Application of Novel Catalytic Platforms to C-C Bond Forming Reactions in Methodology Development and Natural Product Total Synthesis

Abstract

Over the past century, catalysis has emerged as a fundamental, critical approach for the construction of small organic molecules in the fields of agrochemicals, pharmaceuticals, and fine chemical production. Inherent to this impact is the ability of catalysis to render reactions which may have previously been impossible kinetically feasible, by introducing lower-energy pathways and intermediates to product formation. Within the diverse field of catalysis, various platforms have been engaged separately and in conjunction with each other to vastly impact the construction of organic molecules.

Transition metal catalysis has, over the past 50 years, been established as one of the premier platforms for organic molecule construction. In particular, transition metal cross-coupling has enabled the construction of complex molecular scaffolds in a profound sense. As described in Chapter 2, an asymmetric copper-catalyzed arylation of indoles has been exploited for the collective synthesis of polypyrroloindoline natural products, including trimeric hodgkinsine, tetrameric quadrigemine H, and pentameric isopsyschotridine, via catalyst-controlled oligomerization. The modular approach employed also allowed for the synthesis of putatively unnatural tetrameric scaffolds, diastereomeric to quadrigemine H.

Photoredox catalysis has emerged over the past decade as a powerful strategy for harnessing visible light energy to facilitate organic transformations through single-electron transfer events and open-shell intermediates. A critical aspect of photoredox catalysis is the ability of the long-lived (typically triplet) excited state of the photoredox catalyst to perform both single electron oxidation or reduction. The merger of photoredox catalysis with transition metal cross-coupling catalysis, termed metallaphotoredox catalysis, has been a key area of study within our laboratory since 2014. In Chapter 3, the use of ketoacids as an oxidative precursor to acyl radicals is described for the photoredox/nickel-catalyzed acylation of organic halides. In Chapter 4, studies towards the non-light-driven excitation of photosensitizers are described. In collaboration with the Rand Lab in the Department of Electrical Engineering, we are developing a “light-free photoredox” platform which relies upon the potential-driven formation of triplet states in a non-emissive organic polymer matrix, which can subsequently undergo energy transfer to a sensitizer in solution.