TOTAL SYNTHESIS OF BLEOMYCIN A(2) AND RELATED AGENTS .4. SYNTHESIS OF THE DISACCHARIDE SUBUNIT - 2-O-(3-O-CARBAMOYL-ALPHA-D-MANNOPYRANOSYL)-L-GULOPYRANOSE AND COMPLETION OF THE TOTAL SYNTHESIS OF BLEOMYCIN A(2)

The chemical synthesis of 2-O-(3-O-carbamoyl-alpha-D-mannopyranosyl)-L-gulopyranose and its incorporation into a total synthesis of bleomycin A(2) (1) readily adaptable to the preparation of structural analogs are detailed. Key strategic elements of the approach include diastereoselective alpha-O-glycosidation of erythro-N-alpha-CBZ-N-pi-trityl-beta-hydroxy-L-histidine methyl ester with the beta-glycosyl diphenyl phosphate of hexaacetyl 2-O-(3-O-carbamoyl-alpha-D-mannopyranosyl)-L-gulopyranose to provide 4 (63%) with clean inversion of the glycosyl Cl stereochemistry. The subsequent convergent incorporation of 4 into bleomycin A(2) (1) was accomplished through sequential couplings with tetrapeptide S (94%) and N-alpha-BOC-pyrimidoblamic acid (83%), both of which proceeded in exceptionally high yield without protection of the adorning functionality. The precursor disaccharides 2 and 3 were obtained in a diastereospecific glycosidation of benzyl 3,4,6-tri-O-benzyl-beta-L-gulopyranoside (31) with the alpha-glycosyl diphenyl phosphate of 3-O-carbamoyl-2,4,6-tri-O-acetyl-alpha-D-mannose (19), which proceeded in exceptionally good yield (93%) with net retention of the alpha-D-mannopyranosyl Cl stereochemistry. Both the suitably protected D-mannose and L-gulose derivatives 19 and 31 for incorporation into 1-4 were prepared from D-mannose with implementation of a regioselective equatorial C3 alcohol alkylation of the 2,3-O-dibutylstannylene derived from 13 and 23. A tactically simple interconversion of a D-mannose to L-gulose derivative through inversion of the C5 stereochemistry by diastereoselective Rh(I)-catalyzed hydroboration of 28 provided the key transformation for the preparation of 31.