Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids

Keita Nishimura, Tsuyoshi Sakaguchi, Yutaro Nanba, Yuta Suganuma, Masao Morita, Song Hong, Yan Lu, Bokkyoo Jun, Nicolas G. Bazan, Makoto Arita, Yuichi Kobayashi

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5 Citations (Scopus)

Abstract

Synthesis of 14S,21R- and 14S,21S-dihydroxy-DHA (diHDHA) among the four possible stereoisomers of 14,21-diHDHA was studied. Methyl (R)-lactate (>97% ee), selected as a C20-C22 fragment (DHA numbering), was converted to the C17-C22 phosphonium salt, which was subjected to a Wittig reaction with racemic C16-aldehyde of the C12-C16 part with the TMS and TBS-oxy groups at C12 and C14, yielding the C12-C22 derivative with 14R/S and 21R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l-(+)-DIPT/Ti(O-i-Pr)4 afforded 14S-epoxy alcohol and 14R-allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et2AlCN. The 14R-allylic alcohol was also converted to the nitrile via Mitsunobu inversion. Reduction of the nitrile with DIBAL afforded the key aldehyde corresponding to the C11-C22 moiety. The Wittig reaction of this aldehyde with a phosphonium salt of the remaining C1-C10 part followed by functional group manipulation gave 14S,21R-diHDHA. Similarly, ethyl (S)-lactate (>99% ee) was converted to 14S,21S-diHDHA. The chiral LC-UV-MS/MS analysis demonstrated that each of these two 14,21-diHDHAs synthesized using the presented total organic synthesis was highly stereoselective and identical to the macrophage-produced counterpart.

Original languageEnglish
Pages (from-to)154-166
Number of pages13
JournalJournal of Organic Chemistry
Volume83
Issue number1
DOIs
Publication statusPublished - 2018 Jan 5

ASJC Scopus subject areas

  • Organic Chemistry

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    Nishimura, K., Sakaguchi, T., Nanba, Y., Suganuma, Y., Morita, M., Hong, S., Lu, Y., Jun, B., Bazan, N. G., Arita, M., & Kobayashi, Y. (2018). Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids. Journal of Organic Chemistry, 83(1), 154-166. https://doi.org/10.1021/acs.joc.7b02510