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Starting with alkyl carboxylic acids, a simple olefin synthesis using any substitution pattern or geometry, based on amide-bond synthesis with nickel- or iron-based catalysis, is described. Simplified olefin synthesis Olefins are ubiquitous functional groups in organic chemistry and are typically installed in small molecules by the formation of a carbon–carbon double bond. Here, Phil Baran and colleagues report a decarboxylative alkyl-vinyl cross-coupling that offers a cheap and simple route to olefins with defined geometry and substitution pattern. The nickel or iron catalysts extract carbon dioxide from the carboxylic acid, which is activated in a similar way to peptide-bond formation. The alkene is then attached with a vinyl zinc reagent. The authors exemplify their method by preparing more than 60 olefins and synthesizing 16 natural products. One such example offers a short route to macrocyclic polyketides from the commodity chemical diethyl tartrate. Olefin chemistry, through pericyclic reactions, polymerizations, oxidations, or reductions, has an essential role in the manipulation of organic matter 1 . Despite its importance, olefin synthesis still relies largely on chemistry introduced more than three decades ago, with metathesis 2 being the most recent addition. Here we describe a simple method of accessing olefins with any substitution pattern or geometry from one of the most ubiquitous and variegated building blocks of chemistry: alkyl carboxylic acids. The activating principles used in amide-bond synthesis can therefore be used, with nickel- or iron-based catalysis, to extract carbon dioxide from a carboxylic acid and economically replace it with an organozinc-derived olefin on a molar scale. We prepare more than 60 olefins across a range of substrate classes, and the ability to simplify retrosynthetic analysis is exemplified with the preparation of 16 different natural products across 10 different families.

Chiral nitriles and their derivatives are prevalent in pharmaceuticals and bioactive compounds. Enantioselective alkene hydrocyanation represents a convenient and efficient approach for synthesizing these molecules. However, a generally applicable method featuring a broad substrate scope and high functional group tolerance remains elusive. Here, we address this long-standing synthetic problem using dual electrocatalysis. Using this strategy, we leverage electrochemistry to seamlessly combine two canonical radical reactions—cobalt-mediated hydrogen-atom transfer and copper-promoted radical cyanation—to accomplish highly enantioselective hydrocyanation without the need for stoichiometric oxidants. We also harness electrochemistry’s unique feature of precise potential control to optimize the chemoselectivity of challenging substrates. Computational analysis uncovers the origin of enantio-induction, for which the chiral catalyst imparts a combination of attractive and repulsive non-covalent interactions to direct the enantio-determining C–CN bond formation. This work demonstrates the power of electrochemistry in accessing new chemical space and providing solutions to pertinent challenges in synthetic chemistry.A general method for the enantioselective hydrocyanation of alkenes has been a long-standing synthetic challenge. Now, using a dual electrocatalytic approach that combines two synergistic redox catalytic cycles, a wide variety of chiral nitriles can be synthesized from conjugated alkenes in high enantioselectivity.

Enzymes are increasingly explored for use in asymmetric synthesis 1 – 3 , but their applications are generally limited by the reactions available to naturally occurring enzymes. Recently, interest in photocatalysis 4 has spurred the discovery of novel reactivity from known enzymes 5 . However, so far photoinduced enzymatic catalysis 6 has not been used for the cross-coupling of two molecules. For example, the intermolecular coupling of alkenes with α-halo carbonyl compounds through a visible-light-induced radical hydroalkylation, which could provide access to important γ-chiral carbonyl compounds, has not yet been achieved by enzymes. The major challenges are the inherent poor photoreactivity of enzymes and the difficulty in achieving stereochemical control of the remote prochiral radical intermediate 7 . Here we report a visible-light-induced intermolecular radical hydroalkylation of terminal alkenes that does not occur naturally, catalysed by an ‘ene’ reductase using readily available α-halo carbonyl compounds as reactants. This method provides an efficient approach to the synthesis of various carbonyl compounds bearing a γ-stereocentre with excellent yields and enantioselectivities (up to 99 per cent yield with 99 per cent enantiomeric excess), which otherwise are difficult to access using chemocatalysis. Mechanistic studies suggest that the formation of the complex of the substrates (α-halo carbonyl compounds) and the ‘ene’ reductase triggers the enantioselective photoinduced radical reaction. Our work further expands the reactivity repertoire of biocatalytic, synthetically useful asymmetric transformations by the merger of photocatalysis and enzyme catalysis. A transformation in which an ‘ene’ reductase catalyses the visible-light-induced intermolecular radical hydroalkylation of alkenes gives carbonyl compounds with a remote stereocentre in high yield and enantioselectivity.

Aziridines—three-membered nitrogen-containing cyclic molecules—are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products 1 – 3 , and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity 4 – 6 . Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N -alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive 7 amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach. The synthesis of aziridines—three-membered nitrogen-containing heterocycles—is achieved by a new method involving the electrochemical coupling of alkenes and amines, via a dicationic intermediate.

Anti-Markovnikov additions to alkenes have been a longstanding goal of catalysis, and anti-Markovnikov addition of arenes to alkenes would produce alkylarenes that are distinct from those formed by acid-catalysed processes. Existing hydroarylations are either directed or occur with low reactivity and low regioselectivity for the n-alkylarene. Herein, we report the first undirected hydroarylation of unactivated alkenes with unactivated arenes that occurs with high regioselectivity for the anti-Markovnikov product. The reaction occurs with a nickel catalyst ligated by a highly sterically hindered N-heterocyclic carbene. Catalytically relevant arene- and alkene-bound nickel complexes have been characterized, and the rate-limiting step was shown to be reductive elimination to form the C–C bond. Density functional theory calculations, combined with second-generation absolutely localized molecular orbital energy decomposition analysis, suggest that the difference in activity between catalysts containing large and small carbenes results more from stabilizing intramolecular non-covalent interactions in the secondary coordination sphere than from steric hindrance.The anti-Markovnikov hydroarylation of unactivated alkenes with unactivated arenes has been achieved with high selectivity by using nickel catalysts bearing large N-heterocyclic carbene ligands. Energy decomposition analysis indicates that the high activity of the catalysts with large carbene ligands arises from stabilizing non-covalent interactions rather than steric effects.

