The primary objectives of this project are to develop new synthetic methodology based on reactions of organometallic complexes with organic substrates and to investigate thoroughly the mechanisms of these transformations. A rigorous mechanistic approach not only provides new synthetic methodology, but also a fundamental understanding of how transition metals can be used to control various aspects of organic reactions including regio-, stereo- and enantioselectivity. Such fundamental mechanistic studies also permit rational design of new metal- mediated transformations. Invention and study of new asymmetric metal- catalyzed transformations will be particularly emphasized. Specific studies to be undertaken include (a) development of metal-mediated nitrene and carbene transfer reactions including catalytic and asymmetric processes, (b)investigation of cobalt-catalyzed hydrosilation reactions and asymmetric hydrogenation reactions of unactivated alkenes, (c) development of enantiomerically pure Pd(II) complexes ligated by chiral C2-symmetric (bis)imines as catalysts for enantioselective hydrosilations and silaformylations, asymmetric Claisen rearrangements and enantioselective carbene transfer reactions. Mechanistic studies will be performed for all systems and in the case of catalytic reactions will be aimed at revealing the catalyst resting state, the overall catalytic cycle and the basis for enantioselectivity. These studies will serve as a guide to development of more effective """"""""second generation"""""""" catalysts. New reactions will complement existing synthetic methodology and should be applicable to the preparation of a diverse class of naturally occurring and/or biologically active systems. Of particular significance is the emphasis of this work on development of asymmetric catalysts. Since biological activity of complex molecules usually arises from a single enantiomer, there is enormous utility for asymmetric transformations which occur with high enantioselectivity. Catalytic asymmetric processes are especially valuable since large quantities of enantiomerically pure materials can be produced from small amounts of chiral catalyst. Examples of therapeutic agents where enantiomeric purity plays a key role include antibiotics, anti-inflammatory agents, antihistamines, ACE inhibitors, beta-blockers and bronchodilators. This work could serve as the basis for design of more efficient methods for preparing a range of biologically active molecules; specific examples of synthesis of enantiomerically pure anti-inflammatory agents are presented.
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