Highly efficient and scalable total syntheses and stereochemical assignment of potent anti-inflammatory pesimquinolones I and J

Abstract

Based on the goals of sustainability and environmentally conscious science, great progress has been made in the field of green chemical synthesis, but a synthesis that combines high levels of step economy with high levels of efficiency and scalability has remained elusive. In this research, highly efficient and scalable total synthesis of potent anti-inflammatory pesimquinolone I (1) with a unique 6/6/6/6 tetracyclic core was accomplished starting from 2-bromoresorcinol and (1S,4R)-menthadienol in 5 steps. The approach adheres to the ideality principle, and the concepts of atom, step and redox economy, green chemistry, selectivity, and protecting group-free syntheses have been introduced. The synthetic strategy relies on a Lewis acid catalyzed Friedel–Crafts alkylation to form the tricyclic intermediate, a regioselective insertion of arynes into unsymmetric imides and a diastereoselective aldol cyclization to construct the tetracyclic skeleton. Syntheses and stereochemical assignment of the stereoisomer of pesimquinolone I and its analogues (15–19) were also accomplished. Compound 18 showed potent NO inhibitory effects with an IC₅₀ value of 0.44 μM, which was stronger than that of the positive control (indomethacin, IC₅₀ = 50.00 μM), and thus represents a potentially promising lead for anti-inflammatory drug discovery.