The substrate in question, ent-pimara-8(14),15-dien-19-oic acid, is a pimarane-type diterpene carboxylic acid, a molecule built around a rigid tricyclic core decorated with two carbon-carbon double bonds, an internal one at position 8(14) and an external vinyl group at position 15. When the researchers added this compound to growing liquid cultures of the fungus, the organism responded by transforming it into four oxidized products. Two of these, 15,16-epoxy-ent-pimar-8(14)-en-19-oic acid and 15,16-dihydroxy-ent-pimar-8(14)-en-19-oic acid, were known compounds, but the other two, 17-hydroxy-15,16-epoxy-ent-pimar-8(14)-en-19-oic acid and 15-oxo-16-hydroxy-ent-pimar-8(14)-en-19-oic acid, had never been described before. In every case, the fungus attacked the vinyl group and left the internal double bond intact.

That selectivity is what makes the result remarkable. Monosubstituted double bonds like the vinyl group are typically more reactive toward chemical oxidants, yet when chemists treated a related pimaradiene with the classic epoxidation reagent meta-chloroperbenzoic acid, they obtained only epoxides at the internal 8(14) position along with rearranged byproducts, the opposite outcome. Previous microbial studies pointed the same way: a strain of Aspergillus niger oxidized the tricyclic ring system of the same substrate at carbons 1, 6, 7, 11 and the internal double bond while ignoring the vinyl group, and the endophytic fungus Preussia minima also hydroxylated positions away from the vinyl moiety. The new work shows that A. sclerotiorum does essentially the reverse, a biotransformation pattern the authors describe as at least uncommon.

To probe whether this apparent regioselectivity was real, the team challenged the fungus with a second diterpene, abietic acid, a resin acid bearing two endocyclic double bonds at positions 7(8) and 13(14). If the fungus simply preferred external double bonds, abietic acid, which has none, should be metabolized differently. Instead, the organism oxidized a methyl group attached at carbon 13, outside the ring system, producing 16-hydroxyabieta-7(8),13(14)-dien-19-oic acid. This mirrors what it did with the pimarane substrate, where the vinyl group and the methyl group both hang off carbon 13, suggesting the enzymes recognize the spatial region around that carbon rather than a particular bond type.

The structural detective work relied on one- and two-dimensional nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. In the epoxide product, the characteristic ABX spin system of vinylic hydrogens near 5.4 and 4.9 parts per million in the proton spectrum vanished, replaced by new signals between 2.5 and 2.8 parts per million, while carbon-13 signals for the sp2 carbons at 147.2 and 112.9 parts per million gave way to aliphatic signals at 58.9 and 42.5. For the diol product, the carbon-15 resonance appeared at 80.4 parts per million, a deshielded position that literature correlations assign to the 15S configuration. Because an epoxide hydrolase opening the epoxide by an SN2-type attack at carbon 16 would yield only one epimer, whereas an SN1 mechanism through a carbocation would yield both, the researchers could infer that the epoxide products share that same 15S configuration. The hydroxyketone product, carrying a carbonyl signal at 214.8 parts per million, appears to arise from further oxidation of the diol’s C-15 hydroxyl group.

Hunting for the enzyme behind this chemistry, the team scanned publicly available whole-genome shotgun contigs of A. sclerotiorum using tblastn, searching for cytochrome P450 sequences similar to CYP105A1 from Streptomyces griseolus, a bacterial enzyme previously shown to oxidize the C-15 isopropyl group of abietic acid and to epoxidize the vinyl group of an isopimarane diterpene. The search returned two candidate open reading frames, one of 1083 nucleotides encoding 360 amino acids and another of 1641 nucleotides encoding 546 amino acids, with sequence identities of 25 and 24 percent and query coverages of 37 and 35 percent respectively. Crucially, both proteins carry the canonical P450 signature motif FxxGxxxCxG, including the cysteine residue that binds the heme iron, confirming they belong to the cytochrome P450 superfamily.

