Beyond para‐ and meta‐Substitution: Synthesis and Biological Validation of Chalcogen‐Rich Thiabicyclo[3.1.1]heptanes as Bioisosteres of Aryl Thioether Derivatives

Kun‐Ju Wang; Lei Tang; Heng‐Xian He; Yujie Li; Fujian Yang; Yuanjiu Xiao; Wen‐Li Xu; Wei Zhang; Guoqiang Wang; Jian‐Jun Feng

doi:10.1002/anie.5228347

. 2026 May 19;65(29):e5228347. doi: 10.1002/anie.5228347

Beyond para‐ and meta‐Substitution: Synthesis and Biological Validation of Chalcogen‐Rich Thiabicyclo[3.1.1]heptanes as Bioisosteres of Aryl Thioether Derivatives

Kun‐Ju Wang ¹, Lei Tang ¹, Heng‐Xian He ¹, Yujie Li ², Fujian Yang ³, Yuanjiu Xiao ¹, Wen‐Li Xu ¹, Wei Zhang ^2,^✉, Guoqiang Wang ^3,^✉, Jian‐Jun Feng ^1,^✉

PMCID: PMC13360773 PMID: 42154575

ABSTRACT

While bicyclo[3.1.1]heptanes (BCHeps) and oxa‐/aza‐BCHeps have emerged as valuable arene bioisosteres, the corresponding thia‐analogs remain underdeveloped. Notably, synthetic efforts to access aryl thioether mimetics have focused predominantly on strain‐release thiofunctionalization of [1.1.1]propellane or [3.1.1]propellane to access para‐ and meta‐substituted surrogates, whereas three‐dimensional analogs of ortho‐ and 1,2,4‐trisubstituted aryl thioethers remain elusive. Herein, we report a one‐pot stepwise protocol featuring anti‐thio(seleno)sulfonylation/annulation of bicyclo[1.1.0]butanes (BCBs) to enable scalable access to functionalized 2‐thiabicyclo[3.1.1]heptanes (thia‐BCHeps) under mild conditions. The synthetic utility is further demonstrated by diverse derivatization of these thia‐BCHeps building blocks and facile access to bioisosteres of ortho‐, meta‐, and 1,2,4‐trisubstituted aryl thioether derivatives (e.g., aryl sulfones and aryl sulfoximines). DFT calculations revealed that the reaction proceeded via a polar addition pathway, involving nucleophilic attack of cesium methanesulfinate with BCB. The observed diastereoselectivity originates from the stabilization of the anti‐addition transition state by a favorable π–π stacking interaction between two phenyl rings. Crystallographic analysis revealed that these thia‐BCHeps display geometric properties almost identical to those of ortho‐, meta‐, and 1,2,4‐trisubstituted aryl thioethers. Physicochemical studies and biological evaluation further validated these thia‐BCHeps as a new generation of saturated bioisosteres for aryl thioethers.

Keywords: bicyclo[1.1.0]butane, bicyclo[3.1.1]heptane, bioisosteres, medicinal chemistry, sulfur heterocycles

A general and practical approach to functionalized thiabicyclo[3.1.1]heptanes (thia‐BCHeps) enables divergent synthesis of 3D analogs of ortho‐, meta‐, and 1,2,4‐trisubstituted aryl thioether derivatives. Crystallographic analysis, physicochemical studies, and biological evaluation further validated these thia‐BCHeps as a new generation of saturated bioisosteres for aryl thioethers, aryl sulfones, and aryl sulfoximines.

