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For more than one century, photochemical [2+2]-cycloadditions have been used by synthetic chemists to make cyclobutanes, four-membered carbon-based rings. In this reaction, typically two olefin subunits (two π -electrons per olefin) cyclize to form two new C–C σ -bonds. Although the development of photochemical [2+2]-cycloadditions has made enormous progress within the last century, research has been focused on such [2 π +2 π ]-systems, in which two π -bonds are converted into two new σ -bonds 1 , 2 . Here we report an intermolecular [2+2]-photocycloaddition that uses bicyclo[1.1.0]butanes as 2 σ -electron reactants 3 – 7 . This strain-release-driven [2 π +2 σ ]-photocycloaddition reaction was realized by visible-light-mediated triplet energy transfer catalysis 8 , 9 . A simple, modular and diastereoselective synthesis of bicyclo[2.1.1]hexanes from heterocyclic olefin coupling partners, namely coumarins, flavones and indoles, is disclosed. Given the increasing importance of bicyclo[2.1.1]hexanes as bioisosteres—groups that convey similar biological properties to those they replace—in pharmaceutical research and considering their limited access 10 , 11 , there remains a need for new synthetic methodologies. Applying this strategy enabled us to extend the intermolecular [2+2]-photocycloadditions to σ -bonds and provides previously inaccessible structural motifs. A strain-release approach, realized by visible-light-mediated triplet energy transfer catalysis, enabled an intermolecular [2 π +2 σ ]-photocycloaddition.

Pharmaceutical synthesis often requires the formation of adjacent carbon-carbon and carbon-nitrogen bonds. Monos et al. present a method that delivers the carbon and nitrogen components in a single reagent, specifically, an aryl ring tethered through sulfur dioxide to an amide. A light-activated catalyst primes an olefin to react with the nitrogen, which in turn leads to migration of the aryl ring and loss of the sulfur bridge. The efficient room-temperature process is applicable to a variety of different arenes, including heterocycles. Science , this issue p. 1369 Photoredox catalysis activates alkenes to form adjacent C–C and C–N bonds through coupling with a single reagent. Alkene aminoarylation with a single, bifunctional reagent is a concise synthetic strategy. We report a catalytic protocol for the addition of arylsulfonylacetamides across electron-rich alkenes with complete anti-Markovnikov regioselectivity and excellent diastereoselectivity to provide 2,2-diarylethylamines. In this process, single-electron alkene oxidation enables carbon-nitrogen bond formation to provide a key benzylic radical poised for a Smiles-Truce 1,5-aryl shift. This reaction is redox-neutral, exhibits broad functional group compatibility, and occurs at room temperature with loss of sulfur dioxide. As this process is driven by visible light, uses readily available starting materials, and demonstrates convergent synthesis, it is well suited for use in a variety of synthetic endeavors.

Although organic compounds consist mostly of carbon and hydrogen atoms, strategies for chemical synthesis have traditionally targeted the handful of more reactive interspersed oxygens, nitrogens, and halogens. Modifying C–H bonds directly is a more appealing approach, but selectivity remains a challenge. Saint-Denis et al. review recent progress in using transition metal catalysis to break just one of two mirror-image C–H bonds and then append a more complex substituent in its place. Ligand design has proven crucial to differentiate these otherwise similar bonds in a variety of molecular settings. Science , this issue p. eaao4798 Organic molecules are rich in carbon-hydrogen bonds; consequently, the transformation of C–H bonds to new functionalities (such as C–C, C–N, and C–O bonds) has garnered much attention by the synthetic chemistry community. The utility of C–H activation in organic synthesis, however, cannot be fully realized until chemists achieve stereocontrol in the modification of C–H bonds. This Review highlights recent efforts to enantioselectively functionalize C(sp 3 )–H bonds via transition metal catalysis, with an emphasis on key principles for both the development of chiral ligand scaffolds that can accelerate metalation of C(sp 3 )–H bonds and stereomodels for asymmetric metalation of prochiral C–H bonds by these catalysts.

Stereoselective polymerization of chiral or prochiral monomers is a powerful method to produce high-performance stereoregular crystalline polymeric materials. However, for monomers with two stereogenic centers, it is generally necessary to separate diastereomers before polymerization, resulting in substantial material loss and added energy cost associated with the separation and purification process. Here we report a diastereoselective polymerization methodology enabled by catalysts that directly polymerize mixtures of eight-membered diolide (8DL) monomers with varying starting ratios of chiral racemic (rac) and achiral meso diastereomers into stereosequenced crystalline polyhydroxyalkanoates with isotactic and syndiotactic stereodiblock or stereotapered block microstructures. These polymers show enhanced ductility and toughness relative to polymers of pure rac-8DL, subject to tuning by variation of the diastereomeric ratio and structure of the 8DL monomers.

Cytochromes P450 (P450 or CYP) are heme-containing enzymes that catalyze the introduction of one atom of molecular oxygen into nonactivated C–H bonds, often in a regio- and stereoselective manner. This ability, combined with a tremendous number of accepted substrates, makes P450s powerful biocatalysts. Sixty years after their discovery, P450 systems are recognized as essential bio-bricks in synthetic biology approaches to enable production of high-value complex molecules in recombinant hosts. Recent impressive results in protein engineering led to P450s with tailored properties that are even able to catalyze abiotic reactions. The introduction of P450s in artificial multi-enzymatic cascades reactions and chemo-enzymatic processes offers exciting future perspectives to access novel compounds that cannot be synthesized by nature or by chemical routes. Cytochromes P450 are ubiquitous enzymes accepting a tremendous number of substrates and catalyzing a broad range of reactions with potential applications in biotechnology and synthetic biology. P450s were engineered to catalyze abiotic reactions such as carbene or nitrene transfers, opening up completely new perspectives in synthetic chemistry. Lately, P450s have successfully been introduced into artificial multi-enzyme cascades, both in vitro and in vivo, providing alternative routes for retro-synthetic production of high-value oxyfunctionalized compounds. Harnessing the synthetic potential of P450s in chemo-enzymatic processes or as part of reconstituted biosynthetic pathways in microbial hosts provides promising strategies for de novo synthesis of synthons and complex natural products, even though there are still some obstacles to overcome.

