Total Synthesis of Four Stereoisomers of (4Z,7Z,10Z,12E,16Z,18E)‑14,20-Dihydroxy-4,7,10,12,16,18-docosahexaenoic Acid and Their Anti-inflammatory Activities

A novel anti-inflammatory lipid mediator, (4Z,7Z,10Z,12E,14S,16Z,18E,20R)-14,20-dihydroxy-4,7,10,12,16,18-docosahexaenoic acid (1aa), and its three C14,C20 stereoisomers (1ab,ba,bb) were synthesized in a convergent fashion. The carbon backbone of the target compounds was assembled from seven simple...

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Veröffentlicht in:Journal of organic chemistry 2015-08, Vol.80 (15), p.7713-7726
Hauptverfasser: Goto, Tomomi, Urabe, Daisuke, Masuda, Koji, Isobe, Yosuke, Arita, Makoto, Inoue, Masayuki
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container_end_page 7726
container_issue 15
container_start_page 7713
container_title Journal of organic chemistry
container_volume 80
creator Goto, Tomomi
Urabe, Daisuke
Masuda, Koji
Isobe, Yosuke
Arita, Makoto
Inoue, Masayuki
description A novel anti-inflammatory lipid mediator, (4Z,7Z,10Z,12E,14S,16Z,18E,20R)-14,20-dihydroxy-4,7,10,12,16,18-docosahexaenoic acid (1aa), and its three C14,C20 stereoisomers (1ab,ba,bb) were synthesized in a convergent fashion. The carbon backbone of the target compounds was assembled from seven simple fragments by employing two Sonogashira coupling and three SN2 alkynylation reactions. The thus constructed four internal alkynes were chemoselectively reduced to the corresponding (Z)-alkenes by applying a newly developed stepwise protocol: (i) hydrogenation of the three alkynes using Lindlar catalyst and (ii) formation of the dicobalt hexacarbonyl complex from the remaining alkyne and subsequent reductive decomplexation. The synthetic preparation of the stereochemically defined four isomers 1aa,ab,ba,bb permitted determination of the absolute structure of the isolated natural product to be 1aa. Biological testing of the four synthetic 14,20-dihydroxydocosahexaenoic acids disclosed similar anti-inflammatory activities of the non-natural isomers (1ab,ba,bb) and the natural form (1aa).
doi_str_mv 10.1021/acs.joc.5b01461
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Org. Chem</addtitle><date>2015-08-07</date><risdate>2015</risdate><volume>80</volume><issue>15</issue><spage>7713</spage><epage>7726</epage><pages>7713-7726</pages><issn>0022-3263</issn><eissn>1520-6904</eissn><abstract>A novel anti-inflammatory lipid mediator, (4Z,7Z,10Z,12E,14S,16Z,18E,20R)-14,20-dihydroxy-4,7,10,12,16,18-docosahexaenoic acid (1aa), and its three C14,C20 stereoisomers (1ab,ba,bb) were synthesized in a convergent fashion. The carbon backbone of the target compounds was assembled from seven simple fragments by employing two Sonogashira coupling and three SN2 alkynylation reactions. The thus constructed four internal alkynes were chemoselectively reduced to the corresponding (Z)-alkenes by applying a newly developed stepwise protocol: (i) hydrogenation of the three alkynes using Lindlar catalyst and (ii) formation of the dicobalt hexacarbonyl complex from the remaining alkyne and subsequent reductive decomplexation. 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subjects Alkenes - chemistry
Alkynes - chemistry
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - chemistry
Biological Products - chemistry
Docosahexaenoic Acids - chemical synthesis
Docosahexaenoic Acids - chemistry
Stereoisomerism
title Total Synthesis of Four Stereoisomers of (4Z,7Z,10Z,12E,16Z,18E)‑14,20-Dihydroxy-4,7,10,12,16,18-docosahexaenoic Acid and Their Anti-inflammatory Activities
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