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.