Diastereoselective Synthesis of 2-Cyanomethyl-3-hydroxy-5-iodomethyltetrahydrofuran from Isoxazolines by Iodoetheration

Abstract

Diastereoselective 1,3-dipolar cycloaddition reaction of nitrile oxides with 1,5-hexadien-3-ol afforded syn-5-(1-hydroxy-3-butenyl)isoxazolines, which underwent iodoetheration by iodine monochloride to give 2-cyanomethyl-3-hydroxy-5-iodomethyl­tetrahydrofuran with diastereoselectivity. The relative stereo­chemistry of iodomethyl group varied depending on both the 3-substituents and the hydroxy protecting groups.

isoxazoline - magnesium chelation - iodoetheration - tetra­hydrofuran - diastereoselectivity

References

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10

2-t-Butyldimethylsilyloxy-2-phenylacetohydroximoyl chloride was prepared and used immediately without purification from 2-t-butyldimethylsilyloxy-2-phenylacetaldoxime by NCS treatment. 2-t-Butyldimethyl-silyloxy-2-phenylacetaldoxime was prepared from d-mandelic acid by esterification, silylation, reduction by DIBAL-H, and aldoxime formation. 2-t-Butyldimethyl-silyloxy-2-phenylacetaldoxime: ¹H NMR (200 MHz, CDCl₃): δ = 0.07 (d, 6 H, J = 15.5 Hz), 0.94 (s, 9 H), 3.73
(s, 1 H), 5.33 (d, 1 H, J = 7.1 Hz), 7.27-7.43 (m, 6 H). IR (NaCl): 3267, 2929, 2858, 1254, 1066, 838 cm^-1.

11

To a solution of 1,5-hexadien-3-ol (1.55 g, 15.7 mmol) in benzene (50 mL) was slowly added EtMgBr (16.0 mL, 1.5 M in THF) at 0 °C, and stirred for 30 min. Triphenylacetonitrile oxide (3.00 g, 11.6 mmol) in benzene (10 mL) was added dropwise to the reaction mixture at 0 °C. After stirring for 3 h, the reaction mixture was poured into ice-water, extracted with ethyl acetate (80 mL × 2), washed with aq 5% HCl solution (100 mL) and brine, dried over MgSO₄, and then concentrated to give an oil. The oily residue was purified by flash column chromatography (n-hex/EtOAc, 5/1) to afford syn-3 (R¹ = triphenylmethyl) as a pale yellow solid (2.84 g, 71%). ¹H NMR (200 MHz, CDCl₃): δ = 2.30 (dd, 2 H, J = 6.3, 6.7 Hz), 2.86 (dd, 2 H, J = 2.6, 8.5 Hz), 3.50-3.59 (m, 1 H), 4.49-4.61 (m, 1 H), 5.10 (s, 1 H), 5.18 (d, 1 H, J = 4.2 Hz), 5.78-5.92 (m, 1 H) 7.22-7.41 (m, 15 H). MS: m/z (relative intensity) = 383 (0.1) [M⁺ + 1], 312 (1), 244 (2), 226 (1), 215 (2), 165 (22), 77 (84), 51 (24), 41 (100). IR (NaCl): 3442, 2922, 2852, 1506, 1457, 701 cm^-1. HRMS calcd for C₂₆H₂₅NO₂: 383.18852. Found: 383.18829. Anal. Calcd for C₂₆H₂₅NO₂: C, 81.43; H, 6.57; N, 3.65. Found: C, 80.95; H, 6.70; N, 3.36. syn-3 (R¹ = α-(t-Butyldimethylsilyloxy)benzyl): pale yellow oil. ¹H NMR (200 MHz, CDCl₃): δ = 0.09 (d, 6 H, J = 1.7 Hz), 0.94 (s, 9 H), 2.45-2.72 (m, 2 H), 2.89-3.10 (m, 1 H), 3.40-3.56 (m, 1 H), 4.34-4.52 (m, 1 H), 5.01-5.17 (m, 2 H), 5.66-5.86 (m, 2 H), 7.27-7.38 (m, 5 H). MS: m/z (relative intensity) = 346 (3) [M⁺ - CH₃], 304 (100), 262 (2), 221 (14), 181 (12), 149 (14), 130 (7), 107 (13), 75 (42), 43 (13). IR (NaCl): 3430, 2930, 2857, 1468, 1255, 1092, 839 cm^-1. Anal. Calcd for C₂₀H₃₁NO₃Si: C, 66.44; H, 8.64; N, 3.87. Found: C, 66.27; H, 8.86; N, 3.52.

