Copper as a Photocatalyst: Applications in Decarboxylative Fluorination

University Of Wisconsin-Madison, Madison WI

Investigators

Abstract

Alcohols are found in a wide variety of natural products including small molecules and biological polymers. However, the benefit of their incorporation in drug molecules varies greatly. While their ability to act as both hydrogen bond donors and acceptors allows them to form stabilizing hydrogen bonds with proteins, they must be placed in precisely the correct location in the drug structure, otherwise they will be unable to bind to the active site. This, in addition to the high enthalpic barrier for desolvation from water when binding, can limit the use of certain alcohol-containing structures. Therefore, removal or conversion of alcohols to modify the binding and solvation of potential drug molecules quickly and efficiently is a desirable goal. Current methods require harsh conditions or are limited to redox-neutral reactivity. A mild, oxidative approach would allow for the conversion of alcohols to valuable C–O and C–N functionalities. This proposal outlines the oxidative cross-coupling of alcohols through oxidation and subsequent β-cleavage through photochemical ligand-to-metal charge transfer (LMCT) using simple base metals such as Cu or Fe. The base metal also acts as the terminal oxidant, leading to the formation of a carbocation which is then captured by a nucleophile. This decoupling of oxidant and nucleophile allows for the use of a single oxidant for multiple nucleophile classes. In the first aim, this strategy will be applied for the conversion of alcohols to the corresponding ether constitutional isomer where the carbon and oxygen atoms in the product structure are transposed relative to the alcohol. The ether products of this transformation have the same molecular formula but drastically different biological properties than the starting alcohols due to their difference in hydrogen-bonding ability. Preliminary studies show promising yields using Cu as the oxidant. The second aim will utilize oxidative LMCT for the deconstructive functionalization of cyclic, aliphatic alcohols. Deconstruction enables rapid conversion of rigid, cyclic structures to less ordered linear structures. Previous deconstructive methods have been limited by the need for strained rings and limited options for further functionalization. Our approach allows for both ring-opening and subsequent nucleophilic cross-coupling with oxygen or nitrogen nucleophiles with a single set of reaction conditions, allowing access to products previously inaccessible by deconstructive strategies. Preliminary studies show that these conditions enable the fragmentation and cross-coupling of unstrained rings such as aryl cyclohexanols.