First Total Synthesis Of Phytoprostanes With Prostaglandin-Like Configuration, Evidence For Their Formation In Edible Vegetable Oils And Orienting Study Of Their Biological Activity

Phytoprostanes (PhytoP) are natural products, which form in plants under oxidative stress conditions from alpha-linolenic acid. However, their epimers with relative prostaglandin configuration termed phytoglandins (PhytoG) have never been detected in Nature, likely because of the lack of synthetic reference material. Here, the first asymmetric total synthesis of such compounds, namely of PhytoGF(1 alpha) (9-epi-16-F-1t-PhytoP) and its diastereomer ent-16-epi-PhytoGF(1 alpha) (ent-9,16-diepi-16-F-1t-PhytoP), has been accomplished. The synthetic strategy is based on radical anion oxidative cyclization, copper(I)-mediated alkyl-alkyl coupling and enantioselective reduction reactions. A UHPLC-MS/MS study using the synthesized compounds as standards indicates PhytoG formation at significant levels during autoxidation of alpha-linolenic acid in edible vegetable oils. Initial testing of synthetic PhytoGs together with F-1-PhytoP and 15-F-2t-IsoP derivatives for potential interactions with the PGF(2 alpha) (FP) receptor did not reveal significant activity. The notion that PUFA-derived oxidatively formed cyclic metabolites with prostaglandin configuration do not form to a significant extent in biological or food matrices has to be corrected. Strong evidence is provided that oxidatively formed PhytoG metabolites may be ingested with plant-derived food, which necessitates further investigation of their biological profile.