The significance of the target scaffolds is hard to overstate in medicinal chemistry terms. The parent 2-azabicyclo[3.1.0]hexane motif, in which a cyclopropane ring is fused to a pyrrole or indole core, is isosteric with quinoline, meaning it occupies a similar three-dimensional shape while offering different electronic properties. Fusing the rigid cyclopropane onto the nitrogen heterocycle reduces the lipophilicity of the parent pyrroline, alters the electronic environment around the nitrogen atom, and introduces new exit vectors that drug designers can exploit to tune biological activity. Star molecules built on this framework include SUVN-911, a potent α4β2 nicotinic receptor ligand with a strong safety profile at high doses, an inhibitor of NF-κB-inducing kinase, and saxagliptin, the widely used oral dipeptidyl peptidase IV inhibitor for type 2 diabetes.

Yet the two scaffolds targeted in the new study, which carry an additional degree of unsaturation or a third fused ring, have remained chemical backwaters. According to the authors, the reason is simple: practical synthetic routes are scarce, and those that exist tend to involve long sequences, low overall efficiency, and little structural diversity. The team’s own earlier work hints at why closing this gap matters. When they previously incorporated an extra nitrogen into the 2-azabicyclo[3.1.0]hexane framework, the resulting diazabicyclo[3.1.0]hexanes showed promising anti-proliferative activity, suggesting that small structural edits to these rigid frameworks can translate into meaningful pharmacological effects.

Retrosynthetically, chemists have generally attacked these targets in one of two ways. The first strategy constructs the cyclopropane ring onto an existing pyrrole or pyrrolidine core; the second forges both rings simultaneously in a single operation, exemplified by a copper-catalyzed intramolecular reductive isocyanide-alkene (1+2) cycloaddition that gives direct access to 2-azabicyclo[3.1.0]hexanes. While the tandem approach is elegant, the authors note that limitations in preparing the substrates restrict its usefulness for building compound libraries, a critical consideration for medicinal chemistry screening campaigns.

Cyclopropanation of indoles with metal carbenoids has long looked like an attractive route to the benzo-fused analogues, but it comes with a stubborn problem. When 2,3-non-substituted indoles are treated with diazo compounds under various transition-metal catalysts, the desired cyclopropanation competes with formal C(sp2)-H bond alkylation, eroding selectivity and yield. In 2019, Sen and coworkers reported the first selective cyclopropanation of N-acylindoles using aryl diazo esters as donor-acceptor carbenes with a manganese catalyst, but only moderate diastereoselectivities were achieved, with no assignment of the major isomer’s relative configuration. A year later, the Lautens group swapped diazo compounds for cyclopropenes in the cyclopropanation of indoles, benzofurans, and related aromatics, while Jiang and Loh showed that the N-protecting group critically controls the E/Z geometry of the alkene in the product. Even so, selectivity remained unsolved, and pyrroles, which are electronically distinct from their benzofused indole cousins, had never been explored in this chemistry.

The Zhao group’s long-standing expertise in cyclopropene chemistry provided the opening. Cyclopropenes are high-energy, strained three-membered alkenes that transition metals can ring-open to generate alkenyl carbenoids, reactive intermediates capable of cyclopropanating a second π-system. Most catalytic cyclopropanations with cyclopropene precursors had been limited to simple alkenes, with few examples involving electron-rich arenes. Pyrroles are among the most electron-rich aromatic rings known, which makes them reactive but also difficult to control. The team reasoned that dialing back the pyrrole’s reactivity through electronic fine-tuning of the nitrogen substituent could be the key to clean, selective cyclopropanation.

That reasoning proved correct, but only after careful optimization. Because bis-cyclopropanation at both ends of the pyrrole ring would create spiro products with uncontrollable stereochemistry, the chemists started with pyrroles in which one side is blocked, using a cyclohexanone-fused pyrrole derivative as the test substrate. After screening N-protecting groups, they found that simple N-methyl and N-benzyl pyrroles gave no product at all. Introducing electron-withdrawing acyl groups changed everything: a tert-butoxycarbonyl group gave a 45 percent yield, while a benzoyl group boosted the yield to 84 percent. The best result, 91 percent, came from a 3,5-bis(trifluoromethyl)benzoyl group, paired with the dirhodium tetracetate catalyst Rh2(OAc)4 in benzene solvent. Solvent screening showed the reaction is remarkably picky, with toluene, dichloromethane, chlorobenzene, THF, and acetonitrile all giving dramatically lower yields or trace product. Strikingly, across every condition examined, the diastereomeric ratio and E/Z selectivity exceeded 25 to 1.

