General Method for the Synthesis of Phospholipid Derivatives of 1,2-O-Diacyl-sn-glycerols

Article abstract of DOI:10.1021/jo00096a023

An efficient phosphite coupling protocol is described for the syntheses of the major classes of phospholipids that are derived from 1,2-O-diacyl-sn-glycerols and analogues thereof.The symmetrical diacyl glycerols 10c,d were prepared by straightforward acylation of 3-O-benzyl-sn-glycerol (7) with the appropriate carboxylic acid in the presence of dicyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP).A simple method for preparing saturated and unstaturated mixed 1,2-O-diacyl-sn-glycerols was then devised that involved stepwise acylation of 7 with different alkyl carboxylic acids and debenzylation; this procedure is exemplified by the preparation of 10a,b.The 1,2-O-diacyl-sn-glycerols 10a-d were then coupled with suitably protected lipid head groups employing reactive alkyl or aryl dichlorophosphites to give intermediate phosphite triesters in high overall yields.Oxidation or sulfurization of these phosphites proceeded smoothly to give the corresponding phosphate or phosphorothioate triesters, deprotection of which then provided the phosphatidylcholines 16 and 17, the phosphatidylethanolamine 20, the phosphatidylserine 28, and the phosphatidylinositols 37 and 38.Preparation of 37 and 38 required the invention of an improved method for resolving the isopropylidene-protected D-myo-inositol derivative 33.This phosphite coupling procedure was modified to assemble phospholipids bearing polyunsaturated acyl side chains at the sn-2-position as exemplified by the preparation of the phosphatidylethanolamine 26.The one-pot phosphite coupling procedure is also applicable to the syntheses of a variety of other biologically interesting phospholipid analogues.For example, the phosphatidylinositol analogues 49-51, in which the hydroxyl group at C(2) of the inositol ring has been modified, were prepared in excellent overall yields by conjoining the 1,2-O-diacyl-sn-glycerol 10c with the protected inositol derivatives 44, 45, and 48.Phospholipid analogues that contain other replacements of the phosphate group including phosphoramidates and thiophosphates may be prepared as evidenced by the syntheses of 56 and 61 in which the sn-3 oxygen atom of the 1,2-O-diacyl-sn-glycerol moiety is replaced with an N-benzyl group or a sulfur atom, respectively.