Total Synthesis of Oxidized Phospholipids. 3. The (11E)-9-Hydroxy-13-oxotridec-11-enoate Ester of 2-Lysophosphatidylcholine Yijun Deng and Robert G. Salomon* Department of Chemistry, Case Western Reserve University, Cleveland, Ohio 44106-7078 rgs@po.cwru.edu. Received May 26, 2000 A total synthesis of (11E)-9-hydroxy-13-oxotridec-11-enoate ester of 2-lysophosphatidylcholine (HOT-PC) was devised to facilitate identification of this oxidized phospholipid. A lactone, 8-(3-oxo- 1H,6H-2-oxinyl)octanoic acid (1), believed to be generated through an intermediate (11E)-9-hydroxy- 13-oxotridec-11-enoic acid (HOT), is produced upon autoxidation of linoleic acid. A synthesis of lactone 1 methyl ester was accomplished from HOT involving a novel trans-cis isomerization that is driven to completion by cyclization to a hemiacetal. An alternative route to this carbon skeleton was also acheived that provides the lactone 1 itself. Introduction The study of lipid peroxidation is a rapidly growing field in medicine and biology, spurred by increasing evidence that lipid oxidation is involved in the patho- genesis of many chronic diseases, e.g., atherosclerosis, Alzheimer’s disease, Parkinson disease, stroke, and aging. 1 In vivo, most fatty acids are present as esters of cholesterol or glycerol. Phospholipids, esters of glycerol- 3-phosphate, are major components of biological mem- branes and lipoproteins, circulating micellelike particles solubilized with an outer shell of phospholipids. A vast array of aldehydes are produced by oxidative cleavage of polyunsaturated fatty acids and their phospholipid derivatives. 2 Many alkanals and alkenals, some contain- ing hydroxyl or epoxy groups, have been isolated and fully characterized. Some covalently modify proteins, and this may be important for their biological activities, e.g., malondialdehyde, 2(E)-4-hydroxy-2-nonenal and 2(E)-4- hydroxy-2-hexenal. Less is known about aldehyde prod- ucts of lipid peroxidation that remain esterified in phospholipids. To foster progress in this area, we are devising unambiguous chemical syntheses of oxidized phospholipids. 3 Recent studies showed that oxidative cleavage of the arachidonic acid (AA) ester AA-PC of 2-lyso-phosphatidylcholine (PC) generates a phospholipid ester of 5-oxovaleric (OV) acid. 4 OV-PC activates endo- thelial cells to bind monocytes. This may facilitate entry of monocytes into the vessel wall, an important event in atherogenesis. Our chemical synthesis of OV-PC facili- tated its structural and biological characterization. Some of the aldehydes generated by oxidative cleavage of phospholipids avidly bind covalently with proteins, leading to protein modifications that may interfere with biological functions. We previously identified lipid- derived carboxyalkylpyrrole protein modifications in human blood proteins and oxidized low-density lipopro- teins. 5 Carboxyalkylpyrroles are formed by the reaction of γ-hydroxy-R,-unsaturated aldehydic esters of 2-lyso- PC with the primary amino groups of protein lysyl residues. For example, oxidative cleavage of linoleic acid- PC ester (LA-PC) generates protein-based carboxyhep- tylpyrroles by reaction of a 9-hydroxy-12-oxo-10-dode- cenoic acid ester of lyso-PC (HODA-PC) with protein in conjunction with ester hydrolysis (Scheme 1). Very recently, the lactone 1 from (2Z)-5-hydroxy-2- tridecenedioate was identified as a product from the oxidative cleavage of LA. This lactone was postulated to arrise from 9-hydroxy-13-oxo-11-tridecenoic (HOT) acid, a δ-hydroxy-R,-unsaturated aldehydic acid (Scheme 2). 1 To facilitate investigation of the formation of lactone 1 from LA and of various phospholipid derivatives from oxidative fragmentation of LA-PC in vivo, we devised total syntheses of lactone 1 and its putative precursor phospholipid, HOT-PC (2). * To whom correspondence should be addressed. Telephone: 216- 368-2592. FAX: 216-368-3006. (1) Spiteller, G. Chem. Phys. Lipids 1998, 95, 105-62. (2) Esterbauer, H.; Schaur, R. J.; Zollner, H. Free Radic. Biol. Med. 1991, 11, 81-128. (3) , For previous papers in this series, see refs 4 and 6. (4) Watson, A. D.; Leitinger, N.; Navab, M.; Faull, K. F.; Horkko, S.; Witztum, J. L.; Palinski, W.; Schwenke, D.; Salomon, R. G.; Sha, W.; Subbanagounder, G.; Fogelman, A. M.; Berliner, J. A. J. Biol. Chem. 1997, 272, 13597-607. (5) Kaur, K.; Salomon, R. G.; O’Neil, J.; Hoff, H. F. Chem. Res. Toxicol. 1997, 10, 1387-96. Scheme 1 6660 J. Org. Chem. 2000, 65, 6660-6665 10.1021/jo000809u CCC: $19.00 © 2000 American Chemical Society Published on Web 08/31/2000