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Synlett 2006(12): 1933-1937  
DOI: 10.1055/s-2006-948166
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Methodology for the Synthesis of Fumarates and Maleates

Wayne S. Pricea, Steven Fletchera, Michael R. Jorgensen*a,b, Andrew D. Miller*a,b
a Imperial College Genetic Therapies Centre, Department of Chemistry, Flowers Building, Armstrong Road, Imperial College London, London, SW7 2AZ, UK
Fax: +44(20)75945803; e-Mail: a.miller@imperial.ac.uk;
b IC-VEC Ltd., Flowers Building, Armstrong Road, London, SW7 2AZ, UK
e-Mail: m.jorgensen@icvec.com;
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Publication History

Received 24 February 2006
Publication Date:
24 July 2006 (online)

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Abstract

The stereoselectivity of both the Wittig and the Horner-Wadsworth-Emmons reactions allows for the synthesis of ortho­gonally protected fumarates and maleates, respectively, from α-keto esters. This methodology has been shown to be useful in the synthesis of a derivative of the pH sensitive cis-aconitic linker, important for prodrug approaches in drug delivery. We have incorporated this linker into a cholesterol-based PEGylated lipid, for its potential use in liposomal drug and gene delivery. The synthesized lipids have also been shown to be pH degradable using HPLC analyses.

Key words

Wittig - Horner-Wadsworth-Emmons (HWE) - ozonolysis - cis-aconitic - PEGylated lipids

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General Procedure for the Formation of the α-Keto Esters.
O2 gas was bubbled through a solution of cyano keto phosphorane (2 mmol) in CH2Cl2 (25 mL) at r.t. for 10 min, cooled to -78 °C for 5 min. The solution then had O3 bubbled through for 40 min at -78 °C until the color of the solution had changed to a murky green, via a bright yellow. Bubbling N2 gas through the solution still at -78 °C for 10 min quenched the excess O3, once the solution returned to bright yellow in color the alcohol (2.4 mmol) was added. The solution was then purged with N2 and stirred at -78 °C for 2 h until the solution turned colorless. The crude product was purified using flash chromatography on silica gel to afford the α-keto ester as a clear oil.

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Typical Procedure for the Formation of a Fumarate ( 6a). To a solution of the α-keto ester (0.25 mmol) in anhyd THF (6 mL) was added tert-butoxycarbonylmethylene triphenyl phosphorane (0.188 g, 0.5 mmol) dropwise (via syringe pump 2 mL/h) in anhyd THF (4 mL) at 0 °C under a nitrogen atmosphere. After 5 h the reaction was allowed to stir at r.t. for a further 10 h. The crude mixture was then concentrated in vacuo and purified using flash chromatography on silica gel to afford the desired fumarate.
IR (CH2Cl2 film): 3394, 2977, 2935, 1715, 1647, 1518, 1455, 1366, 1273, 1152, 974, 869 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.32-1.38 [2 H, m, CH2 (CH2)2C=C], 1.40-1.52 (4 H, m, 2 ¥ CH2), 1.43 (9 H, s, 3 ¥ CH3), 1.48 (9 H, s, 3 ¥ CH3), 2.72 (2 H, t, J = 7.6 Hz, CH2C=C), 3.07-3.10 (2 H, m, CH2NH), 3.77 (3 H, s, CH3), 4.52 (1 H, br, NH), 6.65 (1 H, s, trans-alkene). 13C NMR (100 MHz, CDCl3): δ = 26.73, 27.49 (2 ¥ CH2), 28.08, 28.48 [2 ¥ C(CH3)3], 28.78 (CH2), 29.72 (CH2), 40.49 (CH2NH), 52.35 (CH3), 78.94, 81.34 [2 ¥ C(CH3)3], 128.80 (CH=C), 145.80 (CH=C), 155.93 (CO2NH), 164.95, 167.65 (2 ¥ CO). MS (CI): m/z calcd for C19H34N1O6: 372.2386; found: 372.2382 [M+ + H]; m/z (%) 389 (15) [M+ + NH4], 372 (100) [M+ + H], 333 (76) [M+ - (CH3)3 + NH4], 272 (52) [M+ - (CH3)3CO2].

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Typical Procedure for the Formation of Maleates. To a stirred suspension of NaH [0.01 g, 0.25 mmol (60% in mineral oil, w/w)] in anhyd THF (1 mL) at 0 °C and under a nitrogen atmosphere, was added tert-butyl-P,P-dimethylphosphonoacetate (0.05 mL, 0.25 mmol) in anhyd THF (1 mL) dropwise. After 30 min, the α-keto phosphorane (0.25 mmol) in THF (2 mL) was added dropwise over 1 h. After 3 h the excess NaH was neutralized with H2O (0.1 mL) and the crude mixture concentrated in vacuo, azetroped with MeOH. The crude mixture was purified using flash chromatography on silica gel (hexane-EtOAc, 7:1) to afford the desired maleate. IR (neat): 3400, 2977, 2934, 2863, 1715, 1519, 1367, 1248, 1159, 1066, 1003, 781 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.32-1.38 [2 H, m, CH2 (CH2)C=C], 1.40-1.52 (4 H, m, 2 ¥ CH2), 1.43 (9 H, s, 3 ¥ CH3), 1.48 (9 H, s, 3 ¥ CH3), 2.31 (2 H, t, J = 7.2 Hz, CH2C=C), 3.07-3.10 (2 H, m, CH2NH), 3.77 (3 H, s, CH3), 4.52 (1 H, br, NH), 5.69 (1 H, t, J = 1.4 Hz, cis-alkene). 13C NMR (100 MHz, CDCl3): δ = 25.98 (CH2), 26.64 (CH2), 27.91 [t-Bu C(CH3)3], 28.32 [Boc C(CH3)3], 29.68 (CH2), 34.08 (CH2C=C), 40.30 (CH2NH), 52.00 (CH3), 78.96 [Boc C(CH3)3], 81.33 [t-Bu C(CH3)3], 121.90 (CH=C), 147.83 (CH=C), 155.90 (CONH), 164.07 (CO), 169.25 (CO). MS (CI): m/z calcd for C19H37N2O6: 389.2651; found: 389.2645 [M+ + NH4 +]; m/z (%) = 389 (60) [M+ + NH4 +], 372 (80) [M+ + H], 333 (65), 316 (35), 277 (100) and 216 (33).