WO2004101476A1 - Reaction de metathese faisant appel a la chaine laterale insaturee d'un acide amine alpha, alpha-disubstitue - Google Patents

Reaction de metathese faisant appel a la chaine laterale insaturee d'un acide amine alpha, alpha-disubstitue Download PDF

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Publication number
WO2004101476A1
WO2004101476A1 PCT/NL2004/000327 NL2004000327W WO2004101476A1 WO 2004101476 A1 WO2004101476 A1 WO 2004101476A1 NL 2004000327 W NL2004000327 W NL 2004000327W WO 2004101476 A1 WO2004101476 A1 WO 2004101476A1
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Prior art keywords
group
amino acid
optionally substituted
formula
process according
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PCT/NL2004/000327
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English (en)
Inventor
Floris Petrus Johannes Theodorus Rutjes
Roy Petrus Maria Storcken
Quirinus Bernardus Broxterman
Bernardus Kaptein
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Dsm Ip Assets B.V.
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Publication of WO2004101476A1 publication Critical patent/WO2004101476A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/30—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a process for the preparation of side chain unsaturated ⁇ , ⁇ -disubstituted- ⁇ -amino acid derivatives with formula 1
  • PG represents an N-protecting group or the C-terminal part of an optionally protected amino acid or peptide chain
  • X represents an optionally substituted amine group or an alkoxy group
  • 5 R 1 represents an optionally substituted alkyl group or aryl group
  • R 2 , R 3 and R 5 each independently represent H, an optionally substituted
  • R 2 and R 5 may form together with the C- atom to which they are attached an optionally substituted hydrocarbon ring, with the proviso that R 2 , R 3 and R 5 do not all represent H at the same time.
  • R 4 represents H, an alkyl group or an aryl group; n represents an integer larger than or equal to 0, 5 in which process the corresponding ⁇ , ⁇ -disubstituted- ⁇ -amino acid derivative with formula 2
  • Side chain unsaturated ⁇ , -disubstituted- ⁇ -amino acid derivatives with formula 1 are precursors of building blocks in a number of important pharmaceuticals, for instance Eflornitine in Vaniga ® as for instance described in USP- 4,413,141 and USP-4,330,559; CNS-agents, such as metabotropic glutamate receptor (ant)agonists as for instance described in WO-A-95/15940; lipophilic Trichogin GA IV peptaibol as for instance described in J. Pept.
  • the process is particularly suited for the preparation of enantiomerically enriched compounds with formula 1 , starting from enantiomerically enriched compounds with formula 2, for instance compounds with formula 1 and/or 2 with an ee higher than 80%, preferably higher than 90%, most preferably higher than 95%.
  • the amino acid derivative substrate to be used in the process according to the invention is an ⁇ . ⁇ -d.substituted-o.-amino acid derivative with formula 2.
  • PG represents an N-protecting group, for instance an acylgroup with e.g. 1 -10 C- atoms, in particular a forr ⁇ yl, acetyl or substituted acetyl group, in particular chlorqacetyl, pH ⁇ na ⁇ etyl, methoxyacetyl or trifluoroacetyl; an alkoxycarbonyl group with e.g.
  • X represents an optionally substituted amino group (NR 8 R 9 ) or an alkoxy group, for instance an alkoxy group with 1 -6 C-atoms, preferably methoxy, ethoxy or t-butoxy.
  • R 8 and R 9 each independently may represent H, an optionally substituted (cyclo)alkyl group, for instance a C1 -C20 (cyclo)alkyl group, in particular a methyl, ethyl and/or benzyl group or can be the N-terminal part of a (protected) amino acid or peptide chain; or R 8 and R 9 may form together with the N atom to which they are attached an optionally substituted for instance 3-8 membered, preferably 5-6 membered ring, which may contain 1 or more, for instance 1 -3, hetero atoms, for instance N or O; an aryl group, for instance a C6-C20 aryl group, for instance phenyl.
  • R represents an optionally substituted (cyclo)alkyl or aryl group, preferably a C1-C10 alkyl group, in particular a methyl, ethyl, propyl, or (substituted) phenyl group.
  • the alkyl group in R 1 may contain one or more substituents. Suitable substituents are for example a halogen, a hydroxy group, a C1-C6 alkoxy group or an optionally substituted phenyl group.
  • a special subgroup of R 1 represents the optionally protected side chains of proteinogenic amino acids.
