Biocatalytic access to α,​α-​dialkyl-​α-​amino acids by a mechanism-​based approach

Recently a biocatalytic approach to enantiopure β-​hydroxy-​α-​amino acids has been developed by application of threonine aldolases and investigated in detail in our group. In a search of potential catalysts for the asym. synthesis of α,​α-​dialkyl-​α-​amino acids, we found two natural threonine aldolases that catalyze the cleavage of racemic α-​methylthreonine (1) to produce acetaldehyde and D-​alanine: an L-​allo-​threonine aldolase from Aeromonas jandaei (L-​TA) and a D-​threonine aldolase from Pseudomonas sp. (D-​TA)​. The reactions proceeded with excellent enantioselectivity: only L-​1 was stereoselectively cleaved by L-​TA and only the D isomers were accepted by D-​TA. Having identified potential donors, we synthesized β-​hydroxy-​α,​α-​dialkyl-​α-​amino acids starting from a range of aldehydes as acceptors and D-​alanine, D-​serine, or D-​cysteine as donors. A wide range of L- and D-​α-​alkylserine derivs. were successfully produced with excellent enantiospecificity at the α-​carbon atom. Our results represent the first example of a biocatalytic asym. aldol synthesis of α-​substituted serine derivs. using threonine aldolases. Moreover, our finding offers the possibility of accessing both enantiomers by choosing either L-​TA or D-​TA.