- Total synthesis of 17-isolevuglandin E4 and the structure of C22-PGF(4α)
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The isolevuglandin 17-isoLGE4 (10-acetyl-11-formyl-14-hydroxynonadeca-4(Z),7(Z),12(E),16(Z)-tet raenoic 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 acis 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.
- Sha, Wei,Salomon, Robert G.
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p. 5315 - 5326
(2007/10/03)
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