Recent advances in the strain-release driven reactions of bicyclobutanes: an emerging landscape in organic synthesis

Abstract

Bicyclo[1.1.0]butanes (BCBs) are among the smallest and most strained carbocycles and have emerged as powerful synthetic building blocks in modern organic chemistry. Recent years have witnessed a surge of interest in understanding and exploiting their unique reactivity. The high strain energy associated with the central C–C bond enables a variety of transformations, including insertions, additions, cycloadditions, and molecular rearrangements, often proceeding under mild conditions. This inherent strain facilitates the rapid and efficient construction of diverse and complex molecular architectures. Moreover, the incorporation of BCB motifs as bioisosteres of benzene derivatives has drawn significant attention in medicinal chemistry, owing to their high sp³ character and three-dimensionality. In this review, we summarize the important structural features and the recent advances in the reactivity of BCBs, highlighting key developments, mechanistic insights and the associated modes of reactivity explored.

---

From left to right: Shiksha Deswal, Rohan Chandra Das and A. T. Biju

Shiksha Deswal (left) was born in Sonipat, Haryana, India. She completed her undergraduate studies at Hindu College, Delhi University and master's degree in chemistry at the IIT, Roorkee. Subsequently, she joined IISc, Bangalore, as a PhD student in 2021, where she is pursuing her research in the Prof. A. T. Biju group as a PMRF. Her research primarily focuses on strain-release chemistry, exploring bicyclobutanes and D–A cyclopropanes. In May 2026, she will join the group of Prof. Thorsten Bach, TU Munich as a Humboldt post-doctoral fellow. Rohan Chandra Das (middle) was born in Jiaganj, West Bengal, India. He received his bachelor's degree from Sripat Singh College and master's degree in chemistry from the University of Kalyani, West Bengal. Subsequently, he joined IISc, Bangalore, as a PhD student in 2021, where he is pursuing his research in the Prof. A. T. Biju group as a PMRF. His research is mainly focused on NHC-catalyzed imine umpolung and strain-release driven reactions of bicyclobutanes. A. T. Biju (right) received his MSc from Sacred Heart College, Thevara, and his PhD with late Dr Vijay Nair from the CSIR-NIIST, Trivandrum. After postdoctoral research with Prof. Tien-Yau Luh (NTU, Taiwan) and as a Humboldt Fellow with Prof. Frank Glorius (University of Münster, Germany), he began his independent career at CSIR-NCL Pune in 2011. In June 2017, he moved to the Department of Organic Chemistry, IISc, Bangalore, where he is a professor presently. His research focuses on developing strategies using NHC-organocatalysis and strain-release driven reactions of arynes, D–A cyclopropanes and bicyclobutanes. He is an Associate Editor of Synthesis.

Key learning points

(1) BCB-derived bicyclic scaffolds as valuable bioisosteres for benzene analogues.

(2) The central C–C bond in BCB possesses significant π character, closely resembling a C=C double bond.

(3) Strategic exploitation of BCB strain fuels innovation in complex bicyclic scaffolds and functionalized cyclobutanes.

(4) BCBs can display both electrophilic and nucleophilic reactivity, depending on the substituents present and the choice of reacting partner.

(5) Established and emerging reactivity of BCBs via different modes of BCB activation.

1. Introduction

Benzene is the most common motif in small-molecule drugs due to its planar geometry, predictable vectors, and favourable interactions with biological targets.^1,2 However, increasing the number of aromatic rings often reduces solubility and increases lipophilicity,³ while phenyl groups are prone to CYP450 metabolism, resulting in the formation of toxic benzoquinone derivatives.⁴ To address these issues, “escaping from flatland” by increasing sp³ carbon content has emerged as a strategy to improve molecular properties and drug success rates.⁵ In recent years, medicinal chemistry has increasingly replaced phenyl groups with saturated bioisosteres to overcome their associated drawbacks.⁶ The focus has shifted from simple isosterism to bioisosterism, aiming to improve pharmacokinetic, physicochemical, and biological properties. While early replacements included pyridines, cyclohexane, and piperidine, modern drug discovery now emphasizes saturated polycyclic scaffolds such as bicyclo[1.1.1]pentanes (BCPs), bicyclo[2.1.1]hexanes (BCHs), bicyclo[3.1.1]heptanes (BCHeps), and bicyclo[4.1.1]octanes (BCOs) for their synthetic appeal and therapeutic potential (Scheme 1A).

Scheme 1 (A) Replacement of benzenes. (B) Modern applications of bioisosteres. (C) Introduction to BCBs – properties, (3-D) structure, and FMO. (D) Reactivity and transformations of BCBs.

Saturated polycyclic frameworks with small rings often surpass arenes as bioisosteres, improving solubility, stability, and permeability. The replacement of an ortho-fluorophenyl with a BCP in a γ-secretase inhibitor by Pfizer enhanced both bioactivity and drug-like properties (Scheme 1B left).⁷ Other scaffolds like BCHs and BCHeps have shown similar benefits, while heteroatom incorporation, as in the oxa-BCH analogue of fluxapyroxad, further improved the solubility and stability (Scheme 1B right).⁸ Despite these advantages, access to saturated polycyclic scaffolds remains challenging due to their high strain and steric congestion. A potential strategy to access these bicyclic scaffolds is through bicyclo[1.1.0]butanes (BCBs), leveraging the intrinsic ring strain of the framework.^9,10

The term “ring strain” was first introduced by Baeyer in 1885, and since then, strain-release-driven reactions have become a central focus for organic chemists.¹¹ The idea of strain release continues to fascinate chemists, especially in highly strained molecules such as BCBs and [1.1.1]propellanes, which have strain energies of 66.3 and 100 kcal mol⁻¹, respectively (Scheme 1C). The use of a modular synthon for the efficient synthesis of structurally diverse cyclic molecules represents a practical and powerful approach in synthetic chemistry. As the chemistry of propellanes has been extensively reviewed, this article mainly emphasizes the reactivity of BCBs.¹² A distinctive feature of the BCB scaffold is its characteristic “butterfly” shape, where the two cyclopropane “wings” form an interflap angle of about 120°. Interestingly, all C–C bonds have nearly the same length (∼1.50 Å), while the exo (1.194 Å), endo (1.167 Å), and bridgehead (1.142 Å) C–H bonds show subtle but clear differences.¹³ Whitman pointed out that the bridgehead C–H bond has more s character, which makes it more acidic,^14a while Alkorta and Elguero estimated its pK_a to be around 37.9.^14b The Walsh model, as explained by Pomerantz and Abrahamson, suggested that the central C1–C3 bond has significant p character, similar to olefins, formed through the overlap of unhybridized 2p orbitals.^14c

The unique reactivity of BCBs arises from the significant strain in their central C–C bond. This strain drives their diverse transformations, enabling BCBs to serve as versatile building blocks for a wide range of structures, from simple cyclobutanes to complex bridged, fused, and spirocyclic frameworks.¹⁰ The exclusive reactivity of BCBs arises from their inherent ring strain and can be broadly divided into two classes: (i) the construction of bicyclic scaffolds through annulation reactions and (ii) the formation of cyclobutane derivatives via ring-opening reactions (Scheme 1D left). Bicyclic scaffolds are accessed through diverse annulation pathways, including (3+1), (3+2), (3+3), (3+4), and higher-order cycloadditions. In contrast, cyclobutane frameworks are formed through the monofunctionalization or difunctionalization of BCBs, as well as via spirocyclization reactions.

The reactivity of BCBs has been extensively utilized, as they can be activated through various pathways and can undergo a wide range of transformations. Both polar and radical reactivities have been documented (Scheme 1D right). In polar mechanisms, BCBs are often activated by Lewis acids and Brønsted acids. More recently, it has been shown that the activation can also occur in the presence of mildly Brønsted acidic hexafluoro isopropanol (HFIP). Transition metal-catalyzed reactivity has been established for many years. Radical reactivity has been observed through different mechanisms, including energy transfer and electron transfer reactions. More recently, the pyridine boryl radical pathway has been recognized as a method to activate BCBs.

2. Synthesis of bicyclic scaffolds

In recent years, small carbocyclic species have gained significant attention in medicinal chemistry, with BCBs emerging as versatile tools for constructing bridged frameworks with structural diversity. These scaffolds serve as valuable bioisosteres for substituted benzenes, often improving drug-like properties.¹⁵ Owing to the weak central C–C bond in BCBs, they readily participate in diverse transformations including the enantioselective ones such as insertion and annulation reactions and molecular rearrangements, thus enabling efficient access to a wide range of bridged architectures.

