1. Introduction

Nitrogen-containing heterocycles, especially pyridine and its derivatives, are among the most essential building blocks in medicinal chemistry and are found in many approved drugs^[1,2]. According to the “Escape from Flatland” concept proposed by Lovering and coworkers^[3,4], increasing molecular saturation can improve its physical properties, make it more selective for its target, and increase its chances of success in clinical trials^[5,6]. Over the past decade, bridged bicyclic scaffolds, particularly bicyclo[1.1.1]pentanes, bicyclo[2.1.1]hexanes (BCHs), and bicyclo[3.1.1]heptanes (BCHeps), have emerged as privileged three-dimensional, C(sp³)-enriched bioisosteres for planar aromatic rings^[7-10]. Nevertheless, the rational design of three-dimensional bioisosteres that can effectively mimic the properties of pyridine remains a significant challenge. Building on the success of using BCHeps to replace benzene rings^[11], Mykhailiuk and coworkers proposed aza-BCHep as a promising bioisostere for pyridine (Figure 1a)^[12]. Supporting this hypothesis, several bioactive molecules incorporating the aza-BCHep scaffold have exhibited potent biological activity or superior physicochemical profiles (Figure 1b)^[13]. Consequently, the development and application of aza-BCHeps as 3D bioisosteres have gained substantial momentum, underscoring their growing importance in drug discovery^[14-16].

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Figure 1. Background and design of the present work. CBA: chiral Brønsted acid; BCHeps: bicyclo[3.1.1]heptanes.

Intramolecular cycloadditions have long served as a primary route for synthesizing aza-BCHeps^[17-21]. Among the earliest examples, Schieweck et al. reported a thermal [2+2] cycloaddition of N-acryloylacrylimides to afford 3-aza-BCHepdiones^[19]. For intermolecular variants, several strategies have been developed, including radical pathways^[22-26], Lewis acid-mediated substrate activation^[27-35], and transition-metal-catalyzed transformations for constructing polysubstituted aza-BCHeps^[36], with additional complementary approaches also reported^[37,38]. Beyond cycloadditions, cyclization strategies represent another major synthetic avenue to aza-BCHeps^[12,39-44].

Despite these achievements, developing general, efficient, and catalytic asymmetric methods for enantioenriched aza-BCHeps remains a considerable challenge. Among the limited successful strategies, two main approaches have emerged. The first relies on chiral transfer from enantiopure starting materials: Hari’s photoredox-catalyzed decarboxylation of chiral redox-active esters generates alkyl radicals that couple with bicyclo[1.1.0]butanes (BCBs)^[45], while Studer’s Lewis acid-catalyzed formal [2σ+2σ] cycloaddition employs chiral aziridines with BCBs^[46]. The second approach involves catalytic asymmetric construction. Deng’s In(OTf)₃/iridium relay catalysis produces 2-aza-BCHeps^[47], wherein In(OTf)₃ promotes BCB ring-opening followed by chiral iridium-catalyzed ring-closure. Separately, Li’s copper-catalyzed asymmetric [4π+2σ] cycloaddition of BCBs with azomethine ylides provides access to enantioenriched 3-aza-BCHeps (Figure 1c)^[48]. Although these pioneering studies offer valuable routes to specific chiral frameworks, a broadly applicable Brønsted acid-catalyzed asymmetric hydrogenation strategy for saturated, enantioenriched aza-BCHeps has yet to be developed.

To address this gap, we sought to develop a catalytic asymmetric transfer hydrogenation protocol employing azabicyclo[3.1.1]heptene as the starting material, a substrate elegantly synthesized by Zheng and co-workers^[23]. Chiral Brønsted acids (CBA), renowned for their bifunctional activation mode in stereoselective transformations^[49-54], provide a particularly attractive platform. While enantioselective Brønsted acid-catalyzed transfer hydrogenation has been well established for diverse imine substrates^[55-59], the asymmetric reduction of imines embedded in conformationally rigid and strained aza-bicyclic frameworks, such as those found in 3-aza-BCHeps, remains unexplored. This unique structural environment poses a distinct challenge for efficient stereocontrol. Herein, we report a CBA-catalyzed asymmetric transfer hydrogenation of imines derived from unsaturated 3-aza-BCHeps, employing Hantzsch ester (HE) as the hydrogen source (Figure 1d). This method enables the synthesis of a broad range of highly enantioenriched 3-aza-BCHeps in generally good yields under mild reaction conditions, with excellent functional group tolerance.

