Development of chiral pyridine catalysts: Applications in kinetic resolution and asymmetric quaternary carbon synthesis

A new chiral 4-(dimethylamino)pyridine (DMAP) analog was developed that used restricted rotation to create a chirotopic environment about the nucleophilic pyridine ring nitrogen. This 2,2,2-triphenyl-1- acetoxyethyl-DMAP (TADMAP) catalyst was prepared racemically in four total steps and 37% overall yield from triphenylacetic acid and DMAP and the enantiomers separated by classical resolution with camphor sulfonic acid. The structure of TADMAP was studied computationally and crystallographically in order to provide a basis for rational design, an understanding of reaction selectivity, and mechanistic rationale for the development of future catalysts. Other trityl-based analogs of TADMAP were prepared in order to probe the effects of substitution on catalyst selectivity. Together, the trityl-based catalysts were evaluated in the kinetic resolution of aryl alkyl carbinols without notable success.; An enantioselective variant of the Steglich reaction was developed that uses TADMAP as the catalyst and provides enantiomerically enriched stereogenic quaternary carbon containing synthons in good yield (>90%) and enantiomeric excess (>91% ee). This methodology was extended to other heteroaromatic enol carbonates including furanone, benzofuranone, and oxindole based substrates. This methodology allowed for the synthesis of a variety of highly functionalized quaternary carbon bearing synthons in good to excellent yield (75--97%) and good to excellent enantiomeric excess (78--93% ee). Based on the structural data obtained from computation and X-ray crystallography, a model for asymmetric induction was developed based on the minimization of steric interactions in the tetrahedral intermediates leading to the desired products.; A family of chiral, amino alcohol-based DMAP analogs were developed, that were designed to retain the gross structural features found in TADMAP, but allow for easier catalyst optimization and enantioselective synthesis. Preliminary work with these catalysts have shown promising results in the kinetic resolution of aryl alkyl carbinols and the enantioselective carboxyl migration reactions.