A convenient synthesis of L-Nτ-methylhistidine and L-Nτ-ethylhistidine (Imidazole chemistry, Part IV)†

Interaction of L-histidine methyl ester (2) with N,N′-carbonyldiimidazole gave near-quantitative ring closure between the Nα and the Nπ function to form (7S)-5,6,7,8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo[1,5-c]pyrimidine (3). Alkylation of 3, e.g. with an alkyl halide, trialkyloxonium tetrafluoroborate or dialkyl sulfate, is then only possible at the “Nτ function” to form (7S)-2-alkyl-5,6,7,8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo[1,5-c]pyrimidinium salt (4). Hydrolysis of 4, aided by hydrochloric acid, afforded L-Nτ-alkylhistidines in high yield. The L-Nτ-methylhistidine (5a) was found to be identical with the costly natural amino acid and optically pure.