Unusual meroterpenoids suggests an unprecedent cascade of Diels-Alder reactions in their biosynthesis

In nature, cascade reactions are used to produce specialised metabolites with highly complex architectures in just a few steps. Understanding their mechanisms paves the way for synthesising a wide variety of innovative three-dimensional structures. In this study, we present the targeted isolation of litseifolins A-C, meroterpenoids with an unusual 6/6/5/6 tetracyclic skeleton and up to five asymmetric centres. We propose a plausible biosynthetic pathway, supported by DFT calculations and experimental synthetic evidence. The study culminated in the biomimetic synthesis of litseifolins A-C under mild conditions. This process started with the putative biosynthetic precursor and involved an original intermolecular Diels-Alder/IMHDA cascade followed by dehydration. This study highlights the importance of combining computational and synthetic approaches for elucidating biosynthesis.