Enantioselective Photoredox Catalysis Enabled by Proton-Coupled Electron Transfer

Abstract

Abstract

The field of asymmetric radical catalysis has witnessed tremendous growth over the last 30 years. However, very few strategies for effectively controlling enantioselectivity have been reported. This deficit reflects the broader challenge connected with generating radical intermediates bound to a chiral catalyst via non-covalent interactions.

This thesis provides the first examples of inducing asymmetry through non-covalent interaction in photoredox processes. The success of this novel strategy stems from the application of proton-coupled electron transfer (PCET) to generate radical intermediates. Taking advantage of the hydrogen-bonding requirements of PCET, we have generated radical intermediates as hydrogen-bonded adducts of chiral anion catalysts, enabling highly enantioselective C-C bond forming reactions.

This strategy has been applied to the first highly enantioselective catalytic aza-pinacol cyclization. Reductive PCET generates ketyl radical intermediates wherein direct hydrogen bonding interactions between these neutral radical intermediates and chiral catalysts provides the basis for asymmetric induction. Detailed mechanistic studies have shed light on the role of chiral phosphate in asymmetric induction. Preliminary studies on intermolecular ketyl-olefin coupling are also reported.

Additionally, oxidative PCET has been applied to the activation of indoles for the concise synthesis of cyclotryptamine natural products. Three step syntheses of (-) chimonanthine and (+) alline are reported. Furthermore, mechanistic studies in support of a concerted PCET mechanism are disclosed.