)pentyl-3-rc/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4 mg, 95%).
-251- 1H NMR (DMSO-d6) δ 7.67(d, J=8.9Hz, 1 H), 5.48(m, 1H), 5.23(m, 1 H), 4.42(m, 1 H), 4.21(m, 1H), 3.58(m, 2H), 3.22(m, 1H), 2.43(m, 1H), 1.82(s, 3H), 1.74(m, 1H), 1.58(dd, J=6.71 , 1.23 Hz, 3H), 1.52(m, 1 H), 1.38(m, 1 H), 1.29(m, 2Hz), 1.13(m, 1 H), 0.80(m, 6H)
MS: (M+H)+=327, (M-H)" =325
Example 70
(±W2R.3S.5R.1'R.2,R)-2-(1-Acetamido-2-hvdroxy-3-ethvnpentyl-3-(c/s-propen-1- vD-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
70A (±W2R.3S.5R.1'R.2'RV1-f-Butoxycarbonyl-2-(1-Acetamido-2-hvdroxy-3- ethyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting 3-pentyl magnesium bromide in place of ethyl magnesium bromide (yield: 13mg, 45%).
MS: (M+H)+=483, (M-H)" =481
-252-
70B (±)-(2R.3S.5R.1'R.2'RV2-(1-Acetamido-2-hvdroxy-3-ethyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-ethyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester (yield: 3 mg, 96%).
1H NMR (DMSO-d6) δ 7.85 (d, J=9.2 Hz, 1 H), 5.47 (m, 1 H), 5.30 (m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.67 (m, 1 H), 3.58 (m, 1H), 3.17 (m, 1 H), 2.43 (m, 1H), 1.81 (s, 3H), 1.63 (m, 1H), 1.58 (dd, J=6.71 , 1.82 Hz, 3H), 1.40 (m, 2H), 1.28 (m, 1H), 1.10 (m, 1H), 1.05 (m, 1 H), 0.83 (m, 6H)
MS: (M+H)+=327, (M-H)" =325
-253- Example 71
fc)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-2-phenvnethyl-3-(cs-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
71A fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-hvdroxy-2- phenyl)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting phenyl magnesium bromide in place of ethyl magnesium bromide (yield: 36 mg, 60%).
MS: (M+H)+= 489, (M+Na)+= 511 , (M-H)- = 487.
71 B (±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-2-phenvhethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-phenyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
-254- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5.5 mg, 100%).
1H NMR (DMSO-de) d 7.79 (d, J= 9.2Hz, 1H), 7.36 (m, 2H), 7.31 (m, 2H), 7.22 (m, 1H), 5.49 (m, 1 H), 5.22 (m, 1 H), 4.94 (d, J= 3.0Hz, 1 H), 4.52 (m, 1H), 4.35 (m, 1H), 3.62 (t, J- 8.5Hz, 1H), 3.22 (m, 1H), 2.46 (m, 1H), 1.77 (m, 1H), 1.65 (s, 3H), 1.57 (dd, J= 6.7, 0.8Hz, 3H).
MS: (M+H)+= 333, (M+Na)+ = 355, (M-H)- = 331.
Example 72
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-phenyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
72A fcW2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-(1-Acetamido-2-oxo-2- phenvDethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-phenyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,rR,2'R)-1-f-butoxycarbonyl 2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 24 mg, 84%).
MS: (M+H)+= 487, (M+Na)+= 509, (M-H)" = 485.
-255-
72B fcW2R.3S.5R.1,R.2'S)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-hvdroxy-2- phenyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-oxo-2-phenyl)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido-2-oxo)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 7.9 mg, 52%).
MS: (M+H)+= 489, (M+Na)+= 520, (M-H)" = 487.
72C fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-phenvnethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-phenyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 7.5 mg, 100%).
-256- 1H NMR (DMSO-de) d 7.83 (d, J= 9.2Hz, 1 H), 7.36 (m, 2H), 7.32 (m, 2H), 7.25 (m, 1 H), 5.47 (m, 1 H), 5.33 (m, 1 H), 4.54 (d, J= 9.8Hz, 1 H), 4.36 (m, 1H), 4.23 (m, 1 H), 3.78 (m 1 H), 3.20 (m, 1 H), 2.43 (m, 1 H), 1.63 (m, 1 H), 1.56 (dd, J= 6.7, 1.2Hz, 3H), 1.53 (s, 3H).
MS: (M+H)+= 333, (M+Na)+= 355, (M-H)" = 331.
Example 73
(±W2R.3S.5R.1 'R.2'R)-2-(1 -Acetamido-2-hvdroxy-2-(thiophen-2-v ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
73A fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-2- (thiophen-2-yl))ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R, 1 'R)-1 -f-Butoxycarbonyl 2-(1 -acetamido-2-formyl)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (40 mg, 0.098 mmol) in THF (2 mL) was added dropwise to a solution of 2-thienyllithium (1M in THF, 0.505 mmol, 5 equivalents) in THF (1 mL) at 25 °C and reacted for 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1 : ethyl acetate/hexane to provide the title compound (yield: 9.5 mg, 20%).
MS: (M+H)+= 495, (M+Na)+= 517, (M-H)" = 493.
-257-
73B fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-2-(thiophen-2-vn)ethyl- 3-(c/'s-propen-1-vD-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-(thiophen-2-yl))ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 4.3 mg, 100%).
1H NMR (DMSO-de) δ 7.86 (d, J= 9.8Hz, 1H), 7.63 (dd, J= 5.4, 1.0 Hz, 1H), 7.07 (m, 1H), 6.98 (m, 1H), 5.58 (m, 1 H), 5.43 (m, 1H), 4.55 (m, 1 H), 4.39 (m, 1H), 3.72 (m, 1 H), 3.11 (m, 2H), 2.43 (m, 1H), 2.04 (s, 3H), 1.80 (m, 1H), 1.57 (m, 3H).
MS: (M+H)+= 339, (M+Na)+ = 361 , (M-H)- = 337.
Example 74
-258- fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-3-(4-methylthiazol-2-yl))propy|- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H,C H,C
74A fcW2R.3S.5R.1'R.2'S) and fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-Acetamido-2-hvdroxy-3-(4-methylthiazol-2-yl))propyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
1.6 M n-Butyllithium (0.125 mL, 0.20 mmol, 4 equivalents) was added to a solution of 2,4-dimethylthiazole (28.3 mg, 0.25 mmol, 5 equivalents) in 1 mL of THF at -78 °C and reacted for 30 minutes. ((±)-(2R,3S,5R,1'R)-1-f- butoxycarbonyl 2-(1 -acetamido-2-formyl)ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5- carboxylic acid f-butyl ester (20.5 mg, 0.050 mmol) in THF (1 mL) was added dropwise to the above solution and reacted for 30 minutes at -78 °C and then for 30 minutes at room temperature. The reaction mixture was quenched with saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/2: ethyl acetate/hexane to provide (±)-(2R,3S,5R, 1 'R,2'S)-1 -f-butoxycarbonyl-2-(1 -acetamido-2-hydroxy-3- (4-methylthiazol-2-yl))propyi-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 3.3 mg, 13%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 7.5 mg, 29%).
-259- (2R,3S,5R,1'R,2'S) MS: (M+H)+=524, (M+Na)+=546, (2M+Na)+=1069, (M- H)"=522.
(2R,3S,5R,1'R,2'R) MS: (M+H)+=524, (M+Na)+=546, (2M+Na)+=1069, (M- H)"=522.
H,C
74B (±W2R.3S.5R.1,R.2'S)-2-(,1-Acetamido-2-hvdroxy-3-(4-methylthiazol-2- yl))propyl-3-(c/'s-propen-1-yl)-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 0.0030 g, 100%).
1H NMR (DMSO-de) δ 9.0 (bs, 1H), 8.10 (d, J=8.3Hz, 1H), 7.11 (d, J=1.0 Hz, 1H), 5.48 (m, 1H), 5.30 (m, 1 H), 4.30 (m, 1 H), 4.10 (m, 1 H), 3.88 (dt, J=9.4,2.6Hz, 1H), 3.78 (m, 1 H), 3.25-3.15 (m, 2H), 2.93 (dd, J=15.1 ,8.3Hz, 1H), 2.41 (dt, J=12.3,7.3Hz, 1H), 2.33 (d, J=1.0Hz, 3H), 1.86 (s, 3H), 1.66 (dt, J=12.7, 10.3Hz, 1H), 1.61 (dd, J=6.8,1.5Hz, 3H).
MS: (M+H)+ = 368, (M+Na)+ = 390, (M-H)" = 366.
-260- Example 75
(±W2R.3S.5R.1 'R.2'RV2-π -Acetamido-2-hvdroxy-3-(4-methylthiazol-2-yl))propyl- 3-(c/'s-propen-1-yl)-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cs-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 0.0030 g, 100%).
1H NMR (DMSO-de) d9.0 (bs, 1 H), 7.77 (d, J=9.3Hz, 1 H), 7.11 (s, 1H), 5.47 (m, 1 H), 5.25 (m, 1H), 4.45 (m, 1H), 4.20 (m, 2H), 3.58 (t, J=9.1 Hz, 1H), 3.19 (m, 1 H), 2.96 (m, 2H), 2.41 (m, 1 H), 2.33 (d, J=1.0Hz, 3H), 1.85 (s, 3H), 1.73 (dt, J=12.7, 10.3Hz, 1H), 1.54 (dd, J=6.9,1.5Hz, 3H).
MS: (M+H)+ = 368, (M+Na)+ = 390, (M-H)" = 366, (M+CF3COOH)"=480, (2M-H)"=733.
Example 76
-261- (±W2R.3S.5R.1'R.2'RS 2-(1-Acetamido-2-hvdroxy-3-(thiazoiin-2-yl))propyl-3- (c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
.OH
. O if
N" S
76A (±)-(2R,3S,5R,1'R,2'RS)-1-f-Butoxycarbonyl-2-(1-Acetamido-2- hydroxy-3-(thiazoiin-2-yl))propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (20.5 mg, 0.05 mmol) in THF (1 mL) was added dropwise to a solution of the (thiazolin-2-yl)methyI lithium (0.20 mmol, 4 equivalents, prepared from 0.025 g of 2-methylthiazoline and 0.125 mL of 1.6 M n-BuLi at -78 °C) in THF (2 mL) at -78 °C and reacted for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and water (5 mL) followed by extraction using dichloromethane (3 X 20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1 : ethyl acetate/hexane to provide the title compound as a mixture of isomers (yield: 10 mg, 40%).
MS: (M+H)+= 512, (M+Na)+=534, (M-H)"=510.
-262- γ__
76B (±W2R.3S.5R.1'R.2'RS)-2-(1-Acetamido-2-hvdroxy-3-(thiazolin-2- yl))propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compounds were prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'RS)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cs-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester n place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 0.003 g, 100%).
Major isomer 1H NMR (DMSO-d6) δ 8.88 (m, 1H), 7.76 (d, J=8.8Hz, 1H), 5.46 (m, 1H), 5.19 (m, 1 H), 4.69 (m, 1 H), 3.90 (m, 1H), 3.85 (m, 1 H), 3.49 (m, 2H), 3.35 (t, J=9.0Hz, 1H), 3.29 (dd, J=17.6,5.9Hz, 1H), 3.04 (t, J=8.9Hz, 1H), 2.78 (dd, J=17.6,8.1Hz, 1 H), 2.7-2.55 (m, 2H), 1.75 (s, 3H), 1.70 (m, 1 H), 1.56 (dd, J=6.8,1.5Hz, 3H).
MS: (M+H)+= 356, (M+Na)+=378, (2M+Na)+=733, (M-H)"=354.
Example 77
-263- (±)-(2R.3S.5R.1'R.2'S)-2-π-Acetamido-2-hvdroxy-3.3-difluoro-3-vinvnpropyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
77A fc)-(2R.3S.5R.1'R.2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-3.3- difluoro-3-vinyl)propyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3- (cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (41 mg, 0.10 mmol) and 1 ,1-difluoroallyl iodide (94 mg, 0.60 mmol, 6 equivalents) in THF (2 mL) was reacted with zinc dust (33 mg, 0.50 mmol, 5 equivalents) at 0°C for 5 minutes and then at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (15 mL) and water (15 mL) and extracted with 3 X 25 mL dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/3: ethyl acetate/hexane to provide the title compound (yield: 35 mg, 71%).
MS: (M+H)+=489, (M+Na)+=511 , (2M+Na)+=999, (M-H)"=487.
-264-
77B fcW2R.3S.5R.1 'R.2'S )-2-(1 -Acetamido-2-hvdroxy-3.3-difluoro-3- vinyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cs-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 0.0026 g, 96%).
1H NMR (DMSO-de) d7.68 (d, J=7.8Hz, 1H), 5.97 (m, 1H), 5.55-5.45 (m, 2H), 5.43 (m, 1H), 5.23 (m, 1 H), 4.45 (m, 2H), 4.10 (m, 1 H), 3.16(quint J=9.1Hz, 1H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 1.72 (s, 3H), 1.70 (dt, J=12.8, 10.3Hz, 1H), 1.61 (dd, J=6.7,1.2Hz, 3H).
MS: (M+H)+=333, (M+Na)+=355, (M-H)"= 331 , (2M-H)"=663.
Example 78
-265- (±)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-3.3-difluoro-3-vinvnpropyl-3- (cs-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
O'Bu
78A fc)-(2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-π-Acetamido-2-oxo-3.3-difluoro- 3-vinyl)propyl-3-(c/s-propen-1-yl)-Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cs-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R,2'R)-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester to provide (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-d ifluoro- 3,3-difluoro-3-vinyl)propyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester (yield: 0.0050g, 44%).
MS: (M+H)+=487, (M+Na)+=509, (M-2F)+=448, (M-H)"=485.
-266-
78B fc)-(2R.3S.5R.1,R.2'R)-1-f-Butoxycarbonyl-2-π-Acetamido-2-hvdroxy-3.3- difluoro-3-vinyl)propyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 42B, substituting (±)-(2R,3S,5R,1'R)-1-t-butoxycarbonyl-2-(1-acetamido- 2-oxo-3-difluoro-3-vinyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (2R,3S,5R,1'R)-2-(1-acetamido-2-oxo)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
78C fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-3.3-difluoro-3- vinv propyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid
The title compound is prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,rR,2'R)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(c s-propen-1-yl)-pyrroiidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1 -acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester.
Example 79
-267- (±)-(2R.3S.5R.1'R.2'R)-2-f1-Acetamido-2-hvdroxy-2-fc/s-buten-2-yl))ethyl-3-fc/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3 AcHN. A .OtBu
" H g0C H3C' ^γ OH °
CH3
79A fc)-(2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-hvdroxy-2- (c/s-buten-2-yl))ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-2-formyl)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (30 mg, 0.073 mmol) in THF (5 mL) was reacted with c/s-2-buten-2-yl lithium (0.75 mL (0.5M), 0.37 mmol) at 25°C for 45 min. The reaction was quenched with saturated aqueous ammonium chloride (5 mL) and water (5mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1 : ethyl acetate/hexane to provide the title compound (yield: 20 mg, 59%).
1H NMR (CDCI3) δ 6.19(d, J=8.9 Hz, 1 H), 5.61(m, 1 H), 5.35(m, 1H), 5.27(m, 1H), 4.48(m, 1H), 4.18(m, 1 H), 4.77(m, 2H), 3.10(m, 1H), 2.72(m, 1H), 1.99(s, 3H), 1.82(m, 1H), 1.73(m, 3H), 1.55(m, 6H), 1.47(s, 9H), 1.44(s, 9H)
MS: (M+H)+= 467, (M-H)" = 465
-268-
79B fcW2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-hvdroxy-2-(c/'s-buten-2-yl))ethyl- 3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-(c/s-buten-2-yl))ethyl-3-(c/s-propen-1-yl)-pyrroiidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 4 mg, 96%).
1H NMR (DMSO-d6) δ 8.09(d, J=9.0 Hz, 1 H), 5.50(m, 1 H), 5.32(m, 1H), 5.16(m, 1H), 4.50(m, 1 H), 4.38(m, 1 H), 4.19(m, 1H), 3.43(m, 1H), 3.20(m, 1H), 2.43(m, 1H), 1.88(s, 3H), 1.74(m, 1 H), 1.70(s, 3H), 1.62(m, 3H), 1.58(m, 3H)
MS: (M+H)+=311, (M-H)" =309
Example 80
-269- fcW2R.3S.5R.1,R.2'R.3'R and (±W2R.3S.5R.1'R.2'R.3,S)-2-n-Acetamido-2- hvdroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
OlBu O'Bu
80A fcW2R.3S.5R.1'R.2'R.3'R) and (±W2R.3S.5R.1'R.2'R.3'S)-1-f- Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-3-methyl)pentyl-3-(c/'s-propen-1-vπ- Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (60 mg, 0.15 mmol) in THF (1 mL) was added dropwise to a solution of 2-butylmagnesium bromide (3M in ether) (0.45 mL, 0.85 mmol) at room temperature and reacted for 40 minutes. The reaction was quenched with saturated NH4CI (1 mL) followed by extraction using dichloromethane (3 x 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compounds (±)-(2R,3S,5R,rR,2'R,3'S)-1-f-butoxycarbonyl 2-(1-acetamido-2- hydroxy-3-methyl)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester Rf= 0.65 (1 :1 ethyl acetate: hexanes) (yield: 19 mg, 27%) and (±)- (2R,3S,5R,1'R,2'R,3'R)-1-f-butoxycarbonyl 2-(1-acetamido-2-hydroxy-3- methyl)pentyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester Rf= 0.5) (1 :1 ethyl acetate: hexanes) (yield: 19 mg, 27%).
Rf= 0.65 1H NMR (CDCI3) δ 5.98 (d, J=8.8Hz, 1 H), 5.62 (t, J=10.5Hz, 1 H), 5.35 (m, 1 H), 4.66 (d, J=4.4Hz, 1H), 4.16 (d, J=9.5Hz, 1H), 3.78 (m, 3H),
-270- 3.12(m, 2H), 2.73 (m, 1 H), 2.0 (s, 3H), 1.81 (d, J=13.2Hz, 1 H), 1.54 (br s, 3H), 1.47 (s, 9H), 1.44 (s, 9H), 1.25 (m, 1 H), 0.81 (m, 6H)
MS: (M-H)" = 467; (M+H)+ = 469.
Rf= 0.5 1H NMR (CDCI3) δ 6.00 (d, J=10.2Hz, 1H), 5.61 (br t, 1H),
5.36 (m, 1H), 4.58 (d, J=4.7Hz, 1 H), 4.14 (d, J=8.8Hz, 1 H), 3.82 (m, 3H), 3.13 (m, 2H), 2.73 (m, 1 H), 1.99 (s, 3H), 1.80 (d, J=13.9Hz, 1 H), 1.54 (br s, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.43 (m, 1 H), 0.97 (d, J=6.8Hz, 3H), 0.81 (t, J=7.2Hz, 3H)
MS: (M-H)" = 467; (M+H)+ = 469.
80B fcW2R.3S.5R.1'R.2'R.3'S)-2-(1-Acetamido-2-hvdroxy-3-methyl)pentyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
(±)-(2R,3S,5R,1'R,2'R,3'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hydroxy- 3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (2.5 mg, 0.005 mmol) was reacted with trifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hrs. The reaction was concentrated in vacuo overnight and triturated with acetonitrile (2 x 1 mL) to provide the title compound (yield: 2.0 mg, 100%).
1H NMR (DMSO-d6) δ 7.68 (d, J=8.8Hz, 1 H), 5.45 (m, 1 H), 5.23 (t, J=7.3Hz, 1H), 4.24 (br t, 1H), 4.18 (m, 1 H), 3.52 (t, J=7.3Hz, 1 H), 3.45 (m, 1H), 3.16 (m, 1H), 2.38 (m, 1 H), 1.83 (s, 3H), 1.68 (m, 1 H), 1.58 (dd, J=2.0, 4.8Hz, 3H), 1.37 (m, 2H), 0.99 (m, 1 H), 0.89 (d, J=6.8Hz, 3H), 0.79 (t, J=7.4Hz, 3H)
-271- MS: (M-H)- = 311 ; (M+H)+ = 313, (M+Na)+ = 335.
Example 81
fc)-(2R.3S.5R.1'R.2'R.3'R)-2-π-Acetamido-2-hvdroxy-3-methvnpentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R,3'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (Rf= 0.5, 1:1, ethyl acetate: hexanes) in place of (±)- (2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1.6 mg, 76%).
1H NMR (DMSO-de) δ 7.55 (d, J=9.3Hz, 1 H), 5.45 (m, 1 H), 5.23 (m, 1H), 4.31 (br t, I H), 4.20 (t, J=8.3Hz, 1 H), 3.51 (t, J=9.3Hz, 1H), 3.43 (d, J=7.4Hz, 1H), 3.17 (m, 1H), 2.40 (m, 1H), 1.80 (s, 3H), 1.70 (m, 1H), 1.55 (dd, J=1.4, 5.4Hz, 3H), 1.36 (m, 2H), 1.14 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H)
MS: (M-H)" = 311 ; (M+H)+ = 313, (M+Na)+ = 335.
-272- Example 82
(±)-(2R.3S.5R.1'R.2'S.3'S -2-(1-Acetamido-2-hvdroxy-3-methvπpentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
OΕu
82A (± -(2R.3S.5R.1'R.3'RS)-1-f-Butoxycarbonyl-2-(1-acetamido-2-oxo-3- methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2'R,3'RS)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'R) 1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl (yield: 12 mg, 63%).
κOlBu o if
82B fcW2R.3S.5R.1'R,2'S.3'S) and fcW2R.3S.5R.1'R.2'S.3'R)-1-f- Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-3-methvπpentyl-3-(c/'s-propen-1-yl)- Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 42B, substituting (±)-(2R,3S,5R,1'R,3'RS)-1-f-butoxycarbonyl-2-(1- acetamido-2-oxo-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid
-273- f-butyl ester (Rf= 0.5 and 0.65, 1:1 , ethyl acetate: hexanes) in place of (2R,3S,5R,1'R)-2-(1-acetamido-2-oxo)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester to give (±)-(2R,3S,5R,1'R,2'S,3'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid f-butyl ester (Rf= 0.15, 1:1 , ethyl acetate: hexanes) (yield: 6.0 mg, 50%) and (±W2R,3S,5R,1'R,2'S,3'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester(Rf= 0.10, 1 :1 , ethyl acetate: hexanes) (yield: 2.5 mg, 63%).
82C fc)-f2R.3S.5R.1'R.2'S.3'S)-2-n-Acetamido-2-hvdroxy-3-methyl)pentyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S,3'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (Rf= 0.15, 1 :1 , ethyl acetate: hexanes) in place of (±)- (2R,3S,5R,rR,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.0 mg, 100%).
1H NMR (DMSO-de) δ 7.78 (d, J=9.2Hz, 1 H), 5.42 (m, 1 H), 5.29 (t, J=10.3Hz, 1 H), 4.08 (m, 1H), 3.96 (br t, 1 H), 3.51 (m, 2H), 3.08 (m, 1 H), 2.33 (m, 1H), 1.78 (s, 3H), 1.56 (d, J=6.3Hz, 3H), 1.52 (m, 1H), 1.40 (m, 1 H), 1.29 (m, 1H), 1.21 (m, 1 H), 0.84 (t, J=7.3Hz, 3H), 0.73 (d, J=6.9Hz, 3H)
MS: (M-H)" = 311 ; (M+H)+ = 313, (M+Na)+ = 335.
-274- Example 83
fcW2R.3S.5R.1'R.2'S.3'R)-2-(1-Acetamido-2-hvdroxy-3-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting(±)-(2R,3S,5R,1'R,2'S,3'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (Rf= 0.10, 1:1 ethyl acetate: hexanes) in place of (±)- (2R,3S,5R,1'R,2,S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.5 mg, 100%).
1H NMR (DMSO-de) δ 7.85 (d, J=8.7Hz, 1H), 5.45 (m, 1H), 5.29 (t, J=9.3Hz, 1H), 4.20 (m, 2H), 3.63 (t, J=8.3Hz, 1 H), 3.42 (br d, 1 H), 3.14 (m, 1H), 2.41 (m, 1H), 1.79 (s, 3H), 1.62 (m, 1H), 1.58 (d, J=5.4Hz, 3H), 1.43 (m, 2H), 1.0 (m, 1H), 0.88 (d, J=6.8Hz, 3H), 0.80 (t, J=7.3Hz, 3H)
MS: (M-H)" = 311 ; (M+H)+ = 313, (M+Na)+ = 335.
-275- Example 84
fc)-(2R.3S.5R.1'R.2'S)-2-π-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
84A fc)-(2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (22 mg, 0.05 mmole) was reacted with methyl iodide (0.016 mL, 0.25 mmole), potassium hydroxide (14 mg, 0.25 mmole) and 18-crown-6 (0.7 mg, 0.0025 mmole) in N,N-dimethylformamide (2 mL) at room temperature for 23 hours. Water (5 mL) was then added to the reaction mixture, followed by extraction with ether (2 x 10 mL). The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 66% ethyl acetate/hexanes to provide the title compound, as a colorless oil (yield: 5.2 mg, 23%).
MS: (M+H)+= 455, (M-H)- = 453.
-276-
84B fc)-(2R.3S,5R.1'R.2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester (yield: 4.7 mg, 98%).
1H NMR (DMSO-d6) δ 7.96 (d, J= 9.2Hz, 1 H), 5.50 (m, 1 H), 5.24 (m, 1H), 4.25 (m, 2H), 3.70 (m, 1 H), 3.23 (s, 3H), 3.19 (m, 2H), 2.40 (m, 2H), 1.86 (s, 3H), 1.68 (m, 2H), 1.62 (dd, J= 7.0, 1.8Hz, 3H), 1.39 (m, 1H), 0.77 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 299, (M+Na)+= 321, (M-H)- = 297
-277- Example 85
fc)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
85A fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R,2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (17 mg, 0.04 mmole) was reacted with methyl iodide (28 mg, 0.19 mmole), potassium hydroxide (8 mg, 0.19 mmole) and 18-crown-6 ( 0.002 mmole) in N,N- dimethylformamide (1.5 mL) at room temperature for 6 hours. Water (5 mL) was then added to the reaction mixture, followed by extraction with ether (2 x 10 mL). The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, (yield: 5 mg, 29%).
MS: (M+H)+=455, (M-H)" =453
-278- CH3 )—, AcH . J. X /OH A OCH«3 {
TFA
85B fcV(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4 mg, 95%).
1 H NMR (DMSO-d6) d 8.00(d, J=9.8HZ, 1H), 5.57(m, 1H), 5.35(m, 1H), 4.42(m, 1H), 4.28(m, 1 H),3.95(m, 1 H), 3.54(m, 1H), 3.28(s, 3H), 2.80(m, 1H), 2.30(m, 1H), 1.92(s, 3H), 1.65(m, 1H), 1.60(m, 3H), 1.43(m, 2H), 0.82(t, J=7.31HZ, 3H).
MS: (M+H)+=299, (M-H)- =297
-279- Example 86
fcW2R.3S.5R.1'R.2'S)-2-π-Acetamido-2-methoxy-3-methvπbutyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
P
86A fcW2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3- methyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound is prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(cs-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
OH
TFA
86B fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-3-methyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
-280- acetamido-2-hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
Example 87
fcW2R.3S,5R.1'R.2'RV2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
86A (±W2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3- methyl)butyl-3-(c/'s-propen-1-yl)-Pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.8 mg, 33%).
MS: (M+H)+= 469, (M+Na)+= 491 , (M-H)" = 467.
-281- OH ϊ O TFA
87B fc)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(c/s- propen-1-v0-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-3-methyl)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 6.6 mg, 100%).
1H NMR (DMSO-de) δ 7.65 (d, J= 9.2Hz, 1 H), 5.43 (m, 1 H), 5.23 (m, 1H), 4.42 (m, 1 H), 4.37 (m, 1 H), 3.56 (m, 1H), 3.46 (s, 3H), 3.17 (m, 2H), 2.44 (m, 1H), 1.80 s, 3H), 1.78 (m, 1 H), 1.70 (m, 1H), 1.57 (dd, J= 6.7, 1.2Hz, 3H), 0.94 (d, J= 6.7Hz, 3H), 0.82 (d, J= 6.7Hz, 3H).
MS: (M+H)+= 313, (M+Na)+ = 335, (M-H)- = 311.
-282- Example 88
fc)-(2R.3S.5R.1 'R,2'S)-2-(1-Acetamido-2-methoxy entyl-3-(c/s-propen-1-vn- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3
AcHN. A \ H
Jyy OCH*°3
88A fcW2R.3S.5R.1 'R.2'S)-1-f-Butoxycarbonyl-2-n-acetamido-2- methoxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 11.9 mg, 36%).
MS: (M+H)+= 469, (M+Na)+= 491 , (M-H)- = 467.
CH3 \ — > AcHN.^X OH NAV^H H O
OCH3
TFA
88B fcW2R.3S.5R.1 'R.2'SV2-(1-Acetamido-2-methoxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1 'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido-
-283- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, (yield: 11.5 mg, 100%).
1H NMR (DMSO-de) δ 7.95 (d, J= 9.8Hz, 1 H), 5.49 (m, 1 H), 5.23 (m, 1H), 4.25 (m, 2H), 3.68 (m, 1 H), 3.24 (s, 3H), 3.22 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.85 (s, 3H), 1.66 (m, 1H), 1.62 (m, 3H), 1.58 (m, 1 H), 1.38 (m, 1 H), 1.27 (m, 2H), 0.86 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 313, (M+Na)+=335, (M-H)- = 311.
Example 89
(±)-(2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-methoxy)pentyl-3-(c/s-propen-1-vn- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
89A fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4.3 mg, 21%).
MS: (M+H)+= 469, (M+Na)+= 491, (M-H)" = 467.
-284- OH o
TFA
89B (±)-(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy)pentyl-3-(cs-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1 'R,2'S)-1-t-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4.8 mg, 100%).
1H NMR (DMSO-de) δ 7.70 (d, J= 9.8Hz, 1 H), 5.45 (m, 1H), 5.24 (m, 1H), 4.40 (m, 1 H), 4.25 (m, 1H), 3.57 (t, J= 8.5Hz, 1H), 3.40 (m, 1H), 3.35 (s, 3H), 3.17 (m, 1 H), 2.42 (m, 1H), 1.82 (s, 3H), 1.69 (m, 1 H), 1.56 (dd, J= 7.1 , 1.2Hz, 3H), 1.24 (m, 4H), 0.88 (t, J= 7.0Hz, 3H).
MS: (M+H)+= 313, (M+Na)+= 335, (M-H)- = 311
-285- Example 90
(±)-(2R.3S,5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-2-allvnethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
OtBu
Y ϋ
3
90A (±)-(2R.3S.5R,1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2- allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 8 mg, 31%).
MS: (M+H)+=467, (M-H)"=465
90B fcW2R.3S.5R.1'R.2'SV2-π-Acetamido-2-methoxy-2-allyl)ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-2-allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 6 mg, 96%).
1H NMR (DMSO-de) δ 8.02(d, J=8.6HZ, 1 H),5.75 (m, 1 H), 5.51(m, 1H), 5.24(m, 1H), 5.05(m, 2H), 4.27(m, 1H), 4.22(m, 1H), 3.74(m, 2H), 3.26(s, 3H),
-286- 3.18(171, 1H), 2.47(m, 1 H), 2.39(m, 1 H), 2.17(m, 1 H), 1.87(s, 3H), 1.67(m, 1H),1.63(dd, J=6.71 , 1.23 HZ, 3H).
MS: (M+H)+=311 , (M-H)" =309
Example 91
(±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy-2-allvnethyl-3-(cs-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
91A fcW2R.3S.5R,1'R.2'R)-1-f-Butoxycarbonyl-2-π-acetamido-2-methoxy-2- allyl)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4.0 mg, 16%).
MS: (M+H)+=467, (M-H)" =465
-287- OH ϊ o
91 B (±V(2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy-2-allvnethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-2-allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrroiidine-5-carboxylic acid f-butyl ester (yield: 3 mg, 96%).
1H NMR (DMSO-de) δ 7.75 (d, J=9.2 HZ, 1 H), 5.75(m, 1 H), 5.47(m, 1H), 5.24(m, 1 H), 5.06(m, 2H), 4.42(m, 1H), 4.25(m, 1 H), 3.58(m, 1 H), 3.50(m, 1H), 3.37(s, 3H), 3.17(m, 1 H), 2.42(m, 1 H), 2.36(m, 1H), 1.33(s, 3H), 1.71(m, 1H), 1.55(dd, J=6.73, 1.83 HZ, 3H)
MS: (M+H)+=311 , (M-H)" =309
-288- Example 92
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-vinvnbutyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
/O'Bu κO'Bu o if
92A (±W2R.3S.5R.1'R.2'S) and fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-4-vinyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting 1-buten-4-yl magnesium bromide for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy-4-vinyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0030 g, 6%) and (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-vinyl)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0145 g, 28%).
(±)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=467, (M+Na)+=489, (2M+Na)+=955, (M-H)"=465.
(±)-(2R,3S,5R,1'R,2'R)- MS: (M+H)+=467, (M+Na)+=489, (2M+Na)+=955, (M-H)"=465.
-289-
TFA
92B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-vinyl)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-vinyl)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0027 g, 100%).
1H NMR (DMSO-de) δ 8.93 (bs, 1 H), 7.90 (d, J=9.2 Hz, 1 H), 5.80 (m, 1H), 5.48 (m, 1H), 5.28 (m, 1H), 5.00 (dd, J=17.1 , 1.8Hz, 1H), 4.94 (dd, J=10.4,1.8Hz, 1H), 4.29 (bt, J=8.3Hz, 1 H), 4.03 (m, 1 H), 3.71 (m, 1H), 3.49 (m, 1 H), 3.15 (quint, J=8.5Hz, 1 H), 2.41 (dt, J=12.8,7.3Hz, 1 H), 2.16 (M, 1 H), 2.05 (m, 1H), 1.83 (s, 3H), 1.79-1.75 (m, 1 H), 1.64 (m, 1H), 1.58 (dd, J=6.7,1.8Hz, 3H), 1.34 (m, 2H).
MS: (M+H)+ = 311 , (M+Na)+ = 333, (M-H)" = 309, (M+CF3COOT=423
-290- Example 93
(±)-(2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-hvdroxy-4-vinyl)butyl-3-(c s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
TFA
93A (±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-4-vinvnbutyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0027 g, 100%).
1H NMR (DMSO-de) δ 7.68 (d, J=9.6 Hz, 1H), 5.81 (m, 1 H), 5.48 (m, 1H), 5.25 (m, 1H), 5.01 (dd, J=17.1 , 1.8Hz, 1H), 4.95 (dd, J=10.3,1.7Hz, 1 H), 4.43 (t, J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.74 (m, 1 H), 3.56 (t, J=8.9Hz, 1 H), 3.16 (quint, J=8.9Hz, 1H), 2.42 (dt, J=12.8,7.3Hz, 1H), 2.11 (M, 1H), 2.07 (m, 1 H), 1.83 (s, 3H), 1.72 (dt, J=12.8, 9.8Hz, 1 H), 1.55 (dd, J=6.7,1.8Hz, 3H), 1.5-1.35 (m, 2H).
MS: (M+H)+ = 311 , (M+Na)+ = 333, (M-H)" = 309, (M+CF3COO")"=423, (2M-H)"=619.
-291- Example 94
(±W2R.3S.5R.1'R.2'S.3'S)-2-(1-Acetamido-2-methoxy-3-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/OH goA
94A fc)-(2R.3S.5R.1'R.2'S.3'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-methoxy- 3-methv0pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound is prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'S,3'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(cs-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
94B fcW2R.3S.5R.1'R.2'S.3'S')-2-(1-Acetamido-2-methoxy-3-methvnpentyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S,3'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-3-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
-292- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
Example 95
fcW2R.3S.5R.1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
OlBu
95A fcW2R.3S.5R.1'RS)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3- heptafluoropropyl)ethyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2'RS)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester for (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.8 mg, 88%).
MS: (M+H)+=579, (M-H)"=577.
-293-
95B (±)-(2R.3S.5R.1'RSV2-π-Acetamido-2-oxo-2-heptafluoropropynethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'RS)-1-t-butoxycarbonyl-2-(1- acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 0.0037 g, 100%).
MS: (M+H)+=423, (M-H)"=421.
Example 96
-294- fc)-(2R.3S.5R.1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
96A fcW2R.3S.5R.1'RS)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3- heptafluoropropyl)ethyl-3-(c/s-propen-1 -vπ-pyrrolidine-5-carboχylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester for (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.8 mg, 88%).
MS: (M+H)+=579, (M-H)"=577.
96B fcW2R.3S.5R.1'RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropynethyl-3- (c/s-propen-1-v0-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-
-295- 2-(1-acetamido-2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 0.0037 g, 100%).
MS: (M+H)+=423, (M-H)"=421.
Example 97
(±W2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo)pentyl-3-(c/s-propen-1-yl)-Pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt.
97A fcV(2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-π-acetamido-2-oxo)pentyl-3-(c/s- propen-1-v0-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 42A, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hdroxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 14 mg, 58%).
MS: (M+H)+ = 453, (M+Na)+ = 475; (M-H)" = 451.
-296-
97B fc)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo)pentyl-3-(c/s-propen-1-vn- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1 'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-oxo)pentyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1.4 mg, 28%).
1H NMR (DMSO-d6) δ 8.31 (d, J=8.3Hz, 1 H), 5.40 (m, 1H), 5.19 (br t, 1H), 4.26 (t, J=6.8Hz, 1H), 3.63 (t, J=8.3Hz, 1H), 3.35 (m, 1H), 2.97 (m, 1H), 2.45 (m, 1 H), 2.34 (dt, J=3.4, 7.4Hz, 1 H), 2.20 (m, 1H), 1.84 (s, 3H), 1.58 (dd, J=2, 4.3Hz, 3H), 1.43 (m, 3H), 0.82 (t, J=7.3Hz, 3H)
MS: (M-H)" = 295; (M+H)+ = 297, (M+Na)+ = 319.
-297- Example 98
(±)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo)butyl-3-(c/'s-propen-1-yl)-ρyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt .
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-oxo)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester prepared in Example 42A in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 5.0 mg, 100%).
1H NMR (DMSO-de) δ 8.52 (d, J= 8.6Hz, 1 H), 5.47 (m, 1H), 5.15 (m, 1H), 4.54 (m, 1H), 4.39 (dd, J= 11.0, 6.7Hz, 1 H), 3.84 (t, J= 9.2Hz, 1H), 3.17 (m, 1H), 2.50 (m, 1H), 2.38 (m, 1 H), 2.33 (m, 1 H), 1.83 (s, 3H), 1.63 (m, 1 H), 1.58 (dd, J= 6.7, 1.8Hz, 3H), 0.94 (t, J= 7.5Hz, 3H).
MS: (M+H)+= 283, (M+Na)+ = 305, (M-H)" = 281.
Examples 99-115
The title compounds were prepared according to the methods described in Examples 20 and 40-42 by substituting the respective reactants.
-298- Example 99
(±)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo-2-allvnethyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 8.38 (d, J= 8.5Hz, 1 H), 5.73 (m, 1 H), 5.37 (m, 1H), 5.05 (m, 3H), 4.32 (t, J= 7.9Hz, 1 H), 3.90 (m, 1H), 3.49 (m, 1 H), 3.13 (m, 2H), 2.98 (m, 1 H), 3.18 (m, 1H), 1.78 (s, 3H), 1.51 (dd, J= 5.5, 1.2Hz, 3H), 1.44 (m, 1 H).
MS: (M+H)+= 295, (M-H)- = 293.
Example 100
OH
(±W2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo-3-methvnbutyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 8.64 (d, J= 8.5Hz, 1H), 5.59 (m, 1 H), 5.08 (d, J= 17.1Hz, 1H), 5.02 (d, J= 9.8Hz, 1H), 4.65 (t, J= 8.6Hz, 1H), 4.32 (m, 1 H), 3.82 (t, J= 9.2Hz, 1 H), 2.82 (m 2H), 2.36 (m, 1H), 1.83 (s, 3H), 1.80 (m, 1H), 1.03 (d, J= 6.7Hz, 3H), 0.97 (d, J= 6.7Hz, 3H).
MS: (M+H)+= 283, (M+Na)+ = 305, (M-H)" = 281.