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Typical Procedure of Iodoetheration (entry 1 in Table [1] ): To a solution of 5-(1-t-butyldimethylsilyloxy-3-butenyl)-3-triphenylmethyl-4,5-dihydroisoxazole (4, 0.80 g, 1.61 mmol) in dichloromethane (5 mL) was dropwise added iodine monochloride (3.2 mL, 1.0 M in dichloromethane) at 0 °C and stirred for 3 h at that temperature. The reaction mixture was washed with aq 20% sodium bisulfite solution (10 mL × 2), dried over MgSO₄, and concentrated to give an oil. The oily residue was purified by flash column chromatography (n-hex/EtOAc, 20/1) to afford trans-5 and cis-5 as pale yellow oils. trans-5 (R² = TBDMS): 0.40 g (65%). ¹H NMR (200 MHz, CDCl₃): δ = 0.11 (d, 6 H, J = 3.9 Hz), 0.89 (s, 9 H), 1.85 (ddd, 1 H, J = 5.1, 9.3, 13.8 Hz), 2.12 (ddd, 1 H, J = 1.5, 6.6, 13.8 Hz), 2.59 (d, 2 H, J = 6.6 Hz), 3.26 (d, 2 H, J = 5.1 Hz), 4.19 (tdd, 1 H, J = 5.1, 6.6, 13.8 Hz), 4.27 (td, 1 H, J = 6.6, 13.8 Hz), 4.42-4.44 (m, 1 H). MS: m/z (relative intensity) = 380 (0.5) [M⁺ + 1], 366 (1), 324 (25), 283 (8), 255 (9), 198 (6), 185 (9), 156 (100), 128 (15), 98 (16), 73 (21). IR (NaCl): 2877, 2253 cm^-1. Anal. Calcd for C₁₃H₂₄INO₂Si: C, 40.95; H, 6.34; N, 3.67. Found: C, 40.96; H, 6.11; N, 3.77. cis-5 (R² = TBDMS): 0.06 g (11%). ¹H NMR (200 MHz, CDCl₃): δ = 0.11 (d, 6 H, J = 3.2 Hz), 0.90 (s, 9 H), 1.99 (ddd, 1 H, J = 3.0, 4.5, 13.8 Hz), 2.29 (ddd, 1 H, J = 6.0, 7.8, 13.8 Hz), 2.61 (d, 2 H, J = 6.0 Hz), 3.26-3.32 (m, 2 H), 4.10-4.20 (m, 2 H), 4.36-4.40 (m, 1 H). trans-5 (R² = TBDPS): ¹H NMR (200 MHz, CDCl₃): δ = 1.09 (s, 9 H), 1.61 (ddd, 1 H, J = 5.1, 8.6, 16.7 Hz), 2.04 (ddd, 1 H, J = 2.5, 8.5, 16.7 Hz), 2.63-2.68 (m, 2 H), 3.17 (d, 2 H, J = 5.1 Hz), 4.18-4.31 (m, 2 H), 4.47-4.53 (m, 1 H), 7.37-7.52 (m, 6 H), 7.63-7.70 (m, 1 H). MS: m/z (relative intensity) = 405 (0.5) [M⁺ - CNCH₂-C(CH₃)₃], 339 (1), 322 (9), 304 (1), 280 (8), 244 (8), 199 (100), 181 (15), 161 (11), 135 (21). IR (NaCl): 2878, 2255 cm^-1. Anal. Calcd for C₂₃H₂₈INO₂Si: C, 54.65; H, 5.58; N, 2.77. Found: C, 55.01; H, 5.59; N, 2.77. cis-5 (R² = TBDPS): ¹H NMR (200 MHz, CDCl₃): δ = 1.10 (s, 9 H), 1.87 (ddd, 1 H, J = 5.5, 7.2, 13.5 Hz), 2.08 (ddd, 1 H, J = 6.7, 13.5, 13.2 Hz), 2.48-2.72 (m, 2 H), 3.22-3.34 (m, 2 H), 3.91-4.09 (m, 2 H), 4.48-4.54 (m, 1 H), 7.36-7.48 (m, 6 H), 7.61-7.68 (m, 1 H). trans-5 (R² = MPM): ¹H NMR (200 MHz, CDCl₃): δ = 1.78 (ddd, 1 H, J = 4.7, 8.2, 16.1 Hz), 2.37 (ddd, 1 H, J = 1.6, 5.9, 16.1 Hz), 2.55-2.77 (m, 2 H), 3.27 (d, 2 H, J = 4.7 Hz), 3.81 (s, 3 H), 4.14-4.26 (m, 2 H), 4.33-4.45 (m, 2 H), 4.58 (d, 1 H, J = 10.2 Hz), 6.89 (d, 2 H, J = 9.7 Hz), 7.28 (d, 2 H, J = 9.2 Hz). MS: m/z (relative intensity) = 388 (78) [M⁺ - 1], 371 (19), 353 (13), 327 (7), 298 (10), 281 (12), 247 (15), 172 (55), 127 (100), 101 (10), 43 (92). IR (NaCl): 2878, 2251 cm^-1. HRMS calcd for C₁₅H₁₈INO₃: 387.03314. Found: 387.03452. Anal. Calcd for C₁₅H₁₈INO₃: C, 46.53; H, 4.69; N, 3.62. Found: C, 46.26; H, 4.79; N, 3.57. trans-5 (R² = MEM): ¹H NMR (200 MHz, CDCl₃): δ = 1.87-1.91 (m, 1 H), 2.32-2.45 (m, 1 H), 2.66-2.77 (m, 2 H), 3.23-3.29 (m, 2 H), 3.39 (s, 3 H), 3.57-3.64 (m, 2 H), 3.72-3.81 (m, 2 H), 4.14-4.19 (m, 2 H), 4.39-4.45 (m, 1 H), 4.79-4.85 (m, 2 H). MS: m/z (relative intensity) = 354(4) [M⁺ + 1], 296 (1), 281 (4), 249 (4), 209 (4), 169 (3), 141 (5), 122 (25), 105 (10), 89 (91), 59 (100). IR (NaCl): 2880, 2254 cm^-1. Anal. Calcd for C₁₁H₁₈INO₄: C, 37.20; H, 5.11; N, 3.94. Found: C, 37.05; H, 5.20; N, 3.81. trans-5 (R² = MEM): ¹H NMR (200 MHz, CDCl₃): δ = 1.86 (ddd, 1 H, J = 4.5, 9.1, 13.2 Hz), 2.38 (ddd, 1 H, J = 1.6, 5.9, 13.2 Hz), 2.62-2.74 (m, 2 H), 3.29 (d, 2 H, J = 4.5 Hz), 3.42 (s, 3 H), 4.15-4.28 (m, 1 H), 4.36-4.44 (m, 2 H), 4.66-4.76 (m, 2 H). MS: m/z (relative intensity) = 310 (2) [M⁺ + 1], 281 (4), 249 (10), 197 (17), 169 (13), 122 (26), 108 (19), 69 (25), 45 (100), 29 (11). IR (NaCl): 2879, 2254 cm^-1. HRMS calcd for C₉H₁₄INO₃: 311.00184. Found: 311.00266. Anal. Calcd for C₉H₁₄INO₃: C, 34.74; H, 4.54; N, 4.50. Found: C, 34.53; H, 4.43; N, 4.78.