To visualize how such an enzyme might steer the substrate, the researchers turned to molecular docking using the crystal structure of a bacterial cytochrome P450 as a proxy, since no structure exists for the Aspergillus enzyme. In the docked complex, the diterpene sits in the active site with its vinyl group and the C-13 methyl group positioned closest to the heme catalytic center, exactly where an oxygenating iron-oxo species would deliver its atom. Basic amino acids, including arginine and asparagine, appear to anchor the molecule through hydrogen bonding and electrostatic interactions with the carboxylic acid at carbon 4, holding the substrate in the orientation that favors oxygenation at the side chain rather than the ring system. The docking picture closely resembles calculations published for CYP105A1 acting on abietic acid, reinforcing the idea that a similar P450 in the fungus drives the observed regioselectivity.

The practical payoff came from antiparasitic testing. The parent diterpene and its four derivatives were evaluated against promastigote forms of Leishmania amazonensis and epimastigote forms of Trypanosoma cruzi, the parasites responsible for cutaneous leishmaniasis and Chagas disease, both neglected tropical diseases that affect millions of people in Latin America and beyond. Oxidation consistently improved activity. Against L. amazonensis, the epoxide and the hydroxyketone derivatives showed IC50 values less than half that of the parent compound. Most strikingly, the hydroxyketone inhibited the trypomastigote stage of T. cruzi with an IC50 of 21.4 micromolar, slightly better than the reference drug benznidazole, which came in at 34.5 micromolar under the same assay conditions. Equally important, cytotoxicity assays against healthy Vero cells showed very low toxicity, particularly for the hydroxyketone, yielding favorable selectivity indices.

The structure-activity picture that emerges suggests that chemical modifications at the vinyl side chain matter more for antiparasitic potency than variations on rings A and B of the ent-pimarane skeleton. Earlier studies had found that hydroxylation near ring A did not substantially enhance activity against another T. cruzi strain, while ent-pimaranes modified at ring B showed IC50 values in the 15 to 20 micromolar range. The new derivatives, functionalized precisely at the side chain, now extend that trend and hint that the side chain is a promising handle for drug design.

Beyond the immediate antiparasitic results, the study validates a broader strategy: mining endophytic fungi from diterpene-producing plants for enzymes that recognize the very molecules their hosts biosynthesize. The intimate evolutionary relationship between endophytes and plant biochemistry may predispose their enzymatic machinery to accept plant terpenes as substrates, and expanding the pool of such microorganisms helps overcome the classic unpredictability of whole-cell biotransformation. With two new diterpenes in hand, a candidate P450 enzyme identified, and a docking model that explains the selectivity, the researchers have laid out a complete chain of evidence from genome to molecule to bioactivity, offering a template for turning humble tree-dwelling fungi into factories for medicinally relevant chemistry.

Subject of Research: Regioselective epoxidation of a plant diterpene by the endophytic fungus Aspergillus sclerotiorum and the antiparasitic activity of the resulting oxidized products.

Article Title: Epoxidation of ent-pimara-8(14),15-dien-19-oic acid by whole cells of the endophytic fungus Aspergillus sclerotiorum

Article References: Din, Z. U., de Medeiros, L. S., Abreu, L. M., Lazarin-Bidóia, D., Scariot, D. B., Garcia, F. P., de Paula, J. C., Nakamura, C. V., Fill, T. P., & Rodrigues-Filho, E. (2026). Epoxidation of ent-pimara-8(14),15-dien-19-oic acid by whole cells of the endophytic fungus Aspergillus sclerotiorum. International Microbiology. https://doi.org/10.1007/s10123-026-00895-0

Image Credits: AI Generated

DOI: 10.1007/s10123-026-00895-0

Keywords: Aspergillus sclerotiorum, biotransformation, diterpene, ent-pimaradienoic acid, epoxidation, cytochrome P450, endophytic fungus, Cupressus lusitanica, Leishmania amazonensis, Trypanosoma cruzi, antiparasitic activity, regioselectivity

The research, published under the title Autonomous migration of a phosphate group along glycerol and inositol scaffolds driven by a phosphodiester reaction cycle, demonstrates that a single phosphate substituent can walk from one oxygen atom to the next along a polyhydroxylated carbon framework without external reagents or catalysts. The driving force is a reaction cycle in which cyclic phosphodiester intermediates form, open, and re-form, each turnover relocating the phosphoryl group to an adjacent hydroxyl. In effect, the scaffold itself acts as both the track and the vehicle, while the phosphate acts as a cargo that repeatedly detaches and reattaches at neighboring positions.