With the optimized conditions in hand, the team mapped the substrate scope. On the cyclopropene partner, strongly electron-withdrawing trifluoromethyl and strongly electron-donating methoxy groups on the aryl ring were both tolerated in excellent yields, as were para-alkyl, chloro, bromo, and naphthyl substituents. The reaction proved sensitive to substitution position: meta-substituted aryl groups gave comparable yields to their para counterparts, but ortho-substituted analogues suffered significantly reduced yields and lower E/Z ratios. Cyclopropenes bearing alkyl groups other than methyl at the carbenoid carbon also performed well, delivering products in 72 to 96 percent yields, and 3,3-dialkyl substitution was tolerated, although two alkyl groups of similar steric bulk dropped the E/Z ratio to an even 52:48. The team also revisited indoles, finding that a 4-methoxybenzoyl protecting group was optimal there, with the reaction reaching 63 percent conversion in 24 hours and the product isolated in 85 percent yield based on recovered starting material but with only a 40:60 E/Z ratio, a comparison that highlights the distinct electronic demands of indole versus pyrrole in this chemistry. Finally, unblocked pyrroles underwent double cyclopropanation to give the biscyclopropanated polycyclic 5-azatricyclo[4.1.0.0^(2,4)]heptane products in moderate to good yields and high diastereoselectivities.

The proposed mechanism explains both the efficiency and the stereochemical outcome. Rh2(OAc)4 first ring-opens the cyclopropene to form a vinyl rhodium carbene complex. The electron-rich pyrrole then attacks this electrophilic carbenoid, generating a zwitterionic rhodium-containing intermediate. Because controlling stereochemistry at the carbene-forming step is inherently difficult, the authors propose that the high E/Z selectivity arises instead from an equilibrium between two zwitterionic complexes, followed by rhodium migration and rotation about a carbon-carbon bond that funnels the reaction toward the thermodynamically favored E-isomer. The ortho-substitution effect fits this picture: steric clash, described as A^(1,3)-strain, in the carbenoid and the subsequent adduct hinders cyclization and can trigger rotation of the allylic rhodium moiety before ring closure, increasing the proportion of Z-product. An instructive control experiment used ethyl diazoacetate, a conventional carbene precursor that would generate a similar alkenyl carbenoid, and produced no product at all, leaving open the question of whether the alkenyl moiety itself drives the high diastereoselectivity. Regardless, the authors point out that using cyclopropene installs an extra alkene handle in the product that can be elaborated further, adding synthetic value beyond the cyclopropanation itself.

The upshot is a protocol characterized by simple operation, mild conditions, low catalyst loading, and high yields and stereoselectivities, with good tolerance for variation on both reaction partners. That combination is exactly what medicinal chemists need to rapidly assemble libraries of these rigid, nitrogen-rich frameworks for biological screening, particularly given the track record of related scaffolds in approved drugs and the team’s own evidence that adding heteroatoms to these bicyclic systems can unlock anti-proliferative activity. The authors report that efforts to expand the reaction’s applications are already underway, and if those efforts succeed, the once-neglected 2-azabicyclo[3.1.0]hex-3-ene and 5-azatricyclo[4.1.0.0^(2,4)]heptane frameworks may soon join the ranks of routinely deployed motifs in drug discovery.

Subject of Research: Rhodium-catalyzed stereoselective cyclopropanation of pyrroles to synthesize azabicyclic and azatricyclic nitrogen heterocycles

Article Title: Highly stereoselective synthesis of 2-Azabicyclo[3.1.0]hex-3-ene and 5-Azatricyclo[4.1.0.02,4]heptane scaffolds via Rh-catalyzed cyclopropanation of pyrrole

Article References: Ju, D., Zhao, C., Liu, B., Ma, J., Chi, S., & Zhao, J. (2026). Highly stereoselective synthesis of 2-Azabicyclo[3.1.0]hex-3-ene and 5-Azatricyclo[4.1.0.02,4]heptane scaffolds via Rh-catalyzed cyclopropanation of pyrrole. Journal of Saudi Chemical Society, 30(2), Article 26. https://doi.org/10.1007/s44442-026-00075-9

Image Credits: AI Generated

DOI: 10.1007/s44442-026-00075-9

Keywords: pyrrole, cyclopropanation, rhodium catalysis, cyclopropenes, 2-azabicyclo[3.1.0]hex-3-ene, 5-azatricyclo[4.1.0.0(2,4)]heptane, nitrogen heterocycles, stereoselectivity, medicinal chemistry, synthetic methodology, carbenoids, drug discovery

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