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Synlett 2019; 30(03): 343-347
DOI: 10.1055/s-0037-1612011
DOI: 10.1055/s-0037-1612011
letter
Stereoselective Synthesis of Maresin-Like Lipid Mediators
This work was supported by USA NIH grant 2R01DK087800-06A1 grant (S. H.) and by an unrestricted departmental grant from Research to Prevent Blindness, Inc., New York, NY (S. H. & N. G. B.). This work was also supported by KAKENHI Grant Number JP15H05904, JP15H05898, JP15H05897, JP15H04648 and the Kobayashi International Scholarship, as well as by USA NIH grant 1R01NS104117-01A1 (N. G. B.).Further Information
Publication History
Received: 02 December 2018
Accepted after revision: 18 December 2018
Publication Date:
14 January 2019 (online)
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 synthesisSupporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1612011.
- Supporting Information
-
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.