At the core of the mechanism is the well-known tendency of vicinal diols, pairs of hydroxyl groups on adjacent carbon atoms, to engage in reversible phosphoryl transfer. When a phosphate ester is installed on one hydroxyl of a glycerol derivative, the neighboring hydroxyl can intramolecularly attack the phosphorus center, displacing the original ester oxygen and generating a cyclic phosphodiester, a five-membered ring in which the phosphate bridges two adjacent oxygens. Hydrolytic or transesterifying opening of that ring can then occur at either of the two phosphorus–oxygen bonds, and if the alternative bond is broken, the phosphate ends up attached to the opposite hydroxyl. Repeating this sequence steps the phosphate along the carbon chain one position at a time.

Crucially, the researchers showed that this is not a one-off rearrangement but a genuine catalytic cycle. The system recycles the key intermediates: formation of the cyclic phosphodiester, nucleophilic ring opening, and re-closure constitute a closed loop of reactions that consumes no stoichiometric reagent in its idealized form. Thermodynamics plays the role of the referee. Because different phosphate esters along the scaffold have slightly different stabilities, influenced by steric congestion, hydrogen bonding, and ring strain in the intermediates, the migration is not random. Over time, the distribution of phosphorylated isomers equilibrates, and under the reported conditions the population shifts toward the thermodynamically favored positions on the glycerol and inositol frameworks.

Glycerol, the simplest triol and the structural basis of all cellular lipids, provided the minimal test bed. The team followed the migration of a phosphate group among the three available hydroxyl positions, distinguishing the primary termini from the secondary center. Inositol, a cyclohexane hexol bearing six hydroxyl groups in a defined stereochemical arrangement, presented a far more demanding challenge. Inositol phosphates, including the ubiquitous signaling molecule inositol trisphosphate and the storage compound phytic acid, feature phosphoryl groups at specific positions, and their synthesis has historically required elaborate protecting-group choreography. The demonstration that phosphate can move under its own motive chemistry across such a scaffold suggests new, shorter routes to these biologically important molecules.

The experimental strategy relied on careful kinetic and structural characterization. By monitoring reaction mixtures over time and quantifying the distribution of regioisomeric phosphate esters, the researchers mapped the pathways of migration and confirmed that isomerization proceeds through the predicted cyclic intermediates. Control experiments with substrates in which neighboring hydroxyls were blocked or removed arrested the migration, consistent with a mechanism that requires an adjacent free hydroxyl to launch each phosphoryl-transfer step. The dependence of migration rates on conditions such as solvent and added water further supported a cycle in which proton transfer and nucleophilic attack are tightly coupled.

Beyond its synthetic utility, the work carries conceptual weight for origins-of-life chemistry. Phosphorylation in water is notoriously difficult because inorganic phosphate is a poor electrophile and its esters are kinetically stable. Yet plausible prebiotic scenarios must explain how phosphorylated sugars, glycerol derivatives, and nucleotides arose. A reaction cycle that autonomously relocates phosphate groups among polyols, without enzymes or activated reagents, offers a model for how positional phosphorylation patterns could have been explored and reshuffled on the early Earth. In such a picture, cyclic phosphodiester intermediates, long considered mere synthetic curiosities, would serve as the engines of a primitive phosphoryl economy.

