Total Synthesis of 17-isoLevuglandin E<sub>4</sub> and the Structure of C22-PGF<sub>4α</sub>

2000-07-21T00:00:00Z (GMT) by Wei Sha Robert G. Salomon
The isolevuglandin 17-isoLGE<sub>4</sub> (10-acetyl-11-formyl-14-hydroxynonadeca-4(<i>Z</i>),7(<i>Z</i>),12(E),16(<i>Z</i>)-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-isoLGE<sub>4</sub> 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-isoLGE<sub>4</sub> carbon skeleton. Attempted construction of the requisite vinyl nucleophile synthon using hydrostannylation of an alkyne was foiled by tri-<i>n</i>-butylstannyl radical-promoted isomerization of a cis to a trans double bond. Derivatization of 17-isoLGE<sub>4</sub> with methoxylamine under anhydrous or wet conditions generated bismethoximes of 17-isoLGE<sub>4</sub> or the isomerized Δ<sup>11</sup>-17-isoLGE<sub>4</sub> respectively. Analysis of the mass spectrum of a bismethoxime−pentafluorobenzyl ester−trimethylsilyl ether derivative of 17-isoLGE<sub>4</sub> provided presumptive evidence that an incorrect structure was proposed earlier for C22-PGF<sub>4α</sub>, the only F<sub>4</sub>-isoprostane which is produced enzymatically. We conclude that the 22-carbon analogue of PGF<sub>2α</sub>, produced from docosahexaenoic acid by a cyclooxygenase from trout gill, does not have the same side chains as 17-isoLGE<sub>4</sub>. Furthermore, we now propose that mass spectral data reported for “C22-PGF<sub>4α</sub>” support a 14-PGF<sub>4α</sub> structure rather than the 17-PGF<sub>4α</sub> structure suggested previously.