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Synlett 2005(17): 2587-2590  
DOI: 10.1055/s-2005-917084
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Stephan D. Stamatov*a, Jacek Stawinski*b,c
a Department of Chemical Technology, University of Plovdiv, 24 Tsar Assen St., Plovdiv 4000, Bulgaria
b Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
Fax: +46(8)154908; e-Mail: js@organ.su.se;
c Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
Further Information

Publication History

Received 27 July 2005
Publication Date:
05 October 2005 (online)

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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.

Key words

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

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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.

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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.

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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.