For laboratory chemists, the immediate implication is a shortcut. Preparing a specific glycerophosphate or inositol phosphate isomer may no longer require installing protecting groups on every hydroxyl and uninstalling them afterward. Instead, one could install a phosphate anywhere on the scaffold and allow the migration cycle to redistribute it, then trap the desired isomer by adjusting conditions or by selective derivatization. The approach converts a regioselectivity problem, one of the most persistent headaches in phosphate chemistry, into an equilibration problem that can be steered by thermodynamic control. The same logic may extend to scaffolds beyond glycerol and inositol, including carbohydrates, nucleoside analogues, and other polyhydroxylated natural products.

The study also adds to a growing body of research on molecular systems that perform directed motion or autonomous reorganization without external intervention. Whereas synthetic molecular machines typically require light, fuel, or ratcheted energy input to achieve directional movement, the phosphate migration described here achieves net repositioning through energy differences between final states rather than through kinetic gating. That distinction makes it less a motor and more a self-sorting shuttle, but it is precisely this simplicity, no fuel, no catalyst, no external signal, that makes the chemistry robust and potentially relevant far outside the specialized laboratory in which it was discovered.

As with any equilibration-driven process, selectivity has limits: isomers that are close in energy will coexist, and applications demanding a single regioisomer will still require a trapping or amplification strategy. Nevertheless, the demonstration that a phosphate group can autonomously tour a biologically central scaffold, driven by a closed phosphodiester cycle, reframes a classic problem in organic chemistry. What once demanded stepwise mechanical manipulation of functional groups can now be viewed as a dynamic system that finds its own way, offering chemists a new dial for controlling the placement of one of nature’s most indispensable chemical ornaments.

Subject of Research: Autonomous intramolecular migration of phosphate groups on polyol scaffolds via a phosphodiester reaction cycle

Article Title: Autonomous migration of a phosphate group along glycerol and inositol scaffolds driven by a phosphodiester reaction cycle

Article References: Hoffmann, P. A., Saha, S., Volk, S., Sun, J., Englert, A., & von Delius, M. (2026). Autonomous migration of a phosphate group along glycerol and inositol scaffolds driven by a phosphodiester reaction cycle. Nature Chemistry. https://doi.org/10.1038/s41557-026-02240-4

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02240-4

Keywords: phosphate migration, phosphodiester, glycerol, inositol, phosphorylation, reaction cycle, organic chemistry, Nature Chemistry, prebiotic chemistry, regioselectivity, polyols, phosphoryl transfer

To appreciate why this advance matters, it helps to revisit the fundamentals of alkene chemistry. When an alkene reacts with a protic acid or certain radical species, the new bond tends to form at the less substituted carbon of the double bond, placing the resulting positive charge or radical at the more substituted position. This regiochemical preference, described by Markovnikov’s rule in the ionic case, means that classical hydroalkylation methods overwhelmingly deliver branched products. Yet for many synthetic targets, the opposite connectivity is desired: a linear product in which the alkyl group attaches to the more substituted carbon, extending the carbon chain rather than creating a branch. Achieving this anti-Markovnikov outcome selectively has been a long-standing goal in method development, because linear connectivity often maps directly onto the skeletal architecture of drug candidates and other high-value molecules.

The challenge is fundamentally one of controlling intermediate stability. In ionic hydroalkylation, the reaction proceeds through a carbocation, and carbocations are inherently more stable when they are more substituted, so the reaction follows the thermodynamic path that produces branched products. Radical-based approaches inherit a similar bias, because the more substituted carbon radical is likewise the more stable one. Bypassing these preferences requires a catalyst system capable of generating radical intermediates under conditions where the usual stability hierarchy no longer dictates the outcome, or where subsequent steps trap the desired regioisomer rapidly and irreversibly before competing pathways can intervene. Photocatalysis, which uses absorbed light to drive single-electron transfer events, has emerged as one of the most powerful tools for accessing such unusual radical manifolds under mild conditions.

