Novel Bioactive Phospholipids:  Practical Total Syntheses of Products from the Oxidation of Arachidonic and Linoleic Esters of 2-Lysophosphatidylcholine¹

Total syntheses of nine novel phospholipids were accomplished to facilitate the identification and biological testing of compounds that are generated upon oxidative cleavage of arachidonate and linoleate esters of 2-lysophosphatidylcholine, the two most abundant polyunsaturated phospholipids in low-density lipoprotein. An efficient general synthesis exploiting 2-lithiofuran as a 4-oxo-2-butenoyl carbanion equivalent provided phospholipids containing γ-keto-α,β-unsaturated carbonyl functional arrays. By exploiting facile cis−trans isomerizations, two commercially available cis alkenes, (2Z)-2-butene-1,4-diol and 2,5-dihydrofuran, could be employed as starting materials for preparing the Horner−Wadsworth−Emmons reagent 4-(diethoxyphosphoryl)-2E-butenal, a valuable building block for the synthesis of 2,4-dienals. The reagent was exploited in a total synthesis of 13-oxotridec-9E,11E-dienoic acid, confirming the identity of this product that is generated upon autoxidation of linoleic acid and by decomposition of 13-hydroperoxy-9,11-octadecadienoate (13-HPODE), especially in the presence of redox active transition metal ions, cytochrome p-450, or hydroperoxide lyase.