New Approaches for Stereoselective Formation of Quaternary Carbon Stereocenters and Fragment Coupling

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The Chemical Synthesis Program of the Chemistry Division supports the project by Professor Overman. Professor Overman is a faculty member in the Department of Chemistry at the University of California, Irvine. He proposes to develop new ways to join complex molecular fragments to prepare high-value organic molecules. By building complex pieces of a molecule independently and then coupling them together at the end of a synthesis, inefficient linear sequences that build the entire structure one step at a time can be avoided. The method under development is particularly impressive in that it combines the complex fragments in a one to one ratio. Thus, it avoids the more common need to waste valuable material by using one of the complex fragments in excess. In these studies, Professor Overman and his coworkers employ photoredox catalysis for the coupling reactions. Such transformation are attractive because they use visible light as the energy source for making new bonds. This use of sustainable energy for the reactions help to minimize their environmental impact. The broad scope of the research involving photocatalysis, mechanistic and target-directed synthesis objectives is well suited for the education of scientists at all levels. Professor Overman's group has a long established record of providing the highest level of education and training for coworkers including those underrepresented in science. Many of these students now hold leading positions in both academics and the pharmaceutical industry. Bimolecular chemical reactions that combine complex fragments in good yield, and, where important, with high stereocontrol, are fundamental for implementing convergent synthetic strategies. When the atoms joined in a fragment-coupling step are chiral, this union is particularly challenging. Recent discoveries from Professor Overman's laboratories show that bimolecular reactions of structurally elaborate tertiary carbon radicals and electron-deficient alkenes can join complex fragments by forming new bonds in high yields and high stereocontrol using equimolar (or nearly equimolar) amounts of the two coupling partners. Such chemical transformations are not currently a common part of the repertoire of organic synthesis, yet hold exciting potential to solve formidable challenges in constructing complex organic molecules. The proposed studies define the mechanism and optimize the generation and coupling of tertiary radicals formed from tertiary alcohol hemioxalate precursors, explore 1,6-additions of carbon radicals to electrophilic dienes and develop multicomponent radical-anionic crossover reactions, and define the utility of tertiary-radical fragment coupling strategies in the enantioselective total synthesis of structurally elaborate diterpenoids harboring dioxobicyclo[3.3.0]octanone fragments and ent-kaurene diterpenoids. These organic reactions have important technical broader impacts on the pharmaceutical industry.