An approach to the synthesis of mitomycin

Abstract

The use of 1,8-dihydroazocines, prepared from cycloaddition reactions of activated acetylenes with 1,2-dihydropyridines, as synthons for the preparations of mitomycin was explored. Our specific aim was to test the ability of appropriately modified azocinyl anions to under-go transannular nucleophilic cyclization reactions to form functionalized pyrrolizidines which compromise the BC ring system of mitomycin. The marked general instability of dihydropyridines necessitated investigation of a variety of nitrogen blocking groups which stabilized the normally labile dihydropyridine and which could be removed later in the sequence when the amide anionic center was required for cyclization. Among the groups tested without success were the carboalkoxy, β-cyanoethyl, vinyl ethylene glycol protected propionaldehyde, and benzhydryl groups. The failure of these to act as effective nitrogen blocking groups was due either to their incompatibility with the general methods used to prepare azocines or to their stability under conditions normally employed for their removal. In contrast to this, it was found that the 1-bromo-2,3-diol protected propionaldehyde and trans- β-styryl groups could successfully be employed in both construction of the azocine ring and in the deblocking stage to furnish the azocinyl free amines..