Organic chemistry

Combinatorial chemistry

Photoredox catalysis

Photocatalysis

Catalysis

Indole test

Chemistry

Indole alkaloid

Monoterpene

Drug discovery

Biochemistry

Accounts of Chemical Research

The monoterpene indole alkaloids, containing over 3000 known members and more than 40 structural types, represent one of the largest natural product families that have proven to be an important drug source. Their complex chemical structures and significant biological activities have rendered these alkaloids attractive targets in the synthetic community for decades. While chemists have developed many synthetic methodologies and tactics toward this end, general strategies allowing divergent access to a large variety of structural types and members of monoterpene indole alkaloids are still limited and highly desirable. Photoredox catalysis has emerged in recent years as a powerful tool to realize chemical transformations via single electron transfer (SET) processes that would otherwise be inaccessible. In particular, when the radical species generated by the visible light photoinduced approach is involved in well-designed cascade reactions, the formation of multiple chemical bonds and the assembly of structurally complex molecules would be secured in a green and economic manner. This protocol might serve to remodel the way of thinking for the preparation of useful pharmaceuticals and complex natural products. Due to a long-standing interest in the synthesis of diverse indole alkaloids, our group previously developed a cyclopropanation strategy ( Qin , Y. Acc. Chem. Res. 2011 , 44 , 447 ) that was versatile to access several intriguing indole alkaloid molecules. With an idea of developing more general synthetic approaches to as many members of various indole alkaloids as possible, we recently disclosed new radical cascade reactions enabled by photoredox catalysis, leading to the collective asymmetric total synthesis of 42 monoterpene indole alkaloids belonging to 7 structural types. Several important discoveries deserve to be highlighted. First, the use of photocatalytic technology allowed us to achieve an unusual reaction pathway that reversed the conventional reactivity between two nucleophilic amine and enamine groups. Second, a crucial nitrogen-centered radical, directly generated from a sulfonamide N-H bond, triggered three types of cascade reactions to deliver indole alkaloid cores with manifold functionalities and controllable diastereoselectivities. Moreover, expansion of this catalytic, scalable, and general methodology permitted the total synthesis of a large collection of indole alkaloids. In this Account, we wish to provide a complete picture of our studies concerning the original synthetic design, method development, and applications in total synthesis. It is anticipated that the visible-light-driven cascade strategy will find further utility in the realm of natural product synthesis.

Indole Alkaloid Synthesis Facilitated by Photoredox Catalytic Radical Cascade Reactions