DIRECT SYNTHESIS OF ALPHA-HALOGENOMETHYL-ALPHA-AMINO ACIDS FROM THE PARENT ALPHA-AMINO-ACIDS

A general approach to the preparation of .alpha.-halogenomethyl-.alpha.-amino acids 2 [.alpha.-(chloromethyl) alanine hydrochloride], 15 [.alpha.-(difluoromethyl) alanine] and 16 [.alpha.-(fluoromethyl) alanine] which are potential enzyme-activated irreversible inhibitors of the parent .alpha.-amino decarboxylases is described. The key step in the synthesis is the regioselective alkylation of a Schiff base ester 6 [methyl-2-(benzylideneamino) propionate] readily available from the parent .alpha.-amino acid, with poly (halomethanes) such as bromochloromethane, chlorofluoromethane and chlorodifluoromethane to give the corresponding .alpha.-halogenomethylated adducts 8 [methyl-2-(benzylideneamino)-2-methyl-3-chloropropionate], 9 [methyl-2-(benzylideneamino)-2-methyl-3,3-difluoropropionate] and 10 [methyl-2-(benzylideneamino)-2-methyl-3-fluoropropionate], respectively. Subsequent removal of the protecting groups from the adducts upon acidic treatment yields the corresponding .alpha.-halogenomethyl-.alpha.-amino acids 2, 15 and 16. The mechanism of the key alkylation reaction appears to depend on the degree and the nature of the substitution of the halomethanes; apparently bromochloromethane and chlorofluoromethane react via an SN2 mechanism, but chlorodifluoromethane reacts by a chain process involving the intermediary of difluorocarbene.