I. Chemoselective and Site Selective Oxidations Mediated by Iminium Organocatalysis II. Synthesis and Evaluation of Advillin Inhibitors as Potential Anti-Cancer Agents

Author: ORCID icon orcid.org/0000-0003-2864-8063
Hahn, Philip, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Hilinski, Michael, AS-Chemistry, University of Virginia

Billions of years of natural evolution have allowed for the synthesis of complex natural products in streamlined ways. Steric and electronic factors permit enzymes to override or mitigate other modes of reactivity to accomplish selective transformations and allow for the rapid buildup of complexity in substrates. The elegant selectivity of enzymatic reactions serves as a blueprint for developing new catalytic procedures capable of late-stage functionalization (LSF) that override the inherent reactivity of a substrate. In this dissertation, we demonstrate work to expand the scope of iminium organocatalysis into a simple, accessible platform capable of chemoselective and site selective oxidations in the presence of other easily oxidizable functionalities.
Heteroaromatic N-oxides have come under growing interest for use as bioactive compounds and for their role as drug metabolites. The oxidation of nitrogen heterocycles in the presence of aliphatic amines is a transformation that requires either a protection–deprotection or overoxidation–selective reduction sequence to achieve the desired mono-N-oxide. We have demonstrated that by using a strong Brønsted acid, more reactive amine sites will be protonated first due to substantial differences in the pKa of the conjugate acids, allowing for selective oxidation by an iminium catalyst of the unprotonated N-heteroaryl moiety. The N-oxide products generated are further amenable to a large selection of known transformations, making this reaction a platform to further LSF of nitrogen heterocycles.
Direct functionalization of unactivated C–H bonds is a field of increasing interest in modern synthetic chemistry. A longstanding problem in the field is a general method to achieve chemoselective C–H oxidations when in the presence of easily oxidized primary and secondary alcohol groups. We have found that with use of a strongly hydrogen-bonding fluoroalcohol solvent, we can deactivate alcohols towards oxidation at the α-position or other proximal locations. To achieve unactivated C–H hydroxylation, we have developed an iminium platform where low-cost, abundant amine and aldehyde components are condensed in situ to form the catalytic species. The reaction is shown to be amenable to various alcohols, ethers, and amine derivatives. Methylene hydroxylation without overoxidation to the ketone is also demonstrated. In addition to the enhanced selectivity shown, among of the best in the field to-date, the in situ catalyst condensation platform gives access to the vast quantity of privileged amine scaffolds known for use in amine organocatalysis, helping to render future work asymmetric.
In Chapter 6 we disclose work on the synthesis, modulation, and biological evaluation of inhibitors for the novel oncogene AVIL. Upregulation of AVIL and its associated protein advillin have recently been linked to glioblastoma multiforme, a deadly form of brain cancer with poor prognosis. Putative protein binders were identified via a high-throughput screen on small molecule microarray. >60 derivatives were synthesized and tested for advillin activity through cell viability assays in U87 GBM cells and astrocytes. In the absence of a protein crystal structure, structure activity relationships are elucidated by a comparison of structurally related drug analogs.

PHD (Doctor of Philosophy)
organocatalysis, iminium, C–H functionalization, late stage functionalization, site-selectivity, chemoselectivity, hydroxylation, N-oxide, AVIL, advillin, medicinal chemistry, glioblastoma multiforme
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