In recent years, photoredox catalysis has come to the forefront in organic chemistry as a powerful strategy for the activation of small molecules. In a general sense, these approaches rely on the ability of metal complexes and organic dyes to convert visible light into chemical energy by engaging in single-electron transfer with organic substrates, thereby generating reactive intermediates. In this Perspective, we highlight the unique ability of photoredox catalysis to expedite the development of completely new reaction mechanisms, with particular emphasis placed on multicatalytic strategies that enable the construction of challenging carbon–carbon and carbon–heteroatom bonds.

Photoredox catalysis and organocatalysis represent two powerful fields of molecule activation that have found widespread application in the areas of inorganic and organic chemistry, respectively. We merged these two catalysis fields to solve problems in asymmetric chemical synthesis. Specifically, the enantioselective intermolecular α-alkylation of aldehydes has been accomplished using an interwoven activation pathway that combines both the photoredox catalyst Ru(bpy)3Cl2 (where bpy is 2,2′-bipyridine) and an imidazolidinone organocatalyst. This broadly applicable, yet previously elusive, alkylation reaction is now highly enantioselective and operationally trivial.

Over the past 30 years, enantioselective catalysis has become one of the most important frontiers in exploratory organic synthetic research. During this time, remarkable advances have been made in the development of organometallic asymmetric catalysts that in turn have provided a wealth of enantioselective oxidation, reduction, π-bond activation, and Lewis acid-catalyzed processes. 1 Surprisingly, however, relatively few asymmetric transformations have been reported which employ organic molecules as reaction catalysts, 2 despite the widespread availability of organic chemicals in enantiopure form and the accordant potential for academic, industrial, and economic benefit. Herein, we introduce a new strategy for organocatalysis that we expect will be amenable to a range of asymmetric transformations. In this context, we document the first highly enantioselective organocatalytic Diels-Alder reaction. 3 We recently embarked upon the development of a general strategy for organocatalytic reactions based upon design features derived from the arena of Lewis acid catalysis. Specifically, we reasoned that (i) LUMO-lowering activation and (ii) the kinetic lability toward ligand substitution that enables Lewis acid-catalyst turnover (eq 1) might also be available with a carbogenic system that exists as a rapid equilibrium between an electron-deficient and a relatively electron-rich state. With this in mind, we hypothesized that the reversible formation of iminium ions from R,β-unsaturated aldehydes and amines (eq 2) might emulate the equilibrium dynamics and π-orbital electronics that are inherent to Lewis acid catalysis, thereby providing a new platform for the design of organocatalytic processes. Significantly, this analysis reveals the attractive prospect that chiral amines might function as enantioselective catalysts for a range of transformations that traditionally utilize metal salts.

The use of small organic molecules as catalysts has been known for more than a century. But only in the past decade has organocatalysis become a thriving area of general concepts and widely applicable asymmetric reactions. Here I present my opinion on why the field of organocatalysis has blossomed so dramatically over the past decade.

Over the past 40 years, transition metal catalysis has enabled bond formation between aryl and olefinic (sp2) carbons in a selective and predictable manner with high functional group tolerance. Couplings involving alkyl (sp3) carbons have proven more challenging. Here, we demonstrate that the synergistic combination of photoredox catalysis and nickel catalysis provides an alternative cross-coupling paradigm, in which simple and readily available organic molecules can be systematically used as coupling partners. By using this photoredox-metal catalysis approach, we have achieved a direct decarboxylative sp3–sp2 cross-coupling of amino acids, as well as α-O– or phenyl-substituted carboxylic acids, with aryl halides. Moreover, this mode of catalysis can be applied to direct cross-coupling of Csp3–H in dimethylaniline with aryl halides via C–H functionalization.