Multicomponent reactions—those where three or more substrates combine into a product—have been highly useful in rapidly building chemical building blocks of increased complexity 1 , but achieving this enzymatically has remained rare 2 , 3 , 4 – 5 . This limitation primarily arises because an enzyme’s active site is not typically set up to address multiple substrates, especially in cases involving multiple radical intermediates 6 . Recently, chemical catalytic radical sorting has emerged as an enabling strategy for a variety of useful reactions 7 , 8 . However, making such processes enantioselective is highly challenging owing to the inherent difficulty in the stereochemical control of radicals 9 . Here we repurpose a thiamine-dependent enzyme 10 , 11 through directed evolution and combine it with photoredox catalysis to achieve a photobiocatalytic enantioselective three-component radical cross-coupling. This approach combines three readily available starting materials—aldehydes, α-bromo-carbonyls and alkenes—to give access to enantioenriched ketone products. Mechanistic investigations provide insights into how this dual photocatalyst–enzyme system precisely directs the three distinct radicals involved in the transformation, unlocking enzyme reactivity. Our approach has achieved exceptional stereoselectivity, with 24 out of 33 examples achieving ≥97% enantiomeric excess. Enantioselective three-component radical cross-coupling is achieved using a thiamine-dependent enzyme and photoredox catalysis, giving access to ketone products with exceptional stereoselectivity.

The development of bimolecular homolytic substitution (S H 2) catalysis has expanded cross-coupling chemistries by enabling the selective combination of any primary radical with any secondary or tertiary radical through a radical sorting mechanism 1 – 8 . Biomimetic 9 , 10 S H 2 catalysis can be used to merge common feedstock chemicals—such as alcohols, acids and halides—in various permutations for the construction of a single C( sp 3 )–C( sp 3 ) bond. The ability to sort these two distinct radicals across commercially available alkenes in a three-component manner would enable the simultaneous construction of two C( sp 3 )–C( sp 3 ) bonds, greatly accelerating access to complex molecules and drug-like chemical space 11 . However, the simultaneous in situ formation of electrophilic and primary nucleophilic radicals in the presence of unactivated alkenes is problematic, typically leading to statistical radical recombination, hydrogen atom transfer, disproportionation and other deleterious pathways 12 , 13 . Here we report the use of bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene. This reaction involves the in situ formation of three distinct radical species, which are then differentiated by size and electronics, allowing for regioselective formation of the desired dialkylated products. This work accelerates access to pharmaceutically relevant C( sp 3 )-rich molecules and defines a distinct mechanistic approach for alkene dialkylation. We use bimolecular homolytic substitution catalysis to sort an electrophilic radical and a nucleophilic radical across an unactivated alkene, accelerating access to pharmaceutically relevant C( sp 3 )-rich molecules and defining a mechanistic approach for alkene dialkylation.

Although the α-alkylation of ketones has already been established, the analogous reaction using aldehyde substrates has proven surprisingly elusive. Despite the structural similarities between the two classes of compounds, the sensitivity and unique reactivity of the aldehyde functionality has typically required activated substrates or specialized additives. Here, we show that the synergistic merger of three catalytic processes—photoredox, enamine and hydrogen-atom transfer (HAT) catalysis—enables an enantioselective α-aldehyde alkylation reaction that employs simple olefins as coupling partners. Chiral imidazolidinones or prolinols, in combination with a thiophenol, iridium photoredox catalyst and visible light, have been successfully used in a triple catalytic process that is temporally sequenced to deliver a new hydrogen and electron-borrowing mechanism. This multicatalytic process enables both intra- and intermolecular aldehyde α-methylene coupling with olefins to construct both cyclic and acyclic products, respectively. With respect to atom and step-economy ideals, this stereoselective process allows the production of high-value molecules from feedstock chemicals in one step while consuming only photons. The catalytic asymmetric α-alkylation of aldehydes has historically been a significant challenge within organic synthesis. Now, this elusive transformation has been achieved through the merger of organocatalysis, photoredox catalysis and hydrogen-atom transfer catalysis to enable the coupling of simple olefins and aldehydes.

The direct functionalization of unactivated sp(3) C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp(3) C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C-H bonds (that is, C-H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds.

The dehydrogenative alkenylation of C-H bonds with alkenes represents an atom- and step-economical approach for olefin synthesis and molecular editing. Site-selective alkenylation of alkanes and aldehydes with the C-H substrate as the limiting reagent holds significant synthetic value. We herein report a photocatalytic method for the direct alkenylation of alkanes and aldehydes with aryl alkenes in the absence of any external oxidant. A diverse range of commodity feedstocks and pharmaceutical compounds are smoothly alkenylated in useful yields with the C-H partner as the limiting reagent. The late-stage alkenylation of complex molecules occurs with high levels of site selectivity for sterically accessible and electron-rich C-H bonds. This strategy relies on the synergistic combination of direct hydrogen atom transfer photocatalysis with cobaloxime-mediated hydrogen-evolution cross-coupling, which promises to inspire additional perspectives for selective C-H functionalizations in a green manner. Dehydrogenative alkenylation of C-H bonds is an atom-economical approach to prepare more complex olefins. Here, the authors use a combination of decatungstate and a cobaloxime catalyst for the photocatalytic dehydrogenative alkenylation of alkanes and aliphatic aldehydes with aryl alkenes.