-299- Example 101
AcHN..^ X /OH
TFA
fcW2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo)propyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 8.96 (d, J= 7.9Hz, 1 H), 5.71 (m, 1 H), 5.27 (d, J=17.7Hz, 1 H), 5.17 (d, J= 11.0Hz, 1 H), 4.38 (m, 1 H), 4.29 (m, 1 H), 3.81 (m, 1H), 2.61 (m, 1 H), 2.22 (m, 1H), 2.13 (s, 3H), 2.01 (s, 3H), 1.24 (m, 1 H).
MS: (M+H)+= 255, (M+Na)+ = 277, (M-H)" = 253.
Example 102
(±W2R.3S.5R.1'RV2-(1-Acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 8.61 (d, J= 8.5Hz, 1 H), 5.60 (m, 1 H), 5.10 (d, J= 17.7Hz, 1H), 5.03 (dd, J= 10.4, 1.2Hz, 1 H), 4.54 (t, J= 8.5Hz, 1 H), 4.38 (dd, J= 11.0, 6.7Hz, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H), 2.52 (m, 1 H), 2.37 (m, 2H), 1.85 (s, 3H), 1.82 (m, 1 H), 0.94 (t, J= 7.0Hz, 3H).
MS: (M+H)+= 269, (M+Na)+ = 291 , (M-H)" = 267.
-300- Example 103
TFA
(±)-(2R.3S.5R.1 'R')-2-π-Acetamido-2-oxo)pentyl-3-vinyl-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 8.60 (d, J= 9.7Hz, 1H), 5.60 (m, 1H), 5.07 (m, 2H), 4.65 (m, 1H), 4.54 (m, 1 H), 4.38 (m, 1 H), 3.86 (m, 1 H), 2.84 (m, 1 H), 2.45 (m, 1 H), 2.36 (m, 1 H), 1.86 (s, 3H), 1.82 (m, 1 H), 1.47 (m, 2H), 0.87 (t, J= 5.8Hz, 3H).
MS: (M+H)+= 283, (M+Na)+= 305, (M-H)" = 281.
Example 104
(±W2R.3S.5R,1'R)-2-π-Acetamido-2-hvdroxy)ethyl-3-vinyl-Pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 8.00 (d, J= 9.9Hz, 1 H), 5.63 (m, 1H), 5.08 (m, 1H), 4.98 (m, 1H), 4.35 (m, 1H), 4.25 (m, 1H), 4.08 (m, 1 H), 3.55 (m, 1H), 3.45 (m, 1 H), 3.38 (m, 1 H), 2.83 (m, 1 H), 2.33 (m, 1 H), 1.78 (s, 3H).
MS: (M+H)+= 243, (M+Na)+= 265, (M-H)- = 241.
-301- Example 105
(±W2R.3S.5R.1'R.2'S 2-(1-Acetamido-2-hvdroxy)propyl-3-vinyl-Pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.96 (d, J= 9.7Hz, 1 H), 5.74 (m, 1 H), 5.12 (m, 1H), 5.03 (m, 1H), 4.27 (m, 1H), 3.96 (m, 1H), 3.77 (m 1H), 3.65 (m, 1H), 2.87 (m, 1H), 2.38 (m, 1H), 1.82 (s, 3H), 1.80 (m, 1 H), 1.08 (d, J= 6.0Hz, 3H).
MS: (M+H)+= 257, (M+Na)+= 279, (M-H)" = 255.
Example 106
(±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
H NMR (DMSO-de) δ7.99 (d, J= 9.0Hz, 1H), 5.75 (m, 1 H), 5.13 (d, J= 17.1Hz, 1H), 5.04 (d, J= 10.5Hz, 1 H), 4.27 (t, J= 8.4Hz, 1 H), 4.04 (m, 1 H), 3.78 (m, 1H), 3.48 (m, 1H), 2.89 (m, 1H), 2.40 (m, 1 H), 1.88 (m, 1 H), 1.85 (s, 3H), 1.54 (m, 1H), 1.28 (m, 1H), 0.86 (t, J= 7.2Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)- = 269.
-302- Example 107
TFA
fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.99 (d, J= 9.9Hz, 1 H), 5.75 (m, 1 H), 5.08 (m, 2H), 4.28 (m, 1 H), 4.03 (m, 1 H), 3.77 (m, 1 H), 3.52 (m, 1 H), 2.88 (m, 1 H), 2.40 (m, 1 H), 1.86 (s, 3H), 1.75 (m, 1 H), 1.45 (m, 2H), 1.25 (m, 2H), 0.87 (t, J= 5.9Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)" = 283.
Example 108
fcW2R.3S.5R, 1 'R.2'S)-2-(1 -Acetamido-2-hvdroxy-3-methvnbutyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.97 (d, J= 9.3Hz, 1 H), 5.75 (m, 1H), 5.12 (d, J= 17.1 Hz, 1H), 5.04 (d, J= 11.2Hz, 1H), 4.24 (m, 1 H), 4.13 (m, 1H), 3.74 (dd, J= 9.8, 6.1Hz, 1H), 3.44 (dd, J= 10.3, 2.0Hz, 1 H), 2.87 (m, 1H), 2.40(m, 1H), 1.84 (m, 1 H), 1.83 (s, 3H), 1.75 (m, 1 H), 0.89 (d, J= 6.8, 3H), 0.75 (d, J= 6.8Hz, 3H).
MS: (M+H)+= 285, (M+Na)+ = 307, (M-H)" = 283.
-303- Example 109
(±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-cvclopropyl)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H NMR (DMSO-de) δ 7.81 (d, J= 10.0Hz, 1H), 5.73 (m, 1 H), 5.05 (m, 2H), 4.39 (m, 1 H), 4.20 (m 1 H), 3.90 (m, 1H), 3.61 (m, 1 H), 3.08 (m, 1 H), 2.86 (m, 1 H), 2.42 (m, 1 H), 1.85 (s, 3H), 0.88 (m, 1 H), 0.45 (m, 1 H), 0.35 (m, 2H), 0.11 (m, 1H).
MS: (M+H)+= 283, (M+Na)+= 305, (M-H)" = 281.
Example 110
fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy)propyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.77 (d, J= 9.7Hz, 1 H), 5.72 (m, 1H), 5.07 (m, 2H), 4.40 (m, 1H), 4.03 (m, 1H), 3.95 (m 1H), 3.57 (m, 1 H), 2.86 (m, 1 H), 2.43 (m, 1H), 1.88 (m, 1 H), 1.84 (s, 3H), 1.04 (d, J= 6.0Hz, 3H).
MS: (M+H)+= 257, (M+Na)+= 279, (M-H)" = 255.
-304- Example 111
TFA
fc)-(2R.3S.5R.1'R.2'R)-2-π-Acetamido-2-hvdroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ7.72 (d, J= 9.8Hz, 1H), 5.73 (m, 1H), 5.08 (d, J= 17.1 Hz, 1H), 5.03 (d, J= 10.4Hz, 1 H), 4.41 (m, 1 H), 4.13 (m, 1 H), 3.68 (m, 1H), 3.63 (m, 1 H), 2.88 (m, 1 H), 2.44 (m, 1 H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.38 (m, 2H), 0.84 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 271, (M+Na)+ = 293, (M-H)" = 269.
Example 112
fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.72 (d, J= 9.9Hz, 1H), 5.72 (m, 1H), 5.06 (m, 2H), 4.42 (m, 1H), 4.09 (m, 1H), 3.77 (m, 1 H), 3.61 (m, 1 H), 2.87 (m, 1 H), 2.43 (m, 1H), 1.90 (m, 1 H), 1.83 (s, 3H), 1.37 (m, 2H), 1.27 (m, 2H), 0.87 (t, J= 5.9Hz, 3H).
MS: (M+H)+= 285, (M+Na)+= 307, (M-H)" = 283.
-305- Example 113
(±W2R.3S.5R.1 'R.2'R)-2-(1 -Acetamido-2-hvdroxy-3-methyl)butyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-d6) δ 7.71 (d, J= 9.3Hz, 1 H), 5.70 (m, 1H), 5.08 (d, J= 17.1 Hz, 1H), 5.03 (d, J= 10.3Hz, 1H), 4.42 (m, 1H), 4.25 (m, 1H), 3.61 (m, 1H), 3.35 (dd, J= 8.3, 2.5Hz, 1 H), 2.90 (m, 1H), 2.44 (m, 1 H), 1.92 (m, 1 H), 1.82 (s, 3H), 1.58 (m, 1 H), 0.95 (d, J= 6.8Hz, 3H), 0.79 (d, J= 6.4Hz, 3H).
MS: (M+H)+= 285, (M+Na)+ = 307, (M-H)- = 283.
Example 114
fcW2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-2-cvclopropyl)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.94 (d, J= 9.6Hz, 1 H), 5.76 (m, 1 H), 5.12 (m, 2H), 4.40 (m, 1H), 4.21 (m, 1 H), 3.90 (m, 1H), 3.53 (m, 1 H), 3.13 (m, 1 H), 2.81 (m,
-306- 1 H), 2.25 (m, 1 H), 1.87 (s, 3H), 0.90 (m, 1 H), 0.47 (m, 1 H), 0.37 (m, 2H), 0.15 (m, 1 H).
MS: (M+H)+= 283, (M+Na)+= 305, (M-H)" = 281.
Example 115
AcHN.
A H H
TFA
fc)-(2R.3S.5R.1'R.2'R)-2-n-Acetamido-2-hvdroxy-4-methvnpentyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.71 (d, J= 9.7Hz, 1 H), 5.83 (m, 1H), 5.06 (d, J= 17.1Hz, 1H), 5.02 (d, J= 10.3Hz, 1H), 4.41 (m, 1H), 4.06 (m, 1H), 3.83 (m, 1H), 3.59 (t, J= 8.8Hz, 1 H), 2.84 (m, 1 H), 2.42 (m, 1H), 1.90 (m, 1H), 1.82 (s, 3H), 1.71 (m, 1 H), 1.34 (m, 1 H), 1.07 (m, 1 H), 0.89 (d, J= 6.8Hz, 3H), 0.86 (d, J= 6.3Hz, 3H).
MS: (M+H)+= 299, (M+Na)+ = 321 , (M-H)- = 297.
-307- Example 116
(±)-(2R.3S.5R.1 'R)-2-(1-Acetamido-2-hvdroxy-2-methyl)propyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt
AcHN. JT\ . /°tBu H Ϊ Boc Olf
OH
116A fcW2R.3S.5R.1'RW-Butoxycarbonyl-2-(1-Acetamido-2-hvdroxy-2- methvπpropyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'R)-f-Butoxycarbonyl 2-(1-acetamido-2-oxo)propyl-3-vinyl- pyrrolidine-5-carboxylic acid t-butyl ester (11 mg, 0.027 mmol) was reacted with methyl magnesium bromide (3 M) ( 0.05mL, 0.134 mmol) in THF (2 mL) at 25 °C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (2 mL) and water (2 mL) followed by extraction using dichloromethane (2 X 5 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1 : ethyl acetate/hexane to provide the title compound (yield: 1.9 mg, 17%).
MS: (M+H)+=427, (M-H)" =425
-308- AcHN. ^ X /OH
,A H OH ϋ TFA
116B fc)-(2R.3S.5R.1 'R)-2-π-Acetamido-2-hvdroxy-2-methyl)propyl-3-vinyl- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 1.6 mg, 99%).
1H NMR (DMSO-d6) δ 7.70(d, J=9.9Hz, 1 H), 5.75(m, 1 H), 5.02(m, 2H), 4.37(m, 1H), 4.15(m, 1 H), 3.61 (m, 1 H), 2.78(m, 1 H), 2.41 (m, 1H), 1.81(s, 3H), 1.20(s, 3H), 1.12(s, 3H)
MS: (M+H)+ =271 , (M+23)+ =293, (M-H)" =269
-309- Example 117
(±)-(2R.3S.5R.1'R)-2-π-Acetamido-2-hvdroxy-2-ethyl)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
AcHN. ^ J /O'Bu
H Boc ϊ ^OH U
117A fcW2R.3S.5R.1'RW-Butoxycarbonyl-2-(1-Acetamido-2-hvdroxy-2- ethvDbutyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'R)-f-Butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-vinyl- pyrrolidine-5-carboxylic acid t-butyl ester (37mg, 0.087 mmol) was reacted with ethyl magnesium bromide (3 M) ( 0.15mL, 0.44mmol) in THF (5 mL) at 25 °C for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride 5 mL) and water (5 mL) followed by extraction using dichloromethane (2 X 10 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 2/1 : ethyl acetate/hexane to provide the title compound (yield: 14 mg, 35%).
MS: (M+H)+= 455, (M-H)" =453
-310- AcHN. ^ X /OH
OH { υ ^ TFA
116B (±)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-hvdroxy-2-ethyl)butyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-ethyl)butyl-3vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5.8 mg, 98%).
1 H NMR (DMSO-de) δ 7.62(d, J=9.6HZ, 1 H), 5.75(m, 1H), 5.03(m, 2H), 4.39(m, 1H), 4.31(m, 2H), 3.87(m, 1 H), 3.38(m, 1 H), 2.88( m, 1H), 2.40(m, 1H), 1.83(s, 3H), 1.55-1.30(m, 4H), 0.86(m, 6H)
MS: (M+H)+ =299, (M-H)" =297
-311- Example 118
(±)-(2R.3S.5R.1,S)-2-(1-Acetamido)allyl-3-(c/s-propen-1-yl)-Pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
O'Bu
118A fc)-(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido)allyl-3-(c s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 20K, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-formyl)methyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- formyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 15.3 mg, 61.4%).
MS: (M+H)+= 409.
TFA
118B fcW2R.3S.5R.1 'S)-2-(1 -Acetamido)allyl-3-(c/s-propen-1 -yl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1- acetamido)allyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S, 5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-
-312- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 13.1 mg, 100%).
1H NMR (DMSO-d6): δ1.58 (dd, 3H), 1.74 (dt, 1 H), 1.88 (s, 3H), 2.41 (dt, 1 H), 3.17 (m, 1 H), 3.56 (dd, 1H), 4.35 (dd, 1 H), 4.70 (dd, 1 H), 5.22-5.30 (m, 3H), 5.51 (m, 1 H), 5.82 (m, 1 H), 8.15 (d, 1 H), 9.18 (br s, 2H).
MS: (M+H)+= 253.
Example 119
(±W2R.3S.5R.1 'SV2-(1-Acetamido-2-(c/s and frar?s)buten-1-yl)-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
o'BU
119A fcW2R.3S,5R.1'S)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-(c/s and frans)buten-1-yl)-3-(c s-propen-1-ylW3yrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 20K, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-formyl)methyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- formyl-pyrrolidine-5-carboxylic acid f-butyl ester and ethyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 12.4 mg, 48.2%).
MS: (M+H)+= 423
-313- H,C
119B (±W2R.3S.5R.1'S)-2-(1-Acetamido-2-(c/s and fraπs)buten-1-yl)-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-(c/s and fraπs)buten-1-yl)-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 11.8 mg, 100%).
1H NMR (DMSO-de): 81.63 (dd, 3H), 1.66 (dd, 3H), 1.74 (m, 1H), 1.88 (s, 3H), 2.41 (dt, 1 H), 3.17 (m, 1 H), 3.50 (dd, 1H), 4.34 (dd, 1H), 4.95 (m, 1 H), 5.23 (m, 1 H), 5.39 (m, 1 H), 5.53 (m, 1H), 5.68 (m, 1 H), 8.21 (d, 1 H), 9.18 (br s, 2H).
MS: (M+H)+= 267
-314- Example 120
fcW2R.3S.5R.1'S)-2-(1-Acetamido-3.3-dimethvnallyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
O'Bu
120A (±)-(2R.3S.5R.1'SV1-f-Butoxycarbonyl-2-(1-acetamido-3.3-dimethvnallyl-3- (c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 20K, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-formyl)methyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3R,5R,1 'S)-1-f-butoxycarbonyl-2-(1 -acetamido-3-methyl)butyl-3- formyl-pyrrolidine-5-carboxyiic acid f-butyl ester and isopropyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 8.2 mg, 25.9%).
MS: (M+H)+= 437
120B fc)-(2R.3S.5R.1'S)-2-(1-Acetamido-3.3-dimethyl)allyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 3,3-dimethyl)allyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in
-315- place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 7.5 mg, 100%).
1H NMR (DMSO-d6): δ1.53 (dd, 3H), 1.57 (s, 3H), 1.61 (s, 3H), 1.66 (m, 1 H), 1.77 (s, 3H), 2.32 (dt, 1 H), 3.07 (m, 1H), 3.39 (dd, 1H), 4.26 (m, 1 H), 4.75 (m, 1 H), 5.07 (d, 1 H), 5.15 (m, 1 H), 5.44 (m, 1 H), 8.06 (d, 1H).
MS: (M+H)+= 281.
Example 121
(±W2R.3S.5R.1'S)-2-(1-Acetamido-2-(c/s and fraπs)penten-1-yl)-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
121A fcW2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-Acetamido -2-(c/s and frans)penten-1-yl)-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- formyl)methyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- formyl-pyrrolidine-5-carboxylic acid f-butyl ester and n-butyl- triphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 21.0 mg, 66.2%).
MS: (M+H)+= 437.
-316-
121 B (±W2R,3S.5R.1'S)-2-(1-Acetamido-2-(c/s and frat?s)penten-1-vn-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-(c/s and frat7s)penten-1-yl)-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester, ester (yield: 16.0 mg, 98.1%).
1H NMR (DMSO-d6): δ 0.93 (t, 3H), 1.62 (dd, 3H), 1.75 (m, 1 H), 1.87 (s, 3H), 2.07 (m, 2H). 2.40 (m, 1 H), 3.17 (m, 1 H), 3.50 (m, 1H), 4.34 (m, 1 H), 4.94 (m, 1 H), 5.23 (m, 1 H), 5.34 (m, 1H), 5.53 (m, 1 H), 5.58 (m, 1 H), 8.24 (d, 1H), 9.25 (br s, 2H).
MS: (M+H)+= 281.
-317- Example 122
(±)-(2R.3S.5R.1'SV2-(1-Acetamido-4-hvdroxy-2- c/s and frans)buten-1-yl)-3-tos- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TBSO
122A fcW2R.3S.5R.1'S -f-Butoxycarbonyl-2-(1-Acetamido-4-(f- butyldimethylsilyloxy)-2-(c/s and fraπs)buten-1-yl)-3-(c/s-propen-1-yl)-pyrrolidine- 5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- formyl)methyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester in place of (±)-(2R,3R,5R,1 'S)-1-f-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3- formyl-pyrrolidine-5-carboxylic acid f-butyl ester and 4-(f-butyldimethylsilyloxy)- butyltriphenylphosphonium bromide for methyltriphenylphosphonium bromide (yield: 23.1 mg, 66.9%).
MS: (M+H)+= 567.
TFA
122B fcW2R.3S.5R.1'S)-2-(1-Acetamido-4-hvdroxy-2-(c/s and frans)buten-1-yl)- 3-(c/s-propen-1-vD-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-
-318- 2-(c/s and fraπs)-4-hydroxy-butenyl-2-yl)-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 16.9 mg, >100%).
1H NMR (DMSO-d6): δ1.67 (dd, 3H), 1.78 (dt, 1H), 1.91 (s, 3H), 2.44 (m, 1H), 2.50 (m, 1H), 2.56 (m, 1H), 2.65 (m, 1H), 3.23 (m, 1H), 3.54 (m, 1H), 4.40 (m, 1 H), 4.47 (m, 2H), 5.01 (m, 1H), 5.26 (m, 1 H), 5.54 (m, 2H), 5.63 (m, 1H), 8.32 (d, 1H), 9.27 (br s, 2H).
MS: (M+H)+= 297.
Example 123
fcW2R.3S.5R,1'S)-2-f1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride
TBDPSO--
Ph
123A fcW2R.3R.5R)-1-Benzyl-2-vinyl-3-f-butyldiphenylsilyloxymethyl- Pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (30.8 g, 97.1 mmol) was reacted with t-butyldiphenylsilyl chloride (49.5 mL, 190.4 mmol) and imidazole in dichloromethane (650 mL) at 0 °C for 1 hour. The reaction was quenched methanol followed by extraction with dichloromethane (600 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column
-319- chromatography on silica gel using 2/1 : chloroform/hexane to provide the title compound (yield: 52.9 g, 98%).
1H NMR (CDCI3) 7.62-7.67 (m, 4H), 7.32-7.44 (m, 6H), 7.25-7.30 (m, 5H), 5.58-5.72 (m, 1 H), 5.06-5.14 (m, 2H), 3.90 (d, 1 H), 3.72-3.78 (m, 1 H), 3.58-3.68 (m, 2H), 3.44-3.52 (m, 2H), 2.26-2.40 (m, 1H), 2.10-2.23 (m, 1 H), 1.68-1.78 (m, 1 H), 1.38 (s, 9H), 1.03 (s, 9H).
MS: (M+H)+=556
TBDPSO-^ \ OlBu y x i
123B (±W2R.3R.5R.1'RSV1-Benzyl-2-(1.2-dihvdroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-f-butyldiphenylsilyloxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester (22.7 g, 41 mmol) was reacted with OsO4 (4%) (2.5 mL, 0.7 mol.%) and N-methyl morpholine N-oxide (18.5 g, 2.77 eq.) in acetone (500 mL) and water (60 mL) for 48h at room temperature. The reaction was quenched with 10% aqueous Na2S2O3 (200 mL). The reaction was concentrated in vacuo and the residue was partitioned between ethyl acetate/water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 35% ethyl acetate/hexane to provide the title compound (yield: 11 g, 55%).
1H NMR (DMSO-de) δ 7.58-7.63 (m, 5H), 7.40-7.48 (m, 7H), 7.20-7.35 (m, 3H), 4.41-4.45 (m, 2H), 3.98 (d, 1 H), 3.75-3.84 (m, 2H), 3.50-3.68 (m, 2H), 3.4- 3.46 (m, 1 H), 3.16-3.25 (m, 1 H), 2.97-3.0 (m, 1 H), 2.09-2.28 (m, 1 H), 1.62-1.89 (m, 1H), 1.34-1.39 (m, 1 H), 1.30 (s, 9H), .98,.96 (2s, 9H).
-320- MS: (M+H)+=590
O'Bu
123C fcW2R.3R.5R.1'RS)-2-π .2-dihvdroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R, 1 'RS)-1 -Benzyl-2-(1 ,2-dihydroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (11 g, 18.7 mmol) was reacted under 1 atmosphere of hydrogen with 20% Pd(OH)2/C (5 g ) and in ethanol (40 mL) vigorously stirred for 2.5 days at room temperature. The reaction was filtered, and the catalyst was washed with methanol (3x30 mL). The filtrate was evaporated in vacuo to give the title compound as an oil (yield: 8 g, 94%)
123D (±W2R.3R.5R.1'RV1-f-Butoxycarbonyl-2-(1.2-dihvdroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 40D, substituting (±)-(2R,3R,5R,1'RS)-2-(1,2-dihydroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R,3R,5R,1'RS)-2-(1 ,2-dihydroxy)ethyl-3-acetoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester. The residue was purified by column chromatography on silica gel using 35% ethyl acetate/hexane to provide the title compound (yield: 20.5 g, 60%).
-321- 1H NMR (DMSO-de) 7.57-7.60 (m, 4H), 7.38-7.48 (m, 6H), 4.85,4.77 (2d, 1 H), 4.45-4.50 (m, 1 H), 4.02-4.10 (m, 1 H), 3.80-3.95 (m, 1 H), 3.73,3.68 (2s, 1 H), 3.45-3.67 (m, 2H),3.18-3.28 (m, 2H), 2.36-2.46 (m, 2H), 1 ;86,1.70 (2d, 1H), 1.40,1.35 (2s, 9H),1.32,1.26 (2s, 9H), 1.0,0.98 (2s, 9H).
MS: (M+H)+= 600
123E (±W2R.3R.5R,1'R)-1-f-Butoxycarbonyl-2-(1-methanesulfonyloxy-2- acetoxy)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R,1'R)-1-f-Butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (20.5 g, 34.2 mmole) was reacted with acetic anhydride (16.1 mL, 171 mmole) and triethylamine (47.7 mL, 342 mmole) in dichloromethane (360 mL) at 0°C for 16h.
The reaction was treated with methanol (35 mL) for 10 minutes and diluted with dichloromethane (1300 mL). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was reacted with methanesulfonyl chloride (4.0 mL, 51.3 mmole) and triethylamine (14.3 mL, 103 mmole) in dichloromethane (350 mL) at 0°C for 1.5 hours. The reaction was quenched with water (300 mL) and diluted with dichloromethane (1200 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound (yield: 23.8 g, 97%).
-322- 1H NMR (DMSO-de) δ7.58-7.62 (m, 4H), 7.38-7.50 (m, 6H), 5.12-5.26 (2m, 1H), 4.06-4.25 (m, 3H), 4.00 (d, 1H), 3.46-3.68 (m, 2H), 3.20,3.18 (2s, 3H), 2.40- 2.48 (m, 1H), 2.02,1.99, (2s, 3H), 1.68-1.88 (m, 1H), 1.42,1.36 (2s, 9H), 1.31 ,1.25 (2s, 9H), 1.00,0.98 (2s, 9H).
MS: (M+H)+= 720, (M+NH4)+=737
TBDPSO— ^ .O'Bu o; π R Bnorc Q r1 '
123F (±W2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-oxiranyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-(1-methanesulfonyloxy-2- acetoxy)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (23.8 g, 33.1 mmole) was reacted with potassium carbonate (10.1 g,66.2 mmole) in methanol (160 mL) and THF (160 mL) at 25 °C for 18 hours. The reaction was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 25% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 16.7 g, 87%).
H NMR (CDCI3) δ 7.60-7.68 (m, 4H), 7.32-7.45 (m, 6H), 4.02-4.28 (m, 2H), 3.67-3.78 (m, 1H), 3.52-3.62 (m, 1 H), 3.0-3.08 (m, 1 H), 2.68-2.75 (m, 1 H), 2.47-2.52 (m, 3H), 1.80-1.90 ( , 1 H), 1.48,1.42 (2s, 9H), 1.37,1.35 (2s, 9H), 1.07,1.03 (2s, 9H).
MS: (M+H)+= 582
-323- HO--
.OlBu H B Q if
123G fcW2R.3R.5R.1 'SV1-f-Butoxycarbonyl-2-oxiranyl-3-hvdroxymethyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R,1'S)-1-f-Butoxycarbonyl-2-oxiranyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (4.17 g, 7.2 mmole) was reacted with tetrabutylammonium fluoride (1 M) (14 mL, 14.0 mmole) in THF (7 mL) for 20 minutes at 0°C then for 1.5 hours at 25°C. The reaction was concentrated in vacuo the residue was dissolved in ethyl acetate and washed with pH 7.0 buffer and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound, as an oil (yield: 2.4 g, 97%).
1H NMR (DMSO-de) δ 4.72-4.78 (m, 1 H), 3.94-4.05 (m, 2H), 3.35-3.47 (m, 1 H), 3.18-3.28 (m, 1 H), 3.03-3.08 (m, 1 H), 2.63-2.73 (m, 1 H), 2.37-2.44 (m, 1 H), 2.30-2.36 (m, 1 H), 2.08-2.20 (m, 1 H), 1.58-1.75 (m, 1 H), 1.40 (s, 9H), 1.37,1.34 (2s, 9H).
MS: (M+H)+= 344, (M+Na)+= 366
-324- o=
O'Bu
V o
123H fcV(2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.
(±)-(2R,3R,5R, 1 'S)-1 -f-Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester (2.4 g, 7.0 mmole) and triethylamine (3.9 mL 28.0 mmole) in dichloromethane (70 mL) at 0°C was reacted with sulfur trioxide pyridine complex (3.35 g, 21.0 mmole) in dimethylsulfoxide (21 mL) by dropwise addition followed by reaction for an additional 3 hours. The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo to provide the title compound (yield: 2.2 g,).
1H NMR (DMSO-de) (rotamers) δ 9.58 and 9.56 (2s, 1H), 4.70 and 4.53 (2m, 1 H), 3.96 (dd, J=1.4, 9.2 Hz, 1H), 3.25-3.20 (m, 1H), 2.91 (m, 1 H), 2.71 (m, 1H), 2.50-2.28 (m, 3H), 1.42, 1.37, 1.34, and 1.30 (4s, 18H)
MS: (M-H)" = 340
O'Bu Cf ή B Bnorc.Y Q
1231 fc)-(2R.3S,5R.1'S)-1-f-Butoxycarbonyl-2-oxiranyl-3-vinyl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.
Triphenylphosphoranylidenemethyl ylide (17.6 mmole) prepared by reacting methyltriphenylphosphonium bromide (12.63 g, 35.4 mmole) and potassium tert-butoxide (1M) (17.6 mL, 17.6 mmole) in THF (70 mL) for 1 hour at
-325- 25°C. (±)-(2R,3R,5R, 1 'S)-1 -f-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester (2.2 g, 6.5 mmole) in THF (10 mL) was added to the above solution at 0°C and stirred for 0.5 hours. The reaction was quenched with saturated ammonium chloride (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water,and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 2 g, 84%).
1H NMR (DMSO-de) δ 5.80-5.95 (m, 1H), 5.08 (d, 1 H), 4.94-5.04 (1H), 4.00-4.07 (m, 1 H), 3.59,3.90 (2t, 1 H), 3.07-3.16 (m, 1 H), 2.73-2.81 (m, 1H), 2.65- 2.72 (m, 1H), 2.35-2.48 (m, 1H), 1.59-1.76 (m, 1 H), 1.42 (s, 9H), 1.38,1.35 (2s, 9H).
MS: (M+H)+ = 340
123J fcW2R.3S.5R,rR)-1-f-Butoxycarbonyl-2-(1-methanesulfonyloxy-3- azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-oxiranyi-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (1.72 g, 5.1 mmole) and ammonium chloride (1.36 g, 25.4 mmole) in ethanol (45 mL) and water (5 mL) was reacted with lithium azide (1.2 g, 24.5 mmole) for 7 hours at 50°C. The reaction was concentrated in vacuo and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue (2.15 g) was dissolved in dichloromethane (50 mL) and reacted with
-326- methanesulfonyl chloride (0.8 mL, 10.2 mmole) and triethylamine (2.8 mL, 20.4 mmole) for 0.5 hours at 0°C. The reaction was quenched with aqueous sodium bicarbonate (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 1.87 g, 80%).
1H NMR (DMSO-de) δ 5.77-5.98 (m, 1 H), 4.94-5.11 (m, 3H), 4.12-4.19 (m, 1H), 3.99-4.06 (m, 1 H), 3.66,3.71 (2d, 1 H), 3.25,3.22 (2s, 3H), 2.92-3.02 (m, 1H), 2.55-2.63 (m, 1 H), 1.68-1.82 (m. 1 H), 1.45,1.42 (2s, 9H), 1.38,1.36 (2s, 9H).
MS: (M+H)+= 461
OΕu H Y
123K (±W2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-methanesulfonyloxy-3- azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (2.12 g, 4.6 mmole) was reacted with triphenylphosphine (1.81 g, 6.9 mmole) in THF (30 mL) and water (7.5 mL) at 65°C for 1 hour. The reaction was concentrated in vacuo and redissolved in ethyl acetate (200 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 4% methanol in dichloromethane to provide 2 g of the crude title compound containing approximately 60% product and 40% Ph3PO which was used directly for acylation.
-327- 1H NMR (DMSO-de) δ 5.78-5.5.98 (m, 1 H), 4.12 (d, 1H), 3.42,3.19 (2d, 1 H), 2.53-2.73 (m, 2H), 2.00-2.15 (m, 1H), 1.68-1.76 (m, 1H), 1.62-1.68 (m, 1H), 1.41 (s, 9H), 1.37,1.36 (2s, 9H).
MS: (M+H)+ = 339, (M+Na)+ = 361
.O'Bu
AcN'^ H Y
123L fcW2R.3S.5R.1'SV1-f-Butoxycarbonyl-2-(N-acetylaziridinvn-3-vinyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (1.03 g, 3.1 mmole) was reacted with acetic anhydride (.42 mL, 4.7 mmole) and triethylamine (1.3 mL, 9.3 mmole) in dichloromethane (30 mL) at 25°C for 1 hours. The reaction was quenched with water (50 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 20% ethyl acetate/hexanes to provide the title compound (yield: .75 g, 64%).
1H NMR (DMSO-de) δ 5.78-5.98 (m, 1 H), 5.05 (d, 1 H), 4.98,4.94 (2d, 1H), 4.12-4.20 (m, 1 H), 3.54,3.42 (2dd, 1H), 2.54-2.98 (m, 3H), 2.40,2.49 (2d, 1H), 2.15,2.19 (2d, 1H), 2.02,2.04 (2s, 3H), 1.68-1.82 (m, 1H), 1.42 (s, 9H), 1.48.1.45 (2s, 9H).
MS: (2M+Na)+= 783
-328-
123M (±)-(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a suspension of copper(l) bromide-dimethyl sulfide complex (0.051g, 0.248 mmol) in THF (1.0 ml) at 0 °C was added ethylmagnesium bromide (1M) (1.0 ml, 1.0 mmol) in THF. After stirring for 10 minutes at 0 °C, a portion of this solution (0.60 ml) was added dropwise to a solution of (±)-(2R,3S,5R,1'S)-1-f- Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.020 g, 0.053 mmole) in THF (0.40 ml) at -78°C. After stirring for 20 minutes at -78°C, the reaction was warmed to 0 °C and stirred for 30 minutes. The reaction was quenched with saturated ammonium chloride (1.0 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-75% ethyl acetate/hexanes to provide the title compound (yield: 0.004 g, 19%).
1H NMR (DMSO-de) (rotamers) δ 7.48 (d, J=9.5Hz, 1 H), 5.98-5.80 (m, 1H), 5.00-4.90 (m, 2H), 4.45-4.25 (m, 1 H), 3.96-3.91 (m, 1 H), 3.60-3.57 and 3.53-3.50 (2m, 1H), 2.91-2.76 (m, 1H), 2.59-2.42 (m, 1 H), 1.80 (s, 3H), 1.73-1.59 (m, 1H), 1.42 and 1.41 (2s, 9H), 1.40-1.15 (m, 4H), 1.37 and 1.34 (2s, 9H), 0.89-0.82 (m, 3H)
MS: (M-H)" = 409, (M+H)+ = 411
-329- χ0H if o
HCl
123N fcV(2R.3S.5R.1 'S -2-(1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1- acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3R,5R, 1 'S)-2-(1 -acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 3.1 mg, 99%).
1H NMR (DMSO-de) δ 8.11 (d, J=7.3Hz, 1H), 5.76-5.69 (m, 1 H), 5.16 (d, J=17.1 Hz, 1 H), 5.07 (dd, J=1.5, 10.3Hz, 1H), 4.30 (dd, J=7.3, 9.8Hz, 1 H), 4.13 (m, 1 H), 3.50 (dd, J=5.9, 9.8Hz, 1 H), 2.90 (m, 1H), 2.39 (m, 1H), 1.92-1.85 (m, 1 H), 1.87 (s, 3H), 1.52-1.18 (m, 4H), 0.85 (t, J=7.3, 3H)
MS: (M-H)"= 253, (M+H)+ = 255
Examples 124-130
1. Organocuprate
O'Bu OH
2. 6N HCl
AcN { Y
O
HCl
The following title compounds were prepared in two steps according to the methods described in Examples 123M and 123N, the denoted reagents and their
-330- respective methods of preparation are substituted in place of diethylcuprate and its preparation in Example 123M for step 1.
Example 124
HCl
(±)-(2R.3S.5R.1'SV2-(1-Acetamido)hexyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 2M butylmagnesium chloride for 1M ethylmagnesium bromide.
1H NMR (MeOD-d3) δ 5.82-5.70 (m, 1H), 5.29 (d, J=17.0Hz, 1 H), 5.17 (dd, J=1.3, 10.2Hz, 1 H), 4.35 (dd, J=7.5, 10.2Hz, 1H), 4.19 (m, 1 H), 3.65 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H), 1.62-1.31 (m, 8H), 0.91 (t, J=6.4Hz, 3H)
MS: (M-H)" = 281, (M+H)+ = 283
-331- Example 125
fcW2R.3S.5R.1'S)-2-(1-Acetamido-4-methvnpentyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substitufing iso-butylmagnesium chloride for ethylmagnesium bromide..
1H NMR (MeOD-d3) δ 5.83-5.71 (m, 1H), 5.29 (dd, J=0.7,17.0Hz, 1H), 5.17 (dd, J=0.7, 10.2Hz, 1H), 4.34 (dd, J=7.5, 10.2Hz, 1H), 4.15 (m, 1H), 3.66 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.55 (m, 1 H), 2.08-1.97 (m, 1 H), 2.04 (s, 3H), 1.65-1.10 (m, 5H), 0.91 (d, J=6.4Hz, 3H), 0.91 (d, J=6.5Hz, 3H)
(M+H)+ = 283
-332- Example 126
fcW2R.3S.5R.1'S)-2-(1-Acetamido-3.3dimethvnbutyl-3-vinyl-Pyrrolidine-5- carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 1M tert-butyimagnesium chloride for 1M ethylmagnesium bromide.
1H NMR (MeOD-d3) δ 5.84-5.71 (m, 1H), 5.31 (d, J=17.0Hz, 1H), 5.19 (d, J=10.2Hz, 1 H), 4.39-4.33 (m, 2H), 3.66 (dd, J=3.4, 9.8Hz, 1 H), 3.02 (m, 1 H), 2.57 (m, 1H), 2.08-1.97 (m, 1H), 2.02 (s, 3H), 1.55 (dd, J=9.5, 14.6Hz, 1H), 1.42 (dd, J=1.4, 14.6Hz, 1H), 0.95 (s, 9H)
(M+H)+ = 283
-333- Example 127
fcW2R.3S.5R.1 'S)-2-(1-Acetamido-2-phenyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt
Lithium diphenylcurpate was prepared according to the method described by Lipshutz, B. H. in Orqanometallics in Synthesis: Schlosser, M., Ed.; Wiley and Sons: New York, 1994; p.292. This cuprate was used according to the methods described in Example 123M, substituting lithium diphenylcuprate for the Grignard derived diethylcuprate complex.
1H NMR (MeOD-d3) δ 7.35-7.21 (m, 5H), 5.87-5.75 (m, 1H), 5.37 (d, J=16.6Hz, 1 H), 5.26 (dd, J=1.0, 10.2Hz, 1H), 4.53 (m, 1 H), 4.37 (dd, J=7.5, 9.8Hz, 1 H), 3.70 (dd, J=3.7, 9.8Hz, 1H), 3.11 (m, 1H), 2.97 (dd, J=6.1 , 14.2Hz, 1H), 2.84 (dd, J=9.5, 14.2Hz, 1H), 2.59 (m, 1 H), 2.08-1.99 (m, 1 H), 1.93 (s, 3H)
(M-H)"= 301, (M+H)+= 303
-334- Example 128
X / 0H o if
fcW2R.3S.5R,1'S 2-(1-Acetamido-4-phenvnbutyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 1M phenethylmagnesium chloride for 1 M ethylmagnesium bromide.
1H NMR (MeOD-d3) δ 7.29-7.13 (m, 5H), 5.77-5.65 (m, 1 H), 5.24 (d, J=16.6Hz, 1 H), 5.13 (dd, J=1.0, 9.8Hz, 1 H), 4.33 (dd, J=7.5, 10.2Hz, 1 H), 4.22 (m, 1 H), 3.62 (dd, J=3.4, 9.8Hz, 1H), 2.98 (m, 1H), 2.63 (m, 2H), 2.54 (m, 1 H), 2.06-1.95 (m, 1H), 2.03 (s, 3H), 1.79-1.55 (m, 4H)
(M-H)"= 329, (M+H)+ = 331
-335- Example 129
(±)-(2R.3S.5R.1'S)-2-π-Acetamido-3-phenyl)butyl-3-vinyl-Pyrrolidine-5-carboxylic Acid Hydrochloric Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 123M, substituting 2M benzylmagnesium chloride for 1M ethylmagnesium bromide.
