A Practical Approach Towards the Asymmetric Synthesis of α,γ-Substituted γ-Sultones

Abstract

The first auxiliary controlled synthesis of enantiopure α,γ-substituted γ-sultones via α-allylated chiral sulfonates is described. The high asymmetric inductions of the α-allylations were reached with our previously described auxiliary 1,2:5,6-di-O-isopropylidene-α-d-allofuranose (de≥98%). Cleavage of the auxiliary and successive diastereoselective ring closure of the sulfonic acid intermediates led to the title compounds in high selectivities (de, ee≥98%) and good to excellent yields (52-90%). Enantiopure α,γ-substituted γ-sultones are interesting intermediates in the reaction with various nucleophiles.

asymmetric synthesis - sugar auxiliary - α-allylation - sulfonates - sultones

References

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2 Fischer RF. Ind. Eng. Chem.  1964,  56:  41 

For reviews on sultone chemistry see:

3a Buglass AJ. Tillet JG. In The Chemistry of Sulfonic Acids, Esters and their Derivatives   Patai S. Rappoport Z. Wiley; Chichester, New York: 1991.  Chap. 19.

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General Procedure for the α-Allylation of Chiral Sulfonates 1: To a solution of enantiopure sulfonate 1 (5.0 mmol) in dry THF (50 mL), n-butyllithium (1.0 equiv) was added dropwise at -(90-95) °C under an argon atmosphere. After stirring at -(90-95) °C for 1 h, the allylic halide (1.5 equiv) was added dropwise. The reaction mixture was stirred for additional 2 h and then stirring was continued at -78 °C over night. The mixture was quenched with water. After separation of the organic layer the aq phase was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with water, brine and dried over MgSO₄. The solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography (SiO₂, n-pentane/diethyl ether 5:1) to afford (R)-2.

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General Procedure for the Removal of the Chiral Auxiliary: The sulfonates (R)-2 (1.0 mmol) were dissolved in a 2% TFA/EtOH solution (40 mL). The solution was refluxed for 24 h after which the solvent was removed under reduced pressure and the crude sulfonic acid was used in the next reaction step without further purification. General Procedure for the Cyclization: The crude product 3 was dissolved in a TFA/CH₂Cl₂ solution (20 mL). The reaction mixture was refluxed for 24 h. After separation of the organic layer the aq phase was extracted with CH₂Cl₂ (3 × 20 mL). The combined organic layers were washed with sat. aq NaHCO₃-solution and brine. After drying over MgSO₄ the solvent was evaporated and the crude product was purified by flash column chromatography (SiO₂, n-pentane/diethyl ether 4:1) to afford 4.
(R,R)-4c: IR (KBr): 3035, 2995, 2973, 1498, 1459, 1387, 1331 (s), 1252, 1194, 1165 (s), 1130, 1113, 1026 (s), 942, 910, 858, 820 (s), 795 (s), 770, 698 (s), 598 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.56 (d, J = 6.0 Hz, 3 H, CH ₃), 2.56 (ddd, J = 10.4, 13.2, 13.2 Hz, 1 H, CHH), 2.79 (ddd, J = 5.5, 6.9, 13.2 Hz, 1 H, CHH), 4.54 (dd, J = 6.9, 13.2 Hz, 1 H, CHPh), 4.78 (m, 1 H, CHO), 7.36-7.45 (m, 5 H, ArH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 20.8 (CH₃), 37.6 (CH₂), 63.25 (CHPh), 77.4 (CHO), 128.6, 128.8, 129.25 (PhCH), 129.3(PhC) ppm. MS (EI, 70eV): m/z = 212 (10)[M⁺], 148 (14), 104 (100), 91 (5), 78 (10).

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All new compounds showed suitable spectroscopic data (NMR, MS, IR) and correct elemental analyses.