Anion Abstraction From Hypervalent Silanes: Enantioselective Synthesis of Compounds Bearing Carbon and Silicon Stereogenic Centers

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Project Summary The incorporation of chiral, stereogenic centers in small molecule drug candidates is statistically linked to success in clinical trials. In order to design more structurally complex bioactive compounds, chemists must rely on efficient synthetic tools. The objective of this proposal is to develop novel modes of reactivity that deliver molecules containing carbon and silicon chiral, stereogenic centers inaccessible through existing methods. Specifically, this proposal outlines a novel application of asymmetric ion-pairing catalysis to hypervalent silicate / chloride ion pairs, engaging hypervalent chlorosilanes with dual hydrogen-bond donor catalysts via an anion- binding mechanism. Mechanistic studies of hypervalent chlorosilanes have established that ionization of the silicon-chloride bond is relevant to many transformations involving organosilanes in the presence of nucleophilic or Lewis basic additives. Despite this evidence, these reactive ion pairs have not been used as handles in the design of asymmetric transformations. Using dual hydrogen-bond donors to catalyze anion binding from hypervalent silicon will be explored in two orthogonal approaches based on shared mechanistic principles. The first approach establishes Lewis acid / hydrogen-bond donor co-catalysis utilizing cationic hypervalent silicates as highly electrophilic Lewis acid catalysts through the design of a tailored bifunctional hydrogen-bond donor catalyst. This cooperative catalytic approach will be applied to an asymmetric Passerini two-component reaction (P-2CR), generating alpha-hydroxy amides, prominent motifs in bioactive molecules. Asymmetric induction through cooperative non-covalent interactions between the silicate-electrophile / chloride-catalyst ion pair is expected to result in high enantioselectivities across a wide substrate scope. If successful, this approach to Lewis acid / HBD co-catalysis provides a new and potentially general approach to enantioselective additions to carbonyl compounds. The second application will apply anion-binding catalysis to the enantioselective synthesis of silicon-stereogenic alkoxyorganosilanes. Few catalytic methods exist to access enantioenriched alkoxyorganosilanes, which have significant, yet underexplored, roles in drug discovery. Kinetic studies and computational evaluation of putative reactive intermediates will help build a comprehensive mechanistic understanding of these reactions, guiding further application of this novel anion-binding approach to additional transformations. It is expected that these methods will aid chemists in the design and synthesis of small molecule drugs and tool compounds that positively impact human health.