Multicatalytic Cerium Photoredox Reactions for the Activation of O-H Bonds and Total Synthesis of (±)-Hyperolactone C

Abstract

Radical chemistry enables a wealth of valuable organic transformations in organic synthesis. Photoredox catalysis has made entry into this high-energy radical regime more appealing and often reveals unique reactivity and functional-group tolerance. Chapter 1 presents an overview of radical chemistry and the key role of photoredox catalysis in modern approaches to chemical synthesis. This thesis focused on the development of new photoredox platforms to access radical intermediates and their application in the synthesis of complex molecules.

In Chapter 2, a cerium photoredox platform was used to generate high energy O-centered radical intermediates from the native O-H bonds of common chemical feedstocks including alcohols, carboxylic acids, and 1,3-dicarbonyls. The multicatalytic system enabled a variety of redox-neutral transformations including fragmentation of lactols and cycloalkanols to the corresponding formate esters and ketones and hydrodecarboxylation. Synergistic application of cerium photoredox and nickel catalysis enabled a remote arylation reaction that furnished distal aryl and alkyl ketones via C(sp²)-C(sp³) and C(sp³)-C(sp³) cross-coupling in moderate to high yields without reliance on cycloalkanol ring-strain or redox-auxiliaries.

In Chapter 3, the photoredox platform was adapted to activate 1,3-dicarbonyl C(sp³)-H acids, forming radical intermediates that performed a plethora of reactions including hydroalkylation, oxidative cyclization, and cross-coupling. The discovery of both cerium-containing and cerium-free conditions prompted detailed mechanistic experiments that gave insight into important reaction. Exploration of reaction scope and mechanistic studies helped to develop our understanding of the platform. NMR and UV/Vis spectroscopy revealed ground-state equilibria between reaction components and the kinetics of thermal oxidation processes. Stern-Volmer fluorescence quenching experiments were used to elucidate the dominant photochemical events from catalyst excited states. Competition experiments and isotope studies helped determine the reaction path of organic substrates. Computational modelling was used to rationalize reaction outcomes including regio- and stereoselectivity, guided us in devising strategies for synthesis of more complex products, and ultimately enabled a total synthesis.

In Chapter 4, total synthesis of the natural product hyperolactone C displayed the utility of the photoredox platform in complex molecule synthesis. The hydroxyfuranoate intermediate was quickly assembled from abundant building blocks and enabled a 4-step synthesis, the shortest route to date. A Au(I)-catalyzed addition of glycolate esters to unsymmetrical propiolate esters, a previously underdeveloped hydroetherification reaction, and a Dieckmann condensation of the resulting Z-enol ether were developed to access hydroxyfuranoate esters. The densely functionalized spirolactone core with two contiguous stereocentres was constructed in the key final step using the oxidative photoredox cyclization that demonstrated remarkable tolerance for the oxidation-sensitive π-excessive furan heterocycle. Using the complementary redox-neutral hydroalkylation, we have also generated several analogues of this bioactive natural product. Inspired by the biosynthetic hypothesis for formation of biyouyanagin natural products, we performed an intramolecular [2+2] reaction to yield a 2-oxatricyclo[3.2.1.0³,⁶]octane-bearing compound that may represent an undiscovered natural product.