Direct Acylation across a Silyloxy System of Glycerol with Carboxylic Acid Anhydrides: A Novel Strategy to the Prodrug Carrier Modules - 1,3-Diacyl-sn-glycerols

Abstract

Trichloroacetylation of 1-acyl-3-O-tert-butyldimethyl­silyl-sn-glycerols, followed by a direct conversion of the silyl protecting group into an ester functionality by means of a reagent system: tetra-n-butylammonium bromide (TBABr)-trimethylsilyl bromide (TMSBr)-carboxylic acid anhydride (CAA), constitutes an efficient protocol for the preparation of enantiomerically pure 1,3-diacyl-sn-glycerols in high yields.

tetra-n-butylammonium bromide - carboxylic acid anhydrides - trimethylsilyl bromide - structured triglycerides - silyl protections - 1,3-diacyl-sn-glycerols - prodrug carriers

References

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<A NAME="RG23805ST-33">33</A>

General Procedure for the Synthesis of Trichloro-acetylated Synthon 2 (Step A).
1-Oleoyl-3-O-tert-butyldimethylsilyl-sn-glycerol (1, 0.857 g, 1.82 mmol) and pyridine (2.91 mL, 36.0 mmol) in alcohol-free CHCl₃ (10.0 mL), was treated with a solution of trichloroacetyl chloride (0.306 mL, 2.73 mmol) in alcohol-free CHCl₃ (10.0 mL), at -20 °C and the reaction mixture was kept at r.t. for 2 h. Solvents were removed under reduced pressure and the thus obtained unsymmetrical diester 2 was isolated in pure state (>99%, ¹H NMR spectroscopy) by flash column chromatography (silica gel, mobile phase: toluene).
Compound 2: yield 1.065 g (95%, colourless oil); R _f = 0.70 (pentane-toluene-EtOAc = 40:50:10, v/v/v); [α]_D ²⁰ +11.87 (c, 10.26; CHCl₃). Anal. Calcd for C₂₉H₅₃Cl₃O₅Si (616.17): C, 56.53; H, 8.67; Cl, 17.26%. Found: C, 56.67; H, 8.60; Cl, 17.30.

<A NAME="RG23805ST-34">34</A>

General Procedure for the Preparation of Triester Congeners of 1,3-DAG 3, 4 (Step B).
To a solution of silyl ether 2 (0.616 g 1.00 mmol) and tetra-n-butylammonium bromide (0.645 g, 2.00 mmol) in alcohol-free CHCl₃ (3.0 mL), a mixture of the selected carboxylic acid anhydride (3.00 mmol) and trimethylbromosilane (0.195 mL, 1.50 mmol) in the same solvent (3.0 mL) was added and the reaction system was kept under argon, in a pressure-proof glass ampoule at 80 °C(bath) for 2 h. Then, CHCl₃ was removed under reduced pressure and the triglyceride 3 or 4 was isolated in pure state (purity >99%, ¹H NMR spectroscopy) by flash column chromatography (silica gel, mobile phase: toluene-EtOAc = 98:2, v/v).
Compound 3 (obtained from 2 and Ac₂O: 0.284 mL, 3.00 mmol). Yield 0.511 g (94%, colourless oil); R _f (pentane-toluene-EtOAc = 40:50:10, v/v/v) = 0.49; [α]_D ²⁰ -0.68 (c, 9.77; CHCl₃). Anal. Calcd for C₂₅H₄₁Cl₃O₆ (543.95): C, 55.20; H, 7.60; Cl, 19.55%. Found: C, 55.30; H, 7.55; Cl, 19.47.
Compound 4 (obtained from 2 and palmitic anhydride: 1.484 g, 3.00 mmol). Yield 0.711 g (96%, colourless oil); R _f = 0.58 (pentane-toluene-EtOAc = 40:50:10, v/v/v); [α]_D ²⁰ 0.00 (c, 4.26; CHCl₃). Anal. Calcd for C₃₉H₆₉Cl₃O₆ (740.32): C, 63.27; H, 9.39; Cl, 14.37%. Found: C, 63.35; H, 9.50; Cl, 14.30.

<A NAME="RG23805ST-35">35</A>

General Procedure for the Preparation of 1,3-Diacyl-glycerols 5, 6 (Step C).
To a solution of 3 or 4 (1.00 mmol) in THF (5.0 mL), a mixture of pyridine (4.0 mL, 50 mmol) and MeOH (20.3 mL, 500 mmol) was added and the reaction system was left at r.t. for 2 h. Solvents were evaporated under reduced pressure (bath temperature 50 °C) and the residue was kept under high vacuum at r.t. for 2-3 h to give the unprotected diglyceride 5 and 6 (purity >99%, ¹H NMR spectroscopy).
Compound 5 (obtained from 3). Yield 0.398 g (100%, colourless oil); R _f = 0.29 (toluene-EtOAc = 80:20, v/v); [α]_D ²⁰ -0.28 (c, 9.15; CHCl₃). Anal. Calcd for C₂₃H₄₂O₅ (398.58): C, 69.31; H, 10.62%. Found: C, 69.19; H, 10.70.
Compound 6 (obtained from 4). Yield 0.595 g (100%, white solid, mp 45.5-47.0 °C from pentane, lit. [15] mp 45-46 °C); R _f = 0.52 ( toluene-EtOAc = 80:20, v/v). Anal. Calcd for C₃₇H₇₀O₅ (594.95): C, 74.69; H, 11.86%. Found: C, 74.81; H, 11.80.