The development of new carbon-nitrogen bond forming reactions: Towards the synthesis of mitomycin C

Mitomycin C (MMC) is a natural product isolated from Streptomyces caespitosus with anticancer properties, and it remains in clinical use today. The overarching goal of my dissertation research is the convergent total synthesis of mitomycin C. In order to achieve this goal, we have developed several new chemical tools: free radical-mediated alkyne aminostannation, Bronsted acid-catalyzed aza-Darzens, and regioselective enamine-quinone couplings. The desire to construct mitomycin C via a convergent pyrrolidine enamine-quinone coupling led us to develop the transformation in which a vinyl radical adds to a pendant ketimine to form a nucleophilic N-alkyl enamine. The free radical-mediated alkyne aminostannation produced a highly nucleophilic (3-stannyl enamine, which was treated with a variety of acid chlorides to provide vinylogous amides. We then investigated the regioselective coupling between a quinone and the beta-stannyl enamine as a model system for the construction of the MMC backbone. Coupling of this reactive enamine with a methoxy, bromo substituted quinone selectively provided the desired regioisomer for the mitomycin C core. Finally, we focused on the synthesis of the aziridine ring. The cis-aziridine of the mitomycins is vital to its mode of biological activation as a DNA cross-linking agent. While targeting more functionally complex aziridines that would serve as precursors to the key pyrrolidinyl enamine intermediate, we discovered and developed the Bronsted acid-catalyzed aza-Darzens synthesis. As part of this methodology, we were able to examine a range of substrates that produced functionally diverse N-alkyl aziridines. The methods developed have enabled us to form the backbone of MMC with key functional groups intact.