Stereoselective Synthesis, Configurational Assignment and Biological Evaluations of the Lipid Mediator RvD2n‐3 DPA

• Published in: Chemistry : a European journal 2022-02, Vol.28 (7), p.e202103857-n/a
• Main Authors: Reinertsen, Amalie F., Primdahl, Karoline G., De Matteis, Roberta, Dalli, Jesmond, Hansen, Trond V.
• Format: Article
• Language: English
• Subjects: Alkynes; Chemical reactions; Chemistry; Chromophores; Cross coupling; Fatty acids; Lipids; Macrophages; n-3 docosapentaenoic acid; Omega-3 fatty acids; Reduction; resolution of bacterial infection and inflammation; resolvins; RvD2n-3 DPA; specialized pro-resolving mediators; Stereoselectivity; Synthesis
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202103857

Herein we report the first total synthesis of RvD2n‐3 DPA, an endogenously formed mediator biosynthesized from the omega‐3 fatty acid n‐3 docosapentaenoic acid. The key steps are the Midland Alpine borane reduction, Sonogashira cross‐coupling reactions, and a Z‐selective alkyne reduction protocol, yielding RvD2n‐3 DPA methyl ester in 13 % yield over 12 steps (longest linear sequence). The physical property data (UV chromophore, chromatography and MS/MS fragmentation) of the synthetic lipid mediator matched those obtained from biologically produced material. Moreover, synthetic RvD2n‐3 DPA also carried the potent biological activities of enhancing macrophage uptake of Staphylococcus aureus and zymosan A bioparticles. RvD2n‐3 DPA, a specialized pro‐resolving mediator, is synthesized for the first time based on the retrosynthetic outline depicted, enabling its structural elucidation and biological evaluations against S. aureus and zymosan A induced inflammation.