Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid that is oxidized by different lipoxygenases to form stereospecific epoxide intermediates. Enzymatic hydrolysis of DHA-derived epoxides results in the formation of specialized pro-resolving mediators (SPM), including resolvins, maresins and protectins. We have previously developed synthetic methodologies for the total synthesis of SPM, that were found to promote the resolution of inflammation in various tissues, and to also promote tissue regeneration. Herein, we will report the stereo-controlled total synthesis of Resolvin D6 (RvD6), which was discovered previously. Notably, it was proposed that the biosynthesis of RvD6 does not involve a reactive epoxide intermediate. In recent studies, one of the other three isomers of RvD6 was found to have a uniquely elevated pro-resolving properties, than the other natural isomers. RvD6 has two stereocenters, with the natural isomer having (4S, 17S) configuration. Hence, we have pursued the total synthesis of each of the unnatural isomers, with the goal of identifying the isomer of interest. We will present our novel approach to the total synthesis of the natural and unnatural isomers of RvD6, an to synthesize stereochemically pure RvD6 isomers. Our approach is rigorously stereocontrolled using various sets of stereoselective and stereospecific synthetic methodologies. Overall, we will discuss the RvD6 isomers with the goal of identifying the isomer of interest as well as its use in biological investigations.

Asymmetric total synthesis of resolvin D6 and its stereoisomers

ACS Fall 2020 Virtual Meeting

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