1. Introduction

The benzene motif, though ubiquitous in drugs, suffers from flat geometry, cytochrome P450‐mediated oxidation, and π‐stacked aggregation that erode pharmacokinetic properties [1, 2, 3]. Therefore, in accordance with the “escape from flatland” concept [4, 5], the utilization of bicyclo[n.1.1]alkanes as bioisosteres for planar aromatic ring structures is increasingly sought in drug development [6, 7, 8, 9, 10]. These scaffolds not only offer unique 3D‐chemical space but also enhance pharmacokinetic and physicochemical properties while preserving bioactivity, thereby offering a promising avenue for developing drug‐like molecules [11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. Among these saturated bridged bicyclic scaffolds, bicyclo[3.1.1]heptanes (BCHeps), which have emerged as promising bioisosteres of substituted arenes, have garnered increasing attention in both medicinal and organic chemistry (Scheme 1a) [23]. In 2022, the Anderson [24] and Uchiyama [25] groups independently reported the synthesis of 1,5‐disubstituted BCHeps via strain‐release difunctionalization of [3.1.1]propellane. Topological analysis, together with pharmacokinetic comparisons to the parent meta‐disubstituted benzenes, certified 1,5‐BCHeps as meta‐benzene surrogates. Mykhailiuk [26] and Ryabchuk [27] subsequently revealed that 3‐oxabicyclo[3.1.1]heptanes replicate the vector map of meta‐benzene while markedly enhancing water solubility. Extending the heteroatom swap, Mykhailiuk's group reported the pioneering synthesis of 3‐azabicyclo[3.1.1]heptanes enabled by reduction of spirocyclic oxetanyl nitriles followed by intramolecular ring‐opening of the oxetane motif. Physicochemical profiling revealed that 3‐aza‐BCHeps can act as three‐dimensional bioisosteres for pyridine rings [28]. These advances have ignited intense interest in all‐carbon [29, 30, 31, 32, 33, 34, 35, 36, 37] and oxa‐/aza‐BCHep cores [38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60], and a series of elegant (hetero‐)BCHep syntheses—particularly (3 + 3) cycloadditions of bicyclobutanes (BCBs)—have since appeared [61, 62, 63, 64, 65, 66, 67, 68].

SCHEME 1 — Research background on the synthesis of thiabicyclo[3.1.1]heptanes and saturated bioisosteres of aryl thioether derivatives.

Organosulfur molecules are ubiquitous in nature, and synthetic sulfur‐containing scaffolds are prevalent in pharmaceuticals [69, 70]; for example, 28% of the “top 200 small‐molecule drugs by retail sales in 2024” contain sulfur [71]. Consequently, developing concise synthetic routes to 2‐thiabicyclo[3.1.1]heptane frameworks is highly desirable. While substantial effort has been devoted to O‐ and N‐embedded BCHeps, thiabicyclo[3.1.1]heptanes remain almost unexplored (during the peer review of this manuscript, Anderson reported the synthesis of 3‐thia‐BCHeps, while our group independently developed a route to 2‐thia‐BCHeps) [72, 73]. To date, only one report has biologically validated thia‐BCHeps as benzene bioisosteres (Scheme 1a) [73]. This gap mainly stems from the scarcity of efficient synthetic access: the precedent reported by Hamanaka requires more than 10 steps from 3‐vinylcyclobutan‐1‐one to deliver 3,4‐disubstituted 2‐thiabicyclo[3.1.1]heptane, a sequence too lengthy for routine medicinal‐chemistry applications [74]. Recent BCB‐based cyclization protocols from Glorius, Peng, and our group enable rapid access to 2‐thia‐BCHeps [75, 76, 77], yet the resulting ring‐fused or diester‐tagged products resist late‐stage diversification, precluding the installation of the pharmacophoric vectors present in parent aromatic drugs (Scheme 1b).

Among organosulfur compounds, arylthioethers and arylsulfones are motifs of significant biological and medicinal importance [78, 79, 80, 81, 82]. For example, vortioxetine—a top‐20 best‐selling small‐molecule neurology drug in 2024—is an antidepressant approved for major depressive disorder in adults [78]; dapsone is an FDA‐approved drug on the market for treating leprosy [79]; amisulpride is a selective dopamine antagonist and atypical antipsychotic [80]; and suloxifen demonstrates anti‐asthmatic efficacy (Scheme 1c) [81]. Consequently, sulfur‐containing aromatic bioisosteres that can fine‐tune physicochemical and pharmacokinetic properties are intensely pursued, yet only sulfur‐decorated BCP and BCHep surrogates—accessible via [1.1.1]‐ or [3.1.1]propellane ring‐opening—have been explored [83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94], and these scaffolds cannot mimic ortho‐substituted or multisubstituted aryl sulfones or thioethers (Scheme 1d). Moreover, no biological validation has been reported for the hypothesis that such bicyclo[n.1.1]alkanes can function as effective aryl thioether‐type bioisosteres.

In this work, we envisioned the ring‐opening/cyclization reaction between acyl BCBs and thiosulfonates as an innovative and practical strategy for constructing 2‐thia‐BCHeps [95, 96, 97, 98, 99]. To realize this proposal, we must address the key challenge of controlling the diastereoselectivity of BCB thiosulfonylation to afford anti‐addition products, thereby ensuring a smooth subsequent cyclization. To validate our central hypothesis—whether 2‐thia‐BCHep can mimic ortho‐ and meta‐substituted benzenes in bioactive compounds—we incorporated 2‐thia‐BCHep into aryl‐sulfone/aryl‐thioether/sulfoximine‐containing drugs and reported a comprehensive study of their crystallographic analysis, physicochemical properties, and biological activity (Scheme 1e).

