Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-04-21
1998-09-01
McKane, Joseph
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D26314
Patent
active
058012486
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB95/02484 filed Oct. 20, 1995
This invention relates to the synthesis of chiral amino acids and to novel ferrocene-substituted oxazolidinone derivatives useful in such syntheses.
As is well known, the synthesis of chiral molecules in substantially enantiomerically pure form (which term is used herein to denote compounds containing at least 80%, advantageously at least 90%, and preferably at least 95% of a desired enantiomer) is of great importance, for example to the pharmaceutical industry, and much attention has been given to stereoselective syntheses which facilitate the preparation of such chiral compounds.
One area of interest within this general field is the stereoselective replacement of a hydrogen atom from the .alpha.-carbon atom of an .alpha.-amino acid (either natural or unnatural), e.g. by electrophilic substitution, to yield a chiral .alpha.-substituted .alpha.-amino acid. Products so obtained may, for example, be useful directly in the manufacture of pharmaceuticals or in preparing chiral auxiliaries of use in the synthesis of chiral molecules (see, for example, our International Patent Publication No. WO 95/18112). Existing methods for the preparation of such substituted .alpha.-amino acids either lead to products with insufficient enantiomeric purity, e.g. as a result of racemisation where the .alpha.-amino acid starting material is a substantially enantiomerically pure chiral compound, or give unacceptably low yields.
The present invention is based on our finding that highly efficient stereoselective substitution at the .alpha.-carbon atom of an .alpha.-amino acid may be effected if the .alpha.-amino acid or a carboxylate salt thereof is reacted with ferrocene carboxaldehyde or a derivative thereof to yield a Schiff's base which is then cyclised, e.g. by reaction with an acylating agent, to yield a chiral ferrocenyl-substituted 1,3-oxazolidin-5-one; the chirality of this molecule may derive from use of a chiral .alpha.-amino acid or, where glycine is chosen as the .alpha.-amino acid, from elsewhere in the molecule, e.g. by appropriate substitution of the ferrocene ring system or by use of a chiral acylating agent. We have found that such chiral oxazolidinones may be obtained in diastereomerically pure form and in substantially quantitative yield as the exclusively formed product; they may therefore be subjected to further reaction, e.g. to stereoselective electrophilic substitution at the .alpha.-carbon atom of the .alpha.-amino acid, without any intermediate separation step. Following such substitution the oxazolidinone may be cleaved to yield substantially enantiomerically pure .alpha.-substituted .alpha.-amino acid and to regenerate the ferrocene carboxaldehyde or derivative thereof.
Thus according to one aspect of the present invention there is provided use of ferrocene carboxaldehyde or a derivative thereof in the preparation of a substantially enantiomerically pure .alpha.-substituted .alpha.-amino acid, for example by stereoselective electrophilic substitution at the .alpha.-carbon atom thereof.
Viewed from another aspect the invention provides a process which comprises the steps: .alpha.-carbon-attached hydrogen atom or a carboxylate salt thereof (hereinafter referred to as the .alpha.-amino acid starting material) with ferrocene carboxaldehyde or a derivative thereof so as to yield a corresponding Schiff's base; 2-ferrocenyl-substituted 1,3-oxazolidin-5-one (hereinafter referred to as the first chiral oxazolidinone); substitution whereby said .alpha.-carbon-attached hydrogen atom is replaced by a substituent to yield a substantially enantiomerically pure second chiral oxazolidinone; and generate a substantially enantiomerically pure .alpha.-substituted .alpha.-amino acid (hereinafter referred to as the substituted .alpha.-amino acid product).
The above described process will now be described in greater detail with regard to the individual process steps, as follows:
The .alpha.-amino acid starting material may, for example, be a compound of general
REFERENCES:
Osman et al., Journal of the Chemical Society of Japan, vol. 48, No. 7, 1975, p. 2226.
Osman et al., Chemical Abstracts, vol. 85, No. 21, 22 Nov. 1976, abstract No. 160286f.
Alonso, Chemical Abstracts, vol. 123, No. 5, 31 Jul. 1995, abstract No. 56524z.
CA 123: 56524 Enantiospecific conversion . . . phenylalanine. Alonso et al., 1995.
Davies Stephen Graham
Polywka Mario Eugenio Cosamino
McKane Joseph
Oxford Asymmetry International PLC.
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