A Facile Solid-Phase Synthesis of Substituted 2(5H)-Furanones with Sulfone Traceless Linker

Abstract

A novel solid-phase synthetic method for substituted 2(5H)-furanones with traceless sulfone linker strategy has been developed. The products were obtained in good yields and excellent purities.

solid-phase organic synthesis - traceless sulfone linker - substituted 2(5H)-furanone

References

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5

Preparation of Polymer-Supported Phenylmethylsulfone 2: Polystyrene/1% divinylbenzene lithium sulfinate (1, 1.0 g, 1.0 mmol), prepared according to literature, [4h] was swollen under nitrogen in THF-DMF (2:1, 10 mL). MeI (5.0 mmol) was added and the reaction mixture was shaken at 80 °C for 15 h. After which, the reaction mixture was cooled to r.t., quenched with H₂O, and filtered. The resin was washed successively with THF-H₂O (2:1, 3 × 10 mL), THF (2 × 5 mL), CH₂Cl₂ (2 × 5 mL) and Et₂O (2 × 5 mL), and then dried under vacuum overnight to afford the pale yellow resin 2. FT-IR (single bead reflection): 1600, 1495, 1452, 1380, 1313, 1150 cm^-1.

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7

General Procedure for the Solid-Phase Synthesis of Target Molecules ( 6): Under nitrogen n-BuLi (2.0 mmol, 1.65 M, 1.2 mL) was added to DMSO (4.0 mmol) in THF (10 mL) at 0 °C and stirred for 5 min. The resulting dimsyl anion solution was transferred to a suspension of polymer 2 (1.0 g, 1.0 mmol) in THF (8 mL) at r.t. After stirring for 30 min, epoxide (3.0 mmol) was added to this mixture and stirred for 2 h, the color of the breads turned light orange. The reaction was quenched with 10% HCl (aq) after 1 h and the resin was filtered, washed and dried to afford resin 3 as pale yellow beads. A solution of methyl chloroformate (2.0 mmol) in THF (2 mL) was added to a suspension of the obtained resin 3 in THF (8 mL) at 0 °C, and followed with pyridine (1.5 mmol, 0.2 mL). The mixture was stirred 0 °C for 1 h and the γ-phenylsulfonylalkyl methyl carbonate resin 4 was collected by filtration and washed successively with 3% HCl (3 × 10 mL), H₂O (3 × 10 mL), THF (3 × 5 mL), and dried in a vacuum. Subsequently, the resin 4 was swollen in THF (10 mL) and treated with LDA (2.0 mmol) at -78 °C for 1 h under dry nitrogen, at 0 °C for 2 h, and then at r.t. for 1 h. The resin 5 was collected by filtration and washed successively with THF-H₂O (1:1, 30 mL), H₂O (3 × 10 mL), and THF (3 × 5 mL). After drying in a vacuum, the resin 5 was swollen in CH₂Cl₂ (10 mL) and treated with Et₃N (5.0 mmol) at r.t. for 10 h. The residual resin was collected by filtration and washed with CH₂Cl₂ (2 × 3 mL). The organic extracts were washed with H₂O, dried over anhyd MgSO₄ and concentrated to afford crude product 6 with 90-95% purity (determined by HPLC), which was further purified by silica gel chromatographic column (petroleum ether-EtOAc = 20:1) affording the pure products for ¹H NMR and MS analysis.