2. Results and Discussion

2.1. Development of One‐Pot Stepwise Protocol and Scalable Synthesis

Given that the pyrazole group is a good leaving group for nucleophilic substitution reactions in cyclization design, acyl pyrazole‐decorated BCB 1a was selected as the model substrate. To explore the 1,3‐thiosulfonylation reaction, 1a was treated with S‐phenyl methanesulfonothioate 2a in the presence of a range of commonly used bases (Table 1). Initial attempts with Na₂CO₃ failed to deliver product 3aa (entry 1). Switching to the stronger base K₂CO₃ furnished 3a in 32% yield (11:1 d.r., entry 2). Systematic evaluation of other inorganic bases identified Cs₂CO₃ as the optimal base (entries 3–6), providing 3a in 95% yield with good diastereoselectivity (entry 5). Further screening of organic bases revealed that Et₃N and DBU did not promote the reaction (entries 7–8); however, DABCO proved effective, delivering 3aa in 93% yield (entry 9). Subsequently, a systematic survey of solvents and other parameters was undertaken. Dimethyl sulfoxide gave a lower yield and diastereoselectivity, whereas CH₂Cl₂, THF, toluene, and ethyl acetate proved ineffective (entries 10–14). Raising the temperature had negligible influence on yield but eroded diastereoselectivity; conversely, lowering the temperature to 0°C markedly reduced the yield (entries 15–17). Altering the catalyst loading to 5 or 15 mol% left the yield essentially unchanged in both cases (entries 18–19). A control experiment confirmed that no product was formed in the absence of base (entry 20).

TABLE 1.

Optimization of the reaction conditions for the 1,3‐thiosulfonylation ^a .


Entry	Base	Solvent	Yield of 3aa (%) ^b	d.r. = trans/cis ^c
1	Na₂CO₃	CH₃CN	0	—
2	K₂CO₃	CH₃CN	32	11:1
3	K₃PO₄	CH₃CN	31	10:1
4	t‐BuOK	CH₃CN	18	10:1
5	Cs₂CO₃	CH₃CN	95	11:1
6	NaOH	CH₃CN	0	—
7	Et₃N	CH₃CN	0	—
8	DBU	CH₃CN	0	—
9	DABCO	CH₃CN	93	11:1
10	Cs₂CO₃	CH₂Cl₂	0	—
11	Cs₂CO₃	THF	0	—
12	Cs₂CO₃	Toluene	0	—
13	Cs₂CO₃	EtOAc	0	—
14	Cs₂CO₃	DMSO	65	8:1
15 ^d	Cs₂CO₃	CH₃CN	10	—
16 ^e	Cs₂CO₃	CH₃CN	95	10:1
17 ^f	Cs₂CO₃	CH₃CN	100	9:1
18 ^g	Cs₂CO₃	CH₃CN	92	10:1
19 ^h	Cs₂CO₃	CH₃CN	95	11:1
20	—	CH₃CN	0	—

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^{^a}

The reactions were performed with 1a (0.1 mmol), 2a (0.12 mmol), and base (10 mol%) in solvent (1.0 mL) at 25°C for 16 h.

^{^b}

Combined NMR yield determined by ¹H NMR spectroscopy with CH₂Br₂ as an internal standard.

^{^c}

Determined by ¹H NMR spectroscopy of the crude reaction mixture.

^{^d}

Run at 0°C.

^{^e}

Run at 40°C.

^{^f}

Run at 60°C.

^{^g}

Base (5 mol%).

^{^h}

Base (15 mol%).

After the establishment of the optimized conditions for the ring‐opening reaction, we shifted our focus to the cyclization of 3aa. Extensive optimization identified t‐BuOK (2.0 equiv.) in THF at room temperature for 1 h as the optimized conditions, affording thia‐BCHep 4aa in 93% NMR yield (see the Supporting Information for the complete set of optimization data, Table S1). Merging the two optimized steps furnishes the one‐pot stepwise protocol outlined in Scheme 2, delivering 4aa directly from BCB 1a and thiosulfonate 2a without isolating or purifying the intermediate. Notably, the scalability of the sequence was demonstrated by a gram‐scale preparation of 4aa (83% yield over two steps, 1.29 g) without erosion of efficiency.

SCHEME 2 — Gram‐scale synthesis of 2‐thia‐BCHep **4aa**.

