Synlett 2017; 28(20): 2876-2880
DOI: 10.1055/s-0036-1589070
letter
© Georg Thieme Verlag Stuttgart · New York

Thiourea-Catalyzed Domino Michael–Mannich [3+2] Cycloadditions: A Strategy for the Asymmetric Synthesis of 3,3′-Pyrrolidinyl-dispirooxindoles

Ying Zhia, Kun Zhaoa, Carolina von Essenb, Kari Rissanenb, Dieter Enders*a
  • aInstitute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Email: enders@rwth-aachen.de
  • bDepartment of Chemistry, Nanoscience Center, University of Jyvaskyla, 40014 JYU, Finland
Financial support from the European Research Council (ERC Advanced Grant 320493 ‘DOMINOCAT’) is gratefully acknowledged.
Further Information

Publication History

Received: 22 May 2017

Accepted after revision: 08 June 2017

Publication Date:
13 July 2017 (eFirst)

Dedicated to Professor Victor Snieckus on the occasion of his 80th birthday

Abstract

The asymmetric synthesis of trifluoromethylated 3,3′-pyrrolidinyl-dispirooxindole derivatives with four contiguous stereogenic centers, including two vicinal spiro-stereocenters, is described. Employing a bifunctional thiourea catalyst, a domino Michael–Mannich [3+2] cycloaddition occurs readily between isatin ketimines and isatin-derived enoates with good yields and very high stereoselectivities, providing a direct entry to the title compounds of potential medical value.

Supporting Information

 
  • References and Notes

  • 1 For a leading review, see: Galliford CV. Scheidt KA. Angew. Chem. Int. Ed. 2007; 46: 8748

    • For selected reviews, see:
    • 2a Marti C. Carreira EM. Eur. J. Org. Chem. 2003; 2209
    • 2b Trost BM. Brennan MK. Synthesis 2009; 3003

    • For an excellent example, see:
    • 2c Antonchick AP. Gerding-Reimers C. Catarinella M. Schürmann M. Preut H. Ziegler S. Rauh D. Waldmann H. Nat. Chem. 2010; 2: 735
    • 2d Tan B. Zeng X. Leong WW. Y. Shi Z. Barbas III CF. Zhong G. Chem. Eur. J. 2012; 18: 63
    • 3a Babu AR. S. Raghunathan R. Mathivanan N. Omprabha G. Velmurugan D. Raghu R. Curr. Chem. Biol. 2008; 2: 312
    • 3b Arun Y. Bhaskar G. Balachandran C. Ignacimuthu S. Perumal PT. Bioorg. Med. Chem. Lett. 2013; 23: 1839
  • 4 Dai W. Jiang X.-L. Wu Q. Shi F. Tu S.-J. J. Org. Chem. 2015; 80: 5737
  • 5 Zhao K. Zhi Y. Li X. Puttreddy R. Rissanen K. Enders D. Chem. Commun. 2016; 52: 2249
    • 6a Hagmann WK. J. Med. Chem. 2008; 51: 4359
    • 6b Purser S. Moore PR. Swallow S. Gouverneur V. Chem. Soc. Rev. 2008; 37: 320
    • 6c Gillis EP. Eastman KJ. Hill MD. Donnelly DJ. Meanwell NA. J. Med. Chem. 2015; 58: 8315

      For reviews on syntheses of spiro compounds, see:
    • 7a Rios R. Chem. Soc. Rev. 2012; 41: 1060
    • 7b Franz AK. Hanhan NV. Ball-Jones NR. ACS Catal. 2013; 3: 540
    • 7c Cheng D. Ishihara Y. Tan B. Barbas III CF. ACS Catal. 2014; 4: 743

    • For selected examples, see:
    • 7d Liu Y.-L. Wang X. Zhao Y.-L. Zhu F. Zeng X.-P. Chen L. Wang C.-H. Zhao X.-L. Zhou J. Angew. Chem. Int. Ed. 2013; 52: 13735
    • 7e Noole A. Ošeka M. Pehk T. Öeren M. Järving I. Elsegood MR. J. Malkov AV. Lopp M. Kanger T. Adv. Synth. Catal. 2013; 355: 829

      For reports from our group, see:
    • 8a Wang C. Yang X. Loh CC. J. Raabe G. Enders D. Chem. Eur. J. 2012; 18: 11531
    • 8b Yang X. Wang C. Ni Q. Enders D. Synthesis 2012; 44: 2601
    • 8c Loh CC. J. Hack D. Enders D. Chem. Commun. 2013; 49: 10230
    • 8d Beceño C. Chauhan P. Rembiak A. Wang A. Enders D. Adv. Synth. Catal. 2015; 357: 672
    • 8e Zhao K. Shu T. Jia J. Raabe G. Enders D. Chem. Eur. J. 2015; 21: 3933
    • 8f Zou L.-H. Philipps AR. Raabe G. Enders D. Chem. Eur. J. 2015; 21: 1004
    • 8g Wang L. Li S. Blümel M. Philipps AR. Wang A. Puttreddy R. Rissanen K. Enders D. Angew. Chem. Int. Ed. 2016; 55: 11110
    • 8h Zhao K. Zhi Y. Shu T. Valkonen A. Rissanen K. Enders D. Angew. Chem. Int. Ed. 2016; 55: 12104
    • 8i Zhao K. Zhi Y. Wang A. Enders D. ACS Catal. 2016; 6: 657
    • 9a Ma M. Zhu Y. Sun Q. Li X. Su J. Zhao L. Zhao Y. Qiu S. Yan W. Wang K. Wang R. Chem. Commun. 2015; 51: 8789
    • 9b Sun Q. Li X. Su J. Zhao L. Ma M. Zhu Y. Zhao Y. Zhu R. Yan W. Wang K. Wang R. Adv. Synth. Catal. 2015; 357: 3187
    • 9c Li X. Su J. Liu Z. Zhu Y. Dong Z. Qiu S. Wang J. Lin L. Shen Z. Yan W. Wang K. Wang R. Org. Lett. 2016; 18: 956
    • 9d Wang Z.-H. Wu Z.-J. Yue D.-F. Hu W.-F. Zhang X.-M. Xu X.-Y. Yuan W.-C. Chem. Commun. 2016; 52: 11708

