Organocatalytic enantioselective synthesis and derivatizations of bridged N,O-acetal bicyclic scaffolds

Abstract

The 7-oxa-2-azabicyclo[3.2.1]octane framework serves as a key structural motif in bioactive natural products, some of whose natural sources were historically used in traditional remedies. Despite this significance, synthetic routes, particularly enantioselective ones, remain highly underdeveloped, limiting broader pharmaceutical exploration. To address this issue, we report a novel organocatalyzed approach enabling highly diastereo- and enantioselective access to related 7-oxa-2-azabicyclo[3.2.1]oct-3-ene cores with modifiable C–C double bonds. This method exhibits broad functional group compatibility, efficiently generating diverse, multifunctional chiral bicyclic products. Successful chirality-preserving transformations into complex polycyclic and fused systems highlight the strategy's synthetic value for accessing drug-like scaffolds. Mechanistic investigations including DFT calculations provide valuable insight into the reaction pathway governing stereoselectivity control. This work significantly expands the accessible chemical space of chiral bicyclic N,O-acetals and establishes a reliable platform for synthesizing enantiopure bridged bicycles.

---

1 Introduction

It remains an ongoing mission for synthetic chemists to expand libraries of artificial compounds beyond natural sources in complexity and diversity,^1–5 thereby addressing growing industrial and daily-life demands. Among the existing developed methods and technical approaches, organocatalytic cascade reactions possess unique advantages and significant applications, efficiently enabling the orchestrated formation of multiple chemical bonds in a single step. This allows chemists, by leveraging diverse known reactivities and combining ingenious substrate design and reaction planning, to facilitate rapid access to structurally complex natural products and biologically active molecules.^6,7

For instance, 7-oxa-2-azabicyclo[3.2.1]octane scaffolds are core structural units in many natural products,^8–19 some of which exhibit remarkable biological activities, such as guiwuline,¹² acotarine B, acotarine E,¹³ SB-219383,^14,15 and so on (Fig. 1a). Notably, certain natural sources have even been used as traditional medicine for a long time.^{12,13,16–19} However, methods for the enantioselective construction of such structures are rather rare. This methodological gap has constrained its broader application, especially within pharmaceutical contexts. With our continuous research interest in reaction discovery and organocatalysis, we hypothesized that starting from a γ-hydroxy enal,²⁰ a simple and readily available compound integrated with alcohol and enal functionalities, would be a potential solution for the synthesis of bridged bicyclic N,O-acetals enabled by asymmetric iminium catalysis.^21–39 The idea is to utilize a nitrogen containing binucleophilic reagent and the ingeniously introduced γ-hydroxyl group on the enal to undergo a highly regio- and stereoselective yet challenging cascade conjugate addition/cyclization to yield the expected bridged bicyclic compounds containing a N,O-acetal motif. Notably, this single-step reaction design forges three bonds consecutively (Fig. 1b), representing a synthetically ambitious endeavor requiring precise orchestration of the stereoselectivity control model and reactants' reactivity to suppress competing pathways (Fig. 1c).^20,40,41

Fig. 1 Organocatalytic enantioselective synthesis of 7-oxa-2-azabicyclo[3.2.1]oct-3-enes and diverse derivatizations. (a) Representative bioactive natural products containing 7-oxa-2-azabicyclo[3.2.1]octane scaffold. (b) Strategic design for chiral bridged N,O-bicyclic scaffold construction. (c) Challenges within this hypothesis. (d) This work: organocatalytic enantioselective synthesis and derivatizations of bridged N,O-acetal scaffolds.

