Studies in Asymmetric Synthesis: Supramolecular Catalysis, C-H Activation, and D-Cycloserine Synthesis

Authors

Nathan C. Thacker, University of Nebraska-LincolnFollow

Date of this Version

2-2014

Document Type

Article

Citation

Nathan C Thacker, "Studies in Asymmetric Synthesis: Supramolecular Catalysis, C-H Activation, and D-Cycloserine Synthesis," PhD Diss. University of Nebraska-Lincoln, February 2014.

Comments

A DISSERTATION Presented to the Faculty of The Graduate College at the University of Nebraska In Partial Fulfillment of Requirements For the Degree of Doctor of Philosophy, Major: Chemistry, Under the Supervision of Professor James M. Takacs. Lincoln, Nebraska: February 2014

Copyright (c) 2014 Nathan C. Thacker

Abstract

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 non-covalent 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 gamma-selective Rh-catalyzed hydroboration of 1,1-disubstituted-beta,gamma-unsaturated alkenes. In the work described herein, analogous oxime-directing 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.