Biomimetic transamination of α-alkyl β-keto carboxylic esters.: Chemoenzymatic approach to the stereochemically defined α-alkyl β-fluoroalkyl β-amino acids

Biomimetic transamination of the commercially available ethyl 2-methyl-3-keto-4,4,4-trifluorobutyrate (4) with benzylamine was shown to provide a simple access to the 2-methyl-3-amino-4,4,4-trifluorobutanoic acids, a hitherto unknown biologically relevant beta-amino acid. In sharp contrast to the alpha-unsubstituted beta-keto carboxylic esters the transamination of alpha-methyl beta-keto carboxylic ester 4 proceeds under mild reaction conditions, presumably, due to relative instability of the intermediate (Z)-enamine 6. Diastereoselectivity of the process was found to be controlled by the nature of the base-catalyst allowing for a stereodivergent preparation of (2R*,3S*)-8a and (2R*,3R*)-8b diastereomers as dominant reaction products. Preparation of all four diastereo- and enantiomerically pure optical isomers of the 2-methyl-3-amino-4,4,4-trifluorobutanoic acid was effectively accomplished by penicillin acylase-catalyzed resolution of the corresponding diastereomerically pure N-phenylacetyl derivatives. The whole process, a stereocontrolled chemoenzymatic approach, including the diastereoselective base-catalyzed [1,3]-proton shift reaction and the enantioselective penicillin acylase-catalyzed resolution, employs a simple set of reactions, inexpensive reagents, and mild reaction conditions, that would render it methodologically useful for preparing biologically interesting alpha,beta-disubstituted fluorinated beta-amino acids.