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SHORT COMMUNICATION Highly Enantioselective Construction of Polycyclic Spirooxindole via Organocatalytic 1,3-Dipolar Cycloaddition of 2-Cyclohexenone Catalyzed by Proline-Sulfonamide Jun-An Xiao,[a] + Qi Liu,[a] + Ji-Wei Ren,[a] Jian Liu,[a] Rich G. Carter,[b] Xiao-Qing Chen,[a] and Hua Yang*[a] Abstract: An enantioselective 1,3-dipolar cycloaddition of 2-cyclohexene-1-one and azomethine ylide generated in situ from isatin and amino ester was developed by employing proline sulfonamide as the catalyst. Consequently, novel polycyclic spirooxindole scaffolds with three contiguous stereocenters were prepared in high yield (up to 95%) with excellent diastereo- (> 20:1 dr) and enantio-selectivity (up to 99% ee).
Thus, it would be highly desirable to explore the 1,3-dipolar cycloadditions using cyclic enone, providing a facile access to novel polycyclic spirooxindole ring systems (as shown in Scheme 1) . On the other hand, the enones and enals activated by lowering the LUMO through the formation of iminium intermediates with chiral amine organocatalysts proved to be highly reactive toward the azomethine ylides in high stereoselectivity. Usually, this protocol is limited to enal and linear enone dipolarophiles, which can easily form iminium species with amine. In 2007, Chen and coworkers reported their elegant work on the organocatalytic enantioselective 1,3-dipolar cycloaddition of cyclohexenone with azomethine imines catalyzed by 9-amino-9-deoxyepicinchona alkaloids. Unfortunately, this research field on the organocatalytic 1,3dipolar cycloaddition using cyclic enone remained dormant since then.
In our previous work, proline p-dodecylphenylsulfonamide (Hua Cat®) was successfully employed to catalyze the [4+2] cycloaddition of cyclohexenone via the HOMO activation. Our continued interest prompted us to investigate this catalytic system in 1,3-dipolar cycloadditions of cyclohexenone with azomethine ylide facilitated by the LUMO activation of cyclohexenone. Herein, we report an organocatalyzed asymmetric 1,3-dipolar cycloaddition using cyclic enone and azomethine ylides to construct novel polycyclic spiro[pyrrolidin3,2′-oxindole] scaffolds.
SHORT COMMUNICATION sizable influence on the stereoselectivity and might be involved with the stereocontrol in this reaction. However, the exact catalytic mechanism still needs further investigation.
Scheme 2. 1,3-Dipolar cycloaddition of N-protected isatins.
To further expand the synthetic utility of this cycloaddition reaction, the reduction and decarboxylation reaction of the corresponding spirooxindoles were carried out (Scheme 3). A simple protocol of sodium borohydride in methanol can successfully afford the corresponding alcohol 11 as a single isomer in 86% yield and 96% ee. On the other hand, the decarboxylated product was obtained via a two-step process, including the mono-hydrolysis of diester followed by decarboxylation. As a result, a mixture of exo:endo isomers (70:30) was obtained. No apparent erosion of enantioselectivity occurred and 91% and 95% ee were observed respectively. Presumably, the exo-isomer would be thermodynamically favourable. More interestingly, ibophyllidine-like compounds 14a-14c were synthesized in moderate yields and high enantiopurity via Fischer indole synthesis. These resulting polycyclic structures simultaneously bear both indole and isatin motifs, which therefore might possess interesting biological activities.
Unless otherwise noted, the reaction was carried out in 0.2 mmol scale in DCM (4 mL) at RT with a molar ratio of 1/2/3 at 1:1.2:1.5. [bDetermined by 1H NMR. [c]Isolated yield. [d]Determined by chiral HPLC.
