Bio-inspired Step-Economical, Redox-Economical and Protecting-Group-Free Enantioselective Total Syntheses of (-)-Chaetominine and Analogues

Full details of the enantioselective four-step and five-step total syntheses of (-)-chaetominine from D-Trp and L-Trp are described. Featuring an oxidative double cyclization reaction, and tandem C14 epimerization-lactamization reactions as key steps, the method provides a rapid access to (-)-chaetominine (6a) and analogues. The total syntheses of (-)-chaetominine (6a) are so far the most concise and efficient. Through comprehensive investigation, the stereochemical requirements for the double cyclization reaction were revealed, and the confusion regarding physicochemical properties of this natural product was clarified. Moreover, short pathways to complexity generation, a scenarios revealed for the biosynthesis of fungal peptidyl alkaloid multi-cyclic scaffolds, have been validated through the chemical synthesis. On the basis of these findings, a plausible biosynthetic pathway for (-)-chaetominine (6a) was suggested.