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

Carbohydrate synthesis sits at the heart of modern drug discovery and chemical biology. Sugars and sugar-like scaffolds appear in antiviral nucleoside analogues, antibiotic natural products such as the gilvocarcins, and a wide range of glycosylated therapeutics. Yet assembling these molecules from scratch has always been difficult. The classic formose reaction, discovered by Alexander Butlerov in 1861 and later elucidated by Ronald Breslow, can generate sugars from formaldehyde, but it produces complex, uncontrolled mixtures. More refined approaches, including the catalytic asymmetric aldol chemistry developed by MacMillan, Wong and others, and the tandem biocatalytic methods reported more recently, still require multiple sequential operations, careful protecting-group management, or enzymatic systems limited to particular substrates.

The central obstacle to a truly iterative, carbonylation-based route to sugars has been what the authors describe as cumulative catalyst deactivation and stereochemical drift. Each carbon monoxide insertion in a cascade adds a new carbon unit and creates a new stereocentre, but as the chain grows, the reactive intermediates become progressively harder to control. Catalysts that perform well in the first insertion may falter in the second or third, and the stereochemical information installed early in the sequence can be eroded before the reaction reaches its endpoint. Previous formal triple-carbonylation reactions, such as the cobalt-catalysed transformation of epoxy alcohols reported by Alper and colleagues in 1990, hinted at the potential of the concept but never delivered a general route to defined carbohydrate products.

The new method hinges on three interlocking design elements. First, precise control of the hydrosilane stoichiometry ensures that the three carbon monoxide insertions occur in kinetic synchrony, so that each reactive intermediate is consumed as soon as it forms rather than accumulating and decomposing. Second, careful ligand selection on the rhodium catalyst tunes the rates of the individual insertion steps, keeping the cascade on a single productive pathway. Third, a silicon-directed cyclization terminates the sequence: the silyl ether installed during the cascade acts as an internal handle that directs ring closure to the furanose architecture, converting a growing acyclic chain into a stable, isolable sugar product.

Stereochemical control, the make-or-break feature of any sugar synthesis, is achieved through what the researchers term a chelation-relay mechanism. As each carbon monoxide unit is inserted, the growing chain coordinates to the metal centre in a way that relays stereochemical information from one centre to the next, propagating a defined three-dimensional arrangement across three contiguous stereocentres. The result is good diastereocontrol, meaning that the products emerge predominantly as single stereoisomers rather than mixtures, a prerequisite for any method intended to feed pharmaceutical discovery, where the biological activity of a sugar derivative can depend entirely on the spatial arrangement of its hydroxyl groups.

The substrate scope is strikingly broad. The authors demonstrate that the cascade tolerates aldehydes ranging from simple aromatic substrates to complex steroidal aldehydes, suggesting that the method can be applied not only to model systems but to real, functionally dense molecules drawn from natural product and medicinal chemistry contexts. This breadth matters because a sugar-building method is only as useful as the molecules it can decorate; a route restricted to benzaldehyde derivatives would be of academic interest alone, whereas one that accepts steroidal aldehydes opens the door to rapid assembly of glycoconjugates and sugar-modified drug candidates.

The synthetic utility of the products is showcased through a series of downstream transformations. The threofuranose scaffolds can be elaborated into N-glycosides and C-glycosides, two classes of compounds of intense pharmaceutical relevance. C-glycosides, in which the sugar is linked to an aglycone through a robust carbon-carbon bond, resist enzymatic cleavage and appear in numerous drug candidates, as reviewed extensively in the chemical literature. The products also serve as entry points to nitrogen heterocycles and polyol motifs, the oxygenated carbon frameworks that recur throughout bioactive natural products. In effect, the cascade delivers a versatile, stereochemically rich platform from which medicinal chemists can branch in multiple directions.

Mechanistic studies underpin the design. The authors draw on decades of precedent in rhodium-catalysed carbonylation chemistry, including the silylformylation of aldehydes first reported by Murai and Sonoda in 1979 and developed by Wright and Cochran, in which hydrosilanes and carbon monoxide combine to extend aldehydes by one carbon. The new work extends that logic across three consecutive insertions, a feat requiring that the catalyst survive repeated cycles of oxidative addition, migratory insertion and reductive elimination without losing activity. Crystallographic data deposited at the Cambridge Crystallographic Data Centre confirm the structures of key products, providing unambiguous evidence for the stereochemical outcomes that the chelation-relay mechanism predicts.

The broader significance of the work lies in its reframing of carbonylation chemistry as a platform for assembling oxygen-rich scaffolds, not merely for installing individual carbonyl groups. Carbon monoxide has long been a workhorse of industrial chemistry, powering hydroformylation processes discovered by Wilkinson and collaborators in the 1960s and more recent achievements such as palladium-catalysed routes to adipic acid esters and non-equivalent diamides. Using CO as a one-carbon building block for carbohydrate construction, however, is a conceptual leap: it suggests that the carbon skeletons of sugars, and perhaps other polyhydroxylated natural products, could be assembled programmatically from aldehyde feedstocks and carbon monoxide, bypassing the extractive sources of sugars that dominate current practice.

For the pharmaceutical industry, the implications are immediate. Nucleoside analogue drugs, including remdesivir, whose development against Ebola virus was reported by Warren and colleagues, depend on precisely constructed sugar cores, and de novo routes to such cores, exemplified by MacMillan’s short synthesis of nucleoside analogues, have transformed access to these molecules. A one-step carbonylative route to threofuranose frameworks offers a complementary and potentially faster entry to related scaffolds, particularly for four-carbon sugar systems such as the alpha-threofuranosyl oligonucleotides explored in the chemical etiology of nucleic acid structure by Schöning and colleagues. With a patent application on the methodology already granted to Sun Yat-Sen University, the triple-carbonylation cascade now stands as a candidate technology for scale-up, and as an invitation for chemists to imagine carbohydrate synthesis not as a sequence of protected intermediates but as a single, catalytically orchestrated cascade from the simplest of starting materials.

Subject of Research: Rhodium-catalysed triple-carbonylation cascade converting aldehydes into stereochemically defined threofuranose sugars

Article Title: De novo synthesis of threofuranoses via a triple-carbonylation cascade of aldehydes

Article References: Shen, X., Nie, R., Jiang, W., & Li, S. (2026). De novo synthesis of threofuranoses via a triple-carbonylation cascade of aldehydes. Nature Chemistry. https://doi.org/10.1038/s41557-026-02258-8

Image Credits: AI Generated

DOI: 10.1038/s41557-026-02258-8

Keywords: threofuranoses, triple carbonylation, rhodium catalysis, aldehydes, carbohydrate synthesis, carbon monoxide, chelation-relay mechanism, C-glycosides, stereoselective synthesis, hydrosilane, Nature Chemistry, novo