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.