UBC Theses and Dissertations

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UBC Theses and Dissertations

Synthesis of cholesterol based model glycolipids Sather, Paula Joan


The synthesis of glycolipids containing a variable length polyethylene glycol spacer group between a glucuronic acid (glu) headgroup and a cholesterol (chol) tail glu-0CH₂(CH₂OCH₂ )nCH₂O-chol is described. The homologs (n=2,3,5) were prepared by reaction of an excess of commercially available tri, tetra and hexaethylene glycols with cholesteryl-p-toluene sulfonate. 3-O-(8-hydroxy-3,6-dioxaoctyl) cholest-5-ene (2), 3-O-(ll-hydroxy-3,6,9-trioxaundecyl)cholest-5-ene (3) and 3-O-(17-hydroxy-3,6,9,12,15-pentaoxaheptadecyl)cholest-5-ene (4) were produced, and yields were dependent on the amount of excess used. The headgroup was prepared by esterification and acetylation of glucuronolactone to produce methyl (1, 2, 3, 4-tetra-O-acetyl-β-D-glucopyran)uronate which was then brominated at the anomeric carbon to produce methyl (2, 3, 4-tri-O-acetyl-α-D-glucopyranosyl bromide)uronate (1). The headgroup was coupled to the cholesteroxy oligoethylene glycols by a Koenig Knorr type reaction using freshly prepared silver carbonate as the catalyst. Methyl[3-O-(3,6-dioxaoctyl)cholest-5-en-3β-y1-2,3,4-tri-O-acetyl-β-D-glucopyranosid] uronate (5), Methyl[3-O-(3,6,9-trioxaundecyl) cholest-5-en-3β-yl-2,3,4-tri-0-acetyl-β-D-glucopyranosid] uronate (6), and Methyl[3-O-(3,6,9,12,15-pentaoxaheptadecyl)cholest-5-en-3β-yl-2, 3, 4-tri-O -acetyl-β-D-glucopyranosid] uronate (7) were produced with yields of up to 30%. The removal of the methyl ester and acetate protecting groups on the headgroup was accomplished using NaOH in a mixture of solvents followed by acidification with HCl to produce 3-O-(3,6-dioxaoctyl)cholest-5-en-3β-yl-β-D-glucopyranosiduronic acid (8) and 3-O-(3,6,9-trioxaundecyl)cholest-5-en-3β-yl-β-D-glucopyranosiduronic acid (9). Octaethylene glycol and dodecaethylene glycol were prepared using a solid supported synthesis. The solid polymer used was a trityl chloride functionalized polystyrene 1% divinyl benzene. Mono protected tetraethylene glycol was prepared and attached to the polymer. The protecting group was removed, and the hydroxy terminal was converted to a mesylate leaving group by reaction with methane sulfonyl chloride. To elongate the chain, the anion of tetraethylene glycol was prepared using sodium hydride in DMF. The tetraethylene glycol bound resin was added, and reaction continued at 120 °C for 24 hours. Cleavage of the resultant product from the polymer support yielded octaethylene glycol. Repetition of the mesylation and elongation steps followed by cleavage yielded dodecaethylene glycol. The oligoethylene glycols were purified by passage through a Fractogel 40S gel permeation column. Two different protecting groups for the tetraethylene glycol were tried. Trialkyl silyl groups were first attempted, but were abandoned due to reduced reactivity and monitoring difficulties during the deprotection. An acetate protecting group was finally used and deprotection was monitored with infrared spectroscopy.

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