2.1. Bicyclo[1.1.1]pentanes (BCPs)

Insertion reactions of BCBs, typically with carbenes, provide a straightforward route to BCPs. The earliest example of carbene insertion into BCBs was developed by Applequist in 1977, employing dichlorocarbenes as the carbene source.¹⁶ In 2019, Bennett^17a and Mykhailiuk^17b independently reported the carbene insertion into BCBs 1 to access difluoro-BCPs 2. Bennett utilized trimethylsilyl 2-(fluorosulfonyl)-2,2-difluoro acetate (TFDA) with NaF, while Mykhailiuk employed CF₃TMS with NaI as the difluorocarbene sources (Scheme 2a). In both cases, difluorocarbenes 3 generated in situ react with BCBs to form intermediate 4, which subsequently adds at the benzylic position of the BCB to furnish the difluoro-BCP derivatives 2. Later, Mykhailiuk's group developed a scalable method for monofluoro-substituted BCPs via bromofluorocarbene (:CFBr) addition to BCBs, followed by dehalogenation with RANEY® Ni.^17c More recently, Tan's group introduced an energy-transfer approach using diazo compounds 5 as the carbene sources (Scheme 2b).^18a Mechanistically, the reaction begins with triplet energy transfer to generate the triplet carbene species 7 (T₁) from 5, which subsequently adds to the BCB to form a biradical intermediate. Radical recombination of this species then furnishes the desired BCP products 6. Additionally, enantioselective strategies for BCP synthesis have also been established.^18b

Scheme 2 Synthesis of BCPs via carbene insertion into BCBs.

2.2. Bicyclo[2.1.1]hexanes (BCHs)

Another class of important bicyclic scaffolds accessible from BCBs are BCHs, typically constructed via (3+2) annulation with diverse coupling partners. These strain-release (3+2) annulations, also termed [2π+2σ] cycloadditions, represent one of the most widely studied transformations of BCBs. These annulations typically construct bicyclohexanes and hetero-bicyclohexanes, which could be potential bioisosteres of benzene rings.

In 2022, Glorius^19a and Brown^19b independently reported the energy-transfer-mediated [2π+2σ] cycloadditions of BCBs with alkenes, employing coumarin 8 and styrene 10 derivatives, respectively, but proceeding through distinct mechanisms. In Glorius's approach, the photoexcitation of coumarin generates an excited species that adds to the BCB to form a biradical intermediate, which undergoes radical recombination to yield the BCH products 9 (Scheme 3a). In contrast, Brown's method involves initial sensitization of the BCB itself, which then reacts with the alkene to furnish the corresponding BCHs 11 (Scheme 3b). In parallel, Procter's group reported a SmI₂-catalyzed insertion of electron-deficient alkenes into BCBs, where SmI₂ catalyzed the activation of BCBs.^19c Later, Wang's group introduced a pyridine boryl radical-mediated activation of BCBs, enabling subsequent [2π+2σ] cycloadditions with alkenes 12 including acrylates and styrenes to afford BCHs 13 (Scheme 3c).^19d

Scheme 3 (3+2) annulation of BCBs under photocatalysis and pyridine-boryl radical catalysis.

Moreover, heteroatom-substituted bridged scaffolds often show improved solubility, stability, and reduced lipophilicity, but their synthesis remains challenging due to limited general methods, prompting the search for efficient strategies.^8,20 In this context, Glorius and co-workers in 2022 reported an Ir-photocatalyzed (3+2) annulation of BCBs with α-keto esters 14 (Scheme 4).²¹ Mechanistically, the reaction proceeds via sensitization of the keto-ester, followed by trapping with BCBs and formation of oxa-BCH 16. Subsequently, aryl migration from 16 ultimately furnished the rearranged oxa-BCH products 15.

Scheme 4 (3+2) annulation of BCBs with α-keto esters under energy transfer catalysis.

The transformations described above primarily rely on photocatalysis to initiate the reaction and trigger BCB strain-release reactivity. However, more recent studies have demonstrated that Lewis acids can also serve as efficient activators of BCBs. The coordination of ester or other electron-withdrawing substituents on BCBs under Lewis acid catalysis facilitates the polarization of the strained central C–C bond, enabling its cleavage and subsequent engagement in diverse annulation pathways. In 2022, the Leitch group^22a pioneered the Lewis acid-catalyzed (3+2) annulation of BCBs with imines 17, enabling the divergent synthesis of aza-BCHs 18 or functionalized cyclobutenes 19 (Scheme 5a).

Scheme 5 Synthesis of hetero-BCHs via (3+2) annulation of BCBs.

Mechanistically, the reaction proceeds with the formation of ester enolate in the presence of a Lewis acid, and subsequent addition to the imine gives intermediate 20. This key intermediate 20 then undergoes a ring-closing nucleophilic attack by nitrogen onto the carbocation when an aryl group is present at imine N to provide access to aza-BCHs 18, or an intramolecular E1 elimination in the presence of an alkyl group to facilitate the formation of cyclobutene derivatives 19. Recently, Feng's group developed an enantioselective zinc-catalyzed variant of this reaction, employing a bis(oxazolinylphenyl)amide (BOPA) ligand to achieve excellent enantioselectivity. Mechanistically the reaction proceeds through a different pathway.^22b

Since then, the synthesis of hetero-BCHs has gained tremendous attention and has made significant progress. Glorius and co-workers made a significant advance by developing a Lewis acid-catalyzed (3+2) annulation of aldehydes 21 with BCBs, which efficiently delivered oxa-BCH frameworks 22 (Scheme 5b, left). Moreover, epoxides can also be utilized as substrates, which in situ generate aldehydes and undergo annulation reaction. The reaction proceeds under mild conditions and shows a broad substrate scope.^23a Later, Studer's group demonstrated the Lewis acid-catalyzed (3+2) annulation of ketenes 23 with BCBs to facilitate the formation of substituted bicyclo[2.1.1]hexane-2-ones 24 (Scheme 5b, right).²⁴ In both aldehyde and ketene annulations, the mechanism involves initial enolate generation from BCBs, followed by addition to the electrophilic coupling partner to furnish the BCH frameworks. Furthermore, transition metal-catalyzed (3+2) annulations of aldehydes and ketones with BCBs have also been developed, employing vinyl-substituted BCBs as substrates.^23b In these reactions, the BCB is activated by a Pd catalyst to generate a π-allyl–Pd complex, which subsequently reacts with aldehydes, followed by catalyst regeneration. Notably, the process can also be performed in an enantioselective fashion, affording the chiral products.

Building on these developments, Deng and Feng groups independently reported the (3+2) annulations of indoles 25 with BCBs via dearomatization of the indole core, further extending the scope of the Lewis acid-catalyzed (3+2) annulation strategy (Scheme 5c).²⁵ Interestingly, these two studies delivered regioisomeric products 26 and 27. Beyond indoles, other coupling partners such as quinoxalinones, silyl enol ethers, dioxopyrrolidines, and oxa(aza)dienes have also been shown to participate in Lewis acid-catalyzed (3+2) annulations with BCBs, providing diverse BCH scaffolds.²⁶

Furthermore, enantioselective (3+2) annulations have also been reported. In 2023, the Bach group reported the first enantioselective [2π+2σ] cycloaddition of quinolones 28 with BCBs, enabled by an oxazole annulated tetraline-derived chiral reagent A for the synthesis of enantioenriched BCH frameworks 29 (Scheme 6). Mechanistic studies revealed that a dual hydrogen-bonding interaction between quinolone 28 and the chiral template governs the high enantioselectivity. The coordination of the quinolone with the chiral complex effectively shields one enantiotopic face, directing the selective addition to the BCB, followed by C–C bond formation to furnish products 29 with high enantioselectivities.²⁷ This strategy paved the way for future enantioselective transformations involving BCBs.

Scheme 6 Asymmetric (3+2) annulation of BCBs with quinolones.

Recently, Jiang and co-workers disclosed an enantioselective [2π+2σ] cycloaddition of BCBs with vinylazaarenes 30 under photoredox catalysis (Scheme 7).²⁸ The process utilizes a polycyclic aromatic hydrocarbon (PAH)-containing chiral phosphoric acid as a bifunctional photosensitizer, allowing for efficient activation and stereocontrol. The reaction displays broad substrate tolerance, accommodating diverse vinylazaarenes and BCB derivatives. Mechanistic studies, supported by DFT calculations, suggest that CPA activation of the BCB promotes diradical 32 formation, followed by water-assisted radical addition to the alkene, generating intermediate 33, and subsequent C–C bond formation to generate 34, ultimately delivering the enantioenriched (3+2) annulated products 31. Subsequently, enantioselective annulation reactions have been further extended to vinyl azides, α,β-unsaturated carbonyls and naphthalenes predominantly under Lewis acid catalysis, underscoring the growing significance of enantioselective strategies in this field.²⁹

Scheme 7 Asymmetric (3+2) annulation of BCBs with vinylazaarenes.