Iron may seem like an unexpected choice of metal for such a sophisticated catalytic role. The photocatalysis literature has been dominated by polypyridyl complexes of ruthenium and iridium, which offer long-lived excited states and tunable redox potentials but come with the drawbacks of cost, scarcity, and environmental baggage. Iron, by contrast, is the most abundant transition metal on the planet, inexpensive, biocompatible, and central to countless biological electron-transfer processes. Its first-row cousins have transformed modern cross-coupling chemistry precisely because they combine reactivity with sustainability. Translating those advantages into photocatalysis has been harder, because many iron complexes suffer from short excited-state lifetimes and rapid deactivation pathways. Nonetheless, the promise of earth-abundant photoredox catalysis has motivated an intense effort to design iron chromophores capable of the same single-electron chemistry that precious-metal catalysts perform routinely.

The new study reported in Nature Catalysis demonstrates that an iron-based photocatalyst can promote the reductive fragmentation of malonic acids, converting them into alkyl radicals that add across alkene bonds to deliver linear hydroalkylation products. Malonic acids are attractive alkyl donors for several reasons. They are readily accessible from commodity starting materials through well-established alkylation chemistry, they are bench-stable and easy to handle, and their decarboxylative fragmentation releases carbon dioxide as the only stoichiometric byproduct of radical generation. This decarboxylative activation strategy converts an otherwise unreactive carbon–carbon single bond framework into a controlled radical source, sidestepping the need for alkyl halides, redox-active esters, or other preactivated substrates that add steps and waste to a synthesis.

Mechanistically, the reaction is believed to proceed through photoinduced electron transfer from the excited iron catalyst to the malonic acid substrate or an activated derivative thereof. The resulting reduced intermediate undergoes rapid decarboxylation, ejecting carbon dioxide and releasing the nucleophilic alkyl radical. That radical then adds to the alkene, and the key to achieving linear selectivity lies in the orientation of this addition step and the fate of the radical adduct that forms. By favoring pathways in which the radical adds to the more substituted terminus of the double bond and the resulting radical intermediate is reduced and protonated in sequence, the catalytic system delivers the anti-Markovnikov hydroalkylation product. This hydrogen-atom and electron relay replaces the chain-breaking steps of classical radical chemistry, ensuring that the product distribution reflects the catalytic design rather than intrinsic radical stability.

The practical consequences of this selectivity reversal are substantial. In traditional hydrofunctionalization chemistry, synthetic chemists who need a linear product are often forced to work backward, choosing awkward starting alkenes or installing and removing directing groups to coerce the desired regiochemistry. A direct anti-Markovnikov hydroalkylation collapses that complexity into a single step. Because both coupling partners can be simple, readily available building blocks—an alkene and a malonic acid derivative—the method offers exceptional convergence, allowing molecular complexity to be assembled late in a synthesis from small fragments. This convergent logic is central to modern medicinal chemistry, where the rapid exploration of structure–activity relationships depends on the ability to vary substituents independently and efficiently.

The sustainability profile of the transformation deserves equal attention. Replacing iridium or ruthenium complexes with an iron catalyst dramatically reduces the cost and environmental footprint of the reaction, a consideration that becomes acute when chemistry is scaled from milligrams in a discovery laboratory to kilograms in a manufacturing setting. Iron salts and complexes are orders of magnitude cheaper than their precious-metal counterparts, and their extraction and use carry far lower toxicity and supply-chain concerns. Combined with the carbon dioxide traceless leaving group and the mild, room-temperature-compatible conditions typical of photocatalysis, the method exemplifies the kind of green chemistry that regulators and the pharmaceutical industry increasingly demand. Visible light, in this framework, is not merely a reagent substitute but an enabling energy source that permits redox chemistry under conditions no thermal protocol could match.

The broader significance of this work extends beyond the specific hydroalkylation reaction. It contributes to a growing recognition that first-row transition metals can do far more in photoredox chemistry than previously assumed, provided their excited-state behavior is harnessed thoughtfully. Every demonstration that an iron catalyst can execute a demanding single-electron transformation with useful selectivity expands the toolkit available to synthetic chemists and reduces the field’s dependence on scarce elements. At the same time, the malonic acid radical-generation platform is modular by design: changing the substituents on the malonic acid changes the alkyl radical delivered, meaning the same catalytic manifold can in principle access a wide structural range of products from a common set of donor reagents.

