During the last eight years of support, our group has made seminal contributions to the discovery and development of enantioselective radical reactions. In the course of developing these novel processes, we have also made fundamental contributions to issues related to rotamer control in acyclic systems. A major goal for the proposed work is the development of radical-based methods for synthesizing highly functionalized chiral building blocks that are constituents of natural and unnatural products of biological significance. The toxicity of tin reagents and difficulties associated in their removal has been a deterrent for the practice of radical methods in the pharmaceutical industry (GMP processes). We will address this issue in our proposed work and aim to develop practical methods that either use tin reagents in catalytic amounts or none at all.
The specific aims for the next grant period are: 1. Development of novel methods for the synthesis of acetate and anti propionate aldols with high enantio- and diastereoselectivity using radical intermediates. 2. Development of practical methods for the synthesis of beta2, beta2,2 and beta2,3-amino acids in enantiomerically pure form. 3. The conversion of readily available pyrones to chiral pyran building blocks, a common skeleton found in marine natural products with potent biological activity. 4. Investigation of enantioselective methods to incorporate functionality into alpha,beta-unsaturated ketones, the more demanding substrates with a single donor atom. 5. Development of methods to reduce the amounts of tin used in radical reactions and a more challenging goal of radical reactions in aqueous media using an organic chain transfer agent thereby eliminating the toxicity related with tin compounds. ? ?
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