Light-Driven Enantioselective Carbene-Catalyzed Radical-Radical Coupling.

An enantioselective carbene-catalyzed radical-radical coupling of acyl imidazoles and racemic Hantzsch esters is disclosed. This method involves the coupling of an N-heterocyclic carbene-derived ketyl radical and a secondary sp3 -carbon radical and allows access to chiral α-aryl aliphatic ketones in moderate-to-good yields and enantioselectivities without any competitive epimerization. The utility of this protocol is highlighted by the late-stage functionalization of various pharmaceutical compounds and is further demonstrated by the transformation of the enantioenriched products to biologically relevant molecules. Computational investigations reveal the N-heterocyclic carbene controls the double-facial selectivity of the ketyl radical and the alkyl radicals, respectively.

Photocatalyzed Direct α-Alkylation of Esters Using Styrenes.

A mild photocatalyzed approach to achieve the α-alkylation of esters via formation of an α -radical is disclosed here. Cesium enolates of esters were generated in situ using Cs2CO3 as a base. A subsequent photocatalyzed oxidation at the α-carbon of these enolates produced an α-radical that was added into activated alkenes. This is the first example accessing the α-carbon radical of esters in photoredox catalyed transformations.

Single-electron Carbene Catalysis in Redox Processes.

Inspired by the role of N-heterocyclic carbenes (NHCs) in natural enzymatic processes, chemists have harnessed the umpolung (polarity reversal) reactivity of these reactive, Lewis basic species over the past few decades to construct key chemical bonds. While NHCs continue to play a role in two-electron transformations, their unique redox properties enable a variety of useful, stabilized radical species to be accessed via single-electron oxidation or reduction. As a result, their utility in synthesis has grown rapidly concurrent with the revival of radical chemistry, highlighted by their extensive use as reactive single-electron species in recent years.

Synthesis of Cyclohexanones by a Tandem Photocatalyzed Annulation.

The rapid synthesis of cyclic scaffolds is of high importance to the chemistry community. Strategies for the convergent synthesis of substituted carbocycles and heterocycles remain underexplored despite the plethora of applications that these cyclic motifs have in the pharmaceutical and materials industries. Reported herein is a tandem carbene and photoredox-catalyzed process for the convergent synthesis of substituted cycloalkanones via a formal [5 + 1] cycloaddition. Featuring two distinct photoredox cycles and a novel α-oxidation of benzylic ketones, this reaction offers a mild approach to construct two contiguous C-C bonds and eliminates the need for strong bases or expensive metal catalysts. The utility of this method is highlighted through various product diversification reactions that allow access to a range of important cyclic scaffolds.

Light-Driven Carbene Catalysis for the Synthesis of Aliphatic and α-Amino Ketones.

Single-electron N-heterocyclic carbene (NHC) catalysis has gained attention recently for the synthesis of C-C bonds. Guided by density functional theory and mechanistic analyses, we report the light-driven synthesis of aliphatic and α-amino ketones using single-electron NHC operators. Computational and experimental results reveal that the reactivity of the key radical intermediate is substrate-dependent and can be modulated through steric and electronic parameters of the NHC. Catalyst potential is harnessed in the visible-light driven generation of an acyl azolium radical species that undergoes selective coupling with various radical partners to afford diverse ketone products. This methodology is showcased in the direct late-stage functionalization of amino acids and pharmaceutical compounds, highlighting the utility of single-electron NHC operators.

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids.

As a key element in the construction of complex organic scaffolds, the formation of C-C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C-C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical-radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.

A Cooperative Hydrogen Bond Donor-Brønsted Acid System for the Enantioselective Synthesis of Tetrahydropyrans.

Carbocations stabilized by adjacent oxygen atoms are useful reactive intermediates involved in fundamental chemical transformations. These oxocarbenium ions typically lack sufficient electron density to engage established chiral Brønsted or Lewis acid catalysts, presenting a major challenge to their widespread application in asymmetric catalysis. Leading methods for selectivity operate primarily through electrostatic pairing between the oxocarbenium ion and a chiral counterion. A general approach to new enantioselective transformations of oxocarbenium ions requires novel strategies that address the weak binding capabilities of these intermediates. We demonstrate herein a novel cooperative catalysis system for selective reactions with oxocarbenium ions. This new strategy has been applied to a highly selective and rapid oxa-Pictet-Spengler reaction and highlights a powerful combination of an achiral hydrogen bond donor with a chiral Brønsted acid.