1H NMR (MeOD-d3) δ 7.30-7.17 (m, 5H), 5.82-5.70 (m, 1H), 5.28 (d, J=17.0Hz, 1H), 5.17 (d, J=11.2Hz, 1H), 4.33 (dd, J=7.5, 10.2Hz, 1H), 4.18 (m, 1H), 3.64 (dd, J=3.4, 9.8Hz, 1 H), 3.01 (m, 1 H), 2.78 (m, 1 H), 2.66-2.50 (m, 2H), 2.07 (s, 3H), 2.07-1.85 (m, 3H)
(M-H)"= 315, (M+H)+ = 317
-336- Example 130
fcW2R,3S.5R.1'SV2-(1-Acetamido-2-propen-2-vnethyl -3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
.O'Bu
BocN'^i H Y
130A fcW2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(N-f-Butoxycarbonylaziridinvn-3- vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (0.058 g, 0.17 mmole) was reacted with di-f- butyldicarbonate (95 mg, 0.44 mmole) and triethylamine (0.12 mL, 0.86 mmole) in dichloromethane (2.0 mL) at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate (1.0 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-15% ethyl acetate/dichloromethane to provide the title compound (yield: 0.060 g, 80%).
1H NMR (DMSO-de) (rotamers) δ 5.97-5.78 (m, 1 H), 5.06-4.93 (m, 2H), 4.15 (dd, J=2.0, 9.8Hz, 1 H), 3.40-3.28 (m, 1H), 2.94-2.49 (m, 3H), 2.39 and 2.33 (2d, J=6.1 , 6.4Hz, 1H), 2.17 and 2.11 (2d, J=3.7, 3.4, 1 H), 1.81-1.69 (m, 1H), 1.42-1.36 (m, 27H)
MS: (M+Na)+= 461 (weak)
-337-
130B fcV(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylamino-2- propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a suspension of copper(l) bromide-dimethyl sulfide complex (0.026g, 0.127 mmol) in THF (1.0 ml) at 0 °C was added isopropenylmagnesium bromide (0.5M) (1.0 ml, 0.50 mmol) in THF. After stirring for 10 minutes at 0 °C, the mixture was cooled to -78 °C and a solution of (±)-(2R,3S,5R,1'S)-1-f- butoxycarbonyl-2-(N-f-butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.030 g, 0.068 mmole) in THF (1.0 ml) was added dropwise. After stirring for 10 minutes at -78°C, the reaction was warmed to 0 °C and stirred for 2 hours. The reaction was quenched with saturated ammonium chloride (1.0 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-10% ethyl acetate/dichloromethane to provide the title compound (yield: 0.026 g, 79%).
1H NMR (DMSO-de) (rotamers) δ 6.64 (m, 1H), 5.96-5.76 (m, 1 H), 4.98- 4.89 (m, 2H), 4.76-4.68 (m, 2H), 4.40-4.25 (m, 1 H), 3.94 (m, 1 H), 3.60-3.53 (m, 1H), 3.02-2.86 (m, 1 H), 2.62-2.42 (m, 1 H), 2.10-1.99 (m, 2H), 1.72 and 1.70 (2s, 3H), 1.72-1.55 (m, 1H), 1.44-1.34 (m, 27H)
MS: (M-H)" = 479, (M+H)+ = 481
-338-
130C fc)-(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-π-N-f-butoxycarbonylacetamido- 2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylamino-2- propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.024 g, 0.050 mmole) was reacted with lithium hexamethyidisilazide (1 M) (0.60 mL, 0.60 mmole) in THF (2.0 mL) at -25°C for 1 hour. To the above reacfion was then added acetyl chloride (0.085 mL, 1.20 mmole) at -25°C and the mixture was stirred for 30 minutes. The reacfion was quenched with saturated sodium bicarbonate (2.0 mL) and stirred for 30 minutes at room temperature. The reaction was diluted with ethyl acetate (20 mL). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using a gradient of 0-15% ethyl acetate/hexanes to provide the title compound (yield: 0.015 g, 58%) along with unreacted starting material.
1H NMR (DMSO-de) (rotamers) δ 6.01-5.84 (m, 1 H), 4.99-4.89 (m, 2H), 4.76-4.58 (m, 3H), 4.33 and 4.23 (2d, J=7.8, 8.1Hz, 1 H), 4.13-4.04 (m, 1 H), 2.69 (m, 1 H), 2.62-2.42 (m, 1H), 2.29 (br s, 3H), 2.35-2.14 (m, 2H), 1.76-1.55 (m, 1H), 1.60 (s, 3H), 1.50-1.35 (m, 27H)
MS: (M+H)+= 523
-339- κOH o if
130D (±W2R.3S.5R.1 'S)-2-(1-Acetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1 'S)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-propen-2-yl)ethyl -3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester, (yield: 12 mg, 99%).
1H NMR (MeOD-d3) δ 5.83-5.70 (m, 1 H), 5.30 (dd, J=0.7, 17.0Hz, 1 H), 5.19 (d, J=10.2Hz, 1 H), 4.79 (s, 1 H), 4.71 (s, 1 H), 4.46 (m, 1 H), 4.30 (dd, J=7.8, 9.8Hz, 1 H), 3.66 (dd, J=3.7, 9.8Hz, 1 H), 3.03 (m, 1 H), 2.56 (m, 1 H), 2.40-2.19 (m, 2H), 2.08-1.96 (m, 1 H), 2.01 (s, 3H), 1.76 (s, 3H)
(M-H)"= 265, (M+H)+ = 267
Examples 131-135
1. Organocuprate
OΕu ■*• /OH
2. LiHMDS
BOCHN: ϊ 3. AcCI if
O O
4 TFA/CH2CI2
TFA
The following title compounds were prepared in 4 steps according to the methods described in Example 130 the denoted reagents for step 1 and their
-340- respective methods of preparation are substituted in place of isopropenyl cuprate and its preparation in 130B
Example 131
TFA
fcW2R.3S.5R.1'S)-2-(1-Acetamido-1-(c/s and fransW)ropen-1-vDethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substitufing 0.5M 1-propenylmagnesium bromide (mixture of cis and trans isomers) for 0.5M isopropenylmagnesium bromide.
1H NMR (MeOD-d3) (2:1 trans is ratio) δ 5.81-5.54 (m, 2H), 5.43-5.30 (m, 1H), 5.33-5.27 (m, 0.33H, cis isomer), 5.31-5.25 (m, 0.66H, trans isomer), 5.20- 5.15 (m, 1H), 4.26-4.17 (m, 2H), 3.65 (dd, J=3.4, 9.8Hz, 1H), 2.98 (m, 1H), 2.58- 2.48 (m, 1 H), 2.45-2.19 (m, 2H), 2.08-1.94 (m, 1 H), 2.02 (s, 3H), 1.68 (m, 2H, trans isomer), 1.63 (m, 1H, cis isomer)
(M-H)"= 265, (M+H)+ = 267
-341- Example 132
ACHN. AΪ .OH
JJ" TFA ϊ
fc)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-allvπmethyl-3-vinvi-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substitufing 1M vinylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
1H NMR (MeOD-d3) δ 5.83-5.70 (m, 2H), 5.28 (d, J=17.0Hz, 1 H), 5.19-5.13 (m, 3H), 4.28 (m, 1H), 4.19 (dd, J=8.5, 9.1 Hz, 1 H), 3.66 (dd, J=3.4, 9.5Hz, 1H), 2.99 (m, 1H), 2.57-2.48 (m, 1H), 2.44-2.26 (m, 2H), 2.05-1.93 (m, 1 H), 2.01 (s, 3H)
(M+H)+ = 253
-342- Example 133
(±)-(2R.3S.5R.1'SV2-(1-Acetamido)-2-(1-buten-2-vnethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substitufing 0.5M 1-buten-2-ylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
H NMR (MeOD-d3) δ 5.81-5.73 (m, 1H), 5.30 (d, J=17.1 Hz, 1 H), 5.19 (d, J=10.0Hz, 1H), 4.93 (s, 1H), 4.83 (s, 1H), 4.45 (m, 1H), 4.31 (dd, J-7.6, 9.8Hz, 1 H), 3.69 (dd, J=3.2, 9.8Hz, 1 H), 3.03 (m, 1H), 2.59-2.53 (m, 1H), 2.38 (dd, J=5.9, 14.9Hz, 1 H), 2.30 (dd, J=9.5, 14.9Hz, 1H), 2.07 (q, J=7.6Hz, 2H), 2.05- 1.99 (m, 1 H), 2.01 (s, 3H), 1.05 (t, J=7.6Hz, 3H)
(M+H)+ = 281
-343- Example 134
fc)-(2R.3S.5R.1'SV2-π-Acetamido-2-(frans-2-buten-2-vnethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substituting 0.5M 1-methyl-1- propenylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
1H NMR (MeOD-d3) δ 5.83-5.71 (m, 1H), 5.41 (q, J=6.8Hz, 1H), 5.31 (d, J=17.3Hz, 1H), 5.19 (d, J=10.2Hz, 1H), 4.42 (m, 1H), 4.31 (dd, J=7.5, 9.8Hz, 1H), 3.61 (dd, J=4.0, 9.8Hz, 1 H), 3.01 (m, 1H), 2.62-2.52 (m, 1 H), 2.46 (dd, J=9.5, 13.9Hz, 1H), 2.26 (dd, J=5.8, 13.9Hz, 1 H), 2.09-1.99 (m, 1 H), 2.00 (s, 3H), 1.72 (s, 3H), 1.59 (d, J=6.8Hz, 3H)
(M+H)+ = 281
-344- Example 135
OH if o
fcW2R.3S,5R.1 'S.3'RSV2-π-Acetamido-3-methvnpentyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
The organocuprate reagent was prepared from a Grignard reagent and a catalytic quantity of copper(l) bromide-dimethyl sulfide complex according to the methods described in Example 130B, substituting 2M sec-butylmagnesium bromide for 0.5M isopropenylmagnesium bromide.
1H NMR (MeOD-d3) (1 :1 mixture of methyl isomers) δ 5.82-5.69 (m, 1H), 5.27 (d, J=17.0Hz, 0.5H), 5.25 (d, J=17.0Hz, 0.5H), 5.15 (d, J=10.2Hz, 1H), 4.33 (m, 1H), 4.18 (dd, J=2.7, 7.5Hz, 0.5H), 4.15 (dd, J=3.0, 7.8Hz, 0.5H), 3.62 (dd, J=3.1 , 9.8Hz, 0.5H), 3.57 (dd, J=4.07, 9.8Hz, 0.5H), 2.97 (m, 1H), 2.57-2.47 (m, 1 H), 2.03-1.92 (m, 1H), 2.03 (s, 1.5H), 2.02 (s, 1.5H), 1.72-1.06 (m, 5H), 0.95- 0.86 (m, 6H)
(M+H)+ = 283
-345- Example 136
fc)-(2R.3S.5R.1'RSV2-n-Acetamido-1-(N-methyl-N-benzylcarbamovnmethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
AcHN. ^X X .OtBu
HO J r a,. {
136A fcW2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-(1-acetamido-1-carboxyl)methyl- 3-vinyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method of Example 2B substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido-1- formyl)methyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester for (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5- carboxylic acid t-butyl ester.
136B (±W2R.3S.5R.1 'RSV-1 -f-Butoxycarbonyl-2-(1 -acetamido-2-(N-methyl-N- benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-1-carboxyl)methyl- 3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester (36 mg, 0.09 mmole) was reacted with N-methyl-N-benzylamine (32 mg, 0.26 mmole), dimethylaminopyridine (1mg, 0.008 mmole) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (30mg, 0.16mmole) in DMF (3 mL) at 25°C for 16 hours. The reaction was quenched with water (3 mL) and diluted with ethyl
-346- acetate ( 20mL). The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound.
MS: (M+H)+=516, (M-H)" =514
AcHN^X X .OH vr l^ψ TFA ^
Ph
136C fcW2R.3S.5R.1 'RS)-2-(1 -Acetamido- 1 -f N-methyl-N- benzylcarbamov0methyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'RS)-1-f-butoxycarbonyl-2-(1- acetamido-2-(N-methyl-N-benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester (yield: 7 mg, 95%).
1H NMR (DMSO-de) δ 8.52( d, J=9.7HZ, 1H), 7.30( m, 5H), 5.65( m, 1H), 5.12(m, 4H), 4.62(m, 1 H), 4.40(m, 2H), 3.70(m, 1 H), 2.90(s, 3H), 2.20(m, 2H), 1.96(s, 3H),
MS: (M+H)+ =360, (M+23)+ =382
-347- Example 138
fc)-(2R.3S.5R.1'R)-2-π-Acetamido-2-(N-phenyl-carbonyloxy)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
138A fcW2R.3S.5R.1'R -1-f-Butoxycarbonyl-2-(1-acetamido-2-N-phenyl- carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3- vinyl-pyrrolidine-5-carboxylic acid f-butyl ester (18 mg, 0.045 mmole) was reacted with phenylisocyanate (16 mg, 0.14 mmole) and pyridine(0.1 ml) in THF (3 mL) at 25°C for 16 hours. The reacfion was quenched with water (2 mL) and diluted with ethyl acetate (10 mL). The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 50% ethyl acetate/hexanes to provide the title compound (yield:7.5 mg, 33%).
MS: (M+H)+=518, (M-H)" =516
-348-
138B (±W2R.3S.5R.1 'R)-2-(1 -Acetamido-1 -(N-phenylcarbonyloxy)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-N-phenyl-carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4 mg, 95%).
1H NMR (DMSO-de) d 8.36( d, J=9.7HZ, 1 H), 7.30(m, 5H), 5.78(m, 1 H), 5.22(m, 1H), 5.10(m, 1H), 4.58(m, 1H), 4.45(m, 1 H), 4.14(, 2H), 3.58(m, 1H), 2.88( m, 1H), 2.27(m, 1 H), 2.12(m, 1H), 1.88(s, 3H)
MS: (M+H)+=362, (M+23)+ =384, (M-H)" =360, (M+35)" =396
-349- Example 139
(±)-(2R.3S.5R.1'R)-2-(1-Acetamido-1-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
139A fcW2R.3S.5R.rR)-1-f-Butoxycarbonyl-2-π-acetamido-2- isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R, 1 'R)-1 -f-Butoxycarbonyl-2-(1 -acetamido-2-hydroxy)ethyl-3- vinyl-pyrrolidine-5-carboxylic acid f-butyl ester (15 mg, 0.04 mmole) was reacted with isobutyryl chloride (8 mg, 0.08 mmole) and triethylamine (8 mg, 0.08 mmole) in dichloromethane (4 mL) at 0°C for 2 hours. The reacfion was quenched with water (3 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 30% ethyl acetate/hexanes to provide the title compound (yield: 11 mg, 63%).
MS: (M+H)+=469, (M-H)" =467
-350-
139B (±)-(2R.3S.5R.1'RV2-(1-Acetamido-1-isobutyryloxy)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6.0 mg, 96%).
1H NMR (DMSO-de) δ 8.00( d, J=9.9HZ, 1 H), 5.63(m, 1H), 5.08(m, 1H), 4.98(m, 1H), 4.35(m, 1 H), 4.25(m, 1H), 4.08(m, 1H), 3.55(m, 1 H), 3.45(m, 1H), 3.38(m, 1H), 2.83(m, 1 H), 2.33(m, 1 H), 1.78(s, 3H)
MS: (M+H)+ =243, (M+23)+ =265, (M-H)" =241
-351- Example 140
(±)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
XBu
O O a ϋ y s N" H ^
140A fcW2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-N-ethyl- thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3- vinyl-pyrrolidine-5-carboxylic acid f-butyl ester (17 mg, 0.04 mmole) was reacted with ethylisothiocyanate ( 19 mg, 0.21 mmole) in pyridine (2 mL) at 70°C for 17 hours. The reaction was quenched with water (3 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water, and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 70% ethyl acetate/hexanes to provide the title compound (yield: 10 mg, 48%).
MS: (M+H)+=486, (M+23)+ =508, (M-H)" = 485
-352-
140B fc)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxyiic acid f- butyl ester in place of (±)-(2R,3S,5R,1 'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester (yield: 7 mg, 94%).
1H NMR (DMSO-de) δ8.30(d, J=9.7HZ, 1 H), 5.78 (m, 1 H), 5.25(m, 1H), 5.12(m, 1H), 4.50(m, 1H),4.33(m, 1H), 4.18(m, 2H), 3.72(m, 1H), 3.55(m, 2H), 2.30(m, 1H), 2.10(m, 1H), 1.82(s, 3H), 1.17(m, 3H)
MS: (M+H)+ =330, (M-H)" =328
-353- Example 141
fc)-(2R.3S.5R.1 'SV2-(1-Acetamido-2-amino)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid HvdrochlorideSalt
AcHN. \ O'Bu ^ Boc
BocHN' O
141 A fcW2R.3S.5R.1'SV1-f-Butoxycarbonyl-2-(1-acetamido-2-f- butoxycarbonylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-azido)ethyl-3-vinyl- pyrrolidine-5-carboxylic acid t-butyl ester (9.5 mg, 0.022 mmole) was reacted with triphenylphosphine (23.5 mg, 0.090 mmole) in ethanol (180 μL) and water (45 μL) at 70°C for 30 minutes. The reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane (220 μL) and to it was added di-fert- butyl dicarbonate (7.3 mg, 0.034 mmol) and N,N-diisopropylethylamine (11.7 mL, 0.067 mmol) at 25°C. After 1 hour the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethane/ethyl acetate to provide the title compound (yield: 7.5 mg, 67%).
1H NMR (DMSO-de) (rotamers) δ 7.51 (d, J=10.5Hz, 1 H), 6.80-6.66(m, 1H), 5.90-5.76(m, 1 H), 5.02-4.90(m, 2H), 4.38-4.19(m, 1 H), 3.98-3.94(m, 1 H), 3.68- 3.62(m, 1H), 3.09-2.73(m, 2H), 2.60-2.42(m, 1 H), 1.80(s, 3H), 1.72-1.62(m, 1H), 1.42-1.34(m, 27H).
MS: (M+H)+=498, (M+Na)+=520, (M-H)"=496, (M+CI)"=532
-354- O
141 B (±W2R.3S,5R.1'S)-2-(1-Acetamido-2-amino)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid DiHvdrochloride
The title compound was prepared according to the method described in Example 1K, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-f-butoxycarbonylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)(2R,3R,5R, 1'S)-2-(1 -acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 3.65 mg, 99%).
1H NMR (DMSO-de) δ 8.24(d, J=7.9Hz, 1 H), 5.75-5.68(m, 1 H), 5.16(d, J=17.1Hz, 1H), 5.06(d, J=10.4Hz, 1H), 4.37-4.27(m, 2H), 3.60-3.16(m, 2H), 3.00- 2.88(m, 2H), 2.46-2.36(m, 1 H), 1.91-1.81(m, 1 H), 1.86(s, 3H).
MS: (M+H)+=242, (M+Na)+=264, (M-H)"=240, (2M-H)"=481
-355- Example 142
fcW2R.3S.5R.1'SV2-π-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloride
AcHN. 1 \ O'Bu H „ B Aoc
AcHN O
142A fcW2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-acetamido)ethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-amino)ethyl-3- vinyl-pyrrolidine-5-carboxylic acid f-butyl ester (9.4 mg, 0.024 mmole) was reacted with acetic anhydride (11.2 μL) and triethylamine (33.1 μL) in dichloromethane (0.23 mL) at 0°C for 1 hour. The reaction was diluted with water (3 mL), extracted with ethyl acetate (12 mL), washed with brine, dried over MgSO , and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% ethyl acetate to 90% ethyl acetate/methanol to provide the title compound (yield: 6.8mg, 66%).
1H NMR (DMSO-de) (rotamers) δ 7.79-7.74(m, 1H), 7.54(d, J=9.8Hz, 1H), 5.97-5.81 (m, 1 H), 5.01-4.91 (m, 2H), 4.36-4.27(m, 1H), 3.97-3.90(m, 1H), 3.68- 3.63(m, 1H), 3.21-3.15(m, 1 H), 3.10-2.76(m, 1 H), 2.88-2.78(m, 1H), 2.58-2.45(m, 1H), 1.81(s, 3H), 1.78(s, 3H), 1.76-1.64(m, 1H), 1.42-1.36(m, 18H).
MS: (M+H)+=439, (M+Na)+=462, (M-H)"=438, (M+35)"=474
-356- /OH if
AcHN O
HCl
142B fc)-(2R.3S,5R.1'SV2-(1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloride
The title compound was prepared according to the method described in Example 1 K, substitufing (±)-(2R,3S,5R,1'S)-2-(1 ,2-di-acetamido)butyl-3-vinyl- pyrrolidine-5-carboxylic acid Hydrochloridesalt in place of (±)(2R,3R,5R,1'S)-2-(1- acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 3.30 mg, 80%).
MS: (M+H)+=284, (M-H)"=282, (M+CI)"=318
Example 143
fcW2R.3S.5R.1'SV2- i-Acetamido-2-azido)ethyl-3-vinyl-Pyrrolidine-5-carboxylic Acid Hydrochloride
143A (±)-f2R.3S.5R.1'S 1-f-Butoxycarbonyl-2-(1-N-acetamido-2-azido)ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (21.6 mg, 0.064 mmole) was reacted with sodium azide (41.6 mg, 0.64 mmole) and ammoniun chloride (34.2 mg, 0.64 mmol) in
-357- ethanol (270 μL) and water (30 μL) at 75°C for 1 hour. The ethanol was then removed in vacuo and the remaining aqueous was extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO , and concentrated in vacuo (crude yield: 20mg, 82%). To the crude mixture was added acetic anhydride (31 μL, 0.33 mmol) and triethylamine (92 μL, 0.66 mmol) in dichloromethane (330 μL) at 0°C for 30 minutes. The reaction mixture was then concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethane/ethyl acetate to provide the title compound (yield: 10 mg, 60%).
1H NMR (DMSO-d6)(rotamers) δ 7.85 and 7.81 (d, J=9.5Hz and 9.8Hz, 1H), 5.94-5.80(m, 1 H), 5.04-4.93(m, 2H), 4.58-4.38(m, 1 H), 4.04-3.96(m, 1H), 3.72-3.66(m, 1H), 3.41-3.21 (m, 2H), 3.09-2.79(m, 1H), 2.59-2.46(m, 1H), 1.84- 1.82(m, 3H), 1.79-1.53(m, 1H), 1.43-1.35(m, 18H).
MS: (M+H)+=424, (M+Na)+=446, (2M+Na)+=869, (M-H)"=422, (M+CI)"=458
AcHN.X^ y OH uj yϊw { °
HCl
143B fcW2R.3S.5R.1'S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloric Salt
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 2.94 mg, 93%).
-358- 1H NMR (DMSO-d6) δ 8.24(d, J=8.55Hz, 1 H), 5.74-5.67(m, 1 H), 5.14(d, J=17.1Hz, 1 H), 5.06(d, J=10.4Hz, 1H), 4.41-4.35(m, 2H), 3.57-3.36(m, 3H), 2.93- 2.90(m, 1H), 2.44-2.38(m, 1H), 1.96-1.84(m, 1 H), 1.84(s, 3H).
MS: (M+H)+=268, (M-H)"=266, (M+CI)"=302
Example 144
fcW2R.3S,5R.1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Dihydrochloride
o'Bu n ϋ
CH3
144A (±W2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-N-acetamido-2-N- methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
Methylamine (.016 g, .53 mmole) was reacted with N,O-bis- trimethylsilylacetamide (.079 g, .39 mmole) in DMSO (0.8 mL) at 0°C for 1 hour. (±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5- carboxylic acid t-butyl ester (.040 g, .11 mmole) was then reacted with the above reagent N-trimethyisilyimethylamine at 75°C for 18 hours. The reaction was diluted with ethyl acetate (7 mL) washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using chloroform-methanol-ammonia to provide the title compound (yield: .011 g, 25%).
-359- 1H NMR (CDCI3) δ 5.78-5.98 (m,1H), 5.90-5.04 (2m, 2H), 4.40-4.55 (brm, 1H), 3.90-4.02 (m, 1 H), 3.64-3.75 (2m, 1 H), 2.25-2.40 (brm 3H), 2.83,2.85 (2d, 3H), 1.42,1.44 (2s, 9H), 1.34,1.37 (2s, 9H).
MS: (M+H)+= 412
144B fcW2R.3S.5R.1'S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
The title compound was prepared according to the method described in Example 1K, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine- 5-carboxylic acid f-butyl ester (yield: 7.2 mg, 99%).
1H NMR (DMSO-de) δ 8.25 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.50 (m,1 H), 4.40 (m,1H), 2.55 (s, 3H), 1.85 (s, 3H).
MS: (M+H)+= 256
-360- Examples 145-164
1 RR'NH , ,
O'Bu „ „„ „„, - AcHN. OH 2 6N HCI T ~N
ACN TH goc i J H ! 0C O R'RNT O
2 HCl
The following title compounds were prepared according to the methods described in Examples 141-144 where R' is equal to hydrogen. Where R or R' are not equal to hydrogen the corresponding amine is used directly without the intermediacy of trimethylsilylation.
Example 145
fcW2R.3S.5R.1'S)-2-π-Acetamido-2-N-isopropylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Pi hydrochloride Salt
H NMR (DMSO-de) δ 8.30 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.40 (br, 2H), 3.52-3.68 (br, 1 H), 3.10-3.20 (br, 1 H), 2.82-2.97 (br, 1H), 2.37-2.47 (br, 1H), 1.88 (s, 3H), 1.25 (d, 6H).
MS: (M+H)+= 284
-361- Example 146
/OH if
HN
2HCI
(±)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-N-butylamino)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihydrochloride Salt
1H NMR (DMSO-d6) δ 8.25 (d, 1 H), 5.70 (m, 1 H), 5.10 (m, 2H),4.50 (m, 1H), 4.38 (m, 1 H), 3.60 (m, 1H), 2.90 (m, 3H), 2.40 (m, 2H), 1.87 (s, 3H), 1.62 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H).
MS: (M+H)+= 298
Example 147
(±W2R.3S,5R.1'S)-2-(1-Acetamido-2-N-benzylamino)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloridesalt
1H NMR (DMSO-de) δ 7.56-7.43(m, 5H), 5.74-5.67(m, 1 H), 5.15-4.99(m, 2H), 4.56(m, 1 H), 4.27-3.93(m, 3H), 3.66-3.15(m, 3H), 2.91-2.88(m, 1 H), 2.64- 2.34(m, 2H), 1.86(s, 3H).
MS: (M+H)+=332, (M+Na)+=354, (M-H)"=330, (2M-H)"=661
-362- Example 148
fcV(2R.3S.5R.1'SV2-(1-Acetamido-2-N-phenethylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.25 (d, 1H), 7.30 (m, 5H), 5.70 (m, 1 H), 5.10 (m, 2H), 4.50 (br, 1 H), 4.35 (br, 1 H), 3.61 (m, 1 H), 3.17 (m, 3H), 2.98 (m, 3H), 2.42 (m, 1 H), 1.88 (s, 3H).
MS: (M+H)+= 346
Example 149
(±W2R.3S.5R.1'S)-2-π-Acetamido-2-N.N-dimethylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.34(d, J=9.2Hz, 1 H), 5.74-5.67(m, 1H), 5.12(d, J=17.1Hz, 1 H), 5.04(d, J=10.4Hz, 1 H), 4.67-4.62(m, 1H), 4.40(dd, J=7.3, 10.4Hz, 1 H), 3.60-3.11 (m, 3H), 2.96-2.83(m, 1 H), 2.50(s, 6H), 2.44-2.38(m, 1 H), 1.92- 1.84(m, 1 H), 1.84(s, 3H).
-363- MS: (M+H)+=270, (M+Na)+=292, (M-H)"=268.
Example 150
AcHN.. ^X X /OH
H K
-N I ' 2HCI °
fc)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-N.N-diethylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.23 (d, 1 H), 5.70 (m, 1H), 5.10 (m, 2H), 4.60 (br, 1H), 4.40 (br, 1H), 3.12 (m, 4H), 2.88 (m, 1 H), 2.42 (m, 1 H), 1.85 (s, 3H), 1.22 (t, 3H).
MS: (M+H)+= 298
-364- Example 151
OH
(±)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-N.N-dibutylamino)ethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.24 (d, 1 H), 5.70 (m, 1 H), 5.08 (m, 2H), 4.48-4.62 (br, 1H), 4.28-4.43 (1H), 3.05 (m, 4H), 2.77-2.92 (br, 1H), 2.34-2.46 (br, 2H), 1.84 (s, 3H), 1.64 (m, 4H), 1.30 (m, 4H), 0.93 (t, 6H).
MS: (M+H)+= 354
Example 152
AcHN. X OH
HN ^OH 2HCI
fc)-(2R.3S.5R.1'S)-2-n-Acetamido-2-(N-2-hvdroxyethylamino))ethyl-3-vinyl- Pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.20 (d, 1H), 5.70 (m, 1 H), 5.15 (d, 1 H), 5.08 (d, 1H), 4.50 (brm, 1H), 4.38 (brm, 1 H), 3.68 (M, 1 H), 3.0 (brm, 2H), 2.90 (m, 1H), 2.41 (m, 1 H), 1.85 (s, 3H).
-365- MS: (M+H)+= 286
Example 153
AcHN. X OH r-U AS { U
L^^OH 2HCI
(±W2R.3S.5R.1 'SV2-(1 -Acetamido-2-(N-2-hvdroxyethyl-N-ethylamino))ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 5.81-5.74(m, 1 H), 5.38(d, J=17.1Hz, 1 H), 5.22(d, J=10.0Hz, 1H), 4.92-4.88(m, 1H), 4.48(dd, J=7.6, 9.8Hz, 1 H), 3.91 (t, J=4.9Hz, 2H), 3.85(dd, J=5.6, 10.0Hz, 1H), 3.63-3.53(m, 2H), 3.46-3.39(m, 4H), 3.16- 3.13(m, 1H), 2.66-2.61 (m, 1H), 2.08(s, 3H), 2.06-2.01 (m, 1 H), 1.38(t, J=7.33, 3H).
MS: (M+H)+=314, (M+Na)+=336, (M-H)"=312, (M+CI)"=348, (2M-H)"=625
-366- Example 154
(±W2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-2-hvdroxyethyl-N-propylamino))ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.36(d, J=8.5Hz, 1 H), 5.75-5.68(m, 1 H), 5.13(d, J=17.1Hz, 1H), 5.04(d, J=10.4Hz, 1H), 4.62(m, 1H), 4.36(m, 1H), 3.77(t, J=4.9Hz, 2H), 3.63-3.59(m, 1 H), 3.50-3.23(m, 3H), 3.22-3.19(m, 2H), 3.08(t, J=7.3Hz, 2H), 2.91-2.87(m, 1H), 2.44-2.39(m, 1 H), 1.99-1.88(m, 1H), 1.84(s, 3H), 1.75-1.70(m, 2H), 0.90(t, J=6.7Hz, 3H).
MS: (M+H)+=328, (M+Na)+=350, (M-H)"=326, (M+CI)"=362, (2M-H)"=653
Example 155
u' 2HCI
(±W2R.3S.5R.1'S)-2-(1-Acetamido-2-(imidazol-1-vn ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid DiHvdrochloride
1H NMR (MeOD-d3) δ.9.06(s, 1 H), 7.72(s, 1 H), 7.58(s, 1 H), 5.84-5.76(m, 1H), 5.39(d, J=17.1 Hz, 1 H), 5.23(d, J=10.25Hz, 1 H), 4.70-4.66(m, 1 H), 4.52-
-367- 4.43(m, 2H), 3.92-3.89(m, 1 H), 3.20-3.17(m, 1 H), 2.67-2.62(m, 1 H), 2.11-2.04(m, 1 H), 1.95-1.89(m, 1 H), 1.91 (s, 3H).
MS: (M+H)+=293, (M-H)"=291 , (M+35)+=327.
Example 156
AcHN.^ OH
— N ϋ
2HCI
HO- .OH
fcW2R.3S.5R.1'S)-2-(1-Acetamido-2-(N.N-di-(2-hvdroxyethylamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
MS: (M+H)+=330, (M+Na)+=352, (M-H)"=328, (M+CI)"=364
Example 157
AcHN..^X >. κOH
H K i
AcN' °
HCl
fcW2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-acetyl-N-methylamino)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (DMSO-de) δ 8.01,7.95 (2d, 1H), 5.68-5.80 (m,1H), 5.02-5.22 (m, 2H), 4.30-4.45 (brm, 2H), 3.26,3.21 (2d, 1 H), 2.82-2.95 (brm, 1 H), 2.38-2.48 (m, 1 H), 1.98,2.02 (2s, 3H),1.79, 1.82 (2s, 3H).
MS: (M+H)+= 298
-368- Example 158
fcW2R.3S.5R.1 'S)-2-(1 -Acetamido-2-(N-2-hvdroxyethyl-N-methylamino ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.35(d, J=9.15Hz, 1 H), 5.74-5.67(m, 1 H), 5.12(d, J=17.1Hz, 1H), 5.04(d, J=10.4Hz, 1 H), 4.70(m, 1H), 4.39(dd, J=7.3, 10.4Hz, 1H), 3.80-3.75(m, 3H), 3.61-3.43(m, 3H), 3.23-3.16(m, 2H), 2.91-2.82(m, 1 H), 2.82(s, 3H), 2.44-2.39(m, 1 H), 1.92-1.84(m, 1 H), 1.84(s, 3H).
MS: (M+H)+=300, (M+Na)+=322, (2M+H-H2O)+=581
Example 159
(±W2R.3S.5R.1'S)-2-π-Acetamido-2-(N-propyl-N-methylamino)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) (broad) δ 8.3(1 H), 5.7(1H), 5.12-5.04(2H), 4.6(1 H), 4.35(1H), 2.61-2.35(11 H), 1.9(3H), 1.78-1.63(2H), 1.9(3H).
MS: (M+H)+=298, (M+Na)+=320, (M-H)"=296, (M+CIV332, (2M-H)"=593
-369- Example 160
fcW2R.3S.5R.1'S)-2-π-Acetamido-2-(N-cvclohexyl-N-methylamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (DMSO-de) δ 8.26(m, 1H), 5.75-5.65(m, 1H), 5.08(d, J=17.1Hz, 1 H), 5.02(d, J=10.3Hz, 1H), 4.62(m, 1H), 4.43-4.40(m, 1 H), 3.62-3.58(m, 1H), 3.46-3.16(m, 2H), 2.89-2.84(m, 1 H), 2.72(s, 3H), 2.44-2.39(m, 1 H), 2.07-1.80(m, 5H), 1.81(s, 3H), 1.63(m, 1H), 1.45-1.06(m, 6H).
MS: (M+H)+=338, (M+Na)+=360, (M-H)"=336, (M+CI)"=372
Example 161
OH
fcW2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-benzyl-N-methylamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.36(m, 1 H), 7.61-7.46(m, 5H), 5.69-5.64(m, 1H), 5.07(d, J=17.1 Hz, 1H), 4.99(d, J=10.1 Hz, 1 H), 4.77(m, 1 H), 4.44-4.39(m, 2H),
-370- 4.25(d, J=12.9, 1 H), 3.61 (m, 1 H), 3.43(m, 1 H), 3.22(m, 1 H), 2.93-2.85(m, 1H), 2.73(s, 3H), 2.44-2.38(m, 1H), 1.92-1.85(m, 1 H), 1.85(s, 3H).
MS: (M+H)+=346
Example 162
AcHN. X .OH
CH3N A H { υ
I ph 2HCI
fc)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-phenethyl-N-methylamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.34(d, J=8.55Hz, 1H), 7.37-7.26(m, 5H), 5.76- 5.69(m, 1 H), 5.14(d, J=17.1 Hz, 1 H), 5.06(d, J=10.4Hz, 1 H), 4.72(m, 1H), 4.46- 4.42(m, 1H), 3.83-3.20(m, 6H), 3.13-2.99(m, 2H), 2.86(s, 3H), 2.95-2.83(m, 1H), 2.46-2.40(m, 1 H), 1.95-1.81 (m, 1 H), 1.86(s, 3H).
MS: (M+H)+=360
-371- Example 163
/OH 2Hα
fcW2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-naphthylmethyl-N-methylamino))ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.41 (d, J=7.3Hz, 1 H), 8.32-7.59(m, 7H), 5.60(m, 1 H), 5.04(d, J=17.1 Hz, 1 H), 4.91(d, J=9.8Hz, 1H), 4.97-4.73(m, 3H), 4.39(m, 1H), 3.70-3.13(m, 3H), 2.90(m, 1 H), 2.72(s, 3H), 2.43-2.41(m, 1H), 2.01-1.74(m, 1H), 1.87(s, 3H).
MS: (M+H)+=395, (M+Na)+=418, (M-H)"=394, (M+CI)"=430, (2M-H)"=789
-372- Example 164
(±W2R.3S.5R.1'S)-2-(1-Acetamido-2-fN-morpholinyl))ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Dihvdrochloride Salt
1H NMR (DMSO-de) δ 8.28 (d, 1 H), 5.75-5.78 (m, 1 H), 5.15 (d,1H), 5.05 (d, 1 H), 4.65 (brm, 1 H), 4.42 (m, 1H), 3.72-3.98 (brm, 3H), 3.62 (m, 1 H), 2.90 (m, 1H), 2.38-2.48 (m, 1H), 1.85 (s, 3H).
MS: (M+H)+= 312
-373- Example 165
fcW2R.3S.5R.1 'S.3'R)-2-f 1 -Acetamido-2-(N-methyl-N-f-butylamino-N- oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
AcHN..^X X X'Bu AcHN. A X yOlBu u H N Rnr I ifi ^ I T ύ H N anr. i <f
>l Boc Boc A
O
N^ O "CH3 ό* *CH3
165A fcW2R.3S.5R.1'S.3'R) and fcW2R.3S.5R.1'S.3'S)-1-f-Butoxycarbonyl-2- (1-acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t- butylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (37 mg, .08 mmole) was reacted with the m-chloroperoxybenzoic acid (20 mg, .08 mmole) in CH2CI2 (0.9 mL) at 0°C for 1 hour. The reaction was chromatographed directly on silica gel eluting with a gradient of acetone to acetone/30% MeOH to provide the title compounds isomer (±)-(2R,3S,5R,1'S,3'R) (yield: .010 g, 27%) and isomer (±)-(2R,3S,5R,1'S,3'S) (yield: .011 g, 29%).
AcHN. ^A X /OH N i
> H H
J CH, HCl
165B fcW2R.3S.5R.1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N- oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
The title compound was prepared according to the method described in Example 15C substitufing (±)-(2R,3S,5R,1'S,3'R)-1-f-butoxycarbonyl-2-(1-
-374- acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- (imidazol-2-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 6 mg, 80%).
1H NMR (CD3OD) δ 5.72-5.87 (m, 1H), 5.40 (d, 1 H), 5.20-5.28 (m, 2H), 4.44-4.53 (dd, 1H), 3.73-3.95 (m, 3H), 3.57 (s, 3H), 3.08-3.19 (m, 1 H), 2.59-2.72 (m, 1 H), 2.05-2.15 (m, 1 H), 2.04 (s, 3H), 1.54 (s, 9H).
MS: (M+H)+= 328
Examples 166-178
1. CPBA
2. chromatographic separation
3. 6 N HCl
HCl
The following title compounds were prepared according to the method described in Example 165.
-375- Example 166
AcHN.^A. /OH
N if
H H o
~N' HCl
O CH3
(±W2R.3S,5R.1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N- oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1 H NMR (MeOD-d3) δ 5.87-5.74 (m, 1H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m,
1H), 5.21-5.18 (m, 1H), 4.50 (dd, J=8.1 , 9.8Hz, 1H), 4.04-3.87 (m, 4H), 3.54 (s, 3H), 3.20-3.14 (m, 1 H), 2.69-2.60 (m, 1 H), 2.12-2.01 (m, 1H), 2.05 (s, 3H), 1.50 (d, J=6.4Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+Na)+=336, (2M+1)+= 627, (2M+Na)+=649.
Example 167
AcHN. X^ X H
*N: ,u H o -CH3 Cl
fcW2R.3S.5R.1'S.3'SV2-n-Acetamido-2-(N-methyl-N-propylamino-N-oxideethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloridesalt
1 H NMR (MeOD-d3) δ 5.87-5.74 (m, 1 H), 5.46-5.40 (m, 1 H), 5.27-5.23 (m, 1 H), 5.21-5.18 (m, 1 H), 4.50 (dd, J=8.1 , 9.8Hz, 1 H), 4.04-3.87 (m, 4H), 3.54 (s,
-376- 3H), 3.20-3.14 (m, 1 H), 2.69-2.60 (m, 1H), 2.12-2.01 (m, 1H), 2.05 (s, 3H), 1.50 (d, J=6.4Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+H-H2O)"=295
Example 168
AcHN. X X OH
H K o if
"N^ CH3
fcW2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide))ethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid HvdrochlorideSalt
1H NMR (MeOD-d3) δ 5.82-5.75 (m, 1H), 5.44(d, J=17.1 Hz, 1 H), 5.26(d,
J=10.4Hz, 1H), 5.14-5.11(m, 1 H), 4.48-4.45(m, 1H), 4.9(d, J=4.9Hz, 2H), 3.87(dd, J=4.9, 10.4Hz, 1H), 3.76(q, J=6.7Hz, 2H), 3.54(s, 3H), 3.17-3.09(m, 1H), 2.68-2.62 (m, 1 H), 2.06(s, 3H), 2.09-2.03 (m, 1 H), 1.45(t, J=7.3Hz, 3H).
