(–)-5-[(4R,5R)-5-(Benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-4,7-dihydro-1,3-dioxepine

Abstract

The synthesis of (−)-5-[(4R,5R)-5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-4,7-dihydro-1,3-dioxepine is reported. Product character-ization was carried out by IR, ¹H NMR, ¹³C NMR, MS, elemental analysis and optical rotation.

Acetals are frequently used as protecting groups for carbonyl groups in organic synthesis mainly due to their stability towards hydrolysis by bases [1]. As well as being remarkable synthetic building blocks, cyclic acetals are also important in nature. For instance, the most stable form of glucose in solution is its cyclic hemiacetal, maltose is an acetal made from two glucose units, and acetaldehyde diethyl acetal is an important flavouring compound in distilled beverages [2]. Pharmaceutical industry has also commercialized a number of bioactive acetonide-containing bioactive products such as fluocinolone acetonide or triamcinolone acetonide, which are potent corticosteroids primarily used in dermatology to reduce skin inflammation [3].

Herein, we report the synthesis of (−)-5-[(4R,5R)-5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-4,7-dihydro-1,3-dioxepine (2) by refluxing the corresponding allylic diol 1 in acetone for 24 h (Scheme 1). Chiral precursor 1 was prepared by reduction of the appropriate butenolide as reported previously [4].

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 on 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 [5]. 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 (−)-5-[(4R,5R)-5-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]-2,2-dimethyl-4,7-dihydro-1,3-dioxepine (2): To a stirred solution of allylic diol 1 (308 mg, 1.0 mmol) in acetone (25 mL), p-toluenesulfonic acid (p-TsOH) (3 mg, 0.017 mmol) was added at room temperature. The reaction mixture was refluxed for 24 h, until the TLC analysis showed that no starting material was present. The solvent was concentrated and the residue diluted with Et₂O (30 mL) and washed with a 5% solution of NaHCO₃. The combined organic phases were dried (MgSO₄), filtered, concentrated, and the residue purified by silica gel column chromatography, eluting with AcOEt:n-hexane 10:90. Product 2 (303 mg, 87% yield) was obtained as a colourless oil: [α]²⁵_D = −12.3 (c 0.70, CHCl₃); ¹H NMR (400 MHz, CDCl₃) δ/ppm = 1.43 (s, 12H), 3.56 (dd, J = 5.2, 10.6 Hz, 1H), 3.63 (dd, J = 3.1, 10.6 Hz, 1H), 3.95 (ddd, J = 3.1, 5.2, 8.6 Hz, 1H), 4.22−4.30 (m, 4H), 4.36−4.40 (m, 1H), 4.57 (d, J = 12.0 Hz, 1H), 4.63 (d, J = 12.0 Hz, 1H), 5.61 (m, 1H), 7.28−7.37 (m, 5H); ¹³C NMR (100 MHz, CDCl₃) δ/ppm = 23.8 (q), 26.9 (q), 60.0 (t), 60.8 (t), 69.4 (t), 73.5 (t), 78.4 (d), 80.1 (d), 102.1 (s), 109.2 (s), 127.6 (d), 127.7 (d), 128.3 (d), 128.5 (d), 137.3 (s), 137.9 (s); FT-IR (thin film) ν_max (cm^-1) 2987, 2933, 2862, 1373, 1218, 1088, 870, 738; MS (EI+) m/z (relative intensity %) 348 (M⁺, 1.3), 333 ([M–CH₃]⁺, 1.2), 290 (4.7), 2.75 (2.4), 260 (4.2), 91 (100); HRMS (EI+) exact mass calculated for C₂₀H₂₈O₅ (M⁺) m/z 348.1931, found m/z 348.1937. Elemental analysis calculated for C₂₀H₂₈O₅: C, 68.94; H, 8.10; found: C, 68.74; H, 7.68.