One-Pot Sequential 1,4- and 1,2-Reductions of α,β-Unsaturated δ-Lactones to the Corresponding δ-Lactols with CuCl and NaBH₄ in Methanol

Abstract

An efficient, one-pot method for the highly chemoselective synthesis of δ-lactols from α,β-unsaturated δ-lactones using CuCl and NaBH₄ in methanol was developed.

Key words

copper - hydrides - lactones - lactols - reduction

• References and Notes


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• 7 It is noteworthy to mention that the reduction of an saturated lactone to a lactol with CuCl and NaBH₄ in MeOH has not been reported previously.
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• 9 General Procedure NaBH₄ (10 mmol, 10 equiv) was added in three roughly equal portions to a stirred solution of an α,β-unsaturated δ-lactone (1.0 mmol) in MeOH (10 mL; lactone concentration, 0.1 M) at –50 °C in a reaction flask connected to a drying tube containing CaCO₃. After the solution was stirred for 15 min at –50 °C, the drying tube was removed, and CuCl (0.5 mmol, 0.5 equiv) was added to the reaction mixture, which immediately turned into a black suspension and evolved H₂ gas (the flask was kept open to let out the gas). The reaction temperature was warmed to –20 °C over the course of 1 h, and the reaction was quenched at that temperature with sat. aq NH₄Cl. Then EtOAc and H₂O were added to the mixture, which was vigorously stirred for 30 min at r.t. The resulting clear solution was extracted with EtOAc, and the combined organic layers were washed with brine, dried over MgSO₄, and concentrated in vacuo. The crude mixture of products was purified by silica gel flash column chromatography with gradient of EtOAc and n-heptane as eluents to afford the desired δ-lactol. 6-Benzyltetrahydro-2H-pyran-2-ol (5b) White solid (90%, cis/trans = 1.4:1). ¹H NMR (600 MHz, CDCl₃): δ = 7.30–7.27 (m, 4 H, cis trans), 7.22–7.20 (m, 6 H, cis trans), 5.28 (br s, 1 H, trans), 4.66 (m, 1 H, cis), 4.19 (m, 1 H, trans), 3.64 (m, 1 H, cis), 3.06 (d, J = 4.0 Hz, 1 H, cis-OH), 2.95 (dd, J = 14.0, 7.0 Hz, 1 H, cis), 2.81 (dd, J = 14.0, 7.0 Hz, 1 H, trans), 2.73 (dd, J = 14.0, 7.0 Hz, 1 H, cis), 2.67 (dd, J = 14.0, 7.0 Hz, 1 H, trans), 2.55 (br s, 1 H, trans-OH), 1.87–1.80 (m, 3 H, cis trans), 1.71–1.42 (m, 6 H, cis trans), 1.35–1.28 (m, 2 H, cis trans), 1.25–1.18 (m, 1 H, cis). ¹³C NMR (150 MHz, CDCl₃): δ = 138.7 (trans), 138.5 (cis), 129.4 (cis), 129.4 (trans), 128.2 (cis), 128.2 (trans), 126.2 (cis), 126.1 (trans), 96.5 (cis), 92.0 (trans), 77.3 (cis), 69.7 (trans), 42.8 (trans), 42.6 (cis), 32.5 (cis), 30.9 (trans), 30.0 (cis), 29.6 (trans), 21.9 (cis), 17.3 (trans). IR (ATR): ν = 3318, 2942, 2861, 1353, 1142, 1047, 1010, 903, 746, 700 cm^–1. HRMS (ESI⁺): m/z calcd for: C₁₂H₂₀NO₂ [M + NH₄]⁺: 210.1489; found: 210.148.