SHORT COMMUNICATION isatin and aminomalonate diester, catalyzed by readily available proline p-dodecylphenylsulfonamide, was developed with high yield and excellent stereoselectivities (up to 99% ee, > 20:1 dr). This catalytic system could effectively activate the cyclohexenone and enable the formation of hydrogen-bonding between catalyst and dipole. It would significantly broaden the synthetic application of cyclic enone in the enantioselective 1,3cycloaddition reaction and afford a facile access to novel polycyclic spirooxindole ring systems, which could provide new opportunities for medicinal chemistry and drug discovery.
Experimental Section Typical experimental procedure for the asymmetric synthesis of polycyclic spirooxindole 4a: Isatin 1a (0.20 mmol), aminomalonate diester 3a (0.30 mmol, 1.5 equiv.), 2-cyclohexane-1-one 2 (23.0 mg, 0.24 mmol, 1.2 equiv.) and catalyst (20 mol%) were added to the designed solvent (2 mL) followed by adding triethylamine (2.00 mg, 10 mol%). After completion of the reaction (monitored by TLC), organic solvent was removed in vacuo. Then the residue was purified via flash chromatography to yield spirooxindole 4a as a white solid (72.0 mg, yield 90%, > 20:1 dr, 96% ee); m.p. 230-231°C; [α]D20 = +17.6 (c=0.3 in CHCl3); 1 H NMR (DMSO-d6, 400 MHz) δ 10.24 (s, 1H), 7.34 (d, J = 7.2 Hz, 1H), 7.17 (t, J = 7.2 Hz, 1H), 6.95 (t, J = 7.4 Hz, 1H), 6.72 (d, J = 7.6 Hz, 1H), 4.08-4.28 (m, 4H), 3.92 (s, 1H), 3.30-3.34 (m, 2H), 1.19-2.11 (m, 2H), 1.64-1.81 (m, 4H), 1.18-1.23 (m, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 207.9, 181.5, 170.1, 169.1, 143.0, 129.9, 129.7, 126.3, 121.6, 110.1, 76.7, 70.4, 62.0, 61.5, 59.5, 45.1, 40.1, 22.9, 22.5, 14.5, 14.3; IR (KBr) ν 3302, 2936, 1725, 1619, 1245, 1187, 1028, 851, 759 cm-1; HRMS (TOFES+) m/z: [M+Na]+ calcd for C21H24N2O6Na 423.1532, found 423.1519; HPLC analysis: (CHIRALCEL OD-H, 30% i-propanol/hexanes, 0.8 mL/min, UV: 254 nm), tR = 14.3 min (minor), 19.9 min (major). Typical experimental procedure of indolospirooxindole 14a: To a solution of polycyclic spirooxindole 4a (0.2 mmol) in acetic acid (2 mL) was added phenylhydrazine 13 (43.3 mg, 0.4 mmol, 2 equiv.). The mixture was then refluxed for 2 hours, and cooled at rt. The acetic acid was removed under reduced pressure. The residue was dissolved in EtOAc (10 mL) and washed with sat. aq. NaHCO3 (30 mL x 2). The aqueous phase was back extracted with EtOAc (5 mL x 2). The combined organic phase was dried, and concentrated under reduced pressure. The crude mixture was purified by silica gel column chromatography to give indolospirooxindole 14a as a white solid (59.6 mg, yield 63%, > 20:1 dr, 99% ee); m.p.＞300°C; [α]D20 = +155.7 (c=0.5 in CHCl3); 1H NMR (DMSO-d6, 400 MHz) δ 10.17 (s, 1H), 10.13 (s, 1H), 7.29-7.31 (m, 1H), 6.93-6.97 (m, 2H), 6.85-6.91 (m, 2H), 6.69-6.84 (m, 2H), 6.52 (t, J = 7.2 Hz, 1H), 4.15-4.31 (m, 4H), 3.99 (d, J = 6.4 Hz, 1H), 3.81 (s, 1H), 2.63-2.94 (m, 2H), 1.84-2.00 (m, 2H), 1.22-1.26 (m, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 181.53, 170.3, 169.3, 142.9, 136.9, 131.3, 130.6, 128.7, 126.4, 125.6, 125.6, 121.4, 120.8, 118.0, 111.2, 109.6, 109.5, 75.8, 69.9, 61.8, 61.4, 44.5, 43.8, 22.3, 19.6, 14.5, 14.3; IR (KBr) ν 3387 (br), 2979, 1732, 1620, 1469, 1248, 1108, 860, 746 cm-1; HRMS (TOF-ES+) m/z: [M+Na]+ calcd for C27H27N3O5Na 496.1848, found 496.1839; HPLC analysis: (CHIRALCEL OD-H, 25% i-propanol/hexanes, 1.0 mL/min, UV: 254 nm), tR = 26.4 min (minor), 29.1 min (major). Supporting Information (see footnote on the first page of this article): Experimental procedures, NMR spectral and analytical data for the 4a4o, 6, 10a, 10b, 11, 12, 14a-14c; HPLC chromatograms for the 4a-4o, 10a, 10b, 11, 12, 14a-14c .
