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Alkenes are essential functional groups in organic chemistry, featuring well-defined geometries and bond orders of 2. In this study, cubene and 1,7-quadricyclene are calculated to possess unusual hyperpyramidalized geometries and low alkene bond orders near 1.5. Their resultant high reactivities ultimately permit access to intricate scaffolds and new chemical space.

An asymmetric organocatalysis strategy is used to control pyramidal nitrogen chirality and to synthesize the enantioselective N-chloroaziridines with a configurationally stable nitrogen stereogenic centre.

Here a Cu(I)/Cu(III)/Cu(II)/Cu(III)/Cu(I) redox sequence is revealed in copper-catalysed aryl iodide coupling, capturing intermediate species and redefining the mechanistic understanding of the reaction.

Biocatalytic strategies typically transform only one alkene isomer into products, limiting the yield. Now a biocatalyst is reported to convert both isomeric silyl enol ethers into chiral α-branched ketones with high efficiency and excellent selectivity.

Directing group strategies have been used extensively in C–H activation reactions but current methods rely heavily on coordination with nitrogen or oxygen atoms in molecules and have therefore been found to exhibit limited generality in asymmetric syntheses. Here, the authors report enantioselective C–H activation with unsaturated hydrocarbons directed by phosphorus centres to rapidly construct libraries of axially chiral phosphines through dynamic kinetic resolution.

It is unclear how phospholipid membranes formed on the early Earth, as modern cells synthesize the phospholipid constituents of their membranes enzymatically. Now, a combination of ion pairing and self-assembly has enabled transacylation of lysophospholipids with acyl donors in water, affording a variety of membrane-forming natural diacylphospholipids in high yields.

Preparation of monocyclic 1,2-azaborines, a unique class of benzene isosteres, has been challenging. Now, an efficient and modular method has been developed to access diverse multi-substituted 1,2-azaborines from readily available cyclopropyl imines/ketones and dibromoboranes. The reaction goes through an unusual ring-opening BN-isostere benzannulation mechanism.

The bridged medium-sized ring bicyclo[m.n.2] family of natural products are commonly found but difficult to synthesize efficiently. Here the authors present a cascade reaction to form the carbon skeleton, via a [3+2] cycloaddition of a captured azavinyl carbene intermediate.

Asymmetric nickel catalysis is used to intercept transient cyclic allene intermediates to achieve stereocontrol.

Empirically observed regiochemistries indicate that the CF₂H radical has a nucleophilic character similar to alkyl radicals, but the CF₃ radical is electrophilic in reactions with heterocycles. Here, the authors report DFT calculations, reproducing experimental selectivities and leading to an explanation of this difference.

A unified catalytic remote-directing template strategy enabled precise differentiation of remote and adjacent C6–H and C7–H bonds, and similar C3–H and C7–H bonds of a pharmaceutically relevant bicyclic aza-arene scaffold.

Iminium-catalysed cycloaddition is a prominent example of organocatalytic reactivity, yet a biological counterpart has not been identified. Now, the authors report biochemical, structural and computational evidence for iminium catalysis by the natural Diels–Alderase SdnG.

Indole C-H silylation preferentially occurs at the C3 and C2 positions, while functionalization of the benzene core (C4-C7 sites) remains challenging. Here, the authors report a regioselective C7-H silylation of indole derivatives assisted by strong coordination of the palladium catalyst with a phosphorus directing group.

Common aromatic rings, such as anilines, arylboronic acids and aryl halides, can be opened up and converted to alkenyl nitriles through carbon–carbon bond cleavage using a copper catalyst.

Axially chiral compounds have proven to be privileged catalysts/ligands for asymmetric catalysis, with BINOL, SPNIOL and their derivatives being particularly successful. Here the authors report a family of axially chiral alkenes, and demonstrate their use in asymmetric catalysis.

Chiral lactams are important pharmacophores and strategies for their synthesis through direct C–H functionalization are highly sought after. Now, intramolecular C–H amidation of dioxazolones via biocatalytic nitrene transfer enables the synthesis of enantioenriched lactams with various ring sizes.

Bicyclo[1.1.1]pentanes are of interest to the pharmaceutical and chemical communities, due largely to their metabolic stability and potential as bioisosteres. Here the enantioselective C–H activation of these carbocycles is reported, giving access to enantioenriched, substituted products while maintaining the carbocyclic framework.