  • R 1 represents an alkyl group with 1-3 C-atoms, optionally substituted with, for instance, one or more OH groups or halogens, for instance one or more F.
  • R 1 are, for instance, methyl, ethyl, propyl, benzyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl and hydroxy methyl.
  • R 4 represents an optionally substituted (cyclo)alkyl or aryl group, preferably a C1-C10 alkyl group, in particular a methyl, ethyl, propyl, or (substituted) phenyl group.
  • the alkyl or aryl group in R 4 may contain one or more substituents. Suitable substituents are for example a halogen, a hydroxy group, a C1-C6 alkoxy group or an optionally substituted phenyl group.
  • R 4 represents an alkyl group with 1 -3 C-atoms, optionally substituted with, for instance, one or more OH groups or halogens, for instance one or more F.
  • Suitable examples of R 4 are, for instance, methyl, ethyl, propyl, benzyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl and hydroxymethyl.
  • a second starting material to be used in the process according to the invention is a compound of formula 3.
  • the compound of formula 3 may be in its (Z) as well as its (£) form or mixtures thereof.
  • R 2 , R 3 and R 5 do not all represent H at the same time, R 2 , R 3 and R 5 , each independently may represent H; an optionally substituted (cyclo) alkyl group, for instance an (cyclo) alkyl group with 1-10 C-atoms, in particular methyl, ethyl, propyl, butyl or pentyl; an optionally substituted (hetero)aryl group, for instance an (hetero)aryl group with 3-18 C-atoms, in particular phenyl, naphthyl or thienyl; a CHO group, (optionally protected as its (cyclic) acetal); a group derived from an O-protected carbohydrate with for instance 8-50 C-atoms; an acyl group, for instance an acyl group with
  • the (hetero)aryl groups may contain one or more S, O, or N atoms.
  • R 2 , R 3 and R 5 each independently may represent a group derived from an O-protected carbohydrate, for instance, a carbohydrate substituent which is fully O-protected and which -in its anomeric (C-1 ) position- is directly linked to the alkenyl group of the compound of formula 3 or which may be linked to the alkenyl group via a linker group consisting of a carbon chain.
  • the group derived from an O-protected carbohydrate (R 2 , R 3 and/or R 5 ) is belonging to the class of C- glycosides.
  • the fully O-protected carbohydrate substituent(s) may for instance also be linked to the alkenyl group of the compound of formula 3 via an O- or N-heteroatom or via a linker group consisting of a carbon chain and a O- or N- heteroatom, for example by cross metathesis reaction with O-protected 1 -O-allyl- ⁇ -D- glucopyranose or O-protected N-acetyl-N-allyl- ⁇ -D-glucosamine.
  • C- glycosides comprise for example D-galactose, D-glucose, D-mannose, L-fucose; sugars of shorter chain-length, for example ribose, arabinose, xylose; sugars with NHAc substituents, for example glucosamine, galactosamine; and furanosides.
  • Protective groups on the heteroatoms can be, for example, alkyl groups (methyl, benzyl, 4-methoxybenzyl (PMB)), esters (acetyl, benzoyl) or silyl groups (trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS), triethylsilyl (TES), t-butyldipropylsilyl (TBDPS).
  • TMS trimethylsilyl
  • TDMS t-butyldimethylsilyl
  • TES triethylsilyl
  • TDPS t-butyldipropylsilyl
  • An example of a compound with formula 3 containing an O-protected carbohydrate group is e.g. 3-(2,3,4,6-tetra-0-benzyl- -D-galactopyranosyl)-1 -propene.
  • R 2 and R 5 may form together with the C-atom to which they are attached an optionally substituted, for instance 3-8 membered, hydrocarbon ring with for instance 3-20 C-atoms. Suitable substituents are, for example, the substituents mentioned above for R 2 , R 3 and/or R 5 .
  • the compound of formula 2 differs from the compound of formula 3. Intermolecular cross metathesis reactions between different starting materials 2 and 3 are preferred in the process of the present invention. In one preferred embodiment, at least one of the substituents R 6 or R 7 in the compound of formula 2 is different from R 2 and R 5 in the compound of formula 3. In another preferred embodiment, at least one of the substituents R 6 or R 7 in the compound of formula 2 is different from R 3 and H in the compound of formula 3.
