Synthesis of 2-methyl and 2-carboxymethyl derivatives of ornithine and arginine

Synthesis and characterization of a dozen derivatives of ornithine and arginine bearing 2-methyl or 2-carboxymethyl substituents are described. These substituents were introduced by dilithiation of 3-(4-methoxybenzylidineamino)-2-piperidinone with lithium diisopropylamide followed by regiospecific alkylation at C-3 with iodomethane or ethyl bromoacetate. 2-Methyl-D,L-ornithine was obtained in three steps from 3-amino-2-piperidinone in 68% overall yield, and 2-carboxymethyl-D,L-ornithine was isolated in 56% overall yield. 2-Methyl- and 2-carboxymethyl-D,L-arginine were obtained by mild acid hydrolysis to remove the 4-methoxybenzylidine group, N-acylation with 4-toluenesulfonyl chloride, mild alkaline hydrolysis of the lactam ring and the ester group, guanidination of the 5-amino group with O-methylisourea, and strong acid hydrolysis to remove the 4-tolunenesulfonyl group. Several of these compounds are inhibitors of carboxypeptidase B.