Catalytic, Enantioselective Dihalogenation of Alkenes

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In this project funded by the Chemical Catalysis Program of the Chemistry Division, Professor Scott E. Denmark at the University of Illinois at Urbana-Champaign is conducting research to develop a new paradigm for the catalytic, enantioselective dichlorination of alkenes. Addition to unsaturated compounds is among the oldest and most reliable of stereospecific transformations. However, the problem of controlling the absolute configuration of the products has proved challenging. The growing number of complex natural products bearing halogen atoms at stereogenic centers has underscored this critical deficiency in synthetic methodology. This proposal addresses the selectivity challenges inherent in the design of enantioselective dihalogenation processes, and formulates mechanism-based solutions to alkene dihalogenations, including those that circumvent the classical haliranium (or alkene-dihalogen pi-complex) intermediates. Professor Denmark has devised a new approach that inverts the classical "anti" addition to the double bonds by the use of a specially designed catalyst based on selenium. The resulting "syn addition" to double bonds enables the rational development of an enantioselective variant. There are several benefits to society: first in providing a highly skilled workforce to aid in the economic health of our chemistry-based industries. Second, the significance of chemical catalysis cannot be overestimated as it accounts for over 20% of the USA GDP. Given the emphasis on single enantiomer substances in many reaches of the chemical enterprise, new general and selective processes that provide such materials are of great current interest. The primary objective of this proposal is to construct the mechanistic/physical organic foundation for the development of generally applicable and highly selective alkene dihalogenations reactions using two different modes of catalysis. These two modes constitute the two Specific Aims of this project, namely: (1) redox active main group catalysis and (2) asymmetric phase transfer catalysis. Within each Specific Aim, we are: (1) learning the structure/reactivity correlations and the rules for achieving high catalytic activity (turnover frequencies and turnover numbers) for the target reactions, (2) carrying out detailed mechanistic investigations of the newly invented catalytic reactions, and (3) designing chiral catalysts that impart high stereoselectivity and high chemical conversion for the introduction of new vicinal stereocenters and (4) demonstrating generality in a variety of substrate classes that represent useful and commonly encountered structural motifs. This award supports an excellent training environment for young scientists in the Denmark group.