Catalytic Enantioselective Desymmetrization of meso-Cyclopropane-Fused Cyclohexene-1,4-diones by a Formal C(sp²)–H Alkylation

Abstract

A bicyclo[4.1.0]heptane framework consisting of cis-fused cyclopropane and cyclohexane rings is found in several bioactive compounds. Given the symmetry of this core, catalytic desymmetrization can be considered as the most straightforward strategy for its enantioselective synthesis. Known desymmetrization reactions of meso-bicyclo[4.1.0]heptane derivatives proceed with opening of the cyclopropane ring. We now report the first ring-retentive desymmetrization of bicyclo[4.1.0]heptane derivatives, namely meso-cyclopropane-fused cyclohexene-1,4-diones, through a formal C(sp²)-H alkylation using a nitroalkane as the alkylating agent. This reaction is catalyzed by a dihydroquinine-derived bifunctional tertiary aminosquaramide and generates the products with up to 97:3 er. An application of this reaction is demonstrated by the first catalytic enantioselective synthesis of the natural product (–)-car-3-ene-2,5-dione.

Key words

organocatalysis - desymmetrization - cyclopropanes - bicyclo­heptanes - fused ring systems

Publication History

Received: 24 June 2022

Accepted after revision: 28 July 2022

Accepted Manuscript online:
28 July 2022

Article published online:
27 September 2022

• References and Notes

• 1a Wiberg KB. Angew. Chem. Int. Ed. Engl. 1986; 25: 312
• 1b Kozina MP, Mastryukov VS, Mil’vitskaya EM. Russ. Chem. Rev. 1982; 51: 765
• 1c von Baeyer A. Ber. Dtsch. Chem. Ges. 1885; 18: 2269
• 2a Ma S, Mandalapu D, Wang S, Zhang Q. Nat. Prod. Rep. 2022; 39: 926
• 2b Sansinenea E, Ortiz A. Eur. J. Org. Chem. 2022; e202200210
• 2c Apel C, Christmann M. Tetrahedron 2021; 82: 131760
• 2d Liu J, Liu R, Wei Y, Shi M. Trends Chem. 2019; 1: 779
• 2e Novakov IA, Babushkin AS, Yablokov AS, Nawrozkij MB, Vostrikova OV, Shejkin DS, Mkrtchyan AS, Balakin KV. Russ. Chem. Bull. 2018; 67: 395
• 2f Wu W, Lin Z, Jiang H. Org. Biomol. Chem. 2018; 16: 7315
• 2g Ebner C, Carreira EM. Chem. Rev. 2017; 117: 11651
• 2h Fan Y.-Y, Gao X.-H, Yue J.-M. Sci. China Chem. 2016; 59: 1126
• 2i Cavitt MA, Phun LH, France S. Chem. Soc. Rev. 2014; 43: 804
• 2j Chen DY.-K, Pouwer RH, Richard J.-A. Chem. Soc. Rev. 2012; 41: 4631
• 2k Tang P, Qin Y. Synthesis 2012; 44: 2969
• 2l Wessjohann LA, Brandt W, Thiemann T. Chem. Rev. 2003; 103: 1625
• 2m Gnad F, Reiser O. Chem. Rev. 2003; 103: 1603
• 2n Lukina MY. Russ. Chem. Rev. 1962; 31: 419
• 2o Perkin WH. J. Chem. Soc., Trans. 1885; 47: 801
• 2p Perkin WH. Ber. Dtsch. Chem. Ges. 1884; 17: 323
• 3 Buzzetti F, Salle E, Lombardi P. DE 3719913 1987
• 4 Chen Y.-P, Ying S.-S, Zheng H.-H, Liu Y.-T, Wang Z.-P, Zhang H, Deng X, Wu Y.-J, Gao X.-M, Li T.-X, Zhu Y, Xu Y.-T, Wu H.-H. Sci. Rep. 2017; 7: 15114
• 5 Hashimoto K, Katsuhara T, Itoh H, Ikeya Y, Okada M, Mitsuhashi H. Phytochemistry 1990; 29: 3571

