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Studies in asymmetric synthesis: Supramolecular catalysis, C-H activation, and D-Cycloserine synthesis

Nathan Christopher Thacker, University of Nebraska - Lincoln


Rh-catalyzed asymmetric hydrogenation has emerged as a powerful tool for the manufacturing of chiral pharmaceuticals. While the mechanism is well understood, catalyst design a priori is not yet possible. Supramolecular catalysis, the use of noncovalent forces to affect a catalytic process, can afford the catalyst diversity required to uncover efficient catalysts and further our understanding. Using a modular design and self-assembly, a large scale supramolecular catalyst screening in a catalyst scaffold optimization study of rhodium-catalyzed asymmetric hydrogenation was carried out. Analyzing the data yields some new insights into the roles of each module making up the supramolecular catalyst. Perhaps most surprisingly, the presence of a chiral recognition element positioned remote to the site of catalysis can significantly impact the catalytic activity and enantioselectivity. 1,1-Disubstituted alkenes are a challenging class of substrates for the asymmetric hydroboration reaction. Differentiation of the prochiral faces has been met with few successes from either stoichiometric or catalytic approaches. Takacs et al. revealed amide and ester groups direct the γ-selective Rh-catalyzed hydroboration of 1,1-disubstituted-β,γ-unsaturated alkenes. In the work described herein, analogous oximedirecting groups were used in an attempt to diversify the substrate scope. Unlike the amide- or ester-directed examples, we find oxime-directed hydroboration proceeds through an unusual C-H activation/metallation that proves crucial to turnover of borylated products. Whereas it was previously presumed that certain reduced byproducts were derived from adventitious H2 reduction, deuterium-labeling experiments suggest competing pathways from a common intermediate leading to both borylated and reduced products. In 1993, the World Health Organization (WHO) declared tuberculosis (TB) a global public emergency. Current drug treatments have reduced the mortality rate 40% since 1990, but increasing numbers of drug-resistant tuberculosis strains have been reported. D-Cyloserine (DCS) is a second line drug for the treatment of TB. In a collaborative effort with Professors Robert Powers (UNL-Chemistry) and Raul Barletta (UNL Veterinary and Biomedical Sciences), experiments with an isotopically-labeled DCS were proposed to elucidate the mechanism. Previously reported routes were not amenable to the milligram quantities available for isotopically labeled serine starting material. The synthetic route that will be described was used to produce both labeled and unlabeled DCS.

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Recommended Citation

Thacker, Nathan Christopher, "Studies in asymmetric synthesis: Supramolecular catalysis, C-H activation, and D-Cycloserine synthesis" (2014). ETD collection for University of Nebraska - Lincoln. AAI3613793.