Actually, by employing a simple unit integration strategy, we have discovered that γ-hydroxy enals/enones can indeed enable a series of novel transformations that differ significantly from those of conventional enal/enone frameworks. These include the neighboring group effect-driven synthesis of polyfunctionalized 5-alkenyl-3-furanones²⁰ and the selective construction of a racemic 2,7-dioxabicyclo[3.2.1]octane scaffold using HCl as a bifunctional catalyst through an in situ generated 2,5-dihydrofuran-2-ol intermediate from γ-hydroxy enones and phenols, which differs a lot mechanistically from this work, and the enantioselectivity control remains challenging.⁴²

Opportunities and challenges go hand in hand; herein, we would like to report an advance in the highly diastereo- and enantioselective synthesis of 7-oxa-2-azabicyclo[3.2.1]oct-3-enes from γ-hydroxy enals and 3-aminoacrylates via organocatalysis. Notable features include: (a) enrichment of the molecule diversity and toolbox for chemists and pharmaceutical scientists; (b) enhanced pharmaceutical potential leveraging the inherent bioactivity of bicyclo[3.2.1]octane cores^43–45 and N,O-acetal motifs;^46–50 (c) olefin functionality handles enabling downstream functionalization; (d) transformable N,O-acetal moieties facilitating access to novel polycyclic and fused systems, enriching the synthetic potential of N,O-acetals;^51,52 (e) broad substrate scope with high efficiency; (f) a green reaction profile with water as the byproduct (Fig. 1d).

2 Results and discussion

2.1 Reaction optimization

Initial reaction screening employed γ-hydroxy enal 1a and ethyl (Z)-3-aminobut-2-enoate 2a with 20 mol% chiral aminocatalyst A and 30 mol% TFA in DCM at 45 °C. Gladly, the desired product 3aa containing a 7-oxa-2-azabicyclo[3.2.1]oct-3-ene scaffold was successfully obtained in 51% yield with 83% ee (Table 1, entry 1).⁵³ Subsequent screening of other chiral amine catalysts revealed A as optimal (for detailed optimizations, see Table S1 in the SI), while catalysts B⁵⁴ and C afforded obviously lower enantioselectivity (Table 1, entries 2 and 3). Subsequent evaluation of Brønsted acids (HCl, trichloroacetic acid, TfOH, TsOH·H₂O) identified TsOH·H₂O as superior, enhancing ee to 85% (Table 1, entry 4). Solvent optimization (DCE, CHCl₃, CCl₄, PhCl, toluene, EtOAc, and MeCN) demonstrated MeCN's advantage taking both efficiency and enantioselectivity into consideration, delivering 68% yield and 90% ee (Table 1, entry 5).

Table 1 Reaction optimization^a

Entry	Variation	Conv. (%)	Yield (%)	ee (%)
a Reaction conditions: (E)-4-hydroxy-4,4-diphenylbut-2-enal 1a (0.2 mmol), ethyl (Z)-3-aminobut-2-enoate 2a (0.4 mmol), catalyst (0.04 mmol) and TFA (0.06 mmol) were stirred in DCM (2 mL) at 45 °C for 12 h. Conversion and yield were determined by NMR using mesitylene as the internal standard. The ee values were determined by HPLC using a chiral stationary phase.
1	None	100	51	83
2	B	100	27	4
3	C	100	41	31
4	TsOH·H2O	100	47	85
5	TsOH·H2O/CH3CN	100	68	90
6	A (25 mol%)/TsOH·H2O/CH3CN	100	78	93
7	NO A based on entry 6	87	32	0
8	NO TsOH·H2O based on entry 6	31	0	—
9	NO A and TsOH·H2O based on entry 6	13	0	—
10	A and TsOH·H2O (25 mol%)/CH3CN	100	81	93

---

Further refinement established a better outcome with 25 mol% A in MeCN: complete conversion within 24 h afforded 3aa in 78% yield and 93% ee (Table 1, entry 6). Notably, a control experiment suggested a possible background reaction enabled by TsOH·H₂O to form racemic 3aa in 32% yield (Table 1, entry 7). Other control experiments demonstrated that no formation of 3aa occurred without the acid or both catalyst A and TsOH·H₂O (Table 1, entries 8 and 9). Finally, fine-tuning of the TsOH·H₂O amount to 25 mol% was proved to be the best, yielding 3aa in 81% yield and 93% ee (Table 1, entry 10).