  • the compounds to be prepared with the process of the present invention are chiral compounds, either as a racemic mixture of the enantiomers or in enantiomerically enriched form. If an enantiomerically enriched compound is aimed at, the starting material with formula 2 should also be in enantiomerically enriched form.
  • Such enantiomerically enriched compounds may be prepared in a manner known per se, for instance via asymmetric synthesis, enzymatic resolution, classical resolution via diastereomeric salt formation, asymmetric transformation or using a chiral auxiliary as for instance described in C. Cataviela, Tetrahedron; Assym. (1998) 9, 3517-3599; J. Jacques, A. Collet, S.H.
  • M represents a metal, for instance Mo, Ru, W, Os or Ta, preferably Ru, or Mo
  • R 14 and R 15 each represent H, an optionally substituted, for instance C1-C20, alkyl, alkenyl, alkynyl, aryl, carboxylate, alkoxy, alken
  • Suitable substituents for the groups in R 14 and R 15 are for example halogens, alkyl, for instance C1 -C5 alkyl, alkoxy, for instance C1 -C5 alkoxy or aryl, for instance C6-C10 aryl.
  • the n and m are integers, for instance 0, 1 or 2
  • each L represents a neutral ligand and each X represents an anionic ligand.
  • Suitable ligands X are, for example, halogenides (CI, Br), alkoxides (neo ' pentanolate, 1 ,1 -bis- (trifluoromethyl)ethoxy), aryloxides (in particular disubstituted phenolates (i-Pr, Br), bisnaphtholates), anilides (derived from 2,6-di-isopropylaniline).
  • Such catalysts e.g. a Schrock catalyst, Blechert modification of the Hoveyda catalyst, first and second generation Grubbs catalyst, are for instance described in A. F ⁇ rstner, Angew. Chem (2000) 37, 3013-3043 and in WO-A-02/00590.
  • the temperature at which the compound with formula 2 is contacted with the compound of formula 3 is not very critical and preferably is between 0-120 °C, most preferably between 20 and 80 °C.
  • the process of the invention may be performed in the presence of a solvent.
  • Suitable solvents that can be used in the process of the present invention are for instance ethers, for example MTBE; (aromatic) hydrocarbons, for example toluene; halogenated hydrocarbons, for example dichloromethane.
  • a preferred solvent is toluene.
  • the double bond in the side chain of the ((Z) and/or (£)) side chain unsaturated , ⁇ -disubstituted- -amino acid derivative with formula 1 may be hydrogenated using methods known in the art, for instance by hydrogenation with H 2 or a H-donor (e.g. ammonium formate) in the presence of a hydrogenation catalyst e.g. Pd/C or platinum oxide.
  • a hydrogenation catalyst e.g. Pd/C or platinum oxide.
  • Example 1 Screening of the cross-metathesis reaction of different amino acid derivatives with styrene
  • Example 2 Screening of the cross-metathesis reaction of DL-Formyl-Mag-OMe with different olefinic substrates
  • Example 3 Screening of the cross-metathesis reaction of DL-Boc-Maq-NHg with different olefinic substrates
  • Example 4 Screening of the cross-metathesis reaction of DL-Formyl-Ma ⁇ -OMe with styrene or 2-vinyl-1.3-dioxolane using different metathesis catalysts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Cette invention concerne un procédé de synthèse d'acides aminés, autrement dit de préparation de dérivés α-amino acides α,α-disubstitués à chaîne latérale insaturée représentés par la formule (1) dans laquelle : * désigne un atome C stéréogénique ; PG désigne un groupe N-protecteur ou la partie terminale C d'un acide aminé ou d'une chaîne peptidique éventuellement protégé ; X désigne un groupe amine éventuellement substitué ou un groupe alcoxy ; R1 désigne un groupe alkyle éventuellement substitué ; Ri désigne R2 ou R3 ; si Ri=R2, alors Rii=R5 et si Rii= R3, alors Rii=H ; R2, R3 et R5 désignent chacun indépendamment H, un groupe (cyclo)alkyle, (hétéro)aryle, acyle, alcoxycarbonyle, cyano, dialkylphosphonyle, oxiranyle éventuellement substitué, un groupe CHO éventuellement protégé comme son acétal ou un groupe dérivé d'un carbohydrate O-protégé, ou R2 et R5 peuvent former, avec l'atome C auquel ils sont fixés, un cycle hydrocarbure éventuellement substitué, à condition que R2, R3 et R5 ne désignent pas tous H simultanément ; R4 désigne H, un groupe alkyle ou un groupe aryle ; n désigne un nombre entier égal ou supérieur à 0. Ce procédé fait appel à une réaction de métathèse entre le précurseur des dérivés amino acides correspondant et un alcène (éventuellement substitué).
PCT/NL2004/000327 2003-05-16 2004-05-13 Reaction de metathese faisant appel a la chaine laterale insaturee d'un acide amine alpha, alpha-disubstitue WO2004101476A1 (fr)

