Sunday, October 27, 2024
10/27/2024
Project Summary/Abstract Interest in organosilane chemistry has increased rapidly in recent years for biomedical research. Because organosilanes are stable, abundant, and virtually nontoxic, they serve as extremely important synthetic building blocks for preparation of a wide range of biomedically important molecules. Despite the advances in organosilane chemistry, the development of broadly applicable, highly selective silylation of unactivated C–C and C–H bonds remains a significant challenge. The long-term goal of this research is to develop highly efficient synthetic methods for the preparation of high-value synthetic building blocks and bioactive molecules. The objective of this proposal is to expand the scope of organosilicon chemistry directed towards organic synthesis by developing new synthetic tools. This entails a new bond activation catalysis that involves C–H and C–C silylation using a traceless N,O-acetal directing group, as well as controlled catalytic hydrosilylation of dicarboxylic acids. The rationale is that the proposed research will significantly improve our knowledge concerning such catalytic strategies, and it will also offer original approaches to structural motifs including readily functionalizable silicon-containing heterocycles. To accomplish the objective, this research program introduces three innovative synthetic strategies. Specific Aim I: develop catalytic C–H silylation of anilines with a traceless N,O-acetal directing group. The hypothesis for Aim I is that an N,O-acetal directs C–H silylation of anilines. The resulting N,O-acetal directing group can be spontaneously removed upon treatment of nucleophilic addition reactions. Specific Aim II: develop catalytic chemo- and stereoselective hydrosilylation of dicarboxylic acid anhydrides and imides. The hypothesis for Aim II is that iridium catalyst with dihydrosilanes to form a binuclear silylene-bridged iridium dimer enables controlled carbonyl hydrosilylation, differentiating between two carbonyls holding different sterics and electronics within 1,3-dicarboxylic acids. Specific Aim III: develop catalytic C–C silylation of cyclopropanols and cyclopropyl amines. The hypothesis for Aim III is that chiral esters and amides can direct silyl acetal to a hindered carbon of cyclopropanols and and cyclopropyl amines regio-, enantio-, and diastereoselectively, leading to a silicon-bearing tetrasubstituted carbon center. The expected outcome of this work is to establish traceless acetal directed silylation strategies for challenging synthetic problems delineated in Aim I–3 that will overcome current limitations and provide high-value synthetic building blocks, substructural units of biomedically relevant targets, and silicon- containing bioactive molecules. The results will have a significant positive impact because the proposed research will be imminently useful to synthetic community and medicinal chemistry areas, specifically in the discovery and production of new therapeutic agents. Finally, we believe that this research program offers exceptional training for young chemists of the future.
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