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.
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. 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).
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Goto
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Urabe
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Masuda
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|§Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Isobe
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.|§Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: †Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D000480:Alkynes / Q000737:chemistry*; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry; D001688:Biological Products / Q000737:chemistry*; D004281:Docosahexaenoic Acids / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D000475:Alkenes; D000480:Alkynes; D000893:Anti-Inflammatory Agents; D001688:Biological Products; D004281:Docosahexaenoic Acids