New Synthetic Methods for the Preparation of Highly Functionalized Heterocycles

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The goal of the Derksen group research program is to develop methods that improve access to highly functionalized heterocycles (cyclic compounds that have at least two different elements forming the ring). These molecules have many potential applications including in the pharmaceutical industry, in materials chemistry, and as ligands for catalysis. Being able to access unique structures is critical to making molecules that have novel properties for these varying applications.  Improving synthetic access to heterocycles will also allow access to more complex molecular scaffolds, while reducing waste and lowering costs which are essential for responsible development in industry. The three main aims of this proposal involve the synthesis of heterocycles and have a particular focus on catalysis and stereochemical challenges of existing methods. Aim 1 is based on the development of atropisomer-selective catalysts for nucleophilic aromatic substitution reactions. As an increasing number of pharmaceutical compounds are moving beyond flat structures, improved methods are needed to control the relative and absolute configuration of these unique scaffolds. Aim two is focused on the synthesis of functionalized azetidines, particularly benzazetidines, and those contain stereogeneic centers. Inspired by the rise of azetidine applications in the literature and the unusual natural product Taichunamide A, this proposal describes our approach to forming complex azetidines using catalytic, asymmetric methods. Aim three of the proposal describes our strategy to improve the product selectivity of cross-electrophile coupling that reduces the amount of homocoupled byproducts found in these reactions. Although significant progress has been made in the cross-electrophile coupling between aryl and alkyl halides, our strategy is to develop a modular catalyst design strategy that can be rapidly and systematically optimized to favor cross coupling. The impact of the work described in this proposal includes the development of new catalytic strategies for stereoinduction, improved access to chiral azetidines, and the development of novel modular ligands for cross electrophile coupling. This work will lead to high impact publications and train HQP, but will also lead to new partnerships with the chemical industry.