A convenient synthesis of L‐N^τ‐methylhistidine and L‐N^τ‐ethylhistidine (Imidazole chemistry, Part IV)

Abstract

Interaction of L-histidine methyl ester (2) with N,N'-carbonyldiimidazole gave nearquantitative ring closure between the N' and the N" function to form (7S)-5,6,7.8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo[l,5-c~]pyrimidine (3). Alkylation of 3, c.g. with an alkyl halide. trialkyloxonium tetrafluoroborate or dialkyl sulfate, is then only possible at the "N' function" to form (7S)-2-alkyl-5,6,7,8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo[ I ,5-r,]pyrimidinium salt (4).Hydrolysis of 4, aided by hydrochloric acid, afforded L-W-alkylhistidines in high yield. The L-Wmethylhistidine (523) was found to be identical with the costly natural amino acid and,optically purc. introductionA method for preparing L-W-methylhistidine was discovered in this Laboratory'. We now wish to report a convenient method for the regioselective synthesis of L-Walkylhistidines in general and of L-N'-methylhistidine (5), a costly natural amino acid, in particular.

ChemInform Abstract: Synthesis of Chiral C2‐Symmetric Binucleating Ligands.

“…9 , 224 (27.4, M + ) , 223 (2.8). 210 (13), 209 (100, [ M -Me]'), 207 ( 5 ) 131 (7), 91 (11) 77 (6). 43 (6), 41 (10).…”

“…EI-MS: 373 (7), 372 (18, (19), 185 (8), 57 (11). 41 (13). -me1hyl-lH-imiduzol-4-yl)me1hyl]oxuzol-2-yl~-3,S-dime1hylphenol (2).…”

“…1076m, 1043m, 1008m, 987w, 957m, 905w, 847w, 737~1, 669w, 636w, 620m. (14), 138 (17), 122 (19), 121 (21), 109 (13), 107 (15), 96 (100, [C5H,N, + HI+), 95 (40), 91 (10). 81 (16), 44 (26), 42 (21).…”

“…The 1-methylhistidinol (16b) and the corresponding hydrochloride 16a were synthesized starting from commercially available histidine methyl ester dihydrochloride (11) (Scheme 3). Selective protection of the amino and imidazole N-atoms (N" and N(3)) of 11 and subsequent methylation were accomplished following a procedure of Noordam et al [13]. Conversion to the pyrimidine 12 with 1,l'-carbonylbis[lHimidazole] followed by methylation yielded the pyrimidinium salt 13 in high yield [13].…”

“…Selective protection of the amino and imidazole N-atoms (N" and N(3)) of 11 and subsequent methylation were accomplished following a procedure of Noordam et al [13]. Conversion to the pyrimidine 12 with 1,l'-carbonylbis[lHimidazole] followed by methylation yielded the pyrimidinium salt 13 in high yield [13]. After acid-catalyzed ring opening, the resulting N-(methoxycarbony1)-protected amino ester 14 could be selectively reduced with NaBH, to give the corresponding alcohol 15 in 90% yield.…”