For the synthetic community, the immediate takeaway is that linear-selective hydroalkylation, long considered an aspirational transformation, is now a practical option for molecular construction. The combination of an earth-abundant metal catalyst, visible-light activation, decarboxylative radical generation, and reliable anti-Markovnikov regiochemistry addresses nearly every limitation that has constrained alkene hydroalkylation in the past. As the methodology is adopted, elaborated, and extended to new substrate classes, it seems likely to find applications ranging from medicinal chemistry route design to the synthesis of fine chemicals and materials. In a field where each step saved and each gram of precious metal eliminated carries real economic and environmental weight, an iron-catalyzed, light-driven route to carbon–carbon bonds from simple alkenes represents exactly the kind of advance that reshapes how molecules are made.

Subject of Research: Anti-Markovnikov alkene hydroalkylation using iron photocatalysis and malonic acid alkyl donors

Article Title: Anti-Markovnikov alkene hydroalkylation via iron photocatalysis

Article References: Anti-Markovnikov alkene hydroalkylation via iron photocatalysis. (n.d.). https://doi.org/10.1038/s41929-026-01600-0

Image Credits: AI Generated

DOI: 10.1038/s41929-026-01600-0

Keywords: iron photocatalysis, anti-Markovnikov, hydroalkylation, alkenes, malonic acids, decarboxylative radical generation, carbon–carbon bond formation, visible-light catalysis, first-row transition metals, regioselectivity, sustainable chemistry, radical chemistry

The new method, developed by Chengmi Huang, Dong Wu, Shiyang Wang, Yangyang Li and Guoyin Yin in the laboratory of Guoyin Yin, with computational contributions from Shuang Deng and Xiaotian Qi, is a sequential three-component coupling of alkynes, organohalides and a diboron reagent. Alkynes are attractive building blocks because they are flat, linear and readily available, and their conversion into substituted alkenes by adding two different groups across the triple bond, a process known as difunctionalization, is a powerful way to generate molecular complexity in a single operation. The difficulty has always been control: which group adds to which end of the alkyne, and whether the two groups end up on the same side or opposite sides of the resulting double bond.

Traditional approaches to alkyne difunctionalization typically rely on predesigned substrates bearing directing groups, or on rigid, single-pathway reaction mechanisms that lock in one regiochemical and stereochemical outcome. That rigidity restricts structural diversity, forcing chemists to redesign substrates and conditions every time a different isomer is needed. The Wuhan team’s solution is conceptually different. Instead of fixing the pathway, they exploit the fact that nickel catalysts can operate through two fundamentally different reactive intermediates, organometallic species on one hand and free radicals on the other, and they show that the choice of ligand determines which of these pathways dominates.

Mechanistic studies, combining experiments with density functional theory calculations, revealed the heart of the switch. The electronic properties of the ligand regulate whether the nickel catalyst generates an organometallic intermediate or a radical intermediate after oxidative addition of the organohalide. When the organometallic pathway prevails, the reaction proceeds through a well-defined nickel-carbon bond and delivers one set of alkene products; when radical generation dominates, the reaction follows an entirely different trajectory. Remarkably, the team found that the intrinsic metal-binding ability of the various radicals further modulates their reactivity, providing a second layer of selectivity control that governs how the radical interacts with the nickel-bound alkyne.

This dual-control architecture allows the researchers to access alkene products that are otherwise difficult to make. Under one set of conditions, the coupling delivers uncommon 1,2-trans alkenes, in which the two newly installed groups sit on opposite carbons of the double bond and point away from each other. Under another set of conditions, the same three components combine to give 2,1-cis alkenes, with the groups on adjacent carbons and on the same face. Achieving both regioselectivity and unique stereoselectivity simultaneously in a single catalytic operation is rare, and the fact that the outcome can be toggled by ligand choice rather than by rebuilding the substrate is what makes the system genuinely programmable.

