. 2024 Oct 25;15(1):9227.

doi: 10.1038/s41467-024-53605-7.

Asymmetric Büchner reaction and arene cyclopropanation via copper-catalyzed controllable cyclization of diynes

Yan-Xin Zheng^#¹, Li-Gao Liu^#², Tian-Qi Hu¹, Xiao Li¹, Zhou Xu³, Xin Hong^{4

5}, Xin Lu¹, Bo Zhou¹, Long-Wu Ye^{6

7}

Affiliations

¹ State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.
² Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China.
³ Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, China.
⁴ State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China. hxchem@zju.edu.cn.
⁵ Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China. hxchem@zju.edu.cn.
⁶ State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China. longwuye@xmu.edu.cn.
⁷ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. longwuye@xmu.edu.cn.

^# Contributed equally.

PMID: 39455569
PMCID: PMC11511906
DOI: 10.1038/s41467-024-53605-7

Asymmetric Büchner reaction and arene cyclopropanation via copper-catalyzed controllable cyclization of diynes

Yan-Xin Zheng et al. Nat Commun. 2024.

. 2024 Oct 25;15(1):9227.

doi: 10.1038/s41467-024-53605-7.

Authors

Yan-Xin Zheng^#¹, Li-Gao Liu^#², Tian-Qi Hu¹, Xiao Li¹, Zhou Xu³, Xin Hong^{4

5}, Xin Lu¹, Bo Zhou¹, Long-Wu Ye^{6

7}

Affiliations

¹ State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China.
² Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China.
³ Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, China.
⁴ State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China. hxchem@zju.edu.cn.
⁵ Center of Chemistry for Frontier Technologies, Department of Chemistry, State Key Laboratory of Clean Energy Utilization, Zhejiang University, Hangzhou, China. hxchem@zju.edu.cn.
⁶ State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen, China. longwuye@xmu.edu.cn.
⁷ State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China. longwuye@xmu.edu.cn.

^# Contributed equally.

PMID: 39455569
PMCID: PMC11511906
DOI: 10.1038/s41467-024-53605-7

Abstract

The asymmetric Büchner reaction and related arene cyclopropanations represent one type of the powerful methods for enantioselective dearomatization. However, examples of asymmetric Büchner reactions via a non-diazo approach are quite scarce, and the related arene cyclopropanation based on alkynes has not been reported. Herein, we disclose an asymmetric Büchner reaction and the related arene cyclopropanation by copper-catalyzed controllable cyclization of N-propargyl ynamides via vinyl cation intermediates, leading to chiral tricycle-fused cycloheptatrienes and benzonorcaradienes in high yields and enantioselectivities. Importantly, this protocol represents an asymmetric arene cyclopropanation reaction of alkynes and an asymmetric Büchner reaction based on vinyl cations.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Asymmetric Büchner and arene cyclopropanation reactions.**
a Traditional asymmetric Büchner and arene cyclopropanation reactions. b Asymmetric Büchner and arene cyclopropanation reactions of alkynes. c This work: Cu-catalyzed asymmetric Büchner and arene cyclopropanation of alkynes.

**Fig. 2. Selected natural products and bioactive molecules containing fused bicyclo[5,4,0] ring and benzonorcaradiene motif.**
Some of representative molecules are listed.

**Fig. 3. Scope of asymmetric Büchner reaction of N-propargyl ynamides 1.**
Reaction conditions: 1 (0.1 mmol), Cu(MeCN)₄PF₆ (0.01 mmol), L9 (0.012 mmol), NaBAr^F₄ (0.012 mmol), toluene (2 mL), −20 °C, in vials; yields are those for the isolated products; ees are determined by HPLC analysis. ^aDCM (2 mL), 20 °C; ^bDCM (2 mL), 30 °C. Ts = p-toluenesulfonyl, Mbs = 4-methoxybenzenesulfonyl, Mts = 2-mesitylenesulfonyl, Bs = 4-bromobenzenesulfonyl, PMP = 4-methoxyphenyl.