Acknowledgements We gratefully acknowledge the financial support from National Natural Science Foundation of China (21175155, 21276282 & 21376270), Hunan Provincial Science & Technology Department (2012WK2007), and Central South University. Keywords: organocatalysis • 1,3-dipolar cycloaddition • spirooxindole • 2-cyclohexene-1-one • isatin  a) A. S. Girgis, Eur. J. Med. Chem. 2009, 44, 91-100; b) R. Murugan, S. Anbazhagan, S. Sriman Narayanan, Eur. J. Med. Chem. 2009, 44, 3272-3279; c) R. S. Kumar, S. M. Rajesh, S. Perumal, D. Banerjee, P. Yogeeswari, D. Sriram, Eur. J. Med. Chem. 2010, 45, 411-422; d) R. R. Kumar, S. Perumal, P. Senthilkumar, P. Yogeeswari, D. Sriram, J. Med. Chem. 2008, 51, 5731-5735; e) A. Thangamani, Eur. J. Med. Chem. 2010, 45, 6120 –6126; f) G. Periyasami, R. Raghunathan, G. Surendiran, N. Mathivanan, Bioorg. Med. Chem. Lett. 2008, 18, 2342-2345; g) P. Prasanna, K. Balamurugan, S. Perumal, P. Yogeeswari, D. Sriram, Eur. J. Med. Chem. 2010, 45, 5653-5661; h) Y. Arun, K. Saranraj, C. Balachandran, P. T. Perumal, Eur. J. Med. Chem. 2014, 74, 5064; i) M. A. Ali, R. Ismail, T. S. Choon, Y. K. Yoon, A. C. Wei, S. Pandian, R. S. Kumar, H. Osman, E. Manogaran, Bioorg. Med. Chem. Lett. 2010, 20, 7064-7066; j) Y. Zhao, L. Liu, W. Sun, J. Lu, D. McEachern, X. Li, S. Yu, D. Bernard, P. Ochsenbein, V. Ferey, J. Carry, J. R. Deschamps, D. Sun, S. Wang, J. Am. Chem. Soc. 2013, 135, 7223-7234.  For reviews, See: a) K. V. Gothelf, K. A. Jørgensen, Chem. Rev. 1998, 98, 863-910; b) G. Pandey, P. Banerjee, S. R. Gadre, Chem. Rev. 2006, 106, 4484-4517; c) L. M. Stanley, M. P. Sibi, Chem. Rev. 2008, 108, 2887-2902; d) I. Coldham, R. Hufton, Chem. Rev. 2005, 105, 2765-2810; e) G. S. Singh, Z. Y. Desta, Chem. Rev. 2012, 112, 6104-6155; f) D. Cheng, Y. Ishihara, B. Tan, C. F. Barbas, ACS Catalysis. 2014, 743-762. h) M. Han, J. Jia, W. Wang, Tetrahedron Lett. 2014, 55, 784-794; i) S. L. D. S. Zheng Wang, Chem.Eur. J. 2013, 19, 6739-6745.  For previous reports on the syntjesis of spirooxindole, see: a) L. Tian, X. Hu, Y. Li, P. Xu, Chem. Commun. 2013, 49, 7213-7215; b) F. Shi, R. Zhu, X. Liang, S. Tu, Adv. Synth.& Catal. 2013, 355, 2447-2458; c) X. Chen, Q. Wei, S. Luo, H. Xiao, L. Gong, J. Am. Chem. Soc. 2009, 131, 13819-13825.  a) D. Du, Y. Jiang, Q. Xu, M. Shi, Adv. Synth.& Catal. 2013, 355, 2249-2256; b) L. Wang, J. Bai, L. Peng, L. Qi, L. Jia, Y. Guo, X. Luo, X. Xu, L. Wang, Chem. Commun. 