2.2 Scope of the reaction

Having established the best conditions for the preparation of 7-oxa-2-azabicyclo[3.2.1]oct-3-ene scaffolds, we next started the substrate scope studies (Fig. 2). Apart from the template product 3aa formed in 79% yield with 93% ee, its enantiomer ent-3aa could be obtained in 74% yield with −94% ee in the presence of ent-A, providing reliable access to both configurations of 7-oxa-2-azabicyclo[3.2.1]oct-3-ene scaffolds. In addition, the γ-substituents could be varied in a broad scope, including phenyls substituted with electron withdrawing 4-fluoride (3ba), 4-chloride (3ca), 4-bromide (3da),⁵⁵ and 3-chloride (3ea), and electron donating 4-methyl (3fa) and 4-methoxy (3ga), to afford the corresponding products in 69–80% yield with 94–95% ee, as well as 2-naphthyl (3ha) in 72% yield with 92% ee, 9-fluorenylidene (3ia) in 67% yield with 93% ee, and 5H-dibenzo[a,d][7]annulen-5-ylidene (3ja) in 84% yield and 90% ee. Besides, the structure and absolute configuration of 3ja were further confirmed by a single-crystal X-ray diffraction study.

Fig. 2 Substrate scope. Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), aminocatalyst (0.1 mmol) and TsOH·H₂O (0.1 mmol) were stirred in ACN (4 mL) at 45 °C for 24–50 h. The ee values were determined by HPLC using a chiral stationary phase. The dr values were determined by ¹H NMR. ^aA2 (0.12 mmol) and TsOH·H₂O (0.12 mmol), rt. ^bRt without acid. ^cA (0.12 mmol) and TsOH·H₂O (0.12 mmol), 10 °C. ^d65 °C. ^eA2 (0.12 mmol) and TsOH·H₂O (0.12 mmol). ^fA (0.12 mmol) and TsOH·H₂O (0.12 mmol), rt.

What's more, alkyl substituents are also tolerated at the γ-position, including methyl (3ka), benzyl (3la), and 1,4-butanediyl (3ma), to afford the products in 58–71% yield with 88–94% ee. Interestingly, the structures of 3ia, 3ja, and 3ma also contain a spirocyclic moiety beyond the 7-oxa-2-azabicyclo[3.2.1]oct-3-ene scaffold. When R¹ and R² at the γ-position are both hydrogens, the desired product 3na is obtained in moderate yield with 95% ee. Notably, the 2-oxa-8-azabicyclo[3.3.1]non-6-ene scaffold 3oa could also be synthesized from a δ-hydroxy enal in high yield with 88% ee. While if R¹ and R² are different, for example, one is phenyl and the other is methyl, 3pa was formed with 1 : 1 dr.

For 3-aminoacrylates, the ester part could be changed to methyl (3ab), isopropyl (3ac), benzyl (3ad), and (E)-3-phenylprop-2-en-1-yl (3ae), affording 52-78% yield with 91-95% ee. Meanwhile, the R³ group could be varied to ethyl, phenyl, 2-thienyl, and 2-furanyl to deliver 3af to 3ai in moderate to good yield with 86–95% ee. Then, N-methyl substituted 3-aminoacrylate also took part in the reaction smoothly to generate 3aj in 59% yield with 91% ee under aminocatalyst A2. The application of this transformation could further be highlighted by the tolerance of sitagliptin (a therapeutic drug for diabetes) derived 3-aminoacrylate to afford 3ak in good enantioselectivity. Starting from (E)-4-hydroxybut-2-enal, the corresponding products 3ne and 3nl were formed smoothly with good enantioselectivity by changing the ester moiety to (E)-3-phenylprop-2-en-1-yl and cyanoethyl, respectively.

2.3 Synthetic potentials and applications

The developed strategy could be applied to the gram scale synthesis of 3aa, while maintaining high enantioselectivity (Fig. 3a). Simultaneously, thanks to the N,O-acetal moiety and olefin functionality, the target 7-oxa-2-azabicyclo[3.2.1]oct-3-ene products enable versatile derivatizations to afford synthetically useful chiral polycyclic and fused systems that otherwise could not be easily accessed (Fig. 3a). For instance, trifluoromethyl containing polycyclic compounds 5 and 5′ were obtained in 74% yield and ∼1.1 : 1 dr with 95% ee and 93% ee, respectively, by the reaction of 3aa with methyl 3,3,3-trifluoropyruvate. The structure and absolute configuration of 5′ were also confirmed by a single-crystal X-ray diffraction study.