**Fig. 4. Scope of asymmetric cyclopropanation of N-propargyl ynamides 3.**
Reaction conditions: 3 (0.15 mmol), Cu(MeCN)₄PF₆ (0.015 mmol), **L12** (0.018 mmol), NaBAr^F₄ (0.018 mmol), 2-MeTHF (3 mL), 0 °C, in vials; yields are those for the isolated products; ees are determined by HPLC analysis.

**Fig. 5. Scale-up reaction and product elaborations.**
a Preparative-scale reaction of 1a and synthetic applications. b Preparative-scale reaction of 3a and synthetic applications. Reagents and conditions: (i) Cu(MeCN)₄PF₆ (5 mol %), NaBAr^F₄ (6 mol %), L9 (6 mol %), toluene, −20 °C, 9 d. (ii) Pd/C (10 mol %), H₂ (1 atm), MeOH, rt, 12 h. (iii) Pd(OH)₂/C (10 mol %), H₂ (8 MPa), AcOH:EA = 1:1, 80 °C, 72 h. (iv) Cu(MeCN)₄PF₆ (10 mol %), NaBAr^F₄ (12 mol %), L9 (12 mol %), DCM, 20 °C, 4 d. (v) Phenylacetylene (4 equiv), Pd(PPh₃)₄ (5 mol %), CuI (10 mol %), THF:Et₃N = 3:1, 50 °C, 1 h. (vi) PhB(OH)₂ (3.5 equiv), Pd(PPh₃)₄ (10 mol %), CsF (2.5 equiv), DME, 50 °C, 8 h. (vii) Cu(MeCN)₄PF₆ (5 mol %), NaBAr^F₄ (6 mol %), **L12** (6 mol %), 2-MeTHF, 0 °C, 51 h. (viii) KOH (10 equiv), THF:MeOH = 1:1, 50 °C, 1.5 h, then DMAP (20 mol %), (Boc)₂O (3 equiv), Et₃N (4 equiv), DCM, rt, 2 h. (ix) NaBH₃CN (5 equiv), DCM:TFA = 10:1, rt, 1 h; Pd/C (10 mol %), H₂ (1 atm), AcOH, 60 °C, 12 h. (x) DMAD (20 equiv), toluene, 60 °C, 12 h. (xi) MeOTf (10 equiv), Et₂O, 0 °C to rt, 2 h; Pd(PPh₃)₂Cl₂ (5 mol %), PhMgBr (2 equiv), THF, rt, 2 h.

**Fig. 6. DFT-computed free energy diagram for the Büchner and arene cyclopropanation reactions.**
Relative free energies (ΔG, in kcal/mol) were computed at: a (PCM, solvent = toluene)-PBE0-D3/6-311 + + G(d,p)-SDD//B3LYP-D3/6-31 G(d)-LANL2DZ level of theory. b (PCM, solvent = 2-MeTHF)-PBE0-D3/6-311 + + G(d,p)-SDD//B3LYP-D3/6-31 G(d)-LANL2DZ level of theory.

**Fig. 7. The geometries and relative free energies (ΔΔG, in kcal/mol) of the transition states CuL9-(S)-TS_B1/CuL9-(R)-TS_B1 and CuL12-(S)-TS_B2/CuL12-(R)-TS_B2 with the chiral ligand L9 and L12.**
All hydrogen atoms are omitted for clarity except for those involved in critical interactions. Relative free energies (ΔΔG, in kcal/mol) were computed at the PCM(toluene)-PBE0-D3/6-311 + + G(d,p)-SDD//B3LYP-D3/6-31 G(d)-LANL2DZ level of theory and PCM(2-MeTHF)-PBE0-D3/6-311 + + G(d,p)-SDD//B3LYP-D3/6-31 G(d)-LANL2DZ level of theory. Color code: red = O; white = H; gray = C; yellow = S; blue = N; brown = Cu.

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Asymmetric Büchner reaction and arene cyclopropanation via copper-catalyzed controllable cyclization of diynes

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Asymmetric Büchner reaction and arene cyclopropanation via copper-catalyzed controllable cyclization of diynes

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