Beyond esoteric interest, organocatalysis has now become one major pillar of asymmetric catalysis. Here, we discuss how new activation modes are conquering challenging stereoselective transformations and the recent integration of organocatalysis with emerging photo- and electrocatalysis, as well as artificial intelligence. Organocatalysis has become a major pillar of (asymmetric) catalysis. Here, the authors discuss recent trends in organocatalytic activation modes for challenging stereoselective transformations and the emerging integration with other fields, such as photoredox catalysis and electrosynthesis.

The catalytic asymmetric construction of C sp 3 –C sp 3 bonds remains one of the foremost challenges in organic synthesis 1 . Metal-catalysed cross-electrophile couplings (XECs) have emerged as a powerful tool for C–C bond formation 2 – 5 . However, coupling two distinct C sp 3 electrophiles with high cross-selectivity and stereoselectivity continues as an unmet challenge. Here we report a highly chemoselective and enantioselective C sp 3 –C sp 3 XEC between alkyl halides and nitroalkanes catalysed by flavin-dependent ‘ene’-reductases (EREDs). Photoexcitation of the enzyme-templated charge-transfer complex between an alkyl halide and a flavin cofactor enables the chemoselective reduction of alkyl halide over the thermodynamically favoured nitroalkane partner. The key C–C bond-forming step occurs by means of the reaction of an alkyl radical with an in situ-generated nitronate to form a nitro radical anion that collapses to form nitrite and an alkyl radical. An enzyme-controlled hydrogen atom transfer (HAT) affords high levels of enantioselectivity. This reactivity is unknown in small-molecule catalysis and highlights the potential for enzymes to use new mechanisms to address long-standing synthetic challenges. A highly chemoselective and enantioselective cross-electrophile coupling using ‘ene’-reductases is reported, and photoexcited enzymes demonstrate the ability to carry out reactions between electrophiles that are not known for small-molecule catalysis.

Deracemization is an attractive strategy for asymmetric synthesis, but intrinsic energetic challenges have limited its development. Here, we report a deracemization method in which amine derivatives undergo spontaneous optical enrichment upon exposure to visible light in the presence of three distinct molecular catalysts. Initiated by an excited-state iridium chromophore, this reaction proceeds through a sequence of favorable electron, proton, and hydrogen-atom transfer steps that serve to break and reform a stereogenic C–H bond. The enantioselectivity in these reactions is jointly determined by two independent stereoselective steps that occur in sequence within the catalytic cycle, giving rise to a composite selectivity that is higher than that of either step individually. These reactions represent a distinct approach to creating out-of-equilibrium product distributions between substrate enantiomers using excited-state redox events.

Enzymes are recognized as exceptional catalysts for achieving high stereoselectivities 1 – 3 , but their ability to control the reactivity and stereoinduction of free radicals lags behind that of chemical catalysts 4 . Thiamine diphosphate (ThDP)-dependent enzymes 5 are well-characterized systems that inspired the development of N -heterocyclic carbenes (NHCs) 6 – 8 but have not yet been proved viable in asymmetric radical transformations. There is a lack of a biocompatible and general radical-generation mechanism, as nature prefers to avoid radicals that may be harmful to biological systems 9 . Here we repurpose a ThDP-dependent lyase as a stereoselective radical acyl transferase (RAT) through protein engineering and combination with organophotoredox catalysis 10 . Enzyme-bound ThDP-derived ketyl radicals are selectively generated through single-electron oxidation by a photoexcited organic dye and then cross-coupled with prochiral alkyl radicals with high enantioselectivity. Diverse chiral ketones are prepared from aldehydes and redox-active esters (35 examples, up to 97% enantiomeric excess (e.e.)) by this method. Mechanistic studies reveal that this previously elusive dual-enzyme catalysis/photocatalysis directs radicals with the unique ThDP cofactor and evolvable active site. This work not only expands the repertoire of biocatalysis but also provides a unique strategy for controlling radicals with enzymes, complementing existing chemical tools. Enzyme-bound ketyl radicals derived from thiamine diphosphate are selectively generated through single-electron oxidation by a photoexcited organic dye and shown to lead to enantioselective radical acylation reactions.

Photoexcitation is a common strategy for initiating radical reactions in chemical synthesis. We found that photoexcitation of flavin-dependent “ene”-reductases changes their catalytic function, enabling these enzymes to promote an asymmetric radical cyclization. This reactivity enables the construction of five-, six-, seven-, and eight-membered lactams with stereochemical preference conferred by the enzyme active site. After formation of a prochiral radical, the enzyme guides the delivery of a hydrogen atom from flavin—a challenging feat for small-molecule chemical reagents. The initial electron transfer occurs through direct excitation of an electron donor-acceptor complex that forms between the substrate and the reduced flavin cofactor within the enzyme active site. Photoexcitation of promiscuous flavoenzymes has thus furnished a previously unknown biocatalytic reaction.