Total synthesis of four stereoisomers of (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid and their anti-inflammatory activities

Tomomi Goto, Daisuke Urabe, Yosuke Isobe, Makoto Arita, Masayuki Inoue

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The four stereoisomers of novel lipid mediator 1, (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid, were synthesized from six simple fragments. Triyne 2 was convergently assembled through three SN2 alkynylation reactions and one Sonogashira coupling reaction. Two of the three alkynes of 2 were hydrogenated using Lindlar catalyst, while the third alkyne was reduced through formation of the alkyne-dicobalt hexacarbonyl complex and subsequent reductive decomplexation, producing the requisite tetraene structure in a stereoselective manner. Next, a two-step functional group manipulation at C1, followed by simultaneous deprotection and epoxide formation, gave rise to the four isomers, (12S,17R,18S)-1aa, (12S,17S,18R)-1ab, (12R,17R,18S)-1ba and (12R,17S,18R)-1bb. The present work allowed determination of the absolute structure of naturally occurring 1 to be 1aa and 1ab, as well as biological evaluation of the two natural (1aa, 1ab) and two unnatural (1ba, 1bb) isomers. Intriguingly, natural 1aa and unnatural 1ba were found to exhibit more potent anti-inflammatory activities than 1ab and 1bb, indicating the greater importance of the stereochemistry of the C17,18-epoxide compared to that of the C12-hydroxy group.

Original languageEnglish
Pages (from-to)8320-8332
Number of pages13
JournalTetrahedron
Volume71
Issue number43
DOIs
Publication statusPublished - 2015 Oct 28
Externally publishedYes

Fingerprint

Arachidonic Acids
Stereoisomerism
Alkynes
Anti-Inflammatory Agents
Epoxy Compounds
Isomers
Stereochemistry
Functional groups
Lipids
Catalysts

Keywords

  • Convergent strategy
  • Eicosapentaenoic acid
  • Lipid mediators
  • Reduction
  • Total synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

Total synthesis of four stereoisomers of (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid and their anti-inflammatory activities. / Goto, Tomomi; Urabe, Daisuke; Isobe, Yosuke; Arita, Makoto; Inoue, Masayuki.

In: Tetrahedron, Vol. 71, No. 43, 28.10.2015, p. 8320-8332.

Research output: Contribution to journalArticle

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abstract = "The four stereoisomers of novel lipid mediator 1, (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid, were synthesized from six simple fragments. Triyne 2 was convergently assembled through three SN2 alkynylation reactions and one Sonogashira coupling reaction. Two of the three alkynes of 2 were hydrogenated using Lindlar catalyst, while the third alkyne was reduced through formation of the alkyne-dicobalt hexacarbonyl complex and subsequent reductive decomplexation, producing the requisite tetraene structure in a stereoselective manner. Next, a two-step functional group manipulation at C1, followed by simultaneous deprotection and epoxide formation, gave rise to the four isomers, (12S,17R,18S)-1aa, (12S,17S,18R)-1ab, (12R,17R,18S)-1ba and (12R,17S,18R)-1bb. The present work allowed determination of the absolute structure of naturally occurring 1 to be 1aa and 1ab, as well as biological evaluation of the two natural (1aa, 1ab) and two unnatural (1ba, 1bb) isomers. Intriguingly, natural 1aa and unnatural 1ba were found to exhibit more potent anti-inflammatory activities than 1ab and 1bb, indicating the greater importance of the stereochemistry of the C17,18-epoxide compared to that of the C12-hydroxy group.",
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AU - Arita, Makoto

AU - Inoue, Masayuki

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N2 - The four stereoisomers of novel lipid mediator 1, (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid, were synthesized from six simple fragments. Triyne 2 was convergently assembled through three SN2 alkynylation reactions and one Sonogashira coupling reaction. Two of the three alkynes of 2 were hydrogenated using Lindlar catalyst, while the third alkyne was reduced through formation of the alkyne-dicobalt hexacarbonyl complex and subsequent reductive decomplexation, producing the requisite tetraene structure in a stereoselective manner. Next, a two-step functional group manipulation at C1, followed by simultaneous deprotection and epoxide formation, gave rise to the four isomers, (12S,17R,18S)-1aa, (12S,17S,18R)-1ab, (12R,17R,18S)-1ba and (12R,17S,18R)-1bb. The present work allowed determination of the absolute structure of naturally occurring 1 to be 1aa and 1ab, as well as biological evaluation of the two natural (1aa, 1ab) and two unnatural (1ba, 1bb) isomers. Intriguingly, natural 1aa and unnatural 1ba were found to exhibit more potent anti-inflammatory activities than 1ab and 1bb, indicating the greater importance of the stereochemistry of the C17,18-epoxide compared to that of the C12-hydroxy group.

AB - The four stereoisomers of novel lipid mediator 1, (5Z,8Z,10E,14Z)-12-hydroxy-17,18-epoxy-5,8,10,14-eicosatetraenoic acid, were synthesized from six simple fragments. Triyne 2 was convergently assembled through three SN2 alkynylation reactions and one Sonogashira coupling reaction. Two of the three alkynes of 2 were hydrogenated using Lindlar catalyst, while the third alkyne was reduced through formation of the alkyne-dicobalt hexacarbonyl complex and subsequent reductive decomplexation, producing the requisite tetraene structure in a stereoselective manner. Next, a two-step functional group manipulation at C1, followed by simultaneous deprotection and epoxide formation, gave rise to the four isomers, (12S,17R,18S)-1aa, (12S,17S,18R)-1ab, (12R,17R,18S)-1ba and (12R,17S,18R)-1bb. The present work allowed determination of the absolute structure of naturally occurring 1 to be 1aa and 1ab, as well as biological evaluation of the two natural (1aa, 1ab) and two unnatural (1ba, 1bb) isomers. Intriguingly, natural 1aa and unnatural 1ba were found to exhibit more potent anti-inflammatory activities than 1ab and 1bb, indicating the greater importance of the stereochemistry of the C17,18-epoxide compared to that of the C12-hydroxy group.

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