Total Synthesis of Ophiorrhine A, G and Ophiorrhiside E Featuring a Bioinspired Intramolecular Diels-Alder Cycloaddition.

We report the first total synthesis of the monoterpene indole alkaloids ophiorrhine A via a late stage bioinspired intramolecular Diels-Alder cycloaddition to form the intricate bridged and spirannic polycyclic system. Several strategies were investigated to construct the indolopyridone moiety of ophiorrhiside E, the postulated biosynthetic precursor of ophiorrhine A. Eventually, the Friedel-Crafts-type coupling of N-methyl indolyl-acetamide with a secologanin-derived acid chloride delivered ophiorrhine G. Cyclodehydration of a protected form of the latter was followed by the desired spontaneous intramolecular Diels-Alder cycloaddition of protected ophiorrhiside E leading to ophiorrhine A.