Chiral benzo[2.2.1] α-hydroxyketones from a dirhodium(II)/bisphosphine-catalyzed desymmetrization addition reaction

Abstract

The [2.2.1]-bridged bicyclic framework represents a privileged structural motif prevalent in numerous bioactive molecules and functional materials. The development of efficient synthetic methods for constructing these valuable architectures remains highly desirable. In this study, we report a dirhodium(II)/bisphosphine-catalyzed desymmetrization reaction of benzobicyclo[2.2.1]heptane-2,3-diones with arylboronic acids. This transformation delivers enantioenriched benzo[2.2.1] α-hydroxy ketones with excellent enantioselectivity (up to 94% ee) across a diverse substrate scope. The synthetic utility of these chiral products is demonstrated through several transformations, including the preparation of a chiral phosphine.

---

Introduction

The [2.2.1]-bridged bicyclic scaffold represents a privileged structural motif that appears extensively in natural products,¹ bioactive molecules,² and functional materials,³ exhibiting remarkable versatility in both biological applications and organic synthesis. This structural framework underpins numerous pharmaceutically significant compounds, exemplified by biperiden, which effectively alleviates extrapyramidal disorders secondary to neuroleptic drug administration with an IC₅₀ value of 9 μM (Fig. 1a).⁴ Cyclothiazide, a potent and orally effective therapeutic agent, is widely employed in the management of hypertension and heart failure.⁵ Natural products containing this scaffold also demonstrate promising bioactivity, as illustrated by guaianodilactone C, a sesquiterpene lactone dimer isolated from Carpesium faberi that exhibits cytotoxicity against human leukemia (CCRF-CEM) cells with an IC₅₀ value of 4.74 μM.⁶

Fig. 1 [2.2.1]Bicycles in (a) bioactive molecules and (b) functional materials.

Beyond pharmaceutical applications, the [2.2.1]bridged bicyclic framework serves as a fundamental component in numerous synthetically valuable molecules (Fig. 1b). Norbornene (NBE) and its derivatives function as crucial shuttles for “palladium migration” in the Catellani reaction,⁷ while OxaPhos represents an important chiral phosphine ligand employed in ruthenium-catalyzed arylation of aldehydes.⁸ Additionally, (R)-THENA-Cl has established itself as an effective chiral resolving agent for the enantiomeric resolution of 7,7′-disubstituted 1,1′-bi-2-naphthols.⁹ These diverse applications underscore the significant synthetic utility and structural importance of the [2.2.1]-bridged bicyclic architecture in contemporary chemical research.

The [2.2.1]-bridged bicyclic framework has attracted significant attention due to its diverse bioactivities and important applications, prompting extensive research into efficient synthetic approaches for constructing these valuable molecular architectures. Current methodologies for accessing enantioenriched [2.2.1]-bridged bicycles primarily include cyclopenta-1,3-diene involved enantioselective cycloaddition reactions¹⁰ and metal-catalyzed addition processes. The latter strategy typically employs metals such as Cu, Co, Fe, Rh, Pd, and Ru with [2.2.1]bicyclic alkenes as substrates, incorporating various nucleophilic reagents including boron, carbon, and nitrogen-based nucleophiles.¹¹ Dirhodium(II) complexes have been extensively utilized as catalysts for carbene and nitrene-mediated X–H insertion reactions, cyclopropanation, etc. These transformations can be rendered asymmetric through the incorporation of chiral carboxylic acids or chiral phosphoric acids. Modification of dirhodium(II) complexes with an additional ligand at the axial site of the paddlewheel Rh(II)–Rh(II) structure induces novel catalytic activities. However, stereochemical control by these complexes is hindered by the significant distance between the reactive site and the chiral ligand, which resides at the opposite axial position, thus limiting applications in asymmetric catalysis. Recently, our laboratory developed a novel dirhodium(II)-bisphosphine catalytic system that exhibits unique reactivity patterns and superior stereochemical control. In this system, one of the phosphine moieties sitting at the bridging site of the dirhodium(II) structure establishes a well-defined chiral environment that enables highly enantioselective addition reactions, demonstrating particular efficiency for cyclic 1,2-dicarbonyl compounds.¹² However, the substrate scope was limited to aryl ketone derivatives. An attempt using 1,2-cyclohexanedione as the substrate was unsuccessful, likely due to its facile enolization. By contrast, the carbonyl groups in the bridged structure of bicyclo[2.2.1]heptane-2,3-diones are known to have a low enolization tendency, making them suitable candidates for 1,2-addition reactions. Building upon these findings, herein we report a Rh₂(O₂CCF₃)₄/GarPhos-catalyzed desymmetrization reaction of benzobicyclo[2.2.1]heptane-2,3-diones, accessing enantioenriched [2.2.1]-bridged bicyclic structures (Scheme 1c).

