Photocatalysis in the Life Science Industry.

In the pursuit of new pharmaceuticals and agrochemicals, chemists in the life science industry require access to mild and robust synthetic methodologies to systematically modify chemical structures, explore novel chemical space, and enable efficient synthesis. In this context, photocatalysis has emerged as a powerful technology for the synthesis of complex and often highly functionalized molecules. This Review aims to summarize the published contributions to the field from the life science industry, including research from industrial-academic partnerships. An overview of the synthetic methodologies developed and strategic applications in chemical synthesis, including peptide functionalization, isotope labeling, and both DNA-encoded and traditional library synthesis, is provided, along with a summary of the state-of-the-art in photoreactor technology and the effective upscaling of photocatalytic reactions.

Amide Synthesis by Nickel/Photoredox-Catalyzed Direct Carbamoylation of (Hetero)Aryl Bromides.

Herein, we report a one-electron strategy for catalytic amide synthesis that enables the direct carbamoylation of (hetero)aryl bromides. This radical cross-coupling approach, which is based on the combination of nickel and photoredox catalysis, proceeds at ambient temperature and uses readily available dihydropyridines as precursors of carbamoyl radicals. The method's mild reaction conditions make it tolerant of sensitive-functional-group-containing substrates and allow the installation of an amide scaffold within biologically relevant heterocycles. In addition, we installed amide functionalities bearing electron-poor and sterically hindered amine moieties, which would be difficult to prepare with classical dehydrative condensation methods.

Transition-Metal-Free, Visible-Light-Enabled Decarboxylative Borylation of Aryl N-Hydroxyphthalimide Esters.

Herein, we report a conceptually novel borylation reaction proceeding via a mild photoinduced decarboxylation of redox-activated aromatic carboxylic acids. This work constitutes the first application of cheap and easily prepared N-hydroxyphthalimide esters as aryl radical precursors and does not require the use of expensive transition metals or ligands. The reaction is operationally simple, scalable, and displays broad scope and functional group tolerance.

Catalytic Access to Alkyl Bromides, Chlorides and Iodides via Visible Light-Promoted Decarboxylative Halogenation.

Herein is reported the catalytic, visible light-promoted, decarboxylative halogenation (bromination, chlorination, and iodination) of aliphatic carboxylic acids. This operationally-simple reaction tolerates a range of functional groups, proceeds at room temperature, and is redox neutral. By employing an iridium photocatalyst in concert with a halogen atom source, the use of stoichiometric metals such as silver, mercury, thallium, and lead can be circumvented. This reaction grants access to valuable synthetic building blocks from the large pool of cheap, readily available carboxylic acids.

Visible Light-Promoted Decarboxylative Di- and Trifluoromethylthiolation of Alkyl Carboxylic Acids.

Described herein is a new and straightforward decarboxylative di- and trifluoromethylthiolation of alkyl carboxylic acids promoted by visible light. This approach enables the synthesis of biologically relevant alkyl SCF2H and SCF3 compounds from cheap and abundant carboxylic acids. The method is operationally simple, using irradiation from household light sources, and its mild reaction conditions make it tolerant of a range of functional groups. The strategy employs electrophilic phthalimide-derived di- and trifluoromethylthiolation reagents and exploits the ability of the imidyl radical to carry a radical chain.

Enantioselective N-Heterocyclic Carbene Catalyzed Diene Regenerative (4 + 2) Annulation.

An enantioselective N-heterocyclic carbene (NHC)-catalyzed diene regenerative (4 + 2) annulation has been achieved through the use of highly nucleophilic morpholinone-derived catalysts. The reaction proceeds with good to excellent yields, high enantioselectivity (most >92% ee), and good diastereoselectivity (most >7:1). The generality of the reaction is high, with 19 examples reported. The utility of the products has been examined with subsequent derivatization in Diels-Alder reactions using electron-poor dienophiles. Furthermore, interception of the proposed ß-lactone intermediate has been achieved, allowing the synthesis of compounds bearing four contiguous stereocenters with high levels of enantio- and diastereoselectivity.

N-Heterocyclic Carbene Catalyzed Synthesis of δ-Sultones via α,ß-Unsaturated Sulfonyl Azolium Intermediates.

A limited array of reactive intermediates have enabled a wealth of discoveries in N-heterocyclic carbene organocatalysis. In this study, the viability of α,ß-unsaturated sulfonyl azoliums as double electrophiles in new reactions is examined. Specifically, the (3+3) annulation of such species with the trimethylsilyl enol ethers of various 1,3-dicarbonyl compounds has been developed. This reaction provides access to a range of novel unsaturated δ-sultones (18 examples) in good yields (40-88 %) under mild reaction conditions. Mechanistic studies and the development of an enantioselective variant (55 % yield, 73:27 e.r.) support the intermediacy of an α,ß-unsaturated sulfonyl azolium species.