For selected reviews, see:
• 6a Nájera C, Foubelo F, Sansano JM, Yus M. Tetrahedron 2022; 106–107: 132629
• 6b Xu Y, Zhai T.-Y, Xu Z, Ye L.-W. Trends Chem. 2022; 4: 191
• 6c Chegondi R, Patel SM, Maurya S, Donthoju A. Asian J. Org. Chem. 2021; 10: 1267
• 6d Das T. ChemistrySelect 2020; 5: 14484
• 6e Borissov A, Davies TQ, Ellis SR, Fleming TA, Richardson MS. W, Dixon DJ. Chem. Soc. Rev. 2016; 45: 5474
• 6f Zeng X.-P, Cao Z.-Y, Wang Y.-H, Zhou F, Zhou J. Chem. Rev. 2016; 116: 7330
• 6g Manna MS, Mukherjee S. Org. Biomol. Chem. 2015; 13: 18
• 6h Fernández-Pérez H, Etayo P, Lao JR, Núñez-Rico JL, Vidal-Ferran A. Chem. Commun. 2013; 49: 10666
• 7a Pirenne V, Muriel B, Waser J. Chem. Rev. 2021; 121: 227
• 7b Xia Y, Liu X, Feng X. Angew. Chem. Int. Ed. 2021; 60: 9192
• 8 Troxler T, Scheffold R. Helv. Chim. Acta 1994; 77: 1193
• 9a Díaz E, Reyes E, Uria U, Carrillo L, Tejero T, Merino P, Vicario JL. Chem. Eur. J. 2018; 24:  8764
• 9b Wallbaum J, Garve LK. B, Jones PG, Werz DB. Chem. Eur. J. 2016; 22:  18756
• 9c Sparr C, Gilmour R. Angew. Chem. Int. Ed. 2011; 50:  8391
• 10 Müller P, Riegert D. Tetrahedron 2005; 61: 4373

For selected examples of such remote stereocontrol, see:
• 11a Lou Y, Wei J, Li M, Zhu Y. J. Am. Chem. Soc. 2022; 144: 123
• 11b Ray S, Mondal S, Mukherjee S. Angew. Chem. Int. Ed. 2022; 61: e202201584
• 11c Genov GR, Douthwaite JL, Lahdenperä AS. K, Gibson DC, Phipps RJ. Science 2020; 367: 1246
• 11d Shi H, Herron AN, Shao Y, Shao Q, Yu J.-Q. Nature 2018; 558: 581
• 11e Su B, Zhou T.-G, Xu P.-L, Shi Z.-J, Hartwig JF. Angew. Chem. Int. Ed. 2017; 56: 7205
• 11f Sarkar R, Mukherjee S. Org. Lett. 2016; 18: 6160
• 11g Manna MS, Sarkar R, Mukherjee S. Chem. Eur. J. 2016; 22: 14912
• 11h Manna MS, Mukherjee S. J. Am. Chem. Soc. 2015; 137: 130
• 11i Zhou F, Tan C, Tang J, Zhang Y.-Y, Gao W.-M, Wu H.-H, Yu Y.-H, Zhou J. J. Am. Chem. Soc. 2013; 135: 10994
• 11j Lewis CA, Gustafson JL, Chiu A, Balsells J, Pollard D, Murry J, Reamer RA, Hansen KB, Miller SJ. J. Am. Chem. Soc. 2008; 130: 16358
• 11k Cefalo DR, Kiely AF, Wuchrer M, Jamieson JY, Schrock RR, Hoveyda AH. J. Am. Chem. Soc. 2001; 123: 3139
• 12 Mal D, Ray S. Eur. J. Org. Chem. 2008; 2008: 3014
• 13 For details, see the Supporting Information

For pioneering work on bifunctional thiourea catalysis, see:
• 14a Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672. For seminal works on cinchonaalkaloid-based bifunctional thiourea catalysts, see
• 14b Li B.-J, Jiang L, Liu M, Chen Y.-C, Ding L.-S, Wu Y. Synlett 2005; 603
• 14c McCooey SH, Connon SJ. Angew. Chem. Int. Ed. 2005; 44: 6367
• 14d Vakulya B, Varga S, Csámpai A, Soós T. Org. Lett. 2005; 7: 1967
• 14e Ye J, Dixon DJ, Hynes PS. Chem. Commun. 2005; 4481
• 15 For seminal work on bifunctional squaramide catalysts, see: Malerich JP, Hagihara K, Rawal VH. J. Am. Chem. Soc. 2008; 130: 14416
• 16 Odriozola A, Oiarbide M, Palomo C. Chem. Eur. J. 2017; 23: 12758