MS: (M+H)+=300, (M+Na)+=322, (M+H-H2O)+=282
-377- Example 169
AcHN.. ^ X /OH
H H N if
\.,A
~ N :"
0 CH3 HCl
(±W2R.3S.5R.1 'SV2-n-Acetamido-2-(N.N-dimethylamino-N-oxide)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (DMSO-de) δ 8.58 (d, 1H), 5.67-5.78 (m, 1H), 5.20 (d, 1H), 5.08 (d, 1H), 4.62-4.78 (brm, 1 H), 4.25-4.42 (brm, 1 H), 4.06 (d, 1H), 3.85-3.95 (brm, 1 H), 3.88-3.98 (brm, 1H), 3.35-3.50 (brs, 6H), 2.36-2.48 (m, 1H), 1.92 (m, 1 H), 1.85 (s, 3H).
MS: (M+H)+= 286
Example 170
AcHN..^ X /OH
PIT ^ ^N^x CH3 H HCI d i
fcW2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N- oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloridesalt
1H NMR (MeOD-d3) δ 7.60-7.47(m, 5H), 5.75-5.65(m, 1H), 5.39(d, J=6.35Hz, 1 H), 5.21(d, J=8.8Hz, 1 H), 5.18-5.11(m, 1 H), 5.00-4.70(m, 2H), 4.35-
-378- 4.27(m, 1H), 4.00-3.94(m, 2H), 3.86-3.79(m, 1 H), 3.20(s, 3H), 3.14-3.05(m, 1H), 2.77-2.50(m, 1 H), 2.08(s, 3H), 2.10-2.94(m, 1 H).
MS: (M+H)+=362, (M+Na)+=385, (M-H)"=360, (M+35)"=396
Example 171
AcHN. X^ /OH
» W o if
N o" "CH 1, HCl 1
fc)-(2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide)ethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloridesalt
1H NMR (CD3OD) δ 5.80 (m, 1H), 5.44 (d, 1H), 5.27 (d, 1H), 5.08 (m, 1H), 4.34-4.44 (dd, 1 H), 3.83-3.94 (m, 3H), 3.38 (s, 3H), 3.02-3.18 (m, 1 H), 2.58-2.72 (m, 1H), 2.08 (s, 3H), 1.97-2.08 (m, 1H), 1.55 (s, 9H).
MS: (M+H)+= 328
-379- Example 172
AcHN..^ /OH
H K o if N
O CH3 HCl
fcW2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N- oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.86-5.74 (m, 1 H), 5.53-5.47 (m, 1 H), 5.29-5.25 (m,
1H), 5.22-5.19 (m, 1H), 4.50 (dd, J=8.1 , 9.5Hz, 1H), 4.13-4.04 (m, 2H), 3.96 (dd, J=4.1 , 10.5Hz, 1H), 3.87-3.82 (m, 1H), 3.39 (s, 3H), 3.23-3.17 (m, 1 H), 2.70-2.61 (m, 1H), 2.11 (s, 3H), 2.08-2.00 (m, 1 H), 1.50 (d, J=6.4Hz, 3H), 1.49(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+Na)+=336, (2M+1)+=627, (2M+Na)+=649.
Example 173
AcHN.^ X /OH
^ 0 χvNX,,CH3 H HCl °
(±W2R.3S.5R.1'S.3'R 2-(1-Acetamido-2-(N-methyl-N-propylamino-N- oxide) ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.82-5.75(m, 1 H), 5.45(d, J=17.1 Hz, 1 H), 5.26(d, J=10.4Hz, 1H), 5.07-5.13(m, 1H), 4.48-4.42(m, 1H), 3.98(d, J=5.5Hz, 2H),
-380- 3.86(dd, J=4.3, 9.8Hz, 1 H), 3.67-3.64(m, 2H), 3.46(s, 3H), 3.16-3.01(m, 1 H), 2.68-2.62(m, 1 H), 2.09-2.02(m, 1 H), 2.06(s, 3H), 1.92-1.86(m, 2H), 1.04(t, J=7.3Hz, 3H).
MS: (M+H)+=314, (M+H-H2O)"=295
Example 174
AcHN..X^ X H
'CH, HCl
fcW2R.3S.5R.1'S.3'R)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide))ethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.82-5.75(m, 1H), 5.45(d, J=17.1Hz, 1 H), 5.26(d,
J=10.4Hz, 1 H), 5.13-5.10(m, 1H), 4.48-4.44(m, 1H), 4.02-3.94(m, 2H), 3.89 (dd, J=4.3, 9.8Hz, 1 H), 3.82(q, J=7.3Hz, 2H), 3.46(s, 3H), 3.18-3.10(m, 1 H), 2.68-2.62 (m, 1 H), 2.09(s, 3H), 2.07-2.02(m, 1H), 1.46(t, J=7.3Hz, 3H).
MS: (M+H)+=300, (M+Na)+=322, (M+H-H2O)+=282
-381- Example 175
AcHN._X X .OH
H K i O
Ph"
O CH,
(±W2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N- oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid HvdrochlorideSalt
1H NMR (MeOD-d3) δ 7.60-7.47(m, 5H), 5.75-5.65(m, 1 H), 5.39(d, J=6.35Hz, 1 H), 5.21(d, J=8.8Hz, 1 H), 5.18-5.11(m, 1 H), 5.00-4.70(m, 2H), 4.35- 4.27(m, 1H), 4.00-3.94(m, 2H), 3.86-3.79(m, 1 H), 3.40(s, 3H), 3.14-3.05(m, 1H), 2.77-2.50(m, 1 H), 2.08(s, 3H), 2.10-2.94(m, 1 H).
MS: (M+H)+=362, (M+Na)+=385, (M-H)"=360, (M+35)"=396
Example 176
AcHN. A^ .OH
^ A H
II KCl i
O
fc)-(2R.3S.5R.1'S 2-f1-Acetamido-2-(N.N-diethylamino-N-oxide))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.84-5.78(m, 1 H), 5.45(d, J=16.85Hz, 1H), 5.26(d, J=10.0Hz, 1 H), 5.09-5.05(m, 1H), 4.45-4.42(m, 1 H), 3.96-3.86(m, 3H), 3.76(q,
-382- J=6.6Hz, 2H), 3.70(q, J=7.3Hz, 2H), 3.15-3.11(m, 1 H), 2.68-2.62(m, 1H), 2.08- 2.02(m, 1 H), 2.08(s, 3H), 1.44-1.38(m, 6H).
MS: (M+H)+=314, (M+Na)+=336, (M+2Na)+=358
Example 177
AcHN. y /OH o H NH Y o
II
O
fc (2R.3S.5R.1'S.3'R)-2-(1-Acetamido-2-(N-pyrrolidinyl-N-oxide))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (DMSO-de) δ 8.74 (d, 1H), 5.65-5.80 (m,1 H), 5.28 (d, 1 H), 5.10 (d,1H), 4.82 (m, 1H), 4.40-4.50 (dd, 1H), 4.30 (d, 1 H), 3.60-4.12 (brm, 5H), 2.98- 3.15 (m, 1 H), 2.38-2.48 (m, 1H), 2.05-2.20 (brm, 5H), 1.88-1.98 (m, 1H), 1.87 (s, 3H).
MS: (M+H)+= 312
-383- Example 178
AcHN._X X /OH
'N
^O HCl
fcW2R.3S.5R.1'SV2-(1-Acetamido-2-fN-morpholinyl-N-oxide)ethvI-3-vinyl- pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (DMSO-de) δ 8.65 (d, 1 H), 5.66-5.80 (m, 1 H), 5.22 (d, 1 H), 5.09 (d, 1 H), 4.78 (brs, 1H), 4.32-4.42 (dd, 1 H), 4.10-4.17 (brm, 2H), 3.50-4.02 (brm, 9H), 2.92-3.04 (brm, 1H), 2.37-2.48 (m, 1 H), 1.88-1.96 (m, 1 H), 1.87 (s, 3H).
MS: (M+H)+= 328
Example 179
(±)-f2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide^ethyl- 3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid HvdrochlorideSalt
0'Bu i
179A fcW2R.3S.5R.1 'S)-1 -f-Butoxycarbonyl-2-oxiranyl-3-(c/s-propen-1 -vIV pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 1231, substitufing ethyltriphenylphosphonium bromide in place of methyltriphenylphosphonium bromide (yield: 350 mg, 77%).
-384- 1H NMR (CDC ) (rotamers) δ 5.55-5.43 (m, 2H), 4.13-4.04 (m, 2H), 3.14- 3.11 (m, 2H), 2.76-2.50 (m, 3H), 1.75-1.70 (m, 1H), 1.64(d, 3H), 1.48-1.43(m, 18H).
MS: (M+H)+=354, (M+Na) +=376, (2M+Na)+=729
O'Bii n °
179B fcW2R.3S.5R.1ΕV1-f-Butoxycarbonyl-2-(1-methanesulfonyloxy-3- azido)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 123J, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-oxiranyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 1.08 g, 84%).
1H NMR (DMSO-de) (rotamers) δ 5.53-5.33 (m, 2H), 5.05-4.93 (m, 1H), 4.20-3.90 (m, 2H), 3.76-3.62 (m, 2H), 3.24 (s, 3H), 2.59-2.49(m, 1H), 1.64- 1.55(m, 5H), 1.43-1.36(m, 18H).
MS: (M+H)+=475, (M+Na)+=497, (2M+Na)+=971
-385- -°tBu N' l s N H Boocc r Q π
179C fc)-(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-(c/s-propen-1-vh- pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 123K, substitufing (2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1- methanesulfonyloxy-3-azido)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1- methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester(crude yield: 564 mg, 71%).
1H NMR(DMSO-de) (rotamers) δ 5.45-5.30 (m, 2H), 4.15-3.99 (m, 1 H), 3.30-3.08 (m, 1H), 3.07-2.84 (m, 1H), 2.68-2.51 (m, 1H), 2.13-1.85(m, 1 H), 1.80- 1.05(m, 3H), 1.57(d, J=5.4Hz, 3H), 1.41-1.35(m, 18H).
MS: (M+H)+=352, (M+23)+=375, (2M+H)+=705, (2M+23)+=727
H I
179D fc)-(2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(N-acetylaziridinvn-3-(c s-propen- 1-vh-Pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 123L, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-aziridinyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-
-386- (2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-aziridinyl-3-vinyi-pyrrolidine-5-carboxylic acid t-butyl ester(yieid: 455 mg, 72%).
1H NMR(DMSO-de) (rotamers) δ 5.74-5.34(m, 2H), 4.17(dd, J=2.4, 6.35Hz, 1 H), 3.41 (dd, J=1.95, 6.35Hz, 1 H), 3.14-2.99(m, 1 H), 2.73-2.58(m, 2H), 2.40(d, J=6.35Hz, 1 H), 2.17-2.12(m, 1 H), 2.05-2.00(m, 3H), 1.66-1.55(m, 1 H), 1.56(d, J=6.8Hz, 3H), 1.41-1.31(m, 18H).
MS: (M+H)+=395, (M+Na)+=417, (M+H+Na)+=418,
179E fc)-(2R.3S.5R.1'SV1-f-Butoxycarbonyl-2-π-acetamido-2-N-ethyl-N- methylamino)ethyl-3-fc/s-propen-1-ylW3yrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 150, substitufing N-ethyl-N-methyl-amine in place of diethylamine (yield: 30 mg, 87%).
MS: (M+H)+=454, (M+Na)+=476, (M-H)"=452, (M+35)"=488
-387-
179E fcW2R.3S.5R.1'S.3'R) and fcW2R.3S.5R.1'S.3'S)-1-f-Butoxycarbonyl-2- (1-acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in Example 165A, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-(N-ethyl-N-methylamino))ethyl-3-(cs-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2- (1-acetamido-2-N-methyl-N-f-butylamino)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid t-butyl ester (yield: 15.2 mg, 51%).
H3C AcHN. OH
H H If
'N: HCl
CH,
179F fcW2R.3S.5R.1'S.3'R)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N- oxide))ethyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3S,5R,1'S,3'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-(N-methyl-N-ethyl-N-oxide))ethyl-pyrrolidine-5-carboxylic acid t-butyl ester for (±)-(2R,3R,5R,1 'S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 8.7 mg, 29%).
1H NMR (MeOD-d3) δ 5.75-5.69(m, 1H), 5.37-5.30(m, 1 H), 5.07-5.04(m, 1 H), 4.49(dd, J=7.8, 10.2Hz, 1 H), 4.05-3.74(m, 4H), 3.61-3.32 (m, 1 H), 3.55(s,
-388- 3H), 2.69-2.60(m, 1 H), 2.04(s, 3H), 1.95-1.84(m, 1H), 1.75(dd, J=2.0, 7.1 Hz, 3H), 1.44 (t, J=7.1Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
Examples 179-184
1 MCPBA
2. chromatographic /OH separation if 3. 6 N HCl
R'RN O
The following title compounds were prepared according to the method described in Example 179.
Example 180
H3C AcHN. ~yH N^ HCl ON *CH3
fcW2R.3S.5R.1 'S.3'S)-2-(1 -Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- 3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.75-5.69(m, 1H), 5.38-5.30(m, 1H), 5.02-4.98(m, 1H), 4.47(dd, J=7.8, 9.8Hz, 1H), 4.02-3.77(m, 4H), 3.56-3.39(m, 1 H), 3.47(s, 3H), 2.69-2.59(m, 1 H), 2.07(s, 3H), 1.95-1.84(m, 1 H), 1.76(dd, J=1.7, 7.1Hz, 3H), 1.46(t, J=7.1Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
-389- Example 181
H3C Y- N AcHN. X X / 0
'N HCl θ' CH3
fc)-(2R.3S.5R.1'S.3'R)-2-π-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1-ylVpyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.76-5.66(m, 1H), 5.39-5.31(m, 1 H), 5.17-5.11(m, 1 H), 4.51(dd, J=7.5, 10.2Hz, 1H), 4.07-3.76(m, 4H), 3.55(S, 3H), 3.52-3.39(m, 1H), 2.69-2.60(m, 1 H), 2.02 (S, 3H), 2.08-1.84(m, 1H), 1.75(dd, J=1.7, 7.1Hz, 3H), 1.50(d, J=6.1Hz, 3H), 1.48(d, J=6.4Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
Example 182
H3C V- AcHN.^ X /OH J H H H O if
'N HCl
O *CH3
(±W2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.76-5.68(m, 1 H), 5.39-5.31 (m, 1 H), 5.10-5.05(m, 1 H), 4.49(dd, J=7.8, 9.8Hz, 1 H), 4.12-3.84(m, 4H), 3.55-3.44(m, 1H), 3.41(S, 3H),
-390- 2.69-2.60(m, 1 H), 2.08(S, 3H), 2.07-1.84(m, 1H), 1.76(dd, J=1.7, 6.8Hz, 3H), 1.51(d, J=2.4Hz, 3H), 1.49(d, J=2.4Hz, 3H).
MS: (M+H)+=314, (M+35)+=348
Example 183
H3C V-
AcHN.^ X OH ύ H N H o
^ N CH3 HCI
(±)-(2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-isobutyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1-vh-Pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.75-5.69(m, 1H), 5.38-5.31(m, 1 H), 5.18-5.12(m, 1H), 4.53(dd, J=7.5, 9.8Hz, 1 H), 4.25-3.42(m, 6H), 3.65 (s, 3H), 2.68-2.58(m, 1H), 2.44-2.36(m, 1H), 2.05(s, 3H), 1.94-1.87(m, 1 H), 1.76(d, J=2.7Hz, 3H), 1.14 (d, J=6.8Hz, 6H).
MS: (M+H)+=342, (M+Na)+=364, (M-H)"=340
-391- Example 184
H C
ACHN..^X ^- 0H H H O
O CH3
fc)-(2R.3S.5R.1'S.3'R)-2-(1-Acetamido-2-(N-isobutyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
1H NMR (MeOD-d3) δ 5.75-5.69(m, 1 H), 5.38-5.31(m, 1 H), 5.06-5.02(m, 1 H), 4.48(dd, J=7.5, 9.8Hz, 1 H), 4.08-3.85(m, 3H), 3.70-3.57 (m, 2H), 3.52(s, 3H), 3.48-3.41 (m, 1 H), 2.70-2.60(m, 1H), 2.40-2.36(M, 1H), 2.08(s, 3H), 1.95- 1.84(m, 1 H), 1.75(dd, J=1.7, 7.1 Hz, 3H), 1.14 (d, J=6.8Hz, 6H).
MS: (M+H)+=342, (M+Na)+=364, (M-H)"=340
-392- Example 185
fc)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-isopropyl-N-hvdroxyamino))ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid HvdrochlorideSalt
AcHN..^ .OlBu
H Boc 0
~N OH
165A fcW2R.3S.5R.rSV1-f-Butoxycarbonyl-2-(1-acetamido-2-(N-isopropy|-N- hvdroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- isopropylamino)ethyl-3-vinyl-pyrroIidine-5-carboxylic acid t-butyl ester (21 mg, 0.048 mmole) was dissolved in 0.95 mL of acetone. It was then titrated with 0.14 mL of a solution of dimethyldioxirane (0.1 M) in acetone at -45°C for 0.5 hour. The reaction was stopped by concentrating the mixture in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 90% dichloromethane/methanol to provide the title compound (yield: 5.3 mg, 24%) and recovered starting material (yield 12 mg, 57%).
1 H NMR (MeOD-d3) δ 5.95-5.89(m, 1H), 5.08-4.94(m, 2H), 4.75-4.68(m,
1H), 4.13-3.83(m, 2H), 2.85-2.47(m, 4H), 1.96(s, 3H), 1.82-1.76(m, 1 H), 1.52- 1.44(m, 18H), 1.45-1.29(m, 1 H), 1.07-1.04(m, 6H).
MS: (M+H)+=456, (M+Na)+=478, (M-H)"=454, (M+35)"=490.
-393- AcHN.^X X /OH
O
HCl
OH
185B fcVf2R.3S.5R.1'S)-2-(1-Acetamido-2-(N-isopropyl-N-hvdroxyamino))ethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid Hydrochloride Salt
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 3.0 mg, 87%).
1 H NMR (MeOD-d3) δ 5.83-5.71 (m, 1 H), 5.40(d, J=17.3Hz, 1H), 5.24(d,
J=10.2Hz, 1 H), 4.48(dd, J=7.8, 10.2Hz, 1H), 3.88-3.59(m, 4H), 3.17-3.10(m, 1H), 2.67-2.58(m, 1 H), 2.10-1.99(m, 1 H), 2.09(s, 3H), 1.33-1.17(m, 1H), 1.38(d, J=6.4Hz, 6H).
MS: (M+H)+=300, (M-H)"=298, (2M-H)"=597
-394- Example 186
(±)-(2R.3S.5R.1'R)-2-(1-Acetamido-2-oxo-2-phenvπethyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-oxo-2-phenyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 5.9 mg, 100%).
H NMR (DMSO-de) δ 8.62 (d, J= 9.8Hz, 1 H), 7.93 (m, 2H), 7.68 (m, 1H), 7.55 (t, J= 7.9Hz, 2H), 5.61 (m, 1H), 5.48 (m, 1 H), 5.19 (m, 1 H), 4.50 (m, 1H), 3.98 (t, J= 9.8Hz, 1 H), 3.30 (m, 1H), 2.38 (m, 1H), 1.73 (m, 1 H), 1.71 (s, 3H), 1.59 (m, 3H).
MS: (M+H)+= 331 , (M+Na)+= 353, (M-H)- = 329.
-395- Example 187
(±)-(2R.3S.5R.1 'R.2'R)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(c s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
OlBu
187A fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-π-acetamido-2-methoxy-4- vinvπbutyl-3-(c/s-propen-1-yl)-Pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound is prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester for (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
187B fcVf2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(c s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-4-vinyl)butyl-3-(c/'s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
-396- Example 188
(±)-(2R.3S.5R.1'R.2'SV2-π-Acetamido-2-methoxy-4-vinvnbutyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
188A (±V(2R.3S.5R.1'R.2'S 1-f-Butoxycarbonyl-2-(1-acetamido-2-methoxy-4- vinvDbutyl-3-(c/'s-propen-1-vD-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester for (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0044 g, 22%).
MS: (M+H)+=481 , (M-H)"=479.
,OH j
TFA
188B fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-4-vinvnbutyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy-4-vinyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
-397- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 0.0031 g, 100%).
1H NMR (DMSO-de) δ 7.93 (d, J=9.2Hz, 1 H), 5.81 (m, 1 H), 5.49 (m, 1 H), 5.26 (m, 1 H), 5.1-4.9 (m, 2H), 4.29 (m 1 H), 4.03 (m, 2H), 3.68 (m, 1 H), 3.26 (m, 1H), 3.25 (s, 3H), 3.18 (quint, J=8.5Hz, 1 H), 2.40 (dt, J=12.7,7.3Hz, 1H), 2.32 (M, 1 H), 2.20 (m, 1 H), 2.02 (m, 1 H), 1.85 (s, 3H), 1.68 (m, 1 H), 1.64 (m, 1H), 1.61 (dd, J=6.7,1.8Hz, 3H), 1.55-1.40 (m, 2H).
MS: (M+H)+=325, (M+Na)+=347, (M-H)"=323.
Example 189
(±)-(2R.3R.5R.1 'R.2'S)-2-(1-Acetamido-2.3-dihvdroxy)propyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
TBDPSO-
MsO OlBu
N XBOC t
189A fc)-(2R.3R.5R.1'SV1-f-Butoxycarbonyl-2-f1-methanesulfonyloxy-3- azido)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 123J substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-oxiranyl-3-f- butyldiphenylsiiyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (2R,3S,5R,1'S)-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 9.0 g, 90%).
-398- 1H NMR (DMSO-de) (rotamers) δ 7.62-7.58 (m, 4H), 7.49-7.38 (m 6H), 4.97-4.79 (m, 1 H), 4.19-4.02 (m, 2H), 3.79-3.48 (m, 2H), 3.15 and 3.13 (2s, 3H), 2.49-2.39 (m, 2H), 1.98-1.74 (m, 1 H), 1.43-1.25 (m, 18H), 1.02 and 1.00 (2s, 9H)
MS: (M+H)+ = 703, (M+Na)+ = 725
TBDPSO-
O'Bu
189B (±W2R.3R.5R.rS -1-f-butoxycarbonyl-2-aziridinyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester
The title compound was prepared according to the method described in Example 123K substituting(±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1- methanesulfonyloxy-3-azido)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2- (1 -methanesulfonyioxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester(yield: 5.9 g, 79%).
1H NMR (DMSO-de) (rotamers) δ 7.60-7.56 (m, 4H), 7.49-7.39 (m 6H), 4.11-4.05 (m, 1 H), 3.67-3.48 (m, 2H), 3.42-3.30 (m, 1 H), 2.49-2.39 (m, 1H), 2.25- 1.61 (m, 5H), 1.40, 1.35, 1.33, and 1.27 (4s, 18H), 0.99 and 0.98 (2s, 9H)
MS: (M+H)+= 581, (M+Na)+ = 603
-399- TBDPSO-
O'Bu
189C fc)-(2R.3R.5R.1'SV1-f-Butoxycarbonyl-2-N-acetylaziridinyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123L substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-aziridinyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.1 g, 96%).
1H NMR (DMSO-de) (rotamers) δ 7.60-7.57 (m, 4H), 7.49-7.39 (m 6H), 4.18-4.11 (m, 1 H), 3.71-3.51 (m, 3H), 2.76-2.68 (m, 1H), 2.58-2.45 (m, 1H), 2.46 and 2.39 (2d, J=6.1 , 6.1 Hz, 1H), 2.40 and 2.47 (2m, 1 H), 2.08 and 2.05 (2d, J=3.1, 3.1 Hz, 1 H), 2.02 and 1.99 (2s, 3H), 1.94-1.79 (m, 1H), 1.41 , 1.36, 1.35 and 1.29 (4s, 18H), 0.99 and 0.98 (2s, 9H)
MS: (M+H)+ = 623, (M+Na)+ = 645
TBDPSO--
189D fcW2R.3R.5R.1 'Rι-1 -f-Butoxycarbonyl-2-(1 -acetamido-2-acetoxytethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-N-acetylaziridinyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (2.75g, 4.40 mmole) was reacted with potassium acetate (2.49 g, 25.37 mmole) and acetic acid (1.45 mL, 25.37 mmole) in DMSO (45 mL) at 100°C for 16 hours. The
-400- reaction was quenched with 1 N NaHCO3 (100 mL) and diluted with ethyl acetate (300 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 100% dichloromethane to 50% dichloromethane/ethyl acetate to provide the title compound (yield: 2.45g, 81%).
MS: (M+H)+=683, (M+Na)+=705, (M-H)"=681 , (M+CI)"=717
TBDPSO— \
HO
189E fc (2R.3R.5R.1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hvdroxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3R,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2-acetoxy)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester (2.45 g, 3.58 mmole) was reacted with potassium carbonate (1.48 g, 10.73 mmole) in methanol (18 mL) and THF (18mL) at 25°C for 45 minutes. The reaction was quenched with water (100 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 85% dichloromethane/ethyl acetate to 100% ethyl acetate to provide the title compound (yield: 2.05 g, 90%).
MS: (M+H)+=641 , (M+Na)+=663, (2M+Na+H)+=1304, (M-H)"=639, (M+CIV =675
-401-
189F fcW2R.3R.5R.1'R -1-f-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 41 A substitufing (±)-(2R,3R,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido-2- hydroxy)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-de) (rotamers) 9.49(d, J=16.3, 1 H), 8.33 and 8.29(2d, J=8.8 and 8.8Hz, 1H), 7.58-7.38(m, 10H), 4.94 and 4.84(2dd, J=4.4, 8.8Hz and 4.4, 8.8Hz, 1H), 4.26-3.37(m, 4H), 2.47-2.30(m, 1 H), 1.97-1.83(m, 1H), 1.92(s, 3H), 1.42-1.18(m, 18H), 1.42-1.18(m, 1 H), 1.00-0.97(m, 9H).
MS: (M+H)+=639, (M-H)"=637
TBDPSO^
189G (±W2R.3R.5R.1'S)-1-f-Butoxycarbonyl-2-π-acetamido-1-vinyl)methyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 118A substituting (±)-(2R,3R,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-formyl)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl 2-(1-
-402- acetamido-2-formyl)ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (DMSO-de) (rotamers) 7.99-7.74(m, 1H), 7.59-7.39(m, 10H), 5.80-5.68(m, 1 H), 5.21-5.01 (m, 3H), 3.97-3.31 (m, 1 H), 3.78-3.74(m, 1 H), 3.60- 3.46(m, 2H), 2.53-2.37(m, 1H), 2.09-1.72(m, 1 H), 1.87(s, 3H), 1.42-1.23(m, 19H), 1.00-0.99(m, 9H).
189H (±W2R.3R.5R.1'R.2'R) and fcW2R.3R.5R.1'R.2'S)-1-f-Butoxycarbonyl-2- (1-acetamido-2,3-dihvdroxy)propyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic Acid f-Butyl Ester
The title compounds were prepared according to the method described in Example 20A substituting (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-vinyl)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrroiidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R)-1-benzyl-2-vinyl-3-t-butyldimethylsilyloxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (±)-(2R,3R,5R,1'R,2'S) isomer (yield: 311mg, 24%) (±)-(2R,3R,5R,1'R,2'R) isomer (yield: 700 mg, 54%).
(±)-(2R,3R,5R,1'R,2'S) 1H NMR (DMSO-d6) (rotamers) 7.62-7.39(m, 11H), 4.56 and 4.51 (d, J=4.8, 1H), 4.46-4.39(m, 2H), 3.97-3.82(m, 1H), 3.74- 3.47(m, 3H), 3.28-3.21 (m, 2H), 2.89-2.64(m, 1 H), 2.51-2.45(m, 1 H), 2.05-1.8(m, 1H), 1.87-1.86(m, 3H), 1.43-1.23(m, 19H), 0.99-0.98(m, 9H).
tø-^R.SR.δR.I'R^R) 1H NMR (DMSO-de) (rotamers) 7.63-7.40(m, 11 H), 4.56-4.54(d, J=4.8, 1H), 4.47-4.33(m, 2H), 3.94-3.80(m, 1 H), 3.85-3.80(m, 1H), 3.76-3.68(m, 1 H), 3.60-3.51 (m, 1 H), 3.44-3.35(m, 1 H), 3.30-3.21 (m, 1H),
-403- 2.78-2.62(m, 1 H), 2.46-2.31 (m, 1 H), 2.07-1.98(m 1H), 1.83(s, 3H), 1.39-1.29(m, 19H), 1.00-0.99(m, 9H).
189! (±W2R.3R.5R.1 'R.2'S)-1 -f-Butoxycarbonyl-2-(1 -acetamido-1 -(2.2- dimethyl-1 ,3-dioxolan-4-yl))methyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic Acid f-Butyl Ester
(±)-(2R,3R,5R,1'R,2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2,3- dihydroxy)propyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f- butyl ester was reacted with 2,2-dimethoxypropane (1.1 ml, 9.09 mmole) and p- Toluenesulfonic acid (4.3 mg, 0.023 mmole) in tetrahydrofuran (4.5 mL) at 25°C for 45 minutes. The reaction was quenched with triethylamine (3 mL). Stirring was continued for an additional 10 minutes. The reaction was then diluted with 10% NaHCO3(15 mL) and extracted with ethyl acetate (45 ml). The organic layer was washed with water,and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was carried over to the next step, purified by chromatography on silica gel using 100% dichlormethane to 94% dichloromethane/methanol to provide the title compound (yield: 194 mg, 91%).
-404-
189J (±W2R.3R.5R.1'R.2'S 1-f-Butoxycarbonyl-2-(1-acetamido-1-(2.2- dimethyl-1.3-dioxolan-4-yl))methyl-3-hvdroxymethyl-pyrrolidine-5-carboxylicAcid f-Butyl Ester
The title compound was prepared according to the method described in Example 123G substitufing (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester for (±)- (2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-oxiranyl-3-f-butyldiphenylsilyloxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester. The resulting residue was purified by chromatography on silica gel using 100% dichlormethane to 94% dichloromethane/methanol to provide the title compound (yield: 194 mg, 91%).
189JJ fcW2R.3R.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-1-(2.2- dimethyl-1 ,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123H substitufing (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-hydroxymethyl-pyrrolidine-
-405- 5-carboxylic acid f-butyl ester for (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2- oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxyiic acid t-butyl ester.
OΕu
189K (±W2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-1-(2.2-dimethyl- 1.3-dioxolan-4-yl))methyl-3-(c/s-propen-1-yl))-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 35A substituting (±)-(2R,3R,5R,1 'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2- (1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 11.5 mg, 59%).
1H NMR (CDC ): δ 6.62 (d, 1 H), 5.56 (m, 1H), 5.40 (m, 1 H), 4.43 (m, 1H), 4.25 (m, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.88 (m, 1 H), 3.54 (m 1 H), 3.14 (m, 1 H), 2.54 (m 1 H), 2.04 (s, 3H), 1.71 (m 1 H), 1.60 (dd, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 1.40 (s, 3H), 1.32 (s, 3H).
MS: (M+H)+=483
-406-
189L fc)-f2R.3S.5R.1 'R.2'S)-2-(1-Acetamido-2.3-dihvdroxy)propyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxyiic acid f-butyl ester in place (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cs-propen-1-yl)-pyrroiidine-5- carboxylic acid f-butyl ester.
1H NMR (DMSO-de): δ 7.84 (d, J=9Hz, 1 H), 5.49 (m, 1H), 5.27 (m, 1H), 4.47 (m, 1H), 4.25 (m, 1 H), 4.17 (m, 1 H), 3.75 (m, 1H), 3.59 (m, 1H), 3.35 (m, 1H), 3.18 (m, 1 H), 2.43 (m, 1H), 1.81 (s, 3H),1.55 (dd, 3H).
MS: (M+H)+=287
-407- Example 190
(±)-(2R.3R.5R.1'R.2'R)-2-(1-Acetamido-2.3-dihvdroxy)propyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
190A fcW2R.3R.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-π-acetamido-1-(2.2- dimethyl-113-dioxolan-4-yl))methyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 1891 substitufing (±)-(2R,3R,5R,rR,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2,3-dihydroxy)propyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'R,2'S)-1-f- Butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy)propyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester.
-408- O'Bu
190B fcW2R.3R.5R.1 'R.2'R)-1 -f-Butoxycarbonyl-2-(1 -acetamido- 1 -(2.2- dimethyl-1.3-dioxolan-4-yl))methyl-3-hvdroxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123G substitufing (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-f- butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester for (±)- (2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-oxiranyl-3-f-butyldiphenylsilyloxymethyl- pyrrolidine-5-carboxylic acid t-butyl ester.
190C (±)-(2R.3R.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-1-(2.2- dimethyl-1 ,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123H substituting (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-hydroxymethyl-pyrrolidine- 5-carboxylic acid f-butyl ester for (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2- oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester.
-409- OlBu
190D fcW2R.3S.5R.1 'R.2'R)-1 -f-Butoxycarbonyl-2-(1 -acetamido-1 -(2.2- dimethyl-1 ,3-dioxolan-4-vπ)methyl-3-(c/'s-propen-1-vπ)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 35A substituting (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2- (1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 42 mg, 61%).
1H NMR (CDCI3): δ 7.88 (d, 1H), 5.52 (m, 1H), 5.34 (m, 1 H), 4.33 (m, 1H), 4.21 (m, 1 H), 3.96 (m, 2H), 3.83 (m, 1H), 3.60 (m, 1H), 3.40 (m, 1 H), 2.53 (m, 1H), 1.98 (s, 3H), 1.66 (dd, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.41 (s, 3H), 1.33 (s, 3H).
MS: (M+H)+=483
-410-
190E (±W2R.3S.5R.1 'R.2'R)-2-(1 -Acetamido-2.3-dihvdroxy)propyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-1-(2,2-dimethyl-1 ,3-dioxolan-4-yl))methyl-3-(c/s-propen-1-yl))- pyrroiidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester.
1H NMR (DMSO-de): δ 7.98 (d, J=9Hz, 1 H), 5.48 (m, 1H), 5.29 (m, 1H), 4.60 (m, 1H), 4.30 (m, 1H), 4.12 (m, 1 H), 3.76 (m, 1 H), 3.52 (m, 1H), 3.46 (m, 1H), 3.32 (m, 1H), 3.18 (m, 1 H), 2.40 (m, 1H), 1.84 (s, 3H), 1.60 (dd, 3H).
MS: (M+H)+=287
-411- Example 193
fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(c s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
193A (±W2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- ethoxy)pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 88A, substitufing ethyl iodide for methyl iodide (yield: 3.6 mg, 28%).
MS: (M+H)+= 483, (M+Na)+= 505, (M-H)" = 481.
193B (±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(c s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substitufing (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-ethoxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 3.2 mg, 100%).
-412- 1H NMR (DMSO-d6) δ 7.92 (d, J= 9.2Hz, 1 H), 5.47 (m, 1 H), 5.25 (m, 1H), 4.25 (m, 2H), 3.70 (m, 1 H), 3.52 (m, 1 H), 3.33 (m, 2H), 3.18 (m, 1 H), 2.39 (m, 1 H), 1.85 (s, 3H), 1.66 (m, 1 H), 1.61 (dd, J= 6.7, 1.8Hz, 3H), 1.56 (m, 1 H), 1.37 (m, 1H), 1.28 (m, 2H), 1.13 (m, 3H), 0.86 (t, J= 7.3Hz, 3H).
MS: (M+H)+= 327, (M+Na)+= 349, (M-H)" = 325.
Example 194
fc)-(2R.3S.5R.1'R.2'RV2-(1-Acetamido-2-ethoxy)pentyl-3-(c/'s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
194A fcW2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- ethoxy pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound is prepared according to the method described in Example 88A, substitufing ethyl iodide for methyl iodide.
-413-
194B (±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-ethoxy)pentyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-ethoxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
Example 195
(±W2R.3S.5R.1'SV2-(1-Acetamido-2-hvdroxy)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
A HO A TFA °"
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 19.9 mg, 100%).
-414- 1H NMR (DMSO-de) δ 7.80 (d, J= 8.8Hz, 1 H), 5.76 (m, 1 H), 5.23 (d, J= 17.1Hz, 1H), 5.15 (m, 1H), 4.31 (m, 1 H), 4.03 (m, 1 H), 3.62 (m, 1 H), 3.53 (m, 2H), 2.79 (m, 1 H), 2.42 (m, 1H), 1.90 (s, 3H), 1.85 (m, 1 H).
MS: (M+H)+= 243, (M+Na)+= 265, (M-H)" = 241.
Example 196
(±W2R.3S.5R.1'R.2'S 2-(1-Acetamido-2-hvdroxy-3-dimethylphosphonvnpropyl- 3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/O •>t'cBu /O'Bu if if
0=P-OCHa 0=P-OCH3
OCH3 OCH3
196A (±W2R.3S.5R.1'R.2'S and (±W2R.3S.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy-3-dimethylphosphonyl)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid f-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (78 mg, 0.19 mmol) in THF (5 mL) was added dropwise to a solution of dimethylphosphonylmethyl lithium (3M) (0.32 mL, 0.95 mmol) in THF (20 mL) at -78°C and reacted for 40 minutes. The reacfion was quenched with water (10 mL) and saturated aqueous ammonium chloride (10 mL) followed by extracfion using dichloromethane (2 x 50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5-10% methanol in dichloromethane to provide the title
-415- compounds (±)-(2R,3S,5R,1'R,2'R) isomer (yield: 27 mg, 27%) and (±)- (2R,3S,5R,1'R,2'S) isomer (yield: 5.5 mg, 6%).
(±)-(2R,3S,5R,1'R,2'R) = 1H NMR (CDCI3) δ 5.98 (m, 1H), 5.58(m, 1H), 5.35(m, 1 H), 4.94(m, 1 H), 4.14(m, 2H), 3.74(m, 8H), 3.06(m, 1 H), 2.64(m, 1H), 2.03(s, 3H), 1.95(m, 1 H), 1.83(m, 3H), 1.53(s, 9H), 1.46(s, 9H)
MS: (M+H)+=535, (M-H)" =533
(±)-(2R,3S,5R,1'R,2'S) MS: (M+H)+=535, (M-H)"=533
196B (±W2R.3S.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxy-3- dimethylphosphonvπpropyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substitufing (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cs-propen-1-yl)-pyrrolidine- 5-carboxyiic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)- 1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 3 mg, 96%).
1H NMR (DMSO-d6) δ 7.98(d, J=9.2 HZ, 1H), 5.48(M, 1H), 5.28(m, 1H), 4.36(m, 1H), 4.30(m, 1H), 4.08(m, 2H), 3.70(m, 2H), 3.60(m, 6H), 3.18(m, 1H), 2.40(m, 1 H), 2.05(m, 1H), 1.85(s, 3H), 1.60(dd, J=6.2, 1.2 HZ, 3H)
-416- MS: (M+H)+=379, (M-H)" =377
Example 197
0=P-OCH3 OCH3
(±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxy-3-dimethylphosphonvnpropyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-dimethylphosphonyi)propyI-3-(c/s-propen-1-yl)-pyrrolidine- 5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 13 mg, 96%).