Fig. 3 Synthetic potentials. (a) Gram-scale reaction and transformation to 5,6,7,7a-tetrahydrofuro[3,4-c]pyridin-3(1H)-ones as well as other applicable structures. (b) Plausible pathway for the formation of 8–11 from 3aa.

Fluoride containing compound 6 could be formed in 78% yield with 95% ee by the simple treatment of 3aa with Selectfluor. Notably, introducing fluoride and fluoride containing groups into the bridged bicyclic compounds would help improve the pharmacokinetic and molecule anti-oxidative properties, thus affording enhanced bioactivities.⁵⁶ Next, the reaction of 3aa with NBS (2.2 equiv.) afforded dibromomethylated product 7 in 66% yield with 95% ee as well. It is of interest that bridged bicyclic 3aa could be transferred to fused compound 8 through skeletal rearrangement in the presence of LiAlH₄ with full enantioselectivity retention.

Herein, LiAlH₄ might first act as a base to remove the proton on nitrogen to form nitrogen anion intermediate Int-A, and then the N,O-acetal decomposes to yield Int-B, followed by lactonization via intramolecular transesterification to generate Int-C. Ultimately, nucleophilic hydride 1,2-addition to an imine would afford 8 containing 5,6,7,7a-tetrahydrofuro[3,4-c]pyridin-3(1H)-one scaffolds (Fig. 3b). Inspired by this skeletal rearrangement strategy, compound 9 was formed in 61% yield with 96% ee from 3aa in the presence of NaOH and an indole nucleophile. It is the nitrogen atom at the 1-position of indole attack the imine in this case based on structural analysis. Remarkably, compound 10 could be formed in 96% yield with 95% ee from the reaction of 3aa and PhMgBr, with the Grignard reagent acting as both the base and the nucleophile. The structure and absolute configuration of 10 are also confirmed by a single-crystal X-ray diffraction study.

When CH₃MgBr was used, corresponding product 11 was obtained in 82% yield and 93 : 7 dr with 95% ee. The tetrahydropyridine ring in 11 could further be oxidized to aromatic pyridine 12 using DDQ. The reaction of 3na with 3-methylindole also afforded 13 in 70% yield and 93% ee.

2.4 Mechanistic studies

To elucidate the mechanism of this reaction, detailed mechanistic studies were undertaken. Initially, the template reaction at room temperature yielded 3aa in 47% yield with 96% ee, along with a byproduct 14 (15% yield, 98% ee). Notably, compound 14 could be converted to the product 3aa under the standard conditions in 80% yield (>99% ee), concomitantly generating 2a in 61% yield (Fig. 4a, condition A). The release of 2a from 14 was shown to be independent of the aminocatalyst, as 3aa formation proceeded with nearly identical results using only 25 mol% TsOH·H₂O (Fig. 4a, condition B). In contrast, the reaction conducted in the absence of both an aminocatalyst and TsOH·H₂O afforded 3aa in only 25% yield and 2a in 21% yield, with 54% of compound 14 recovered (Fig. 4a, condition C). These findings strongly suggest that compound 14 likely acts as an intermediate and that the acid TsOH·H₂O is responsible for its transformation into the final product 3aa. Further evidence from the reaction monitoring also supported the intermediacy of 14.

Fig. 4 Mechanistic studies. (a) Characterization of the possible intermediate. (b) Effect of N-substitution on the 3-aminoacrylate: yield and ee. (c) Effect of Z/E configuration on the 3-aminoacrylate: yield and ee. (d) Non-linear effect study.

