(4+3) Cycloaddition of Pyrroles and its Application to the Synthesis of Class II Galbulimima Alkaloids

Abstract

The (4+3) cycloaddition is a convergent reaction to assemble seven-membered rings.[1] However, the majority of these reactions engage furan as it is the most reactive diene. Pyrroles, on the other hand, are much less used.[2] This is because of the challenges to synthesize substituted pyrroles, as well as their reactivity—instead of undergoing cycloaddition which results in their dearomatization, they often undergo bond formation and terminate to yield Friedel-Crafts products instead. We have found that activated epoxy enolsilanes undergo intramolecular (4+3) cycloaddition readily with pyrroles of a variety of electronic demands.[3] Furthermore, the reaction is directed by the stereochemistry of the epoxide, so that optically-enriched aza-bridged cycloadducts can be obtained. Interestingly, this is also the first intramolecular (4+3) cycloaddition of pyrroles that was able to generate seven-membered carbocycles. To demonstrate the scope and functional group compatibility of this cycloaddition, we have successfully applied this reaction as a key step in the asymmetric synthesis of the pentacyclic core structure common to all of the Class II galbulimima alkaloids.