The Asymmetric Synthesis of d-Galactose via an Iterative syn-Glycolate Aldol Strategy

Abstract

The asymmetric synthesis of d-galactose has been completed in eight steps and in >14% yield from simple starting materials via an iterative syn-glycolate aldol strategy.

asymmetric synthesis - monosaccharides - iterative glycolate aldol reaction - d-galactose

References

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Experimental Procedure for Aldol Reactions: CF₃SO₃H (1.2 equiv) was added to BEt₃ (1 M in hexanes, 1.2 equiv) at r.t. then warmed to 40 °C for 10 minutes before cooling to 0 °C and subsequent addition via cannula to a solution of N-acyl-oxazolidin-2-one (1 equiv) in CH₂Cl₂. After 10 minutes, i-Pr₂NEt (1.4 equiv) was added and the reaction mixture stirred for a further 20 minutes before cooling to -78 °C and the addition of freshly distilled aldehyde (1.1 equiv). After 30 minutes the reaction mixture was warmed to 0 °C and stirred for a further hour before the addition of MeOH-H₂O₂ (v/v, 1:1). The reaction mixture was extracted with CH₂Cl₂, washed with brine, dried and concentrated in vacuo before purification by flash column chromatography.

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Experimental Procedure for DIBALH Reduction: DIBALH (1 M in hexanes, 2 equiv) was added to a stirred solution of N-acyl-oxazolidin-2-one (1 equiv) in anhydrous CH₂Cl₂ at
-78 °C. After 30 minutes, the reaction mixture was quenched with saturated aqueous NH₄Cl solution and stirred for a further 20 minutes. The resultant emulsion was filtered through Celite®, dried and concentrated in vacuo before purification by flash column chromatography.

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¹H NMR data for tetrose 8; δ_H (400 MHz, CDCl₃) 0.01, 0.04 [2 × 3 H, s, Si(CH₃)₂ t-Bu], 0.86 [9 H, s, SiC(CH ₃ )₃], 3.53 [1 H, dd, J = 9.8 Hz, 4.9, C(4)H _A ], 3.61 [1 H, dd, J = 9.8 Hz, 5.6, C(4)H _B ], 3.88 [1 H, dd, J = 4.5 Hz, 1.3, C(2)H], 4.16-4.19 [1 H, m, C(3)H], 4.48 [2 H, ABq, J = 12.2 Hz, OCH ₂ Ph], 4.57 [1 H, AB, J = 12.0 Hz, C(2)OCH _A H_BPh], 4.77 [1 H, AB, J = 12.0 Hz, C(2)OCH _A H _BPh], 7.27-7.37 (10 H, m, PhH), 9.76 (1 H, d, J = 1.3 Hz, CHO).

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¹H NMR data for lactone 10; δ_H (400 MHz, CDCl₃) 2.56 (1 H, d, J = 2.3 Hz, OH), 3.68-3.76 [2 H, m, C(6)H ₂ OBn], 4.08-4.11 [1 H, m, C(3)H], 4.17 [1 H, t, J = 2.3 Hz, C(4)H], 4.32 [1 H, d, J = 9.7 Hz, C(2)H], 4.43-4.47 [1 H, m, C(5)H], 4.52 [2 H, ABq, J = 11.7 Hz, C(6)H₂OCH ₂ Ph], 4.62 [1 H, d, J = 11.2 Hz, C(4)OCH _A H_BPh], 4.72 [1 H, d, J = 11.2 Hz, C(2)OCH _A H_BPh], 4.85 [1 H, d, J = 11.2 Hz, C(4)OCH_A H _B Ph], 5.19 [1 H, d, J = 11.2 Hz, C(2)OCH_A H _B Ph], 7.21-7.43 (15 H, m, PhH).

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Commercially available from the Aldrich Chemical company.