Docosahexaenoic acid (DHA) is an important omega-3 polyunsaturated fatty acid that is oxidized by lipoxygenase enzymes into several epoxide intermediates, that are subsequently converted into hydroxylated specialized pro-resolvin lipid mediators (SPMs), including the Maresins, the Protectins, and the D-series Resolvins. Extensive investigations of the biological actions of SPMs have established their key roles in promoting the resolution of inflammation. The DHA-derived epoxides were recently found to have an additional important role, which involves their conversion into bioactive sulfidoconjugate derivatives that promote tissue regeneration, that leads to restoration of homeostasis. Several series of sulfidoconjugates are generated via enzyme-mediated opening of the DHA epoxides with the cysteine moiety of glutathione and related cysteinyl derivatives. These include the Maresin Conjugates in Tissue Regeneration (MCTRs), the corresponding sulfidoconjugates from Protectins (PCTRs), and the analogous sulfidoconjugates obtained from Resolvins (RCTRs). Herein, we will present our stereocontrolled methodologies for the total synthesis of stereochemically pure MCTRs, as well as RCTRs from the RvD3/RvD4 series Resolvins. Our approach involves the stereocontrolled total synthesis of the corresponding epoxide intermediates, followed by epoxide opening with glutathione and related cysteinyl derivatives. We will also present our synthesis of isotopically labelled sulfidoconjugates, which help to enable analytical efforts with these types of bioactive compounds.

Total synthesis of DHA-derived epoxides and their tissue regenerative sulfido-conjugates

2019 Fall National Meeting

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