2012, 48, 5175-5177; c) C. E. Puerto Galvis, V. V. Kouznetsov, Org. Biomol. Chem. 2013, 11, 7372-7386; d) Y. Kia, H. Osman, R. S. Kumar, V. Murugaiyah, A. Basiri, S. Perumal, I. A. Razak, Bioorg. & Med. Chem. Lett. 2013, 23, 2979-2983; e) J. Naga Siva Rao, R. Raghunathan, Tetrahedron Lett. 2013, 54, 6568-6573; f) S. N. Singh, S. Regati, A. K. Paul, M. Layek, S. Jayaprakash, K. V. Reddy, G. S. Deora, S. Mukherjee, M. Pal, Tetrahedron Lett. 2013, 54, 5448-5452; g) Y. Kia, H. Osman, R. S. Kumar, A. Basiri, V. Murugaiyah, Bioorg. & Med. Chem. 2014, 22, 1318-1328; h) S. Lanka, S. Thennarasu, P. T. Perumal, Tetrahedron Lett. 2014, 55, 2585-2588; i) Y. Kia, H. Osman, R. S.
SHORT COMMUNICATION Kumar, V. Murugaiyah, A. Basiri, S. Perumal, H. A. Wahab, C. S. Bing, Bioorg. & Med. Chem. 2013, 21, 1696-1707.  For selected recent reviews on asymmetric organocatalysis, see: a) J. Li, T. Liu, Y. Chen, Acc. Chem. Res. 2012, 45, 1491-1500; b) W. Sun, L. Hong, G. Zhu, Z. Wang, X. Wei, J. Ni, R. Wang, Org. Lett. 2014. (DOI: 10.1021/ol4034226); c) K. Albertshofer, B. Tan, C. F. Barbas, Org. Lett. 2012, 14, 1834-1837; d) I. C. Y. L. Mattia Silvi, Angew. Chem. Int. Ed. 2013, 52, 10780-10783; e) H. Guo, H. Liu, F. Zhu, R. Na, H. Jiang, Y. Wu, L. Zhang, Z. Li, H. Yu, B. Wang, Y. Xiao, X. Hu, M. Wang, Angew. Chem. Int. Ed. 2013, 52, 1264112645; f) B. Tan, G. Her-nández-Torres, C. F. Barbas, J. Am. Chem. Soc. 2011, 133, 12354-12357; g) C. F. Nising, U. K. Ohnemüller Née Schmid, S. Bräse, Angew. Chem. Int. Ed. 2006, 45, 307-309; h) X. Feng, Z. Zhou, C. Ma, X. Yin, R. Li, L. Dong, Y. Chen, Angew. Chem. Int. Ed. 2013, 52, 14173-14176; i) G. Pandey, P. Banerjee, R. Kumar, V. G. Puranik, Org. Lett. 2005, 7, 37133716.  F. Shi, Z. Tao, S. Luo, S. Tu, L. Gong, Chem.Eur. J. 2012, 18, 68856894.  For selected examples on the synthesis of spirooxindole and pyrrolidine derivatives, see: a) B. Tan, N. R. Candeias, C. F. Barbas, Nat. Chem. 2011, 3, 473-477; b) T. Liu, Z. He, Q. Li, H. Tao, C. Wang, Adv. Synth.& Catal. 2011, 353, 1713-1719; c) X. Li, L. Stuart, C. Chen, J. Am. Chem. Soc. 2003, 125, 10174-10175; d) J. Hernández-Toribio, S. Padilla, J. Adrio, J. C. Carretero, Angew. Chem. Int. Ed. 2012, 124, 8984-8988; e) C. Guo, J. Song, L. Gong, Org. Lett. 2013, 15, 2676-2679; f) L. M. Castelló, C. Nájera, J. M. Sansano, O. Larrañaga, A. D. Cózar, F. P. Cossío, Org. Lett. 2013, 15, 2902-2905; g) Q. Li, T. Liu, L. Wei, X. Zhou, H. Tao, C. Wang, Chem. Commun. 2013, 49, 9642-9644; h) P. Yuvaraj, B. S. R. Reddy, Tetrahedron Lett. 2014, 55, 806-810; i) A. P. Antonchick, H. Schuster, H. Bruss, M. Schürmann, H. Preut, D. Rauh, H. Waldmann, Tetrahedron. 2011, 67, 10195-10202; j) X. Chen; W.