Nitrile-containing molecules and their biosynthetic enzymes are uncommon in nature. Now, a nitrile-forming diiron enzyme involved in the biosynthesis of aetokthonotoxin—the ‘eagle-killing’ neurotoxin—has been characterized using biochemical, structural and biophysical methods. High-resolution protein crystal structures together with the identification of catalytically relevant tryptophan-based products provide mechanistic insights into this unusual nitrile-forming reaction.

A new synthetic method provides a coveted motif, the bicyclo[2.1.1]hexane scaffold, using the uncommon coupling of two strained diradicaloid fragments: transiently generated cyclic allenes and bicyclo[1.1.0]butanes.

Exo-selective Diels–Alderases with a broad substrate scope for synthetically valuable reactions are lacking. Now, a highly exo-selective Diels–Alderase compatible with a wide range of diene and dienophile substrates is discovered, its X-ray structure solved and the catalytic mechanism defined.

Catalysed oxidative C-C bond formation reactions are important in the synthesis of natural products, but poorly tolerated by polyphenolic flavones. Here the authors report the reactivity of molecular oxygen in alkaline water without added catalyst for the synthesis of a collection of flavone dimers and trimers.

Cycloaddition reactions are among the most useful reactions in chemical synthesis, but biosynthetic enzymes with 2 + 2 cyclase activity have yet to be observed. Now it is shown that a β-barrel-fold protein catalyses competitive 2 + 2 and 4 + 2 cycloaddition reactions. This protein can be engineered to preferentially produce the exo-2 + 2, exo-4 + 2 or endo-4 + 2 product.

Pericyclase enzymes are an expanding family of enzymes. Here, the authors identify the norbornene synthase SdnG, a pericyclase for the intramolecular Diels-Alder reaction between a cyclopentadiene and an olefinic dienophile to form the sordaricin norbornene structure, and reconstitute the sordaricin biosynthesis.

Six-membered cyclic 1,2,3-trienes are geometrically distorted, short-lived intermediates that have high reactivity. Now, azacyclic 1,2,3-trienes can be generated and trapped, allowing for the synthesis of annulated pyridones.

The use of biocatalysis to support early-stage drug discovery campaigns remains largely untapped. Here, engineered biocatalysts enable the synthesis of sp³-rich polycyclic compounds through an intramolecular cyclopropanation of benzothiophenes, affording a class of complex scaffolds potentially useful for fragment-based drug discovery campaigns.

Guiding chemical reactions in a predictable and controllable manner is an ultimate goal of chemistry. Here, the authors show tuning of the single-molecule Mizoroki-Heck catalytic cycle through electrical gating and direct in-situ detection.

Two glycosylated enzymes, EupfF and PycR1, have now been characterized and shown to independently catalyse the tandem intermolecular [4 + 2] cycloaddition in the biosynthesis of bistropolone-sesquiterpenes. Through analysis of enzyme–substrate co-crystal structures, together with computational and mutational studies, the origins of their catalytic activity and stereoselectivity were elucidated.

Insights on the mechanistic differences between artificial metalloenzymes (ArMs) with non-native metal centres and the free cofactor or natural enzymes are scarce. Now, a detailed mechanistic analysis of a cyclopropanation reaction catalysed by such an ArM is provided, revealing intriguing differences to the natural system.

The condensation domains of non-ribosomal peptide synthetases use a concerted reaction mechanism in which the active site histidine probably serves as a crucial stabilizing hydrogen bond acceptor for the developing ammonium.

Effective strategies for direct arene C−H functionalization are sought after. Here arene C−H functionalization via iridium nitrenoid-catalysed nucleophilic aromatic substitution allows the coupling of aryl azides with different carbon nucleophiles and is applied to the enantioselective synthesis of NOBINs

Although conventional analytical techniques can measure ensemble averages, single-molecule junctions can sense molecular reaction processes at the single-event level. The integration of a single-molecule Pd catalyst into a gapped graphene junction enables the electrical detection of a full catalytic cycle of the Suzuki–Miyaura coupling and clarifies the controversial transmetallation mechanism.

A halogenase enzyme uses the copper in its active site to catalyse iterative chlorinations on multiple unactivated carbon−hydrogen bonds, enabling carbon−hydrogen functionalization that is not achievable with an iron-based halogenase.