2.2. Substrate Scope

With the optimized conditions for synthesizing thia‐BCHeps in hand, we subsequently explored the substrate scope, and the results are summarized in Scheme 3. First, the substrate scope with respect to thiosulfonates was explored. Generally, no significant electronic effects were observed in the reaction of thiosulfonates containing electron‐withdrawing groups (4ab–4af; e.g., halides, NO₂ (4ae) and CN (4af) groups) or electron‐donating groups (4ag–4ah; e.g., alkyl and methoxy) under the standard conditions. Thiosulfonates 2 featuring para‐, meta‐ (4ai–4ak) and even ortho‐substituted phenyl rings (4al) afforded the corresponding thia‐BCHep products in good yields (up to 86% yield). Thiosulfonates substituted by heteroaryl groups, such as 2‐pyridinyl and 2‐thienyl groups, were also amenable to this reaction, furnishing products 4aq (71% yield) and 4ar (80% yield), respectively. Additionally, S‐alkyl methanesulfonothioates including methyl, n‐butyl, benzyl, and cyclohexyl proved feasible, affording the desired products 4am–4ap in 50%–80% yields. Compared with S‐phenyl methanesulfonothioate, the reaction using S‐phenyl ethanesulfonothioate as the substrate led to the formation of the highly substituted thia‐BCHep with a slightly decreased yield (4as vs. 4aa), likely due to the steric effect. α‐Phenyl‐substituted sulfone 2t furnished 4at in 42% yield, indicating its suitability as a substrate. Notably, this transformation could be extended to selenosulfonates, furnishing 4au–4aw with acceptable efficiency.

SCHEME 3 — Substrate scope investigation for the ring‐opening/cyclization reaction^{[a, b]}. ^[a] A mixture of 1 (0.2 mmol), 2 (0.24 mmol) and Cs₂CO₃ (10 mol%) in CH₃CN (2 mL) was stirred at 25°C for 16 h. After removal of CH₃CN under reduced pressure, THF (4 mL) was added, followed by t‐BuOK (0.40 mmol). The resulting mixture was stirred at 25°C for 1 h. ^[b] 20 mol% Cs₂CO₃ used, 24 h. ^[c] The corresponding ring‐opening product was purified by flash chromatography. ^[d] 2.0 mmol scale.

Subsequently, we explored the substrate scope of BCBs. The substituents on the benzene ring of the BCB, including F (4ba, 4ja, and 4ma), Cl (4ca, 4ka), benzyloxy (4fa), methoxy (4ga), alkyl (4ia, 4la), and medicinally relevant trifluoromethyl (4da) and trifluoromethoxy (4ea, 4ha) groups at the para‐, meta‐, or ortho‐positions, were studied. The desired products (4ba–4ma) were obtained in 46%–88% yields. In general, BCBs containing electron‐deficient aryl substituents consistently outperformed their electron‐rich counterparts. Gratifyingly, the reaction was not limited to 1‐acylpyrazole‐3‐aryl‐BCBs; acyl‐pyrazole‐decorated BCBs bearing methyl (4na, 4nc, and 4ne), vinyl (4oa), or ethynyl (4pa) groups at the bridgehead position also underwent the reaction smoothly. Notably, monosubstituted BCB 1q participated smoothly in this reaction, affording the desired product 4qa in acceptable yield.

2.3. Study of Reaction Mechanism

Thiosulfonates are useful bifunctional reagents that undergo 1,n‐thiosulfonylation reactions, typically via a radical pathway [95, 98]. To probe the mechanism, the ring‐opening reactions of 1a and 2a were carried out in the presence of radical scavengers such as TEMPO and 1,1‐diphenylethylene under standard conditions. However, the addition of these scavengers had virtually no effect on the yield (Scheme 4a). This result indicates that the reaction likely proceeds via an ionic rather than a radical pathway.

SCHEME 4 — Mechanistic studies. (a) Control experiments. (b) Computed reaction coordinate for Cs₂CO₃‐catalyzed ring‐opening reaction of BCB 1a with phenylmethanethiosulfonate 2a (Gibbs free energies are in kcal/mol, distances are shown in Å, natural charges are in a.u.). Color code: H, white; C, gray; N, blue; O, red; S, yellow; Cs, purple. (c) Plot of *k_in* versus [Cat.] with a linear regression fit. The curve depicts the results of an unweighted least‐squares fit to y = a * x + b (a = 0.6375, b = −0.375, R ² = 0.9852). (d) Effect of reaction temperature on diastereoselectivity. (e) Interaction region indicator analysis on the key diastereoselectivity‐determining step.

