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

• Published in: Journal of organic chemistry 2018-01, Vol.83 (1), p.154-166
• Main Authors: Nishimura, Keita, Sakaguchi, Tsuyoshi, Nanba, Yutaro, Suganuma, Yuta, Morita, Masao, Hong, Song, Lu, Yan, Jun, Bokkyoo, Bazan, Nicolas G, Arita, Makoto, Kobayashi, Yuichi
• Format: Article
• Language: English
• Subjects: Medicin och hälsovetenskap
• ISSN: 0022-3263; 1520-6904; 1520-6904
• DOI: 10.1021/acs.joc.7b02510

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.