Switchable annulation paths to diverse N-bridged bicyclic scaffolds via ligand-directed dicarbonylation

Article https://doi.org/10.1038/s41467-026-74395-0 Switchable annulation paths to diverse N-bridged bicyclic scaffolds via liganddirected dicarbonylation Received: 20 January 2026 Check for updates 1234567890():,; 1234567890():,; Accepted: 2 June 2026 Yu-Kun Liu1, Peng Yang1, Le-Cheng Wang1,2, Zhi-Peng Bao1,2 & Xiao-Feng Wu 1,2 N-Bridged bicyclic scaffolds bearing 3-azabicyclo[3.2.0]heptane and 3-azabicyclo[3.1.1]heptane cores have emerged as privileged bioisosteres of piperidine and meta-substituted pyridine, offering enhanced conformational rigidity and improved pharmacokinetic profiles. However, existing synthetic approaches are typically restricted to single scaffolds, limiting scaffold diversity. Here, we report a ligand-controlled, palladium-catalyzed tandem dicarbonylation of readily available cyclobutenols and amines, enabling divergent access to both 3-azabicyclo[3.2.0]heptane and 3-azabicyclo[3.1.1]heptane scaffolds from the same substrate. This strategy overcomes key challenges associated with strained-ring systems-including ring-opening side reactions and complex regio-, stereo-, and diastereoselective control-through fine-tuning of the catalyst environment. The method demonstrates excellent selectivity, broad substrate compatibility, and operational simplicity, accommodating 20 derivatives of bioactive molecules. This work provides a modular and general platform for the synthesis of structurally distinct Nbridged heterobicycles, addressing a critical gap in the development of bioisosteric nitrogen-containing scaffolds. Analysis of FDA-approved small-molecule drugs from 2013 to 2023 highlights the predominance of nitrogen-containing heterocyclesparticularly six-membered ones-which appear in the majority of newly approved therapeutics1,2. Within this context, piperidine- and pyridinebased scaffolds are regarded as among the most prevalent N-heterocyclic frameworks in pharmaceutical chemistry3–7. In recent years, replacing piperidine and pyridine rings with bridged bicyclic scaffolds in drug molecules and bioactive compounds has attracted increasing attention (Fig. 1a)8–10, as this strategy is widely recognized to block metabolically vulnerable sites and increase molecular rigidity, thereby improving physicochemical properties and pharmacokinetic profiles11–14. Notably, 3-azabicyclo[3.2.0]heptanes and piperidine both adopt intrinsically three-dimensional architectures, whereas 3-azabicyclo[3.1.1]heptanes conform to the ‘escape-from-flatland’ design principle. As a result, these scaffolds represent promising bioisosteres of piperidine and meta-substituted pyridine, respectively (Fig. 1b)9,10,15–17. Consequently, the development of modular and efficient strategies for the construction of structurally diverse and bioisosteric nitrogen-containing ring scaffolds from readily accessible starting materials is of urgent importance. 3-Aza-BCHep scaffolds exhibit pronounced conformational rigidity, making them inherently difficult to access through conventional alkylation-based methods18. Consequently, most synthetic approaches toward 3-azabicyclo[3.2.0]heptane frameworks rely on cycloaddition reactions, including (3 + 2)19,20and (2 + 2)21–28 processes under metal, thermal, or photocatalytic conditions (Fig. 1c, left). Nevertheless, these strategies are often constrained by the requirement for activated substrates and with limited dipolarophile scope. In contrast, bicyclo[1.1.0]butanes (BCBs) have emerged as privileged strain-release intermediates for constructing bridged bicyclic 1 Leibniz-Institut für Katalyse e. V., Rostock, Germany. 2Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of e-mail: Sciences, Dalian, Liaoning, China. Nature Communications | (2026)17:5130 1 Article https://doi.org/10.1038/s41467-026-74395-0 a) Bioactive molecules containing 3-azabicyclo[3.2.0]heps and 3-azabicyclo[3.1.1]heps F F Cl O F F O N CO2H N N N N NH O H 2N N N N N H N NMe N N N O O S Me Belaperidone Ecenofloxacin antischizophrenia agent antibacterial agent N H KIF18A inhibitor 3D-analogue of Rupatadine IC50 = 43 nM b) Bioisosteres of piperidine and pyriding 125˚ 125˚ Bioisosteres 3D 109˚ Bioisosteres 2D Het N N N 112˚ 5.0 Å 4.8 Å meta-Substituted Pyridines flat aromatic ring 3-Azabicyclo[3.1.1]Heps sp3-hybridized N atom 3D-shape 4.9 Å Piperidine 3D saturated ring 3-Azabicyclo[3.2.0]Heps rigidified 3D similarity Escaping from flatland N N 6-Membered N-heterocycle c)Synthetic approaches to 3-aza-bridged bicyclic frameworks and retrosynthetic analysis + N (2+2) Cycloaddition Highly strained four-membered ring + C1 + C1 N (2+2) Cycloaddition N O Readily available N-sources O + d) Pathways for multisite-selective dicarbonylation 1 2 3 4 1 3 4 4 2 CO 2 3 4 or 2 1 3 4 Subsequent carbonylation 2 CO and 3 3 1 4 1 2 Specific dicarbonylation 3 1 2 4 CO 4 Subsequent carbonylation 1 2 3 4 Initial carbonylation Common intermediate Multisite Monocarbonylation non-BCB routes are scarce 3 1 CO or Initial carbonylation X = C, N, O LiAlH4 Then isomerization e) Our concept: Divergent dicarbonylation via a common intermediate 1 2 CN O X * N * C1 source + H 2N N or 1,3-Dipolar & & & (3+3) Cycloaddition or (3+2) Cycloaddition Vinyl azides then ring expansion N3 X N + & (3+2) Cycloaddition Multisite Multiple dicarbonylation f) Ligand-controlled tandem dicarbonylation for divergent synthesis of 3-aza-bridged bicycles frameworks (This work) O O N O Pd CO 2 1 3 OH 4 Pd NH2 + NiXantphos 2,3-Cyclization 5-exo-trig r.r. > 19:1, dr > 20:1 Broad coupling partners > 100 examples; 20 bioactive derivatives MePhos 2 or 2' 1 Readily available Highly strained N-sources four-membered ring N O 1,3-Cyclization 6-endo-trig r.r. > 19:1 Readily avaliable substrates Divergent synthesis of 3-aza-Heps Excellent regio- and diastereselectivity Excellent functional group compatibility Fig. 1 | The applications and preparation of N-bridged bicyclic scaffolds, and site-selective dicarbonylation strategies for their synthesis. a Bioactive molecules containing 3-azabicyclo[3.2.0]heps and 3-azabicyclo[3.1.1]heps. b Bioisosteres of piperidine and pyriding. c Synthetic approaches to 3-aza-bridged Nature Communications | (2026)17:5130 CO bicyclic frameworks and retrosynthetic analysis. d Pathways for multisite-selective dicarbonylation. e Our concept: Divergent dicarbonylation via a common intermediate. f Ligand-controlled tandem dicarbonylation for divergent synthesis of 3aza-bridged bicycles frameworks (This work). 2 Article frameworks29–40. Notably, (3 + 3) cycloadditions with 1,3-dipoles41–47 and dipolar (3 + 2) annulations of vinyl azides have enabled access to 3azabicyclo[3.1.1]heptane architectures48,49, the latter typically proceeding via subsequent isomerization (Fig. 1c, right). Beyond BCBbased approaches, only a few non-BCB strate (...truncated)