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.

Key words

resolvin D6 - resolvin E2 - stereoselective synthesis - epoxide ring opening - semi-hydrogenation - zinc - enynes

• References and Notes

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• 16 Synthesis of (S,E)-1-[(tert-Butyldimethylsilyl)oxy]oct-5-en-7-yn-4-ol (15) To a solution of trimethylsilylacetylene (0.43 mL, 3.05 mmol) in THF (0.3 mL) was added dropwise n-BuLi (1.70 mL, 2.67 mmol, 1.57 M in hexane) at –78 °C. After 15 min of stirring at rt, HMPA (0.69 mL, 3.97 mmol) and a solution of epoxy alcohol 13 (100 mg, 0.331 mmol) in THF (0.15 mL) were added. The solution was stirred at rt for 5 h and then diluted with saturated NH₄Cl. The product was extracted with EtOAc and passed through a short column of silica gel for the next reaction. A mixture of the above enyne and K₂CO₃ (212 mg, 1.53 mmol) in MeOH (1 mL) was stirred at rt for 2 h and then diluted with saturated NH₄Cl. The product was extracted with EtOAc and purified by chromatography on silica gel to give alcohol 15 (34 mg, 42% over two steps); colorless oil; R_f = 0.37 (hexane/EtOAc, 4:1); [α]_D ²⁰ –22 (c 1.1, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 0.07 (s, 6 H), 0.90 (s, 9 H), 1.53–1.80 (m, 4 H), 2.87 (d, J = 2.1 Hz, 1 H), 3.25 (d, J = 4.0 Hz, 1 H), 3.66 (t, J = 5.2 Hz, 2 H), 4.16–4.25 (m, 1 H), 5.74 (dt, J = 16.0 Hz, 2.1 Hz, 1 H), 6.25 (dd, J = 16.0 Hz, 5.4 Hz, 1 H). ¹³C–APT NMR (75 MHz, CDCl₃): δ = –5.4 (+), 18.4 (–), 26.0 (+), 28.6 (–), 34.6 (–), 63.5 (–), 71.3 (+), 77.6 (–), 82.0 (–), 108.3 (+), 147.9 (+). HRMS–FAB⁺: m/z [M + H]⁺ calcd for C₁₄H₂₇O₂Si: 255.1780; found: 255.1782.