TOTAL SYNTHESIS OF GAMMA-HYDROXY-ALPHA,BETA-UNSATURATED ALDEHYDIC ESTERS OF CHOLESTEROL AND 2-LYSOPHOSPHATIDYLCHOLINE

Free radical-induced oxidation of polyunsaturated fatty eaters in low- density lipoproteins (LDLs) generates 2-lysophosphatidylcholine (PC) a nd cholesterol esters of gamma-hydroxy-alpha,beta-unsaturated aldehydi c acids that covalently modify LDL protein, and protein adducts of the corresponding acids are found in human blood. The chemistry and struc tures of these compounds resemble those of (E)-4-hydroxy-2-nonenal (HN E), previously considered the most cytotoxic aldehyde released during peroxidation of linoleate and arachidonate esters. The present report details total syntheses of 2-lyse-PC and cholesteryl esters of (E)-9-h ydroxy-12-oxododec-10-enoic and (E)-5-hydroxy-8-oxooct-6-enoic acid th at presumably are derived in vivo from linoleate and arachidonate este rs, respectively. The syntheses depend on the use of a 3,3-dimethyl-2, 4-dioxolanyl moiety as a latent aldehyde from which the chemically sen sitive gamma-hydroxy-alpha,beta-unsaturated aldehyde array can be gene rated in the final step. For the cholesteryl esters, generation of the aldehyde group by oxidative cleavage of a vicinal diol could be accom plished in very good yields with periodate. However, for esters of 2-l yso-PC, the target aldehydes were not obtained upon treatment of vicin al diol precursors with periodate owing to a novel oxidative cleavage of the gamma-hydroxy-alpha,beta-unsaturated aldehydes by periodate. Fo rtunately, treatment of the vicinal diol precursors with Pb(OAc)(4) at -80 degrees C delivered good yields (82-85%) of the desired phospholi pid aldehydes.