To further elucidate the mechanistic details, density functional theory (DFT) calculations were conducted on the model reaction of phenylmethanethiosulfonate 2a, BCB 1a, and Cs₂CO₃. Computations were performed at the B3LYP‐D3/def2‐TZVP (PCM, MeCN)//def2‐SVP level of theory [100, 101, 102, 103, 104] (see the Supporting Information for details). Molecular structures were visualized using CYLview software [105]. The key elementary steps along the reaction coordinate were initially explored using the integrated molecular dynamics and coordinate driving method (MD/CD) developed by our group (see Supporting Information for the related results) [106, 107, 108]. As shown in Scheme 4b, the reaction starts with the endergonic coordination of 2a with Cs₂CO₃ to form complex IM1 (ΔG = 4.5 kcal/mol). Analysis of IM1 reveals the activation of the disulfide moiety as evidenced by the elongation of the S–S bond (from 2.169 Å in 2a to 2.214 Å) and a significant increase in positive charge on the –SPh fragment (from –0.056e in 2a to 0.987e in IM1). This charge redistribution enhances the electrophilicity of the S1 atom, priming it for nucleophilic attack. For IM1, the carbonate anion approaches S1 through TS1, generating cesium methanesulfinate (INT1) and cesium phenylthiocarbonate (INT2) (ΔG = –1.9 kcal/mol). INT1 then acts as a nucleophile, attacking the bridgehead carbon of BCB 1a. This step proceeds via TS2 with an activation barrier of 16.3 kcal/mol. In this transition state, C–S bond formation and C–C bond cleavage occur synchronously to afford enolate intermediate IM2. Finally, the enolate intermediate IM2 attacks the electrophilic sulfur atom of INT1, accompanied by the S–O bond cleavage, to regenerate the Cs₂CO₃ catalyst and deliver the anti‐addition product 3aa via TS3. The overall rate‐determining step is the nucleophilic ring‐opening with a barrier of 16.3 kcal/mol (TS2), which is consistent with the observed smooth reaction at ambient temperature. Initial‐rate measurements at varying Cs₂CO₃ concentrations revealed an approximately linear dependence of the reaction rate on [Cs₂CO₃] (Scheme 4c, R ² = 0.985). This supports a first‐order role for Cs₂CO₃ in the rate‐determining step and also indicates that the inclusion of one explicit Cs₂CO₃ molecule in the computational model is reasonable.

In addition to the formation of the anti‐addition product, IM2 could also react with INT2 through the same side of the methanesulfinate group to afford the syn‐addition product 3aa’ (as shown in Scheme 4b, gray line, via TS3’). It was found that this competing pathway requires a higher barrier than the anti‐addition transition (ΔG^≠ = 10.0 kcal/mol vs. 7.2 kcal/mol for TS3). This barrier difference is in qualitative agreement with the experimentally observed diastereoselectivity (trans/cis = 11:1). It should be noted that the formation of the trans‐addition product is both kinetically and thermodynamically favorable. However, both the trans and cis addition pathways might be microscopically reversible, with corresponding activation barriers of 25.0 and 26.6 kcal/mol, respectively (3aa/3aa’ → TS3/TS3’ → IM2). The reverse reaction of the trans addition might occur more easily, suggesting that the diastereoselectivity of the reaction could be influenced by changing the reaction temperature.

Further experimental studies reveal that as the reaction temperature is gradually increased from 25°C to 60°C, the diastereoselectivity progressively decreases (d.r. = 11:1 → 9:1, Scheme 4d). This trend is qualitatively consistent with our computational results. In addition, calculations on alkyl‐substituted thiosulfonates 2m (methyl) gave trans/cis transition‐state barrier differences of 1.8 kcal/mol (see Figure S20), which is also consistent with the experimentally observed diastereoselectivity.

Furthermore, interaction region indicator (IRI) analyses of weak interactions [109, 110] were performed to elucidate the origin of the diastereoselectivity. As shown in Scheme 4e, the anti‐addition transition state TS3 is stabilized by a favorable π–π stacking interaction between the two phenyl rings (highlighted in red), which likely leads to a lower activation barrier. In comparison, TS3' adopts a less favorable spatial orientation that lacks this stabilization, resulting in a higher energy barrier. These results indicate that the favorable π–π stacking in the anti‐addition pathway is a key factor governing the preferential formation of 3aa.

