Total Synthesis of (+)-Herpotrichones A–C

Epoxyquinoids herpotrichones A-C exhibit unique 6/6/6/6/3 pentacyclic frameworks and potent neuroprotective effects. Inspired by their proposed biosynthetic origins, we completed a total synthesis of herpotrichones A-C by devising a <i>de novo</i> synthesis of epoxyquinol monomer and leveraging a key Diels-Alder (DA) reaction between epoxyquinol monomer-based dienophiles and delitpyrone C-derived dienes. DFT calculations anticipated competing pathways, including homodimerization and regio- and stereoisomers formation, necessitating precise control over reaction selectivity during the key DA reaction. We discovered that the C2' hydroxyl configuration of delitpyrone C is critical in directing the desired DA reaction, with hydrogen bonding playing a decisive role in product formation. This strategy enabled synthetic access to the herpotrichone core and facilitated the first total synthesis of all known herpotrichones.