Scheme 1 Enantioselective strategies for the synthesis of [2.2.1]-bridged bicycles.

Results and discussion

Optimization

To test our hypothesis, we initiated our investigation using 1,4-dihydro-1,4-methanonaphthalene-2,3-dione (1a)¹³ and naphthalen-2-ylboronic acid as model substrates. Our initial screening revealed that electron-deficient biphosphine ligands were essential for this reaction. Specifically, the catalyst system comprising Rh₂(O₂CCF₃)₄ and (R)-BTFM-GarPhos (L1) afforded the desired product 3a in 62% yield with 87% enantiomeric excess (Table 1, entry 1). In contrast, replacing the trifluoromethyl groups with methyl groups, as in (R)-xyl-GarPhos (L2), completely suppressed product formation (entry 2). The Josiphos ligand family (L3–L5) proved similarly ineffective, generating only trace amounts of 3a with poor enantioselectivity (entries 3–5). We then explored different base additives to improve the reaction's performance. Potassium fluoride (KF) enhanced both yield and stereoselectivity, which was even more effective than CsF (entries 8 and 9), whereas K₂CO₃ and organic bases such as DABCO showed little to no activity (entries 6 and 7). Subsequently, we re-examined the effectiveness of other rhodium catalysts, Rh₂(OAc)₄ and Rh₂(O₂CC₇H₁₅-n)₄, which resulted in slightly lower yields (entries 10 and 11). The addition of 15 mol% CF₃CO₂Na, thought to suppress decomposition of Rh₂(O₂CCF₃)₄, further improved the yield (entry 12). Moreover, with 3.5 mol% Rh₂(O₂CCF₃)₄, optimizing the loading of CF₃CO₂Na led to an optimal yield of 98% (with 30 mol% CF₃CO₂Na) without compromising enantioselectivity (entries 13 and 14). The reaction also proceeded smoothly on a 1.0 mmol scale, demonstrating the robustness of this protocol (entry 15).

Table 1 Optimization of reaction conditions^a

Entry^a	[Rh]	Ligand	Base/equiv.	Solvent	Additive per mol%	Yield^b/%	ee^c/%
a Conditions: 1a (0.10 mmol), 2a (0.20 mmol, 2.0 equiv.), [Rh2X4] (2.5 mol%), ligand (5.0 mol%), and base (2.0 equiv.) in toluene/H2O = 2.0/0.2 mL at 80 °C for 24 h. b Isolated yields are given. c ee values were determined by HPLC on a chiral column. d [Rh2(O2CCF3)4] (3.5 mol%) and L1 (6.0 mol%). e The reaction scale of 1a was 1.0 mmol.
1	Rh2(O2CCF3)4	L1	LiOH·H2O (5.0)	Toluene	—	62	87
2	Rh2(O2CCF3)4	L2	LiOH·H2O (5.0)	Toluene	—	ND	—
3	Rh2(O2CCF3)4	L3	LiOH·H2O (5.0)	Toluene	—	Trace	36
4	Rh2(O2CCF3)4	L4	LiOH·H2O (5.0)	Toluene	—	Trace	35
5	Rh2(O2CCF3)4	L5	LiOH·H2O (5.0)	Toluene	—	Trace	15
6	Rh2(O2CCF3)4	L1	K2CO3 (1.0)	Toluene/H2O (10 : 1)	—	Trace	90
7	Rh2(O2CCF3)4	L1	DABCO (1.0)	Toluene/H2O (10 : 1)	—	ND	—
8	Rh2(O2CCF3)4	L1	KF (2.0)	Toluene/H2O (10 : 1)	—	76	90
9	Rh2(O2CCF3)4	L1	CsF (2.0)	Toluene/H2O (10 : 1)	—	65	90
10	Rh2(OAc)4	L1	KF (2.0)	Toluene/H2O (10 : 1)	—	73	90
11	Rh2(O2CC7H15)4	L1	KF (2.0)	Toluene/H2O (10 : 1)	—	70	90
12	Rh2(O2CCF3)4	L1	CsF (2.0)	Toluene/H2O (10 : 1)	CF3CO2Na (15)	80	91
13^d	Rh2(O2CCF3)4	L1	KF (2.0)	Toluene/H2O (10 : 1)	CF3CO2Na (20)	91	91
14^d	Rh2(O2CCF3)4	L1	KF (2.0)	Toluene/H2O (10 : 1)	CF3CO2Na (30)	98	91
15^d^,^e	Rh2(O2CCF3)4	L1	KF (2.0)	Toluene/H2O (10 : 1)	CF3CO2Na (30)	95	91

