Biomimetic Transamination of α-Alkyl β-Keto Carboxylic Esters. Chemoenzymatic Approach to the Stereochemically Defined α-Alkyl β-Fluoroalkyl β-Amino Acids

Abstract

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 β-amino acid. In sharp contrast to the α-unsubstituted β-keto carboxylic esters the transamination of α-methyl β-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 α,β-disubstituted fluorinated β-amino acids.