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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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

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Docosahexaenoic Acids
Macrophages
Aldehydes
Nitriles
Lactic Acid
Salts
Alcohols
Stereoisomerism
Epoxidation
Chirality
Functional groups
Derivatives
Kinetics
allyl alcohol

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Nishimura, K., Sakaguchi, T., Nanba, Y., Suganuma, Y., Morita, M., Hong, S., ... 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

Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids. / Nishimura, Keita; Sakaguchi, Tsuyoshi; Nanba, Yutaro; Suganuma, Yuta; Morita, Masao; Hong, Song; Lu, Yan; Jun, Bokkyoo; Bazan, Nicolas G.; Arita, Makoto; Kobayashi, Yuichi.

In: Journal of Organic Chemistry, Vol. 83, No. 1, 05.01.2018, p. 154-166.

Research output: Contribution to journalArticle

Nishimura, K, Sakaguchi, T, Nanba, Y, Suganuma, Y, Morita, M, Hong, S, Lu, Y, Jun, B, Bazan, NG, Arita, M & Kobayashi, Y 2018, 'Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids', Journal of Organic Chemistry, vol. 83, no. 1, pp. 154-166. https://doi.org/10.1021/acs.joc.7b02510
Nishimura, Keita ; Sakaguchi, Tsuyoshi ; Nanba, Yutaro ; Suganuma, Yuta ; Morita, Masao ; Hong, Song ; Lu, Yan ; Jun, Bokkyoo ; Bazan, Nicolas G. ; Arita, Makoto ; Kobayashi, Yuichi. / Stereoselective Total Synthesis of Macrophage-Produced Prohealing 14,21-Dihydroxy Docosahexaenoic Acids. In: Journal of Organic Chemistry. 2018 ; Vol. 83, No. 1. pp. 154-166.
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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.",
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AU - Nishimura, Keita

AU - Sakaguchi, Tsuyoshi

AU - Nanba, Yutaro

AU - Suganuma, Yuta

AU - Morita, Masao

AU - Hong, Song

AU - Lu, Yan

AU - Jun, Bokkyoo

AU - Bazan, Nicolas G.

AU - Arita, Makoto

AU - Kobayashi, Yuichi

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N2 - 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.

AB - 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.

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