Total Synthesis of Iso[7]-Levuglandin D2

Iso[7]-levuglandin D2 (iso[7]-LGD2, 9-acetyl-8-formyl-5-hydroxy-6(E),11(Z)-heptadecadienoic acid) is a structural isomer of levuglandin D2 (9-acetyl-8-formyl-12-hydroxy-5(Z),10(E)-heptadecadienoic acid) that we postulate to be generated during nonenzymatic free radical-induced oxidation of arachidonic acid. To facilitate detection and identification in biological samples, a total synthesis of iso[7]-LGD2 was devised. The functionality in iso[7]-LGD2 is diverse and chemically sensitive, and an acid-catalyzed lactonization of the allylically activated δ-hydroxy acid array present in the synthetic target was encountered that occurs readily in aqueous solution. Nevertheless, conjugate addition of a multifunctional vinyl cyanocuprate to achieve the final carbon−carbon bond-forming step, followed by a sequence of functional and protecting group manipulations, reproducibly delivered a readily separable 3:7 mixture of iso[7]-LGD2 lactone and the free acid.