Project Summary/Abstract This objective of this proposal is to develop new synthetic methods for the enantioselective synthesis of bioactive molecules. Studies are centered on utilizing a new class of atropisomeric chiral biaryl ligand being developed in our laboratory. Preliminary work has found that imidazole-based biaryl P,N-ligands excel at promoting enantioselective copper catalyzed carbon-carbon bond-forming reactions. Our goal is to capitalize on the differences in behavior between these ligands and existing biaryl ligands to enable new reaction technology for applications in discovery chemistry. The research in this application is focused on gaining a mechanistic understanding of the structural underpinnings responsible for new and unique reactivity imparted by this new ligand scaffold. Our first aim outlines plans to develop new dearomatization reactions of nitrogen heterocycles. In this aim we describe chemistry that will push the field past chiral carbocycles and single-heteroatom heterocycles to heterocycles with >1 heteroatom. Through preliminary results we demonstrate addition to pyridine, but more importantly pyrazine, pyridazine, and pyrimidine. These latter examples are unprecedented in the literature and the success of these catalytic enantioselective dearomatization reactions is developed here to provide rapid access to complex natural products like svetamycin B, saxitoxin, and batzellidine B as well as additional chiral nitrogen-containing building blocks. The second aim is focused on catalytic enantioselective addition reactions to C=N Bonds independent of nitrogen substitution. In catalytic enantioselective processes, it is common for iminium ions to require 2 identical N-substituents to avoid the E/Z issue. We have found that catalytic enantioselective alkynylation using StackPhos lifts this requirement and the use of two different N- substituents is possible. This breakthrough allows the move from bis-protected amines (e.g. N,N-dibenzyl) to the incorporation of groups needed for the synthesis. Here we capitalize on this for an expedient synthesis of kopsanone and other chiral heterocycles such as morpholines. In addition, through preliminary results, we also demonstrate that addition to imines and nitrones in high ee is possible, despite the E/Z-isomer issue. Extensive preliminary results support these aims and we predict that the chemistry developed here will be of broad impact to practitioners in academia and industrial settings, particularly the pharmaceutical and biotech sectors.

PROJECT NARRATIVE Small molecule therapeutics have tremendously improved human health and the ability to gain access to these materials is fundamental to this endeavor, but the science required towards this goal must continuously evolve to meet contemporary challenges. Here, we aim to develop novel chemical transformations that enable the efficient preparation of chiral scaffolds found in preclinical and clinical agents. The resulting reaction technology will be of utility to discovery chemists and have widespread impact on the synthesis of bioactive molecules.