---

Substrate scope

With the optimized conditions established, we investigated the substrate scope of this reaction as detailed in Scheme 2. First, we examined a diverse array of arylboronic acids as arylation reagents, including substituted phenylboronic acids, heteroarylboronic acids, and naphthylboronic acids. Phenylboronic acids bearing various para-substituents demonstrated good reactivity (3b–3m). The weakly electron-withdrawing, electron-donating, and neutral groups maintained high stereoselectivity (3b–3e, 3h, and 3i–3k), while strongly electron-withdrawing substituents would slightly diminish the enantioselectivity (3f, 3g, 3l and 3m). Substituents at the meta and ortho positions of phenylboronic acids exhibited similar electronic effects on stereoselectivity (3n–3v); however, 3,5-dimethylphenylboronic acid unexpectedly resulted in low enantioselectivity (82% ee) (3x). Furthermore, heterocyclic boronic acids, e.g. 3-furyl and 3-thiophenyl boronic acids, proved to be compatible substrates, providing corresponding α-hydroxy ketones 3y and 3z with moderate yields and enantiomeric excesses. Benzo-heterocyclic and 9H-fluorenyl-derived boronic acids were also well-tolerated, affording the desired products (3aa–3hh) in excellent yields with good enantiopurity. However, 2-pyridinylboronic acid failed to give the desired product. When substituted naphthyl-2-boronic acids containing various functional groups were subjected to the optimal conditions, the corresponding products (3ii–3oo) maintained both good stereoselectivity and high yields. We further evaluated the scope of bridged [2.2.1]diketones. All tested naphtho- and substituted benzo-derivatives were smoothly converted to their corresponding alcohols (3pp–3ss) with good yields and high enantiomeric excesses. In contrast to 1a, bicyclo[2.2.1]hept-5-ene-2,3-dione, which lacks the fused benzene ring, afforded only a trace mixture, likely comprising the exo and endo isomers.

Scheme 2 Substrate scope. Conditions: 1 (0.20 mmol), 2 (0.40 mmol, 2.0 equiv.), Rh₂(O₂CCF₃)₄ (3.5 mol%), L1 (6.0 mol%), CF₃CO₂Na (30 mol%), and KF (2.0 equiv.) in toluene/H₂O = 4.0/0.4 mL at 80 °C for 24 h.

To demonstrate the synthetic utility of these compounds, we performed a series of transformations, as shown in Scheme 3. The hydroxyl group in compound 3a could be methylated with methyl iodide to afford methyl ether in moderate yield. Notably, treatment of 3a with TMSN₃ in HFIP/CF₃CO₂H produced compound 5 with inversion of the corresponding chiral center from S to R configuration, suggesting the involvement of a carbocation intermediate. Subsequently, compound 4 was subjected to reduction with SmI₂ in a THF/MeOH mixed solvent, furnishing the corresponding ketone 6 in 99% yield. Deprotonation of 6 with NaH, followed by a reaction with PhNTf₂, yielded trifluoromethanesulfonate 7 in a moderate yield. This intermediate was further utilized in a palladium-catalyzed coupling reaction with diphenylphosphine oxide, followed by reduction, to deliver a chiral phosphine 9. Additionally, compound 6 smoothly underwent Baeyer–Villiger oxidation: treatment with MMPP·6H₂O in methanol provided good chemoselectivity, with compound 11 as the major product (10 : 11 = 1 : 8.3), while the reaction involving m-CPBA as the oxidant delivered a mixture of 10 and 11 with low regioselectivity (see the SI for details). Notably, Baeyer–Villiger oxidation of 4 with either MMPP·6H₂O or mCPBA was unsuccessful, resulting in a complicated mixture.

