Organocatalytic Asymmetric Synthesis of Pentasubstituted Tetrahydrothiopyrans Bearing a Quaternary Centre through a Double Michael Reaction

Abstract

An organocatalytic, asymmetric, double-Michael strategy has been developed employing trans-α-cyano-α,β-unsaturated ketones for the synthesis of pentasubstituted tetrahydrothiopyrans bearing a quaternary center. A proline-derived bifunctional thiourea was found to be the most effective catalyst for this reaction. With 10 mol% of catalyst, good yields and good to high diastereomeric ratios, as well as excellent enantioselectivities, were obtained with a variety of tetrahydrothiopyrans under mild reaction conditions.

Key words

tetrahydrothiopyrans - Michael reaction - organocatalysis - enantioselectivity - quaternary centers

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• 17 Pentasubstituted Tetrahydrothiopyrans 3aa–ja; General Method An oven-dried round-bottomed flask was charged with 1 (0.1 mmol), 2 (0.12 mmol), catalyst VI (10 mol%). MTBE (0.4 mL) was added, and the mixture was stirred at r.t. for 5 d until the reaction was complete (TLC). The solvent was removed and the mixture was directly purified by column chromatography [silica gel, hexane–EtOAc (10–15%)]. 2,4-Dibenzoyl-5-(2-oxo-2-phenylethyl)-3-phenyltetrahydro-2H-thiopyran-4-carbonitrile (3aa) White solid; yield: 37.0 mg (70%), dr 6:1 (¹H NMR), ee 90% (HPLC); mp 65–67 °C. HPLC: Chiralpak IA [hexane–i-PrOH (90:10), flow rate: 1.0 mL/min, λ = 254 nm]; t _major = 13.6 min, t _minor = 16.4 min. ¹H NMR (600 MHz, CDCl₃): δ = 8.02 (d, J = 7.4 Hz, 2 H), 7.90 (d, J = 7.5 Hz, 2 H), 7.57 (d, J = 7.6 Hz, 3 H), 7.54 (s, 1 H), 7.49 (dd, J = 15.9, 7.8 Hz, 5 H), 7.41 (t, J = 7.8 Hz, 2 H), 7.34 (t, J = 7.8 Hz, 2 H), 7.14–7.05 (m, 3 H), 5.54 (d, J = 11.4 Hz, 1 H), 4.44 (d, J = 11.3 Hz, 1 H), 4.13 (d, J = 14.4 Hz, 1 H), 3.93 (dd, J = 18.7, 7.4 Hz, 1 H), 3.85–3.80 (m, 1 H), 3.62 (dd, J = 18.6, 2.5 Hz, 1 H), 2.90 (dd, J = 14.6, 3.3 Hz, 1 H). ¹³C NMR (151 MHz, CDCl₃): δ = 197.1, 194.9, 194.0, 137.0, 136.5, 136.4, 135.7, 134.0, 133.8, 133.2, 128.9, 128.8, 128.7, 128.4, 128.4, 128.1, 120.9, 58.4, 46.8, 44.4, 36.6, 36.4, 32.2. HRMS (ESI): m/z [M + NH₄]⁺ calcd for C₃₄H₃₁N₂O₃S: 547.2055; found: 547.2055.