Stereoselective Synthesis of Maresin-Like Lipid Mediators

Abstract

14S,22-Dihydroxy-docosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (maresin-L1) and 14R,22-dihydroxy-docosa-4Z,7Z,10Z, 12E,16Z,19Z-hexaenoic acid (maresin-L2) were chemically synthesized. They were identical to activated macrophage-produced counterparts and their total synthesis was highly stereoselective, as revealed by chiral LC-UV-MS/MS analysis. The synthesis involved the following steps: (1) kinetic resolution of a racemic allylic alcohol by the asymmetric epoxidation; (2) transformation of the epoxy alcohol to γ-hydroxyenal derivative; and (3) the Wittig reaction to furnish the Z-olefin.

Key words

maresin-like - diHDHA - chiral LC-UV-MS/MS - lipid mediators - stereoselective organic synthesis

• References and Notes

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• 15 To an ice-cold solution of phosphonium salt 3 (967 mg, 1.58 mmol) in THF (20 mL) was added a solution of NaN(TMS)₂ (1.0 M in THF, 1.54 mL, 1.54 mmol). After 5 min at 0 °C, a solution of aldehyde (S)-4 (250 mg, 0.570 mmol) in THF (5 mL) was added to the mixture at –78 °C. The cooling bath was removed, and the mixture was stirred at rt for 10 min before addition of saturated NH₄Cl solution. The mixture was extracted with EtOAc, and the product was purified by chromatography on silica gel to afford (S)-13, which was used for the next reaction without further purification. The ¹H NMR spectrum is attached in the Supporting Information. To a solution of the above product in THF (20 mL) was added TBAF (1.0 M in THF, 4.80 mL, 4.80 mmol) dropwise. After 30 min at rt, the reaction was stopped by adding saturated NH₄Cl solution. The resulting mixture was extracted with EtOAc, and the product was purified by chromatography on silica gel to afford diol ester (S)-14 (198 mg, 84% over two steps): [α]_D ²⁰ –21 (c 0.95, CHCl₃). The ¹H and ¹³C–APT NMR spectra are attached in the Supporting Information. A mixture of ester (S)-14 (100 mg, 0.240 mmol) and LiOH·H₂O (300 mg, 7.16 mmol) in MeOH (2.5 mL) and H₂O (2.5 mL) was stirred at rt of 22 h and diluted with MacIlvaine’s phosphate buffer (pH 5.0, 80 mL). The mixture was extracted with Et₂O, and the product was purified by chromatography on silica gel to afford acid 1 (51 mg, 59%), which was further purified by using recycle HPLC (LC-Forte/R equipped with YMC-Pack SIL-60, EtOAc/hexane = 2:1, 20 mL/min): [α]_D ²⁰ +4 (c 0.52, MeOH). The ¹H and ¹³C–APT NMR spectra and HRMS analysis are attached in the Supporting Information.