10.1021/jo00392a018
The research focuses on the development of a new strategy for the regiospecific imidazole alkylation of protected histidines, with the aim of synthesizing modified versions of the natural amino acid that could potentially be used as enzyme inhibitors or hormone antagonists. The study introduces a phenacyl group as a protecting group for the distal imidazole nitrogen atom, allowing for the efficient alkylation at the N(3) position of N-BOC-1-phenacyl-L-histidine methyl ester. The subsequent reductive removal of the phenacyl group from N(1) of the resulting imidazolium intermediate with zinc and acetic acid provides a flexible route to 3-substituted L-histidines. The research successfully demonstrates the synthesis of various 3-substituted histidines using this method, which is particularly useful for introducing secondary benzylic alkyl groups and electron-rich benzyl substituents. Chemicals used in the process include L-histidine methyl ester, N,N-carbonyldiimidazole, phenacyl bromide, alkyl and aryl halides, zinc, acetic acid, and various solvents such as chloroform, dichloromethane, acetonitrile, and tetrahydrofuran.
