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

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

Key words

asymmetric synthesis - dispirooxindole - organocatalysis - domino reaction - Michael–Mannich [3+2] cycloaddition

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• 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 3a–q. 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.