Stereocontrolled Synthesis of Resolvin D4

摘要

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 CD_(3)OD was observed to be stable at room temperature for several weeks, whereas 20% of the acid in CDCl_(3) was converted into the γ-lactone after 24 h at rt.