Next, although the N-methyl substituted substrate ultimately afforded product 3aj in satisfactory yield and enantioselectivity after simple optimization, the N-substituents on the 3-aminoacrylates exerted a significant influence on both the yield and enantioselectivity. For example, under the standard conditions: N-unsubstituted ethyl (Z)-3-aminobut-2-enoate (2a) afforded 3aa in 79% yield with 93% ee; N-methyl substituted ethyl (Z)-3-(methylamino)but-2-enoate (2j) afforded 3aj in 68% yield with a significantly lower ee of 58%; N-benzyl substituted ethyl (Z)-3-(benzylamino)but-2-enoate (2l) afforded 3al in only 46% yield with 24% ee (Fig. 4b). These results demonstrate the pronounced impact of steric hindrance on both reactivity and enantioselectivity.

Furthermore, the geometry of the double bond in the 3-aminoacrylates also significantly affected the reaction yield. As shown, the reaction utilizing predominantly the Z-isomer 2a (Z/E > 20 : 1) afforded 3aa in 81% yield with 93% ee. In contrast, employing a mixture of 2a (Z/E = 4 : 1) afforded 3aa in a lower yield of 72% (94% ee). Increasing the loading of this Z/E mixture (4 : 1) to 2.5 equivalents improved the yield of 3aa to 78% while maintaining the same enantioselectivity (94% ee) (Fig. 4c). These results suggest a difference in reactivity between the Z- and E-configured olefins in the transition state. A study of the nonlinear effect revealed a clear linear correlation between the ee of the product and that of the catalyst. This linear relationship demonstrates that only one chiral aminocatalyst molecule is involved in the enantioselectivity-control step (Fig. 4d).

Based on the mechanistic investigations, a preliminarily plausible reaction mechanism was proposed (Fig. 5). The chiral iminium intermediate Int-D forms from γ-hydroxy enal 1a and the aminocatalyst. Subsequently, 2a undergoes a stereoselective nucleophilic 1,4-addition to Int-D, affording intermediate Int-E. Within this step, the Z-configured isomer of 2a likely exhibits higher reactivity than its E-counterpart, potentially due to an intramolecular hydrogen-bonding interaction.⁵⁷ Intermediate Int-E then diverges along two possible pathways: (i) hydrolysis of Int-E yields Int-F, which goes through consecutive intramolecular cyclization to afford bridged bicyclic product 3aa ensured by the γ-OH and the NH₂ moiety in the 3-aminoacrylate (Fig. 5, Path A);⁵⁸ (ii) a second molecule of 2a undergoes 1,2-addition to the imine moiety in Int-E, leading to the formation of Int-G. Hydrolysis of Int-G then affords Int-H. Subsequently, intramolecular condensation generates Int-I, with elimination of one water molecule assisted by the acid. Therefore, two competing pathways exist. As compound 14 is observed in the reaction, it can be explained by the cyclization from another molecule of 3-aminoacrylate via Int-I, followed by imine-enamine isomerization (Int-J). The other possibility involves the direct intramolecular attack of the γ-OH to the imine within Int-I to afford Int-K, accompanied by the elimination of one molecule of 2a. Final isomerization would yield product 3aa. Notably, the conversion between Int-I/Int-J and compound 14 should be reversible as 14 could be transferred to 3aa in the presence of acid as proved by mechanistic studies in Fig. 4a (Fig. 5, Path B).

Fig. 5 Plausible mechanism.

Further density functional theory (DFT) calculations were conducted on the nucleophilic attack steps (Fig. 6). Our calculations show that 2a is more stable with the intramolecular hydrogen bond and this trend is preserved in transition states (see Fig. S6 in the SI), which is consistent with the experimental observations that the Z/E ratio of 2a does not affect the stereoselectivity. Herein, our discussion is focused on the transition states with this intramolecular hydrogen bond retained. As shown in Fig. 6, compared with the most favorable transition state TS_RS, in both TS_SS and TS_SR, 2a approaches the β-carbon of Int-D from the upper side, which is congested due to the steric hindrance of the catalyst, evidenced by an elongated C–C bond length (larger than 2.34 Å). Further distortion/interaction analysis identified significantly weaker interaction energies between the catalyst and 2a. On the other hand, in TS_RR, the steric hindrance from the methyl group of 2a induces the distortion of the C=C double bond of the eniminium ion intermediate with a smaller Wiberg bond index (WBI) of 1.603 (see the Newman projection). This distortion does not occur in TS_RS because the methyl group is oriented towards empty space, and the corresponding C=C double bond has a stronger WBI of 1.626. These results are consistent with the observed enantioselectivity and X-ray analysis of the products.

