Synthesis of phosphatidylcholine analogs with an alkyl group at C1 or C3 of the glycerol moiety.

The syntheses of 1,2-di-(O-hexadecyl)-rac-glycero-3-phosphocholines containing a methyl group at either C1 or C3 of the glycerol moiety are described. The methyl group was introduced at C1 in a synthetic scheme beginning with the hydroxylation of methyl vinyl ketone. The primary hydroxyl was protected by tritylation and the carbonyl group was reduced with sodium borohydride. Di-O-alkylation with 1-bromohexadecane was accomplished using finely powdered potassium hydroxide in refluxing toluene. Detritylation afforded two diastereomers of 2,3-di-(1-hexadecyloxy)butanol. Reaction with the simple phosphorylating agent, dimethylphosphoryl chloride (Bittman, R., A. F. Rosenthal, and L. A. Vargas. 1984. Chem. Phys. Lipids. 34: 201-205), followed by conversion to the phosphatidic acid and condensation with choline tosylate in the presence of trichloroacetonitrile afforded the diastereomers of 1-methyl-1,2-di-(O-hexadecyl)-rac-glycero-3-phosphocholine. The analog bearing a methyl group at C3 was prepared in a synthetic scheme beginning with the hydroxylation of acrolein dimethyl acetal. After di-O-alkylation with 1-bromohexadecane and sodium hydride in dimethyl sulfoxide/toluene, the acetal was converted to the aldehyde. Reaction with methylmagnesium bromide afforded the diastereomers of 1,2-di-(1-hexadecyloxy)-3-butanol, which were converted to the phosphocholine derivatives. These diether phosphatidylcholine analogs may be useful for investigating the effect of steric bulk at C1 and C3 of the glycerol moiety on the interactions with membrane components.