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 are currently no efficient synthetic roadmaps. 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 palladium- and iridium-catalyzed stereoselective alkylation reactions that produce densely substituted, acyclic building blocks for synthesis, b) the development of novel nickel- and copper-catalysis for asymmetric alkylation and acylation processes, c) the development of these novel methods specifically for the preparation of all-carbon quaternary stereocenters and arrays of quaternary centers, and d) the implementation of these new tactics in the syntheses of highly complex, bioactive bis-indole alkaloids. Specifically, we outline approaches to leucophyllidine, strempeliopidine, and norpleiomutine. 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.
to Public Health: 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 implemention of these methods in highly complex situations relevant to human medicine.
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