WO1995008553A1 - Synthese de ligands de selectine - Google Patents

Synthese de ligands de selectine Download PDF

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Publication number
WO1995008553A1
WO1995008553A1 PCT/US1994/010790 US9410790W WO9508553A1 WO 1995008553 A1 WO1995008553 A1 WO 1995008553A1 US 9410790 W US9410790 W US 9410790W WO 9508553 A1 WO9508553 A1 WO 9508553A1
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WIPO (PCT)
Prior art keywords
compound
yield
equivalents
cho
sulfated
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Application number
PCT/US1994/010790
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English (en)
Inventor
K. C. Nicolaou
Nicholas J. Bockovich
Daniel R. Carcanague
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The Scripps Research Institute
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Publication date
Application filed by The Scripps Research Institute filed Critical The Scripps Research Institute
Priority to AU78782/94A priority Critical patent/AU7878294A/en
Publication of WO1995008553A1 publication Critical patent/WO1995008553A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/18—Acyclic radicals, substituted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/04—Disaccharides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H3/00—Compounds containing only hydrogen atoms and saccharide radicals having only carbon, hydrogen, and oxygen atoms
    • C07H3/06—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the invention relates to the total syntheses of the naturally occurring sulfated Le and Le" tetrasaccharides and related compounds. More particularly, the invention relates to compounds which are truncated analogs of sulfated Le x and Le", to key intermediates in the synthesis of sulfated Le x and Le" tetrasaccharides and related compounds and to multivalent Le x selectin ligands.
  • Sialyl Lex-type molecules serve as ligands to E-selectin and contribute to the recruitment of leukocytes to inflammation sites.
  • Several investigators contributed to the initial identification of sialyl Lex-type molecules as ligands to E-selectin, e.g., M. Bevilacqua et al. (Science 1989, 243, 1160), J. Lowe et al. (Cell 1990, 63, 475), M. Phillips et al. (Science 1990, 250, 1130), G. alz et al. (Science 1990, 250, 1132) and M. Tiemeyer et al. (Proc. Nat/. Acad. Sci., USA 1991, 88, 1138).
  • the invention relates to the synthesis of sulfated Le x -type tetrasaccharides. More particularly, the invention is the total syntheses of sulfated Le x 1 and of sulfated Le* 2 and related
  • Compounds 1 and 2 are tetrameric carbohydrates having four rings, viz. ring A, ring B, ring C, and ring D.
  • the invention includes the synthesis of truncated analogs of sulfated Le x 1 and sulfated Le" 2 such as compounds 3 and 4, indicated below.
  • Compound 3 is a truncated version of Le x 1
  • compound 4 is a truncated version of Le" 2.
  • the truncated compounds 3 and 4 lack ring A.
  • the invention also includes various key intermediates employed in the syntheses of sulfated Le x 1 and of sulfated Le* 2, i.e., compounds 5 - 10 and includes multivalent Le x selectin legands.
  • Compounds 1 - 4 and 5 - 10 are illustrated in Fig. 1.
  • the synthesis of the sulfated Le x -type tetrasaccharide 1 is summarized in Scheme I.
  • the glycosyl donor 10 is coupled with the glycosyl acceptor 5 under standard Mukaiyama conditions, i.e., AgC10 4 -SnCl 2 (T. Mukaiyama et al., Chem. Lett. 1981, 431) .
  • the resultant glycoside 11 is stereoselectively ⁇ -linked and is produced with a 90% yield.