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EP03076479 2003-05-16

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2210870A1 (fr) * 2009-01-23 2010-07-28 Evonik Degussa GmbH Liaisons d'hydroxy-aldéhyde fonctionnelles
WO2014169080A1 (fr) * 2013-04-09 2014-10-16 Materia, Inc. Préparation de tensioactifs par métathèse croisée
WO2014169055A1 (fr) * 2013-04-09 2014-10-16 Materia, Inc. Métathèse croisée de polyoléfines poly-ramifiées
US9758445B2 (en) 2013-04-09 2017-09-12 Materia, Inc. Preparation of surfactants via cross-metathesis

Non-Patent Citations (6)

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Title
BIAGINI, STEFANO C. G. ET AL: "Cross- metathesis of unsaturated.alpha.-amino acid derivatives", JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY (1998), (16), 2485-2500, 1998, XP002258660 *
HOFFMANN T ET AL: "Rational molecular design and EPC synthesis of a type VI beta -turn inducing peptide mimetic", ANGEW. CHEM. INT. ED.;ANGEWANDTE CHEMIE - INTERNATIONAL EDITION SEP 17 2001, vol. 40, no. 18, 17 September 2001 (2001-09-17), pages 3361 - 3364, XP002258663 *
KAPTEIN B ET AL: "Enantiopure Clpha-tetrasubstituted alpha-amino acids. Chemo-enzymatic synthesis and application to turn-forming peptides", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 57, no. 30, 23 July 2001 (2001-07-23), pages 6567 - 6577, XP004275079, ISSN: 0040-4020 *
SCHAFMEISTER C E ET AL: "An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides [8]", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 21 JUN 2000 UNITED STATES, vol. 122, no. 24, 21 June 2000 (2000-06-21), pages 5891 - 5892, XP002258662, ISSN: 0002-7863 *
UNDHEIM K ET AL: "Ru(II)-Catalyzed Ring Closing Metathesis in Stereoselective Spiroannulations and Cascade Reactions of Cyclic Dipeptide Substrates", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 56, no. 28, July 2000 (2000-07-01), pages 4847 - 4857, XP004208197, ISSN: 0040-4020 *
WALTER, ARMIN ET AL: "Synthesis of C-glycosylated amino acids - suitable building blocks for th synthesis of glycopeptide mimics", PROCEEDINGS OF ECSOC-3, [AND] PROCEEDINGS OF ECSOC-4, SEPT. 1-30, 1999 AN 2000 (2000), MEETING DATE 1999-2000, 1338-1345. EDITOR(S): POMBO-VILLAR, ESTEBAN. PUBLISHER: MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL, BASEL SWITZ., 2000, XP009018557 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2210870A1 (fr) * 2009-01-23 2010-07-28 Evonik Degussa GmbH Liaisons d'hydroxy-aldéhyde fonctionnelles
WO2010083934A1 (fr) * 2009-01-23 2010-07-29 Evonik Degussa Gmbh Composés à fonction hydroxy et aldéhyde
US8455698B2 (en) 2009-01-23 2013-06-04 Evonik Degussa Gmbh Hydroxy- and aldehyde functional compounds
WO2014169080A1 (fr) * 2013-04-09 2014-10-16 Materia, Inc. Préparation de tensioactifs par métathèse croisée
WO2014169055A1 (fr) * 2013-04-09 2014-10-16 Materia, Inc. Métathèse croisée de polyoléfines poly-ramifiées
US20160107980A1 (en) * 2013-04-09 2016-04-21 Materia Inc. Cross metathesis of poly-branched poly-olefins
US20160145204A1 (en) * 2013-04-09 2016-05-26 Materia, Inc. Preparation of surfactants via cross-metathesis
US9663440B2 (en) 2013-04-09 2017-05-30 Materia, Inc. Cross metathesis of poly-branched poly-olefins
US9663459B2 (en) 2013-04-09 2017-05-30 Materia, Inc. Preparation of surfactants via cross-metathesis
US9758445B2 (en) 2013-04-09 2017-09-12 Materia, Inc. Preparation of surfactants via cross-metathesis

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