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

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journal contribution
posted on 21.07.2000, 00:00 by Wei Sha, Robert G. Salomon
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, the only F4-isoprostane which is produced enzymatically. We conclude that the 22-carbon analogue of PGF, 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” support a 14-PGF structure rather than the 17-PGF structure suggested previously.