Scheme 3 Synthetic applications.

Based on the above results, previous work, and relevant literature,^14,15 we propose a plausible mechanism for this arylation process (Scheme 4). The catalytic cycle begins with the formation of the active catalyst complex M2, which is generated from precatalyst M1 through dissociation of one molecule of the biphosphine ligand L1. This is followed by intramolecular coordination of the remaining phosphine at the bridging site of the dirhodium core. Subsequent transmetalation of M2 with arylboronic acid, activated by a fluoride anion, produces the arylrhodium species M3. This intermediate then undergoes stereoselective 1,2-addition to a diketone substrate, forming the alkoxide complex M4. Finally, hydrolysis of M4 releases an enantioenriched product while regenerating the active catalyst M2, thus completing the catalytic cycle.

Scheme 4 Plausible catalytic cycle.

Conclusions

In summary, we have developed a Rh₂(CF₃CO₂)₄/(R)-BTFM-GarPhos-catalyzed enantioselective arylation of benzobicyclo[2.2.1]heptane-2,3-diones. The incorporation of CF₃CO₂Na as an additive significantly enhanced reaction efficiency without compromising stereoselectivity. This protocol provides expedient access to enantioenriched [2.2.1]-bridged bicyclic compounds with good yields and enantioselectivity across a diverse array of arylboronic acids and diketone substrates. The synthetic versatility of these enantioenriched products was demonstrated through various transformations, including the synthesis of a chiral phosphine ligand.

Author contributions

S. Zhan: methodology, investigation, data curation, and writing – original draft. C. Wang: methodology and investigation. L. Duan: supervision and funding acquisition. Z. Gu: conceptualization, funding acquisition, writing – original draft, and writing– review & editing. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

CCDC 2452797 and 2452798 contain the supplementary crystallographic data for this paper.^16a,b

The data that support the findings of this study are available in the SI or on request from the corresponding authors. Supplementary information contains experimental procedures, new compounds characterization data, and copies of NMR spectra and HPLC traces. See DOI: https://doi.org/10.1039/d5sc03779d.

Acknowledgements

The authors are grateful for financial support from the National Natural Science Foundation of China (22301291 and 22471254) and the Open Research Fund of the State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University. This work was partially carried out at the Instruments Center for Physical Science, University of Science and Technology of China.

