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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• 作者：Tomomi Goto ; Daisuke Urabe ; Koji Masuda ; Yosuke Isobe ; Makoto Arita ; Masayuki Inoue
• 刊名：Journal of Organic Chemistry
• 出版年：2015
• 出版时间：August 7, 2015
• 年：2015
• 卷：80
• 期：15
• 页码：7713-7726
• 全文大小：749K
• ISSN：1520-6904

文摘

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 S_N2 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).