Total Synthesis of γ-Hydroxy-α,β-Unsaturated Aldehydic Esters of Cholesterol and 2-Lysophosphatidylcholine

Abstract

Free radical-induced oxidation of polyunsaturated fatty esters in low-density lipoproteins (LDLs) generates 2-lysophosphatidylcholine (PC) and cholesterol esters of γ-hydroxy-α,β-unsaturated aldehydic acids that covalently modify LDL protein, and protein adducts of the corresponding acids are found in human blood. The chemistry and structures of these compounds resemble those of (E)-4-hydroxy-2-nonenal (HNE), previously considered the most cytotoxic aldehyde released during peroxidation of linoleate and arachidonate esters. The present report details total syntheses of 2-lyso-PC and cholesteryl esters of (E)-9-hydroxy-12-oxododec-10-enoic and (E)-5-hydroxy-8-oxooct-6-enoic acid that presumably are derived in vivo from linoleate and arachidonate esters, respectively. The syntheses depend on the use of a 3,3-dimethyl-2,4-dioxolanyl moiety as a latent aldehyde from which the chemically sensitive γ-hydroxy-α,β-unsaturated aldehyde array can be generated in the final step. For the cholesteryl esters, generation of the aldehyde group by oxidative cleavage of a vicinal diol could be accomplished in very good yields with periodate. However, for esters of 2-lyso-PC, the target aldehydes were not obtained upon treatment of vicinal diol precursors with periodate owing to a novel oxidative cleavage of the γ-hydroxy-α,β-unsaturated aldehydes by periodate. Fortunately, treatment of the vicinal diol precursors with Pb(OAc)4 at −80 °C delivered good yields (82−85%) of the desired phospholipid aldehydes.