2. Methods

2.1 Typical procedure for enantioselective synthesis chiral 3-aza-BCHeps

An oven-dried 25 mL Schlenk tube equipped with a magnetic stir bar was charged with imine 1 (0.2 mmol, 1.0 equiv.), HE (0.5 mmol, 2.5 equiv.), and C7 (10 mol%). The tube was evacuated and backfilled with argon three times. Mesitylene (4 mL) was then added, and the mixture was stirred at 50 °C for 72 h. After cooling to room temperature, chloranil (0.2 mmol, 1.0 equiv.) was added, and the mixture was stirred for an additional 20 min. The reaction was quenched with saturated aqueous NaHCO₃. The mixture was washed with aqueous NaOH (2 M, 2 × 10 mL), the aqueous phase was extracted with CH₂Cl₂ (3 × 10 mL), and the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel basified with triethylamine to give product 2. Further details are provided in the Supplementary materials.

3. Results and Discussion

To develop an efficient asymmetric synthesis of 3-aza-BCHeps, we investigated the CBA-catalyzed transfer hydrogenation of unsaturated imine 1a using HE as the hydrogen source. Initial experiments showed that the reaction was sluggish at room temperature. Optimization began with imine 1a (0.05 mmol), HE1 (3.0 equiv.), and catalyst C1 (10 mol%) in mesitylene at 50 °C, affording product 2a in 49% yield with 70% ee (Table 1, entry 1). We next evaluated CBAs of different atropisomeric backbones and varied substituents to identify the superior catalyst (Table 1, entries 2-6). The catalyst C3, which features a 4,4’-dimethyl substituted 1,1’-spirobiindane-7,7’-diol (Me-SPINOL) backbone and 9-anthryl groups at the 6,6’-positions, delivered the best performance in terms of enantioselectivity (90% ee). Given the most promising performance of 9-anthryl-derived catalyst (C3, entry 3), the substituent effect at the C10-position was evaluated (entry 7). Pleasingly, the installation of a 3,5-bis(trifluoromethyl)phenyl group at the C10-position of the anthryl ring further boosted both yield and enantioselectivity, furnishing 2a in 78% yield with 94% ee (entry 7). Subsequent optimization of reaction parameters was carried out using C7. Evaluation of alternative reductants, including differently substituted HEs and benzothiazolines (BTs), proved less effective (entries 8-11). Reducing the loading of the original HE1 to 2.5 equiv. maintained high reaction efficiency (81% yield, 94% ee, entry 12). A solvent survey identified mesitylene as optimal; aromatic solvents generally provided higher enantioselectivity than chlorinated or ethereal solvents (entries 13-17), suggesting that the aromatic environment plays a beneficial role in the stereodetermining step. While raising the temperature to 60 °C slightly decreased the enantioselectivity (92% ee, entry 18), extending the reaction time to 72 hours provided the optimal outcome, yielding 2a in 89% isolated yield with 94% ee (entry 19).

Table 1. Screening reaction conditions^a.

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entry	Cat.	solvent	hydrogen source	yield (%)b	ee (%)c
1	C1	mesitylene	HE1	49	70
2	C2	mesitylene	HE1	82	76
3	C3	mesitylene	HE1	74	90
4	C4	mesitylene	HE1	85	77
5	C5	mesitylene	HE1	66	-28
6	C6	mesitylene	HE1	50	-8
7	C7	mesitylene	HE1	78	94
8	C7	mesitylene	HE2	66	93
9	C7	mesitylene	HE3	62	72
10	C7	mesitylene	BT1	8	6
11	C7	mesitylene	BT2	45	46
12d	C7	mesitylene	HE1	81	94
13d	C7	PhCF3	HE1	81	90
14d	C7	toluene	HE1	78	92
15d	C7	EtOAc	HE1	45	84
16d	C7	THF	HE1	39	84
17d	C7	CH2Cl2	HE1	62	86
18d,e	C7	mesitylene	HE1	80	92
19d,f	C7	mesitylene	HE1	94 (89)	94

^a: Unless otherwise indicated, all reactions were performed with 1a (0.05 mmol) and hydrogen source (0.15 mmol) in the presence of catalyst (10 mol%) in solvent (1.0 mL) at 50 °C under argon atmosphere for 48 h; ^b: The yields were determined by ¹H NMR spectra using triphenylmethane as an internal standard; ^c: The ee values were determined by chiral HPLC analysis; ^d: 2.5 equiv. of HE1 was used; ^e: At 60 ℃; ^f: For 72 h, isolated yield was provided in parentheses. HE: Hantzsch ester.