  • the precise chemical mechanism ccounting for the stereoselectivity of this glycoside bond ormation is unknown but presumed to involve the participation of the neighboring group.
  • Treatment of glycoside 11 with MeNHNH 2 in refluxing ethanol resulted in removal of both the acetate and the phthalimide groups leads to the corresponding amino alcohol.
  • the hydroxyl compound 16 may then be coupled with the fucosyl fluoride derivative 7 (AgC104-SnCl2) by the method of K.C. Nicolaou et al., (J. Am. Chem. Soc. 1990, 112, 3693) to give, stereoselectively, tetrasaccharide 17 with the desired ⁇ -fucose anomeric linkage with a yield of 85%. Reaction of tetrasaccharide 17 with thiourea leads to selective removal of the chloroacetyl group to afford alcohol 18 with a yield of 81%.
  • alcohol 18 may be converted to the sulfated compound 19, in 95% yield, by exposure to S0 3 -NMe 3 complex in anhydrous pyridine.
  • deacetylation of compound 19 followed by hydrogenolysis gives the targeted sulfated Le x tetrasaccharide 1 in 80% overall yield.
  • Fluoride 28 can serve as a common precursor to both sulfated Le* 2 and the truncated version of sulfated Le* 4.
  • the synthesis of the tetrasaccharide 2 is achieved using a seguence involving the coupling of compound 28 with the galactose derivative 5 (Cp 2 HfCl 2 -Ag0Tf) .
  • the chloroacetate moiety can be removed from compound 29 and the sulfate group can be attached in its place (S0 3 -NMe 3 ), furnishing compound 31 via compound 30 with an overall yield of 40%.
  • the phthalimide and acetate groups are both removed from compound 31 by treatment with NH 2 NH 2 -H 2 0 at 100°C. This may then be followed by acetylation of the generated amino group to give the amide 32 in 73% overall yield.
  • Final deprotection to generate the naturally occurring compound 2 is then achieved by hydrogenolysis with a 95% yield.
  • Synthesis of the trisaccharide 4 may proceed by glycosylating benzyl alcohol with fluoride 28. This leads to compound 33 with a yield of 95%. Compound 33 is then converted to trisaccharide 4 as described above for tetrasaccharide 2 (Scheme III) .
  • Fig.l illustrates sulfated Lewis x (1,3) and Lewis* (2,4) target molecules and key intermediates (5 - 10) for their chemical synthesis.
  • Yields refer to chromatographically and spectroscopically ( J H NMR) pure materials. NMR spectra were recorded on Bruker AMX-500 MHz spectrometer at ambient temperature. Chemical shifts are reported relative to the residual solvent peak. Multiplicities are designated as singlet (s) , doublet (d) , triplet (t) , pseudo triplet (PT) , quartet (q) , multiplet (m) , broad (b) , apparent (app) or obstructed (obs) .
  • IR samples were prepared by evaporation of a solution of the compound in CHC1 3 or CDC1 3 onto a NaCl plate under a stream of argon.1 IR spectra were recorded on a Perkin elmer 1600 series FT-IR spectrophotometer. Optical rotations were measured using a Perkin Elmer 241 polarimeter. High resolution mass spectra (HRMS) were recorded on a VG ZAB-ZSE mass spectrometer under Fast Atom Bombardment (FAB) conditions. Melting points were obtained with a Thomas Hoover Unimelt apparatus and are uncorrected. Microanalyses were performed at the Scripps ?Research Institute.
  • TES -SiEt 3
  • TBS -Si l BuMe 2
  • THP tetrahydropyranyl-
  • Ts p-MePhS0 2
  • DMAP p -(dimethylamino)pyridine
  • M.S. molecular sieves
  • pyr pyridine
  • MEM methoxyethoxymethyl-
  • Ms -S0 2 Me
  • Tf -S0 2 CF 3
  • PMB p- methoxybenzyl-
  • TMS -SiMe 3 .
  • Sulfated Le x tetrasaccharide (compound 1) : A method for synthesizing sulfated Le x tetrasaccharide, i.e. compound 1, is illustrated in Scheme I (supra) .
