Enzymatic hydrolysis of methyl 3,3-difluoro-2-amino esters. Synthesis of D- and L-3,3-difluoro-2-amino acids and their derivatives

Article abstract of DOI:10.1016/0022-1139(94)03224-N

The hydrolysis of methyl D,L-3,3-difluorophenyl alanate (1a) and methyl D,L-3,3-difluoro-2-aminobutanoate (1b) and their N-acetyl derivatives 2a and 2b by subtilisin has been studied.All derivatives examined were enzymatically resolved to separable mixtures of the corresponding 3,3-difluoro-L-amino acids (3a and 3b) or N-acetylamino acids (5a and 5b) and the unchanged 3,3-difluoro-D-amino esters (4a and 4b) or N-acetylamino esters (6a and 6b).Acidic hydrolysis of methyl 3,3-difluoro-D-phenyl alanate (4a) or its N-acetyl derivative 6a led to 3,3-difluoro-D-phenyl alanine (8a).In the same manner, L- and D-2-amino-3,3-difluorobutanoic acids 7b and 8b were prepared starting from 5b and 6b.Optical purity and enantiomeric excess were determined by GC analysis of the N-acetyl esters and by NMR analysis determined in the presence of Eu(tfc)3.By these methods, unchanged methyl 3,3-difluoro-D-amino ester derivatives showed an ee of >/= 90percent while L-amino acids were estimated to have >/= 95percent ee. - Keywords: Enzymatic hydrolysis; Methyl difluoroamino esters; Difluoroamino acids; NMR spectroscopy; Subtilisin Carlsburg; Optical activity