Prins Cyclization Using Magnesium Halides: Mild Access to 4-Halogenated Polysubstituted Tetrahydropyrans with a Special Feature

Abstract

Different 4-halo-substituted polyfunctionalized tetra­hydropyrans were easily synthesized by segment-coupling Prins cyclization utilizing magnesium halides. The moderate Lewis acidity allows transformation of substrates bearing acid-labile functional groups. A solvent dependency of the stereochemistry at the C4 carbon was observed.

Key words

Prins cyclization - magnesium halides - halogenated tetrahydropyrans - solvent-dependent stereochemistry - polysubstituted tetrahydropyrans

• References and Notes

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The chiral diol ligand prepared according to:
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• 16 General Procedure for Prins Cyclization of 8 Magnesium halide (2 equiv) was added to a solution of acetoxy ether 8 in the respective solvent (mixture; 5–10 mL/mmol of 8) at given temperatures. Reaction mixture was stirred for 1–2 h and quenched with sat. NaHCO₃ solution and extracted three times with CH₂Cl₂. The combined organic extracts were washed with brine, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (pentane–Et₂O, 7:1). Spectroscopical Data for (2R,3S,4R,6R)-2-(2-Benzyloxyethyl)-4-bromo-6-[(4R,5S)-2,2-dimethyl-5-vinyl-1,3-dioxolan-4-yl]-3-methyltetrahydropyran (7a) Yield 82%; colorless oil; [a]_D +43 (c 2.00, CHCl₃). ¹H NMR (600 MHz, CDCl₃): δ = 7.27–7.37 (5 H, m, C₆H₅), 5.83 (1 H, ddd, J = 16.8, 10.0, 6.5 Hz, CH=CH₂), 5.34 (1 H, dd, J = 17.1, 1.5 Hz, CH=CH ₂), 5.14 (1 H, d, J = 10.5 Hz, CH=CH ₂), 4.64 (1 H, dd, J = 6.3, 6.3 Hz, CHCH=CH₂), 4.44–4.51 (2 H, m, CH₂Ph), 4.42 (1 H, dt, J = 12.8, 4.3 Hz, H-4), 3.97 (1 H, dd, J = 8.4, 6.3 Hz, 6-CH), 3.39–3.52 (1 H, m, H-2), 3.48–3.52 (2 H, m, CH₂CH ₂OBn), 3.36 (1 H, td, J = 9.8, 2.4 Hz, H-6), 2.20 (1 H, dt, J = 10.2, 2.8 Hz, H-5), 1.92–1.99 (2 H, m, H-5 and H-3), 1.78–1.85 (1 H, m, CH ₂CH₂OBn), 1.60–1.66 (1 H, m, CH ₂CH₂OBn), 1.45 [3 H, s, C(CH₃)₂], 1.36 [3 H, s, C(CH₃)₂], 1.07 (3 H, d, J = 6.9 Hz, 3-CH₃). ¹³C NMR (100 MHz, CDCl₃): δ = 138.2 (C_ar,q), 133.6 (CH=CH₂), 128.4 (C_ar), 127.6 (C_ar), 117.4 (CH=CH₂), 108.7 [C(CH₃)₂], 79.2 (6-CH), 78.6 (CHCH=CH₂), 76.6 (C-2), 76.3 (C6), 73.0 (CH₂Ph), 66.9 (CH₂ CH₂OBn), 54.0 (C-4), 39.7 (C-3), 34.6 (C-5), 33.9 (CH₂CH₂OBn), 27.7 [C(CH₃)₂], 25.3 [C(CH₃)₂], 7.6 (3-CH₃). MS: m/z (%) = 424 (70), 422 (70), 301 (50), 231 (75), 141 (55), 137 (70), 127 (100). HRMS: m/z calcd for C₂₂H₃₁BrO₄: 438.1403 [M]⁺; found: 438.1404.