TOTAL SYNTHESIS OF STREPTONIGRONE

The first total synthesis of streptonigrone (1) is detailed and is based on the implementation of a room-temperature, inverse electron demand Diels-Alder reaction of the N-sulfonyl-1-aza-1,3-butadiene 11 for introduction of the fully substituted pyridone (C ring) central to the agent structure. Azadiene 11 generation was effectively accomplished through conversion of the corresponding oxime to the O-sulfinate followed by in situ, room-temperature homolytic rearrangement to the N-sulfonylimine. Following the room-temperature [4 + 2] cycloaddition of 11 with 1,1-dimethoxypropene, which completed the assemblage of the carbon skeleton of 1, a unique reaction sequence leading to aromatization of the central C ring was implemented taking special advantage of a base-catalyzed elimination of the methanesulfonamide via a sulfene. Subsequent introduction of the C ring C5 amine through modified Curtius rearrangement of the carboxylic acid 18 preceded a gratifying selective Fremy's salt oxidation of 20 to the key 7-bromoquinoline-5,8-quinone 21 conducted under biphasic, phase-transfer reaction conditions. The late-stage introduction of the 7-amino-6-methoxyquinoline-5,8-quinone AB ring system completed the synthesis of 1 and required the development and implementation of an improved metal-catalyzed (Ti(O-i-Pr)4) methoxide C6 nucleophilic substitution reaction.