  • the reaction conditions for each step of Scheme I are provided as follows:
  • Step "B” Compound 11 was then combined with a (1:1) mixture of hydrazine-EtOH at 95°C for 48 hours to produce compound 12.
  • Step “C” Compound 12 was then combined with an excess of Ac 2 0 and with an excess of Et 3 N, using p- (dimethylamino)pyridine (DMAP) as a catalyst, in CH 2 C1 2 at 25°C for 4 hours to produce compound 13 with an overall yield of 80% for the two steps.
  • DMAP dimethylaminopyridine
  • Step “D” Compound 13 was then combined with 2.0 equivalents of Bu 4 NF in THF at 25°C for 1 hour to produce compound 14 with a yield of 95%.
  • Step “E” Compound 14 was then combined with 2.0 equivalents of compound 6, 3.0 equivalents of AgC10 4 and 3.0 equivalents of SNC1 2 with 4A molecular sieves in CH 2 C1 2 and allowed to react for 5 hours starting at 0°C and increasing to 25°C to yield compound 15 with a 75% yield.
  • Step “F” Compound 15 was then combined with a catalytic amount of H 2 Ru(PPh 3 ) 4 in EtOH at 95°C for 4 hours; the product was then combined with a catalytic amount of p-TsOH in MeOH at 25°C for 1 hour to produce compound 16 with a 81% yield.
  • Step “G” Compound 16 was then combined with 2.0 equivalents of compound 7, 3.0 equivalents of AgC10 4 and 3.0 equivalents of SNC1 2 with 4A molecular sieves in CH 2 C1 2 and allowed to react for 4 hours starting at 0°C and increasing to 25°C to yield compound 17 with a 85% yield.
  • Step “H” Compound 17 was then combined with 5.0 equivalents of thiourea, 2.0 equivalents of 2,6- lutidine in EtOH at 65°C for 5 hours to produce compound 18 with an 81% yield.
  • Step “I” Compound 18 was then combined with 20 equivalents of S0 3 -NMe 3 in pyridine at 25°C for 24 hours to produce compound 19 with a 95% yield.
  • Step “J” Compound 19 was then combined with 2.0 equivalents of NaOMe in MeOH at 45°C for 5 hours; and then deprotected with H 2 using Pd(0H) 2 in a 2:1 mixture of MeOH-H 2 0 for 48 hours to produce compound 1 with a yield of 80%.
  • Truncated sulfated Le x (trisaccharide 3) : A method for synthesizing truncated sulfated Le x , i.e., the trisaccharide 3, is illustrated in Scheme II (supra). The reaction conditions for each step of Scheme II are provided as follows:
  • Step “A” Compound 5 was combined with 2.0 equivalents of compound 6 with 3.0 equivalents of AgC10 4 and 3.0 equivalents of SnCl 2 with 4A molecular sieves in CH 2 C1 2 and allowed to react for 4 hours starting at 0°C and increasing to 25°C to yield compound 20 with a 81% yield.
  • Step “B” Compound 20 was then combined with a catalytic amount of H 2 Ru(PPh 3 ) 4 in EtOH at 80°C for 1 hour; the product was then combined with a catalytic amount of p-TsOH in a 4:1 mixture of MeOH-CH 2 Cl 2 at 25°C for 2 hours to produce compound 21 with a 82% yield.
  • Step "C” Compound 20 was combined with 2.0 equivalents of compound 7 with 3.0 equivalents of AgC10 4 and 3.0 equivalents of SnCl 2 with 4A molecular sieves in a 3:1 mixture of Et 2 0-THF and allowed to react for 3 hours starting at -15°C and increasing to 0°C to yield compound 22 with a 85% yield.
  • Step “D” Compound 22 was then combined with 5.0 equivalents of thiourea, 2.0 equivalents of 2,6- lutidine in a 1:1 mixture of EtOH-CH 2 Cl 2 at 65°C for 5 hours to produce compound 23 with a 90% yield.
  • Step “E” Compound 23 was then combined with 20 equivalents of S0 3 -NMe 3 in pyridine at 25°C for 24 hours to produce compound 24 with a 86% yield.
  • Step M F Compound 24 was then combined with 2.0 equivalents of NaOMe in MeOH at 25°C for 4 hours; and then deprotected with H 2 using Pd(OH) 2 in MeOH for 7 days to produce compound 3 with a yield of 74%.
