Total Synthesis of (+)-Mintlactone and (–)-Isomintlactone via SmI₂-Induced Radical Cyclization

^◊ These authors contributed equally

Abstract

A divergent strategy has been used to concisely and efficiently complete the synthesis of (+)-mintlactone and (–)-isomintlactone via SmI₂-induced intramolecular radical cyclization, two rings and a stereocenter were constructed in one step. In the synthesis, the stereochemistry of the final natural product is set relative to the stereocenter of (–)-citronellol and favored coordination transition state of samarium atom with substrate.

Key words

SmI₂-induced radical cyclization - (+)-mintlactone - (–)-isomintlactone - total synthesis - γ-butenolides

• References and Notes

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• 9 Preparation of (+)-Mintlactone (1) To the freshly made Sm powder (0.24 g, 1.6 mmol) was added THF (4.0 mL) and CH₂I₂ (0.40 g, 1.5 mmol) at the r.t. and the mixture was stirred for 40 min (the color of the solution turns to dark blue). Then to the solution was added t-BuOH (0.15 g, 2.0 mmol) at –20 °C. After stirring for 5 min, substrate 7 (0.1 g, 0.5 mmol) in anhydrous THF (1.0 mL) was added dropwise. After stirring for 2 h, sat. NH₄Cl was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The solvents were evaporated under reduced pressure, and the crude product was purified by flash column chromatography to yield 57 mg of the crude lactone product. 100 mg of crude lactone product was dissolved in anhydrous THF (2 mL), KHMDS (0.90 mL, 1 mmol/L in THF) was added at –78 °C. After stirring for 20 min, TMSCl (83 mg, 0.76 mmol) was added. To the resultant solution, NBS (139 mg, 0.78 mmol) in THF (2 mL) was added after a further 15 min. The reaction mixture was stirred at –78 °C for 4 h. And then sat. NH₄Cl (1 mL) was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The solvents and the crude bromolactone were evaporated under reduced pressure. To a solution of the crude bromolactone obtained above in toluene (4 mL), DBU (91 mg, 0.60 mmol) was added. The reaction mixture was refluxed for 90 min, and solvent was removed under reduced pressure to furnish a residue. Then the residue was purified with column chromatography to afford 1 (mixture of isomers, 67 mg, 68%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.60 (dd, J = 11.3, 6.1 Hz, 1 H), 2.77 (ddd, J = 14.2, 4.3, 1.8 Hz, 1 H), 2.45–2.36 (m, 1 H), 2.17 (td, J = 13.8, 5.6 Hz, 1 H), 1.99–1.88 (m, 1 H), 1.79 (d, J = 1.5 Hz, 3 H), 1.75–1.64 (m, 1 H), 1.06–0.93 (m, 5 H). ¹³C NMR (101 MHz, CDCl₃): δ = 174.8, 162.3, 119.6, 79.9, 42.0, 34.6, 29.8, 25.5, 21.2, 8.2. ESI-HRMS: m/z calcd for C₁₀H₁₈NO₂ [M + NH₄]⁺: 184.1332; found: 184.1332.
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• 12 Preparation of (–)-Isomintlactone (2) The compound 12 was synthesized according to the procedures employed by the preparation of 8 to give the crude lactone product as a light yellow oil. 90 mg of crude lactone 12 was dissolved in anhydrous THF (2 mL), KHMDS (0.64 mL, 1.0 mmol/L in THF) was added at –78 °C. After stirring for 20 min, PhSeCl (134 mg, 0.70 mmol) in THF (2 mL) was added. The reaction mixture was stirred at –78 °C for 4 h. Then sat. NH₄Cl (1 mL) was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 5 mL). The solvents were evaporated under reduced pressure to give crude selenolactone. To the crude product dissolved in THF (4 mL), 30% H₂O₂ (0.1 mL) was added at 0 °C. After stirring for 3 min, the reaction was allowed to warm to r.t. to stir another 3 min. And then the reaction was quenched with aq Na₂S₂O₃ and extracted with EtOAc (3 × 5 mL). The solvents were evaporated under reduced pressure, and the crude product was purified by flash column chromatography to yield 2 (mixture of isomers, 45 mg, 51%) as a light yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 4.77 (dd, J = 11.0, 6.2 Hz, 1 H), 2.66 (ddd, J = 14.3, 4.6, 1.7 Hz, 1 H), 2.42–2.23 (m, 3 H), 1.79–1.77 (m, 4 H), 1.58–1.46 (m, 1 H), 1.33 (td, J = 12.0, 4.6 Hz, 1 H), 1.12 (d, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 174.9, 163.0, 119.3, 77.4, 39.6, 31.7, 27.3, 21.8, 17.2, 8.1. ESI-HRMS: m/z calcd for C₁₀H₁₅O₂ [M + H]⁺: 167.1067; found: 167.1067.
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