Thus far, the reactions discussed have focused on the synthesis of bicyclohexanes via annulation of BCBs with C=C, C=N, or C=O double bonds, while the use of C≡C triple bonds remained unexplored. In this context, Chen and Zhou^30a and our group^30b independently demonstrated the Lewis acid-catalyzed (3+2) annulation of ynamides 35 with BCBs, where the C≡C triple bond of ynamide participates in the BCH 36 formation. Mechanistic experiments suggest that the reaction initiates with the coordination of BCBs with Lewis acid, followed by the nitrogen lone pair-assisted nucleophilic attack of the alkynyl moiety of the ynamide on the activated BCB to form intermediate 37. Subsequently, intermediate 37 undergoes intramolecular addition of the keto enolate to the keteniminium moiety, which affords amino-bicyclo[2.1.1]hexenes (Scheme 8).

Scheme 8 Lewis-acid catalyzed (3+2) annulation of BCBs with ynamides.

Although significant progress has been made in activating BCBs via photocatalysis and Lewis acid catalysis, their activation using HFIP has not been studied. Recently, Wang and Zhu's group developed an HFIP-mediated (3+2) annulation of BCBs with para-quinone methides 38 to synthesize spiro-BCHs 39. In this strategy, HFIP serves both as a hydrogen-bond donor to activate the BCB and as the solvent, eliminating the need for any additional catalyst for activation (Scheme 9).³¹ In this context, it is important to note that, recently, Werz's group realized the (3+2) annulation of thio-ketones with BCBs to afford thia-BCHs without any catalyst for the activation of BCBs.³²

Scheme 9 HFIP-mediated synthesis of spiro-BCHs using p-QMs.

2.3. Bicyclo[3.1.1]heptanes (BCHeps)

Along with (3+2) annulation of BCBs for the direct access to bicyclo[2.1.1]hexanes, methods for the construction of bicyclo[3.1.1]heptane (BCHep) frameworks using BCBs under photocatalysis and Lewis acid catalysis have also been developed. These scaffolds are typically obtained from BCBs via (3+3) annulation reactions and serve as valuable bioisosteres of meta-substituted benzene rings. In 2022, Molander and coworkers disclosed the first photoinduced [3σ+2σ] cycloaddition of BCBs with aminocyclopropanes 40 for the construction of amino-substituted BCHeps 41 (Scheme 10). The reaction utilizes an Ir photocatalyst that matches the oxidation potential of cyclopropyl amines. The reaction operates under mild conditions and shows broad substrate scope. Mechanistically, photoexcitation of the Ir catalyst initiates SET to cyclopropylamine 40, generating a radical cation species 42 followed by ring-opening via β-scission to provide radical cation 43 that subsequently adds to BCB, forming a benzylic radical intermediate 44. Cyclization of this radical furnishes a radical cation 45, which is then reduced either by Ir(II) in the photoredox cycle or by cyclopropylamine, with the latter pathway considered more plausible.³³

Scheme 10 Ir-photocatalyzed synthesis of BCHeps using amino-cyclopropanes.

Subsequently, Li's group developed a pyridine boryl radical strategy to access BCHeps 47via (3+3) annulation of BCBs with cyclopropyl ketones 46. The reaction, catalyzed by B₂pin₂ and 3-pentyl isonicotinate, proceeds under mild conditions and demonstrates broad substrate scope. DFT studies provided mechanistic insights, demonstrating that the process begins with the formation of PyBpin radical 48, followed by pyridine-to-ketone radical transfer generating the cyclopropylmethyl radical, which undergoes a C–C bond-cleavage to form the homoallyl radical 49. Subsequent C–C bond cleavage upon reaction with BCB 1 generates the radical intermediate 50, via strain release. Ring-closure then produces the radical intermediate 51, which undergoes a pyridine-mediated stepwise boronyl transfer to deliver the BCHep scaffolds 47 (Scheme 11).³⁴

Scheme 11 Pyridine boryl radical-catalyzed synthesis of amino-substituted BCHeps.

Glorius' group later reported a silver-catalyzed (3+3) annulation of BCBs with isocyanides 52, enabling the synthesis of polysubstituted aza-BCHeps 53. The reaction was proposed to proceed through a formal (3+3)/(3+2)/retro-(3+2) cycloaddition sequence (Scheme 12). Mechanistic studies suggest that the reaction begins with the formation of a silver–isocyanide complex 55 from 52 and base, which undergoes (3+3) annulation with BCB to generate the key intermediate 57via the formation of 56. Protonolysis of 57 affords intermediate 54 while regenerating Ag₂CO₃. Intermediate 54 then reacts with another molecule of isocyanide via (3+2) annulation to form intermediate 58, which subsequently releases AgCN via a retro-(3+2) process to deliver the aza-BCHep derivatives 53.³⁵

Scheme 12 Ag-catalyzed construction of aza-BCHeps utilizing isocyanides.

Aldimine esters are well known as three atom synthons for the (3+3) annulation reactions. In this context, Li and co-workers reported an enantioselective (3+3) annulation of aldimine esters 59 with BCBs, enabling the synthesis of aza-BCHeps 60 bearing multiple stereocenters, including two quaternary centers, with excellent stereocontrol under copper catalysis (Scheme 13a).³⁶ These scaffolds, serving as potential bioisosteres of polysubstituted pyridines, were obtained across a broad substrate scope with high tolerance to various functional groups. Control experiments provided mechanistic insight, suggesting that the reaction begins with the formation of a chiral nucleophilic Cu-azomethine ylide 61 from the aldimine ester via deprotonation. This intermediate undergoes a facially selective nucleophilic attack on the electrophilic BCB, generating a key intermediate 62, which subsequently undergoes cyclization to furnish enantioenriched aza-BCHeps 60 while regenerating the catalyst. Zheng and co-workers later discovered that vinyl azides 63 are effective substrates for (3+3) annulation with BCBs, showing catalyst-controlled divergent reactivity (Scheme 13b).³⁷ When a Ti catalyst was employed, the reaction proceeded through a radical pathway via intermediate 66 to furnish 2-aza-BCHeps 64, whereas with a Sc catalyst, it followed an ionic pathway which proceeds via67 with elimination of N₂ to deliver 3-aza-BCHeps 65.

Scheme 13 Synthesis of aza-BCHeps via (3+3) annulation of BCBs.

So far, the discussion has focused on (3+3) annulations involving three-atom partners; however, an alternative strategy for accessing BCHeps employs 1,3-dipoles via the 1,3-dipolar cycloaddition reactions. In this context, Chen, Zhou, and co-workers reported the first example of such a transformation (Scheme 14a left),^38a using nitrones 68 as dipoles with BCBs under Lewis acid catalysis to generate heteroatom-substituted BCHeps 69. Building on this, our group demonstrated the use of isatogens 70, a class of cyclic nitrones, to construct aza-oxa-BCHeps 71, thereby broadening the scope of dipolar partners (Scheme 14a right).^38b In both cases, the mechanism proceeds via nucleophilic addition of dipoles to the Lewis acid-activated BCBs, followed by intramolecular cyclization. Furthermore, an enantioselective 1,3-dipolar cycloaddition of BCBs with nitrones under Lewis acid catalysis has also been reported.^38c These works underscored the usage of 1,3-dipoles in BCB chemistry, inspiring a series of subsequent studies that expanded the scope of dipolar cycloaddition reactions involving BCBs.

Scheme 14 Dipolar cycloaddition of BCBs via (3+3) annulation.

Subsequently, Feng and co-workers reported a divergent strategy for the synthesis of thia-bicyclic scaffolds through the cycloaddition of pyridinium-derived zwitterionic thiolates with BCBs (Scheme 14b).³⁹ Pyridine-derived thiolates 72 led to (3+3) annulation products 74, whereas isoquinoline-derived thiolates 73 favoured the formation of (5+3) annulated frameworks 75. The process involves nucleophilic attack of the thiolate on the BCB, followed by a second addition dictated by the pyridine or quinoline ring. Preliminary studies of an asymmetric variant of (5+3) annulation were also demonstrated. Subsequently, other dipoles like isoquinolium methylides and azomethine imines were illustrated for the dipolar cycloaddition onto BCBs.⁴⁰ Thus far, the focus has been on preformed dipoles; however, in situ generated dipoles have also been utilized for constructing heteroatom-substituted bicycloheptanes. In this context, Feng and co-workers reported the use of diaziridines 76, which generate dipole 78in situ, enabling a (3+3) annulation with BCBs to furnish aza-BCHeps 77 (Scheme 14c).^41a Similarly, hydrazonyl chlorides can generate nitrile imines in situ, which subsequently undergo dipolar cycloaddition with BCBs.^41b

Indolyl alcohols are well-recognized three-component coupling partners. Recently, both the Studer group and our group have independently employed indolyl alcohols with BCBs to construct tetracyclic indole frameworks.⁴² The Studer group utilized N–H indolyl alcohols 79 under chiral phosphoric acid (CPA) catalysis (Scheme 15a), whereas our group employed N-substituted indolyl alcohols 81 using HFIP as an activator (Scheme 15b). Mechanistically, both reactions follow a similar pathway, initiating with the activation of BCB to generate an ester enolate 84, along with the formation of indolenium ions 83 from the indolyl alcohol under CPA or HFIP conditions followed by ester enolate addition to indolenium ions to form intermediate 85, which upon C3 addition from indole generates intermediate 86 or 87. The key mechanistic distinction arises at the spirocyclic intermediate stage. In Studer's case, free N–H spiro intermediate 87 undergoes further activation by the CPA, followed by migration and aromatization to yield the BCHep product 80. In our case, the N-substituted spiro intermediate 86 is intrinsically activated due to its instability, obviating the need for an additional activation and directly undergoing migration and aromatization to furnish the tetracyclic indole products 82.

