Stereocontrolled Synthesis of Resolvin D4.

Abstract

The stereoselective synthesis of resolvin D4 (RvD4) was achieved using the Wittig reaction of the C1-C10 dienal with the known C11-C22 phosphonium salt. The ( S, E)-enantiomer ( S)-10, corresponding to the C1-C8 part, was synthesized in 95% ee by the asymmetric transfer hydrogenation reaction of the corresponding acetylenic ketone followed by Red-Al reduction. Sharpless epoxidation of this alcohol using Ti(O- i-Pr)4/l-(+)-DIPT as a catalyst produced anti epoxy alcohol with >99% ee as the sole product in 82% yield. A subsequent functional group manipulation, including removal of the PMB group, produced the alcohol, which upon Swern oxidation afforded anti 4-hydroxy-5-TBS-oxy enal via epoxide ring opening of the resulting aldehyde. The Horner-Wadsworth-Emmons reaction was used to add the C9-C10 enal part to this aldehyde, and the resulting dienal was subjected to the Wittig reaction with C11-C22 phosphonium salt to furnish the entire structure of RvD4. Conversion of the primary alcohol to the methyl ester and deprotection of the three TBS groups with TBAF afforded 5,17-dihydroxy-γ-lactone, which was hydrolyzed to RvD4. Additionally, anti-4,5-dihydroxydodecanoic acid, a model compound of RvD4, in CD3OD was observed to be stable at room temperature for several weeks, whereas 20% of the acid in CDCl3 was converted into the γ-lactone after 24 h at rt.