Unified total synthesis of the limonoid alkaloids: Strategies for the de novo synthesis of highly substituted pyridine scaffolds

Abstract

Highly substituted pyridine scaffolds are found in many biologically active natural products and therapeutics. Accordingly, numerous complementary de novo approaches to obtain differentially substituted pyridines have been disclosed. This article delineates the evolution of the synthetic strategies designed to assemble the demanding tetrasubstituted pyridine core present in the limonoid alkaloids isolated from Xylocarpus granatum, including xylogranatopyridine B, granatumine A and related congeners. In addition, NMR calculations suggested structural misassignment of several limonoid alkaloids, and predicted their C3-epimers as the correct structures, which was further validated unequivocally through chemical synthesis. The materials produced in this study were evaluated for cytotoxicity, anti-oxidant effects, anti-inflammatory action, PTP1B and Nlrp3 inflammasome inhibition, which led to compelling anti-inflammatory activity and anti-oxidant effects being discovered.