Scheme 15 Synthesis of tetracyclic indoles via BCB (3+3) annulation.

2.4. Bicyclo[4.1.1]octanes (BCOs)

The previous sections focused on the annulation of BCBs towards the synthesis of BCHs and BCHeps. While (3+2) and (3+3) annulations are well established in BCB chemistry, the construction of bicyclo[4.1.1]octanes (BCOs) through (4+3) annulation has remained relatively unexplored. The first example of such a transformation was reported by the Waser group,⁴³ who employed silyl dienol ethers 88 under Lewis acid catalysis (Scheme 16). The resulting (4+3) adducts 89 underwent subsequent acidic hydrolysis to furnish BCO diketones 90. The reaction features a broad substrate scope and tolerates diverse substituents. Mechanistically, the reaction proceeds via the Lewis acid activation of BCB, followed by the nucleophilic attack of the enol moiety of the diene, generating intermediate 91. Intermediate 91 then undergoes cyclization via conjugate addition of enolate to the enone, affording silyl enol ether 89, which, upon acidic hydrolysis, yields the desired BCO products 90. Overall, this (4+3) annulation strategy has introduced a new entry point into the chemical space of BCOs, paving the way for further developments.

Scheme 16 Synthesis of BCOs via (4+3) annulation of silyl enol ethers with BCBs.

Meanwhile, our group reported a Lewis acid-catalyzed (4+3) annulation of BCBs with para-quinone methides (p-QMs) 92 to construct BCOs (Scheme 17a).⁴⁴ Interestingly, instead of yielding the expected addition–cyclization product 94, the reaction underwent a rearrangement to form an unusual (4+3) annulated scaffold 93. To gain mechanistic insights, several control experiments were carried out. The proposed pathway involves an initial 1,6-addition of the BCB ester enolate to the p-QM generating intermediate 95, followed by selective C2-addition from the phenolic ring. Subsequent C–C bond cleavage of intermediate 96 generates the quinone intermediate 97, which undergoes an intramolecular 1,6-addition of the phenoxide to furnish the major product 93. Alternatively, direct trapping of the cyclobutyl cation 95 by the phenolic oxygen accounts for the formation of the minor regioisomer 94.

Scheme 17 Lewis acid-catalyzed (4+3) annulation of BCBs.

Benzylidene thiones have also been explored as coupling partners for the (4+3) annulation with BCBs. Feng and co-workers developed a Lewis acid-governed switchable reactivity using thiones 98 with BCBs.^45a Using Zn(OTf)₂ as the catalyst, the reaction proceeded through a stepwise addition–cyclization sequence to furnish the (4+3) annulated BCO product 99 (Scheme 17b left), whereas Sc(OTf)₃ promoted a concerted pathway leading to the (3+2) annulated BCH scaffold 100 (Scheme 17b right). Benzylidene thione 98 exists in its dimeric form 101, which dissociates to monomer 98 under Lewis acidic conditions. Mechanistic studies, supported by control experiments and DFT calculations, provided insights into the origin of this divergent reactivity. More recently, the same group reported an enantioselective (4+3) annulation of enaminothiones with BCBs under Lewis acid catalysis, enabling efficient access to thia-BCOs.^45b Remarkably, the reaction outcome was highly dependent on the choice of Lewis acid, where an alternative catalyst redirected the pathway to form thia-BCHs instead.

Beyond Lewis acid catalysis, (4+3) annulations have also been realized under photochemical and transition metal-catalyzed conditions. Feng's group has employed a transition metal-catalyzed strategy for the (4+3) annulation of BCBs with 2-alkylidenetrimet-hylene carbonates 102 (ADTMCs), enabling the synthesis of oxa-BCOs 103. In contrast to Lewis acid-mediated systems, where BCB activation is common, here the ADTMC is selectively activated by Pd catalysis. The process begins with the oxidative addition of ADTMC to Pd, forming a π-allylpalladium carbonate intermediate 104, which subsequently undergoes decarboxylation to yield intermediate 105. The oxygen-centered anion in the resulting zwitterionic allylpalladium 105 promotes nucleophilic ring-opening of the BCB, leading to intermediate 106. Finally, intramolecular allylation furnishes the oxa-BCO scaffold 103 while regenerating the Pd catalyst (Scheme 18).⁴⁶

Scheme 18 Transition-metal catalyzed (4+3) annulation of BCBs.

Subsequently, Guo and co-workers developed a Ru-photocatalyzed defluorinative (4+3) annulation of BCBs with gem-difluoroalkenes 107, providing access to fluorine-containing bicyclo[4.1.1]octenes 108 (Scheme 19).⁴⁷ The reaction features mild conditions, excellent functional group tolerance and good to excellent yields. The reaction proceeds via an initial single-electron transfer (SET) from the excited Ru(II)* species to the difluoroalkene to generate intermediate 109, which then undergoes regioselective addition to the BCB, affording intermediate 110. A second SET event occurs to facilitate the formation of intermediate 111, and finally β-fluorine elimination affords the desired octene product 108.

Scheme 19 Synthesis of fluoro substituted bicyclo[4.1.1]octenes via energy transfer catalysis.

2.5. Higher order annulations

The formal cycloaddition of BCBs with two-, three-, or four-atom partners has been extensively explored for the construction of bicyclohexanes, bicycloheptanes, or bicyclooctanes; however, applications to the synthesis of higher order bridged carbocycles have remained limited. Usually, the bridged scaffolds are accessed through the peripheral cyclization of substrates with BCBs, but the insertion of BCBs leading to bicyclic frameworks has not been realized.

In 2023, the Glorius group disclosed the first example of BCB insertion into thiophenes through a photocatalytic dearomative ring-expansion strategy, enabling the construction of sulfur-containing bridged motifs (Scheme 20).⁴⁸ Both thiophenes 112 and benzothiophenes 113 participated in the reaction, delivering products with reversed regioselectivities. The reaction tolerates a variety of (benzo)thiophene derivatives and BCBs, and the generated cyclobutyl-incorporated scaffold can be further functionalized. Mechanistic insights, supported by control experiments and DFT studies, elucidated the reaction pathway. In the case of thiophene, the reaction proceeds with photocatalyst-assisted oxidation of thiophene to a radical cation intermediate 116, followed by BCB addition at the C2 position. Subsequent C–S bond formation furnishes intermediate 117, which upon reduction gives intermediate 118. Finally, C–S bond cleavage delivers the desired BCB-inserted product 114. For benzothiophenes, the reaction proceeds through BCB addition at the sulfur center of the radical cation heteroarene intermediate 119, followed by C–C bond formation at the C2 position. Subsequent reduction of intermediate 120 generates 121, which then undergoes C–S bond cleavage to furnish the BCB-inserted product 115, displaying regioselectivity opposite to that observed in thiophenes.

Scheme 20 First (5+3) annulation of thiophenes via insertion of BCBs.

Another example of higher order bicyclo[n.1.1]alkane (n > 4) synthesis involves the utilization of imidazolidines and hexahydropyrimidines 122 (Scheme 21). In 2024, Peng and co-workers developed a B(C₆F₅)₃-catalyzed strategy enabling both (5+3) and (6+3) annulations of BCBs.⁴⁹ Specifically, imidazolidines undergo (5+3) annulation to furnish 2,5-diazabicyclo [5.1.1]nonanes, while hexahydropyrimidines participate in (6+3) annulation to construct 2,6-diazabicyclo [6.1.1]decane scaffolds. Mechanistic studies suggest that the reaction begins with the activation of the BCB by the B(C₆F₅)₃ catalyst. Then, nucleophilic addition of the imidazolidine or hexahydropyrimidine onto BCB forms intermediate 124, which undergoes ring-opening to give a zwitterionic iminium species 125. Finally, intramolecular cyclization delivers the corresponding annulated products 123, with regeneration of the B(C₆F₅)₃ catalyst.

Scheme 21 Synthesis of higher cycloaddition adducts under Lewis-acid catalysis.