Zhang; L. Z. Gong, J. Am. Chem. Soc. 2008, 130, 5652-5653; k) C. Wang; X. Chen; S. Zhou; L. Z. Gong, Chem. Commun. 2010, 46, 1275-1277; l) T. Liu; Z. Xue; H. Tao; C. J. Wang, Org. & Biomol. Chem. 2011, 9, 1980-1986.  a) C. Zhang, S. Yu, X. Hu, D. Wang, Z. Zheng, Org. Lett. 2010, 12, 5542-5545; b) S. Mutti, C. Daubié, F. Decalogne, R. Fournier, P. Rossi, Tetrahedron Lett. 1996, 37, 3125-3128; c) Z. He, T. Liu, H. Tao, C. Wang, Org. Lett. 2012, 14, 6230-6233; d) I. Oura, K. Shimizu, K. Ogata, S. Fukuzawa, Org. Lett. 2010, 12, 1752-1755; e) G. Bhaskar, Y. Arun, C. Balachandran, C. Saikumar, P. T. Perumal, Eur. J. Med. Chem. 2012, 51, 79-91.  a) J. L. Vicario, S. Reboredo, D. Badía, L. Carrillo, Angew. Chem. Int. Ed. 2007, 46, 5168-5170; b) W. Chen, X. Yuan, R. Li, W. Du, Y. Wu, L. Ding, Y. Chen, Adv. Synth.& Catal. 2006, 348, 18181822.  W. Chen, W. Du, Y. Duan, Y. Wu, S. Yang, Y. Chen, Angew. Chem. Int. Ed. 2007, 119, 7811-7814.  H. Yang, R. G. Carter, J. Org. Chem. 2009, 74, 5151-5156.  CCDC-996984 (racemic 4m) and CCDC-996985 (enantiopure 4j) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.  For the application of Fischer indole synthesis, see: a) L. Kötzner, M. J. Webber, A. Martínez, C. De Fusco, B. List, Angew. Chem. Int. Ed. 2014, 53, 1-5; b) H. Huang, K. Zhu, W. Wu, Z. Jin, J. Ye, Chem. Commun. 2012, 48, 461-463; c) C. Li, J. Chen, G. Fu, D. Liu, Y. Liu, W. Zhang, Tetrahedron. 2013, 69, 6839-6844; d) M. López-Iglesias, E. Busto, V. Gotor, V. Gotor-Fernández, J. Org. Chem. 2012, 77, 8049-8055.
SHORT COMMUNICATION What proline sulphonamide organocatalyst can do? The highly enantioselective construction of polycyclic spirooxindole via 1,3-dipolar cycloaddition of cyclohexenone with azomethine ylide was achieved by employing prolinosulphonamides as the catalyst. This catalytic system essentially benefited from the iminium activation and hydrogen-bonding formation induced by the prolinosulphonamides.
Report "ejoc John Wiley & Sons, Inc. Accepted Manuscript"

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