Novel Methods for C–O and C–C Bond Formation via Photoredox Catalysis

Abstract

Visible light photoredox catalysis has emerged in the past decade as a powerful method for the development of new synthetic transformations. Notable among these is the use of photoredox catalysis in the activation of abundant, native functionality such as carboxylic acids, alcohols or C–H bonds, via conversion to radical intermediates which may then be used for the construction of valuable products. Especially powerful as a method for the construction of new bods is the merger of photoredox and transition metal catalysis, allowing the unique modes of activation of both catalytic manifolds to enable unique bond disconnections not accessible via other means. This thesis details the development of new photocatalytic methods for the construction of pharmaceutically valuable products.

In this vein, the direct conversion of aliphatic carboxylic acids to their dehomologated carbonyl analogues has been accomplished through photocatalytic decarboxylative oxygenation. This transformation is applicable to an array of carboxylic acid motifs, producing ketones, aldehydes, and amides in excellent yields. Preliminary results demonstrate that this methodology is further applicable to aldehyde substrates via in situ oxidation to the corresponding acid, a strategy we have exploited for the sequential oxidative dehomologation of linear aliphatic chains. We have further used this decarboxylative oxygenation methodology to develop a protocol for the controlled excision of methylene units form rings via an oxygenation-bromination/Favorskii rearrangement mechanism.

Artificial amino acids are a highly versatile motif in both medicinal and synthetic chemistry. The production of a wide array of chirally pure unnatural amino amino acids from serine has been accomplished, utilizing a cross electrophile coupling protocol between a bromoalanine intermediate and a wide array of aryl halides. This protocol has been utilized to synthesize a number of artificial analogues of phenylalanine, tryptophan and histidine. Preliminary results have also been obtained for the use of this protocol for the production of Csp3-Csp3 coupled adducts. Furthermore, the application of this protocol to large scale synthesis of complex pharmaceutical scaffolds via flow technology and through the use of high intensity lasers has been demonstrated.