Stereodivergent synthesis of all 15-F(2) isoprostanes

Isoprostanes, lipid metabolites generated from free radical oxidation of membrane-bound arachidonic acid, have been detected in organisms subjected to oxidative stress; however, the function and cellular targets of the isoprostanes are unclear. As an initial step toward studying the biological role of these molecules, we report the preparation of all known and anticipated 15-F2 isoprostanes. The stereodivergent strategy to the complete isoprostane library features a ring-opening metathesis to introduce the cis-alkyl side chains that are characteristic of this class of molecules. Resolution to the individual stereoisomers can be accomplished by either a catalytic asymmetric reduction or an auxiliary-based separation protocol. In either case, the individual isomers can be converted to the corresponding 15-F2 isoprostanes through a straightforward functionalization of the carboxylic acid-containing side chain. The availability of this complete 15-F2 isoprostane library, containing both known and anticipated lipid metabolites, allows for the first time the side-by-side evaluation of these compounds in a variety of biological assays.