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trans-5 (R² = H): ¹H NMR (200 MHz, CDCl₃): δ = 1.97 (dd, 1 H, J = 7.1, 21.1 Hz), 2.26 (dd, 1 H, J = 4.9, 17.3 Hz), 2.71 (d, 2 H, J = 7.1 Hz), 3.29 (d, 2 H, J = 4.9 Hz), 4.23-4.37 (m, 2 H), 4.47-4.61 (m, 1 H), 4.35-4.42 (m, 1 H). MS: m/z (relative intensity) = 267 (5) [M⁺], 197 (8), 169 (5), 140 (100), 126 (73), 99 (8), 82 (52), 71 (19). IR (NaCl): 2878, 2251 cm^-1. HRMS calcd for C₇H₁₀INO₂: 266.97605. Found: 266.97563. Anal. Calcd for C₇H₁₀INO₂: C, 31.48; H, 3.77; N, 5.24. Found: C, 31.84; H, 3.59; N, 5.45. cis-5 (R² = H): ¹H NMR (200 MHz, CDCl₃): δ = 1.78 (dd, 1 H, J = 5.7, 23.1 Hz), 2.25 (dd, 1 H, J = 5.5, 14.3 Hz), 2.63 (d, 2 H, J = 5.7 Hz), 3.31 (d, 2 H, J = 5.5 Hz), 4.25-4.35 (m, 2 H), 4.49-4.61 (m, 1 H). IR (NaCl): 3460, 2925, 2252, 1082 cm^-1. HRMS calcd for C₇H₁₀INO₂: 266.97605. Found: 266.97634.