Heterogeneously catalyzed direct C-H thiolation of heteroarenes.

The first general methodology for the direct thiolation of electron-rich heteroarenes was developed by employing Pd/Al2 O3 , a recoverable and commercially available heterogeneous catalyst, and CuCl2 . This method represents an operationally simple approach for the synthesis of these valuable compounds. Preliminary mechanistic studies indicate a heterogeneous catalytic system, in which both metals play a complementary role in the formation of the thiolated products.

N-Heterocyclic carbene catalysed redox isomerisation of esters to functionalised benzaldehydes.

N-Heterocyclic carbene catalysed redox isomerisation with reduction about the carbonyl has been developed in the transformation of trienyl esters to tetrasubstituted benzaldehydes. The reaction proceeds in good to excellent yield, and in cases that provide 2,2'-biaryls, enantioselectivity is observed. Mechanistic studies demonstrate the intermediacy of a cyclohexenyl ß-lactone, while implicating formation of the homoenolate as turnover limiting.

Enantioselective all-carbon (4+2) annulation by N-heterocyclic carbene catalysis.

The enantioselective vinylogous Michael/aldol cascade is an underdeveloped approach to cyclohexenes. Herein we describe a highly enantioselective (most ≥ 98:2 er) and diastereoselective (all ≥ 15:1 dr) N-heterocyclic carbene catalyzed cycloisomerization of acyclic dienyl esters to cyclohexyl ß-lactones. Derivatizations avail cyclohexenes bearing four contiguous stereogenic centers, while mechanistic studies support olefin isomerization prior to cyclization.

Acyl anion free N-heterocyclic carbene organocatalysis.

Reaction discovery using N-heterocyclic carbene organocatalysis has been dominated by the chemistry of acyl anion equivalents. Recent studies demonstrate that NHCs are far more diverse catalysts, with a variety of reactions discovered that proceed without acyl anion equivalent formation. In this tutorial review selected examples of acyl anion free NHC catalysis using carbonyl compounds are presented.

N-heterocyclic carbene-catalyzed Ireland-Coates Claisen rearrangement: synthesis of functionalized ß-lactones.

The N-heterocyclic carbene (NHC)-catalyzed Claisen rearrangement of hybrid Ireland-Coates structures has been achieved, allowing the stereoselective synthesis of highly functionalized ß-lactones. The reaction proceeds with high diastereoselectivity (>20:1) and affords a diverse range of ß-lactone fused cyclopentanes. Mechanistic studies are detailed.

Concise formal synthesis of (-)-7-deoxyloganin via N-heterocyclic carbene catalysed rearrangement of α,ß-unsaturated enol esters.

NHC catalysed rearrangement of α,ß-unsaturated enol esters derived from formyl acetates and cyclopentyl annulated α,ß-unsaturated acids provides the cyclopentapyranone core of (-)-7-deoxyloganin (1) with diastereo- and chemoselectivity in 6 steps starting from (-)-citronellal. The elaboration to the natural product has been investigated using two new approaches. The most successful intercepts our previous work on (-)-7-deoxyloganin (1) allowing completion of a formal total synthesis in 10-steps.

N-Heterocyclic carbene-catalyzed (4+2) cycloaddition/decarboxylation of silyl dienol ethers with α,ß-unsaturated acid fluorides.

Herein we report the first all-carbon N-heterocyclic carbene-catalyzed (4 + 2) cycloaddition. The reaction proceeds with α,ß-unsaturated acid fluorides and silyl dienol ethers and produces 1,3-cyclohexadienes with complete diastereocontrol (dr >20:1) while demonstrating a new type of reaction cascade exploiting α,ß-unsaturated acyl azoliums.

The total synthesis of (-)-7-deoxyloganin via N-heterocyclic carbene catalyzed rearrangement of α,ß-unsaturated enol esters.

The diastereoselective N-heterocyclic carbene (NHC) catalyzed rearrangement of α,ß-unsaturated enol ester (S)-2b has been used to assemble dihydropyranone (S)-3b, a material embodying the bicyclic core of the iridoid family of natural products. Elaboration of this intermediate, by chemoselective reduction followed by stereoselective ß-glycosylation, has allowed the total synthesis of (-)-7-deoxyloganin (1) to be achieved in four subsequent steps.

N-heterocyclic carbene-catalyzed generation of alpha,beta-unsaturated acyl imidazoliums: synthesis of dihydropyranones by their reaction with enolates.

Catalytic generation of alpha,beta-unsaturated acyl imidazolium cations and enolates has been achieved, and their involvement in a Michael addition acylation sequence exploited, to provide a range of dihydropyranones. alpha,beta-Unsaturated enol esters, or alpha,beta-unsaturated acid fluorides in association with TMS enol ethers, serve as appropriate substrates for this reaction. The transformation can also be achieved enantioselectively using catalysts derived from chiral triazolium salts.