A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro-Resolving Lipid Mediator of Neuroinflammation.

Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB ₄ ) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB ₄ in 25 % overall yield in just 10 steps. For the first time, LXB ₄ has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB ₄ showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB ₄ , enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.
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