Stereoisomeric enrichment of 2-amino-3-hydroxy-3-phenylpropionic acids using d-threonine aldolase
AssigneeCelgene Corporation
InventorsDavid I. Stirling, Muppala S. Raju, Andrew L. Zeitlin
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Abstract
Mixtures of enantiomeric D,L-threo 2-amino-3-hydroxy-3-phenylpropionic acids can be stereoisomerically enriched by contacting the mixture with a D-threonine aldolase. In a typical embodiment, D- and L-threo 2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid is treated with D-threonine aldolase to produce L-threo 2-amino-3-hydroxy-3-(4-methylsulfonylphenyl)propionic acid with a high ee. The benzaldehyde and amino acid formed from the D-threo isomer can be recycled.
Claims17
A process for the enantiomeric enrichment of a mixture of D- and L-threo 2-amino-3-hydroxy-3-phenylpropionic acids of the formula:
- ##STR4## in which each of R.sup.1 and R.sup.2, independently of the other, is hydrogen, hydroxy, halo, nitro, trifluoromethyl, lower alkyl, lower alkoxy, lower alkylsulfonyl, lower alkylsulfinyl, or lower alkylthio;
- R.sup.3 is hydrogen or methyl;
- and
- R.sup.4 is hydrogen or a carboxylic acid protecting group;
- and
- the salts thereof with base when R.sup.4 is hydrogen, which comprises bringing said mixture into contact in an aqueous medium with D-threonine aldolase which is enzymatically active with respect to the D-threo enantiomer but substantially inactive with respect to the L-threo enantiomer, until the D-threo enantiomer is converted to the corresponding benzaldehyde and an amino acid derivative of the formula R.sup.3 CH(NH.sub.2)COOR.sup.4, while the L-threo enantiomer remains substantially unconverted.
In a process for the preparation of an L-threo 2-amino-3-hydroxy-3-phenylpropionic acid which is unsubstituted or substituted in the phenyl ring in which a correspondingly unsubstituted or substituted benzaldehyde is condensed with glycine and the D,L-threo enantiomeric forms of the resultant 2-amino-3-hydroxy-3-phenylpropionic acid thereafter are separated, the improvement comprising subjecting said enantiomeric forms of D,L-threo 2-amino-3-hydroxy-3-phenylpropionic acid to the action of D-threonine aldolase to preferentially cleave the D-threo 2-amino-3-hydroxy-3-phenylpropionic acid to glycine and the corresponding benzaldehyde.
In the preparation of 2-amino-2-methyl-3-(3,4-dihydroxyphenyl)propionic acid in which an isomeric mixture of 2-amino-2-methyl-3-hydroxy-3-(3,4-dihydroxyphenyl)propionic acid having the D- and L-configuration about the .alpha.-carbon atom are resolved and the intermediate having the L-configuration about the .alpha.-carbon atom is hydrogenated to remove the hydroxy group in the 3-position, the improvement comprising subjecting said isomeric mixture to the action of a D-threonine aldolase to selectively cleave the isomer having the D-configuration about the .alpha.-carbon atom.
Dependencies are inferred from the claim text.