Another notable example of higher order cycloaddition of BCBs involves their reaction with azaheptafulvenes. Recently, the Li group reported an FeCl₃-promoted (8+3) annulation between BCBs and azaheptafulvenes 126, affording cycloheptatriene-fused 2-azabicyclo[3.1.1]heptanes 127 (Scheme 22).^50a This transformation exhibited broad substrate scope, tolerating a wide range of BCBs and azaheptafulvenes. Furthermore, the synthetic utility of the product was demonstrated through various derivatizations, including late-stage modifications of drug molecules, underscoring their practical relevance. DFT calculations provided mechanistic insights, suggesting that the process begins with nucleophilic addition of the azaheptafulvene 126 to the activated BCB, followed by enolate addition to generate an enolate intermediate 128. This intermediate then undergoes annulation and catalyst regeneration, delivering the desired cycloheptatriene-fused bicyclic product 127. Subsequently, the Peng group disclosed a related (8+3) annulation of BCBs with a variety of troponoid derivatives, including aza-, oxa-, and thia-analogues, under Ni(OTf)₂ catalysis.^50b This study further highlighted the broad applicability and versatility of the method in constructing diverse heteroatom-containing bridged frameworks.

Scheme 22 First (8+3) annulation of BCBs with azaheptafulvenes.

3. Synthesis of cyclobutane frameworks

3.1. Importance of the cyclobutane core

The synthesis of cyclobutanes is of great importance, as the unique and rigid three-dimensional structure of the cyclobutane ring plays a crucial role in the design of natural products and drug candidates.⁵¹ Incorporation of the cyclobutane motif into biologically active molecules enhances the sp³ character, which can, in turn, improve key drug-like properties such as metabolic stability, potency, and solubility. For example, linsitinib,⁵² a well-known drug, which contains a cyclobutane framework, serves as an anti-cancer agent (Scheme 23). Also, MK-0916, a selective 11β-HSD1 inhibitor⁵³ and pestalotiopsin,⁵⁴ an immunosuppressive agent, has a cyclobutane core integrated in the skeleton, which is responsible for their observed activities. Therefore, the synthesis of cyclobutanes, particularly multisubstituted variants, holds significant value in drug discovery and innovative routes to natural products.

Scheme 23 Cyclobutane core in drug candidates.

3.2. Different strategies towards synthesis of cyclobutanes

The highly strained central C–C bond in BCBs often renders them a prime candidate for 1,3-difunctionalization. Wiberg, Gaoni and others have done the initial studies on reactivity of BCBs utilizing the strained C–C bond.⁵⁵ These studies primarily focused on the structural conformation and mechanistic aspects. In 1988, Gaoni and co-workers have shown the addition of hydrazoic acid to BCBs to obtain cyclobutane containing amino acid residues.⁵⁶ Also, Gaoni and co-workers studied the addition of organo-cuprate reagent to BCBs in an endo-selective manner.⁵⁷ These initial studies set the basis for the extensive exploration of the reactivity of BCBs. For example, in 2013, the Fox group reported an efficient approach for the synthesis of enantiomerically enriched cyclobutanes through the homoconjugate addition of organocuprates to bicyclo[1.1.0]butyl carboxylates, followed by enolate trapping with electrophiles.⁵⁸ Furthermore, different modes of reactivity utilizing BCBs for the synthesis of variously substituted cyclobutanes have been divided into sub-categories depending on the type of substitution in cyclobutene and are presented in the following section.

3.2.1. Amination and phosphination of bicyclo[1.1.0] butanes. In 2016, Baran and co-workers developed a strategy for the amination of strained rings, significantly broadening the synthetic accessibility of these frameworks and revitalizing organic chemist's interest in this field (Scheme 24).⁵⁹ In this work, they were able to overcome the issues associated with the previously known methods⁶⁰ including use of high temperature, requirement of excess aminating agents and limited scope. It was shown that an electronically orchestrated sulfonyl bicyclo [1.1.0] butane 129 can be used successfully to “cyclobutylate” amines under mild conditions, which after further reduction led to formation of cyclobutyl amine derivative 130. It was also demonstrated that an in situ generated aza-bicyclo [1.1.0] butane 131 can undergo difunctionalization leading to formation of multi substituted azetidine derivative 132 under mild conditions.

Scheme 24 Baran's strain-release driven amination strategy.

Later in 2016, Wipf's group has utilized, for the first time, phosphorous based nucleophiles for the strain-release driven hydrophosphination of BCBs (Scheme 25).⁶¹ In this strategy, phosphino-boranes 134 were added to the nitrile BCBs 133 under basic conditions to synthesize cyclobutylated phosphino-borane derivative 135 under mild conditions. Later, nitrile cyclobutane derivative 135 was shown to reduce to the corresponding aldehyde cyclobutane 136. Furthermore, 136 was reduced to give the corresponding alcohol cyclobutane derivative. As a part of the application of the strategy, they have synthesized enantiomerically pure biaryl phosphinated cyclobutane derivative 137, which can be used as a ligand for the enantioselective reduction of activated double bonds with higher efficacy.

Scheme 25 Wipf's strain-release driven hydrophosphination strategy.

3.2.2. Synthesis of functionalized borylated cyclobutanes. Aggarwal's group reported the synthesis of bicyclo[1.1.0] butyl boronate species and their reactivity towards different electrophiles (Scheme 26).⁶² Reacting the in situ generated bicyclo[1.1.0] butyl lithium species 138 with a pinacol boronic ester led to the formation of bicyclo[1.1.0] butyl boronate 139. This boronate 139 can result in the carbofunctionalization of a strained C–C σ-bond via 1,2-boron to carbon shift followed by trapping with a suitable electrophile, generating borylated cyclobutanes 140. Using mechanistic studies, they showed that bulkier migrating groups and less reactive electrophiles undergo a concerted mechanism, affording the cis product with high diastereoselectivity. In contrast, smaller migrating groups and more reactive electrophiles can proceed through both concerted and stepwise pathways, resulting in reduced diastereoselectivity. Also, 140 can undergo various transformations around the installed boronate functional group, generating various classes of multi-substituted cyclobutane derivatives 141.

Scheme 26 Aggarwal's borylated cyclobutane synthesis via 1,3-difunctionalization of BCBs.

Later in 2021, Aggarwal's group developed a strain-release driven strategy for the synthesis of borylated cyclobutane and cyclopropane derivatives (Scheme 27).⁶³ In this study, it was shown that the nucleophile adds to the α-position of BCB-Bpin 142 unlike other BCBs that contain electron-withdrawing groups, where the nucleophile adds to the β-position. So, when 142 was treated with different oxygen, nitrogen and sulphur-based nucleophiles in the presence of base, the reaction furnished α,α-disubstituted borylated cyclobutane derivatives 143 in excellent yields under mild conditions. In the presence of base, the anion generated from the corresponding nucleophile can add to BCB-Bpin 142, leading to intermediate 143_Int. This led to the formation of the desired product 143via a transition state 143_TS, where a boron to carbon shift followed by protonation at the β-position took place. In the absence of base, especially with bulkier nitrogen-based nucleophiles, BCB-Bpin 142 undergoes protonation at the α-position, leading to the formation of stable cyclopropyl carbinyl cation intermediate 144_Int. This can be trapped by the generated aza-anion leading to the formation of trans-selective borylated cyclopropane derivative 144. In a related report, the same group has disclosed the trifluoro methylation of BCB-boronate complexes via homolytic cleavage of bridgehead bonds upon irradiation of blue LED light.⁶⁴

Scheme 27 Synthesis of borylated-cyclobutane and α-selective cyclopropane ring-opening.

3.2.3. Synthesis of functionalized cyclobutanes via homolytic approaches. In this connection, Lin and co-workers developed a Ti^III-catalyzed radical alkylation of BCBs with relatively unreactive tertiary alkyl chlorides.⁶⁵ In 2020, Jui's group developed a C–H cyclobutylation of anilines via the generation of α-amino radicals from N-methyl aniline and subsequent addition to BCBs.⁶⁶ Later in 2020, Ernouf's group developed a mild photoredox mediated decarboxylative Giese-type addition of C(sp³)-centered radicals generated from 145 to bicyclo[1.1.0] butane 146 for the synthesis of 1,3-disubstituted cyclobutanes 147 (Scheme 28).⁶⁷ Under their optimized conditions, they were able transfer a diverge range of α-amino and α-oxy radicals to BCBs along with some complex C(sp³)-centered radicals derived from dipeptides and drug molecules. Mechanistically, the reaction was initiated by SET between the photoexcited Ir^III catalyst and in situ generated Cs carboxylate 145_Int-I. This leads to the formation of α-carboxyl radical 145_Int-II, which undergoes decarboxylation to generate carbon centered radical 145_Int-III. This radical then adds to the highly strained BCB 146 across the C–C α-bond to furnish intermediate 147_Int-I. This radical intermediate undergoes reduction with highly reducing Ir^II to generate the corresponding anion intermediate 147_Int-II, which upon protonation leads to the formation of desired product 147.

Scheme 28 Ernouf's cyclobutylation of C(sp³)-centered radicals.

