Asymmetric Desymmetrization of 2-Substituted 1,3-Propanediols by Using Oxazaborolidinone-Mediated Enantioselective Ring-Cleavage of Prochiral Acetal Derivatives

Abstract

Nonenzymatic desymmetrization of 2-substituted 1,3-propanediols leading to the enantiomerically enriched 3-benzyloxy-1-propanols was achieved by using oxazaborolidinone-mediated enantioselective ring-cleavage reaction of the dioxane acetal derivatives.

Key words

asymmetric synthesis - acetals - cleavage - diols - Lewis acids

References and Notes

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5

The relative configuration of the major diastereomers was assigned tentatively based on the assumption of the introduction of the nucleophile with inversion of the acetal carbon. [4e] [6]

8

Treatment of 2-phenyl-1,3-propanediol and 1-naphthaldehyde (1.1 equiv) under the conventional reaction conditions (p-TsOH, refluxing) gave acetal 1e (trans:cis = 6:1) in quantitative yield. A pure trans isomer obtained by recrystallization from ethyl acetate and hexane was used in ring-cleavage reaction.

9

Acetal 1c with the electron-withdrawing p-chlorophenyl group showed slightly higher enantioselectivity. Electron-withdrawing character of the 1-naphthyl group relative to the phenyl group may also be responsible for the high selectivity observed for 1d.

10

Typical experimental procedure: To a solution of N-tosyl-l-(2-naphthyl)alanine (177 mg, 0.480 mmol) in CH₂Cl₂ (5.0 mL) at room temperature under argon was added dibromo(p-chlorophenyl)borane (72 µL, 0.48 mmol). [4d] After being stirred for 30 min, the mixture was concentrated in vacuo and the residue was dissolved in CH₂Cl₂ (0.5 mL). To the resulting solution of oxazaborolidinone 3g at -50 °C were added Et₂O (0.12 mL) and a solution of acetal 1d (116 mg, 0.400 mmol) and silyl ketene acetal 2 (226 mg, 1.20 mmol) in CH₂Cl₂ (0.5 mL). After being stirred for 20 h at -50 °C, the mixture was quenched by the addition of aqueous NaHCO₃ and filtered. The filtrate was extracted twice with ether. The organic layers were dried and concentrated in vacuo. The residue was treated with aqueous AcOH (70%, 2 mL) and THF (2 mL) at room temperature for 1 h. The mixture was diluted with water, extracted twice with ether, and washed with aqueous NaHCO₃. The organic layers were dried and concentrated in vacuo. Purification of the residue by flash column chromatography (SiO₂, 5-20% ethyl acetate in hexane) gave 147 mg (91% yield) of 4a: ¹H NMR (500 MHz, CDCl₃) δ 1.02 (3 H, s), 1.25 (3 H, s), 1.32 (3 H, t, J = 7.2 Hz), 2.20 (1 H, br), 3.12 (1 H, quint, J = 5.5 Hz), 3.58-3.64 (2 H, m), 3.84 (1 H, dd, J = 5.7 and 11.0 Hz), 4.03 (1 H, dd, J = 7.5 and 11.0 Hz), 4.20 (2 H, m), 5.70 (1 H, br), 7.15-7.30 (5 H, m), 7.47-7.56 (4 H, m), 7.83 (1 H, d, J = 8.3 Hz). 7.89 (1 H, m), 8.20 (1 H, m) [a minor diastereomer resonated at δ 3.91 (1 H, dd, J = 5.0 and 11.0 Hz)]; IR (liquid film): 3475(br), 1725 cm^-1; HRMS (CI) calcd for C₂₆H₃₁O₄ (MH⁺) 407.2222, found; 407.2219.