1H NMR (DMSO-de) δ 7.72 (d, J=9.2 HZ, 1H), 5.48(m, 1 H), 5.24(m, 1H), 4.44(m, 1 H), 4.15(m, 2H), 3.62(m, 7H), 3.54(m, 1H), 3.15(m, 1 H), 2.40(m, 1H), 1.95(m, 1H), 1.82(s, 3H), 1.72(m, 1H), 1.54(dd, J=6.7, 1.2 HZ, 3H)
MS: (M+H)+= 379, (M-H)" = 377
-417- Example 198
(±W2R.3S.5R.1'S)-2-(1-Acetamido-3-hvdroxy propyl-3-(c s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/O'Bu
Olf
OCHq
198A (±W2R.3S,5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-1-(c/s and frans-2- methoxwinv0)methyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (113 mg, 0.28 mmol) was added to a solution of (methoxymethyl)triphenylphosphonium bromide (240 mg, 0.70 mmol) and potassium f-butoxide (0.56 mL, 0.56 mmol, 1 M in THF) in toluene (3 mL) at 0°C for 15 minutes. The reacfion was quenched with saturated aqueous ammonium chloride (3 mL) followed by extracfion using dichloromethane (2 X 3 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compounds
1H NMR (CDCI3) δ 8.65 (br d, 1H) 6.01 (d, J=5.7Hz, 1 H), 5.40 (m, 3H), 5.11 (br t, 1 H), 4.15 (m, 2H), 3.72 (m, 1H) 3.61 (s, 3H), 3.00 (m, 1 H), 2.42 (m, 1H), 1.94 (s, 3H), 1.64 (dd, J=1.4, 5.0Hz, 3H), 1.45 (m, 9H), 1.25 (m, 9H)
MS: (M+H)+ = 439.
-418-
198B fcW2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-formvnethyl-3- (cs-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-(c/s and trans-2- methoxyvinyl))methyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (21 mg, 0.048 mmol) was reacted with LiBr (37 mg, 0.43 mmol) and AG50W-X2 ion exchange resin in CH3CN (2 mL) and water (0.1 mL) at room temperature for 45 minutes. The reacfion was filtered and quenched with saturated aqueous sodium bicarbonate (1 mL) followed by extraction using dichloromethane (2 X 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4:' ethyl acetate/hexane to provide the title compound.
1H NMR (CDCI3) δ 9.70 (dd, J=1.3, 2.4Hz, 1H), 8.11 (d, J=7.8Hz, 1 H), 5.54 (m, 1H), 5.41 (t, J=5.8Hz, 1H), 4.52 (m, 1H), 4.13 (dd, J=4.4, 4.8Hz, 1 H), 3.75 (dd, J=2.7, 3.1Hz, 1H), 2.86 (m, 1 H), 2.47 (m, 3H), 1.99 (s, 3H), 1.63 (dd, J=1.6, 5.1Hz, 3H), 1.46 (s, 9H), 1.45 (m, 1H), 1.44 (s, 9H)
MS: (M+H)+ = 425; (M-H)" = 423.
-419- CH3 AcHN. Ji ,OtBu
H Boc O
198C fcW2R.3S.5R.1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-3-hvdroxy)propyl-3- (c/s-propen-1-vB-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (9 mg, 0.02 mmol) was reacted with sodium borohydride (1 mg, 0.02 mmol) in methanol (0.1 mL) at room temperature for 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride (1 mL) followed by extraction using dichloromethane (2 X 1 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/4: ethyl acetate/hexane to provide the title compound.
1H NMR (CDCI3) δ 8.45 (d, J=7.5Hz, 1 H), 5.55 (m, 1 H), 5.34 (t, J=7.8Hz, 1H), 4.20 (dd, J=3.0, 5.4Hz, 2H), 3.71 (d, J=6.1Hz, 1H), 3.62 (m, 1H), 3.50 (t, J=9.1Hz, 1 H), 2.92 (m, 1 H), 2.41 (m, 1 H), 2.04 (s, 3H), 1.66 (dd, J=2.0, 5.1Hz, 3H), 1.62 (m, 1 H), 1.47 (s, 9H), 1.45 (m, 1 H), 1.43 (s, 9H), 1.22 (m, 2H)
MS: (M+H)+ = 427; (M-H)" = 425.
-420-
198D (±W2R.3S,5R,1 'S 2-(1-Acetamido-3-hvdroxy)propyl-3-(c/'s-propen-1-vh- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)propyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)- 1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 4.6 mg, 100%).
1H NMR (DMSO-de) δ 9.25 (br s, 1H), 8.13 (d, J=7.3Hz, 1H), 5.52 (m, 1H), 5.28 (brt, 1H), 4.32 (brt, 1H), 4.22 (m, 1H), 3.49 (m, 4H), 3.18 (m, 1H), 2.40 (m, 1 H), 1.90 (s, 3H), 1.73 (m, 1H), 1.63 (dd, J=1.8, 5.5Hz, 3H), 1.57 (m, 1H)
MS: (M-H)" = 269; (M+H)+ = 271.
-421- Example 199
fc)-(2R.3S.5R.1 'S.3'S)-2-(1-Acetamido-3-hvdroxy)pentyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/O'Bu /O'Bu if o if
OH
199A (±W2R.3S.5R.1'S.3'S) and (±W2R.3S.5R.1'R.3'R)-1-f-Butoxycarbonyl-2- (1-acetamido-3-hvdroxy)ethyl-3-(c/'s-propen-1-vπ-pyrrolidine-5-carboxylic Acid f- Butyl Ester
(±)-(2R,3S,5R,1'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (26 mg, 0.061 mmol) was reacted with ethylmagnesium bromide (3.0 M) (0.122 mL, 0.367 mmol) in THF (4 mL) at room temperature for 30 minutes. The reaction was quenched with saturated aqueous ammonium chloride (10 mL) and water (10 mL) followed by extracfion using ethyl acetate (3 X 25 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 1/1 ethyl acetate/hexane followed by 2/1 ethyl acetate/hexane to provide the title compounds (±)-(2R,3S,5R,1'S,2'S) (yield: 6.7 mg, 24%) and (±)-(2R,3S,5R,1'S,2'R) (yield: 6.8 mg, 24%).
(±)-(2R,3S,5R,1'S,2'S) MS: (M+H)+=455, (M+Na)+=477, (M-H)"=453.
(±)-(2R,3S,5R,1'S,2'R) MS: (M+H)+=455, (M+Na)+=477, (M-H)"=453.
-422-
199B (±W2R.3S.5R.1'S.3'S)-2-(1-Acetamido-3-hvdroxy)pentyl-3-(c/s-propen-1- yl)-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'S,3'S)-1-f-butoxycarbonyl-2-(1- acetamido-3-hydroxy)pentyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 6.2 mg, 100%).
1H NMR (DMSO-de) δ 9.20 (bs, 1H), 8.18 (d, J=7.3 Hz, 1 H), 5.51 (m, 1H), 5.27 (m, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 3.58 (m, 1H), 3.41 (m, 1 H), 3.18 (m, 1H), 2.39 (m, 1 H), 1.90 (s, 3H), 1.75 (m, 1H), 1.64 (dd, J=7.5,1.5Hz, 3H), 1.51 (M, 1 H), 1.38 (m, 1H), 1.32 (m, 1H), 0.83 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321 , (M-H)" = 297, (2M-H)"=595.
-423- Example 200
fcW2R.3S.5R.1'S.3'R)-2-f1-Acetamido-3-hvdroxy)pentyl-3-(c/s-propen-1-ylV pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
/OH
Y TFA
The title compound was prepared according to the method described in Example 41C, substitufing (±)-(2R,3S,5R,1'S,3'R)-1-f-butoxycarbonyl-2-(1- acetamido-3-hydroxy)pentyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 6.5 mg, 100%).
1H NMR (DMSO-de) δ 9.25 (bs, 1 H), 8.15 (d, J=7.3 Hz, 1 H), 5.52 (m, 1H), 5.27 (m, 1H), 4.31 (m, 2H), 3.52 (m, 1H), 3.36 (m, 1 H), 3.19 (quint, J=8.5Hz, 1H), 2.38 (m, 1H), 1.92 (s, 3H), 1.75 (m, 1 H), 1.64 (dd, J=7.3,1.5Hz, 3H), 1.48 (m, 1H), 1.33 (m, 2H), 0.85 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 299, (M+Na)+ = 321 , (M-H)" = 297, (2M-H)"=595.
Example 201
-424- fc)-(2R.3S.5R.rR)-2-(1-Acetamido-2-oxo-3.3-difluoro-3-vinyl)propyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- Acetamido-2-oxo-3,3-difluoro-3-vinyi)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic Acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 0.0050 g, 100%).
1H NMR (DMSO-de) δ 8.67 (d, J=8.5Hz, 1 H), 6.1-5.95 (m, 1H), 5.78 (dd, J=17.1 , 2.4Hz, 1 H), 5.71 (d, 11.0Hz, 1 H), 5.45 (m, 1 H), 5.12 (m, 1H), 4.94 (t, J=9.2Hz, 1H), 4.51 (dd, J=12.2,6.1Hz, 1 H), 3.98 (m, 1H), 3.24 (m, 1H), 2.32 (m, 1H), 1.73 (s, 3H), 1.66 (q, J=11.9Hz, 1 H), 1.57 (dd, J=6.7,1.8Hz, 3H).
MS: (M+H)+ = 331 , (M+H2O)+=349, (M+Na)+ = 353, (M-H)" = 329, (2M-HV =659.
-425- Example 202
202A fcW2R.3R.5R.1'R.2'S) and fcW2R.3R.5R.1'R.2'R)-1-f-Butoxycarbonyl-2- (1-acetamido-2-hvdroxy)butyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5- carboxylic Acid f-Butyl Ester
The title compounds were prepared according to the method described in Example 41 B substitufing (±)-(2R,3R,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-formyl)ethyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido-2- formyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester to provide (±)-(2R,3R,5R,1'R,2'S) isomer (yield: 370 mg, 17%) and (±)- (2R,3R,5R,1'R,2'R) isomer (yield: 1.2 g, 55%).
(±)-(2R,3R,5R,1'R,2'S) H NMR(d6-DMSO) δ 7.4-7.65 (m, 10H), 4.47
(d, 1 H), 4.32 (m, 1H), 3.87 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 (m, 1H), 2.7 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1 H), 1.83 (d, 3H), 1.28-1.4 (m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H)
MS: (M-H)- = 667, (M+35)+ = 703; (M+H) + = 669, (M+Na) + = 691
(±)-(2R,3R,5R,1'R,2'R) ^ H NMR(d6-DMSO) δ 7.4-7.65 (m, 10H), 4.40
(dd, 1H), 4.12-4.32 (m, 1 H), 3.82-3.96 (m, 1 H), 3.66 (m, 2H), 3.52 (t, 1 H), 2.6-2.8 (m, 1H), 2.45 (m, 1H), 1.76-2.0 (m, 1 H), 1.87 (d, 3H), 1.25-1.4 (m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H).
MS: (M-H)- = 667, (M+35)+ = 703; (M+H) + = 669, (M+Na) + = 691
-426-
202B (±W2R.3R.5R.1'R.2'SV1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
(±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2- hydroxy)butyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxyiic acid f-butyl ester (0.58 g,0.87 mmole) was reacted with methoxymethyl chloride (1.15 mL, 10.07 mmole) and diisopropylethylamine (3.5 mL, 20.1 mmole) in dichloromethane (1 mL) at room temperature for 5 hours. The reaction was quenched with saturated NH CI (100 mL) and diluted with ethyl acetate (200 mL). The organic layer was washed with water, and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 5% methanol/methylene chloride to provide the title compound (yield: 0.64 g, 98%).
1 H NMR(d6-DMSO) δ 7.4-7.65 (m, 10H), 4.70 (s, 1H), 4.62 (s, 1H), 4.35-
4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1 H), 3.55 (m, 1 H), 3.25 (m, 1 H), 3.24 (s, 3H), 2.55 (m, 1 H), 2.45 (m, 1H), 2.0 (m, 1 H), 1.85 (s, 3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H)
MS: (M-H)- = 755, (M+35)+ = 791 ; (M+H) + = 757, (M+Na) + = 779
-427-
202C fc)-(2R.3R.5R.1'R.2'SV1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-hvdroxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123G substituting (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine- 5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl- 2-oxiranyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.416 g, 95%).
H NMR(d6-DMSO) δ 7.45 (t, 1H), 4.62-4.74 (m, 3H), 4.48 (m, 1 H), 3.85
(m, 2H), 3.55-3.6 (m, 2H), 3.45 (t, 1H), 3.2-3.4 (m, 2H), 3.25 (d, 3H), 2.4 (m, 2H), 1.82 (d, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.82 (dt, 3H).
MS: (M-H)- = 517, (M+35)+ = 553; (M+H) + = 519, (M+Na)+ = 541
-428-
202D fcW2R.3R.5R.1'R.2'S -f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123H substitufing (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-oxiranyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.335 g, 80.8%).
1H NMR(d6-DMSO) δ 9.55 (d, 1H), 7.48 (m, 1 H), 4.55-4.72 (m, 4H) 3.9
(d, 1 H), 3.6 (m, 2H), 3.45 (m, 3H), 3.32 (s, 3H), 3.05 (t, 1 H), 2.25-2.45 (m, 4H), 1.83 (s, 3H), 1.58 (m, 3H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).
MS: (M-H)" = 515, (M+35)+= 551 ; (M+H)+ = 517
-429- OH
≡≡—f
O'Bu o i
0
202E (±W2R.3R.5R.1'R.2'S.1"RS)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(1 -hvdroxy-2-propyn-1 vO-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 38A substituting (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-(1-acetamido-3- methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.27 g, 83%).
MS: (M-H)" = 541 , (M+35)+ = 577; (M+H)+ = 543, (M+Na)+ = 565
O'Bu
202F (±W2R.3R.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid f- Butyl Ester
The title compound was prepared according to the method described in Example 38B substituting fc)-(2R,3R,5R,1'R,2'S,1"RS)-1-f-butoxycarbonyl-2-(1-
^430- acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrroiidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S,1"RS)-1-f- butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-hydroxy-2-propyn-1-yl)- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.2 g, 74%).
1H NMR(d6-DMSO) δ7.49 (br d, 1H), 5.0 (d, 1H), 4.7 (br s, 1H), 4.55-4.7
(m, 3H), 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H)
MS: (M-H)" = 539, (M+35)+ = 575; (M+H)+ = 541 , (M+Na)+ = 563
202G (±)-(2R.3R.5R.1'R.2'SV1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(pyrazol-3-vn-Pyrrolidine-5-carboxvlic Acid f-Butvl Ester
The title compound was prepared according to the method described in Example 38C substituting (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2- (1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 180 mg, 87%).
-431- 1H NMR(d6-DMSO) δ 7.57 (br t, 2H), 6.1 (d, 1H), 4.50-4.7 (m, 4H) 3.95
(m, 1 H), 3.4-3.6 (m, 3H), 3.3-3.4(m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H), 2.2 (m, 1 H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (dt, 3H).
MS: (M-H)" = 553, (M+35)+ = 589; (M+H)+ = 553, (M+Na)+ = 577
HN
N
202H fcV(2R.3R.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxy)butyl-3-(pyrazol-3-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 1 K, substituting (±)-(2R,3R,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3- methoxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester. Chromatography on silica gel with 2-propanol:acetic acid.ethyl acetate:water 1:1 :3:1 followed by the addition of 0.1 % trifluoroacetic acid gave the title compound (yield: 15 mg, 55%).
lH NMR(dβ-DMSO) δ 7.95 (d, 1H), 7.65 (br s, 1H), 6,18 (d, 1 H), 4.37 (m,
1 H), 4.23 (m, 1 H), 4.38 (m, 1H), 4.56 (m, 1H), 2.63 (m, 1 H), 2.10 (m, 1H), 1.78 (s, 3H), 1.50 (m, 1 H), 1.25 (m, 1H), 0.83 (t, J=7.46 Hz, 3H).
MS: (M-H)- = 309, (M+35)+ = 345; (M+H) + = 311 , (M+Na) + = 333
-432- Example 203
(±W2R.3R.5R.1 'R.2'R)-2-(1 -Acetamido-2-hvdroxy)butyl-3-(pyrazol-3-vπ- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
203B fcW2R.3R.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compounds were prepared according to the method described in Example 202B substitufing (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-f-butyldiphenylsilyioxymethyl-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'R,2'S)-1-f- butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-f-butyldiphenylsilyloxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.217 g, 96%).
1H NMR(d6-DMSO) δ7.4-7.65 (m, 10H), 4.70 (s, 1 H), 4.62 (s, 1 H), 4.35-
4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1H), 3.55 (m, 1 H), 3.25 (m, 1 H), 3.24 (s, 3H), 2.55 (m, 1H), 2.45 (m, 1 H), 2.0 (m, 1 H), 1.85 (s, 3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H).
MS: (M-H)- = 755, (M+35)+ = 791 ; (M+H) + = 757, (M+Na) + = 779
-433-
203C (±)-(2R.3R.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-hvdroxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123G substituting (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine- 5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl- 2-oxiranyl-3-f-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.124' g, 83%).
1H NMR(d6-DMSO) δ 7.42 (dd, 1H), 4.62-4.8 (m, 3H), 4.48 (m, 1H), 3.6-
3.85 (m, 3H), 3.35-3.6 (m, 4H), 3.25 (s, 3H), 2.25 (m, 1H), 2.4 (m, 1 H), 2.28 (m, 1H), 1.82 (s, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.9 (dt, 3H).
MS: (M-H)" = 517, (M+35)+ = 553; (M+H)+ = 519, (M+Na)+ = 541
-434-
203D fcW2R.3R.5R.1 'R.2'RV1 -f-Butoxycarbonyl-2-(1 -acetamido-2- methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 123H substitufing (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyi-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2-oxiranyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 0.106 g, 86%).
H NMR(d6-DMSO) δ9.58 (d, 1H), 7.58 (dd, 1H), 4.6-4.72 (m, 3H),
4.48(d, 1H), 3.88 (d, 1H), 3.4-3.65 (m, 5H), 3.24 (s, 3H), 3.15 (dd, 1 H), 2.20-2.48 (m, 4H), 1.86 (s, 3H), 1.58 (m, 3H), 1.30-1.40 (m, 18H), 0.86 (t, 3H).
MS: (M-H)" = 515, (M+35)+ = 551 ; (M+H)+ = 517
-435- OH
J
203E (±W2R.3R.5R.1'R.2'R.1"RS)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(1-hvdroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 38A substitufing (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3R,5R,1'S,1"RS)-1-f-butoxycarbonyl-2-(1- acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 32 mg, 76%).
MS: (M-H)" = 541 , (M+35)+ = 577; (M+H)+ = 543, (M+Na)+ = 565
203F (±W2R.3R.5R.1'R.2'RV1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic Acid f- Butyl Ester
The title compound was prepared according to the method described in Example 38B substituting (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1-
-436- acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S,1"RS)-1-f- butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)- pyrroiidine-5-carboxylic acid f-butyl ester (yield: 25 mg, 78%).
1 H NMR(d6-DMSO) δ 7.49 (br d, 1 H), 5.0 (d, 1 H), 4.7 (br s, 1 H), 4.55-4.7
(m, 3H) 3.88 (br d, 1 H), 3.5-3.7 (m, 2H), 3.43 (t, 2H), 3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7 (m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).
MS: (M-H)" = 539, (M+35)+ = 575; (M+H)+ = 541 , (M+Na)+ = 563
HN^
O'Bu
203G (±W2R.3R.5R.1'R.2'R)-1-f-Butoxycarbonyl-2-(1-acetamido-2- methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 38C substituting (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-f-butoxycarbonyl-2- (1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 18 mg, 72%).
-437- H NMR(d6-DMSO) δ 7.57 (m, 2H), 6.1 (d, 1H), 4.40-4.7 (m, 4H) 3.93 (m,
1 H), 3.4-3.6 (m, 3H), 3.3-3.4(m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1 H), 2.2 (m, 1 H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (m, 3H).
MS: (M-H)" = 553, (M+35)+ = 589; (M+H)+ = 553, (M+Na)+ = 577
/OH {
TFA
203H (±W2R.3R.5R.1'R.2'RV2-(1-Acetamido-2-hvdroxy)butyl-3-(pyrazol-3-vh- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 15B, substituting (±)-(2R,3R,5R,1'R,2'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3- ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester. Chromatography on silica gel with 2-propanol:acetic acid:ethyl acetate:water 1 :1:3:1 followed by the addition of 0.1% trifluoroacetic acid gave the title compound (yield: 4 mg, 45%).
1 H NMR(d6-DMSO) δ 7.65 (d, 1H), 7.64 (d, 1H), 6,16 (d, 1H), 4.37 (m,
1 H), 4.23 (m, 1 H), 4.38 (m, 1 H), 4.56 (m, 1H), 2.63 (m, 1 H), 2.10 (m, 1 H), 1.74 (s, 3H), 1.25-1.40 (m, 2H), 0.83 (t, J=7.46 Hz, 3H).
MS: (M-H)" = 309, (M+35)+ = 345; (M+H)+ = 311 , (M+Na)+ = 333
-438- Example 204
fc)-(2R,3R,5R)-2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic Acid Hydrochloride.
TBDMSO--N
H 2 ^ λ. /0tBu
Ph
204A (±V(2R.3R.5R)-1-Benzyl-2-aminomethyl-3-f-butyldimethylsilyloxymethyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound is prepared according to the method described in Example 1 F, substituting (±)-(2R,3R,5R)-1-benzyl-2-formyl-3-f- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-t-butyldimethylsilyloxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
MS: (M+H)+= 435
TBDMSO--
AcNH. X OtBu π Ph i
204B (±W2R.3R.5R)-1 -Benzyl-2-acetamidomethyl-3-f- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound is prepared according to the method described in Example 1G, substituting (±)-(2R,3R,5R)-1-benzyl-2-aminomethyl-3-f- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'R)- and (±H2R,3R,5R,rS)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3- t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxyiic acid f-butyl ester.
-439- 1H NMR (CDCI3): δ 7.2-7.35 (m, 5H), 6.14 (br, 1H), 3.86 (dd, J=18Hz, 13.5Hz, 2H), 3.67 (m, 1 H), 3.60 (m, 1 H), 3.49 (m, 1 H), 3.28 (m, 1 H), 3.06 (m, 1H), 2.19 (m, 2H), 1.95 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H), 0.07 (s, 6H).
MS: (M+H)+= 477
HO^
Ac H^ X OtBu
Ph
204C (±W2R.3R.5RV1-Benzyl-2-acetamidomethyl-3-hvdroxymethyl-pyrrolidine- 5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 1H, substituting (±)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-f- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-f- butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester. o
H J
AcNH. OtBu
Ph
204D fcW2R,3R.5R)-1-Benzyl-2-acetamidomethyl-3-formyl-pyrrolidine-5- carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 2A, substituting (±)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3- hydroxymethyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydrxoxymethyl- pyrrolidine-5-carboxylic acid f-butyl ester.
-440- 1H NMR (CDCI3): δ 9.70 (s, 1H), 7.22-7.36 (m 5H), 5.82 (br, 1H), 3.83 (dd, J= 3.3Hz, 13.5Hz, 2H), 3.74 (m, 1 H), 3.56 (d, J= 9Hz, 1 H), 3.15 (m, 1H), 2.73 (m, 1 H), 2.36-2.10 (m, 2H), 1.98 (s, 3H), 1.45 (s, 9H).
MS: (M+H)+= 361
O
CH30 J
AcNH. ^ X OtBu
»l Ph ϊ
204E fcW2R.3R.5R)-1-Benzyl-2-acetamidomethyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 2B and 2C, substituting (±)-(2R,3R,5R)-1 -benzyl -2-acetamidomethyl-3- formyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-1- benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylic acid f-butyl ester.
1H NMR (CDCI3): δ 7.45-7.20 (m, 5H), 5.96 (br, 1 H), 3.90-3.73 (m, 4H), 3.71 (s, 3H), 3.52 (dd, J=9Hz, 2Hz, 1 H), 3.13 (m, 1H), 2.84 (m, 1 H), 2.36 (m, 1H), 2.18 (m, 1H), 1.97 (s, 3H), 1.45 (s, 9H).
MS: (M+H)+= 391
-441- O
CH30 J
AcNH^ J X OtBu
H ϊ H ϊ O
204F (±W2R.3R.5R)-2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5- carboxylic Acid f-Butyl Ester
The title compound was prepared according to the method described in Example 2D, substituting (±)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3- methoxycarbonyl-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)- (2R,3R,5R,1'S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl- pyrroiidine-5-carboxylic acid f-butyl ester.
1H NMR (CDCI3): δ 6.19 (br, 1 H), 3.72 (m, 2H), 3.70 (s, 3H), 3.43 (m, 1H), 3.28 (m, 1H), 2.74 (m, 1 H), 2.44 (m 1 H), 2.21 (m, 1H), 2.00 (s, 3H), 1.48 (s, 9H).
MS: (M+H)+= 301
O
CH3O J
AcNH^ X OH
HCl
204G (±W2R,3R.5RV2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5- carboxylic Acid Hydrochloride.
The title compound was prepared according to the method described in Example 2E substituting (±)-(2R,3R,5R)-2-acetamidomethyl-3-methoxycarbonyl- pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3R,5R,1'S)-2-(1- acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylic acid f-butyl ester.
-442- 1H NMR (D20): δ 4.42 (t, J=8.25Hz, 1 H), 4.22 (m, 1 H), 3.83 (m, 1 H), 3.75 (s, 3H), 3.70-3.60 (m, 2H), 3.26 (m, 1H), 2.78 (m, 1H), 2.43 (m, 1 H), 2.03 (s, 3H).
MS: (M+H)+= 245
Examples 205-213 HO-. R
AcHN O'Bu AcHN. X PH
N Boc Y II M H Y o
Example 204C
The following title compounds were prepared according to the methods described in Examples 1-39 from the common intermediate prepared as described in Example 204C.
Example 205
.0
O J(
AcHN^ \ OH
" TAFA t
(±)-(2R.3R,5R)-2-Acetamidomethyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) δ 4.30 (t, J=8.2Hz, 1H), 4.21 (m, 3H), 3.62 (dd, J=2.4, 3.4Hz, 2H), 3.23 (m, 1 H), 2.74 (m, 1H), 2.38 (m, 1 H), 2.02 (s, 3H), 1.26 (m, 3H)
MS: (M+H)+ = 259; (M-H)" = 257.
-443- Example 206
X"N HN-
HCl
(±)-(2R.3R.5R)-2-Acetamidomethyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylic Acid Hydrochloride
1H NMR (D2O): δ 7.46 (s, 2H), 4.53 (dd, J=9.5Hz, J=8.5 Hz, 1H), 4.28 (m, 1 H), 3.96 (m, 1 H), 3.65 (m, 2H), 3.03 (dt, J=13.5Hz, J=7.6Hz, 1H), 2.46 (m, 1H), 1.94 (s, 3H).
MS: (M+H)+=253, (M-H)"=251
Example 207
H H
TFA
(±)-(2R.3S,5R)-2-Acetamidomethyl-3-vinyl-Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) δ 5.74 (m, 1 H), 5.24 (m, 2H), 4.20 (dd, J=1.7, 8.1 Hz, 1H), 3.65 (m, 2H), 3.50 (m, 1 H), 2.84 (m, 1 H), 2.61 (m, 1 H), 2.03 (s, 3H), 1.95 (m, 1H)
-444- MS: (M+H)+ = 213.
Example 208
H3C
H3C '/— ΛcHNχ^.γOH
H O TFA
(±)-(2R.3R.5R)-2-Acetamidomethyl-3-(2,2-dimethyl-vinvh-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) δ 5.01 (br d, 1H), 4.18 (dd, J=2.1, 8.1Hz, 1 H), 3.53 (m, 3H), 3.04 (m, 1H), 2.55 (m, 1 H), 2.0 (s, 3H), 1.75 (m, 1H), 1.72 (s, 3H), 1.67 (s, 3H)
MS: (M+H)+ = 241 , (M+Na)+ = 263; (M-H)" = 239.
Example 209
H3C 0
NX
H3C '/— V
AcHN rJ H H y £0H HCl
(±)-(2R.3R.5RV2-Acetamidomethyl-3-(N.N-dimethylcarbamoyl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) δ 4.60 (t, J=8.4Hz, 1 H), 4.23 (m, 1 H), 3.56 (d, J=5.8Hz, 2H) 3.50 (m, 1H), 3.10 (s, 3H), 2.94 (s, 3H), 2.88 (m, 1 H), 2.19 (m, 1 H), 2.00 (s, 3H)
MS: (M+H)+ = 258, (M-H)" = 256.
-445- Example 210
H3C o
HNX" . /0H
AcHN Y β TFA
(±W2R,3R,5R)-2-Acetamidomethyl-3-(N-methylcarbamoyl)-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) 4.49 (t, J=8.5Hz, 1 H), 4.10 (m, 1 H), 3.57 (d, J=5.8Hz, 2H), 3.03 (m, 1H), 2.76 (m, 1 H), 2.74 (s, 3H), 2.29 (m, 1 H), 2.00 (s, 3H)
MS: (M+H)+ = 244.
Example 211
H3C p y/
• /OH
AcHN ■ ■ π o TFA
(±)-(2R.3R,5R)-2-Acetamidomethyl-3-propionyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) δ 4.24 (m, 2H), 3.55 (d, J=4.7Hz, 1 H), 3.40 (m, 1 H), 2.85 (m, 1H), 2.64 (m, 3H), 2.16 (m, 1H), 2.01 (s, 3H), 1.02 (t, J=7.1Hz, 3H)
MS: (M+H)+ = 243; (M-H)" = 241.
-446- Example 212
H3C
AcHN H H £ HCl
(±)-(2R.3R.5R 2-Acetamidomethyl-3-methoxymethyl-pyrrolidine-5-carboxylic Acid Hydrochloride
1H NMR (D2O): δ 4.44 (t, J=6Hz, 2H), 3.77 (m, 1H), 3.65-3.48 (m, 3H), 3.35 (s, 3H), 2.64 (m, 1 H), 2.56 (m, 1 H), 2.03 (s, 3H), 2.00 (m, 1H).
MS: (M+H)+= 231 , (M-H)" = 229
Example 213
H3Q,
AcHN Ύ £OH TFA
(±W2R.3S,5RV2-Acetamidomethyl-3-methyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
1H NMR (D2O) δ 4.30 (m, 1 H), 3.64 (m, 1 H), 3.48 (m, 1H), 3.20 (m, 1H), 2.64 (m, 1H), 2.03 (s, 3H), 1.76 (m, 1 H), 1.32 (br t, 1H), 1.12 (m, 4H)
MS: (M+H)+ = 201 , (M+Na)+ = 223.
-447- Example 214
(±W2R.3S.5R.1 'RV2-(1 -Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
214A (±)-(2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-(1-f-butoxycarbonylamino-2- ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
To a solution of ethanethiol (0.047 mL, 0.63 mmol) in THF (2 mL) at 0°C was added 2.5 M n-BuLi/hexane (0.248 mL, 0.62 mmol). The reaction mixture was stirred for 45 minutes and a solution of (±)-(2R,3S,5R,1'S)-1-f- butoxycarbonyl-2-(N-f-butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (0.08 g, 0.182 mmole) in THF (0.5 mL) was added followed by DMF (1.5 mL) and stirred at room temperature for 2 hours. The reaction was quenched with 1N NaHCO3 (10 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water.and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 61 mg, 67%).
1 H NMR(d6-DMSO) δ 6.74 (br d, 1 H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.20 (m, 1H), 3.95 (m, 1H), 3.75 (d, 1H), 2.8-3.0 (dd, 1H), 2.5 (m, 3H), 1.65 (m, 1H), 1.32-1.45 (m, 27H), 1.17 (dt, 3H).
MS: (M-H)" = 499; (M+H)+ = 501, (M+Na)+ = 523
-448-
214B fcW2R.3S.5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylacetamido- 2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylamino-2- ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (58 mg, 0.116 mmole) was reacted with lithium hexamethyldisilazide (1 M) (1.16 mL, 1.16 mmole) in THF (3 mL) at -78 °C. After 0.5 hour at -78 °C and 1 hour at -40 °C, the above reaction mixture was reacted with acetyl chloride (0.166 mL, 2.33 mmole) at -30 °C for 0.3 hours. The reaction was quenched with 1N NaHCO3 (10 mL) and extracted with ethyl acetate (20 mL). The organic layer was washed with water.and brine, dried over MgSO , filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel using 10% ethyl acetate/hexanes to provide the title compound (yield: 28 mg, 44%).
1H NMR(d6-DMSO) δ 5.88 (m, 1 H), 4.9-5.0 (m, 2H), 4.52 (m, 1H), 4.33
(m, 1 H), 4.1 (m, 1 H), 2.78 (dd, 1 H), 2.3-2.5 (m, 6H), 1.7 (m, 1H), 1.32-1.5 (m, 27H), 1.11 (t, 3H).
MS: (M+H) + = 543.
-449-
214C (±W2R.3R.5R.1'RV2-(1-Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)butyl-3-(c s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 7 mg, 95%).
H NMR(d6-DMSO) δ 8.15 (d, 1H), 5.72 (m, 1 H), 5.05-5.2 (m, 2H), 4.2-
4.4 (m, 2H), 4.33 (m, 1H), 2.93 (m, 1 H), 2.7-2.8 (2d, 1 H), 2.3-2.6(m, 3H), 1.85- 1.95 (m, 1H), 1.93 (s, 3H), 1.17 (t, J=7.46 Hz, 3H)
MS: (M+H) + = 287.
-450- Example 215
(±W2R.3S.5R.1 'R.3'S)-2-(1 -Acetamido-2-ethylsulfinvπethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
215A (±W2R.3S.5R.1'R.3'S) and (±W2R.3S.5R.1'R.3'R)-1-f-Butoxycarbonyl-2- (1-N-f-butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylacetamido- 2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (72 mg, 0.132 mmole) was reacted with 55% m-chloroperoxybenzoic acid (41 mg, 0.132 mmole) in CHCI3 (1.5 mL) at -40 °C for 30 minutes. The reacfion was concentrated in vacuo. The residue was purified by chromatography on silica gel using ethyl acetate to provide the title compounds (±)-(2R,3S,5R,1'R,3'S) isomer (yield: 14 mg, 18.9%) and (±)-(2R,3S,5R,1'R,3'R) (yield: 45 mg, 60.7%).
(2R,3S,5R,1'R,3'S) 1 H NMR(d6-DMSO) δ 5.88 (m, 1H), 4.9-5.0 (m, 2H),
4.50 (m, 1H), 4.0-4.15 (m, 1H), 2.7-2.9 (m, 3H), 2.55 (m, 1 H), 2.37 (s, 3H), 1.7 (m, 1H), 1.32-1.5 (m, 27H), 1.12 (t, 3H)
MS: (M+H) + = 559, (M+Na) + = 581
-451- (2R,3S,5R,1'R,3'R) 1 H NMR(d6-DMSO) δ 5.88 (m, 1H), 4.9-5.0 (m, 2H),
4.50 (m, 1 H), 4.03-4.15 (m, 1H), 3.2 (m, 1 H) 3.1 (dd, 1 H), 2.5-2.7(m, 2H), 2.38 (s, 3H), 1.75 (m, 1 H), 1.32-1.5 (m, 27H), 1.12 (t, 3H)
MS: (M+H) + = 559, (M+Na) + = 581
215B (±)-(2R.3S.5R.1'R.3'SV2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,3'S)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester, ester (yield: 9 mg, 86%).
H NMR(dβ-DMSO) δ 8.39 (d, 1 H), 5.72 (m, 1H), 5.15-5.2 (dd, 2H), 4.5
(m, 1 H), 4.37 (m, 1H), 3.65 (m, 1H), 2.85-3.04 (m, 3H), 2.6-2.85 (m, 2H), 2.4 (m, 1H), 1.83-1.95 (m, 1H), 1.86 (s, 3H), 1.20 (t, J=7.46 Hz, 3H).
MS: (M-H)" =301; (M+H)+ = 303, (M+Na)+ = 325
-452- Example 216
fcW2R.3S.5R.1 'R.3'R)-2-(1 -Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
OH
The title compound was prepared according to the method described in Example 41C, substitufing (±)-(2R,3S,5R,1'R,3'R)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl 2-(1- acetamido-2-hydroxy)butyl-3-(c s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 12 mg, 94%).
1H NMR(d6-DMSO) δ 8.39 (d, 1H), 5.72 (m, 1 H), 5.15-5.2 (dd, 2H), 4.53
(m, 1 H), 4.41 (t, 1H), 3.65 (m, 1 H), 3.2 (dd, 1H), 2.9-3.0 (m, 2H), 2.65-2.9(m, 2H), 2.4(m, 1 H), 1.83-1.95 (m, 1 H), 1.83 (s, 3H), 1.20 (t, J=7.46 Hz, 3H)
MS: (M-H)- =301 ; (M+H) + = 303, (M+Na) + = 325
-453- Example 217
(±W2R.3S.5R.1'R)-2-(1-N-f-butoxycarbonylacetamido-2-ethylsulfonvnethyl-3- vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
217A (±W2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylacetamido- 2-ethylsulfonv0ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1'R,3'R)-1-f-Butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (25 mg, 0.0448 mmole) was reacted with 55% m- chloroperoxybenzoic acid (14 mg, 0.0448 mmole) in CHCI3 (1.5 mL) at 0 °C for one hour. The reacfion was concentrated in vacuo. The residue was purified by chromatography on silica gel using 25% ethyl acetate/hexane to provide the title compound (yield: 23.7 mg, 92%).
H NMR(d6-DMSO) δ 5.88 (m, 1 H), 4.85-5.0 (m, 2H), 4.38 (m, 1 H), 4.15
(m, 1H), 3.7 (m, 1H) 3.45 (dd, 1 H), 2.9-3.2 (m, 3H), 2.5-2.7 (m, 1 H), 2.3-2.4 (m, 3H), 1.6-2.04 (m, 1 H), 1.35-1.55 (m, 27H), 1.15 (t, 3H)
MS: (M+H)+ = 575
-454- AcHN, / \ OH
0 0 TFA
217B (±)-(2R.3S.5R.rRV2-(1-Acetamido-2-ethylsulfonvnethyl-3-vinyl-pyrrolidine- 5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substitufing (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyI-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 12 mg, 94%).
1 H NMR(d6-DMSO) δ 8.34 (d, 1 H), 5.72 (m, 1 H), 5.05-5.25 (dd, 2H), 4.68
(m, 1H), 4.39 (dd, 1 H), 3.7 (2d, 1 H), 3.48 (dd, 1 H), 3.3-3.4 (dd, 2H), 3.08 (q, 2H), 2.95 (m, 1H), 2.42 (m, 1 H), 1.9 (m, 1 H), 1.84 (s, 3H), 1.23 (t, J=7.46 Hz, 3H).
MS: (M-H)" = 317, (M+35)+ = 353; (M+H)+ = 319, (M+Na)+ = 341
Examples 218. 220
1. RSH O'Bu
D Y 2- LiHMDS/AcCI
BocHN J H BOC H 3- TFA/CH2CI2
The following title compounds were prepared in 3 steps according to the methods described in Example 214.
-455- Example 218
(±W2R.3S.5R.1'R)-2-(1-Acetamido-2-isopropylthio ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
BocHN. O'Bu
218A (±W2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylamino-2- isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 214A, substituting isopropylthiol in place of ethanethiol (yield: 22 mg, 62%).
1 H NMR(d6-DMSO) δ 6.73 (d, 1H), 5.85 (m, 1 H), 4.9-5.0 (m, 2H), 4.18 (m,
1 H), 3.95 (m, 1 H), 3.75 (br d, 1 H), 2.8-3.0 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 (m, 27H), 1.18 (dd, 6H)
MS: (M-H)- = 513; (M+H) + = 515, (M+Na) + = 537
218B (±V(2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-(1-(N-f-butoxycarbonyl-N- acetamido)-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 214B, substituting (±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f- butoxycarbonylamino-2-isoproylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-
-456- butyl ester in place of (±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f- butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 12 mg, 50%).
1 H NMR(d6-DMSO) δ 5.86 (m, 1 H), 4.88-5.0 (m, 2H), 4.54 (m, 1 H), 4.33
(m, 1 H), 4.13 (d, 1H), 3.05 (m, 1H), 2.73-2.84 (m, 2H), 2.38 (br s, 3H), 1.72 (m, 1H), 1.32-1.5 (m, 27H), 1.14 (dd, 6H).
MS: (M+H) + = 557, (M+Na) + = 579
AcH . JL y OH
., » TAFA
218C (±W2R.3S.5R.1'R)-2-(1-Acetamido-2-isopropylthio)ethyl-3-vinyl- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 15B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 8 mg, 97%).