Notes and references

1. (a) B. Liu, S. Fu and C. Zhou, Nat. Prod. Rep., 2020, 37, 1627–1660; (b) B. Zhou and J. M. Yue, Nat. Prod. Rep., 2024, 41, 1368–1402.
2. (a) T. P. Stockdale and C. M. Williams, Chem. Soc. Rev., 2015, 44, 7737–7763; (b) Y. Chang, C. Sun, C. Wang, X. Huo, W. Zhao and X. Ma, Nat. Prod. Rep., 2022, 39, 2030–2056; (c) X. Wang, W. Zhang, T. Wen, H. Miao, W. Hu, H. Liu, M. Lei and Y. Zhu, Eur. J. Med. Chem., 2023, 250, 115187; (d) Y. Wu, Z. Liu, Z. He, J. Yi, X. Qiao, C. Tan, Y. Xing, Y. Zeng, D. Yang, J. Yin, B. Fan and G. Zeng, Eur. J. Med. Chem., 2023, 260, 115731.
3. (a) C. R. Ratwani, A. R. Kamali and A. M. Abdelkader, Prog. Mater. Sci., 2023, 131, 101001; (b) K. K. Oehlenschlaeger, J. O. Mueller, J. Brandt, S. Hilf, A. Lederer, M. Wilhelm, R. Graf, M. L. Coote, F. G. Schmidt and C. Barner-Kowollik, Adv. Mater., 2014, 26, 3561–3566; (c) T. M. Tran and J. R. Alaniz, J. Am. Chem. Soc., 2024, 146, 20972–20981.
4. (a) D. B. Calm and J. L. Reid, Drugs, 1972, 4, 49–74; (b) C. Richardson, D. L. Kelly and R. R. Conley, Am. J. Psychiatry, 2001, 158, 1329–1341; (c) C. Caflisch, B. Figner and D. Eich, Am. J. Psychiatry, 2003, 160, 386.
5. W. B. Schwartz, N. Engl. J. Med., 1949, 240, 173–177.
6. X. K. Xu, J. Ye, L. P. Chen, W. D. Zhang, Y. X. Yang and H. L. Li, Tetrahedron Lett., 2015, 56, 6381–6384.
7. (a) M. Catellani, F. Frignani and A. Rangoni, Angew. Chem., Int. Ed., 1997, 36, 119–122; (b) N. Della Ca’, M. Fontana, E. Motti and M. Catellani, Acc. Chem. Res., 2016, 49, 1389–1400; (c) J. Ye and M. Lautens, Nat. Chem., 2015, 7, 863–870; (d) R. Li and G. Dong, Angew. Chem., Int. Ed., 2018, 57, 1697–1701; (e) H. Shi, A. N. Herron, Y. Shao, Q. Shao and J.-Q. Yu, Nature, 2018, 558, 581–585; (f) Y. Hua, Z.-S. Liu, P. P. Xie, B. Ding, H.-G. Cheng, X. Hong and Q. Zhou, Angew. Chem., Int. Ed., 2021, 60, 12824–12828; (g) X. Sui, R. Zhu, G. Li, X. Ma and Z. Gu, J. Am. Chem. Soc., 2013, 135, 9318–9321.
8. Z. Lu, H. Zhang, Z. Yang, N. Ding, L. Meng and J. Wang, ACS Catal., 2019, 9, 1457–1463.
9. (a) K. Dolsophon, N. Ruangsupapichat, J. Soponpong, S. Sungsuwan, S. Prabpai, P. Kongsaeree and T. Thongpanchang, Tetrahedron Asymmetry, 2016, 27, 1113–1120; (b) S. Sungsuwan, N. Ruangsupapichart, S. Prabpai, P. Kongsaeree and T. Thongpanchang, Tetrahedron Lett., 2010, 51, 4965–4967.
10. (a) E. J. Corey and H. E. Ensley, J. Am. Chem. Soc., 1975, 97, 6908–6909; (b) E. J. Corey, R. Imwinkelried, S. Pikul and Y. B. Xiang, J. Am. Chem. Soc., 1989, 111, 5493–5495; (c) E. J. Corey, N. Imai and S. Pikul, Tetrahedron Lett., 1991, 32, 7517–7520; (d) E. J. Corey, T. P. Loh, T. D. Roper, M. D. Azimioara and M. C. Noe, J. Am. Chem. Soc., 1992, 114, 8290–8292; (e) K. V. Gothelf, R. G. Hazell and K. A. Jørgensen, J. Am. Chem. Soc., 1995, 117, 4435–4436; (f) D. A. Evans and D. M. Barnes, Tetrahedron Lett., 1997, 38, 57–58; (g) H. B. Kagan and O. Riant, Chem. Rev., 1992, 92, 1007–1019; (h) D. Carmona, M. P. Lamata and L. A. Oro, Coord. Chem. Rev., 2000, 200–202, 717–772.
11. (a) Q. Lin and D. Yang, Adv. Synth. Catal., 2023, 365, 4440–4457; (b) S.-V. Kumar, A. Yen, M. Lautens and P.-J. Guiry, Chem. Soc. Rev., 2021, 50, 3013–3093.
12. L. Shi, X. Xue, B. Hong, Q. Li and Z. Gu, ACS Cent. Sci., 2023, 9, 748–755.
13. S. Ando, R. Miyata, H. Matsunaga and T. Ishizuka, J. Org. Chem., 2019, 84, 128–139.
14. (a) B. Hong, L. Shi, L. Li, S. Zhan and Z. Gu, Green Synth. Catal., 2022, 3, 137–149; (b) W. Guo, S. Zhan, H. Yang and Z. Gu, Org. Lett., 2023, 25, 3281–3286; (c) S. Zhan, H. Xu, B. Hong and Z. Gu, Org. Lett., 2024, 26, 8023–8027.
15. G. Xu, H. Chen and X. Wang, Sci. Chin. Chem., 2025, 68, 3138–3146.
16. (a) S. Zhan, C. Wang, L. Duan and Z. Gu, CCDC 2452797: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2nbbhv; (b) S. Zhan, C. Wang, L. Duan and Z. Gu, CCDC 2452798: Experimental Crystal Structure Determination, 2025,  DOI:10.5517/ccdc.csd.cc2nbbjw.

---