Asymmetric Radical Catalysis in the Synthesis of Pyrroloindoline Alkaloids

Abstract

In recent years, the use of radicals in catalysis has rapidly expanded in parallel with the development of new methods for their generation. However, the stereochemical fate of these reactions remains difficult to control, as the intermediates formed in such processes are highly reactive. One solution to this challenge would be to couple the redox event to the binding of substrate with a chiral catalyst, ensuring that the radical is formed only as a catalyst-bound adduct. This basic design principle is manifested in a mechanism known as proton-coupled electron transfer (PCET), wherein a hydrogen-bonding interaction between the substrate and Brønsted catalyst is necessary for electron transfer to occur.

This dissertation first details the development of an enantioselective radical reaction using an oxidative PCET mechanism, wherein a chiral phosphate base functions jointly with a photocatalytic oxidant to form an indole radical cation intermediate. The resulting key hydrogen-bonded indole radical cation intermediate is trapped with the persistent radical TEMPO• to generate enantioenriched 3a-TEMPO-substituted pyrroloindolines.

These initial studies then led to the discovery that TEMPO-derived alkoxyamines could undergo subsequent one-electron oxidation to catalytically generate carbocation intermediates via mesolytic C–O bond cleavage. We used this method to access a variety of enantioenriched 3a-functionalized pyrroloindolines from a common synthetic intermediate. The development, mechanistic study, and scope of these reactions are described herein, along with their application in the synthesis of several pyrroloindoline natural products.