Synthetic Innovations Towards the Total Synthesis of Natural Product Derivatives for Drug Development

In order to provide scalable, efficient and selective routes towards pharmaceutically relevant compounds, we have focused on improving the economical viability and practicality of strained-silane Lewis acid activation. Towards these goals, the Leighton group has developed a new mode of anion catalysis to activate silane Lewis acids. Weakly coordinating anions have been used to access hyper-coordinate silicon species with unprecedented levels of reactivity, which have facilitated previously unattainable complex fragment couplings. A highly enantioselective and efficient method for anion catalyzed nucleophilic addition to aldehydes has enabled the synthesis of rationally designed, structurally simplified D-ring modified analogs of spongistatin 1. The completion of a step-economical route towards extremely potent, linker-handle equipped spongistatin 1 analogs and their application to targeted drug delivery will be discussed.