A Diels–Alderase that catalyses the inherently disfavoured cycloaddition and forms a bicyclo[2.2.2]diazaoctane scaffold with a strict α-anti-selectivity has now been discovered. This Diels–Alderase, called CtdP, is an NmrA-like protein. Isotopic labelling, structural biology and computational studies reveal that the CtdP-catalysed Diels–Alder reaction involves a NADP⁺/NADPH-dependent redox mechanism.

The strained C₆H₆ isomer 1,2,3-cyclohexatriene and its derivatives participate in a host of reaction modes which demonstrate their potential for selective chemical transformations and provide an unconventional entryway to complex scaffolds.

Although biaryl rings can be easily formed via cross coupling, their tetrahedral, high-fraction sp³ equivalents cannot. Now the scope, mechanism and biological profile of a general attached-ring synthesis has been probed. This provides direct access to full bridgehead substitution via sp³–sp³ coupling and enables rapid entry to natural product space.

Although π-bonds are typically associated with having well-defined arrangements of atoms, ring constraints can lead to geometric distortion, resulting in heightened reactivity. These effects can be leveraged to enable synthetic transformations. This Review features processes wherein geometric distortion is leveraged to provide rapid access to structurally complex products.

Directed evolution of the final enzyme in the lovastatin biosynthetic pathway yields a variant with 29 mutations that does not require a carrier protein and displays altered dynamics of the catalytic residues, spending more time in the catalytically active conformation.

Direct stereoselective amination of tertiary C–H bonds without the assistance of directing groups is a challenging task in synthetic organic chemistry. Now a nitrene transferase is engineered to aminate tertiary C–H bonds with high enantioselectivity, providing direct access to valuable chiral α-tertiary primary amines.

LepI is an S-adenosylmethionine-dependent pericyclase that catalyses the dehydration, hetero-Diels–Alder reaction and retro-Claisen rearrangement reactions that occur in the formation of the 2-pyridone natural product leporin C. Now, the mechanistic details that underpin this range of catalytic reactions have been uncovered from the crystal structures of LepI and LepI in complex with ligands.

Most chemical glycosylation methods operate by acid-promoted, ionic activation of donors. Now, by exploiting the formation of a halogen-bond complex, the activation of glycosyl donors was achieved via a visible light-promoted radical cascade process, resulting in a general, simple and mild way to build challenging 1,2-cis-glycosidic bonds.

A deep-learning-based strategy is used to design artificial luciferases that catalyse the oxidative chemiluminescence of diphenylterazine with high substrate specificity and catalytic efficiency.

Although enzymes are able to cleave amide bonds in nature, it is difficult to selectively break the carbon–nitrogen bond of an amide using synthetic chemistry; now the activation and cleavage of these bonds using nickel catalysts is used to convert amides to esters.

A metal–organic framework (MOF) has been prepared that features dynamic rotors embedded within its crystalline lattice. The dipolar F₂-functionalized carboxylate linkers—rapidly rotating at room temperature—show correlated behaviour upon cooling, converting the paraelectric MOF into an ordered antiferroelectric one below 100 K.

The use of acyl functional groups as nucleophilic synthons in transition metal-catalysed carbometallation of unsaturated hydrocarbons remains challenging. Here, nickel-catalysed acylzincation reactions of alkynes and alkenes with organozinc reagents under 1 atm of CO are developed, featuring high functional group tolerance, a broad substrate scope and mild conditions.

Analysis of two homologous groups of fungal pericyclases demonstrates how they can catalyse either an Alder-ene reaction—which has not previously been found in nature—or a hetero-Diels–Alder reaction.

Catalytic asymmetric dearomatization is a powerful tool for the rapid construction of diverse chiral cyclic molecules from cheap and easily available arenes. Here the authors show an organocatalytic enantioselective dearomatization of substituted thiophenes in the context of a rare remote asymmetric 1,10-conjugate addition.

Tetraarylmethanes display special properties due to their spherical nature and are applied in various areas, but strategies for their asymmetric production are lacking. Now, their enantioselective synthesis is reported and in vitro studies indicate their potential as anticancer agents.

The structure of a Stig cyclase, HpiC1, reveals how it catalyzes Cope rearrangement and 6-exo-trig cyclization, including how it controls the position of electrophilic aromatic substation that distinguishes hapalindole from fischerindole alkaloids.