The programmability extends beyond stereochemistry into molecular homologation. By controlling the incorporation of two alkyne units into the product, the team accomplished the divergent synthesis of conjugated diene homologues, molecules that differ by the number of conjugated alkene units in their backbone. Conjugated dienes are ubiquitous structural motifs: they appear in natural products such as the sorbicillinoid family, in agrochemicals including neonicotinoid insecticides, and in functional materials where the extent of conjugation dictates optical and electronic properties. Being able to prepare two different conjugated diene homologues from the same reaction setup, choosing between them with the catalyst rather than with new starting materials, offers a modular route to libraries of these valuable compounds.

The concept of radical sorting has been gaining momentum in catalysis research in recent years. Landmark studies from the MacMillan group on alkene dialkylation by triple radical sorting, and from other laboratories on cross-couplings enabled by bimolecular homolytic substitution, have shown that selectively channelling different radical species through a catalytic cycle can enable transformations that would otherwise be hopelessly scrambled. The Wuhan work pushes this idea further by sorting not just among radicals but between radical and organometallic regimes, effectively giving the chemist a switch that selects the reactive personality of the catalyst. The authors’ computational analysis, including average local ionization energy mapping of nickel(I) intermediates and buried-volume steric maps of the ligand environment, provided a quantitative picture of how ligand electronics and sterics steer the competition between pathways.

Detailed mechanistic experiments underpinned the proposal. The team examined how different ligands altered the fate of the alkenyl-nickel and alkenyl-radical intermediates that arise after the first addition across the alkyne, and their calculations compared the competing pathways for two distinct ligand frameworks, designated L4 and L6, at a high level of theory in solvents matching the experimental conditions. The results showed that chemoselectivity, whether the intermediate continues down the productive coupling channel or diverts into an unproductive one, is dictated by the interplay of ligand electronics and the radical’s affinity for the metal centre. This mechanistic clarity is valuable in its own right, because it converts what could have been an empirical observation into a set of design principles that other laboratories can apply to their own catalytic problems.

The practical scope of the method was demonstrated across a broad collection of substrates, with crystallographic data for seven representative products deposited at the Cambridge Crystallographic Data Centre to confirm the assigned structures unambiguously. The authors also showcased synthetic applications, including downstream transformations of the borylated alkene products and an application to the synthesis of histamine H3 receptor inverse agonists, a class of pharmacologically active compounds, illustrating how the reaction could feed directly into medicinal chemistry workflows. Because the products carry a boronate handle, they are primed for further diversification through well-established organoboron chemistry, multiplying the value of each coupling event.

The work was supported by the National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, the Shenzhen Science and Technology Program and institutional funds from Wuhan University, and it was peer reviewed by experts including Javier Corpas, Albert Poater and Qiuling Song. Beyond its immediate synthetic utility, the study signals a broader shift in how chemists think about selectivity. Rather than accepting the selectivity dictated by a substrate’s inherent bias, catalysts can now be engineered to override that bias and impose an outcome chosen by the operator. As switchable catalysis matures, the prospect of running a single reaction flask and extracting whichever molecular isomer a drug discovery or materials program requires, simply by swapping a ligand, moves from aspiration toward routine practice, and this nickel-catalysed alkene construction provides a compelling demonstration of that future.

Subject of Research: Ligand-switchable nickel catalysis for programmable regio-, stereo- and homologation-divergent construction of alkene skeletons from alkynes, organohalides and diboron reagents.

Article Title: Programmable alkene skeleton construction via switchable radical and organometallic sorting

Article References: Huang, C., Deng, S., Wu, D., Wang, S., Li, Y., Qi, X., & Yin, G. (2026). Programmable alkene skeleton construction via switchable radical and organometallic sorting. Nature Chemistry. https://doi.org/10.1038/s41557-026-02242-2

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02242-2

Keywords: nickel catalysis, alkyne difunctionalization, radical sorting, organometallic chemistry, alkene synthesis, conjugated dienes, stereoselectivity, regioselectivity, ligand control, diboron reagent, homologation, synthetic methodology