Allylic amines are everywhere in biologically active chemistry. They appear as substructures in natural products, in pharmaceutical candidates, and in the alkene isosteres used to mimic peptide bonds in drug design. Their appeal as building blocks goes beyond mere prevalence: because an allylic amine carries an alkene, an amine and a stereocentre in close proximity, each of these reactive sites can be manipulated independently, a property chemists describe as orthogonal reactivity. That versatility makes them ideal launch pads for constructing value-added targets, from aza-heterocycles to modified alkaloids. Yet most existing routes to their chiral versions rely on pre-activated substrates such as allylic acetates, on stoichiometric chiral auxiliaries, or on multi-step sequences that erode efficiency.

The conceptual heart of the new method is homologation — the controlled lengthening of a molecular skeleton. Homologation strategies have enjoyed a renaissance in recent years, with one-carbon extensions of carboxylic acids, alkenes and organoboron compounds all demonstrating how growing a carbon chain catalytically can shortcut traditional synthesis. The Shu group applies this logic to enamines, nitrogen-substituted alkenes that are cheap, electron-rich and easily prepared from carbonyl compounds. By coupling an enamine with an alkyne under nickel catalysis, the reaction effectively inserts the alkyne-derived fragment onto the enamine framework, converting it into an allylic amine that is one hydrocarbon unit longer and, crucially, chiral.

Technically, the transformation is an enantioselective C(sp2)–C(sp3) cross-coupling, a class of reaction that has become one of the most competitive arenas in modern catalysis. Nickel is the metal of choice for several reasons: it is earth-abundant compared with palladium, it readily shuttles between oxidation states, and it tolerates the kind of unactivated alkyl intermediates that would decompose on more precious metals. In the reported system, a chiral ligand environment around nickel governs both the regiochemistry — which carbon of the alkyne receives which partner — and the enantioselectivity, delivering products in good yields with excellent enantiomeric excess across a broad substrate scope.

Perhaps the most striking feature is the chemoselectivity that makes the reaction possible at all. Mechanistic investigations by the team revealed that the catalytic cycle hinges on a selective hydrometallation step in which nickel hydride adds preferentially to the electron-rich alkene of the enamine rather than to the more electrophilic linear alkyne present in the same flask. That preference runs counter to what simple electronic intuition might predict, since electrophilic alkynes typically react faster with metal hydrides. By favouring the less obvious partner, the catalyst generates an alkyl-nickel species that then engages the alkyne in the bond-forming event, setting up the stereochemistry-defining step of the cycle.

The scope of the reaction, documented across the paper’s substrate tables and crystallographically confirmed structures, spans a wide range of alkynes and enamines. Six crystal structures deposited with the Cambridge Crystallographic Data Centre underpin the structural assignments, giving the community unambiguous three-dimensional confirmation of the products’ configurations. The breadth matters practically: medicinal chemists rarely work with a single substrate class, and a method that accommodates varied substitution patterns on both coupling partners is far more likely to be adopted in late-stage or discovery settings than one restricted to narrow examples.

The synthetic utility is demonstrated most convincingly in the applications section, where the authors show that the reaction provides a convenient route to a range of bioactive molecules and key intermediates. Among the targets accessible through the chemistry are motifs related to monoamine oxidase inhibitors and CCR3 antagonist scaffolds, compounds whose chiral allylic amine cores have traditionally demanded lengthy asymmetric sequences. Because the products retain multiple reactive handles — the alkene, the amine and any additional functionality inherited from the alkyne — they can be elaborated further, meaning the reaction functions not just as an endpoint but as a strategic gateway within a longer synthesis.

The work also fits into a broader pattern in the Shu group’s research programme, which has focused on nickel-catalysed asymmetric cross-hydrodimerization and hydroalkylation reactions of unsaturated partners. Earlier contributions from the same laboratory include enantioselective alkyl–alkyl couplings of alkenes and cobalt-catalysed cross-hydrodimerizations of dienes with alkynes. The new enamine homologation extends this reactivity-mode thinking to nitrogen-containing substrates, showing how the same mechanistic family — hydrometallation followed by controlled C–C bond formation — can be redirected toward different product classes by changing the coupling partners and ligand design.

For the pharmaceutical industry, the significance is twofold. First, the method converts commodity starting materials into high-value chiral intermediates in a single step, which translates directly into fewer operations, less waste and lower cost in process chemistry. Second, because the products are enantioenriched aliphatic allylic amines rather than aryl-substituted analogues, the chemistry reaches a subclass that asymmetric hydrogenation and classical imine alkenylation methods have served poorly. Homologation itself is increasingly recognised in medicinal chemistry as a powerful strategy for exploring the property space around a lead compound, and a catalytic, enantioselective homologation of amines gives drug hunters a new dial to turn when optimising potency, selectivity and metabolic stability.

The study, supported by the National Natural Science Foundation of China and regional funding bodies in Guangdong and Sichuan, was peer reviewed at Nature Synthesis with crystallographic and mechanistic evidence available in the supplementary materials. As nickel catalysis continues to displace precious-metal chemistry across the synthesis landscape, this enamine-to-allylic-amine homologation stands out as a template for how careful mechanistic insight — here, the counterintuitive selectivity of hydrometallation — can unlock transformations that were previously out of reach, and it is likely to inspire a wave of follow-up work aimed at extending homologation logic to other functional groups and feedstock combinations.

Subject of Research: Nickel-catalysed regio- and enantioselective homologation of enamines with alkynes to synthesize chiral allylic amines

Article Title: Synthesis of chiral allylic amines through regio- and enantioselective homologation of enamines using Ni catalysis

Article References: Du, Y.-M., You, L.-X., Li, Y.-L., Yu, Q., & Shu, W. (2026). Synthesis of chiral allylic amines through regio- and enantioselective homologation of enamines using Ni catalysis. Nature Synthesis. https://doi.org/10.1038/s44160-026-01172-8

Image Credits: AI Generated

DOI: 10.1038/s44160-026-01172-8

Keywords: nickel catalysis, chiral allylic amines, enamines, alkynes, homologation, asymmetric catalysis, cross-coupling, hydrometallation, reaction mechanism, drug discovery, synthetic methodology, Nature Synthesis

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