(E)-2-((4R,5R)-5-((Benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-ene-1,4-diol

Abstract

The synthesis of (E)-2-((4R,5R)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-ene-1,4-diol by a one-step reduction of the appropriate 2-substituted butenolide is reported. Product characterization was carried out by IR, ¹H NMR, ¹³C NMR, MS, elemental analysis and optical rotation.

2-Alkylbut-2-ene-1,4-diols are present in a number of natural products and constitute highly versatile synthetic precursors [1,2,3,4,5,6,7]. For instance, biologically active 2-substituted 1,4-diacetoxy-butadienes [8,9,10], acyclic sesquiterpenoids and acyclic diterpenoids [11,12,13,14,15,16] can be easily synthesized from the above building blocks. From a synthetic point of view, 2-alkylbut-2-ene-1,4-diols are typically prepared, among different methods [17,18], by hydrostannation [9] or addition of Grignard reagents to but-2-ynediols [19].

Herein, we report the facile synthesis of (E)-2-((4R,5R)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-ene-1,4-diol (3) by treatment of the corresponding 2-substituted butenolide 2 at 0 °C under reductive conditions, employing DIBAL-H as reducing agent (Scheme 1). Chiral precursor 2 was prepared by acid-mediated regioselective oxidation of the appropriate 3-substituted furan 1 as previously described in the literature [20]. All stereochemical assignments were further confirmed by differential nOe experiments (see Supplementary Files). Compound 3 represents a practical polyoxygenated chiral synthon in which each hydroxy group could be independently functionalized.

Experimental

General

¹H and ¹³C NMR spectra were recorded at 25 °C on a Bruker Avance 500 spectrometer in CDCl₃ as solvent, and chemical shifts are reported relative to Me₄Si (δ = 0). Low- and high-resolution mass spectra were obtained by using a Micromass VG Autospec spectrometer. Elemental analysis was performed on a Fisons Instrument EA 1108 CHNS-O analyzer. Infrared spectra were recorded on a Bruker IFS 55 spectrophotometer for compounds dispersed on a NaCl disc. Optical rotations were determined for solutions in chloroform with a Perkin Elmer 343 polarimeter using a sodium lamp (589 nm). Thin-layer chromatography was carried out on Merck aluminium sheets coated with silica gel 60 F₂₅₄. Compounds were visualized by use of 254 nm UV light and/or phosphomolybdic acid 20 wt.% solution in ethanol with heating. All solvents were purified by standard techniques [21]. Flash chromatography was performed on Merck silica gel 60 (0.040–0.063 mm, 230–400 mesh ASTM). Anhydrous magnesium sulfate was used for drying solutions.

Synthesis of (E)-2-((4R,5R)-5-((benzyloxy)methyl)-2,2-dimethyl-1,3-dioxolan-4-yl)but-2-ene-1,4-diol (3)

To a stirred solution of butenolide 2 (35 mg, 0.115 mmol) in dry Et₂O (5 mL) was added dropwise diisobutylaluminium hydride (DIBAL-H) (0.5 mL of a 1M solution in cyclohexane, 0.5 mmol) under a nitrogen atmosphere at 0 °C. The reaction was allowed to continue at that temperature until no more starting material was detected by TLC analysis (1 h). Then H₂O (0.2 mL) was added to the mixture under vigorous stirring to destroy excess DIBAL-H. MgSO₄ was directly added to the reaction mixture and filtered through a short pad of Celite. The filtrate was washed several times with Et₂O until no more product could be detected by TLC analysis. The solution was concentrated and the crude material was purified by silica gel column chromatography, eluting with AcOEt:n-hexane 30:70. Product 3 (24.7 mg, 71% yield) was obtained as a colourless oil: [α]²⁵_D = + 0.99 (c 1.60, CHCl₃); ¹H NMR (500 MHz, CDCl₃) δ/ppm = 1.45 (s, 3H), 1.48 (s, 3H), 2.91 (brs, 2H), 3.61−3.66 (m, 2H), 4.03 (ddd, J = 4.4, 4.4, 8.8 Hz, 1H), 4.14−4.27 (m, 4H), 4.34 (d, J = 8.6 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.62 (d, J = 12.0 Hz, 1 H), 5.88 (dd, J = 6.5, 6.5 Hz, 1H), 7.29−7.38 (m, 5H); ¹³C NMR (125 MHz, CDCl₃) δ/ppm = 26.9 (q), 27.0 (q), 57.2 (t), 58.3 (t), 69.5 (t), 73.7 (t), 78.8 (d), 82.0 (d), 109.3 (s), 127.8 (d), 128.4 (d), 132.5 (d), 137.6 (s), 137.7 (d), 137.8 (s); FT-IR (thin film) ν_max (cm^-1) 3400, 2986, 2930, 2870, 1374, 1219, 1086, 1020, 741; MS (EI+) m/z (relative intensity %) 293 [M–CH₃]⁺ (5.8), 232 (3.6), 214 (2.8), 190 (3.0), 172 (8.6), 149 (6.9), 117 (53.4), 111 (21.9), 107 (38), 91.0 (100); HRMS (EI+) exact mass calculated for C₁₆H₂₁O₅ (M–CH₃)⁺ 293.1388, found 293.1389. Elemental analysis calculated for C₁₇H₂₄O₅: C, 66.21; H, 7.84; found: C, 65.78; H, 8.05.