Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes

Article https://doi.org/10.1038/s41467-024-50434-6 Facile access to bicyclo[2.1.1]hexanes by Lewis acid-catalyzed formal cycloaddition between silyl enol ethers and bicyclo[1.1.0] butanes Received: 11 April 2024 Sai Hu1,2,3,4, Yuming Pan2,3,4, Dongshun Ni 2,3 & Li Deng 2,3 1234567890():,; 1234567890():,; Accepted: 11 July 2024 Check for updates Saturated three-dimensional carbocycles have gained increasing prominence in synthetic and medicinal chemistry. In particular, bicyclo[2.1.1]hexanes (BCHs) have been identified as the molecular replacement for benzenes. Here, we present facile access to a variety of BCHs via a stepwise two-electron formal (3 + 2) cycloaddition between silyl enol ethers and bicyclo[1.1.0]butanes (BCBs) under Lewis acid catalysis. The reaction features wide functional group tolerance for silyl enol ethers, allowing the efficient construction of two vicinal quaternary carbon centers and a silyl-protected tertiary alcohol unit in a streamlined fashion. Interestingly, the reaction with conjugated silyl dienol ethers can provide access to bicyclo[4.1.1]octanes (BCOs) equipped with silyl enol ethers that facilitate further transformation. The utilities of this methodology are demonstrated by the late-stage modification of natural products, transformations of tertiary alcohol units on bicyclo[2.1.1]hexane frameworks, and derivatization of silyl enol ethers on bicyclo[4.1.1]octanes, delivering functionalized bicycles that are traditionally inaccessible. The strategic replacement of benzene with conformationally rigid and stable C(sp3)-enriched polycyclic scaffolds in small molecules represents an emerging trend in medicinal chemistry. Attributed to their constrained geometries and precisely oriented pendant substituents, these saturated polycycles effectively emulate the topological characteristics of substituted benzenes, which allows for the preservation of desired interactions with biomacromolecules while enhancing the pharmacokinetics, solubility, and metabolic stability of drug candidates1–5. Recent studies have identified 1,2-disubstituted bicyclo[2.1.1]hexanes as potential bioisosteres for ortho-disubstituted benzenes with retained biological activity validated by in vitro experiments (Fig. 1a)6,7. Hence, there is an increasing demand for development of efficient strategies for streamlined access to these bicycles6–32. One of most common methods to construct BCH skeleton is by an intramolecular [2 + 2] cycloaddition of 1,5-diene under the irradiation of light6–14. Alternatively, an intermolecular cycloaddition between bicyclo[1.1.0]butanes (BCBs) and alkenes is highly desirable since it allows the efficient construction of bicyclic ring through the fusion of two readily available starting materials. Pioneering studies were disclosed by Blanchard16 in 1966 and De Meijere17 in 1986. Subsequently, Wipf group reported an intramolecular variant of this cycloaddition under thermal condition in 200618. More recently, by taking advantage of the ready availability and inherent ring strain of BCBs20,33, the exploration of new strategies to the cycloaddition between BCBs and alkenes in the generation of various BCHs has attracted intensive attentions19–32,34–39. According to the reported reaction processes, most methods could be categorized into two modes: 1) radical pathway; and 2) two-electron pathway 1 Department of Chemistry, Zhejiang University, Hangzhou, China. 2Key Laboratory of Precise Synthesis of Functional Molecules of Zhejiang Province, School of Science and Research Center for Industries of the Future, Westlake University, Hangzhou, China. 3Institute of Natural Sciences, Westlake Institute for e-mail: ; Advanced Study, Hangzhou, China. 4These authors contributed equally: Sai Hu, Yuming Pan. Nature Communications | (2024)15:6128 1 Article https://doi.org/10.1038/s41467-024-50434-6 Fig. 1 | Importance of bicyclo[2.1.1]hexanes (BCHs) and synthetic strategies by formal cycloaddition between bicyclo[1.1.0]butanes (BCBs) and alkenes. a BCHs behave as bioisosteres of ortho- and meta-substituted benzenes. b State of the art in the cycloaddition of BCBs and alkenes to access BCHs. c Cycloaddition of BCBs and silyl enol ethers to access BCHs. (Fig. 1b). By utilizing the photoinduced energy transfer strategy, Glorius19 and Brown20 groups respectively described elegant cycloaddition of BCBs and alkenes toward bicyclo[2.1.1]hexanes. The reaction was initiated by the excitation of either alkene or BCB to generate a diradical intermediate. Subsequently, Bach and coworkers achieved an enantioselective cycloaddition of 2(1H)‑quinolones and BCBs with a chiral mediator22. Recently, Jiang and coworkers developed a highly enantioselective cycloaddition of vinylazaarenes and BCBs under photosensitized chiral phosphoric acid catalysis23. Li24 and Wang26 groups developed a boryl-pyridine catalytic system to activate BCB as a cyclobutyl radical intermediate. Meanwhile, Procter group applied SmI2 as a single electron reductant to achieve the insertion of electrondeficient alkene into BCB25. Very recently, Zheng group described a Ticatalyzed formal cycloaddition of BCB and 2-azadienes to synthesize aminobicyclo[2.1.1]hexanes27. Lately, Glorius accomplished the coupling of phenol and BCB by leveraging a photoredox process, which has been applied in the formal cycloaddition of non-activated alkenes (Fig. 1b, 1)28,29. All the reactions above entailed the generation of radical species, which limited the substrate scope. Bicyclo[1.1.0]butanes could be activated as an enolate nucleophile upon central σ-bond cleavage mediated by Lewis acid to attack electrophilic reagents such as aryl aldimine by Leitch group30, aldehyde by Glorius group32, or ketene by Studer group31, followed by the intramolecular cyclization to complete the formal cycloadditions. We demonstrated that Lewis acid could activate BCBs as electrophiles to react with indoles as the nucleophiles to construct complex indoline polycycles (Figs. 1b, 2)34. Notably, if a wide variety of nucleophiles could be utilized, this approach could be developed into a versatile strategy that complements existing methods involving radical or ionic intermediates to access BCHs. More recently, Feng reported the use of silver triflate to promote reactions of BCBs and indoles but with opposite regioselectivity35,36. Very recently, Leitch group described a formal cycloaddition of BCBs via an enolate intermediate Int 4 by treatment of glycine imine or arylacetate derivatives with stoichiometric amount of LHMDS37. Despite these successful examples, there is a huge and unexplored chemical space for these bicycles, and a more general strategy to expediently construct such moieties with simple alkenes is highly demanded. Here, we envisaged that the silyl enol ether, as the nucleophile, would be a suitable candidate in this scenario due to its importance in different cycloaddition reactions40–48. It is noteworthy that silyl e (...truncated)