Studies on Glycosylation of erythro-β-Hydroxy-l-histidine. A Key Step of Bleomycin Total Synthesis

Abstract

Abstract To improve the synthetic yield of bleomycin and its analogues, it is necessary to find the high yield procedure for condensation of sugar portion with the hydroxyl group of erythro-β-hydroxy-l-histidine moiety, preventing the N-glycosylation to imidazole. The present studies include the condensations of 4,6-di-O-acetyl-2,3-di-O-methyl-α-d-glucopyranosyl bromide (10) or 3,4,6-tri-O-acetyl-2-O-(2,4,6-tri-O-acetyl-3-O-carbamoyl-α-d-mannopyranosyl)-α-l-gulopyranosyl bromide (3) and 3,4,6-tri-O-acetyl-2-O-[2,4,6-tri-O-acetyl-3-O-(N-acetylcarbamoyl)-α-d-mannopyranosyl]-α-l-gulopyranosyl bromide (28) with a variety of protected derivatives of erythro-β-hydroxy-l-histidine. The results revealed that a) Nim-tosyl group is most effective to prevent the Nim-glycosylation, b) use of silver carbonate and silver perchlorate at low temperature (−55 °C) gave the desired α-glycosides in satisfactory yields, and c) among the esters (methyl and p-nitrobenzyl) and the N-protecting groups (Z, Boc, and pMZ) of erythro-β-hydroxy-l-histidine, methyl and Z were the best groups, respectively. Using the method thus improved, the desired O-α-l-guloside, that is, erythro-β-O-[3,4,6-tri-O-acetyl-2-O-(2,4,6-tri-O-acetyl-3-O-carbamoyl-α-d-mannopyranosyl)-α-l-gulopyranosyl]-Nα-benzyloxycarbonyl-Nim(τ)-tosyl-l-histidine p-nitrobenzyl ester (31) was successfully prepared.