Total synthesis of 17-isolevuglandin E-4 and the structure of C22-PGF(4 alpha)

The isolevuglandin 17-isoLGE(4) (10-acetyl-11-formyl-14-hydroxynonadecatetr aenoic acid) is a levulinaldehyde derivative that is expected to be generat ed during the free radical-induced oxidation of docosahexaenoic acid. A tot al synthesis was executed to facilitate detection and identification of 17- isoLGE(4) in biological samples. Conjugate addition of a higher order vinyl cyanocuprate to a gamma-alkoxy enone achieved the final carbon-carbon bond formation to complete a convergent elaboration of the 17-isoLGE(4) carbon skeleton. Attempted construction of the requisite vinyl nucleophile synthon using hydrostannylation of an alkyne was foiled by tri-n-butylstannyl radi cal-promoted isomerization of a cis to a trans double bond. Derivatization of 17-isoLGE(4) with methoxylamine under anhydrous or wet conditions genera ted bismethoximes of 17isoLGE(4) or the isomerized Delta(11)-17-isoLGE(4) r espectively. Analysis of the mass spectrum of a bismethoxime-pentafluoroben zyl ester-trimethylsilyl ether derivative of 17-isoLGE(4) provided presumpt ive evidence that an incorrect structure was proposed earlier for C22-PGF(4 alpha), the only F-4-isoprostane which is produced enzymatically. We concl ude that the 22-carbon analogue of PGF(2 alpha), produced from docosahexaen oic acid by a cyclooxygenase from trout gill, does not have the same side c hains as 17-isoLGE(4). Furthermore, we now propose that mass spectral data reported for "C22-PGF(4 alpha)" support a 14-PGF(4 alpha) structure rather than the 17-PGF(4 alpha) structure suggested previously.