Hydrophobically Assisted Separation-Friendly Mitsunobu Reaction

Abstract

A separation-friendly Mitsunobu reaction using hydrophobic-tagged acids is reported. Commercially available or simply prepared and recyclable hydrophobic-tagged acids can react with various alcohols to afford the target products in high yield with easy purification based on C-18 silica solid-phase extraction or normal silica gel filtration.

Key words

Mitsunobu reaction - esterification - hydrophobic tag - solid-phase extraction - inversion of configuration

• References and Notes

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• 13 In SPE operation, double hydrophobic chain tagged products remained quantitatively adsorbed on the C-18 silica when rinsing the support with MeOH/water (95:5), even MeOH for the first 10 mL, whereas the other molecules without the tag were found to be completely rinsed out of the support, including the hydrophobic starting materials
• 14 Mitsunobu Reaction and Purification by C-18 SPE; Typical Procedure (14h): To a solution of acid 13 (68.0 mg, 0.1 mmol), alcohol h (67.0 mg, 0.12 mmol), and Ph₃P (53.0 mg, 0.2 mmol) in THF (6 mL) under argon, was added DEAD (37.0 mg, 0.21 mmol) dropwise at 0 °C. The mixture was stirred for 1 h at 0 °C and for 2 h at r.t. C-18 silica gel [500 mg, LiChroprep RP-18 (40–63 μm)] was added to the reaction vessel and the solvents were removed. The dry C-18 silica gel with the adsorbed reaction mixture on it was transferred to a column (1.8 cm diameter) that was previously filled to a height of 1 cm with C-18 silica gel. The C-18 silica gel was washed with MeOH–H₂O (2:1, 30 mL), MeOH (2 × 20 mL), and acetone (30 mL) under reduced pressure. The filtrates containing the desorbed product were collected and concentrated to give 14h (114 mg, 94% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃): δ = 8.18 (d, J = 8.2 Hz, 2 H), 7.93 (d, J = 8.2 Hz, 2 H), 7.60 (d, J = 6.2 Hz, 4 H), 7.49–7.18 (m, 16 H), 5.50 (dd, J = 9.4, 4.8 Hz, 1 H), 4.61 (t, J = 12.6 Hz, 1 H), 4.55 (d, J = 12.1 Hz, 1 H), 4.49 (d, J = 12.1 Hz, 1 H), 4.12 (td, J = 7.9, 4.2 Hz, 1 H), 3.78–3.73 (m, 4 H), 2.91 (br s, 1 H), 1.94–1.67 (m, 5 H), 1.58–1.53 (m, 3 H), 1.50–1.12 (m, 64 H), 1.00 (s, 9 H), 0.88 (t, J = 6.5 Hz, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 164.59, 142.23, 138.23, 137.85, 135.51, 134.72, 133.64, 133.54, 130.30, 129.65, 128.85, 128.38, 128.30, 127.77, 127.65, 127.59, 75.05, 74.43, 73.19, 73.12, 68.26, 64.68, 59.91, 33.54, 31.91, 29.68, 29.58, 29.51, 29.34, 29.27, 27.89, 26.84, 26.75, 22.67, 19.12, 14.08. MS (MALDI): m/z calcd for C₇₇H₁₁₆NaO₇SSi: 1235.8; found: 1235.6. Anal. Calcd for C₇₇H₁₁₆O₇SSi: C, 76.19; H, 9.63. Found: C, 76.09; H, 9.53
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