Ring Expansion Approach to Roseophilin

Roseophilin is an ansa-bridged potent cytotoxic compound that has generated continual interest from synthetic chemists since its discovery in 1992. As a synthetic target, roseophilin's most difficult challenge is the construction of the eight-carbon ansa chain that bridges the azafulvene unit. Such features traditionally have been installed via some form of macrocyclization reaction. Macrocyclization reactions typically require high dilution conditions that limit their utility on a preparative scale. This is especially true of entropically constrained systems such as roseophilin's core. Herein, we report an efficient and potentially scalable synthesis of a cyclopentenone-fused pyrrolophane, which serves as a model for the tricyclic core of roseophilin. The synthetic scheme features a palladium-catalyzed annulation and oxidative cleavage sequence to provide a macrocyclic keto-ester. Modified Paal-Knorr pyrrole synthesis and Friedel-Crafts acylation complete the pyrrolophane model system. Elaboration of the scheme, which avoids macrocyclization reactions, may facilitate large-scale prodution of roseophilin and analogs in due course.