ASYMMETRIC-SYNTHESIS OF UNUSUAL AMINO-ACIDS - AN EFFICIENT SYNTHESIS OF OPTICALLY PURE ISOMERS OF BETA-METHYLPHENYLALANINE

Substitution of the diastereotopic beta-hydrogens of many alpha-amino acids provides an approach to the three dimensional topographic control of peptide structure. Asymmetric synthesis of the desired amino acids is needed to facilitate these studies. All four individual isomers of beta-methylphenylalanine, (2S,3S)-, (2R,3R)-, (2S,3R)- and (2R,3S)-beta-methylphenylalanine have been synthesized in high optical purity. The stereochemistry at the beta-center was set by the choice of starting material, either (+)- or (-)-3-phenylbutyric acid. These acids were attached to the appropriate D- or L-auxiliary (a 4-phenylmethyl-2-oxazolidinone) to give a 3'-3'-phenylbutanoyl-4-phenylmethyl-2-oxazolidinone, Asymmetric bromination was accomplished via the chiral imide enolate bromination methodology of Evans and co-workers (J. Am. Chem. Soc. 1990, 112, 4011-40). Evidence for asymmetric induction was obtained from the X-my structure of one of the intermediate bromides. The bromide was converted to the diastereoisomeric azide by SN2 displacement using tetramethylguanidinium azide. After recovery of the chiral auxiliary by catalyzed hydrolysis, the chiral amino acid was obtained by catalytic hydrogenation over 10% Pd/C. All four isomers were obtained in enantiomeric purities of 95:5 to 99:1.