2.4. Synthetic Applications and Incorporation Into Bioactive Compounds

To highlight synthetic utility, the ketone and thioether motifs were leveraged as versatile handles for downstream transformations (Scheme 5a). The carbonyl functional group on 4aa was converted to tertiary alcohol 5 and secondary alcohol 7 in 45% and 96% yields by treating with Grignard reagent and NaBH_4, respectively. Compound 7, featuring a hydroxyl group, serves as a versatile handle for appending medicinally relevant motifs—such as Ataluren (7→15) and Probenecid (7→16)—onto the three‐dimensional thia‐BCHep scaffold via esterification. Moreover, dehydration of 7 mediated by Martin's sulfurane efficiently affords 2‐thiabicyclo[3.1.1]heptene 12. Selective late‐stage oxygenation of 4na to form sulfone 6 and sulfoxide 8 can be precisely controlled by adjusting the equivalence of mCPBA and the reaction temperature. The alkylation of 4aa with 1,2‐dibromoethane can afford the medicinally relevant spirocyclic compound 9. Furthermore, the carbonyl group on 4aa can be readily transformed into the enol triflate 10, which serves as a versatile coupling partner for a series of cross‐coupling reactions. For example, compound 10 underwent Sonogashira coupling with 5‐hexyn‐1‐ol to afford compound 11 and Suzuki coupling with p‐tolylboronic acid to produce 13. Additionally, the internal alkene in compound 12 was prepared from ketone 4aa by reduction of the derived enol triflate 10 with tributyltin hydride. NH‐sulfoximine (14), which is attracting growing interest among medicinal chemists, can be prepared from thioether 12.

To showcase the potential of 2‐thia‐BCHep cores as bioisosteres for aryl sulfones and aryl sulfoximine‐type drugs, as well as the feasibility of our synthetic procedures in drug discovery, we devised a four‐step and a five‐step synthetic protocol for the preparation of compound 18 and compound 22 (the 3D analog of Suloxifen), respectively. Furthermore, in the aryl thioether‐type anti‐inflammatory agent 24, we successfully replaced the ortho‐substituted benzene with the 2‐thia‐BCHep core to produce the saturated analog 23.

2.5. Crystallographic Analysis and Physicochemical Properties

Next, we conducted a comparative analysis of the geometric parameters between thia‐BCHeps and their aromatic counterparts—namely, ortho‐, meta‐, and 1,2,4‐trisubstituted benzenes (23 vs. 24, 18 vs. 26, 7 vs. 25; see Figures S8–S11 for details). As shown in Scheme 6a, the relative spatial arrangement of the vectors is described by four geometric parameters: the distance between carbon atoms (r), the distance between two carbon substituents (d), the dihedral angle (θ), and the angle (Φ), which is the angle between two bonds originating from the centroid of the ring and extending to the atoms connected to the ring. For thia‐BCHep 23, computational evaluation revealed that the parameters d, r, and Φ are nearly identical to those of the corresponding ortho‐substituted parent benzene 24. While the ortho‐benzene systems adopt a nearly planar geometry (θ = 3°), the 4,5‐disubstituted thia‐BCHeps (θ = 36°) possess a distinctly three‐dimensional architecture. For 1,5‐disubstituted thiabicyclo[3.1.1]heptene 18, the distances between key atoms (d and r) and the dihedral angle (θ) are comparable to those of the corresponding meta‐substituted benzene 26. However, the angle (Φ) is 13° larger than that observed in meta‐benzene. Exit vector analysis for compound 7 in comparison to 1,2,4‐trisubstituted benzene 25 was carried out (Figure S11). These results, together with the conformational overlay analysis, validate that 1,4,5‐trisubstituted thia‐BCHeps mimic the critical structural information of 1,2,4‐trisubstituted benzenes.

SCHEME 6 — Exit vector analysis and assessment of physicochemical parameters. *Solubility* (in µM) refers to the experimental kinetic solubility in phosphate‐buffered saline at pH 7.4; *clogP* is the calculated lipophilicity; *logD (7.4)* refers to the experimental distribution coefficient in n‐octanol/phosphate‐buffered saline at pH 7.4; *CL_int* is the experimental metabolic stability in human liver microsomes (µL min⁻¹ mg⁻¹); *t_1/2* (min) is the experimental half‐time of a metabolic decomposition.

We subsequently investigated the impact of replacing the phenyl ring with thia‐BCHep scaffolds on the physicochemical properties of bioactive compounds (Scheme 6b).

2.5.1. Water Solubility

The anti‐inflammatory agent 24, featuring an ortho‐substituted phenyl ring, and the 1,2,4‐trisubstituted benzene 25 both exhibited poor solubility in water. Replacing the phenyl ring with saturated thia‐BCHep‐type bioisosteres (compounds 23 and 7) resulted in a remarkable increase in solubility by over 120‐fold for agent 24 and 3‐fold for benzene 25, respectively. Similarly, replacing the meta‐substituted phenyl ring in compound 26 and the monosubstituted benzene in Suloxifen with the unsaturated thiabicyclo[3.1.1]heptene core also led to a significant increase in solubility: 58.1 (26) versus 176 (18); 111 (Suloxifen) versus 210 (22).