  • Sulfated Le (tetrasaccharide 2 and trisaccharide 4)
  • Step "B” Compound 25 was then combined with 10.0 equivalents of NaCNBH 3 and excess ethereal HC1 with 3A molecular sieves in THF at 0°C for 30 minutes to produce compound 26 with a yield of 76%.
  • Step "C” Compound 26 was then combined with 2.0 equivalents of compound 7 with 4.0 equivalents of AgC10 4 and 4.0 equivalents of SnCl 2 with 4A molecular sieves in a 5:1 mixture of Et 2 0-THF and allowed to react for 1 hour starting at -15°C and increasing to 0°C to yield compound 27 with a 95% yield.
  • Step "D” Compound 27 was then combined with 3.0 equivalents of DAST and 1.25 equivalents of NBS in CH 2 C1 2 for 2 hour starting at -78°C and increasing to -20°C to yield compound 28 with a 80% yield.
  • Step "G” Compound 29 or 33 was then combined with
  • Step “H” Compound 30 or 34 was then combined with 20 equivalents of S0 3 -NMe 3 in pyridine at 25°C for 24 hours to produce compound 31 with a 50% yield or compound 35 with a 76% yield, respectively.
  • Step "I” Compound 31 or 35 was then first combined with a 1:1 mixture of hydrazine hydrate-EtOH at 100°C for 3 hours; the product was then combined with an excess of Ac 2 0 and with an excess of Et 3 N in MEOH at 25°C for 10 minutes to produce compound 32 with an overall yield of 73% for the two steps or to produce compound 36 with an overall yield of 50%, respectively.
  • Step "J” Compound 32 or 36 was then deprotected with H 2 using Pd(OH) 2 in a 2:1 mixture of MeOH-H 2 0 for 48 hours at 25°C to produce compound 2 with a yield of
  • Step "A” Compound 37 was combined with 3.0 equivalents of benzaldehyde dimethyl acetal, with a catalytic amount CSA in THF for 16 hours at 55°C to produce compound 8 with a yield of 85%.
  • Step "B” Compound 8 was then combined with 2.0 equivalents of NaH, 2.0 equivalents of allyl bromide, and 0.1 equivalent of Bu 4 NI in THF for 16 hours starting at 0°C and ending at 50°C to produce compound
  • Step "C” Alternatively, compound 37 was combined with 10.0 equivalents of NaCNBH 3 and excess ethereal HCl with 3A molecular sieves in THF for 1 hour starting at 0°C and ending at 25°C to produce compound 39.
  • Step “D” Compound 39 was then combined with 1.5 equivalents of t-butyldimethylsilyl triflate (trifluoromethanesulphonate) , 1.7 equivalents of 2,6- lutidine in CH 2 C1 2 for 1.5 hours starting at 0°C and ending at 25°C to produce compound 40 with a 75% yield for two steps.
  • Step “E” Alternatively, compound 39 was then combined with 3.0 equivalents of DAST and 1.2 equivalents of dimethyl(methylthio)sulfonium triflate (trifluoromethanesulphonate) , i.e., DMTST, in CH 2 C1 2 for 1 hour at -10°C to produce compound 10 with a 50% yield.
  • Step “A” Compound 41 was combined with excess 2,2-dimethoxypropane and a catalytic amount CSA in acetone for 48 hours at 25°C to produce compound 42 with a yield of 56%.
  • Step “B” Compound 42 was then combined with 3.0 equivalents of NaH, 3.0 equivalents of benzyl bromide, and a catalytic amount Bu 4 NI in THF for 2 hours starting at 0°C and ending at 50°C to produce compound 43 with a yield of 89%.
  • Step “C” Compound 43 was then combined with 3.0 equivalents of DAST and 1.2 equivalents of NBS in CH 2 C1 2 for 4 hour starting at -5°C and increasing to 10°C to yield compound 44 with a 80% yield.
  • Step "D” Alternatively, compound 41 was then combined with 3.0 equivalents of benzyl alcohol, 3.0 equivalents of AgC10 4 , and 1.5 equivalents of Cp 2 ZrCl 2 with 4A molecular sieves in benzene for 2 hours to NOT FURNISHED UPON FILING