Fig. 6 DFT calculations of the stereo-determining transition states.

3 Conclusions

In conclusion, an innovative and efficient organocatalytic strategy has been developed for the highly diastereo- and enantioselective synthesis of 7-oxa-2-azabicyclo[3.2.1]oct-3-ene scaffolds. This reaction demonstrates good functional group tolerance, providing access to a series of multifunctional chiral bridged bicyclic compounds. These products feature modifiable N,O-acetals, C–C double bonds, and carboxylic acid derivatives, offering enhanced potential for facile modification. Detailed mechanistic studies provide valuable understanding of the complex pathway involving concurrent formation of three bonds in a single step. Further DFT calculations disclosed the origination and control of enantioselectivity within the conjugate addition step. Subsequent synthetic transformations and skeletal rearrangement to diverse polycyclic and fused ring systems with complete chirality transfer underscore the method's potential utility in organic synthesis and drug discovery. This approach not only enriches the molecular diversity of chiral bridged bicyclic N,O-acetals but also establishes a robust platform for preparing optically active bridged bicyclic compounds. Research applying this strategy to construct further chiral bridged bicyclic compounds is currently underway in our laboratory.

Author contributions

D. M. designed the project and directed the work. J. T. and N. Y. developed the reaction, investigated the substrate scope and studied the reaction mechanism. Y. W. directed the bioactivity test work. J. Z. investigated the anti-proliferative activity studies. X. J. performed the DFT calculations under the guidance of Z. Z. All authors contributed to the experimental design and the interpretation of data. J. T., Z. Z., Y. W., and D. M. wrote the paper with input from all authors.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2489425–2489427 ((for 3ja), (for 5′), and (for 10)) contain the supplementary crystallographic data for this paper.^59a–c

The supporting data have been provided as part of the supplementary information (SI). Supplementary information: Table S1, NMR spectra and further experimental details. See DOI: https://doi.org/10.1039/d6sc01676f.

Acknowledgements

Financial support from the National Natural Science Foundation of China (Grant No. 22201187) and the starting grant from Capital Medical University (Grant No. 3100-12500121 and 3100-12600118) are gratefully acknowledged. The authors thank the assistance provided by the Analytical Testing Center of Capital Medical University.