1H NMR(d6-DMSO) δ 8.14 (d, 1 H), 5.72 (m, 1 H), 5.05-5.2 (dd, 2H), 4.2-
4.4 (m, 2H), 3.68 (dd, 1 H), 2.93 (m, 2H), 2.74 (dd, 1 H), 2.58 (dd, 1 H), 1.93 (m, 1 H), 1.87 (s, 3H), 1.2 (t, 6H)
MS: (M-H)- = 299; (M+H) + = 301, (M+Na) + = 323
-457- Example 219
(±W2R.3S.5R.1 'R)-2-(1-Acetamido-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloride
219A (±)-(2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-amino-2-phenylthio)ethyl-3- vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R,1 'S)-1-f-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrroiidine-5- carboxylic acid t-butyl ester (20.3 mg, 0.06 mmole) was reacted with the phenylthiol (19.9 mg, 0.18 mmol) and triethylamine (0.047 mL, 0.34 mmol) in MeOH (0.06 mL) at ambient temperature for 3.5 hours. The reaction solution was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel using ethyl acetate/methanol/ammonium hydroxide, 99/0.05/0.05, to provide the title compound (yield: 20.7 mg, 77%).
1 H NMR (d6-DMSO) δ 7.31 (m, 4H), 7.17 (m, 1H), 5.87 (m, 1 H), 5.03 (d, J=17Hz, 0.4H), 5.01 (d, J=17Hz, 0.6H), 4.91 (d, J=11 H, 0.4H), 4.90 (d, J=11Hz, 0.6H), 4.15 (m, 1 H), 3.82 (m, 0.6H), 3.76 (m, 0.4H), 3.39(m, 1 H), 2.92 (m, 2H), 2.55 (m, 1 H), 1.64 (m, 2H), 1.42 (s, 5.4H), 1.37 (s, 3.6H), 1.34 (s, 5.4H), 1.22 (s, 3.6H)
MS: (M+H)+ = 449, (M+Na)+ = 471
-458-
219B (±)-(2R.3S.5R.1'R 1-f-Butoxycarbonyl-2-(1-acetamido-2-phenylthio ethyl- 3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
(±)-(2R,3S,5R, 1'R)-1-f-Butoxycarbonyl-2-(1 -amino -2-phenylthio)ethyl-3- vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (17.2 mg, 0.04 mmole) was reacted with the acetic anhydride (0.011 mL, 0.11 mmol) and triethylamine (0.032 mL, 0.23 mmol) in CH2CI2 (0.3 mL) at rt for 4.25 hours. The reaction solution was concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel using 5% methanol/dichloromethane to provide the title compound.
1H NMR (ds-DMSO) d 7.75 (d, J=9Hz, 0.6H), 7.73 (d, J=9Hz, 0.4H), 7.32 (m, 4H), 7.19 (m, 1H), 5.87 (m, 1H), 5.04 (d, J=17Hz, 0.4H), 5.00 (d, J=17Hz, 0.6H), 4.95 (d, J=10Hz, 0.6H), 4.93 (d, J=10Hz, 0.4H), 4.59 (m, 0.4H), 4.45(m, 0.6H), 3.99 (dd, J=10Hz, 2Hz, 0.6H), 3.94 (dd, J=10Hz, 2.5Hz. 0.4H), 3.84 (m, 0.6H), 3.77 (m, 0.4H), 3.07 (dd, 13Hz, 5Hz, 0.6H), 2.95 (m, 1.8H), 2.83 (br t, J=8Hz, 0.6H), 2.48 (m, 1H), 1.84 (s, 1.2H), 1.81 (s, 1.8H), 1.68 (m, 1 H), 1.41 (s, 5.4H), 1.36 (s, 3.6H), 1.34 (s, 5.4H), 1.26 (s, 3.6H)
MS: (M-H)" = 489, (M+35V; (M+H)+ = 490, (M+Na)+ = 513
-459- AcHN. \ OH
S' HCl °
219C (±)-(2R.3S.5R.1'RV2-(1-Acetamido-2-phenylthio ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Hydrochloride
The title compound was prepared according to the method described in Example 1K, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester in place of (±)- (2R,3R,5R,1'S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5- carboxylic acid f-butyl ester (yield: 14.6 mg, 100%.)
1H NMR(d4-methanol) δ 7.43 (m, 2H), 7.31 (m, 3H), 5.75 (ddd, J=17Hz,
10Hz, 8Hz, 1 H), 5.32 (br d, J=17Hz, 1H), 5.19 (dd, J=10Hz, 1.4Hz, 1H), 4.58 (m, 2H), 3.89 (dd, J=10Hz, 3Hz, 1 H), 3.19 (dd, J=14Hz, 6Hz, 1H), 3.09 (dd, J=14Hz, 9Hz, 1H), 3.04 (m, 1H), 2.57(dt, J=13Hz, 7Hz, 1H), 2.04 (s, 3H), 2.03 (m, 1H)
MS: (M-H)" = 333; (M+H)+ = 335, (M+Na)+ = 357
-460- Example 220
(±)-(2R.3S.5R.1'R -2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidiπe-5- carboxylic Acid Trifluoroacetic Acid Salt
BocHN. ^y.^ /°'Bu yjJ" goc °
220A (±)-(2R.3S.5R.1'R -1-f-Butoxycarbonyl-2-(1-N-f-butoxycarbonylamino-2- benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester
The title compound was prepared according to the method described in Example 214A, substituting benzylmercaptan in place of ethanethiol (yield: 28 mg, 72%).
H NMR(d6-DMSO) δ 7.2-7.35 (m, 5H), 6.80 (br d, 1 H), 5.84 (m, 1 H),
4.86-4.96 (m, 2H), 4.25(m, 1 H), 3.95 (m, 1H), 3.7-3.8 (m, 3H), 2.76-2.94 (m, 1H), 2.35-2.45 (m, 2H), 1.65 (m, 1 H), 1.32-1.45 (m, 27H)
MS: (M-H)- = 561; (M+H) + = 563, (M+Na) + = 585
-461-
220B (±W2R.3S.5R.1'R -1-f-Butoxycarbonyl-2-(1-(N-f-butoxycarbonyl- acetamido)-2-benzylthio thyl-3-vinyl-pyrrolidine-5-carboxylic Acid t-Butyl Ester.
The title compound was prepared according to the method described in Example 214B, substituting (±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f- butoxycarbonylamino-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t- butyl ester in place of (±)-(2R,3S,5R,1'R)-1-f-Butoxycarbonyl-2-(1-N-f- butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester (yield: 3.3 mg, 61%).
H NMR(d6-DMSO) δ 7.2-7.35 (m, 5H), 5.84 (m, 1 H), 4.86-4.96 (m, 2H),
4.55(m, 1H), 4.32 (d, 1H), 4.05 (d, 1 H), 3.56-3.65 (m, 2H), 2.9 (m, 1H), 2.3-2.65 (m, 3H), 2.42 (s, 3H), 1.76 (d, 1H), 1.25-1.55 (m, 27H)
MS: (M+H) + = 605, (M+Na) + = 627
220C (±W2R.3S.5R.1'R)-2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-N-f- butoxycarbonylacetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid
-462- t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 2.2 mg, 95%).
H NMR(d6-DMSO) δ 8.18 (d, 1H), 7.2-7.32 (m, 5H), 5.68(m, 1 H), 5.02-
5.2 (m, 2H), 4.3-4.45 (m, 2H), 3.76 (s, 2H), 3.68 (dd, 1H), 2.92 (m, 1 H), 2.62 (dd, 1 H), 2.32-2.55(m, 2H), 1.85-1.95 (m, 1H), 1.89 (s, 3H).
MS: (M-H)" = 347; (M+H)+ = 349, (M+Na)+ = 371
Example 221
(±W2R.3S.5R.1'R)-2-(1-Acetamido-2-(4-pyridinethio)ethyl-3-vinyl-Pyrrolidine-5- carboxylic Acid Dihvdrochloride.
The title compound was prepared according to the method of Example 219A-C substituting 4-thiopyridine for thiophenol as the reagent in Example 219A.
1H NMR(d4-methanol) d 8.57 (d, J=7Hz, 2H), 7.97 (d, J=7Hz, 2H), 5.85 (ddd, J=17Hz, 10Hz, 9Hz, 1H), 5.40 (br d, J=17Hz, 1H), 5.25 (dd, J=17Hz, 10Hz, 1H), 4.67 (dt, J=10Hz, 4Hz, 1H), 4.47 (dd, J=10Hz, 8Hz, 1 H), 4.01 (dd, J=10Hz, 4Hz, 1H), 3.68 (dd, J=14Hz, 5Hz, 1 H), 3.45 (dd, J=14Hz, 10Hz, 1 H). 3.16 (m, 1H), 2.65 (dt, J=14Hz, 7Hz, 1H), 2.07 (m, 1H), 2.04 (s, 3H)
MS: (M-H)" = 334; (M+H)+ = 336, (M+Na)+ = 358
-463- Example 222
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy butyl-3-(c s-propen-1-vn- pyrrolidine-5-carboxylic Acid Ethyl Ester.
Thionyl chloride (1.49 mL, 20.5 mmol) was reacted with ethanol (25 mL) at 0°C for 10 minutes. (±)-(2R,3S,5R, 1 'R,2'S)-2-(1 -Acetamido-2-hydroxy)butyl-3- (c s-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (815 mg, 2.05 mmol) in ethanol (50 mL) was added to the above solution and reacted at room temperature for 17 hours. The reaction was concentrated in vacuo and the residue was purified by chromatography on silica gel with 90/10/0.5 dichloromethane / methanol / ammonium hydroxide to provide the title compound as a white solid (yield: 462 mg, 72%).
1H NMR (DMSO-de) δ 7.49 (d, J = 9.8 Hz, 1 H), 5.31 (m, 2H) 4.11 (m, 2H), 3.72 (t, J = 7.7 Hz, 1 H), 3.69 (m, 1 H), 3.42 (m, 1 H), 3.07 (m, 1 H), 2.85 (m, 1 H), 2.22 (m, 1 H), 1.76 (s, 3H), 1.54 (d, J = 5.6 Hz, 3H), 1.45 (m, 1 H), 1.39 (m, 1 H), 1.21 (m, 1 H), 1.19 (t, = 7.0 Hz, 3H), 0.83 (t, J = 7.3 Hz, 3H).
MS: (M+H)+= 313, (M+Na)+= 335, (M-H)" = 311.
-464- Example 223
(±W2R.3R.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy)butyl-3-(pyrazol-3-vh- pyrrolidine-5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in Example 222, substitufing (±)-(2R,3R,5R,1'R,2'S)-2-(1-acetamido-2- hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (±)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic trifluoroacetic acid salt (yield: 32 mg, 52%).
1H NMR(d6-DMSO) δ 7.6 (br s, 1H), 6.1 (br s, 1H), 4.08 (q, J=7.12Hz,
2H), 3.78 (m, 1 H), 3.65 (m, 1H), 3.55 (m, 1H), 3.45 (m, 1 H), 3.25 (m, 1H), 3.45 (m, 1 H), 1.72 (s, 3H), 1.45 (m, 1 H), 1.2 (m, 1H), 1.16 (t, J=7.12 Hz, 3H), 0.82 (t, J=7.46 Hz, 3H).
MS: (M-H)" = 337, (M+35)+ = 373; (M+H)+ = 339, (M+Na)+ = 361
-465- Example 224
fcW2R.3S.5R.1'S.3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in Example 222, substituting (±)-(2R,3S,5R,1'S,3'S)-2-(1-acetamido-2-(N-isopropyl)- N-methylamino-N-oxide))ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (±)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2- hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 25 mg, 34%).
1H NMR (MeOD-d3) δ 5.51-5.43(m, 1 H), 5.34-5.27(m, 1 H), 4.36-4.30(m, 1H), 4.18(q, J=7.1Hz, 2H), 3.88(dd, J=6.8, 8.8Hz, 1H), 3.82-3.67(m, 2H), 3.49- 3.42(m, 1H), 3.34(s, 3H), 3.14-2.96(m, 1H), 2.42-2.33(m, 1H), 1.92(s, 3H), 1.64- 1.52(m, 1H), 1.63(dd, J=1.7, 6.8Hz, 3H), 1.41-1.24(m, 1 H), 1.39(d, J=6.4Hz, 3H), 1.31(d, J=6.4Hz, 3H), 1.26(t, J=7.1 Hz, 3H).
MS: (M+H)+=356, (M+Na)+=378, (M-HV=354, (M+35)+=390.
-466- Example 225
(±)-(2R.3S.5R.1'S)-2-(1-Acetamido-3-methvnbutyl-3-(c/s-propen-1-vπ-pyrrolidine- 5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in Example 222, substituting (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3- (c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid trifluoroacetic acid salt in place of (±)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 838 mg, 94%).
1H NMR (CDCI3): δ 5.50 (m, 1H), 5.41 (m, 1H), 5.28 (m, 1H), 4.21 (q, J=7.5Hz, 2H), 4.06 (m, 1H), 3.87 (t, J=7.5Hz, 1H), 3.10 (m, 1H), 2.97 (m, 1H), 2.39 (m, 1H), 1.97 (s, 3H), 1.66 (dd, 3H), 1.60 (m, 1H), 1.40 (m, 2H), 0.94 (d, J=7.5Hz, 3H), 0.93 (d, J=7.5 Hz, 3H).
MS: (M+H)+=311
-467- Example 226
Cl X,/ 0Et
fc)-(2R.3S.5R.1'S)-2-(1-Acetamido-3-methyl)butyl-3-(c/'s-2-chloro-vin-1-vn- pyrrolidine-5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in Example 222, substituting (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3- (c/s-2-chloro-vin-1-yl)-pyrrolidine-5-carboxyiic acid trifluoroacetic acid salt in place of (±)-(2R,3S,5R,rR,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 46%).
1H NMR (CDCI3): δ 6.05 (d, J=7.5Hz, 1 H), 5.90 (dd, J1=9 Hz, J2=6Hz, 1H), 5.31 (d, J=9Hz, 1 H), 4.19 (q, J=7.5Hz, 2H), 4.06 (m, 1 H), 3.82 (t, J=7.5Hz, 1H), 3.17 (m, 2H), 2.45 (m, 1H), 1.98 (s, 3H), 1.67 (m, 1 H), 1.60 (m, 1 H), 1.37 (m, 2H), 1.27 (t, J=7.5Hz, 3H), 0.91 (d, J=7.5Hz, 3H), 0.89 (d, J=7.5Hz, 3H).
MS: (M+H)+= 331
Example 227
Intentionally blank.
-468- Example 228
(±W2R.3S.5R.1'S -2-(1-Acetamido-3-methvnbutyl-3-(2.2-difluoro-vinvn- pyrrolidine-5-carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in Example 222, substituting (±)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3- (2,2-difluoro-vinyl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (±)-(2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 28 mg, 57%).
1H NMR (CDCI3): δ 4.22 (q, J=7.5 Hz, 2H), 4.14 (m, 1H), 4.03 (m, 1H), 3.29 (br, 1 H), 2.85 (m, 1H), 2.52 (m, 1H), 2.01 (s, 3H), 1.77 (m, 2H), 1.64 (m, 2H), 1.49 (m, 1 H), 1.38 (m, 1H), 1.29 (t, J=7.5Hz, 3H), 0.93 (d, J=7.5Hz, 3H), 0.90 (d, J=7.5Hz, 3H).
MS: (M+H)+= 333
-469- Example 229
(±W2R.3R.5R.rSV2-(1-Acetamido-3-methvnbutyl-3-(pyrazol-3-vπ-pyrrolidine-5- carboxylic Acid Ethyl Ester
The title compound is prepared according to the method described in Example 222, substituting (±)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3- (pyrazol-3-yl)-pyrrolidine-5-carboxylic acid trifluoroacetic acid salt in place of (±)- (2R,3S,5R,1'R,2'S)-2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid trifluoroacetic acid salt (yield: 48 mg, 75.5%).
1H NMR (CDCI3): δ 7.49 (d, 1H), 7.26 (s, 1H), 6.18 (d, 1 H), 4.18 (q, J=7.5Hz, 2H), 4.12 (m, 1H), 3.91 (t, J=7.5Hz, 1H), 3.51 (t, J=7.5Hz, 1 H), 3.40 (q, J=9Hz, 1 H), 2.64 (m, 1 H), 2.00 (m, 1H), 1.82 (s, 3H), 1.75 (m, 1 H), 1.36 (m, 1H), 1.26 (t, J=9Hz, 3H), 0.855 (d, 3H), 0.84 (d, 3H).
MS: (M+H)+= 337
-470- Example 230
(±W2R.3S.5R.1'R)-2-(1-Acetamido-2-ethyl-2-hvdroxy')butyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
AcHN3^ - °,Bu
H Boc
OH O
230A (±)-(2R.3S.5R.1'RV1-f-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2- hvdroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-oxo)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester for (±)- (2R,3S,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester to provide the title compound (yield: 0.021 g, 51%).
MS: (M+H)+ = 469, (M+Na)+ = 491, (2M+Na)+=959, (M-H)" = 467.
230B (±)-(2R.3S.5R.1'RV2-(1-Acetamido-2-ethyl-2-hvdroxy)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-ethyl-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-
-471- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0039 g, 100%).
1H NMR (DMSO-de) δ7.52 (d, J=10.3Hz, 1 H), 5.45 (m, 1 H), 5.28 (m, 1H), 4.32 (m, 2H), 3.68 (t, J=8.8Hz, 1 H), 3.16 (quint, J=8.5Hz, 1 H), 2.41 (dt, J=13.2,8.3Hz, 1 H), 1.81(s, 3H), 1.59 (m, 1 H), 1.53 (dd, J=6.8,1.5Hz, 3H), 1.52- 1.42 (m, 3H), 1.30 (m, 1 H), 0.86 (t, J=7.3Hz, 3H), 0.83 (t, J=7.3Hz, 3H).
MS: (M+H)+ = 313, (M+Na)+ = 335, (M-H)" = 311 , (2M-H)" = 623.
Example 231
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-2-methvnpentyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
231 A (±V(2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-2- methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-oxo)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester for (±)- (2R,3S,5R,1'R)-1-f-Butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester and methylmagnesium bromide for ethylmagnesium bromide to provide the title compound (yield: 0.0285 g, 45%).
MS: (M+H)+ = 469, (M+Na)+ = 491.
-472-
231 B (±)-(2R.3S.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxy-2-methvnpentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-2-methyl)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0040 g, 100%).
1H NMR (DMSO-de) δ9.25 (bs, 1 H), 8.75 (bs, 1H), 7.54 (d, J=10.3Hz, 1H), 5.45 (m, 1H), 5.29 (m, 1 H), 4.37 (bt, J=8.3Hz, 1 H), 4.22 (t, J=9.7Hz, 1H), 3.62 (t, J=8.8Hz, 1H), 3.12 (quint, J=8.5Hz, 1 H), 2.41 (dt, J=12.7,7.8Hz, 1H), 1.78 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,2.0Hz, 3H), 1.4-1.25 (m, 4H), 1.17 (s, 3H), 0.81 (t, J=6.5 Hz, 3H).
MS: (M+H)+ = 313, (M+Na)+ = 335, (M-H)" = 311 , (2M-H)" = 623
-473- Example 232
(±)-(2R.3S.5R.1'R,2'S)-2-(1-Acetamido-2-ethyl-2-hvdroxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt .
232A (±W2R.3S.5R.1'R.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2- hvdroxy)pentyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 41 B, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-oxo)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester for (±)- (2R,3S,5R,1'R)-1-f-butoxycarbonyl 2-(1-acetamido-1-formyl)methyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester to provide the title compound (yield: 0.0222 g, 33%).
MS: (M+H)+ = 483, (M+Na)+ = 505, (M-H)"=481.
232B fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-hvdroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-ethyl-2-hydroxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
-474- acetamido-2-hydroxy)butyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 0.0035 g, 100%).
1H NMR (DMSO-de) δ 9.1 (bs, 1 H), 8.75 (bs, 1 H), 7.53 (d, J=9.8Hz, 1H), 5.44 (m, 1H), 5.28 (m, 1H), 4.35-4.25 (m, 2H), 3.67 (m, 1H), 3.16 (quint, J=8.5Hz, 1H), 2.41 (dt, J=12.8,7.9Hz, 1H), 1.81 (s, 3H), 1.60 (m, 1 H), 1.53 (dd, J=6.7,1.8Hz, 3H), 1.46 (m, 2H), 1.4-1.20 (m, 4H), 0.86 (t, J=7.3Hz, 3H), 0.82 (t, J=6.7 Hz, 3H).
MS: (M+H)+ = 327, (M-H)" = 325, (M+CF3COOH)"=439, (2M-H)" = 651
Example 233
(±)-(2R.3S.5R.1'RV2-(1-Acetamido-2-propyl-2-hvdroxy)pentyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 232 substituting propyl magnesium bromide for ethyl magnesium bromide.
1H NMR (DMSO-d6): δ 0.81 (t, 3H), 0.91 (t, 3H), 1.24-1.49 (m, 8H), 1.54 (dd, 3H), 1.60 (m, 1 H), 1.81 (s, 3H), 2.41 (m, 1 H), 3.15 (m, 1 H), 3.69 (t, 1H), 4.28 (t, 1H), 4.35 (t, 1H), 5.17 (br s, 1 H), 5.28 (td, 1 H), 5.45 (dq, 1 H), 7.54 (d, 1 H), 8.80 (br s, 1 H), 9.12 (br s, 1 H).
MS: (M+H)+= 341.
-475- Example 234
(±)-(2R.3S.5R.1 'R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(c/s-propen-1-vh- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3 \— , AcHN. jL X /OtBu
HEX
s—
234A (±)-(2R.3S.5R.1'RV1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2- (methylthio)methyloxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid t- Butyl Ester
(±)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2- methoxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxyiic acid t-butyl ester was reacted with dimethylsufoxide and acetic anhydride according to the method of Marshall, J. A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.
CH3 AcHN..^ /O Bu
H _oc
'OCH 3
234A fcW2R.3S.5R.1'R.2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2- methoxy)butyl-3-(c/s-propen-1-vD-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(±H2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2- (methylthio)methyloxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxyiic acid t-
-476- butyl ester is reacted with Raney Nickel according to the procedure of Marshall, J. A. in J. Org. Chem. 1979, vol. 44, p 2994 to provide the title compound.
Ac^N. JJΛ OH
OCH3 ° TFA
fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1 'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-ethyl-2-methoxy)butyl-3-(c/s-propen-1-yl)-pyrroiidine-5-carboxylic acid t-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f-butyl ester.
Example 235
H,C
.*OHCHH3 A U
TFA
(±W2R.3S.5R.1'R.2'S 2-(1-Acetamido-2-ethyl-2-methoxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound is prepared according to the method described in Example 234 substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-ethyl-2-hydroxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic
-477- acid f-butyl ester for (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido-2- ethyl-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in 234A.
Example 236
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxymethyl-2-hvdroxy pentyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
236A (± (2R.3S.5R.1'R.2'SV1-t-Butoxycarbonyl-2-(1-Acetamido-2-((1- ethoxy)ethyloxymethvπ-2-hvdroxy)pentyl-3-(cs-propen-1-yl)-pyrrolidine-5- carboxylic Acid t-Butyl Ester
(±)-(2R,3S,5R, 1 'R,2'S)-1 -t-Butoxycarbonyl-2-(1 -acetamido-2-oxo)pentyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester (50 mg, 0.11 mmole) was reacted with (ethoxyethyloxymethyl)tributylstannane (260 mg, 0.66 mmole) according to the method of Still, W. C. (J. Am. Chem. Soc, 100, 1481(1978)) to provide the title compound (yield: 26.8 mg, 43.8%).
1H NMR (CDCI3): δ 0.89 (t, 3H), 1.19 (m, 3H), 1.29 (dd, 3H), 1.45 (s, 9H), 1.46 (s, 9H), 1.52-1.73 (m, 8H), 1.99 (s, 3H), 2.44 (m, 1 H), 3.24-3.74 (m, 5H), 3.91-4.22 (m, 3H), 4.49 (m, 1H), 4.62 (m, 1H), 5.37 (m, 1 H), 5.64 (m, 1H), 5.97- 6.41 (m, 1H).
MS: (M+H)+= 557.
-478-
236B (± -(2R,3S.5R.1'R.2'SV2-(1-Acetamido-2-hvdroxymethyl-2-hvdroxy)pentyl- 3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
(±)-(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-(1-ethoxy-2- ethoxymethyl)-2-hydroxy)pentyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester (13.5 mg, 0.024 mmol) was dissolved in THF (1 mL) and treated with 0.5 N HCl ( 1 mL) at room temperature for 1 hr. The solvents were removed and the resulting white solid was reacted with trifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hours. The reaction was concentrated in vacuo overnight to provide the title compound (yield: 10.7 mg) as a off white solid.
1H NMR (DMSO-de): δ 0.81 (t, 3H), 1.24-1.38 (m, 4H), 1.52 (dd, 3H), 1.62 (m, 1H), 1.78 (s, 3H), 2.41 (m, 1H), 3.11 (m, 1H), 3.51 (qAB, 2H), 3.77 (t, 1H), 4.23 (t, 1 H), 4.40 (m, 1 H), 5.27 (t, 1 H), 5.45 (m, 1 H), 7.55 (d, 1 H), 8.87 (br s, 1 H), 9.26 (br s, 1H).
MS: (M+H)+= 329
-479- Example 237
fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-allyloxy-2-vinyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
. /OtBu
Y O
237A (±W2R.3S.5R.1 .2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2- vinyl)ethyl-3-(c/s-propen-1-v0-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(2R,3S,5R,1'R,2'S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2- vinyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted according to the method described in Example 84A substituting allyl iodide for methyl iodide (yield: 28 mg, 80%).
MS: (M+H)+= 479, (M-H)" = 477
237B (±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-allyloxy-2-vinyl)ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-allyloxy-2-vinyl)ethyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
-480- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, (yield: 4 mg, 100%).
1H NMR (DMSO-d6) δ 7.98 (d, J=7.8 Hz, 1H), 5.90 (m, 1 H), 5.55 (m, 1H), 5.48 (m, 1 H), 5.32 (m, 2H), 5.26 (m, 2H), 5.16 (m, 1 H), 4.28 (m, 2H), 3.96 (m, 1H), 3.79 (m, 1 H), 3.73 (m, 1 H), 3.66 (m, 1H), 3.26 (m, 1 H), 2.40 (m, 1H), 1.81 (s, 3H), 1.70 (m, 1 H), 1.64 (dd, J=6.9, 1.5 Hz, 3H).
MS: (M+H)+= 323, (M-H)" = 321.
Example 238
fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-1-(2.5-dihvdrofuran-2-vn)methyl-3-(cis- propen-1-vD-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
238A (±W2R.3S.5R.1'R.2'S)-2-(1-Acetamido-1-(2.5-dihvdrofuran-2-vn)methyl-3- (cis-propen-1 -yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(±)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2- vinyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (21 mg, 0.044 mmole) prepared according to the procedure of Example 237A was reacted with b/s(tricyciohexylphosphine)benzylidine ruthenium(IV) dichloride [Grubb's catalyst] (7.5 mg, 0.009 mmole) in methylene chloride (5 mL) at 25°C for 2 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 75% ethyl acetate/hexanes to provide the title compound (yield: 18 mg, 90%).
-481- MS: (M+H)+= 451, (M-H)" = 449.
H3C AcHN. x OH Nx
H H Y
O o
TFA
\\
238B fc (2R,3S.5R,1'R.2'S)-2-(1-Acetamido-1-(2.5-dihvdrofuran-2-vn)methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-Butoxycarbonyl-2-(1- acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl- 2-(1-acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f- butyl ester, (yield: 7 mg, 100%).
H NMR (DMSO-d6) δ 8.09 (d, J=8.8 Hz, 1 H), 6.10 (m, 1 H), 5.87 (m, 1H), 5.50 (m, 1H), 5.27 (m, 1 H), 4.68 (m, 2H), 4.58 (m, 1 H), 4.33 (m, 1 H), 4.06 (m, 1H), 3.68 (m, 1 H), 3.18 (m, 1 H), 2.40 (m, 1 H), 1.85 (s, 3H), 1.68 (m, 1H), 1.60 (dd, J=6.8, 1.5 Hz, 3H),
MS: (M+H)+= 295, (M-H)" = 293.
-482- Example 239
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt
239A (±)-(2R.3S.5R.1'R.2'SV1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2- allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(2R,3S,5R, 1 'R,2'S)-1 -t-Butoxycarbonyl-2-(1 -acetamido-2-hydroxy-2- allyl)ethyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester was reacted according to the method described in Example 84A substituting allyl iodide for methyl iodide iodide (yield: 19 mg, 36%).
MS: (M+H)+= 493, (M-H)" = 491.
239B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-allyloxy-2-allvπethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- Acetamido-2-allyloxy-2-allyl)propyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-t-butoxycarbonyl-2-(1-
-483- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester, (yield: 5.7 mg, 100%).
1H NMR (DMSO-d6) δ 8.06 (dd, J= 8.8 Hz, 1 H), 6.92 (m, 1H), 6.77 (m, 1 H), 5.50 (m, 1 H), 5.29 (m, 2H), 5.17 (m, 1 H), 5.05 (m, 2H), 4.27 (m, 2H), 4.10 (dd, J= 12.2, 5.4 Hz, 1 H), 3.83 (m, 1 H), 3.78 (m, 1 H), 3.40 (m, 1 H), 3.20 (m, 1 H), 2.46 (m, 1H), 2.38 (m, 1H), 2.20 (m, 1H), 1.88 (s, 3H), 1.69 (m, 1H), 1.63 (dd, J= 6.8, 1.5 Hz, 3H).
MS: (M+H)+= 337, (M+Na)+= 359, (M-H)" = 335.
-484- Example 240
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-1-(3.6-dihvdro-2-H-pyran-2-vn)methyl-3- (c/s-propen-1-ylVpyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
240A fcW2R.3S.5R.1'R.2'S)-2-(1-Acetamido-1-(3.6-dihvdro-2-H-pyran-2- yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid t-Butyl Ester
(±)-(2R,3S,5R,1*R,2'S)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (11.5 mg, 0.023 mmole) prepared according to the procedure of Example 239A was reacted with b/s(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride [Grubb's catalyst] (3.8 mg, 0.005 mmole) in methylene chloride (3 mL) at 25°C for 3 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo and the resulting residue purified by chromatography on silica gel using 75% ethyl acetate/hexanes to provide the title compound (yield: 5.7 mg, 53%).
MS: (M+H)+= 465, (M+Na)+= 487, (M-H)" = 463
240B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-1-(3.6-dihvdro-2-H-pyran-2- yl))methyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
-485- The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(c s-propen-1-yl)-pyrrolidine-5- carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1 'R,2'S)-1-f-butoxycarbonyl- 2-(1 -acetamido-2-hydroxy)butyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester, (yield: 5.9 mg, 100%).
1H NMR (DMSO-d6) δ 8.04 (d, J= 8.8Hz, 1H), 5.77 (m, 2H), 5.50 (m, 1H), 5.25 (m, 1H), 4.21 (m, 2H), 4.14 (m, 1 H), 4.04 (m, 1 H), 3.81 (m, 1 H), 3.40 (m, 1 H), 3.23 (m, 1 H), 2.41 (m, 1 H), 2.09 (m, 1 H), 1.88 (s, 3H), 1.83 (m, 1 H), 1.70 (m, 1 H), 1.63 (d, J= 6.8Hz, 3H).
MS: (M+H)+ = 309, (M+Na)+ = 331 , (M-H)" = 307
The following compounds were synthesized according to the methods previously described in Examples 1-240
Example 241
(±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-1-(3.6-dihvdro-2-H-pyran-2-yl))propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-d6) δ 7.90 (d, 9.1Hz, 1H), 5.79 (m, 2H), 5.48 (m, 1H), 5.23 (m, 1 H), 4.43 (m, 1 H), 4.24 (m, 2H), 4.17 (m, 2H), 3.73 (m, 1 H), 3.64 (m, 1H), 3.19 (m, 1 H), 2.42 (m, 1H), 2.02 (m, 1H), 1.85 (s, 3H), 1.78 (m, 1 H), 1.75 (m, 1H), 1.56 (dd, J= 7.5, 1.5 Hz, 3H).
MS: (M+H)+ = 309, (M+Na)+ = 331 , (M-H)" = 307.
-486- Example 242
(±W2R.3S.5R.1'S.2'RS 2-(1-Acetamido-2-hvdroxy)pentyl-3-(c/s-propen-1-vn- Pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO) δ 7.7 (d, J= 9.8 Hz, 1H), 5.61 (m, 1H), 5.19 (dt, J= 1.8, 11.0 Hz, 1H), 4.33 (dd, J= 6.7, 10.3 Hz, 1H), 3.81 (m, 1H), 3.70 (dd, 1.8, 10.3 Hz, 1H), 3.54 (q, J= 6.1 Hz, 1 H), 3.10 (m, 1H), 2.35 (dt, J= 12.8, 6.8 Hz, 1H), 1.90 (s, 3H), 1.7 (m, 1H), 1.59 (dd, J= 0.7, 7.3 Hz, 3H), 1.4 (m, 3H), 1.2 (m, 2H), 0.90 (t, J= 6.7 Hz, 3H).
MS: (M+H)+= 299
Example 243
(±W2R.3S.5R.1'S.2'RSV2-(1-Acetamido-2-hvdroxy-3-ethoxycarbonvnpropyl-3- (c/s-propen-1-vP-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO) δ 7.75 (m, 1H), 5.60 (m, 1 H), 5.29 (m, 1 H), 4.55-4.25 (m, 3H),4.15-4.0 (m, 3H), 3.9-3.6 (m, 3H), 3.15 (m, 1H), 2.45-2.3 (m 2H), 1.9 (s, 3H), 1.8-1.5 (m, 5H), 1.2 (m, 3H).
-487- MS: (M+H)+= 343
Example 244
TFA
fc)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-2-vinvnethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-d6) d 7.91 (d, J=8.05Hz, 1H), 5.50(m, 2H), 5.30(m, 3H), 4.27(m, 1H), 4.23(m, 1 H), 3.75(m, 1 H), 3.48(m, 1 H), 3.23(m, 1H), 3.15(s, 3H), 2.40(m, 1H), 1.80(s, 3H), 1.68(m, 1H), 1.64(dd, J=1.83, 7.32Hz, 3H)
MS: (M+H)+ = 297, (M-H)"= 295
Examo Ie 245
-''.
H3C
AcHN OH
Ύ 0 (I ϊ 1 TFA
(±)-(2R.3S.5R.1'R.2,SV2-(1-Acetamido-2-ethoxy-2-vinvnethyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR(DMSO-de) d 7.90(d, J=7.85Hz, 1 H), 5.57(m, 2H), 5.48(m, 3H), 4.27(m, 1H), 4.22(m, 1 H), 3.77(m, 1 H), 3.60(m, 1 H), 3.46(m, 1H), 3.23(m, 2H), 2.39(m, 1H), 1.80(s, 3H), 1.70(m, 1 H), 1.64(dd, J=1.47, 6.73Hz, 3H), 1.12(t, J=6.83 Hz, 3H)
-488- MS: (M+H)+= 311 , (M-H)" = 309
Example 246
fcW2R.3S.5R.1'R.2,S)-2-(1-Acetamido-2-hvdroxy-2-(propenv-2-vπ)ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR(DMSO-d6) δ 7.69(d, J=9.75Hz, 1 H), 5.47(m, 1H), 5.28(m, 1H), 5.03(m, 1H), 4.86(m, 1H), 4.40(m, 1H), 4.30(m,1 H), 4.18(m, 1H), 3.97(m, 1H), 3.68(m, 1 H), 3.21 (m, 1 H), 2.43(m, 1H), 1.82(m, 1H), 1.73(s, 3H), 1.64(s, 3H), 1.59(m, 3H)
MS: (M+H)+= 297, (M-H)"= 295
Example 247
(±)-(2R.3S.5R.1'R.2,R)-2-(1-Acetamido-2-hvdroxy-2-(propenv-2-vnethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.65(d, J=9.80 HZ, 1 H), 5.48(m, 1 H), 5.23(m, 1H), 4.99(s, 1 H), 4.88(s, 1 H), 4.46(m, 1 H), 4.30(m, 1 H), 4.19(m, 1H), 3.55(m, 1 H),
-489- 3.22(m, 1 H), 2.44(m, 1 H), 1.78(s, 3H), 1.75(m, 1 H), 1.65(s, 3H), 1.58(dd, J=1.23, 6.70HZ, 3H)
MS: (M+H)+= 297, (M-H)"=295
Example 248
OH i Of TFA
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-methoxy-2-(propenv-2-yl))ethyl-3-(c/s- propen-1-vπ-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) d 7.77(d, J=9.8 Hz, 1 H), 5.49 (m, 1H), 5.25(m ,1H), 5.07(m, 1 H), 4.94(m, 1 H), 4.32(m, 1H), 4.25(m, 1H), 3.75(m, 1), 3.48(m, 1 H), 3.25(m, 1H), 3.08(s, 3H), 2.40(m, 1 H), 1.77(s, 3H), 1.68(m, 1 H), 1.64(dd, J=1.22, 6.71Hz, 3H), 1.56(s, 3H)
MS: (M+H)+=311 , (M-H)"=309
-490- Example 249
~'
H3C AcHN OH
H H Ύ 0
TFA
(±V(2R.3S.5R.1'R 2-(1-Acetamido-2-ethvnbutyl-3-(c/s-propen-1-vh-pyrrolidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.62(d, J=9.21 Hz, 1 H), 5.58(m, 1 H), 5.28(m, 1H), 4.37(m, 1H), 3.98(m, 1 H), 3.57(m, 1H), 3.10(m, 1H), 2.45(m, 1H), 1.92(s, 3H), 1.76(m, 1 H), 1.62(dd, J=1.83, 6.72Hz, 3H), 1.24(m, 5H), 0.84(t, J=7.61Hz, 3H), 0.77(t, J=7.61Hz, 3H)
MS: (M+H)+=297, (M-H)"=295
Example 250
— _^,
H3C AcHN. . /OH
H H Y 0 TFA
(±W2R.3S.5R.1'SV2-(1-Acetamido-2-ethvπbutyl-3-(c/s-propen-1-yl)-Pyrroiidine-5- carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 7.76(d, J=9.2 Hz, 1 H), 5.46(m, 1H), 5.29(m, 1H), 4.23(m, 1H), 3.63(m, 1 H), 3.15(m, 1 H), 3.01(m, 1 H), 2.38(m, 1 H), 1.87(s, 3H), 1.71(m, 1H), 1.60(m, 3H), 1.36(m, 1 H), 1.20(m, 4H), 0.83 (t, J=7.3Hz, 6H)
MS: (M+H)+=297, (M-H)"=295
-491- Example 251
OEt
(-W2R.3S.5R.1'SV2-(1-Acetamido-2-ethvnbutyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic Acid Ethyl Ester and (+W2S.3S.5S.1'RV-2-(1-Acetamido-2-ethyl)butyl- 3-(c/s-propen-1-v0-pyrrolidine-5-carboxylic Acid Ethyl Ester
(±)-(2R,3S,5R,rS)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid ethyl ester (100 mg) was chromatographed in one injection on a chiral HPLC column of dimensions 5 x 30 cm. The column was packed with Chiralpak AD chiral stationary phase packing from Chiral Technologies. The mobile phase consisted of 1:9 ethanol:hexanes at a flow rate of 117 mlJmin. Two peaks were observed at (24-36) minutes (-)-(2R,3S,5R,1'S) (yield: 45 mg) and at (66-96) min (+)-(2S,3S,5S,1'R) (yield: 45 mg).
(-)-(2R,3S,5R,1'S) [α]D = -26° (c=0.78, dichloromethane)
-492- Example 252
(-)-(2R.3S.5R.1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-vn-pyrrolidine-5- carboxylate Ammonium Salt
θ"NH4 +
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic acid ethyl ester (4.9 mg, 0.0157 mmole) prepared according to the procedure of Example 251 was reacted with lithium hydroxide (0.75 mg, 0.0314 mmole) in a mixture of methanol (0.75 mL) and water (0.25 mL) at 0°C for 7 hours. Then 0.1 N aqueous Hydrochloric acid (1 mL) was added, the reacfion was concentrated in vacuo and the resulting residue purified by ion exchange chromatography on Aldrich Dowex 50WX8-400 strongly acidic resin. The residue was placed on the column and washed with water (5 mL) followed by elution using 0.5 N aqueous Ammonium hydroxide to provide the title compound as a colorless solid (yield: 3.9 mg, 83%). [α]o = - 40° , c=0.08 (water).