2.5.2. Lipophilicity

To assess the impact of replacing the benzene ring with a thia‐BCHep scaffold on lipophilicity, we utilized two parameters: calculated lipophilicity (cLogP) and experimental lipophilicity (logD). In all four compounds containing monosubstituted (Suloxifen), ortho‐(24), meta‐(26), and 1,2,4‐trisubstituted benzenes (25), replacing the corresponding substituted phenyl ring with the thia‐BCHep scaffold resulted in a decrease in both clogP and logD values by 1.0–3.2 units.

2.5.3. Metabolic Stability

The impact of the thia‐BCHep scaffold on metabolic stability was also examined. For compounds 26, Suloxifen, and 25, incorporating the thia‐BCHep scaffold (in compounds 18, 22, and 7) significantly enhanced metabolic stability by two‐ to threefold, as measured by using t_1/2 (min). In contrast, in the anti‐inflammatory agent 24, the incorporation of the thia‐BCHep core (23) resulted in a slight decrease in metabolic stability: CL_int (µL min⁻¹ mg⁻¹) = 424.3 (23) versus 343.6 (24).

2.6. Biological Activity

It has been established that ortho‐amino phenyl sulfide derivatives (compound 24) possess potent anti‐inflammatory reactivity [82]. Therefore, the biological activity of the newly synthesized thia‑BCHep compound 23 was evaluated using compound 24 as the reference. Firstly, the cytotoxicity of both compounds was assessed in MDCK cells. As shown in Scheme 7a, thia‐BCHep 23 (CC₅₀ = 117.2 ± 3.78 µM) exhibited significantly lower cytotoxicity than compound 24 (CC₅₀ = 45.47 ± 1.23 µM), showing approximately 2.6‑fold greater cellular tolerance. Their anti‑inflammatory effects were then examined in LPS‑stimulated RAW264.7 macrophages. As displayed in Scheme 7b, both compounds effectively suppressed the mRNA expression of key pro‑inflammatory cytokines (IL‑6, IL‑1β, and TNF‑α). While showing comparable potency, compound 24 was marginally more effective; in contrast, compound 23 provided a notably wider therapeutic window owing to its substantially lower cytotoxicity. These findings support the potential of thia‑BCHep 23 for further biological evaluation.

SCHEME 7 — In vitro cytotoxicity and anti‐inflammatory activity of compounds 23 and 24. (a) Cytotoxicity evaluation in MDCK cells. Cells were seeded in 96‐well plates (2 × 10³ cells/well) and treated with serially diluted compounds (10–125 µM) for 72 h. (b) Inhibitory effects on LPS‐induced inflammatory response in RAW264.7 macrophages. Cells were pretreated with compounds 24 or 23 (0, 10, 30 µM) for 1 h, followed by stimulation with LPS (100 ng/mL) for 2 h. The mRNA expression levels of IL‐6, IL‐1β, and TNF‐α were quantified by qRT‐PCR. Data are presented as the mean ± SD from three independent experiments. *P < 0.05, **P < 0.01, ***P < 0.005.

3. Conclusion

In conclusion, by developing a one‐pot synthetic strategy involving base‐catalyzed diastereoselective thio(seleno)sulfonylation of bicyclo[1.1.0]butanes and base‐promoted cyclization, we have successfully established a robust platform for constructing chalcogen‐rich 2‐thiabicyclo[3.1.1]heptane scaffolds (thia‐BCHeps) that are inaccessible by conventional methods. This protocol is characterized by readily available starting materials, mild and operationally simple conditions, broad functional‐group tolerance, and scalability to gram quantities. Unlike previous thiosulfonylation reactions of strained rings proceeding predominantly via radical mechanisms [95, 98], our mechanistic studies demonstrate that the transformation follows an ionic pathway, involving the nucleophilic ring‐opening of BCB by cesium methanesulfinate. The observed diastereoselectivity is primarily driven by a π–π stacking interaction in the key transition state, favoring the anti‐addition product. These new thia‐BCHeps feature diverse synthetic handles enabling divergent elaboration to thia‐BCHep‐sulfones, ‐sulfoximines, ‐sulfoxides, and 1,5‐disubstituted thiabicyclo[3.1.1]heptenes. Their successful incorporation into three bioactive compounds—including analogs of Suloxifen and Dapsone—demonstrates their potential. Crystallographic analyses revealed that 1,4,5‐trisubstituted thia‐BCHeps, 4,5‐disubstituted thia‐BCHeps, and 1,5‐disubstituted thiabicyclo[3.1.1]heptenes mimic the spatial arrangements of 1,2,4‐trisubstituted, ortho‐, and meta‐disubstituted benzenes, respectively. Relative to their parent aryl thioether derivatives, these sulfur‐functionalized thia‐BCHeps display markedly improved water solubility and reduced lipophilicity. Furthermore, they also possess high metabolic stability. Replacement of the ortho‐substituted phenyl ring in anti‐inflammatory agent 24 with thia‐BCHep dramatically improved aqueous solubility (> 120‐fold), reduced lipophilicity (2‐fold), mitigated cytotoxicity, and retained comparable bioactivity. This study provides the first biological validation that chalcogen‐rich 2‐thiabicyclo[3.1.1]heptane scaffolds can serve as 3D‐bioisosteres of benzene rings, offering a toolbox of saturated bioisosteres for aryl thioether drug discovery.

