Direct Trifluoroacetylation Across a Trimethylsilyloxy System as a Stereo­specific, Chemo- and Regioselective Approach to C3-Vicinal Halohydrins

 

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Abstract

Trifluoroacetylation across the silyloxy system of 1-acyl-2-O-trimethylsilyl-3-haloglycerols with trifluoroacetic anhydride (TFAA) in the presence of a halide anion (e.g. Bu₄NX; X = Cl, Br or I), followed by removal of the trifluoroacetyl transient protection, provides a new, efficient entry to configurationally pure C3-vicinal halohydrins.

References and Notes

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Typical Procedure for the Conversion of the Silyl Ethers 1-4 into the Corresponding Trifluoroacetate Derivatives 5-8 (Step A)
To a solution of silyl ether 1-4 (1.00 mmol) and tetra-n-butylammonium halide (2.00 mmol) in alcohol-free CH₃Cl (5.0 mL), TFAA (0.278 mL, 2.00 mmol) was added and the reaction system was kept under argon at r.t. for 4-5 h. CH₃Cl and volatile reaction components were evaporated in vacuo, the residue was taken in toluene (5.0 mL) and passed through a pad of silica gel (ca. 5 g) prepared in the same solvent. The support was washed with toluene (ca. 100 mL), fractions containing the target compounds were combined, the eluent was removed under reduced pressure, and the residue was kept under high vacuum at r.t. for 2-3 h to afford trifluoro-acetate 5-8 in >90% yields (purity >99% by ¹H NMR).
1-Oleoyl-2-trifluoroacetyl-3-chloro-sn-glycerol (5): obtained from 1 (0.447 g, 1.00 mmol) and Bu₄NCl (0.556 g, 2.00 mmol) for 5 h. Yield 0.429 g (91%, colorless oil); R _f = 0.66 (pentane-toluene-EtOAc, 40:50:10); [α]_D ²⁰ +0.28 (c 9.65, CHCl₃). Anal. Calcd (%) for C₂₃H₃₈ClF₃O₄ (470.99): C, 58.65; H, 8.13; Cl, 7.53. Found: C, 58.61; H, 8.10; Cl, 7.53%.
1-Oleoyl-2-trifluoroacetyl-3-bromo-sn-glycerol (6): obtained from 2 (0.492 g, 1.00 mmol) and Bu₄NBr (0.645 g, 2.00 mmol) for 4 h. Yield 0.490 g (95%, colorless oil); R _f = 0.69 (pentane-toluene-EtOAc, 40:50:10); [α]_D ²⁰ +3.47 (c 8.05, CHCl₃). Anal. Calcd (%) for C₂₃H₃₈BrF₃O₄ (515.44): C, 53.59; H, 7.43; Br, 15.50. Found: C, 53.62; H, 7.37; Br, 15.55.
1-Oleoyl-2-trifluoroacetyl-3-iodo-sn-glycerol (7): obtained from 3 (0.539 g, 1.00 mmol) and Bu₄NI (0.739 g, 2.00 mmol) for 4 h. Yield 0.529 g (94%, colorless oil); R _f = 0.70 (pentane-toluene-EtOAc, 40:50:10); [α]_D ²⁰ +6.40 (c 10.01, CHCl₃). Anal. Calcd (%) for C₂₃H₃₈IF₃O₄ (562.44): C, 49.11; H, 6.81; I, 22.56%. Found: C, 49.10; H, 6.80; I, 22.59.
1-Benzoyl-2-trifluoroacetyl-3-bromo-rac-glycerol (8): obtained from 4 (0.331 g, 1.00 mmol) and Bu₄NBr (0.645 g, 2.00 mmol) for 4 h. Yield 0.334 g (94%, colorless oil); R _f = 0.59 (pentane-toluene-EtOAc, 40:50:10). Anal. Calcd (%) for C₁₂H₁₀BrF₃O₄ (355.10): C, 40.59; H, 2.84; Br, 22.50. Found: C, 40.57; H, 2.80; Br, 22.50.

Typical Procedure for the Conversion of Trifluoro-acetates 5-8 into the Corresponding Halohydrin Derivatives 9-12 (Step B) To a solution of trifluoroacetyl halohydrin 5-8 (1.00 mmol) in pentane-CH₂Cl₂ (3:1, v/v, 5.0 mL), a mixture of pyridine (0.8 mL, 10 mmol) and MeOH (10.1 mL, 250 mmol) in the same solvents (5.0 mL) was added at 0 °C and the reaction system was left at r.t. for 20 min. Solvents were evaporated under reduced pressure (bath temp. 50 °C) and the residue was kept under high vacuum at r.t. for 2-3 h to afford the deprotected haloalkanols 9-12 practically quantitatively (purity >99% by ¹H NMR).
1-Oleoyl-3-chloro-sn-glycerol (9): obtained from 5 (0.471 g, 1.00 mmol). Yield 0.375 g (100%, colorless oil); R _f = 0.32 (pentane-toluene-EtOAc, 40:50:10); [α]_D ²⁰ +3.00 (c 5.66, CHCl₃). Anal. Calcd (%) for C₂₁H₃₉ClO₃ (374.98): C, 67.26; H, 10.48; Cl, 9.45. Found: C, 67.30; H, 10.42; Cl, 9.42.
1-Oleoyl-3-bromo-sn-glycerol (10): obtained from 6 (0.515 g, 1.00 mmol). Yield 0.418 g (100%, colorless oil); R _f = 0.33 (pentane-toluene-EtOAc, 40:50:10); [α]_D ²⁰ +2.45 (c 8.53, CHCl₃). Anal. Calcd (%) for C₂₁H₃₉BrO₃ (419.44): C, 60.13; H, 9.37; Br, 19.05. Found: C, 60.13; H, 9.42; Br, 19.10.
1-Oleoyl-3-iodo-sn-glycerol (11): obtained from 7 (0.562 g, 1.00 mmol). Yield 0.466 g (100%, white solid); R _f = 0.36 (pentane-toluene-EtOAc, 40:50:10); [α]_D ²⁰ +2.39 (c 8.37, CHCl₃); mp 33.0-33.6 °C; lit. [3] [α]_D ²⁰ +1.9 (c 10, CHCl₃); mp 33.4 °C. Anal. Calcd (%) for C₂₁H₃₉IO₃ (466.44): C, 54.07; H, 8.43; I, 27.21. Found: C, 54.15; H, 8.40; I, 27.27.
1-Benzoyl-3-bromo-rac-glycerol (12): obtained from 8 (0.355 g, 1.00 mmol). Yield 0.259 g (100%, colorless oil); R _f = 0.32 (pentane-toluene-EtOAc, 40:50:10). Anal. Calcd (%) for C₁₀H₁₁BrO₃ (259.10): C, 46.36; H, 4.28; Br, 30.84. Found: C, 46.42; H, 4.24; Br, 30.80.