Chiral Bifunctional Sulfide-Catalyzed Enantioselective Synthesis of α-Substituted γ-Lactones Bearing a γ-Quaternary Stereocenter

Abstract

Catalytic highly enantioselective syntheses of α-spiro-γ-lactones and α-substituted γ-lactones bearing a γ-quaternary stereocenter have been achieved through chiral bifunctional sulfide-catalyzed asymmetric bromolactonizations. The synthetic utility of the optically active γ-lactone products was demonstrated by transformations into functionalized γ-lactones and epoxides possessing a quaternary stereocenter.

Key words

asymmetric synthesis - halogenation - lactones - organocatalysis - sulfides - bromolactonization

• References and Notes

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• 7 Asymmetric Bromolactonization; General Procedure A solution of the appropriate substrate 2 (0.10 mmol) and catalyst (S)-1b (4.5 mg, 0.010 mmol, 10 mol %) in toluene (1.5 mL)–CH₂Cl₂ (0.5 mL) was cooled to –78 °C and stirred for 10 min at –78 °C. NBP (27.1 mg, 0.12 mmol, 1.2 equiv) was added to the cooled reaction solution and the resulting mixture was stirred for 24 h at –78 °C. The reaction was then quenched with sat. aq Na₂SO₃ (3 mL) at –78 °C and stirred for 10 min at –78 °C. The mixture was then diluted with CH₂Cl₂ (2 mL) and H₂O (2 mL) and warmed to r.t. The organic materials were extracted with CH₂Cl₂ (3 × 5 mL), and the combined extracts were dried (Na₂SO₄) and concentrated. The residue was purified by flash column chromatography (silica gel) to give product 3. The enantioselectivities of the isolated products 3 were determined by HPLC analysis on a chiral stationary phase. (3R)-3-(Bromomethyl)-3-phenyl-2-oxaspiro[4.4]nonan-1-one (3b) Colorless oil; yield: 29.1 mg (94%); [α]_D ²¹ +14.6 (c = 1.4, CHCl₃; 94:6 er). HPLC [Daicel Chiralpak IC-3, hexane–2-propanol (20:1), flow rate = 0.5 mL/min, λ = 254 nm]: t _R: 25.7 min (major); 36.8 min (minor). IR (neat): 2958, 1767, 1145, 1035, 996, 973, 767, 702 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.32 (m, 5 H), 3.73 (d, J = 11.2 Hz, 1 H), 3.65 (d, J = 11.2 Hz, 1 H), 2.77 (d, J = 13.0 Hz, 1 H), 2.55 (d, J = 13.0 Hz, 1 H), 2.27–2.20 (m, 1 H), 1.89–1.50 (m, 6 H), 1.26–1.18 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 181.2, 141.3, 128.7, 128.4, 125.0, 83.6, 50.1, 46.7, 41.1, 39.2, 38.0, 25.4, 25.2. HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₇BrO₂: 308.0412; found: 308.0412. (5R)-5-(Bromomethyl)-3,3-diethyl-5-phenyldihydrofuran-2(3H)-one (3g) Colorless oil; yield: 28.0 mg (90%); [α]_D ²⁵ +9.3 (c = 1.1, CHCl₃; 97:3 er). HPLC [Daicel Chiralpak IE-3, hexane–2-propanol (20:1), flow rate = 0.5 mL/min, λ = 254 nm] t _R = 28.2 min (minor); 30.5 min (major). IR (neat): 2968, 1768, 1120, 1032, 703 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.45–7.32 (m, 5 H), 3.71 (d, J = 11.2 Hz, 1 H), 3.62 (d, J = 11.4 Hz, 1 H), 2.80 (d, J = 13.3 Hz, 1 H), 2.44 (d, J = 13.5 Hz, 1 H), 1.75 (q, J = 7.6 Hz, 2 H), 1.39–1.25 (m, 2 H), 1.00 (t, J = 7.5 Hz, 3 H), 0.65 (t, J = 7.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 179.5, 141.8, 128.8, 128.4, 124.9, 83.0, 48.7, 42.1, 41.3, 29.2, 27.9, 8.8, 8.4. HRMS (EI): m/z [M⁺] calcd for C₁₅H₁₉BrO₂: 310.0568; found: 310.0568.
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• 11 A transition-state model for the chiral bifunctional sulfide (S)-1b-catalyzed bromolactonization in the synthesis of γ-lactones bearing a γ-quaternary stereocenter is discussed in our previous report.^3c