A Versatile Chemo-Enzymatic Route to Enantiomerically Pure β-Branched α-Amino Acids

Abstract
A series of diastereoisomers of β-methyl-β-phenylalanine analogues 1a−f have been prepared in enantiomerically pure form using a combination of chemo- and biocatalysis. Starting from l-threonine methyl ester 2, a range of β,β-disubstituted didehydroamino acids were obtained as their (Z)-isomers 6a−f. Asymmetric hydrogenation of these alkenes, using either the [Rh(R,R)-Et-DuPhos(COD)]BF4 or [Rh(S,S)-Et-DuPhos(COD)]BF4 catalyst, followed by hydrolysis yielded two of the four possible sets of diastereoisomers of the β-branched amino acid. Subsequent stereoinversion, using a stereoselective amino acid oxidase in combination with a nonselective reducing agent, furnished the remaining two sets of diastereomers.

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