GENERAL-METHOD FOR THE SYNTHESIS OF PHOSPHOLIPID DERIVATIVES OF 1,2-O-DIACYL-SN-GLYCEROLS

An efficient phosphite coupling protocol is described for the synthese s of the major classes of phospholipids that are derived from 1,2-O-di acyl-sn-glycerols and analogues thereof. The symmetrical diacyl glycer ols 10c,d were prepared by straightforward acylation of 3-O-benzyl-sn- glycerol (7) with the appropriate carboxylic acid in the presence of d icyclohexylcarbodiimide (DCC) and 4-(dimethylamino)pyridine (DMAP). A simple method for preparing saturated and unstaturated mixed 1,2-O-dia cyl-sn-glycerols was then devised that involved stepwise acylation of 7 with different alkyl carboxylic acids and debenzylation this procedu re is exemplified by the preparation of 10a,b. The 1,2-O-diacyl-sn-gly cerols 10a-d were then coupled with suitably protected lipid head grou ps employing reactive alkyl or aryl dichlorophosphites to give interme diate phosphite triesters in high overall yields. Oxidation or sulfuri zation of these phosphites proceeded smoothly to give the correspondin g phosphate or phosphorothioate triesters, deprotection of which then provided the phosphatidylcholines 16 and 17, the phosphatidylethanolam ine 20, the phosphatidylserine 28, and the phosphatidylinositols 37 an d 38. Preparation of 37 and 38 required the invention of an improved m ethod for resolving the isopropylidene-protected D-myo-inositol deriva tive 33. This phosphite coupling procedure was modified to assemble ph ospholipids bearing-polyunsaturated acyl side chains at the sn-2-posit ion 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 modifie d, were prepared in excellent overall yields by conjoining the 1,2-O-d iacyl-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 maybe pr epared as evidenced by the syntheses of 56 and 61 in which the sn-3 ox ygen atom of the 1,2-O-diacyl-sn-glycerol moiety is replaced with an N -benzyl group or a sulfur atom, respectively.