With the optimized reaction conditions in hand, we evaluated the substrate scope of this asymmetric transfer hydrogenation. As depicted in Figure 2, the model reaction of substrate 1a proceeded smoothly on a 0.2 mmol scale, providing 2a in improved isolated yield with excellent enantioselectivity. We then examined a broad range of substituted 3-aza-BCHeps to test the robustness and generality of the protocol. First, variations at the para, meta and ortho-positions of the aryl group attached to the imine were explored. Installation of an electron-donating (2b), electron-neutral (2d), or electron-withdrawing (2e-2h) group at the para-position of the aromatic ring had minimal impact on the reaction outcome, affording the corresponding chiral 3-aza-BCHeps in 85-92% yields with 90-96% ee; a slight erosion in enantioselectivity was observed only with the para-methoxy group (2c). meta-substituted hydrogenation products (2i-2l) exhibited comparable efficiency and enhanced enantiocontrol, whereas ortho-substitution led to a significant decrease in both reactivity and stereoselectivity (2m), likely due to steric hindrance. Replacement of the phenyl ring with a 2-thienyl group or alkyl chain also proved viable (2n-2o). Subsequently, the substituent effect of the bridgehead aryl group was investigated. The electronic nature of the para-substituent exerted negligible influence on the transformation, with the corresponding products (2p-2s) obtained in 79-93% yields with 90-95% ee. However, removal of this aryl group caused a significant erosion in both yield and enantioselectivity (2t). Furthermore, replacement of the benzoyl group at the other bridgehead with 2-thenoyl or acetyl groups afforded products (2u-2v) with excellent stereoselectivity. Finally, substrates decorated with two substituted aryl moieties were examined in this transformation. Functional groups including methyl, fluoro, chloro, and methoxy, regardless of the para- or meta-position on the phenyl ring, were well accommodated with no obvious influence on the efficacy (2w-2aa). The absolute configuration of product 2a was determined by X-ray crystallographic analysis, and those of other products in Figure 2 were assigned by analogy. In summary, the protocol demonstrates a broad substrate scope, accommodating diverse electronic and steric profiles with generally high yields and excellent enantiocontrol, highlighting its synthetic utility for accessing enantioenriched 3-aza-BCHeps.

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Figure 2. Substrate scope of 3-aza-BCHeps. All reactions were performed with 1 (0.2 mmol), HE1 (0.5 mmol) and C7 (10 mol%) in mesitylene (4.0 mL) at 50 °C under argon atmosphere. Isolated yields are shown. ^*Reaction was conducted for 168 hours. BCHeps: bicyclo[3.1.1]heptanes; HE: Hantzsch ester.

To demonstrate the practical utility of our method, we first evaluated its scalability. Under the standard conditions, a scale-up reaction of substrate 1a (2 mmol) provided 3-aza-BCHep 2a in 95% yield with 94% ee. Similarly, 2f was synthesized efficiently on scale (1 mmol), affording the product in 84% yield with 96% ee (Figure 3a). With sufficient quantities of these chiral building blocks available, a series of synthetic transformations were performed. Treatment of 2a with O-(diphenylphosphinyl)hydroxylamine (DPPH) under nitrogen-deletion conditions afforded the saturated BCH 3a in 86% yield^[60-62], with complete preservation of enantioselectivity (94% ee) (Figure 3b), and the configuration of 3a was confirmed by single crystal X-ray diffraction analysis. The same strategy was successfully applied to substrates 2b, 2g, and 2j, affording the corresponding products in good yields with full enantiopurity retention, demonstrating the reliability of this scaffold as a precursor to other high-value bridged systems. Subsequent transformations of 2a gave alcohol 4 (91%) as a pair of diastereoisomers upon reduction with NaBH₄, and afforded terminal alkene 5 (73%) via Wittig olefination (Figure 3c). Moreover, 2h underwent late-stage derivatization via a Buchwald–Hartwig coupling with apixaban, furnishing the drug-conjugated product 6 in 73% yield (Figure 3d). To further explore the catalytic potential of these scaffolds, we evaluated 3-aza-BCHeps 2f and 4 as novel chiral secondary amine organocatalysts. In the asymmetric Friedel–Crafts alkylation of indoles with an α,β-unsaturated aldehyde, these catalysts delivered the desired product 7 in up to 93% yield with 68% ee (Figure 3e). Collectively, these results validate the 3-aza-BCHep framework as a promising new entry for asymmetric organocatalysis. Collectively, these developments in scalable synthesis, strategic skeletal editing, derivatization, and catalytic application validate 3-aza-BCHeps as highly versatile three-dimensional molecular building blocks for synthetic and medicinal chemistry.

