Synthesis of Resolvin D6 and the Silyl Ether of the Resolvin E2 Methyl Ester via trans-Enynyl Alcohols

Abstract

Two trans-enynyl alcohol intermediates corresponding to the C1–C8 and C13–C22 parts of resolvin D6 (RvD6) were prepared through the Hudrlik–Peterson reaction of the TMS-substituted trans-epoxy alcohols with TMS-acetylide and subsequent TMS-desilylation. These intermediates were coupled with a 1,4-dihalo-2-butyne derivative under copper catalysis, and the resulting acetylene was reduced with Zn(Cu/Ag) to afford the TBS ether of RvD6 methyl ester. Desilylation with TBAF yielded the γ-lactone of RvD6, which was hydrolyzed to RvD6. The total yield of RvD6 was 1.9% in 19 steps from (3-trimethylsilyl)propargyl alcohol. The TBS ether of RvE2 methyl ester was also synthesized.

Resolvins, Protectins, and Maresins: DHA-Derived Specialized Pro-Resolving Mediators, Biosynthetic Pathways, Synthetic Approaches, and Their Role in Inflammation

“…Kobayashi and co-workers [ 95 ] have recently reported another approach for the total synthesis of RvD6, by using intermediates 182 , 183 , and 184 ( Scheme 23 ), envisioning a strategy based on Sonogashira coupling of 183 and 184 to 182 , followed by hydrogenation with experimental conditions, affording the required double bonds ( Scheme 24 ).…”

“… Strategy for the synthesis of RvD6 and preparation of the intermediates 183 and 184 , as reported by Kobayashi and co-workers [ 95 ]. Reagents and conditions: ( A ).…”

“… Synthesis of RvD6, as reported by Kobayashi and co-workers [ 95 ]. Reagents and conditions: i. NaI (2 equiv.…”

Stereoselective syntheses and biological activities of E-series resolvins

“…53 Recently, Kobayashi and co-workers also synthesized the bis-TBS ether of the RvE2 methyl ester (102), as briefly outlined in Scheme 16. 54 In this synthesis, the propargylic alcohol 103 was converted to epoxy (S)-alcohol 104 (syn/anti = 3:2) using Red-Al followed by epoxidation of the resulting allylic alcohol with m-CPBA. Addition of TMS-acetylide to the epoxide in a Hudrlick-Peterson reaction 55 gave enyne 105 after a selective desilylation.…”