Bio-Inspired Transformations for Late Stage Molecular Diversification

Author: ORCID icon
Shuler, William, Chemistry - Graduate School of Arts and Sciences, University of Virginia
Hilinski, Michael, Department of Chemistry, University of Virginia

Billions of years of evolutionary pressure have fueled the development of highly selective enzyme-catalyzed reactions that deliver densely functionalized bioactive compounds through step economical and high yielding processes. One such highly efficient pathway commonly used in the biosynthesis of natural products involves a two-phase process. In the first phase, simple precursors are combined to form the core structure of the molecule. In the second phase, selective modifications of this core scaffold produce the natural product.(1)

This approach to natural product synthesis has been difficult to translate into a laboratory setting due to a lack of synthetic techniques that mimic enzymatic selectivity.(2) To address this deficiency, we have pursued bio-inspired transformations that capture enzymatic reactions.

We have introduced a Lewis acid catalyzed (3+2) cyclization of epoxides and alkenes. The reaction conditions employed allow modestly diastereoselective cyclizations of aryl epoxides with styrenes, dienes, and alkynes in modest to good yields using low catalyst loading of metal triflate salts. This methodology generates stereodefined natural product cores from petrochemical feedstock on decagram scale in under 10 minutes.

We have developed new organocatalytic strategies for the hydroxylation of aliphatic C-H bonds. Reactive substrates using this methodology include C-H bonds present in naturally occurring motifs that are commonly oxidized in vivo with enzymatic catalysis. Initial exploration of organocatalysts derived from natural products has been conducted, in search of catalysts that capture the catalyst-controlled site- and stereo-selectivity observed in enzymatic systems.

1. Chen, K.; Baran, P. S.; Nature, 2009, 459, 824–828.
2. Kamil Godula, D. S; Science, 2006, 312, 67–73.

PHD (Doctor of Philosophy)
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