In 2020, Gryko and co-workers developed an umpolung strategy, which generates a carbon-centered radical from the 3-position of the sulfonyl BCB 148 using a vitamin B₁₂ based Co(I) catalyst upon irradiation with a blue LED (Scheme 29).⁶⁸ Utilizing this radical, they were able to develop different strategies. In one case, they were able to trap this radical with an activated olefin in a Giese-type addition to synthesize alkylated cyclobutanes 149. On the other hand, utilizing a Ni-based catalyst, this radical was used in cross-coupling reaction to install the aryl group at the 3-position of BCB to afford arylated cyclobutanes 150. The reaction proceeds via the generation of Co(III)-alkyl complex 148_Int-1 in the presence of super-electrophilic Co(I), which undergoes conjugate type addition to the C–C σ-bond of BCB 148. This under irradiation of blue light generates alkyl radical 148_Int-2, which can be subsequently trapped by different SOMOphiles to furnish either alkylated or arylated cyclobutanes.

Scheme 29 Gryko's polarity-reversal strategy.

In 2021, Studer and co-workers demonstrated that the silyl radical generated via the photoredox catalysis can be added to BCBs 151 to synthesize silylated cyclobutane derivatives 152 (Scheme 30).⁶⁹ Mechanistically, the reaction proceeds via the single electron transfer between photoexcited Ir^III catalyst and the silyl radical precursor, which in the presence of HFIP liberates a silyl radical. This radical adds to the BCB 151 to generate silyl-cyclobutane radical intermediate 151_Int-I. This radical intermediate 151_Int-I undergoes reduction with Ir^II to generate silyl-cyclobutane anion 151_Int-II, which after protonation forms the desired product 152.

Scheme 30 Studer's strain-release driven silyl radical addition.

3.2.4. Synthesis of functionalized cyclobutanes via heterolytic approaches. In 2023, our group disclosed a Lewis acid-catalyzed highly diastereoselective carbofunctionalization of BCB 154 with 2-naphthols 153 as a carbon nucleophile (Scheme 31).⁷⁰ DFT studies suggested that the origin of diastereoselectivity is due to the formation of a bicoordinated bismuth complex formed between BCB and 2-naphthol. A similar strategy was also developed by the Feng group, where they used substituted 2-naphthols using π-acid catalyst AgBF₄ to activate BCB.⁷¹

Scheme 31 Diastereoselective carbofunctionalization of BCB with 2-naphthols.

Subsequently, our group reported a formal ene reaction between thioindolinones and BCB, where BCB acts as an enophile for the synthesis of substituted cyclobutanes.⁷² As shown in Scheme 32, when the monosubstituted BCB 157 was used as an enophile, thioindolinone 156 undergoes a Sc(OTf)₃-catalyzed ene reaction to furnish 1,3-disubstituted cyclobutane derivative 158 with higher regio- and diastereoselectivities. On the other hand, when a disubstituted BCB 159 was used,⁷³ the reaction furnished tetrasubstituted cyclobutane derivative 160via a spirocyclic intermediate. The formation of 160 is the result of a formal C=S insertion of 156 into the BCB 159.

Scheme 32 Diastereoselective multisubstituted cyclobutane synthesis using thioindolinones.

Very recently, HFIP-mediated addition of hydroperoxide 162 to BCB 161 for the diastereoselective synthesis of peroxycyclobutane 163 has been developed by our group (Scheme 33).⁷⁴ The key to the formation of the cis-diastereomer of the product was due to formation of a six-membered transition state with the aid of HFIP, which is responsible for the smooth proton transfer.

Scheme 33 HFIP-mediated ring opening of BCB with hydroperoxide.

Very recently, Zhang's group has showcased a regiodivergent hydrophosphination of BCB for the synthesis of multisubstituted phosphinylated cyclobutane derivatives.⁷⁵ In this strategy, by tuning the reaction conditions, especially by changing the catalyst combination, synthesis of both the α- and β-phosphinylated cyclobutanes in a highly regio- and diastereoselective manner was possible. The phosphine derivative 165 undergoes a strain-release driven addition to BCB 164 under a combination of Cu-catalyst and Zn(OTf)₂ followed by oxidation to furnish α-phosphinylated cyclobutane 166. Notably, the reaction performed using a different Cu-catalyst resulted in the formation of β-phosphinylated cyclobutanes 167 after required oxidation in a diastereoselective manner. Independently, a similar regiodivergent and diastereoselective hydrophosphination of acyl bicyclobutanes was reported by Feng's group, where they showed the switchable α- and β′- hydrophosphination strategy (Scheme 34).⁷⁶

Scheme 34 Catalyst-controlled regiodivergent hydrophosphination of BCB.

4. Summary and outlook

BCBs continue to captivate the attention of synthetic chemists due to their exceptional strain energy and remarkable reactivity profile. Their unique structural attributes and extremely short and tensioned central σ-bonds make them ideal substrates for a diverse array of bond-forming processes. The recent surge in methodological advancements demonstrates how the release of strain in BCBs can be harnessed to drive synthetically valuable transformations such as cycloadditions, insertions, and molecular rearrangements, often under mild and operationally simple conditions. Beyond their utility as reactive intermediates, BCBs have also gained prominence as benzene bioisosteres, offering a distinct three-dimensional, saturated alternative with improved physicochemical properties for drug design.

This review summarizes the recent progress in this rapidly advancing field and aims to develop conceptually innovative catalytic strategies. Recent mechanistic investigations have significantly enhanced our understanding of the complex reaction pathways of BCBs, revealing the subtle interplay among electronic factors, substituent effects, and reaction conditions that dictate selectivity and product distribution. Collectively, the methodologies and concepts presented herein establish a strong foundation for continued innovation and exploration within the chemistry of strained-ring systems.

Although substantial progress has been achieved in the realm of strain-release-driven strategies, several aspects of BCB chemistry still warrant deeper investigation. For instance, multicomponent reactions involving BCBs remain underexplored, particularly those integrating other valuable systems. Furthermore, group-transfer reactions that exploit the intrinsic strain energy of BCBs could open new avenues for the synthesis of valuable molecular building blocks. While carbene insertion reactions have been extensively studied, the exploration of in situ-generated nitrene insertion could significantly expand the repertoire of bridged scaffolds with potential biological relevance. In addition, most reported transformations employ unsubstituted BCBs at the methylene positions, which limits opportunities for achieving high levels of enantioselectivity, an aspect that future studies could strategically address through substrate design or catalyst development. Molecular rearrangements involving BCB frameworks also represent a promising yet underdeveloped area for uncovering novel and synthetically useful pathways. Although notable progress has recently been made in enantioselective transformations of BCBs, further advancements, particularly those leveraging organocatalysts as chiral sources, are anticipated to enrich the field and expand its synthetic and mechanistic horizons.

Overall, the expanding chemistry of BCBs represents a compelling paradigm in modern synthesis, where strain energy is not a limitation but a strategic asset for innovation. Continued exploration of their reactivity and applications promises to uncover new dimensions in molecular design, enabling the creation of more diverse, functional, and three-dimensional chemical entities for future research and practical applications.

Author contributions

S. D. and A. T. B. proposed the topic of the review. S. D. and R.C.D. collected the literature and prepared the first draft of the manuscript with inputs from A. T. B. The manuscript was then edited by A. T. B. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

Financial support by the Science and Engineering Research Board (SERB), Government of India (File Number: SCP/2022/000837) is greatly acknowledged for our work in the area of BCB chemistry. S. D. and R. C. D. thank the Ministry of Education, Govt. of India, for the Prime Minister Research Fellowship (PMRF).

