Sustainable Transitions -Metal Catalysts for Radical Reactions

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Radicals are versatile intermediates for construction of complex molecules. They can be generated under mild conditions, their bond-forming reactions are predictable, and their tolerance of functional groups is high. However, the potential of radicals in sustainable synthesis remains largely untapped. This is so for two reasons. First, conducting radical reactions as chain processes in the traditional way results in the environmentally inacceptable generation of stoichiometric amounts of waste; when tin hydrides are used, the waste is highly toxic. Second, radical reactions have seldom been carried out catalytically. In the proposed work the principles of sustainable catalysis will be applied to radical chemistry. This will be done in an interdisciplinary manner, combining a quantum chemist (Grimme), a mechanistic inorganic chemist (Norton), and a synthetic methods chemist (Gansäuer) with a specialist in the synthesis of biologically active compounds by radical cyclizations (Li). The first-row transition metals investigated in this proposal (V, Ti, Co, and Cr) are ideally suited for sustainable catalysis. They are nontoxic in the Oxidation states to be used, and will replace older Systems employing complexes of the rare and expensive metals Ir and Rh. Employing fib as the terminal reductant will resolve the longstanding environmental and toxicity issues associated with reductive radical reactions. New catalysts will be synthesized and quantum chemical methods used for virtual catalyst screening and mechanism determination. Sustainable methods will be developed for catalyzing the hydrogen-mediated reduction of epoxides to alcohols, for catalyzing reductive radical cyclizations with Hb as the only stoichiometric reagent, and for catalyzing radical cycloisomerizations by various dienes, enynes and epoxyenes. These methods will be applied into the efficient, general and stereoselective synthesis of functionalized eight- and nine-membered ring lactams and cyclic amines, and to the synthesis of polycyclic Aspidosperma and Kopsia indole alkaloids such as voafinidine and grandilodine A.