Rhodium Catalyst Forges Rare Drug-Like Ring Systems from Pyrroles in One Step

Chemists have long prized the compact, strained ring systems known as azabicyclo[3.1.0]hexanes, nitrogen-containing frameworks that appear in a surprising number of clinical drugs. Now a research team led by Jinbo Zhao at Changchun University of Technology, working with colleagues at INSA Rennes, has reported a rhodium-catalyzed reaction that builds two rarer cousins of these scaffolds, 2-azabicyclo[3.1.0]hex-3-ene and 5-azatricyclo[4.1.0.0^(2,4)]heptane, in a single operation from pyrrole starting materials. The work, published open access in the Journal of the Saudi Chemical Society, delivers the products in good yields with exceptional stereochemical control, addressing a long-standing gap in the synthetic toolbox for these under-explored ring systems.

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