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
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Abstract

L'invention concerne les synthèses totales de tétrasaccharides Le?x et Lea¿ sulfatés d'origine naturelle, des analogues de trisaccharides de Le?x et Lea¿ sulfatés, et des ligands de sélectine Lex multivalents.
PCT/US1994/010790 1993-09-22 1994-09-22 Synthese de ligands de selectine WO1995008553A1 (fr)

Priority Applications (1)

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AU78782/94A AU7878294A (en) 1993-09-22 1994-09-22 Synthesis of selectin ligands

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US12559293A 1993-09-22 1993-09-22
US08/125,592 1993-09-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0687684A1 (fr) * 1993-03-04 1995-12-20 Mect Corporation Compose associe au systeme de lewis, procede d'obtention de ce compose et anti-inflammatoire
WO2000042057A1 (fr) * 1999-01-18 2000-07-20 Alchemia Pty. Ltd. Groupes protecteurs pour la synthese de glucides
JP2000256385A (ja) * 1999-01-07 2000-09-19 Seikagaku Kogyo Co Ltd オリゴ糖の製造方法ならびに新規オリゴ糖およびそれを含む医薬組成物

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0416396A2 (fr) * 1989-09-04 1991-03-13 MERCK PATENT GmbH Tetrasaccharides et procédé pour leur préparation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0416396A2 (fr) * 1989-09-04 1991-03-13 MERCK PATENT GmbH Tetrasaccharides et procédé pour leur préparation

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHANDRASSEKARAN E.V. ET AL.: "Ovarian Cancer alpha 1,3-L-Fucosyltransferase", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 267, no. 33, 25 November 1992 (1992-11-25), BALTIMORE, MD US, pages 23806 - 23814 *
JAIN R.K. AND MATTA K.L.: "Synthesis of oligosaccharides containing the X-antigenic trisaccharide (alpha-L-Fucp-(1-3)-[beta-D-Galp-(1-4)]-beta-D-GlcpNAc) at their nonreducing ends", CARBOHYDRATE RESEARCH, vol. 226, 1992, AMSTERDAM NL, pages 91 - 100 *
NICOLAOU K.C. ET AL.: "Stereocontrolled Synthesis of Sialyl Lex, the Oligosaccharide Binding Ligand to ELAM-1 (Sialyl = N-acetylneuramin)", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL COMMUNICATIONS, 1991, LETCHWORTH GB, pages 870 - 872 *
NICOLAOU K.C. ET AL.: "Total synthesis of Sialyl Dimeric Lex", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 114, 1992, WASHINGTON, DC US, pages 3126 - 3128 *
NICOLAOU K.C. ET AL.: "Total Synthesis of Sulfated Lex and Lea-Type Oligosaccharide Selectin Ligands", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 115, no. 19, 22 September 1993 (1993-09-22), WASHINGTON, DC US, pages 8843 - 8844 *
PAULSEN H. ET AL.: "Entwicklung eines syntheseblocks der 3-O-beta-D-Galactopyranosyl-D-galactopyranose", CARBOHYDRATE RESEARCH, vol. 144, 1985, AMSTERDAM NL, pages 45 - 55 *
YUEN C.-T. ET AL.: "Novel Sulfated Ligands for the Cell Adhesion Molecule E-Selectin Revealed by the Neoglycolipid Technology among O-Linked Oligosaccharide on an Ovarian Cystadenoma Glycoprotein", BIOCHEMISTRY, vol. 31, 1992, EASTON, PA US, pages 9126 - 9131 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0687684A1 (fr) * 1993-03-04 1995-12-20 Mect Corporation Compose associe au systeme de lewis, procede d'obtention de ce compose et anti-inflammatoire
EP0687684A4 (fr) * 1993-03-04 1998-03-04 Kanto Ishi Pharma Co Ltd Compose associe au systeme de lewis, procede d'obtention de ce compose et anti-inflammatoire
US5763413A (en) * 1993-03-04 1998-06-09 Mect Corporation Lewis-associated compound, process for producing the same, and anti-inflammatory
JP2000256385A (ja) * 1999-01-07 2000-09-19 Seikagaku Kogyo Co Ltd オリゴ糖の製造方法ならびに新規オリゴ糖およびそれを含む医薬組成物
WO2000042057A1 (fr) * 1999-01-18 2000-07-20 Alchemia Pty. Ltd. Groupes protecteurs pour la synthese de glucides
US6953850B1 (en) 1999-01-18 2005-10-11 Alchemia Pty. Ltd. Protecting groups for carbohydrate synthesis

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