Notes and references

1. (a) R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem., 2014, 57, 5845; (b) A. Nilova, L.-C. Campeau, E. C. Sherer and D. R. Stuart, J. Med. Chem., 2020, 63, 13389.
2. L. Salonen, M. Ellermann and F. Diederich, Angew. Chem., Int. Ed., 2011, 50, 4808.
3. T. J. Ritchie and S. J. F. Macdonald, Drug Discovery Today, 2009, 14, 1011.
4. J. L. Bolton and T. Dunlap, Chem. Res. Toxicol., 2017, 30, 13.
5. (a) F. Lovering, J. Bikker and C. Humblet, J. Med. Chem., 2009, 52, 6752; (b) F. Lovering, MedChemComm, 2013, 4, 515.
6. (a) N. A. Meanwell, J. Med. Chem., 2011, 54, 2529; (b) T. J. Ritchie and S. J. F. Macdonald, Eur. J. Med. Chem., 2016, 124, 1057; (c) P. K. Mykhailiuk, Org. Biomol. Chem., 2019, 17, 2839.
7. A. F. Stepan, C. Subramanyam, I. V. Efemov, J. K. Dutra, T. J. O'Sullivan, K. J. DiRico, W. S. McDonald, A. Won, P. H. Dorff, C. E. Nolan, S. L. Becker, L. R. Pustilnik, D. R. Riddell, G. W. Kauffman, B. L. Kormos, L. Zhang, Y. Lu, S. H. Capetta, M. E. Green, K. Karki, E. Sibley, K. P. Atchison, A. J. Hallgren, C. E. Oborski, A. E. Robshaw, B. Sneed and C. J. O'Donnell, J. Med. Chem., 2012, 55, 3414.
8. A. Denisenko, P. Garbuz, N. M. Voloshchuk, Y. Holota, G. Al-Maali, P. Borysko and P. K. Mykhailiuk, Nat. Chem., 2023, 15, 1155.
9. (a) J. A. Milligan and P. Wipf, Nat. Chem., 2016, 8, 296; (b) A. Fawcett, Pure Appl. Chem., 2020, 92, 751; (c) J. Turkowska, J. Durkaab and D. Gryko, Chem. Commun., 2020, 56, 5718; (d) M. A. A. Walczak, T. Krainz and P. Wipf, Acc. Chem. Res., 2015, 48, 1149.
10. (a) C. B. Kelly, J. A. Milligan, L. J. Tilley and T. M. Sodano, Chem. Sci., 2022, 13, 11721; (b) M. Golfmann and J. C. L. Walker, Commun. Chem., 2023, 6, 9; (c) Q.-Q. Hu, J. Chen, Y. Yang, H. Yang and L. Zhou, Tetrahedron Chem., 2024, 9, 100070; (d) X. Liu, J. He, K. Lin, X. Wang and H. Cao, Org. Chem. Front., 2024, 11, 6942; (e) Y. Koo, J. Jeong and S. Hong, ACS Catal., 2025, 15, 8078; (f) Y. Xiao, L. Tang, X.-C. Yang, N.-Y. Wang, J. Zhang, W.-P. Deng and J.-J. Feng, CCS Chem., 2025, 7, 1903; (g) X.-C. Yang, J.-J. Wang, Y. Xiao and J.-J. Feng, Angew. Chem., Int. Ed., 2025, 65, e202505803.
11. (a) A. Baeyer, Ber. Dtsch. Chem. Ges., 1885, 18, 2269; (b) K. B. Wiberg, Angew. Chem., Int. Ed. Engl., 1986, 25, 312.
12. (a) A. M. Dilmaç, E. Spuling, A. de Meijere and S. Bräse, Angew. Chem., Int. Ed., 2017, 56, 5684; (b) J. Kanazawa and M. Uchiyama, Synlett, 2019, 1; (c) X. Ma and L. Nhat Pham, Asian J. Org. Chem., 2020, 9, 8 ; for a recent work, see: ; (d) G. A. Kadam, S. Midya, V. Levchenko, V. Sham, P. K. Mykhailiuk and D. P. Hari, J. Am. Chem. Soc., 2026, 148, 388.
13. (a) S. Meiboom and L. C. Snyder, Acc. Chem. Res., 1971, 4, 81; (b) P. G. Gassman, M. L. Greenlee, D. A. Dixon, S. Richsmeier and J. Z. Gougoutas, J. Am. Chem. Soc., 1983, 105, 5865.
14. (a) R. Whitman and J. F. Chiang, J. Am. Chem. Soc., 1972, 94, 1126; (b) I. Alkorta and J. Elguero, Tetrahedron, 1997, 53, 9741; (c) M. Pomerantz and E. W. Abrahamson, J. Am. Chem. Soc., 1966, 88, 3970.
15. M. A. M. Subbaiah and N. A. Meanwell, J. Med. Chem., 2021, 64, 14046.
16. D. E. Applequist and J. W. Wheeler, Tetrahedron Lett., 1977, 18, 3411.
17. (a) X. Ma, D. L. Sloman, Y. Han and D. J. Bennett, Org. Lett., 2019, 21, 7199; (b) R. M. Bycheck, V. Hutskalova, Y. P. Bas, O. A. Zaporozhets, S. Zozulya, V. V. Levterov and P. K. Mykhailiuk, J. Org. Chem, 2019, 84, 15106; (c) R. Bychek and P. K. Mykhailiuk, Angew. Chem., Int. Ed., 2022, 61, e202205103.
18. (a) J.-T. Che, H.-B. Zhang, W.-Y. Ding, S.-H. Xiang and B. Tan, J. Am. Chem. Soc., 2025, 147, 33879; (b) J.-T. Che, W.-Y. Ding, H.-B. Zhang, Y.-B. Wang, S.-H. Xiang and B. Tan, Nat. Chem., 2025, 17, 393.
19. (a) R. Kleinmans, T. Pinkert, S. Dutta, T. O. Paulisch, H. Keum, C. G. Daniliuc and F. Glorius, Nature, 2022, 605, 477; (b) R. Guo, Y.-C. Chang, L. Herter, C. Salome, S. E. Braley, T. C. Fessard and M. K. Brown, J. Am. Chem. Soc., 2022, 144, 7988; (c) S. Agasti, F. Beltran, E. Pye, N. Kaltsoyannis, G. E. M. Crisenza and D. J. Procter, Nat. Chem., 2023, 15, 535; (d) Y. Liu, S. Lin, Y. Li, J.-H. Xue, Q. Li and H. Wang, ACS Catal., 2023, 13, 5096.
20. V. V. Levterov, Y. Panasyuk, V. O. Pivnytska and P. K. Mykhailiuk, Angew. Chem., Int. Ed., 2020, 59, 7161.
21. Y. Liang, R. Kleinmans, C. G. Daniliuc and F. Glorius, J. Am. Chem. Soc., 2022, 144, 20207.
22. (a) K. Dhake, K. J. Woelk, J. Becica, A. Un, S. E. Jenny and D. C. Leitch, Angew. Chem., Int. Ed., 2022, 61, e202204719; (b) F. Wu, W.-B. Wu, Y. Xiao, Z. Li, L. Tang, H.-X. He, X.-C. Yang, J.-J. Wang, Y. Cai, T.-T. Xu, J.-H. Tao, G. Wang and J.-J. Feng, Angew. Chem., Int. Ed., 2024, 63, e202406548.
23. (a) Y. Liang, F. Paulus, C. G. Daniliuc and F. Glorius, Angew. Chem., Int. Ed., 2023, 62, e202305043; (b) T. Qin, M. He and W. Zi, Nat. Synth., 2024, 4, 124.
24. N. Radhoff, G. C. Daniliuc and A. Studer, Angew. Chem., Int. Ed., 2023, 62, e202304771.
25. (a) D. Ni, S. Hu, X. Tan, Y. Yu, Z. Li and L. Deng, Angew. Chem., Int. Ed., 2023, 62, e202308606; (b) L. Tang, Y. Xiao, F. Wu, J.-L. Zhou, T.-T. Xu and J.-J. Feng, Angew. Chem., Int. Ed., 2023, 62, e202310066.
26. (a) K. Zhang, S. Tian, W. Li, X. Yang, X.-H. Duan, L.-N. Guo and P. Li, Org. Lett., 2024, 26, 5482; (b) S. Hu, Y. Pan, D. Ni and L. Deng, Nat. Commun., 2024, 15, 6128; (c) J. Li, C. Xie, R. Zeng, W. Yuan, Y. Lei, T. Qi, H. Leng and Q. Li, ACS Catal., 2025, 15, 6025; (d) J.-Y. Su, J. Zhang, Z.-Y. Xin, H. Li, H. Zheng and W.-P. Deng, Org. Chem. Front., 2024, 11, 4539.
27. M. de Robichon, T. Kratz, F. Beyer, J. Zuber, C. Merten and T. Bach, J. Am. Chem. Soc., 2023, 145, 24466.
28. Q. Fu, S. Cao, J. Wang, X. Lv, H. Wang, X. Zhao and Z. Jiang, J. Am. Chem. Soc., 2024, 146, 8372.
29. (a) H. Ren, Z. Lin, T. Li, Z. Li, X. Yu and J. Zheng, ACS Catal., 2025, 15, 4634; (b) J. Jeong, S. Cao, H.-J. Kang, H. Yoon, J. Lee, S. Shin, D. Kim and S. Hong, J. Am. Chem. Soc., 2024, 146, 27830; (c) W.-J. Shen, X.-X. Zou, M. Li, Y.-Z. Cheng and S.-L. You, J. Am. Chem. Soc., 2025, 147, 11667.
