Studies directed towards synthesis of the mitoenes : chemistry and synthesis of appropriately functionalized perhydroazocines and their conversion to functionalized pyrrolizidines

Abstract

The mitosenes (mitomycin analogs lacking the 9a-methoxy group) possess antiviral and antibacterial activity. Structurally they are centered around a pyrrolizidine BC-ring bearing a carbamate terminated side chain, a functionalized quinone A-ring, and an aziridine D-ring. Due to their therapeutic potential and interesting structural features, we have undertaken studies directed towards the development of synthetic methodology which might be useful in the preparation of members of this class of compounds. During the course of these studies we have developed methods for the preparation of highly substituted pyrrolizidines bearing the necessary functionality for use as precursors in the total synthesis of the mitosenes. The pyrrolizidines were generated by transannular cyclization of functionalized perhydroazocines which were obtained by reaction of appropriately 1-blocked-1,2-dihydropyridines with electron deficient acetylenes. Efficient methods for synthesis of the requisite acetylenes t-butyl 2-methyl-4-oxo-7-hydroxyhept-5-ynoate tetrahydropyranyl ether and n-butyl 2-methyl-4-oxo-7-dimethyl-t-butylsilyloxyhept-5-ynoate from succinic anhydride were developd. This approach allowed for selective differentiation of the succinoyl carbonyls at various stages of the synthesis. The acetylenes were reacted with 1-styryl-1,2-dihydropyridine to give 3-{t-butyl 2-methylsuccinoly}-4-tetrahydropyranyloxymethyl-1-styryl-1,8-dihydroazocine and 3-{n-butyl 2-methylsuccinoyl}-4-dimethyl-t-butylsilyloxymethyl-1-styryl-1,8-dihydroazocine. These azocines were then reacted with ozone followed by catalytic hydrogenation to give 3-{t-butyl 2-methylsuccinoyl}-4-hydroxymethyltetrahydropyranyloxymethyl-1-formyl-1,6,7,8-tetrahydroazocine and 3-{n-butyl 2-methylsuccinoyl}-4-dimethyl-t-butylsilyloxymethyl-1-formyl-1,6,7,8-tetrahydroazocine, the major compounds of study. ...