Synthesis of Azotomycin

Total synthesis of the Streptomyces ambofaciens anticancer constituents (–)-azotomycin (1) from γ-OBzb N-Boc-L-Glu (3) has been accomplished in nine steps. Selective protection with N-tert-butoxycarbonyl and N-trifluoroacetyl for the amino groups and benzyl or methyl esters for carboxyl groups, combined with the mixed carbonic anhydride peptide bond forming procedure, comprised the general strategy. Synthesis of bis diazo ketone 9 from dicarboxylic acid 8a proved challenging and required development of precise experimental conditions for treating the diacid chloride intermediate with diazomethane. The (–)-azotomycin synthesis presents a useful alternative to the original fermentation-isolation route.