Advances in Organocatalytic Site Selective Oxidations

Dyer, Robert, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Hilinski, Michael, AS-Chemistry (CHEM), University of Virginia

Billions of years of evolution have led to the biosynthesis of complex molecules that dictate and control life from simple precursors. Synthetic chemists have continued to pursue discoveries that mimic the capability of enzymatic biosynthesis. In following this pursuit, we have focused on developing new methods that enable site selective oxidations and improve upon current methodology of iminium organocatalysis.
Heteroaromatic N-oxides are an important class of molecules as bioactive compounds, drug metabolites, and synthetic precursors. The oxidation of nitrogen heterocycles in the presence of aliphatic amines is a transformation that typically requires exhaustive oxidation followed by selective reduction to achieve. We have developed a method using a strong Brønsted acid that protonates and deactivates the more electron rich aliphatic amine, enabling selective oxidation of less electron-rich heterocyclic nitrogen by an iminium catalyst. The N-oxide products can be subjected to a large selection of known transformations. This method can be used as a platform to synthesize enzymatic metabolites or as means for late-stage functionalization of nitrogen heterocycles.
Direct oxidation of unactivated C–H bonds is a field of increasing importance in modern synthetic chemistry. A longstanding problem in the is the lack of a general method to achieve chemoselective C–H oxidations when in the presence of other oxidizable groups. Our lab has previously developed two methods utilizing the same iminium catalyst for selective C–H hydroxylation and amination. We have streamlined and improved the synthesis of this iminium catalyst and have developed a library of new iminium salts to pursue a second-generation catalyst improving on our hydroxylation and amination methodology. Additionally, we have introduced new conditions and iminoiodinane reagents to improve our iminium catalyst’s amination capabilities. These new iminoiodinane reagents can be used in intramolecular and intermolecular aminations and provide enhanced reactivity over traditional iminoiodinane reagents.

PHD (Doctor of Philosophy)
Iminium, N-Oxide, insertion, C–H Functionalization, heteroatom, catalysis, organocatalysis
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