A new approach for the synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] is described, compatible with unsaturated fatty acid esters, as well as phosphorothioate and acetylenic analogues. This strategy depends on masking the phosphate charges with base-labile cyanoethyl esters, and the hydroxyls of the target with mild acid-labile protecting groups. A two-step basic then acidic global unblocking of orthogonal protecting groups provides the target lipid. A xanthenylidene acetal was used for key temporary protection of the 4,5-diol, and the 6-O was protected with a 1-(4-chlorophenyl)-4-ethoxypiperidin-4-yl (Cpep) acetal.
