Total synthesis of Iso[4]-levuglandin E-2

Iso[4]-levuglandin E-2 (iso[4]-LGE(2), 5-acetyl-6-formyl-9-hydroxy-7(E),11(Z)-heptadecadienoic acid) is a structural isomer of levuglandin E-2 (8-acetyl-9-formyl-12-hydroxy-5(Z),10(E)-heptadecadienoic acid) that we postulate to be generated during autoxidation of arachidonic acid or arachidonate esters. To facilitate detection and identification of iso[4]-LGE(2) in biological samples, a succinct total synthesis was developed that depends on conjugate addition of a higher order vinyl cyanocuprate to a gamma-alkoxy enone to provide a key carbon-carbon bond-forming step. Bismethoxime pentafluorobenzyl ester trimethylsilyl ether derivatives of LGE(2) and iso[4]-LGE(2) were prepared and shown to be suitable for mass spectral identification of these highly oxidized lipids.