Diether Analogues of Lecithins

Considerable interest has developed recently in naturally occurring phosphatides containing ether groups. Two classes of ether-containing phosphatides can be envisaged, i.e. monoether, monoester phosphatides, and diether phosphatides. To date, t,he only monoether, monoester phosphatides known to occur naturally are analogues of phosphatidylethanolamine (1-4) and phosphatidylcholine (5, 6). A chemical synthesis of phosphatides of this class, namely DL-a-octadecyl, fl-stearoyland DL-LYstearoyl, P-octadecylglycerylphosphorylethanolamine, has been achieved by Malkin and colleagues (7, 8). The corresponding lecithin analogues have not yet been synthesized. Phosphatides containing two ether groups have recently been discovered (9, 10). Marinetti, Erbland, and Stotz (9) obtained a phosphatide fraction from a hydrogenated mixture of beef heart phosphatides, which on acid hydrolysis yielded an 01 ,pdialkyl glycerol ether. Sehgal, Kates, and Gibbons (IO) found that the phosphatides of Halobacterium cutirubrum, after acid hydrolysis, also yielded a diether of glycerol. The synthesis of I)and DL-a , /3-diether glycerols containing long chain n-alkyl radicals has been reported recently by Kates, Chan, and Stanacev (11). The synthesis of diether analogues of the major groups of glycerol phosphatides is being undertaken in anticipation of the isolation from natural sources of such phosphatides. This paper reports the synthesis of the first diether una.Zogue of a lecithin. phosphatides have the D configuration, it is most likely that the a, P-dialkyl glycerol moieties of naturally occurring diether analogues of phosphatides will possess the same configuration. Hence, D-CY ,/?-dioctadecyl glycerol (I) was selected for the starting material. It was phosphorylated with monophenylphosphoryl dichloride in the presence of pyridine. This reaction gave rise to the formation of dioctadecyl-L-Lu-glyceryl(phenyl)phosphoryl chloride (II) and tetra-O-octadecyl bis-(L-oc-glyceryl)phosphoric acid phenyl ester (III). Without isolating Intermediate II, it was esterified with choline iodide. The mixture of reaction products then was freed from bis-Compound III and from water-soluble material, and the crude dioctadecyl L-ol-glyceryl(phenyl)phosphoryl choline iodide (IV) was purified by crystallization from acetone. Removal of the phenyl group of Compound IV by catalytic hydrogenolysis was slow and incomplete. The reaction mixture contained, in addition to L-cu-(dioctadecyl)lecithin and starting material, considerable amounts of the ether analogues of phosphatidic acid-like compounds. The latter most likely were formed during the reduction by acid hydrolysis (HI) of the ether lecithin and its phenyl ester. This difficulty was overcome by removing the iodide ion of Compound IV with silver carbonate prior to the reduction. The catalytic hydrogenolysis of the iodine-free Compound IV proceeded smoothly and gave in a good yield the desired diether lecit,hin (V).