Total Synthesis of 17-isoLevuglandin E₄ and the Structure of C22-PGF_4α

The isolevuglandin 17-isoLGE₄ (10-acetyl-11-formyl-14-hydroxynonadeca-4(Z),7(Z),12(E),16(Z)-tetraenoic acid) is a levulinaldehyde derivative that is expected to be generated during the free radical-induced oxidation of docosahexaenoic acid. A total synthesis was executed to facilitate detection and identification of 17-isoLGE₄ in biological samples. Conjugate addition of a higher order vinyl cyanocuprate to a γ-alkoxy enone achieved the final carbon−carbon bond formation to complete a convergent elaboration of the 17-isoLGE₄ carbon skeleton. Attempted construction of the requisite vinyl nucleophile synthon using hydrostannylation of an alkyne was foiled by tri-n-butylstannyl radical-promoted isomerization of a cis to a trans double bond. Derivatization of 17-isoLGE₄ with methoxylamine under anhydrous or wet conditions generated bismethoximes of 17-isoLGE₄ or the isomerized Δ¹¹-17-isoLGE₄ respectively. Analysis of the mass spectrum of a bismethoxime−pentafluorobenzyl ester−trimethylsilyl ether derivative of 17-isoLGE₄ provided presumptive evidence that an incorrect structure was proposed earlier for C22-PGF_4α, the only F₄-isoprostane which is produced enzymatically. We conclude that the 22-carbon analogue of PGF_2α, produced from docosahexaenoic acid by a cyclooxygenase from trout gill, does not have the same side chains as 17-isoLGE₄. Furthermore, we now propose that mass spectral data reported for “C22-PGF_4α” support a 14-PGF_4α structure rather than the 17-PGF_4α structure suggested previously.