      For selected reports involing 3-olefinic oxindoles, see:
    • 10a Jiang K. Jia Z.-J. Chen S. Wu L. Chen Y.-C. Chem. Eur. J. 2010; 16: 2852
    • 10b Jia Z.-J. Jiang H. Li J.-L. Gschwend B. Li Q.-Z. Yin X. Grouleff J. Chen Y.-C. Jørgensen KA. J. Am. Chem. Soc. 2011; 133: 5053
    • 10c Yang L. Wang F. Chua PJ. Lv Y. Zhong L.-J. Zhong G. Org. Lett. 2012; 14: 2894
    • 10d Sun W. Zhu G. Wu C. Li G. Hong L. Wang R. Angew. Chem. Int. Ed. 2013; 52: 8633
    • 10e Sun W. Hong L. Zhu G. Wang Z. Wei X. Ni J. Wang R. Org. Lett. 2014; 16: 544
    • 10f Monari M. Montroni E. Nitti A. Lombardo M. Trombini C. Quintavalla A. Chem. Eur. J. 2015; 21: 11038
    • 10g Sun Q.-S. Zhu H. Chen Y.-J. Yang X.-D. Sun X.-W. Lin G.-Q. Angew. Chem. Int. Ed. 2015; 54: 13253
    • 10h Xie D. Yang L. Lin Y. Zhang Z. Chen D. Zeng X. Zhong G. Org. Lett. 2015; 17: 2318
    • 10i Zhu L. Chen Q. Shen D. Zhang W. Shen C. Zeng X. Zhong G. Org. Lett. 2016; 18: 2387
  • 11 While this manuscript was in preparation, an elegant paper by Lu, Weng, Lin and co-workers appeared and described a similar reaction catalyzed by chiral squaramides rather than thioureas: Huang W.-J. Chen Q. Lin N. Long X.-W. Pan W.-G. Xiong Y.-S. Weng J. Lu G. Org. Chem. Front. 2017; 4: 472
  • 12 General Procedure for the Synthesis of 3,3′-Pyrrolidinyl-dispirooxindoles 3a–q A glass tube equipped with a stirring bar was charged with trifluoroethylisatin ketimine 1 (0.40 mmol, 1.0 equiv), 3-olefinic oxindole 2 (0.48 mmol, 1.2 equiv), catalyst J (0.04 mmol, 10 mol%), and CCl4 (4.0 mL). The resulting solution of the reaction mixture was cooled to 4 °C and was stirred at 4 °C for 12 h. The solvent was evaporated to give the crude product, which was directly purified by flash chromatography (pentane/Et2O) to provide the desired products 3aq. Analytical Data for Compound 3a Compound 3a was obtained as a light yellow solid (0.223 g, 87% yield), mp 162–164 °C; [α]D 25 +58.9 (c 1.0, CHCl3). HPLC: CHIRALPAK IC; n-heptane/i-PrOH = 9:1; flow rate 1.0 mL/min; temp 30 °C; t R = 6.80 min (major), 10.58 min (minor); ee 92%. 1H NMR (600 MHz, CDCl3): δ = 7.76 (d, J = 8.4 Hz, 1 H), 7.54 (d, J = 7.8 Hz, 1 H), 7.38–7.34 (m, 3 H), 7.33–7.30 (m, 2 H), 7.28–7.24 (m, 2 H), 7.01 (t, J = 7.8 Hz, 1 H), 6.59–6.56 (m, 1 H), 6.53 (d, J = 7.8 Hz, 1 H), 6.47 (d, J = 8.4 Hz, 1 H), 5.24 (d, J = 15.6 Hz, 1 H), 5.07 (d, J = 9.0 Hz, 1 H), 4.97–4.92 (m, 1 H), 4.46 (d, J = 15.6 Hz, 1 H), 3.84–3.74 (m, 2 H), 2.81 (br s, 1 H), 1.56 (s, 9 H), 0.81 (t, J = 7.2 Hz, 3 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 175.4, 170.0, 167.6, 148.7, 143.7, 140.0, 135.5, 130.4, 130.1, 128.7 (2 C), 127.6 (2 C), 127.5, 125.3 (q, J = 279.9 Hz), 125.2 (2 C), 124.0, 123.9, 123.4, 121.9, 115.3, 109.3, 84.5, 72.5, 63.1, 61.4, 60.2 (q, J = 32.2 Hz), 51.2, 44.5, 28.1 (3 C), 13.4 ppm. IR (ATR): 3823, 3456, 2969, 2655, 2330, 2089, 1889, 1741, 1366, 1216, 811, 687 cm–1. ESI-MS: m/z = 658.2 [M + Na]+. ESI-HRMS: m/z [M + Na]+ calcd for C34H32N3O6F3Na+: 658.2135; found: 658.2136.
  • 13 CCDC 1549337 contains the supplementary crystallographic data for the compound 4. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/getstructures.