1H NMR (DMSO-d6) δ 7.71 (d, J= 9.2 Hz, 1 H), 5.38 (m, 1 H), 5.29 (m, 1H), 3.92 (m, 1H), 3.65 (t, J= 8.5 Hz, 1 H), 3.43 (m, 1 H), 3.33 (m, 1 H), 2.98 (m, 1 H), 2.23 (m, 1H), 1.76 (s, 3H), 1.54 (dd, J= 6.7, 1.8 Hz, 3H), 1.46 (m, 2H), 1.23 (m, 1 H), 0.84 (t, J= 7.3 Hz, 3H).
MS: (M+H)= 285, (M+Na)+= 307, (M-H)- = 283.
[α]D = - 40° , (c=0.08, water).
Example 253
-493-
(±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2.3-dimethoxy)propyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (MeOD-d3) δ.7.8(d, J=9.3Hz, 1H), 5.49-5.43(m, 1 H), 5.25(dd, J=1.95, 9.3Hz, 1 H), 4.38-4.31 (m, 2H), 3.57-3.50(m, 1 H), 3.46(dd, J=4.9, 10.3Hz, 1H), 3.42(s, 3H), 3.35-3.32(m, 2H), 3.27(s, 3H), 3.16-3.09 (m, 1 H), 2.46-2.40(m, 1 H), 1.80(s, 3H), 1.72-1.65(m, 1 H), 1.55(d, J=6.8Hz, 3H).
MS: (M+H)+=315, (M+Na)+=337, (M-H)"=313, (M+Cl)"=349, (2M-H)"=627.
Example 254
OCH3
TFA
(±W2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2.3-dimethoxy)propyl-3-(c/s-propen-1-ylV pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (MeOD-d3) δ.8.04(d, J=8.5Hz, 1 H), 5.52-5.48(m, 1 H), 5.27- 5.22(m, 1H), 4.32-4.25(m, 2H), 3.74-3.71 (m, 1H), 3.53(dd, J=2.4, 10.1 Hz, 1H), 3.33-3.25(m, 2H), 3.31 (s, 3H), 3.25(s, 3H), 3.21-3.17(m, 1H), 2.42-2.36(m, 1H), 1.86(s, 3H), 1.71-1.63(m, 1H), 1.62(d, J=7.3Hz, 3H).
MS: (M+H)+=315, (M+Na)+=337, (M-H)"=313, (M+CI)"=349, (2M-H)"=627
-494- Example 255
(± (2R.3S.5R.1'R.2'R)-2-(1-Acetamido-2-hvdroxyethyl-2-hvdroxy)pentyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de): δ 7.60 (m, 1H), 5.46 (m, 1 H), 5.30 (m, 1H), 4.54 (m, 1H), 4.35 (m, 1H), 4.03 (m, 1 H), 3.96 (m, 1 H), 3.69 (m, 1 H), 3.15 (m, 1H), 2.40 (m, 1H), 1.98 (m, 2H), 1.80 (s, 3H), 1.70-1.50 (m, 5H), 1.38 (m, 3H), 0.83 (m, 3H).
MS: (M+H)+=343, (M-H)"=341
Example 256
TFA
(±W2R.3S.5R.1'R)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(c/s-propen-1-vπ- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (MeOD-d3) δ 5.69-5.59 (m, 1H), 5.33-5.25 (m, 1 H), 4.39 (m, 1H), 4.34 (dd, J=7.8, 10.2Hz, 1 H), 3.73 (dd, J=4.8, 10.2Hz, 1 H), 3.58-3.47 (m, 2H),
-495- 3.38-3.24 (m, 1 H), 3.27-3.20 (m, 1 H), 2.61-2.52 (m, 1H), 2.02 (s, 3H), 1.90-1.78 (m, 1 H), 1.70 (dd, J=1.7, 6.8Hz, 3H), 1.60-1.50 (m, 4H), 0.92 (t, J=7.5Hz, 6H)
(M+H)+ = 327, (M+Na)+ = 349
Example 257
H3C )— λ AcH HNN.. 1 y OH
H H H N
O" J
TFA
(±W2R.3S.5R.1'SV2-(1-Acetamido-2-(3-pentyloxy^ethyl-3-(c s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (MeOD-d3) δ 5.73-5.66 (m, 1H), 5.32-5.25 (m, 1H), 4.36 (dd, J=7.8, 10.2Hz, 1 H), 4.09 (m, 1 H), 3.68 (dd, J=6.1 , 10.2Hz, 1 H), 3.61 (d, J=4.4Hz, 2H), 3.35-3.23 (m, 1H), 3.24-3.16 (m, 1H), 2.65-2.55 (m, 1 H), 2.03 (s, 3H), 1.92- 1.80 (m, 1 H), 1.70 (dd, J=2.0, 7.1 Hz, 3H), 1.59-1.47 (m, 4H), 0.94-0.88 (m, 6H)
(M+H)+ = 327, (M+Na)+ = 349
^96- Example 258
(±W2R.3S.5R.1 'R.2'S)-2-(1-Acetamido-2-ethoxy-3-vinvπpropyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-d6) δ 8.01 (d, J= 8.6Hz, 1 H), 5.76 (m, 1H), 5.49 (m, 1H), 5.25 (m, 1H), 5.05 (m, 2H), 4.28 (m, 1H), 4.02 (m, 1H), 3.77 (m, 1H), 3.62 (m, 1H), 3.36 (m, 1 H), 3.29 (m, 1 H), 3.18 (m, 1 H), 2.43 (m, 1 H), 2.38 (m, 1H), 2.16 (m, 1H), 1.87 (s, 3H), 1.69 (m, 1H), 1.63 (dd, J=6.7, 1.2 Hz, 3H), 1.12 (t, J=6.7 Hz, 3H).
MS: (M+H)= 325, (M-H)- = 323
Example 259
.OH Y o
V1 TFA fcW2R.3S.5R.1'RV2-(1-Acetamido-2-allyloxy)ethyl-3-(c/'s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de) δ 9.16 (m,2H), 8.13(d,J=7.5Hz,1H), 5.88(m,1H), 5.50 (m,1H), 5.15-5.32(m, 3H), 4.35(m,2H), 3.95(m,2H), 3.61(m,1 H), 3.40(m,2H), 3.20(m, 1 H), 2.40(m,1H), 1.87(s,3H), 1.72(m,1 H), 1.62(d, J=6.2,3H)
-497- MS: (M+1)=297, (M+23)=319, (2M+23)=615
Example 260
\
H3C
AcHN V O I H
A xHTN H" ϊ ADH 0
A OE°t TFA
(±W2R.3S.5R.1'R.2'RS)-2-(1-Acetamido-2-hvdroxy-2-(2-ethoxycarbonvn pentyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
1H NMR (DMSO-de): δ 7.57 (d, J=10Hz, 1H), 5.45 (m, 1H), 5.29 (m, 1 H), 4.35 (m, 1H), 4.09 (m, 1H), 3.68 (m, 1H), 3.44 (m, 1H), 3.17 (m, 1H), 2.87 (m, 1H), 2.64 (m, 1 H), 2.39 (m, 1H), 1.80 (s, 3H), 1.65-1.56 (m, 2H), 1.53 (m, 3H), 1.50-1.30 (m, 3H), 1.21 (t, J=7.5Hz, 3H), 0.80 (t, J=7.5Hz, 3H).
MS: (M+H)+=385, (M-H)"=383
Example 261
-498- (±W2R.3S.5R.1 'S.3'R)-2-(1-Acetamido-3,4-dihvdroxy)butyl-3-(c/s-propen-1-ylV pyrrolidine-5-carboxyiic Acid Trifluoroacetic Acid Salt
1H NMR (CD3OD) δ 5.58-5.70 (m, 1 H), 5.24-5.38 (m, 1 H), 4.34-4.50 (m, 2H), 3.58-3.72 (m, 2H), 3.42-3.48 (d, 2H), 2.50-2.63 (m, 1 H), 2.04 (s, 3H), 1.77- 1.95 (m, 1 H), 1.65-1.76 (m, 4H), 1.50-1.63 (m, 1 H).
MS: (M+H)+= 301
Example 262
(±W2R.3S.5R.1'S.3'S)-2-(1-Acetamido-3.4-dihvdroxy)butyl-3-(c s-propen-1-ylV pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
H NMR (CD3OD) δ 5.58-5.72 (m, 1 H), 5.25-5.37 (m, 1 H), 4.30-4.45 (m, 2H), 3.63-3.77 (m, 2H), 3.44-3.49 (d, 2H), 2.50-2.63 (m, 1 H), 2.03 (s, 3H), 1.76- 1.95 (m, 2H), 1.65-1.75 (m, 4H).
MS: (M+H)+= 301
-499- Example 263
fcW2R.3S.5R.1'R)-2-(1-Acetamido-2-methoxy)ethyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
CH3 )—
AcHN. _X J /O'Bu
H3CO XBOC U
263A (±W2R.3S.5R.1'R)-1-f-Butoxycarbonyl-2-(1-Acetamido-2-methoxy)ethyl-3- (c/'s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compound was prepared according to the method described in Example 84A, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1-acetamido- 2-hydroxy)ethyl-3-(c/'s-propen-1-yl)-pyrroiidine-5-carboxylic acid f-butyl ester for (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 4.2 mg, 20%).
MS: (M+H)+=427, (M+Na)+=449, (M-H)"=425.
/OH if
H3CO O TFA
263B (±W2R.3S.5R.1'R)-2-(1-Acetamido-2-methoxy)ethyl-3-(c/s-propen-1-vn- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt.
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R)-1-f-butoxycarbonyl-2-(1- acetamido-2-methoxy)ethyl-3-(c/'s-propen-1 -yl)-pyrrolidine-5-carboxylic acid f- butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-
-500- 2-hydroxy)butyl-3-(c/'s-propen-1-yl)-pyrrolidine-5-carboxyiic acid f-butyl ester (yield: 0.0031 g, 100%).
1H NMR (DMSO-de) δ 8.12 (d, J=7.9Hz, 1H), 5.50 (m, 1H), 5.23 (m, 1H), 4.33 (m 1 H), 3.56 (dd, J=9.7,8.0Hz, 1H), 3.4-3.3 (m, 2H), 3.26 (s, 3H), 3.19 (m, 1 H), 2.39 (dt, J=12.8,7.3Hz, 1 H), 1.86 (s, 3H), 1.71 (m, 1 H), 1.61 (dd, J=6.7,1.8Hz, 3H).
MS: (M+H)+=271 , (M+Na)+=293.
Example 264
(±W2R.3S.5R, 1 'R.2'S)-2-(1 -Acetamido-2-hvdroxy-3-dimethyl)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt .
264A fcW2R.3S.5R.rR.2'S)-1-f-Butoxycarbonyl-2-(1-acetamido-2-hvdroxy-3- dimethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid f-Butyl Ester.
The title compounds were prepared according to the method described in Example 41 B, substituting f-butyl lithium for ethyl magnesium bromide to provide (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3- dimethyl)butyl-3-(cs-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.5 mg, 11%)
(±)-(2R,3S,5R,1'R,2'S) MS: (M+H)+ = 469; (M-H)" = 467.
-501-
264B (±)-(2R.3S.5R.1'R.2'S)-2-(1-Acetamido-2-hvdroxy-4-vinyl)butyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt
The title compound was prepared according to the method described in Example 41 C, substituting (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy-3-dimethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester in place of (±)-(2R,3S,5R,1'R,2'S)-1-f-butoxycarbonyl-2-(1- acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic acid f-butyl ester (yield: 2.3 mg, 100%).
1H NMR (D2O) δ 5.40 (m, 1H), 5.10 (t, J=5.5Hz, 1 H), 4.13 (t, J=9.2Hz, 1 H), 3.46 (m, 1 H), 3.22 (d, J=7.3Hz, 1 H), 3.00 (m, 1H), 2.41 (m, 1H), 1.70 (s, 3H), 1.45 (m, 1 H), 1.39 (d, J=4.9Hz, 3H), 1.07 (t, J=5.5Hz, 1 H), 0.70 (s, 9H)
MS: (M+H)+ = 313.
Using the methods described above and the general knowledge of one skilled in the art, compounds of the invention can be prepared which are represented by taking one core from Table 1 (wherein Ac is acetyl), one Y substituent from Table 2, one R substituent from Table 3 and one R3 substituent from Table 4a, 4b, 4c, 4d, 4e, 4f or 4g.
-502- Table 1
Y
AcHN. AcHN. .OR O R 33 H ^ o 1 2
Y
CH3SO2ΉN. 1^ \j 0R CH3SO2ΉN. ^OR i^fl o R3H H 0
O Y O
II II
CF3C-HN OR CF3C-HN
RJ 3"H H I Of
Table 2
H H,C H
HN
N
H-,C CI
H3C H3C ,0
Ό H3C
H S^N s- H
10 11 12
-503- HN ^ X"N A FQC
N=<°
CI
13 14 15 16
H,C H3C H F,C
CI F^C
17 18 19 20
H3C
HN . ^ ' ιN N*X tr N=< H3C «*^ \^'v
21 22 23 24
F,C F,C
N* ,S N=<
F C Ci
25 26 27 28
H
NH
N=
Et Et Et
29 30 31 32
F3C CI CI Et H3C 0 ^ F ^\/w F-,C (.j =\ — « H3C . \~
33 34 35 36
H CH3 CI
CI H H
37 38 39 40
HO .0 O
N= N N-N
41 42 43 44
-504- HN > N ^
N ^-N N-N ww %
45 46 47 48
N. ,N.
HN ^N HN N HN ^N
N
49 50 51 52
H
HN f o- N-N
53 54 55 56
wvw
57 o N=A
58 59 60
.N.
61 62 63 64
H r F A
65 66 67 68
R CH, H,C CH,
69 70 71 72
H3C CH CI CI. CI
H,C A CI ~ — -
73 74 75 76
-505- CI CI CF, F,C CF,
CI ^ww* CI A
77 78 79 80
H F3C CI. CI. CH,
F3C F3C . H,C CI
81 82 83 84
CI CH, F3C CF3 H,C CI
H,C CI F,C H,C
85 86 87 88
CH, H3C CI H,C CH, CI. CH
89 90 91 92
R CH, H3C CI
H3C CI
93 94 95 96
CI. CI PH3 R CH,
H,C H,C H,C
97 98 99 100
H,C R CH, H,C F R F
H3C ww
101 102 103 104
H,C F3C HoC CF, rl-aC CH
AA
F3C H3C H Ho XC F,C
105 106 107 108
-506- H3C CF, F,C CH CF, F3C. CH3
H,C F,C
109 110 111 112
CH, H3C 3 F3C CF3 CI.
113 114 115 116
CI R CI CI. CI
117 118 119 120
CI F CI CI F\ F
CI CI «~»~v CI ,ΛΛ~
121 122 X A
123 124
CI. CI. CI CI. CI. CF,
F,C F,C
125 126 127 128
F3C CI F,C CI F3C CI F3C CF3
F,C CI CI
129 130 131 132
CF, CI CI. CF, CI. CF
CI F,C CI F,C'
133 134 135 136
R CF, R CF, R CF, R F
F,C F,C
137 138 139 140
-507- F3C F,C CF, F,C
F,C
141 142 143 144
F3C CF3 H3C H,C CI
145 146 147 148
CI F R Fχ C CII R , CCHH33 CI, CH3
\
/ C') /
H3C — H3C CI F
149 1 15500 1 15511 152
H3C CF3 H3C _/CI CI\=/CF3 F3C\ C1
C .I/ \ F3C~ ^~ HsC H3C
153 154 155 156
F3C CH3 CI\_/CH3 H3C CF3 H3Cv /
Ql -v 3 f y 3C
157 158 159 160
F\ F3 F\_/CF3 F3C\=/F F3C CH3
H3C H3C ^~ H3C F
161 162 163 164
F)= pH3 clχ=< F3 a )= F>χCF3
F3C ""^ F ^^~- F3C ΛW» CI -Λ -
165 166 167 168
NH H2N H2N
X N== = — ^ H3C y
169 170 171 172
-508- H N. NH
H9N—
NH
173 1 4
Table 3
-H 1 ~Λ
CH 3 2 -CH 3 3
CH3
CH, -CH, CH3 5
CH3 CH, -(r-CH3
CH 3 7 K CH 3 8
H,C X CH3 CH,
-CH, ^ — (^-CH,
10 CH CH
3 11 3 12
CH3 CH, A"CH3
-N
-CH 3 ι: CH 3 14 -CH 3 15
-509- Table 4a
CH CH
H,C H,C OH OH OH
CH,
3
H,C OH H, 3C^
CH3 CH, H3C CH,
H,C 10 11
H,CV
OH
H3C CB OH H,C CH
13 14 15 16
CH CH
H,C OCH3 H,C
OCHa OCH3
CH,
17 18 19 20
H,C H3° u
CH3 CH3 3 H C CH3
21 22 23 24
-510- H 3C CH, J
25 26 27
H3C CHs-p
H,C
0CH3 Λ CJΛn < rμ_ M
OCH, M H3 r<-' V CuH,0CH OCH,
H3C CH
29 30 31 32
H,C H,C OCH, OCH,
H C H3C CH H3C CH H3C CH 33 34 35 36
H3C
H C , H3C\^^ H r'
1,3^ ' 'OOHH 'OH 'OH
OH
37 38 39 40
OH OH
OH OH
H3C CH3
41 42 43 44
HoC C
H ι,C A H, 3u H,C
OCHa OCH3 OCH3
OCH3
45 46 47 48
OCH, OCH,
OCH3 OCH,
H3C CH3
49 50 51 52
-511- Table 4b
*OH )CH3 '0 CH3
OH OH OH O rH σ CH3 2 3
H OCH3 ^ H3
O r O H OH OH O rH ^ 1 CH3 6 7 8
HO" OH HO" Y >CH3 HO' Υ "*θ' "CH3 HQ- OH
OH OH OH CH3 9 10 11 12
HO" A" ^OH HO" V "OCH3 HO T ° CHs HO" ^Y" 'O
OH OH °H OH CH3
13 14 15 16
HtV^V OH HO-"A^OCH3 HCT ^ O"^CH3 HO^ ^O^
OH OH OH OH CH3
17 18 19 20
HO" "γ" ~OH HO" Υ" ~OCH3 H0 T ~° CH3 HO" "γ" XT
OH OH 0H OH CH3
21 22 23 24
•O-^j f ° l HO^A^O^ HO-^A^O^
OH " OH " OH " OH "
25 26 27 28
-512- HO' O HO
OH T OH ° *OCH3 ~OCH3
OCH3 OCH3
29 30 31 32
CH3O Y ^OCH3 CH3O >r ^OCH3 CH3O y CH3 CH30 y ~OCH3
OCH3 OCH3 OCH3 OCH3 33 34 35 36
H3C H3C H3C H3CX
'OH OCH, H C' H3C H3C "CH, H3C-
OH OH OH OH CH3
37 38 39 40
H3°J>\ OH H3C ^Y^OCH, H3C"^A^0^CH3 H3c J OH H H33CC 2 OOHH H H33CC Q
H3C O^H CH3
41 42 43 44
H3 C^^OH H3C ^OCH3 H3C ^O^CH3 h3
OH OH OH OH CH3
45 46 47 48
OH H3C *OCH3 H3C O CH3 HoC
A 'O
OH
OH OH OH CH3
49 50 51 52
H3C—S H ""SAjCH, H3C- θ"^CH3 H3 -0
OH OH OH OH CH3
53 54 55 56
H3C
HsC^X ^OH H3C OCH 3 H3C u CH3 3 v "*0" OH
OH OH OH CH3
57 58 59 60
-513- H3C H3C
OH H3C A "3 A0CH3 H3C. H3C CH3 H3C
OH H3° 0H OH OH CH3
61 62 63 64
CH
OH 3^ ΌCH3 H3CA ~0 CH, X _' O OHH
H3C OH H3C
H3C OH CH,
65 66 67 68
H3C OH H3C OH H,C OCH H3C OCH3
CH3 -CH3 CH, -CH3
OH OH OH OH
69 70 71 72
H3C OH HoC- -OH HoC OCH H3C OCH3 CH3 -CH3 CH3 --CHs
OH OH OH OH
73 74 75 76
HjCA-OH HaC^ -OH H3C^-OCH3 H3C OCH3 H3C- HCH3 H3C H ^CH3 H3C ACH3 H3C -CH3
OH
77 78 79 80
OH
H3C ?H CH3~-j~ H3C A-OCH 13 H3C OCH3 H3C~A H;3 "CH3 H3C OH OH OH C rH^3H^3
81 82 83 84
Table 4c
CH H,C
H3C ^A^-CH3
H3C"V CH3 CH3 3 OH OH CH3 OH
-514- "CH3 CH3 CH3 'CH3 CH3 CH3 CH3 CH3 8
CH
H
"CH, H,C "CH, CH, , 3C^ CH,
CH3 CH,
10 11 12
CH
"CH, H,C "CH, H,C 'CH, "CH, CH, H3C CH3 13 14 15 16
H,C„ H3C
"CH, 'CH, 'CH3 'CHa H3C
CH, CH,
17 18 19 20
CH 'CH, "CH, 'CH, "CH,
H3C CH, CH3 CH3 H3C CH3 1 22 23 24
H,C
H3C~
"CH, "CH, "CH, 'CH,
OH OH
OH OH
25 26 27 28
CH CH H,C
'CH, 'CH, 'CH, 'CH,
OH OH
OH OH
29 31
-515- OH CH3 "CH, "CH, 'CH,
OH OH H,C CH 3 34 J:>
H3C "CH, *CH, c CH, CH, 7 38 39 40
CH, CH,
CH, 1 42 43 44
C CHH,3 -p H, H,C H3 H,C" *C T CH3 CH, CH3 CH, 5 46 47 48
CH
H,C 'CH3 H,C CH A CH3 CH, H3C CH3 9 50 51 52
H3C H3C
CH3 ^Y^CH3 H3C
CH, CH3
53 54 55 56
CH CH, CHa CH,
H3C CH3 CH, CH, H3C CH3
57 58 59 60
-516- H,C
H3C CH, CH,
OH OH
OH OH 1 62 63 64
CH CH H,C
CH, CH,
OH OH OH OH 5 66 67 68
OH OH j CH, CH, cHa
OH OH H3C CH3 9 70 71 72
H3C
H3C X -CH3 H3C CH, H, XH3
73 74 7 c5 . -C
76
uc ^
-CH, ,»Cπ*a -CH,
-CH,
CH,
77 78 79 80
CH, CH3
-CH, H3C -CH3 ^- ^CH3 HsC^^-^CHs
T CH3
CH3
81 82 83 84
CH
-CH3 H,C -CH3 CH,
H,C * -CH, CH, H3C CH3 85 86 87 88
-517- H,C. -CH, H3C -CH, CH,
- -CH, H3C
CH, CH,
89 90 91 92
CH
-CH, CH3 CH,
•y ■ -CH,
H3C CH, CH, CH, H3C CH, 93 94 95 96
H,C~ -CH, CH3
• -CH3 -CH,
OH OH OH OH
97 98 99 100
CH3 CH, H3C
-CH3 -CH3 .CH3 CH'i
OH OH OH OH
101 102 103 104
OH -CH -CH3 -CH,
OH OH CH3
105 106 107 108
r r* CH3 -γ H3C
H3C"^CH H H3 3C
13(- C^ ^-CH3 ^^CH3 ^^-CH3
109 110 111 112
^ CH* CK3
^
^ ^^\i ^^/C^
CH3
113 114 115 116
-518- CHj -
H3C CH,
^ ^/C4 ChJ CH3 CH,
CH3
117 118 119 120
CH
^^CH, CH3 CH,
H3C H3C CH,
CH3
H3C H3C CH3 121 122 123 124
H,C CH, CH,
H3C CH, CH,
CH3 CH3
125 126 127 128
CH
CH, CH, CH,
H3C CH3 CH, CH3 H3C CH, 129 130 131 132
H3C
H,C CH, CH3 CH,
OH OH OH OH
133 134 135 136
CH3 H3C
H,C CH, -CH3 CH3 CH,
OH OH OH OH
137 138 139 140
OH CH, CH3 CH,
OH H3C CH3
141 142 143 144
-519- - CH3 CH, CH CH3 H3C
CH,
H H33CC..
H 1,3C'
145 146 147 148
CH, CH,
CH, CH, ^
CH3
149 150 150A 150B
CH, CH, CH3 CH CH,
H3C H3 3 J C^
CH,J"'
CH3
151 152 153 154
CH3 9H3-p CH3 CH,
CH,
H3C - H3 CH3 H3C CH y3 155 156 157 158
I γH3 I yH3 j CH, CH,
H3C^ .^ TO^J- r^ " A
CH3 H3° CH3 J
159 160 161 162
CH, CH3 ~ CH3 CH, CH, CH,
H3C CH, CH, CH, H3C CH3 163 164 165 166
CH3 CH3 ~ CH3 H3C CH3 CH,
HaC.
OH OH OH OH
167 168 169 170
-520- CH, T CH3 CH, T CH, H3C CH, CH,
OH OH OH OH
171 172 173 174
OH CH, OH CH, OH CH
CH A
OH OH CH,
175 176 177 178
CH, CH3 CH3 CH, H3C
H3C
H3C
179 180 181 182
CH, CH3
CH3
183 184 185 186
CH3 CH3 CH3 CH CH3
CH,
H3C H3C CH3
CH3
187 188 189 190
CH, CH3 T CH3 CH3 T CH3
H3C"^J^ H3C ^ n
H3C CHs CH3 191 192 193 194
H3C H3C
CH, CH3
195 196 197 198
-521- CH CH,
H3C CH3 CH, CH, H3C CH,
199 200 201 202
CH, CH, H3C
H,C
OH OH OH OH
203 204 205 206
CH CH, CH CH, H3C
OH OH OH OH
207 208 209 210
OH CH3
OH OH CH,
211 212 213 214
U -uu C U ""XJJ
215 216 217 218
i.j CH3 J
219 220 221 222
CH Tj HSC^. j ^ J
CH, CH3
223 224 225 226
-522- CH, - „ CH3*γ~ II -^ _
H,C CH, H H
H3 H,3CC C CH,3
227 228 229 230
H,C. HaC^ J-.^
CH, H3C H,
231 232 233 234
j j C CHH3 >
H3C CH, CH3 CH3 H3C CH,
235 236 237 238
T" II CH3 r ιι H33 C0^.
H3C^ . cςλ M
OH O OHH OH OH
239 240 241 242
j yJJ "3 I T JJ
OH OH OH OH
243 244 245 246
OAJ y 1ϊj j *j H3CJ * . ,
OH OH CH3J
247 248 249 250
- II "A ll CH3 ., H3C.
HSCA ^ H3Cy u \ j
251 252 253 254
-523-
CH,
255 256 257 258
CH
H3C H,C
CH, CH,
259 260 261 262
CH
H3C H,C
CH, H3C CH3 264 265 266
H3C H3C
CH, CH3
267 268 269 270
CH
H3C CH, CH3 CH, H3C CH,
271 272 273 274
H3C
HoC
OH OH
OH OH
275 276 277 278
CH CH H,C
OH OH OH OH
279 280 281 282
-524- OH
OH OH CH,
283 284 285 286
H CH3
H3C J H3C.
287 288 289 290
H,C
H,C
CH,
291 292
Table 4d
H,C. -CH, H,C. -CH, H,C
W JJ
HoC- O H3C^A 0 H3C
10 11 12
-525- H3C- H,C H3C I
V. H3C. 14 jy 16
H3C- H3C 18 19 20
H3C I H3C 22 23 JJ 24
H3C I H3C I H3c ^"0 H3c ^O 31 32
34
-526- Table 4e
H,C
H,C . DH H3C OH A A. ^OH -OH
-OH -OH -OH -OH
CH,
CH
-OH HoC -OH -OH -OH
CH, CH,
10 11 12
CH -A ^
-OH -OH OH
HoC H,C • CH3 H3C A CH. OH ,. -
13 14 15 16
H,C. -OH H3C -OH OH
■ -OH H3C
CH, CH,
17 18 19 20
CH
-OH OH OH
■V • -OH
HoC CHq CH, CH, H3C CH3
21 22 23 24
-527- H,C
H3C^/A^OH OH
■y -OH -OH
OH OH
OH OH
25 26 27 28
CH CH H,C
-OH -OH OH -OH ■
OH OH
OH OH
29 30 31 32
OH -OH -OH -OH -OH
OH OH H,C CH,
33 34 35 36
CH ,C
HaC OH H OH OH OH
37 38 39 40
OH OH OH OH
CH,
41 42 43 44
CH
OH HaC OH H,C"^ OH
CH,
45 47 48
I CH3 - CH3 -*ρ ^ ^^ ^0H HaC^^ oH H Ha3CC^ ^yy^>y^~ L SA^^OH
H,C CH3 H3C CH3
49 50 51 52
-528- H,C OH H3C OH H3C
CH, CH,
53 54 55
CH
OH OH OH
HQC CH*a CH, CH3 H3C CH3
57 58 59 60
H,C OH L OH OH
OH OH
OH OH
61 62 63 64
CH H,C
H,C OH OH OH
OH OH OH OH
65 66 67 68
OH OH OH
-OH OH -OH -OH
OH H3C CH3
69 70 71 72
OH OH
HO. OH H3C OCH3 69 70 71 72
-529- Table 4f
CH HoC
H3c " CH3 H H,3CC.\^-CH3 CH3 OH OH CH3 OH
CH CH3 CH3 CH3 CH, CH3 CH3 H3C CH3
CH3
CH,
H,C CH3 H,C CH3
£ H* H3 3
CH, CH,
10 11 12
CH ^
CH3 -CH CH3
H,C HoC CH3
CH, CH3 CH,
H3C CHa 3""3
13 14 15 16
H3C^ / -CH3 H3C>A -CH3 CH3 CH3 T CH3 HoC" ! CH3 CH3 3 CH3
17 18 19 20
CH3 - CH3 ? AH3 CH3 " ^TΛ.-CH3 -CH3 CH3 Λ CH3 T CH3 CHa H3C CH3 CH3 CH3 H3C CH, 21 22 23 24
-530- CH3 j H,C ^Λ-CHa CH3 T CH3
OH OH OH OH 5 26 27 28
CH CH H3C
CH3 "CH3 CHa CH3 CH3
OH OH OH OH 9 30 31 32
OH "CH3 "CH3 -CH3 H3 3 CH3 3 CH,
OH H3C
OH CH3
33 34 35 36
H3C-
I /CH3
HoC -CH3
HaC ^
CH3 H3C CH3 CH3
37 38 39 40
* \/CH3
1 ^CH,
CH3 44
CH
,CH3 CH3
CH3 J CH, H3C"
CH3 CH, -CH,
CH,
45 46 47 48
CH 3 CH3 .CH3
CH,
H,C H3C CH, CH, CH, H3C CH 50 51 52
-531- H,C
5CH, 'CH,
53 54 55 56
CH, CH CH3 y
CH3 CH, CH, CH,
H3C CH, CH, CH3 H3C CH,
57 58 59 60
CH3
/ CH3 CH,
H,C CH3 CH, CH3 CH,
OH OH OH OH
61 62 63 64
CH CH, H3C
J CH3 CH3
CH, CH, CH3 CH,
OH OH OH OH
65 66 67 68
OH CH CH3 CH,
OH H3C CH, 71 72
H,C
H,C- H3C"^ 1
73 74 75 76
77 78 79 80
-532- H3C^
H,C- H,C
82 84
H,C
H,C
85 86 87 88
H,C
H,C
89 90 91 92
CHo H,C
HsC-y "CH, CH3 CH,
^•CH, CH,
93 94 95 96
CH,
CH3 CH3
97 100
CH,
H3C
101 102 103 104
105 107
-533- V CπH3,
HO. CH3 HO CH3 HO. CH3
CH,
109 110 Ill 112
HO' A/\-CH3 HO CH3 HO CH3
CH3 ii: 114 115
.OH H
OH CH, n 3,C
OH
H,C H,C
OH
HO OH OH
117 118 119 120
-OH H, OH
H,C
-OH -OH
121 122 123 124
Table 4g
~~ CH 3 -
H,
H,CV CH3 C ^- -CCHH 3 ^- - CH CH3 OH OH OH OH
1 2 3
T CH3 CH3 CH3 ~~ CH3 II T" CH,
J .y
H3C"Λ 3 OH OH OH
-534- r CH3 CH, CH3 -CH -CH,
H,C.
H3C 0H OH OH OH
10 11 12
CH,
H'C -AH OH OH
13 14 15 16
CH
H,C"Λ CH3 3C\^ -CH 3 CH3 CH3 OCH3 OCH3 OCH3 OCH3
17 18 19 20
CH, CH3 CH3
H,C. .yy y 3
HoC X O-CH, 0CH3 xj 0CH3 0CH3
21 22 23 24
- ^CH3 T~ r-C 3 CH3 -γ~ ^CH3 -CH,
JJ HaC^. J /
HsC OCH, 0C 3 C5CH3 OCHa
25 26 27 28
CH
HoC
H3C A O-CH3 OCH3 OCH, OCH3
29 30 31 32
CH
H,C . ^- -OOHH H3C\ A^-OH -OH OH
' CH, CH3 CH3 CH3
33 34 35 36
H3C^
H,C :-OH J^-OH
-CH3 ^-CHa CH3 CH3
37 38 39 40
-535- H,C OH
H,C
CH3 CH3 CH3 CH3 41 42 43 44
H,C
HaC
45 48
CH
H,C A OCH3 H,C OCH3 -OCH3 OCH3 CH3 CH3 CH3 CH3
49 50 51 52
-OCH3 H,C
H,C -CH3 CH3 CH3 CH3 53 54 55 56
H,C -OCH3 HoC
CH3 CH3 CH3 CH3
57 58 59 60
H,C
H3C
"CH3 CH3 CH3 OH
65 66 67 68
-536- CH, CH3 CH,
.. / y J CH, y OH
69 70 71 72
r CH3 -CH, -CH3 -CH, OH
73 74 75 76
OH
77 78 79 80
-CH3 CH3 -CH3 CH3 OCH3
81 82 83 84
CH3 CH3 CH3 CH3
. / CH3
85 86 87 88
r CH, -CH, CH3 CH, OCH3
89 90 91 92
OCH3
93 94 95 96
CH,
-OH -OH OH -OH
CH3 CH3
97 98 99 100
-537- CH3 CH3 CH3 CH3
101 102 103 104
CH3 CH3
CH3 CH3
105 106 107 108
-OH Λ
109 110 111
CH3
-OCH3 OCH3 CH3 CH3
113 115 116
CH,
CH3 CH3 CH3
117 118 JJ% 11ι9 120
CH
\ CH3 CH3
CH3
121 122 123
127
-538- H,C
OH OH OH 129 130 131
H,C OH
OH OH
OH
133 134 135 136
H,C OCH
OCH3 OCH3
OCH
137 138 139 140
H,C OH OH OH OH
141 142 143 144
H3C OH OH OH OH
145 146 147 148
CH3 ~
AA -OCHa ^— OCH3 OCH3 OCH3 149 150 151 152
OH OH OH OH
153 154 155 156
-539- -OCH3
OCH3 OH OH -OH OH
157 158 159 160
H,C. -OCH3 OCH3 - -OOCCHH3 --OCH
CH- 3 OCH3 OCH3 161 162 163 164
CH3 .
H,C OH OH OH OH
OH OH OH
OH 165 166 167 168
H,C A- OCH, CJZ OCH3 U- OCH3 OCH,
OH OH OH
OH
169 170 171 1 2
~ CH3 ~ || T~
H3 C^-U0CH3 ^-OCH3 AOr OCCH3
■OCH,
OCH OCH3 OCH3
OCH3
173 174 175 176
H3C OH A^A-OH OH OH -OH ^— OH -OH -OH
177 178 179 180
CH3 r
H,C OCH3 ^J-OCH3 OCH3 OCH3 -OH ^-OH -OH -OH 181 182 183 184
-540- H,C OCH3 A^A-OCH3 OCH3 OCH3 -OCH3 ^OCH3 -OCH3 -OCH3
185 186 187 188
OH \A-OH ^ -OH -OH -OH OH -OH
189 190 191 192
OCH3 \Ar-OCH3 OCH3 OCH3 y\ —OH -OH -OH
193 194 195 196
H3C OCH3 \- -OCH3 AO OCH3 OCH3 /J — OCH3 y\ S— OCH3
CH, -OCH3
197 198 199 200
σ™ ό -OCH3 -OH
201 202 203 0 -OCH3
204
OCH, /— OCH3 W 207 208
— -0cH3 / — ^-OCH3
209 α 0H 210 211 212
-541- OCH,
213 214 215 216
CH,
O CH3
217 220
A CH,
221 222 223 224
The ability of the compounds of the invention to inhibit neuraminidase in vitro can be determined according to the method described below. Neuraminidase Inhibition Assay:
Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity of fertilized eggs and purified by sucrose density gradient centrifugation (Laver, W. G. (1969) in "Fundamental Techniques in Virology" (K. Habel and N. P. Salzman, eds.) pp. 92-86, Academic Press, New York). Influenza virus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatents of virus grown on MDCK cells. Neuraminidase from B/Memphis/3/89 virus was prepared by digestion of the virus with TPCK-trypsin followed by centrifugation and then purification of the neuraminidase catalytic fragment using sucrose density gradient centrifugation and dialysis as described previously (Air, G. M., Laver, W. G., Luo, M., Stray, S. J., Legrone, G., and Webster, R. G. (1990) Virology 177, 578-587).
-542- The neuraminidase inhibition assays used the neuraminidase enzymatic activity associated with the A/N1/PR/8/34 or A/N2/Tokyo/3/67 whole virus, or the B/Memphis/3/89 catalytic head fragment. The whole virus or catalytic fragment was diluted appropriately with 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day of the experiment. Neuraminidase inhibition assays were conducted in 20 mM N-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO. Reaction mixtures included neuraminidase, inhibitor (test compound) and 20-30 μM 4-methylumbelliferyl sialic acid substrate in a total volume of 200 L and were contained in white 96-well U-shaped plates. Typically, five to eight concentrations of inhibitor were used for each Ki value measurement. The reactions were initiated by the addition of enzyme and allowed to proceed for 30-60 minutes at room temperature. The fluorescence for each well of the plate was measured once each minute during the reaction period by a Fluoroskan II plate reader (ICN Biomedical) equipped with excitation and emission filters of 355 +/- 35 nm and 460 +/- 25 nm, respectively. The plate reader was under the control of DeltaSoft II software (Biometallics) and a Macintosh computer. If the compound exhibited linear reaction velocities during the reaction period, then the reaction velocities for the dose-response study were fit to equation 1 using a nonlinear regression program (Kaleidagraph) to determine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics, pp. 105-106, Wiley-lnterscience, New York).
(1 - Vo) = [I]/ {[I] + Ki(1 + [S]/Km)} eqn 1
In equation 1 , Vi and Vo represent inhibited and uninhibited reaction velocities, respectively, and Km = 16 - 40 μM depending on the neuraminidase strain tested. For those compounds exhibiting slow-binding inhibition (Morrison, J. F. (1982) Trends Biochem. Sci. 7, 102-105), a second experiment was performed in a manner identical to the first except that neuraminidase and inhibitor were
-543- preincubated in the absence of substrate for 2 hours at room temperature prior to initiating the reactions with substrate. Data analysis for the resulting linear velocities was conducted as described above.
Equation 2 was used to measure Ki values in the sub-nanomolar range (Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophvs. 2, 347- 368).
V = A{sqrt{(Ki' + It -Et)Λ2 + 4Ki'Et} - (Ki' + It - Et)] eqn. 2
In equation 2, V = velocity; A = αkcat[S]/2(Km + [S]); a is a factor to convert fluorescence units to molar concentrations; Ki' = Ki(1 + [S]/Km); It = total inhibitor concentration and Et = total active concentration of neuraminidase.
The compounds of the invention inhibit influenza A neuraminidase and influenza B neuraminidase with Kj values between about 0.1 nanomolar and about 500 micromolar. Preferred compounds of the invention invention inhibit influenza A neuraminidase and influenza B neuraminidase with Kj values between about 0.1 nanomolar and about 3.5 micromolar.
The ability of the compounds of the invention to inhibit plaque formation in cell culture can be determined by the method described below.
Cell Culture Plaque Formation Inhibition Assay
Cell Cultures: MDCK cells obtained from the American Type Culture Collection were grown in Dulbecco's Modified Eagle Medium (DMEM) high glucose (GibcoBRL) supplemented with 10% fetal calf serum (JRH Biosciences), 40 mM HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL). Cells were routinely cultured in flasks or roller bottles at 37°C and 5% CO2. At confluence cells were reduced to a density of 500,000 cells in a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayer followed by cell centrifugation, resuspension, and
-544- dilution into growth media. Cells were planted at a volume to surface area ratio of 1 ml over 1 cm2 of growth surface.
Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth media was removed and the cells were overlaid with 1.5 ml of assay media (DMEM with 1% fetal calf serum, 40 mM HEPES buffer and antibiotics) containing pre-mixed virus (influenza A/Tokyo/3/67 [H2N2]) (40 -100 plaque forming units) and 2x concentration test compound. The plates were placed on a rocker and incubated for 2 hours at room temperature. During the virus adsorption period agar overlay media was prepared. In a microwave oven 2X agarose (final concentration of 0.6% agarose) in overlay media (DMEM with 40 mM HEPES buffer) was melted and then placed in a 48°C water bath for temperature equilibration. After the virus adsorption period was completed 1.5 ml agar over media was added and mixed with the 1.5 mi virus and test compound containing media per well. Cultures were incubated at 35°C for the period required for plaque development, usually several days. Plaques were fixed with 3.7% formalin in PBS for 20 minutes followed by removal ofthe agar overlay and staining with 0.1% crystal violet in distilled water for 15 minutes. Plaques were counted and EC 50 concentration determined from multiple concentrations of the tested compound using regression analysis.
Viral Stocks: Stocks were prepared in MDCK confluent roller bottles incubated at 37°C in DMEM supplemented with 1% FCS, 40mM HEPES buffer, and antibiotics. Bottles were inoculated with a multiplicity of infection of approximately 0.1 plaque forming unit for each cell. Roller bottles were harvested after the cytopathic effect of the virus was observed to be complete. Stocks were prepared from the supernatant resulting from the low speed centrifugation of the media and cell lysate. Stocks were titered and stored at -80°C.
-545- Compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 100 micromolar and about 1 nanomolar. Preferred compounds of the invention provided plaque formation inhibition for influenza virus A/N2/Tokyo in MDCK cells with EC50 values between about 1 micromolar and about 1 nanomolar.
The compounds of the invention can be tested for in vivo antiviral activity using the method described below.
In Vivo Antiviral Efficacy Method
Female BALB/c mice were placed under anesthesia (sevoflurane) and inoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (Puerto Rico PR8- 34) at 10"2 (diluted from frozen stock). This viral concentration consistently produced disease in mice within 5 days of inoculation. Animals were treated 4h. pre-infection and 4h. post-infection, andperiodically thereafter, with one of the following therapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/day BID, PO); or vehicle (sterile water BID, PO). A group of ten animals (designated as control) was inoculated with 0.9% saline. Percent survival was determined. On day five, lungs were harvested, weighed and assigned scores of 0,1 , 2, 3 or 4 based on percentage consolidation (0; 10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pair was image analyzed to determine objective lung consolidation percentages.
The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-
-546- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p- toluenesulfonate and undecanoate. Also, basic nitrogen-containing groups can be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid. Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, lithium, calcium or magnesium or with ammonium or N(R**)4 + salts (where R** is loweralkyi).
In addition, salts of the compounds of this invention with one of the naturally occurring amino acids are also contemplated.
Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate.
The compounds of the formula I, II and III of this invention can have a substituent which is an acid group (for example, -CO2H, -SO3H, -SO2H, -PO3H2, -PO2H). Compounds of the formula I, II and III of this invention having a substituent which is an ester of such an acidic group are also encompassed by this invention. Such esters may serve as prodrugs. The prodrugs of this invention are metabolized in vivo to provide the above-mentioned acidic substituent of the parental compound of formula I, II or III. Prodrugs may also
-547- serve to increase the solubility of these substances and/or absorption from the gastrointestinal tract. These prodrugs may also serve to increase solubility for intravenous administration of the compounds. Prodrugs may also serve to increase the hydrophobicity of the compounds. Prodrugs may also serve to increase the oral bioavailability of the compounds by increasing absorption and/or decreasing first-pass metabolism. Prodrugs may also serve to increase tissue penetration of the compounds, thereby leading to increased activity in infected tissues and/or reduced rate of clearance.
Such esters contemplated by this invention include:
alkyl esters, especially loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and the like;
alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including, but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl, isopropoxymethyl, t-butoxymethyl esters and the like;
alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substituted loweralkyi esters, including, but not limited to, 2-methoxyethoxymethyl esters and the like;
aryloxyalkyl esters, especially, aryloxy-substituted loweralkyi esters, including, but not limited to, phenoxymethyl esters and the like, wherein the aryl group is unsubstituted or substituted as previously defined herein;
haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkyi esters, including, but not limited to, 2,2,2-trichloroethoxymethyl esters and the like;
alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substituted loweralkyi esters, including, but not limited to, methoxycarbonylmethyl esters and the like;
-548- cyanoalkyi esters, especially, cyano-substituted loweralkyi esters, including, but not limited to, cyanomethyl, 2-cyanoethyl esters and the like;
thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methyl esters, including, but not limited to, methylthiomethyl, ethylthiomethyl esters and the like;
alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substituted loweralkyi esters, including, but not limited to, 2-methanesulfonylethyl esters and the like;
arylsulfonylalkyl esters, especially, arylsulfonyl-substituted loweralkyi esters, including, but not limited to, 2-benzenesulfonylethyl and 2- toluenesulfonylethyl esters and the like;
acyloxyalkyl esters, especially, loweralkylacyloxy-substituted loweralkyi esters, including, but not limited to, formyloxymethyl, acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl esters and the like;
cycloalkylcarbonyloxyalkyl esters including, but not limited to, cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl, cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and the like;
arylcarbonyloxyalkyl esters including, but not limited to, benzoyloxymethyl esters and the like;
(alkoxycarbonyloxy)alkyl esters, especially, (loweralkoxycarbonyloxy)- substituted loweralkyi esters, including, but not limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1- (methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl esters and the like;
(cycloalkyloxycarbonyloxy)alkyl esters, especially, (cycloalkyloxycarbonyloxy)-substituted loweralkyi esters, including, but not limited
-549- to, cyclohexyioxycarbonyloxymethyl, cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl esters and the like;
oxodioxolenylmethyl esters including, but not limited to, (5-phenyl-2-oxo- 1 ,3-dioxolen-4-yl)methyl, [5-(4-methylphenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, [5- (4-methoxyphenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, [5-(4-fluorophenyl)-2-oxo-1 ,3- dioxolen-4-yl]methyl, [5-(4-chlorophenyl)-2-oxo-1 ,3-dioxolen-4-yl]methyl, (2-oxo- 1 ,3-dioxolen-4-yl)methyl, (5-methyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-ethyl-2- oxo-1 ,3-dioxolen-4-yl)methyl, (5-propyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5- isopropyl-2-oxo-1 ,3-dioxolen-4-yl)methyl, (5-butyl-2-oxo-1 ,3-dioxolen-4-yl)methyl esters and the like;
phthalidyl esters wherein the phenyl ring of the phthalidyl group is unsubstituted or substituted as defined previously herein, including, but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl esters and the like;
aryl esters including, but not limited to, phenyl, naphthyl, indanyl esters and the like;
arylalkyl esters, especially, aryl-substitued loweralkyi esters, including, but not limited to, benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl esters and the like, wherein the aryl part of the arylalkyl group is unsubstituted or substituted as previously defined herein;
dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkyi esters, including, but not limited to, 2-(N,N-dimethylamino)ethyl, 2-(N,N- diethylamino)ethyl ester and the like
(heterocyclic)alkyl esters, especially, heterocyclic-substituted loweralkyi esters wherein the heterocycle is a nitrogen-containing heterocycle, including, but not limited to, (heterocyclic)methyl esters and the like, wherein the heterocyclic part of the (heterocyclic)alkyl group is unsubstituted or substituted as previously defined herein; and
-550- carboxyaikyl esters, especially, carboxy-substituted loweralkyi esters, including, but not limited to carboxymethyl esters and the like;
and the like.
Preferred prodrug esters of acid-containing compounds of the Formula I, II or III are loweralkyi esters, including, but not limited to, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl esters and benzyl esters wherein the phenyl ring is unsubstituted or substituted as previously defined herein.
Methods for the preparation of prodrug esters of compounds of the Formula I, II or III are well-known in the art and include:
reacting the acid with the corresponding halide (for example, chloride or acyl chloride) and a base (for example, triethylamine, DBU, N,N- dimethylaminopyridine and the like) in an inert solvent (for example, DMF, acetonitrile, N-methyipyrrolidone and the like);
reacting an activated derivative of the acid (for example, an acid chloride, sulfonyl chloride, monochlorophosphonate and the like) with the corresponding alcohol or alkoxide salt; and the like.
Other examples of prodrugs of the present invention include esters of hydroxyl-substituted compounds of formula I, II or ill which have been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R100C(O)- or R100C(S)- wherein R100 is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue ofthe formula Ra-C(Rb)(R-)-C(O)- or Ra-C(R )(Rd)-C(S)- wherein Rb and Rd are independently selected from hydrogen or lower alkyl and Ra is -N(Re)(R ), -ORe or -SRe wherein Re and Rf are independently selected from hydrogen, lower alkyl and haloalkyl, or an amino-acyl residue having the formula R101NH(CH2)2NHCH2C(O)- or
-551- R101NH(CH2)2OCH2C(O)- wherein R101 is hydrogen, lower alkyi, (aryl)alkyl, (cycloalkyl)alkyl, acyl, benzoyl or an α-amino acyl group. The amino acid esters of particular interest are of glyciπe and lysine; however, other amino acid residues can also be used, including any of the naturally occuring amino acids and also including those wherein the amino acyl group is -C(O)CH2NR102R103 wherein R102 and R103 are independently selected from hydrogen and lower alkyl, or the group -NR102 R103, where R102 and R103, taken together, forms a nitrogen containing heterocyclic ring.
Other prodrugs include a hydroxyl-substituted compound of formula I, II or III wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R104)OC(O)R105 or -CH(R104)OC(S)R105 wherein R105 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R104 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.
The preparation of esters of hydroxyl-substituted compounds of formula formula I, II or III is carried out by reacting a hydroxyl-substituted compound of formula formula I, II or III, with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative.
Prodrugs of hydroxyl-substituted-compounds of the invention can also be prepared by alkylation ofthe hydroxyl substituted compound of formula formula I, II or III, with (halo)alkyl esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
In preparing prodrugs it often is necessary to protect other reactive functional groups, in order to prevent unwanted side reactions. After protection of
-552- the reactive groups the desired group can be functionalized. The resulting functionalized product is then deprotected, to remove the protecting groups that were added to prevent unwanted side reactions. This will provide the desired prodrug. Suitable reaction conditions for preparing protecting groups are well known in the art. One source for reaction conditions is found in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).
This invention also encompasses compounds of the Formula I, II or III which are esters or prodrugs and which are also salts. For example, a compound of the invention can be an ester of a carboxylic acid and also an acid addition salt of an amine or nitrogen-containing substituent in the same compound.
The compounds of the present invention are useful for inhibiting neuraminidase from disease-causing microorganisms which comprise a neuraminidase. The compounds of the invention are useful (in humans, other mammals and fowl) for treating or preventing diseases caused by microorganisms which comprise a neuraminidase
The compounds of the present invention are useful for inhibiting influenza A virus neuraminidase and influenza B virus neuraminidase, in vitro or in vivo (especially in mammals and, in particular, in humans). The compounds of the present invention are also useful for the inhibition of influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the inhibition of influenza A viruses and influenza B viruses in humans and other mammals. The compounds of the present invention are also useful for the treatment of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo, especially the human diseases caused by influenza A and influenza B viruses. The compounds of the present invention are also useful for the prophylaxis of infections caused by influenza viruses, orthomyxoviruses, and paramyxoviruses in vivo in humans and other mammals, especially the prophylaxis of influenza A
-553- and influenza B viral infections; and, in particular, the prophylaxis of influenza A and influenza B viral infections in human subjects who are at high risk of developing other respiratory diseases concurrent with or as a consequence of influenza virus infections, or who suffer from chronic respiratory illness, such as asthma, emphysema, or cystic fibrosis.
Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
Administration of a compound of this invention will begin before or at the time of infection or after the appearance of established symptoms and/or the confirmation of infection.
The compounds of the present invention may be administered orally, parenterally, sublingually, intranasally, by intrapulmonary administration, by inhalation or insufflation as a solution, suspension or dry powder (for example, in a spray), or rectally, in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The
-554- term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert
-555- diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more anti-infective agents and/or other agents used to treat other acute or chronic respiratory ailments. Other agents to be administered in combination with a compound of the present invention include: an influenza vaccine; other influenza inhibitors such as, for example, amantadine, rimantadine, ribavirin, and the like; another influenza neuraminidase inhibitor, such as, for example, zanamivir or GS 4104 and the like; agents used to treat respiratory bacterial infections and bronchitis, such as, for example, erythromycin, clarithromycin, azithromycin and the like; and agents used to treat asthma, such as, for example, zileuton, albuterol (salbutamol), salmeterol, formoterol, ipratropium bromide, inhaled steroids and the like, or anti-inflammatory agents for treating asthma such as, for example, beclomethasone dipropionate, fluticasone propionate,
-556- budesonide, triamcinolone acetonide, flunisolide, cromolyn, zafirlukast, montelukast used in combination with a compound of the present invention.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes which are obvious to one skilled in the art are intended to be within the scope and nature ofthe invention which are defined in the appended claims.
-557-

Claims

CLAIMSWhat is claimed is:
1. A compound of the formula:
or a pharmaceutically acceptable salt, ester or prodrug thereof, wherein R1 is selected from the group consisting of
(b) -CO2H, (b) -CH2CO2H, (c) -SO3H, (d) -CH2SO3H, (e) -SO2H,
(g) -CH2SO2H, (g) -PO3H2, (h) -CH2PO3H2, (i) -PO2H, (j) -CH2PO2H,
(I) tetrazolyl, (I) -CH2-tetrazolyl, (m) -C(=O)-NH-S(O)2-R11,
(o) -CH2C(=O)-NH-S(O)2-R11, (o) -SO2N(T-R11)R12 and
(p) -CH2SO2N(T-R11)R12 wherein T is selected from the group consisting of
(i) a bond, (ii) -C(=O)-, (iii) -C(=O)O-, (iv) -C(=O)S-, (v) -C(=O)NR3┬░-,
(vi) -C(=S)O-, (vii) -C(=S)S-, and (viii) -C(=S)NR 3-560-,
R ) 11 is selected from the group consisting of
(i) C C╬╣2 alkyl, (ii) C2-C12 alkenyl, (iii) cycloalkyl, (iv) (cyclo- alkyl)alkyl,
(w) (cycloalkyl)alkenyi, (vi) cycloalkenyl, (vii) (cycloalkenyl)alkyl,
(ix) (cycloalkenyl)alkenyl, (ix) aryl, (x) (aryl)alkyl, (xi) (aryl)alkenyl,
-558- (xvii) heterocyclic, (xiii) (heterocyclic)alkyl and (xviii) (xiv) (heterocyclic)alkenyl; and R12 and R36 are independently selected from the group consisting of (i) hydrogen, (ii) C╬╣-C╬╣2 alkyl, (iii) C2-C12 alkenyl, (iv) cycloalkyl, (v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl, (viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi) (aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv) (heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;
X is selected from the group consisting of
(a) -C(=O)-N(R*)-, (b) -N(R*)-C(=O)-, (c) -C(=S)-N(R*)-, (d) -N(R*)-C(=S)-,
(e) -N(R*)-SO2-, and (f) -SO2-N(R*)- wherein R* is hydrogen, C C3 loweralkyi or cyclopropyl;
R2 is selected from the group consisting of
(a) hydrogen, (b) C C6 alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl,
(e) C5-C6 cycloalkenyl, (f) halo C╬╣-C6 alkyl and (g) halo C2-C6 alkenyl; or R2-X- is
,J
Y2 < wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)(Rbb)- wherein Raa and Rbb are indepedently selected from the group consisting of hydrogen,
C1-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl,
1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from the group consisting of
(a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e) aryl and
-559- (f) -Z-R14 wherein Z is
(ii) -C(R37a)(R37 )-, (ii) -C(R47)=C(R48)-, (iii) -CΓëíC-, (iv) -C(=O)-,
(v) -C(=S)-, (vi) -C(=NR15)-, (vii) -C(R37a)(OR37c)-, (viii) - C(R37a)(SR37c)-,
(ix) -C(R37a)(N(R37b)(R37c))-, (x) -C(R37a)(R37b)-O-,
(xi) -C(R37a)(R37b)-N(R37c)-, (xii) -C(R37a)(R37b)-N(O)(R37c)-,
(xiii) -C(R37a)(R37b)-N(OH)-, (xiv) -C(R37a)(R37b)-S-,
(xv) -C(R37a)(R37b)-S(O)-, (xvi) -C(R37a)(R37b)-S(O)2-,
(xviii) -C(R37a)(R37b)-C(=O)-, (xviii) -C(R37a)(R37b)-C(=S)-,
(xxi) -C(R37a)(R37b)-C(=NR15)-, (xx) -C(R37a)(OR37c)-C(=O)-,
(xxi) -C(R37a)(SR37c)-C(=O)-, (xxii) -C(R37a)(OR37c)-C(=S)-,
(xxiii) -C(R37a)(SR37c)-C(=S)-, (xxiv) -C(=O)-C(R37a)(OR37c)-,
(xxv) -C(=O)-C(R37a)(SR37c)-, (xxvi) -C(=S)-C(R37a)(OR37c)-,
(xxvii) -C(=S)-C(R37a)(SR37c)-, (xxviii) -C(R37a)(OR37c)-C(R37a)(OR37c)-,
(xxix) -C(R37a)(SR37c)-C(R37a)(OR37c)-,
(xxx) -C(R37a)(OR37c)-C(R37a)(SR3"h
(xxxi) -C(R37a)(SR37c)-C(R37a)(SR c)-, (xxxii) -C(=O)-C(=O)-,
(xxxiii) -C(=S)-C(=S)-, (xxxiv) -C(=O)-O-. (xxxv) -C(=O)-S-,
(xxxvi) -C(=S)-O-, (xxxvii) -C(=S)-S-, (xxxviii) -C(=O)-N(R37a)-,
(xxxix) -C(=S)-N(R37a)-, (xl) -C(R3 a)(R37 )-C(=0)-N(R37a)-,
-560- (xli) -C(R37a)(R37b)-C(=S)-N(R37a)-, (xiii) -C(R37a)(R37b)-C(=O)-O-,
(xliii) -C(R37a)(R37b)-C(=O)-S-, (xliv) -C(R37a)(R37b)-C(=S)-O-,
(xiv) -C(R37a)(R37b)-C(=S)-S-, (xlvi) -C(R37a)(R37b)-N(R37b)-C(=O)-,
(xlvii) -C(R37a)(R37b)-N(R37b)-C(=S)-, (xlviii) -C(R37a)(R37b)-O-C(=O)-,
(xlix) -C(R37a)(R37b)-S-C(=O)-, (I) -C(R37a)(R37b)-O-C(=S)-,
(Ii) -C(R37a)(R37 )-S-C(=S)-, (Iii) -C(R37a)(R37b)-N(R37b)-C(=O)-N(R37a)-,
(liii) -C(R37a)(R37b)-N(R37b)-C(=S)-N(R37a)-,
(liv) -C(R37a)(R37b)-N(R37b)-C(=O)-O-,
(lv) -C(R37a)(R37b)-N(R37 )-C(=O)-S-,
(lvi) -C(R37a)(R37b)-N(R37b)-C(=S)-O-,
(lvii) -C(R37a)(R37b)-N(R37b)-C(=S)-S-,
(lviii) -C(R37a)(R37b)-O-C(=O)-N(R37a)-,
(lix) -C(R37a)(R37b)-S-C(=O)-N(R37a)-,
(lx) -C(R37a)(R37b)-O-C(=S)-N(R37a)-,
(Ixi) -C(R37a)(R37b)-S-C(=S)-N(R37a)-, (Ixii) -C(R37a)(R37b)-O-C(=O)-O-,
(Ixiii) -C(R37a)(R37b)-S-C(=O)-O-, (Ixiv) -C(R37a)(R37b)-O-C(=O)-S-,
(Ixv) -C(R37a)(R37b)-S-C(=O)-S-, (Ixvi) -C(R37a)(R37b)-O-C(=S)-O-,
(Ixvii) -C(R37a)(R37b)-S-C(=S)-O-, (Ixviii) -C(R37a)(R37b)-O-C(=S)-S-,
(Ixix) -C(R37a)(R37b)-S-C(=S)-S- or (Ixx) -C(R37a)(R37b)-C(R37a)(OR37c)-;
is
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) hydroxyalkyi,
-561- (v) thiol-substituted alkyl, (vi) R37cO-substituted alkyl,
(vii) R37cS-substituted alkyl, (viii) aminoalkyl,
(ix) (R37c)NH-substituted alkyl, (x) (R37a)(R37c)N-susbstituted alkyl,
(xi) R37aO-(O=)C-substituted alkyl, (xii) R37aS-(O=)C-substituted alkyl, (xiii) R37aO-(S=)C-substituted alkyl,
(xix) R37aS-(S=)C-substituted alkyl,
(xx) (R37aO)2-P(=O)-substituted alkyl, (xvi) cyanoalkyi,
(xxi) C2-C╬╣2 alkenyl, (xviii) haloalkenyl, (xix) C2-C╬╣2 alkynyl,
(xxii) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,
(xxiv) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,
(xxv) (cycloalkenyl)alkyl,
(xxvii) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii) aryl,
(xxx) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,
(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,
(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,
with the proviso that R14 is other than hydrogen when Z is
-C(R37a)(R37b)-N(R37b)-C(=O)-O-, -C(R37a)(R37b)-N(R37b)-C(=S)-O-,
-C(R37a)(R37b)-N(R37b)-C(=O)-S-, -C(R37a)(R37b)-N(R37 )-C(=S)-S-,
-C(R37a)(R37b)-O-C(=O)-O-, -C(R37a)(R37b)-O-C(=S)-O-,
-C(R37a)(R37b)-S-C(=O)-O-, -C(R37a)(R37b)-S-C(=S)-O-,
-562- -C(R37a)(R37b)-O-C(=O)-S-, -C(R37a)(R37b)-O-C(=S)-S-,
-C(R37a)(R37b)-S-C(=O)-S- or -C(R37a)(R37b)-S-C(=S)-S-;
R37a, R37b, R47, and R48 at each occurrence are independently selected from the group consisting of
(i) hydrogen, (ii) C╬╣-C╬╣2 alkyl, (iii) haloalkyl, (iv) hydroxyalkyi,
(v) alkoxyalkyl, (vi) C2-C╬╣2 alkenyl, (vii) haloalkenyl,
(viii) C2-C╬╣2 alkynyl, (ix) cycloalkyl,
(x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii) (cycloalkyl)alkynyl,
(xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv) (cycloalkenyl)- alkenyl,
(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,
(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,
(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and
(xxiv) (heterocyclic)alkynyl;
R37c at each occurrence is independently selected from the group consisting of
(i) hydrogen, (ii) C C╬╣2 alkyl, (iii) haloalkyl, (iv) C2-C╬╣2 alkenyl,
(v) haloalkenyl, (vi) C2-C╬╣2 alkynyl, (vii) cycloalkyl,
(viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x) (cycloalkyl)alkynyl,
(xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl,
-563- (xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl,
(xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic,
(xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,
(xxiv) (heterocyclic)alkynyl, (xxiii) -C(=O)-R14, (xxiv) -C(=S)-R14,
(xxv) -S(O)2-R14 and (xxvi) hydroxyalkyi;
or when Z is -C(R37a)(R37b)-N(R37c)-, then N(R37c) and R14 when taken together are an azido group;
or when Z is -C(R37a)(R37b)-N(O)(R37c)-, then N(O)(R37c) and R14 when taken together are an N-oxidized 3-7 membered heterocyclic ring having at least one N-oxidized ring nitrogen atom;
or when Z is -C(R37a)(OR37c)-, -C(R37a)(SR37c)- or
-C(R37a)(N(R37b)(R37c))-, then R37a, R14 and the carbon atom to which they are bonded when taken together form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl ring;
R15 is selected from the group consisting of
(i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C╬╣-C╬╣2 alkyl, (v) haloalkyl,
(vi) C2-C╬╣2 alkenyl, (vii) haloalkenyl, (viii) cycloalkyl,
(ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl,
(xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl,
(xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic,
(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;
-564- or R3 and R4 taken together, with the atom to which they are attached, form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;
R5 is selected from the group consisting of
(a) hydrogen, (b) -CH(R38)2, (c) -O-R40, (d) C2-C4 alkynyl, (e) cyclopropyl,
(f) cyclobutyl, (g) -C(=Q1)-R17, and (h) -N(R19)2
wherein Q1 is O, S, or N(R18);
R17 and R18 are independently selected, at each occurrence, from the group consisting of hydrogen, methyl, and ethyl;
R19, R38, and R40 are independently selected, at each occurrence, from the group consisting of
(i) hydrogen, (ii) C1-C12 alkyl, (iii) haloalkyl, (iv) C2-C12 alkenyl,
(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,
(viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl,
(xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv) (aryl)alkenyl,
(xv) heterocyclic, (xvi) (heterocyclic)alkyl and
(xvii) (heterocyclic)alkenyl;
Y is selected from the group consisting of
(a) hydrogen, (b) C C5 alkyl, (c) C1-C5 haloalkyl, (d) C2-C5 alkenyl,
(e) C2-C5 haloalkenyl, (f) C2-C5 alkynyl, (g) C3-C5 cycloalkyl,
(h) C3-C5 cycloalkyl-C╬╣-to-C3-alkyl, (i) C5 cycloalkenyl, (j) C5 cycloalkenyl-C-i-to- C3-alkyl, (k) C5 cycloalkenyl-C2-to-C3-alkenyl, (I) -(CHR39)nOR20, (m) -CH(OR20)-
-565- CH2(OR20), (n) -(CHR39)nSR21, (o) -(CHR39)nCN, (p) -(CHR39)nN3, (q) phenyl, (r) halo-substituted phenyl, (s) -(CHR39)nC(=Q2)R22, (t) -(CHR39)nN(=Q3), (u) -N(O)=CHCH3, (v) -(CHR39)nNR23R24, (w) halo and (x) a heterocyclic ring having from 3 to 6 ring atoms;
wherein n is 0, 1 , or 2; Q2 is O, S, NR25, or CHR26; and Q3 is NR41, or CHR42; R20 at each occurrence is independently
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) C-1-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl,
(x) allyl, (xi) C2-C3 haloalkenyl, (xii) amino, (xiii) -NHCH3, (xiv) -N(CH3)2,
(xv) -NHCH2CH3, (xvi) -N(CH3)(CH2CH3), (xvii) -N(CH2CH3)2 or
(xviii) -N(=CH2);
R21 is hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) d-C3 haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x) allyl or (xi) C2-C3 haloalkenyl;
R22 is
(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,
(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,
(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv) ethylthio,
(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii) vinyl,
(xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii) -N(R28a)(R28b),
(xxv) -CH2R29, (xxiv) aminomethyl, (xxv) hydroxymethyl,
-566- (xxvi) thiolmethyl, (xxvii) -NHNH2, (xxviii) -N(CH3)NH2 or
(xxix) -NHNH(CH3);
R23 and R39 are independently hydrogen or methyl;
R41 and R42 are independently hydrogen, methyl, or ethyl;
R24 is selected from the group consisting of
(i) hydrogen, (ii) C╬╣-C alkyl, (iii) C2-C4 alkenyl, (iv) C2-C4 alkynyl,
(v) cyclopropyl, (vi) -C(=Q4)-R30, (v) -OR31, and (vi) -N(R32)2,
wherein Q4 is O, S, or N(R33);
R25 is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
R26 group is hydrogen, methyl or ethyl ;
R28a hydrogen, hydroxy, methyl, ethyl, amino, -NHCH3, -N(CH3)2, methoxy, ethoxy, or -CN;
R28b is hydrogen, methyl or ethyl;
or R28a, R28b and the nitrogen to which they are bonded taken together represent azetidinyl;
R29 group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy, ethoxy, methylthio, ethylthio, methylamino or ethylamino;
R30 group is hydrogen, methyl, ethyl, -OR34, -SR34, -N(R35)2, -NHOH, -NHNH2, -N(CH3)NH2, or -N(CH2CH3)NH2;
R31 and R32 substituents, at each occurrence, are independently hydrogen, methyl or ethyl;
R33 group is hydrogen, hydroxy, methyl, ethyl, amino, -CN, or -NO2;
-567- R34 group is methyl or ethyl;
R35 group is independently hydrogen, methyl or ethyl;
with the proviso that when Q2 is CHR26 then R22 is selected from the group consisting of hydrogen, -CH3, -C2H5, -C3H7, -OCH3, -SCH3, -O-C2H5, and -S-C2Hs,
and with the proviso that when R3 and R4 are each hydrogen, then Y is other than hydrogen;
R6 and R7 are independently selected from the group consisting of
(c) hydrogen, (b) C C╬╣2 alkyl, (c) C2-C╬╣2 alkenyl, (d) cycloalkyl,
(e) (cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h) (cyclo- alkenyl)alkyl,
(j) (cycloalkenyl)alkenyl, (j) aryl, (k) (aryl)alkyl, (I) (aryl)alkenyl, (m) heterocyclic,
(o) (heterocyclic)alkyl and (o) (heterocyclic)alkenyl; and
R8, R9, and R10 are independently selected from the group consisting of
(a) hydrogen, (b) C╬╣-C╬▓ alkyl, (c) C2-C6 alkenyl, (d) C3-C6 cycloalkyl,
(e) C3-C6 cycloalkenyl, and (f) fluorine, with the proviso that the total number of atoms, other than hydrogen, in each of R8, R9, and R10, is 6 atoms or less.
-568-
2. The compound according to Claim 1 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
3. The compound according to Claim 1 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
-569-
4. The compound according to Claim 1 wherein
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C C3 loweralkyi, halo C1-C3 loweralkyi, C2-C3 alkenyl or halo C2-C alkenyl or -X-R2 is
V,A
ΓÇó ╬│2 wherein Y1 is -CH2-, -O-, -S- or -NH- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
C1-C3 loweralkyi, hydroxy methyl, 1 -hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are independently hydrogen or loweralkyi;
R8 and R9 are independently hydrogen, fluoro or loweralkyi;
R10 is hydrogen, fluoro or loweralkyi; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl, -C(=Q2)R22, -N(=Q3), -N(O)=CHCH3, -NR23R24 or a heterocyclic ring having from 3 to 6 ring atoms, wherein R22, R23, R24, Q2 and Q3 are as defined therein.
-570-
5. The compound according to Claim 4 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
6. The compound according to Claim 4 having the relative stereochemistry depicted by formula :
>9
Ra
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
7. The compound according to Claim 1 wherein wherein
-571- -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C-1-C3 loweralkyi, halo C1-C3 loweralkyi, C2-C3 alkenyl or halo C2-C3 alkenyl or -X-R2 is
,J
Y2 wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)( R b)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
C C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are independently hydrogen or loweralkyi;
R8 and R9 are independently hydrogen or loweralkyi;
R10 is hydrogen or loweralkyi; and
Y is C2-C5 alkenyl, C2.C5 haloalkenyl, -C(=Q2)R2
-N( f=-Qs^J), -N(O)=CHCH3 or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds, wherein R22, Q2 and Q3 are as defined therein.
-572-
8. The compound according to Claim 7 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
9. The compound according to Claim 7 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
10. A compound according to Claim 1 wherein
-573- -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi, halo d-C loweralkyi, C2-C3 alkenyl or halo C1-C3 alkenyl or -X-R2 is
Ύ2 < wherein Y1 is -CH2- and Y2 is -C(=O)- or -C(Raa)( Rbb)- wherein Raa and Rbb are independently selected from the group consisting of hydrogen,
d-C3 loweralkyi, hydroxymethyl, 1 -hydroxyethyl and 2-hydroxyethyl;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are independently hydrogen or loweralkyi;
R8 and R9 are independently hydrogen or loweralkyi;
R10 is hydrogen or loweralkyi; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
-574-
11. The compound according to Claim 10 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
12. The compound according to Claim 10 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
13. A compound according to Claim 1 wherein
R is -CO2H;
-575- -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo- d-C3 loweralkyi;
R3 and R4 are independently selected from hydrogen, heterocyclic and
-Z-R14 wherein Z and R14 are as defined therein and wherein one of R3 and R4 is other than hydrogen;
R5 is hydrogen or loweralkyi;
R6 and R7 are hydrogen independently hydrogen or loweralkyi;
R8 and R9 are hydrogen independently hydrogen or loweralkyi;
R10 is hydrogen or loweralkyi; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
14. The compound according to Claim 13 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
-576-
15. The compound according to Claim 13 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
16. The compound according to Claim 1 wherein
R1 is -CO2H;
-X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo- d-Qj loweralkyi;
R4 is hydrogen or loweralkyi and R3 is heterocyclic or -Z-R14 wherein Z and R14 are as defined therein;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
-577-
17. The compound according to Claim 16 having the relative stereochemistry depicted by the formula:
R9
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
18. The compound according to Claim 16 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
19. The compound according to Claim 1 wherein
R1 is -CO2H;
-578- -X-R2 is R -C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo C1-C3 loweralkyi;
R4 is hydrogen or loweralkyi and R3 is (a) heterocyclic, (b) alkyl,
(d) cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g) -C(=O)-R14,
(h) -C(R37a)(OR37c)-R14 or (i) -C(R37a)(R37b)-N(O)(R37c)R14 wherein R14 is
(j) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyi, (xii) alkoxyalkyl, (xiii) cyanoalkyi, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) loweralkyi or (iii) loweralkenyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2.Cs haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
-579-
20. The compound according to Claim 19 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
21. The compound according to Claim 19 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
22. The compound according to Claim 1 wherein
R1 is -CO2H;
-580- -X-R2 is R2-C(=O)-NH-, R2-NH-C(=O)-, R2-NH-SO2- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo C1-C3 loweralkyi;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)- R14 wherein R14 is
(ii) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v) haloalkyl,
(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,
(x) (heterocyclic)alkyl, (xi) hydroxyalkyi, (xii) alkoxyalkyl, (xiii) cyanoalkyi, (xiv) (R37aO)-(O=)C-substituted alkyl or (xv) (R37aO)2-P(=O)-substituted alkyl;
R37a and R37b are independently selected from the group consisting of
(i) hydrogen, (ii) loweralkyi and (iii) loweralkenyl; and
R37c is
hydrogen, (ii) C1-C3 loweralkyi or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen ;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
-581-
23. The compound according to Claim 22 having the relative stereochemistry depicted by the formula:
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
24. The compound according to Claim 22 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
25. The compound according to Claim 1 wherein
R1 is -CO2H;
-582- -X-R2 is R2-C(=O)-NH- or R2-S02-NH- wherein R2 is C1-C3 loweralkyi or halo C1-C3 loweralkyi;
R4 is hydrogen and R3 is (a) heterocyclic, (b) alkyl or (c) -C(R37a)(OR37c)- R14 wherein R14 is
(i) loweralkyi, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkyi or
(iv) alkoxy-substituted loweralkyi;
R37a is
(i) hydrogen, (ii) loweralkyi or (iii) loweralkenyl; and
R37c is
(i) hydrogen, (ii) C1-C3 loweralkyi or (iii) allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
-583-
26. The compound according to Claim 25 having the relative stereochemistry depicted by the formula:
R9
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
27. The compound according to Claim 25 having the relative stereochemistry depicted by formula :
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
28. The compound according to Claim 1 wherein
R is -CO2H;
-584- -X-R2 is R2-C(=O)-NH- or R2-SO2-NH- wherein R2 is C1-C3 loweralkyi or halo d-C-3 loweralkyi;
R4 is hydrogen and R3 is -C(R37a)(OR37c)-R14 wherein R14 is
loweralkyi or loweralkenyl;
R37a is
loweralkyi or loweralkenyl; and
R37c is
hydrogen, C1-C3 loweralkyi or allyl;
R5 is hydrogen;
R6 and R7 are hydrogen;
R8 and R9 are hydrogen;
R10 is hydrogen; and
Y is C2-C5 alkenyl, C2-C5 haloalkenyl or a heterocyclic ring having 5 ring atoms and also containing one or two double bonds.
29. The compound according to Claim 28 having the relative stereochemistry depicted by the formula:
-585- wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
30. The compound according to Claim 29 having the relative stereochemistry depicted by formula :
R
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X and Y are as defined therein and wherein R3 and R4 are not both the same.
31. A compound selected from the group consisting of:
(┬▒)-(2R,3S,5R,1 'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(c/'s-propen- 1-y|)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ;
-586- (┬▒)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ; .
(-)-(2R,3S,5R,1'S)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylate Ammonium Salt;
(┬▒)-(2R,3S,5R,rR,2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rS)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒H2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3R,5R,rR,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid ;
-587- (┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxyiic Acid ;
(┬▒)-(2R,3S,5R,1'R,2,S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2,S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrroIidine-5-carboxylic Acid ;.
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3SI5R,1'R,2,S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2,S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1 'R,2,S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid ;
-588- (±)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)ρropyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxyiic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(c/'s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine- 5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cs-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-hydroxy)ethyl-3-('c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
-589- (┬▒)-(2R,3S,5R,rS)-2-(1-acetamido-3-methyl)butyl-3-(c/s-2-chloro-vin-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,rS,3'R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3R,5R,rS)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'S)-1- f-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol- 2-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5- Carboxylic Acid ;
-590- (┬▒)-(2R,3R,5R,1'S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5- carboxylic Acid ; and
(┬▒)-(2S,3R,5R,1'S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5- carboxylic Acid; or a pharmaceutically acceptable salt, ester or prodrug thereof.
32. A compound selected from the group consisting of:
(┬▒)-(2R,3S,5R,1'R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(c/s-propen- 1-y|)-pyrro!idine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt ;
(┬▒)-(2R,3R,5R,1'R,2'R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ; .
(-)-(2R,3S,5R,rS)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylate Ammonium Salt;
(┬▒)-(2R,3S,5R,rR.2'R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
-591- (┬▒)-(2R,3S,5R,1 'S)-2-(1-Acetamido-2-ethyl)butyl-3-(c/s-propen-1-yl)-pyrrolidine-5- carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N- oxide))ethyl-3-(c/s-propen-1 -yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'S,3'S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl- 3-(c/s-propen-1-yl)-pyrrolidine-5-carboxyiic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-methoxy)pentyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3R,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-hydroxy)butyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3- (cis-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(c/'s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S,3'S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid ;
-592- (┬▒)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3- (c/s-propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(c/s-propen-1-yl)- pyrrolidine-5-carboxylic Acid :
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1 'R,2'S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(c/'s-propen-1-yl)- pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(c/s-propen- 1-yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,rR,2'S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(c/s- propen-1-yl)-pyrrolidine-5-carboxylic Acid ; and
(┬▒)-(2R,3S,5R,1'R,2'S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(c/s-propen-1- yl)-pyrrolidine-5-carboxylic Acid ;
or a pharmaceutically acceptable salt, ester or prodrug thereof.
33. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
34. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
-593-
35. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 1.
36. A pharmaceutical composition for inhibiting influenza neuraminidase comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 31.
37. A pharmaceutical composition for treating an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 31.
38. A pharmaceutical composition for preventing an influenza infection comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of Claim 31.
39. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
40. The method of Claim 39 wherein the disease-causing microorganism is a virus.
41. The method of Claim 40 wherein the virus is influenza virus.
42. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
43. The method of Claim 42 wherein the disease-causing microorganism is a virus.
44. The method of Claim 43 wherein the virus is influenza virus.
-594-
45. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 1.
46. The method of Claim 45 wherein the disease-causing microorganism is a virus.
47. The method of Claim 46 wherein the virus is influenza virus.
48. A method for inhibiting neuraminidase from a disease-causing microorganism comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 31.
49. The method of Claim 48 wherein the disease-causing microorganism is a virus.
50. The method of Claim 49 wherein the virus is influenza virus.
51. A method for treating a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 31.
52. The method of Claim 51 wherein the disease-causing microorganism is a virus.
53. The method of Claim 52 wherein the virus is influenza virus.
54. A method for preventing a disease caused by a microorganism which has a neuraminidase, comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of a compound of Claim 31.
55. The method of Claim 54 wherein the disease-causing microorganism is a virus.
-595-
56. The method of Claim 55 wherein the virus is influenza virus.
-596-
EP99917414A 1998-04-23 1999-04-12 Pyrrolidines as inhibitors of neuraminidases Withdrawn EP1315698A1 (en)

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