Cascade Syntheses Routes to the Centrocountins

Cascade and domino reactions that proceed through multiple steps in one pot and include multiple bond formations are promising methods for the rapid and efficient generation of complex molecular architectures, including the scaffolds of classes of complex natural product. We describe the development of various one-pot cascade reaction sequences to yield centrocountins, which are tetracyclic indole derivatives with the basic scaffold of numerous polycyclic alkaloids. The mechanistic investigation of a sequence employing readily available alkynes and 3-formylchromones as starting materials provided evidence that this one-pot synthesis proceeds through at least twelve consecutive transformations and includes at least nine different chemical reactions, making it the longest cascade reaction sequence known to date. We describe the scope and limitations of the cascade synthesis approaches and the development of an enantioselectively catalyzed centrocountin synthesis.