The objective of this research program is to discover and develop new reaction methodology en route to the synthesis of complex bioactive molecules. Our proposed studies will focus on the investigation and optimization of technologies that enable the synthesis of core structural and stereochemical subunits prevalent in many bioactive, polycyclic natural products. The processes that we develop will find utility in the synthesis of a variety of structures for which there is currently no efficient synthetic roadmap. Importantly, the methods presented in this application will be useful outside of the contexts described herein and will arm practitioners of synthetic chemistry (in academic, government, and industrial laboratories) with a new set of important tools to access enantioenriched and functionally diverse chemical building blocks for synthesis. The research proposed in this grant application is focused on a) the development of new iridium- and palladium-catalyzed stereoselective alkylation reactions that produce densely substituted building blocks for synthesis, b) the development of palladium- catalyzed conjugate addition processes, c) the utilization of these novel methods for the synthesis of fused, spiro, and bridged ring system arrays, and d) the implementation of these new tactics in the syntheses of multiple natural and non-natural bioactive small molecules. Specifically, we outline approaches to isopalhinine A, the yuccaols A-E, and the abietane diterpenoids. These molecules are not only important from a biological standpoint, they also serve as a testing ground for our new technologies. As a consequence of this approach, we will have access to a) novel, medicinally relevant structures, b) a general platform for their synthesis, and c) new synthetic methodology that will impact a host of diverse applications.
At the core of chemistry lies the power to manipulate the elements for the preparation of specific arrays of atoms in a predictable and reliable fashion. As synthetic chemists, our ability to construct molecules with exquisite precision is unique within the sciences. In this proposal, we outline several new approaches toward the construction of important linkages and describe the implementation of these methods in highly complex situations relevant to human medicine.
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