Notes and references

1. K. C. Nicolaou, C. R. H. Hale, C. Nilewski and H. A. Ioannidou, Chem. Soc. Rev., 2012, 41, 5185–5238.
2. L. Yang, K. L. Chan, K. K. Cheung, P. Chiu, Z. Lin and J. Sun, Nat. Synth., 2025, 4, 1223–1231.
3. S. Caille, S. Cui, M. M. Faul, S. M. Mennen, J. S. Tedrow and S. D. Walker, J. Org. Chem., 2019, 84, 4583–4603.
4. B. A. Wright and R. Sarpong, Nat. Rev. Chem., 2024, 8, 776–792.
5. L. Min, Y.-J. Hu, J.-H. Fan, W. Zhang and C.-C. Li, Chem. Soc. Rev., 2020, 49, 7015–7043.
6. C. Grondal, M. Jeanty and D. Enders, Nat. Chem., 2010, 2, 167–178.
7. P. Bonilla, Y. P. Rey, C. M. Holden and P. Melchiorre, Angew. Chem., Int. Ed., 2018, 57, 12819–12823.
8. F.-P. Wang, Z.-B. Li, X.-P. Dai and C.-S. Peng, Phytochemistry, 1997, 45, 1539–1542.
9. D.-L. Chen, L.-Y. Lin, Q.-H. Chen, X.-X. Jian and F.-P. Wang, J. Asian Nat. Prod. Res., 2003, 5, 209–213.
10. P. Tang, D. L. Chen, X. X. Jian and F. P. Wang, Chin. Chem. Lett., 2007, 18, 704–707.
11. W. Xu, L. Shan, S. Huang, S. Li and X. Zhou, Chin. J. Org. Chem., 2016, 36, 2739–2742.
12. D.-P. Wang, H.-Y. Lou, L. Huang, X.-J. Hao, G.-Y. Liang, Z.-C. Yang and W.-D. Pan, Bioorg. Med. Chem. Lett., 2012, 22, 4444–4446.
13. Y. Si, X. Ding, T. A. Adelakuna, Y. Zhang and X.-J. Hao, Fitoterapia, 2020, 147, 104738.
14. A. L. Stefanska, N. J. Coates, L. M. Mensah, A. J. Pope, S. J. Ready and S. R. Warr, J. Antibiot., 2000, 53, 345–350.
15. C. S. V. Houge-Frydrych, S. A. Readshaw and D. J. Bell, J. Antibiot., 2000, 53, 351–356.
16. T.-P. Yin, L. Cai, Y. Xing, J. Yu, X.-J. Li, R.-F. Mei and Z.-T. Ding, J. Asian Nat. Prod. Res., 2016, 18, 603–610.
17. R. Guo, C. Guo, D. He, D. Zhao and Y. Shen, Chin. J. Chem., 2017, 35, 1644–1647.
18. T. Yin, Y. Shu, R. Mei, J. Wang, L. Cai and Z. Ding, Biochem. Syst. Ecol., 2018, 81, 99–101.
19. Z. Lv, L. Gao, C. Cheng, W. Niu, J.-L. Wang and L. Xu, Chem.–Asian J., 2018, 13, 955–958.
20. J. Tan, C. Xie, Y. Qiu and D. Ma, Chin. J. Chem., 2025, 43, 1643–1650.
21. A. Erkkilä, I. Majander and P. M. Pihko, Chem. Rev., 2007, 107, 5416–5470.
22. D. W. C. MacMillan, Nature, 2008, 455, 304–308.
23. G. Bartoli and P. Melchiorre, Synlett, 2008, 12, 1759–1772.
24. S.-H. Xiang and B. Tan, Nat. Commun., 2020, 11, 3786.
25. Z.-C. Chen, W. Du and Y.-C. Chen, Chin. J. Chem., 2021, 39, 1775–1786.
26. G. Zhan, W. Du and Y.-C. Chen, Chem. Soc. Rev., 2017, 46, 1675–1692.
27. Y. Gu, Y. Wang, T.-Y. Yu, Y.-M. Liang and P.-F. Xu, Angew. Chem., Int. Ed., 2014, 53, 14128–14131.
28. A. Noole, M. Borissova, M. Lopp and T. Kanger, J. Org. Chem., 2011, 76, 1538–1545.
29. G. Bergonzini and P. Melchiorre, Angew. Chem., Int. Ed., 2012, 51, 971–974.
30. X. Jiang, B. Tan and C. F. Barbas III, Angew. Chem., Int. Ed., 2013, 52, 9261–9265.
31. G. Luo, Z. Huang, S. Zhuo, C. Mou, J. Wu, Z. Jin and Y. R. Chi, Angew. Chem., Int. Ed., 2019, 58, 17189–17193.
32. S. Hu, J. Wang, G. Huang, K. Zhu and F. Chen, J. Org. Chem., 2020, 85, 4011–4018.
33. K. Daskalakis, N. Umekubo, S. Indu, G. Kawauchi, T. Taniguchi, K. Monde and Y. Hayashi, Angew. Chem., Int. Ed., 2025, 64, e202500378.
