The total syntheses of bleomycin A(2) (1) by two routes are described. The final step in the synthesis of bleomycin A(2) involves methylation of bleomycin demethyl A(2) (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)-alpha-D-mannopyranosyl]-beta-L-gulopyranose (3) was converted quantitatively to its disaccharide chloride (4), the latter of which was condensed with N-alpha,N-im-bis(t-Boc)-(S)-erythro-beta-hydroxyhistidine (7) to provide alpha-O-glycosidated product 16. The subsequent couplings with benzyl valerate 8, threonylbithiazole 9, and N-alpha-t-Boc-pyrimidoblamic acid (10) afforded access to bleomycin demethyl A(2) (2) and decarbamoyl bleomycin demethyl A(2) (26). Although it was obtained as a byproduct of the synthesis of BLM, the synthesis of decarbamoyl bleomycin demethyl A(2) nonetheless constitutes the first report of synthetic access to this BLM congener that is of particular importance from a mechanistic perspective. This BLM can be used to resolve the issue of the participation of the carbamoyl group as a metal ligand in metallobleomycins. Also reported is a new route to bleomycin demethyl A(2) that employed an unprotected carbamoyl group throughout the synthesis. In conjunction with the use of the uncharged methylthiopropylamide C-substituent, the latter strategy permitted improved functional group manipulation and thereby afforded intermediates that could be purified with greater facility. Because the synthesis of bleomycin is limited by the efficiency of elaboration of the carbohydrate moiety, a study was carried out to define improved methods for the preparation of this constituent of BLM. Three new routes were explored, and a route involving the intermediacy of disaccharide activated as a glycosyl bromide was found to be particularly efficient and convenient. Also of importance was the finding that activation of carbohydrate intermediates as their glycosyl trichloroacetimidates permitted the requisite couplings to be carried out conveniently and in good yields. Synthetic BLM demethyl A(2) was shown to have the same potency as a naturally derived sample in a plasmid DNA relaxation assay. The sequence selectivity of DNA cleavage by synthetic and authentic Fe(II).BLMs was also shown to be the same. Also established for the first time for any synthetic bleomycin was the actual chemistry of DNA degradation, which is the same as that for naturally derived bleomycins.