Author Contributions

Kun‐Ju Wang: investigation, data curation. Lei Tang: investigation, data curation. Heng‐Xian He: investigation, data curation, funding acquisition. Yujie Li: investigation. Fujian Yang: investigation, software. Yuanjiu Xiao: investigation, funding acquisition. Wen‐Li Xu: investigation, data curation. Wei Zhang: writing – original draft, funding acquisition, supervision, data curation, resources. Guoqiang Wang: software, funding acquisition, writing – original draft, supervision, data curation, resources. Jian‐Jun Feng: conceptualization, methodology, writing – original draft, writing – review and editing, project administration, funding acquisition, supervision, data curation, resources.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting File 1: anie72757‐sup‐0001‐Data.zip.

ANIE-65-e5228347-s002.zip^{(236.6KB, zip)}

Supporting File 2: anie72757‐sup‐0002‐SuppMat.pdf.

ANIE-65-e5228347-s001.pdf^{(8.6MB, pdf)}

Acknowledgments

We are grateful for financial support from the National Natural Science Foundation of China (no. 22471068 to Jian‐Jun Feng, no. 225B2105 to Heng‐Xian He, and no. 82371812 to Wei Zhang); the Natural Science Foundation of Hunan Province (no. 2026JJ60013 to Yuanjiu Xiao); the China Postdoctoral Science Foundation (no. 2025M780931 to Yuanjiu Xiao); and the Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (no. JYB2025XDXM309 to Guoqiang Wang). The authors acknowledge the robotic AI‐Scientist platform of the Chinese Academy of Sciences for its assistance with the automated reaction pathway searching. Part of the theoretical calculations were performed at the High‐Performance Computing Center (HPCC) of Nanjing University.

Contributor Information

Wei Zhang, Email: zhangwei@njucm.edu.cn.

Guoqiang Wang, Email: wangguoqiang710@nju.edu.cn.

Jian‐Jun Feng, Email: jianjunfeng@hnu.edu.cn.

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting File 1: anie72757‐sup‐0001‐Data.zip.

ANIE-65-e5228347-s002.zip^{(236.6KB, zip)}

Supporting File 2: anie72757‐sup‐0002‐SuppMat.pdf.

ANIE-65-e5228347-s001.pdf^{(8.6MB, pdf)}

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article

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PERMALINK

Beyond para‐ and meta‐Substitution: Synthesis and Biological Validation of Chalcogen‐Rich Thiabicyclo[3.1.1]heptanes as Bioisosteres of Aryl Thioether Derivatives

Kun‐Ju Wang

Lei Tang

Heng‐Xian He

Yujie Li

Fujian Yang

Yuanjiu Xiao

Wen‐Li Xu

Wei Zhang

Guoqiang Wang

Jian‐Jun Feng

ABSTRACT

1. Introduction

SCHEME 1.

2. Results and Discussion

2.1. Development of One‐Pot Stepwise Protocol and Scalable Synthesis

TABLE 1.

SCHEME 2.

2.2. Substrate Scope

SCHEME 3.

2.3. Study of Reaction Mechanism

SCHEME 4.

2.4. Synthetic Applications and Incorporation Into Bioactive Compounds

SCHEME 5.

2.5. Crystallographic Analysis and Physicochemical Properties

SCHEME 6.

2.5.1. Water Solubility

2.5.2. Lipophilicity

2.5.3. Metabolic Stability

2.6. Biological Activity

SCHEME 7.

3. Conclusion

Author Contributions

Conflicts of Interest

Supporting information

Acknowledgments

Contributor Information

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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