34. F. Wu, Q. Peng, Y.-J. Li, Y. Xiao and J.-J. Feng, Chin. J. Chem., 2026, 44, 241–250.
35. S. Brandau, A. Landa, J. Franzén, M. Marigo and K. A. Jørgensen, Angew. Chem., Int. Ed., 2006, 45, 4305–4309.
36. A. Carlone, S. Cabrera, M. Marigo and K. A. Jørgensen, Angew. Chem., Int. Ed., 2007, 46, 1101–1104.
37. S. Cabrera, J. Alemán, P. Bolze, S. Bertelsen and K. A. Jørgensen, Angew. Chem., Int. Ed., 2008, 47, 121–125.
38. E. Reyes, H. Jiang, A. Milelli, P. Elsner, R. G. Hazell and K. A. Jørgensen, Angew. Chem., Int. Ed., 2007, 46, 9202–9205.
39. G. Dickmeiss, K. L. Jensen, D. Worgull, P. T. Franke and K. A. Jørgensen, Angew. Chem., Int. Ed., 2011, 50, 1580–1583.
40. J. Tan, C. Xie, N. Yusuipujiang, M. Xu, L. Wang and D. Ma, J. Org. Chem., 2025, 90, 8687–8692.
41. T. Lei, J. Tan, Y. Zhang and D. Ma, Org. Biomol. Chem., 2025, 23, 8170–8175.
42. C. Xie, J. Tan, J. Zhang, Y. Zhang, Y. Wang and D. Ma, Chin. J. Chem., 2026, 44, 1419–1425.
43. M.-H. Filippini and J. Rodriguez, Chem. Rev., 1999, 99, 27–76.
44. M. Presset, Y. Coquerel and J. Rodriguez, Chem. Rev., 2013, 113, 525–595.
45. K. Gao, J. Hu and H. Ding, Acc. Chem. Res., 2021, 54, 875–889.
46. R. A. Mosey and P. E. Floreancig, Nat. Prod. Rep., 2012, 29, 980–995.
47. R. H. Cichewicz, F. A. Valeriote and P. Crews, Org. Lett., 2004, 6, 1951–1954.
48. R. N. Enright, J. L. Grinde, L. I. Wurtz, M. S. Paeth, T. R. Wittman, E. R. Cliff, Y. T. Sankari, L. T. Henningsen, C. Tan, J. D. Scanlon and P. H. Willoughby, Tetrahedron, 2016, 72, 6397–6408.
49. A. D. Kouvelas, M. G. Kallitsakis and I. N. Lykakis, Chem.–Eur. J., 2025, 31, e202500413.
50. J. S. Novais, M. F. Carvalho, M. S. Ramundo, C. O. Beltrame, R. B. Geraldo, A. K. Jordão, V. F. Ferreira, H. C. Castro and A. M. S. Figueiredo, Sci. Rep., 2020, 10, 19631.
51. J. Sun, S. Wang, K. C. Harper, Y. Kawamata and P. S. Baran, Nat. Chem., 2025, 17, 44–53.
52. P. Oroz, C. Bretón, M. Torres, I. Olagaray, E. Sainz, C. M. Segovia, A. Avenoza, J. H. Busto, F. Corzana, G. Jiménez-Osés and J. M. Peregrina, J. Org. Chem., 2025, 90, 16238–16248.
53. Hantzsch ester byproduct 4aa (14% yield) was formed alongside via aldehyde cyclization (for details, see Table S1). The possible mechanism for its formation is also proposed in the SI, see Fig. S4..
54. M. Silvi, C. Verrier, Y. P. Rey, L. Buzzetti and P. Melchiorre, Nat. Chem., 2017, 9, 868–873.
55. Initial screening revealed anti-proliferative properties against 4T1 cells in several compounds, with 3da exhibiting an IC50 of 31.3 ± 7.2 µM. For details, see the anti-proliferative activity test part in the SI..
56. S. Baldon, L. Dell'Amico and S. Cuadros, Eur. J. Org Chem., 2024, 27, e202400604.
57. X. Zhang, X. Lu, Y. Zou, J. Lang, Y. Wang and G. Zhao, Org. Biomol. Chem., 2025, 23, 4884–4887.
58. For a more detailed mechanism diagram, see Fig. S3 in the SI..
59. (a) CCDC 2489425: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2pkg1s; (b) CCDC 2489426: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2pkg2t; (c) CCDC 2489427: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2pkg3v.

---

Footnote

† These authors contributed equally.

---