Catalytic Enantioselective Alkylative Desymmetrization of meso-Cyclopropane-Fused Cyclohexene-1,4-Diones; General ProcedureA glass vial was charged with freshly activated 5 Å MS (150 mg), catalyst III (0.06 mmol, 0.2 equiv), Na₂CO₃ (0.45 mmol, 1.5 equiv), and the appropriate cyclopropane-fused enedione 10 (0.30 mmol, 1.0 equiv) under a positive argon pressure. Distilled CHCl₃ (3.0 mL) was added and the resulting suspension was stirred at 25 °C for 10 min. Nitroalkane 11 (11b or 11c: 3.0 mmol; 11c–f: 1.5 mmol) was then added, and the resulting mixture was stirred at 25 °C until complete conversion of 10 (TLC). The mixture was then diluted with CH₂Cl₂ (2 mL) and filtered through Celite, which was washed with additional CH₂Cl₂ (3 × 5 mL). The combined organic phase was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel).(1R,6S)-3-Methylbicyclo[4.1.0]hept-3-ene-2,5-dione (12aa)Prepared according to the general procedure, and purified by flash column chromatography (silica gel, 20–25% EtOAc–PE) to give a thick yellow oil; yield: 36 mg (0.264 mmol, 88%); [α]_D ²² –83.7 (c 1.0, CHCl₃) for an enantiomerically enriched sample with 92:8 er. HPLC [Daicel Chiralpak IG, hexane–EtOH (60:40), 1.0 mL/min, 20 °C, λ = 254 nm]: t _minor = 14.7 min, t _major = 17.5 min. FTIR (thin film): 3340 , 3062 , 2924 , 1726 , 1674 , 1620 , 1440 , 1348 , 1282 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.29 (s, 1 H), 2.55–2.46 (m, 2 H), 1.95 (s, 3 H), 1.67 (dt, J ₁ = 8.7, J ₂ = 4.9 Hz, 1 H), 1.58 (q, J = 5.1 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.7, 194.8, 146.4, 133.7, 27.8, 27.0, 20.1, 16.5. HRMS (APCI): m/z [M + H]⁺ calcd for C₈H₉O₂: 137.0603; found: 137.0605. (1R,6S)-3-Benzylbicyclo[4.1.0]hept-3-ene-2,5-dione (12ac)Prepared according to the general procedure and purified by flash column chromatography (silica gel, 12–15% EtOAc–PE) as a yellow oil; yield: 33 mg (0.155 mmol, 52%); [α]_D ²² –43.3 (c 2.0, CHCl₃) for an enantiomerically enriched sample with 79:21 er.HPLC [Daicel Chiralpak IG, hexane–EtOH (60:40), 1.0 mL/min, 20 °C, λ = 254 nm]: t _minor = 10.9 min, t _major = 27.5 min. FTIR (thin film): 3061 , 3028 , 2924 , 1675 , 1614 , 1495 , 1346 , 1279 , 1041 , 700 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.26–7.22 (m, 2 H), 7.20–7.18 (m, 1 H), 7.07 (d, J = 7.1 Hz, 2 H), 6.00 (br m, 1 H), 3.57 (dd, J ₁ = 29.6, J ₂ = 16.2 Hz, 2 H), 2.50–2.40 (m, 2 H), 1.61–1.55 (m, 1 H), 1.47 (q, J = 5.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.1, 194.9, 149.2, 136.5, 133.3, 129.3, 129.0, 127.1, 35.8, 27.9, 27.2, 19.9. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₄H₁₃O₂: 213.0916; found: 213.0918.(–)-Car-3-ene-2,5-dione (12ca)Prepared according to the general procedure and purified by flash column chromatography (silica gel, 15–17% EtOAc–PE) as a yellow crystalline solid; yield: 31 mg (0.183 mmol, 61%); mp 77–79 °C; [α]_D ²² –13.9 (c 0.25, CHCl₃) for an enantiomerically enriched sample with 94.5:5.5 er.HPLC [Daicel Chiralpak IG, hexane–EtOH (60:40), 1.0 mL/min, 20 °C, λ = 254 nm]: t _minor = 9.4 min, t _major = 17.3 min. FTIR (thin film): 3034 , 2962 , 1662 , 1447 , 1370 , 1289 , 1125 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 6.50–6.49 (br m, 1 H), 2.35–2.30 (m, 2 H), 1.97 (d, J = 1.3 Hz, 3 H), 1.32 (s, 3 H), 1.31 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 195.1, 194.5, 150.1, 137.8, 40.0, 39.1, 33.7, 29.2, 16.3, 15.6. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₀H₁₃O₂: 165.0916; found: 165.0918.
• 18 Galin FZ, Kashina YA, Zainullin RA, Kukovinets OS, Khalilov LM, Tolstikov GA. Russ. Chem. Bull. 1998; 47: 185
• 19 Gomes SQ, Salles AG. Jr. Synth. Commun. 2019; 49: 3389