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Figure 3. Scale-up experiments and further synthetic applications.

Based on experimental observations and precedents in CBA catalysis^[63-69], we propose a plausible mechanism for the asymmetric transfer hydrogenation (Figure 4). The imine substrate 1a is first activated by catalyst C7 through hydrogen bonding, generating intermediate I. The stereoselective hydride transfer then proceeds via a proposed transition state II, which assembles the activated iminium ion, the HE, and the catalyst in a well-organized network of non-covalent interactions. This key step facilitates the facial-selective reduction, delivering the enantioenriched amine 2a and generating the Brønsted acid–pyridine complex III. Finally, a proton transfer event releases the pyridine byproduct and regenerates the active CBA catalyst, thereby closing the catalytic cycle.

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Figure 4. Proposed reaction pathway.

4. Conclusion

In summary, we have developed a practical and efficient Brønsted acid-catalyzed asymmetric transfer hydrogenation for the synthesis of enantioenriched 3-aza-BCHeps. This method facilitates the transformation of readily accessible unsaturated precursors into chiral saturated architectures under mild conditions, characterized by a broad substrate scope and exceptional enantioselectivity. The high degree of stereocontrol is rationalized by a proposed mechanism involving a well-defined non-covalent interaction network. The synthetic utility of the resulting aza-BCHeps is highlighted by their stereospecific conversion into BCHs via nitrogen deletion, their diverse downstream functionalization, and their successful application as a novel class of chiral secondary amine organocatalysts. Overall, this work provides a robust and step-economical route to an important class of three-dimensional, sp³-rich bioisosteres, thereby expanding the synthetic toolkit for both drug discovery and asymmetric catalysis.

Supplementary materials

The supplementary material for this article is available at: Supplementary materials.

Acknowledgements

We appreciate the assistance of SUSTech Core Research Facilities. Additionally, we would like to acknowledge the AI language models DeepSeek-V3.2 and Doubao Seed 2.0 (March 2026 releases) for their valuable assistance with linguistic revision of this manuscript. The authors take full responsibility for the integrity, originality, and accuracy of the work.

Authors contribution

Tan B, Ding WY: Conceptualization, supervision, writing-original draft.

Deng MX: Investigation, data curation, writing-original draft.

Liu HH: Investigation, formal analysis.

Xiang SH: writing-original draft.

Conflicts of interest

Bin Tan is an Editorial Board Member of Chiral Chemistry. The other authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

The data reported in this paper are available in the main text or supplementary information, including methods, NMR data, HRMS data, HPLC spectra Crystal data and NMR spectra. Crystallographic data for the structures reported in this article have been deposited at the Cambridge Crystallographic Data Centre, under deposition numbers CCDC 2544558 (2a) and CCDC 2544448 (3a).

Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 22301125 to Wei-Yi Ding, Nos. 22425011 and 22231004 to Bin Tan, and No. 22271135 to Shao-Hua Xiang), National Key R&D Program of China (Grant No. 2022YFA15 03703 to Bin Tan), Guangdong Basic and Applied Basic Research Foundation (Grant No. 2026A1515011280 to Wei-Yi Ding and No. 2024B1515020055 to Shao-Hua Xiang), Shenzhen Science and Technology Program (Grant No. KQTD20210811090112004 to Bin Tan) and High Level of Special Funds (Grant No. G03050K003 to Bin Tan).

Copyright

© The Author(s) 2026.