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

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Synthesis of 14 S,21 R - and 14 S,21 S -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 14 R / S and 21 R chirality. Kinetic resolution using Sharpless asymmetric epoxidation of the TBS-deprotected allylic alcohol with l -(+)-DIPT/Ti(O- i -Pr) 4 afforded 14 S -epoxy alcohol and 14 R -allylic alcohol with >99% diastereomeric excess (de) for both. The CN group was introduced to the epoxy alcohol by reaction with Et 2 AlCN. The 14 R -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 14 S,21 R -diHDHA. Similarly, ethyl ( S )-lactate (>99% ee) was converted to 14 S,21 S -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.