This research proposal reflects our interest in the development of new reaction processes and reagents in the areas of asymmetric catalysis and acyclic stereocontrol. The objectives that we intend to pursue will focus on the development and application of chiral silane reagents, although intensive activity in methodology development is outside the scope of this program. A new direction to be pursued during the budget period of this proposal will focus on the improvement of a existing reaction methodology concerning catalytic asymmetric carbene insertions into heteroatom-hydrogen bonds. We will also continue the development of double stereodifferentiating reactions and applications to the synthesis of anti-tumor antibiotics derived from terrestrial sources as well as marine sources. We intend to continue our efforts aimed at the completion of the asymmetric synthesis of herbimycin A, gledanamycin, and reblastatin. It is our objective to synthesize cyclotrienin and analogs. Cytotrienin A will be evaluated for its effect on the mitogene- activated protein kinase pathway using Saccharomyces cerevisiae as a model organism and genome-wide transcription polling techniques. It is our continuing objective to complete the asymmetric synthesis of ulapualide A, and confirm its stereochemical assignment. It is our continuing aim to identify and develop chiral metal catalysts for the catalyzed asymmetric intermolecular carene insertion reactions into heteroatom-hydrogen (cf Si-H and Sn-H) bonds. Although an in-depth mechanistic evaluation is outside the scope of this program, it is our short term objective to develop a number of useful synthetic transforms using this methodology, which include new approach to the synthesis of new chiral allylic silanes and stannanes.
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