30. (a) Q.-Q. Hu, L.-Y. Wang, X.-H. Chen, Z.-X. Geng, J. Chen and L. Zhou, Angew. Chem., Int. Ed., 2024, 63, e202405781; (b) D. Sarkar, S. Deswal, R. C. Das and A. T. Biju, Chem. Sci., 2024, 15, 16243.
31. H. Wu, M. Sun, J. Zhang, Z. Wang, J. Yang and G. Zhu, Org. Chem. Front., 2025, 12, 1951.
32. D. A. Knyazev, M. George and D. Werz, Chem. Sci., 2025, 16, 8588.
33. Y. Zheng, W. Huang, R. K. Dhungana, A. Granados, S. Keess, M. Makvandi and G. A. Molander, J. Am. Chem. Soc., 2022, 144, 23685.
34. T. Yu, J. Yang, Z. Wang, Z. Ding, M. Xu, J. Wen, L. Xu and P. Li, J. Am. Chem. Soc., 2023, 145, 4304.
35. Y. Liang, R. Nematswerani, C. G. Daniliuc and F. Glorius, Angew. Chem., Int. Ed., 2024, 63, e202402730.
36. X. Wang, R. Gao and X. Li, J. Am. Chem. Soc., 2024, 146, 21069.
37. Z. Lin, H. Ren, X. Lin, X. Yu and J. Zheng, J. Am. Chem. Soc., 2024, 146, 18565.
38. (a) J. Zhang, J.-Y. Su, H. Zheng, H. Li and W.-P. Deng, Angew. Chem., Int. Ed., 2024, 63, e202318476; (b) S. Deswal, R. C. Das, D. Sarkar and A. T. Biju, JACS Au, 2025, 5, 136; (c) X. G. Zhang, Z. Y. Zhou, J. X. Li, J. J. Chen and Q. L. Zhou, J. Am. Chem. Soc., 2024, 146, 27274; (d) W. Wu, B. Xu, X. Yang, F. Wu, H. He, X. Zhang and J. Feng, Nat. Commun., 2024, 15, 8005.
39. Y. Xiao, F. Wu, L. Tang, X. Zhang, M. Wei, G. Wang and J.-J. Feng, Angew. Chem., Int. Ed., 2024, e202408578.
40. (a) Q. Jiang, J. Dong, X. Zhou, H. Liao, J. Zhou and D. Xue, Org. Lett., 2024, 43, 9311; (b) X.-C. Yang, F. Wu, W.-B. Wu, X. Zhang and J.-J. Feng, Chem. Sci., 2024, 15, 19488.
41. (a) H.-X. He, F. Wu, X. Zhang and J.-J. Feng, Angew. Chem., Int. Ed., 2025, 64, e202416741; (b) H. Liao, J. Dong, X. Zhou, Q. Jiang, Z. Lv, F. Lei and D. Xue, Chem. Sci., 2025, 16, 4654.
42. (a) S. Dutta, C. G. Daniliuc, C. Mück-Lichtenfeld and A. Studer, J. Am. Chem. Soc., 2025, 147, 4249; (b) S. Deswal, R. C. Das, D. Sarkar and A. T. Biju, Angew. Chem., Int. Ed., 2025, 64, e202501655.
43. S. Nicolai and J. Waser, Chem. Sci., 2024, 15, 10823.
44. S. Deswal, A. Guin and A. T. Biju, Angew. Chem., Int. Ed., 2024, 63, e202408610.
45. (a) J.-J. Wang, L. Tang, Y. Xiao, W.-B. Wu, G. Wang and J.-J. Feng, Angew. Chem., Int. Ed., 2024, 63, e202405222; (b) L. Tang, W. Bai, K.-J. Wang, F. Wu, Q. Peng, G. Huang and J.-J. Feng, ACS Catal., 2025, 15, 7877.
46. X.-Y. Gao, L. Tang, X. Zhang and J.-J. Feng, Chem. Sci., 2024, 15, 13942.
47. K. Zhang, Z. Gao, Y. Xia, P. Li, P. Gao, X.-H. Duan and L.-N. Guo, Chem. Sci., 2025, 16, 1411.
48. H. Wang, H. Shao, A. Das, S. Dutta, H. T. Chan, C. Daniliuc, K. N. Houk and F. Glorius, Science, 2023, 381, 75.
49. L. Yang, H. Wang, M. Lang, J. Wang and S. Peng, Org. Lett., 2024, 26, 4104.
50. (a) S. Zhu, J. Lei, S. Yang, Z. Zhao, N. Liu and S.-W. Li, Org. Lett., 2025, 27, 3831; (b) C. Peng, Y. Xu, W. Liu, Y. Yuan, H. Wang, P. Huang, G. Huang and S. Peng, Org. Lett., 2025, 27, 7088.
51. (a) T. G. Archibald, L. G. Garver, K. Baum and M. C. Cohen, J. Org. Chem., 1989, 54, 2869; (b) R. D. Taylor, M. MacCoss and A. D. G. Lawson, J. Med. Chem., 2014, 57, 5845.
52. A. Philippou, P. F. Christopoulos and D. M. Koutsilieris, Mutation Res., 2017, 772, 105.
53. P. U. Feig, S. Shah, A. Hermanowski-Vosatka, D. Plotkin, M. S. Springer, S. Donahue, C. Thach, E. J. Klein, E. Lai and K. D. Obes, Metab., 2011, 13, 498.
54. J. Patocka and K. Kuca, Mil. Med. Sci. Lett., 2013, 82, 162.
55. (a) K. B. Wiberg, G. M. Lampman, R. P. Ciula, D. S. Connor, P. Schertler and J. Lavanish, Tetrahedron, 1965, 21, 2749; (b) S. Hoz and D. Aurbach, J. Org. Chem., 1984, 49, 4144; (c) S. Hoz and D. Aurbach, J. Org. Chem., 1984, 49, 3285; (d) S. Hoz, M. Livneh and D. Cohen, J. Org. Chem., 1986, 51, 4537.
56. Y. Gaoni, Tetrahedron Lett., 1988, 29, 1591.
57. (a) Y. Gaoni and A. Tomazic, J. Org. Chem., 1985, 50, 2948; (b) Y. Gaoni, Tetrahedron, 1989, 45, 2819.
58. R. Panish, S. R. Chintala, D. T. Boruta, Y. Fang, M. T. Taylor and J. M. Fox, J. Am. Chem. Soc., 2013, 135, 9283.
59. (a) R. R. Gianatassio, J. M. Lopchuk, J. Wang, C. Pan, L. R. Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M. Gallego, N. W. Sach, J. E. Spangler, H. Zhu, J. Zhu and P. S. Baran, Science, 2016, 351, 241; (b) M. Lopchuck, K. Fjelbye, Y. Kawamata, L. R. Malins, C. Pan, R. Gianatassio, J. Wang, L. Prieto, J. Bradow, T. A. Brandt, M. R. Collins, J. Elleraas, J. Ewanicki, W. Farrell, O. O. Fadeyi, G. M. Gallego, J. J. Mosseau, R. Oliver, N. W. Sach, J. K. Smith, J. E. Spangler, H. Zhu, J. Zhu and P. S. Baran, J. Am. Chem. Soc., 2017, 139, 3209.
60. (a) Y. Gaoni, Org. Prep. Proced. Int., 1995, 27, 185; (b) Y. Gaoni, Tetrahedron. Lett., 1988, 29, 1591.
61. J. A. Milligan, C. A. Busacca, C. H. Senanayake and P. Wipf, Org. Lett., 2016, 18, 4300.
62. S. H. Bennett, A. Fawcett, E. H. Denton, T. Biberger, V. Fasano, N. Winter and V. K. Aggarwal, J. Am. Chem. Soc., 2020, 142, 16766.
63. L. Guo, A. Noble and V. K. Aggarwal, Angew. Chem., Int. Ed., 2021, 60, 212.
64. M. Silvi and V. K. Aggarwal, J. Am. Chem. Soc., 2019, 141, 9511.
65. X. Wu, W. Hao, K.-Y. Ye, B. Jiang, G. Pombar, Z. Song and S. Lin, J. Am. Chem. Soc., 2018, 140, 14836.
66. C. J. Pratt, R. A. Aycock, M. D. King and N. T. Jui, Synlett, 2020, 51.
67. G. Ernouf, E. Chirkin, L. Rhyman, P. Ramasami and J. Cintrat, Angew. Chem., Int. Ed., 2020, 59, 2618.
68. M. Ociepa, A. J. Wierzba, J. Turkowska and D. Gryko, J. Am. Chem. Soc., 2020, 142, 5355.
69. X. Yu, M. Lübbesmeyer and A. Studer, Angew. Chem., Int. Ed., 2021, 60, 675.
70. A. Guin, S. Bhattacharjee, M. S. Harariya and A. T. Biju, Chem. Sci., 2023, 14, 6585.
71. L. Tang, Q.-N. Huang, F. Wu, Y. Xiao, J.-L. Zhou, T.-T. Xu, W.-B. Wu, S. Qu and J.-J. Feng, Chem. Sci., 2023, 14, 9696.
72. A. Guin, S. Deswal, M. S. Harariya and A. T. Biju, Chem. Sci., 2024, 15, 12473.
73. P. Roy, S. Deswal and A. T. Biju, Org. Lett., 2025, 27(38), 10916.
74. P. Gupta, P. Roy and A. T. Biju, Org. Lett., 2025, 27(37), 10477.
75. Z. Huang, H. Tan, R. Cui, Y. Hu, S. Zhang, J. Jia, X. Zhang and Q.-W. Zhang, Nat. Commun., 2025, 16, 6216.
76. H.-X. He, F. Wu, K. J. Wang, L. Wang and J.-J. Feng, Nat. Commun., 2025, 16, 6639.

---