Total Synthesis of Bleomycin Group Antibiotics. Total Syntheses of Bleomycin Demethyl A2, Bleomycin A2, and Decarbamoyl Bleomycin Demethyl A2

Abstract

The total syntheses of bleomycin A2 (1) by two routes are described. The final step in the synthesis of bleomycin A2 involves methylation of bleomycin demethyl A2 (2). This bleomycin derivative is of interest mechanistically, and can also provide access to other bleomycins via its known chemical conversion to bleomycinic acid. Accordingly, the synthetic strategy presented represents a particularly versatile approach for the elaboration of a wide variety of BLM congeners. Bleomycin was constructed from five key intermediates, the syntheses of which are described. 1,6-Di-O-acetyl-3,4-di-O-benzyl-2-O-[2,4,6-tri-O-acetyl-3-O-(N-acetylcarbamoyl)-α-d-mannopyranosyl]-β-l-gulopyranose (3) was converted quantitatively to its disaccharide chloride (4), the latter of which was condensed with Nα,Nim-bis(t-Boc)-(S)-erythro-β-hydroxyhistidine (7) to provide α-O-glycosidated product 16. The subsequent couplings with benzyl valerate 8, threonylbithiazole 9, and Nα-t-Boc-pyrimidoblamic acid (10) afforded access to bleomyc...