The legacy of Gilbert Newton Lewis (1875-1946) pervades the lexicon of chemical bonding and reactivity. The power of his concept of donor-acceptor bonding is evident in the eponymous foundations of electron-pair acceptors (Lewis acids) and donors (Lewis bases). Lewis recognized that acids are not restricted to those substances that contain hydrogen (Bronsted acids), and helped overthrow the "modern cult of the proton". His discovery ushered in the use of Lewis acids as reagents and catalysts for organic reactions. However, in recent years, the recognition that Lewis bases can also serve in this capacity has grown enormously. Most importantly, it has become increasingly apparent that the behavior of Lewis bases as agents for promoting chemical reactions is not merely as an electronic complement of the cognate Lewis acids: in fact Lewis bases are capable of enhancing both the electrophilic and nucleophilic character of molecules to which they are bound. This diversity of behavior leads to a remarkable versatility for the catalysis of reactions by Lewis bases.

Lewis Base Catalysis in Organic Synthesis

This Concept article discusses the potential of oxidative carbene catalysis in synthesis and comprehensively covers pioneering studies as well as recent developments. Oxidative carbene catalysis can be conducted by using inorganic and organic oxidants. Applications in cascade processes, in enantioselective catalysis, and also in natural product synthesis are discussed.

Catalysis with N‐Heterocyclic Carbenes under Oxidative Conditions

During recent years, the direct transformation of aldehydes into esters or amides has developed into a vigorous research area and powerful one-pot oxidative esterification and amidation procedures have been reported. Several concepts that are often complementary in substrate scope, functional group tolerance, and reaction outcome have emerged, thus providing a wide range of alternatives to classical ester and amide synthesis via carboxylic acid intermediates.

One‐Pot Oxidative Esterification and Amidation of Aldehydes

Pyruvate ferredoxin oxidoreductase (PFOR), which catalyzes the oxidative decarboxylation of pyruvate to form acetyl-CoA and CO2, belongs to the family of 2-keto acid oxidoreductases. This CoA-dependent enzyme uses thiamine pyrophosphate (TPP) as an additional cofactor. The anaerobic decarboxylation is a reversible process, and the two electrons obtained during one turnover are transferred to ferredoxine via [Fe4S4] clusters. [1] The initial steps of the oxidative decarboxylation resemble those of the aerobic TPP-dependent 2-oxoacid dehydrogenases. Pyruvate reacts with A to form B after proton transfer, and B subsequently undergoes CO2 elimination to generate C (Scheme 1). Electron transfer to a [Fe4S4] cluster leads to radical cation D. Although intensive studies (X-ray and EPR) have been conducted on D, the structure of the radical cation is still under debate. Renewed electron transfer in the presence of CoASH eventually leads to CoASAc. In aerobic organisms lacking the [Fe4S4] clusters, C reacts with the dithiolane ring of a lipoyl group in a formal twoelectron transfer to an acetyl lipoamide thioester intermediate, which is further transformed in the presence of CoASH using another enzyme to CoASAc. The liberated dithiol is eventually reoxidized to the cyclic disulfide by a FADdependent dihydrolipoyl dehydrogenase. It is known in synthesis that reaction of aldehydes with thiazolium carbenes leads to intermediates of type C which react as “umpoled” nucleophiles with aromatic aldehydes (benzoin condensation) or with electron-poor olefins (Stetter reaction). Recently, N-heterocyclic carbene (NHC) catalyzed transformations have gained increasing attention. However, these investigations have focused on ionic processes. Guided by PFOR we planned to oxidize enamines of type C by organic single-electron transfer (SET) oxidants. The process would represent a biomimetic transition-metalfree organocatalytic oxidation of an aldehyde. As the oxidant we used 2,2,6,6-tetramethylpiperidine N-oxyl radical (TEMPO), which has been used successfully by our group in transition-metal-mediated reactions and in various radical processes. Hence, the oxidizing [Fe4S4] clusters in PFOR can be replaced by two oxidizing TEMPO units [Eq. (1)].

F. Pujol

Papers

Oxidative benzoin reactions