Synthesis of β,β-Disubstituted γ-Butyrolactones by Chemo­selective Oxidation of 1,4-Diols and γ-Hydroxy Olefins with RuCl₃/NaIO₄

Abstract

Substituted γ-butyrolactones represent an important group of structural fragments commonly found in natural products, receptor ligands, and drug molecules. Interest in preparing a library of substituted γ-butyrolactones and finding that limited routes to β-substituted lactones exist, led to the development of an efficient approach for the synthesis of β,β-disubstituted γ-butyrolactones. Readily prepared substituted 1,4-diols and γ-hydroxy olefins were treated with the ­RuCl₃/NaIO₄ oxidation system to provide the target β,β-disubstituted γ-butyrolactones in modest to good yields. The reaction goes through a lactol intermediate that was isolated and characterized for selected compounds. The approach supplies an efficient and versatile method for the synthesis of these important heterocyclic structures. Importantly, the present work is the first report that demonstrates the ability of RuCl₃/NaIO₄ to selectively oxidize primary hydroxyl groups in the presence of secondary alcohols to prepare lactones in good yields.

Key words

lactones - cyclization - ruthenium - alkenes - diols

• References and Notes

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• 14 General Procedure for 6a–6f: To a stirred mixture of γ-hydroxy olefins (3a–3f, 3.16 mmol), RuCl₃ stock solution [(4.51 mL, 0.035 M in H₂O), MeCN (81 mL) and distilled H₂O (9 mL), NaIO₄ (4.06 g, 18.96 mmol)] was added in portions over a period of 30 min at r.t. The suspension was allowed to stir at r.t. overnight. The reaction was quenched with sat. aq solution of Na₂S₂O₃ and the two layers were separated. The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with brine, dried over anhyd MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography to give desired aldehyde product (silica gel, EtOAc–hexanes, 0–25%). 2-Oxaspiro[4.4]nonan-3-one (6a): colorless oil, yield: 72%. ¹H NMR (400 MHz, CDCl₃): δ = 4.10 (s, 2 H), 2.44 (s, 2 H), 1.69 (m, J = 5.2, 2.5 Hz, 8 H). ¹³C NMR (101 MHz, CDCl₃): δ = 177.2, 78.6, 47.7, 41.4, 36.9, 24.4. General Procedure for 7a–7i: To a stirred mixture of 1,4-diols (3.16 mmol), RuCl₃ stock solution [(4.51 mL, 0.035 M in H₂O), MeCN (81 mL) and distilled H₂O (9 mL), NaIO₄ (4.06 g, 18.96 mmol)] was added in portions over a period of 30 min at r.t. The suspension was allowed to stir at r.t. overnight. The reaction was quenched with sat. aq solution of Na₂S₂O₃ and the two layers were separated. The aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layer was washed with brine, dried over anhyd MgSO₄, filtered, and concentrated. The residue was purified by flash column chromatography to give the desired aldehyde product (silica gel, EtOAc–hexanes: 0–25%). 5-Methyl-4,4-diphenyldihydrofuran-2(3H)-one (7a): colorless semisolid, yield: 81%. ¹H NMR (400 MHz, CDCl₃): δ = 7.13–7.32 (m, 6 H), 7.05–7.13 (m, 2 H), 6.94 (m, 2 H), 5.34 (q, J = 6.4 Hz, 1 H), 3.41 (d, J = 16.9 Hz, 1 H), 2.88 (d, J = 16.9 Hz, 1 H), 1.06 (d, J = 6.5 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 175.3, 145.1, 142.1, 129.0, 128.6, 128.1, 127.4, 127.3, 127.1, 82.4, 55.5, 43.0, 17.9. HRMS (CI): m/z [M + H] calcd for C₁₇H₁₆O₂: 253.1229; found: 253.1225.