Regio- and Chemoselective One-Step 3-O-Alkylenation of Unprotected Ascorbic Acid Using ω-Iodoalkanols

Abstract

A regio- and chemoselective alkylenation employing unprotected ascorbic acid and a series of unprotected iodoalkanols in the presence of sodium hydrogen carbonate in dimethyl sulfoxide is described. This atom economic high yielding procedure delivers the corresponding 3-O-alkylene ethers in a single step without prior protection. Specific 3-O-etherification was also observed with ­unprotected 16-iodohexadecanoic acid and with 2-(10-iododecyl)isoindole-1,3-dione. Furthermore, an 2-O-alkylene derivative was obtained when 3-O-benzyl ascorbic acid was reacted with unprotected 10-iododecanol under slightly modified conditions. Finally, the antioxidative activity of all compounds was determined and compared to vitamin C and E.

Key words

ascorbic acid - regioselective - chemoselective - 3-O-alkylenation - ω-iodoalkanols

References and Notes

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16

Typical Experimental Procedure; Preparation of ( R )-5-[( S )-1,2-Dihydroxyethyl)]-3-hydroxy-4-(10-hydroxy-decyloxy)furan-2 (5 H )-one (11b): Ascorbic acid (3.20 g, 18.20 mmol, 2.5 equiv) and NaHCO₃ (1.83 g, 21.85 mmol, 3 equiv) were added to a solution of 10-iododecanol (2.07 g, 7.28 mmol, 1 equiv) in anhyd DMSO (18 mL) and the resulting mixture was heated at 60 ˚C. After 3 h, DMSO was evaporated under reduced pressure and the residue was suspended in ethanol (12 mL) and brine (12 mL). EtOAc (200 mL) was added to the suspension which was then dried over MgSO₄, filtered and evaporated under reduced pressure. The crude was purified via silica gel column chromatography (CH₂Cl₂-MeOH, 9:1) and was recrystallized (EtOAc-hexane) to give a white solid (80%). R _f = 0.30 (EtOAc); mp 71-73 ˚C. IR (CHCl₃): 3396 (OH), 1748 (CyO), 1693 (CyO) cm^-¹. ^¹H NMR (300 MHz, CD₃OD): δ = 1.31 (br s, 12 H, H-3′ to H-8′), 1.51 (m, 2 H, H-9′), 1.72 (m, 2 H, H-2′), 3.52 (t, J = 6.6 Hz, 2 H, H-10′), 3.64 (m, 2 H, CH₂OH), 3.82 (m, 1 H, CHOH), 4.48 (m, 2 H, H-1′), 4.75 (d, J = 1.8 Hz, 1 H, CH). ^¹³C NMR (75 MHz, CD₃OD): δ = 25.2, 25.5 (C-2′, C-3′), 28.2-29.2 (C-4′ to C-8′), 32.2 (C-9′), 61.6 (CH₂OH), 70.0 (CHOH), 70.5 (C-10′), 72.4 (C-1′), 75.2 (CH), 119.0 (=COH), 150.8 (=CO-alkyl), 171.8 (C=O).