Stereocontrolled cyclization of inherently chiral medium-sized rings

Asymmetric catalysis evolved as an elegant, efficient and sustainable approach for the synthesis of a multitude of chiral molecules.1 However, imparting high levels of stereocontrol in the synthesis of complex forms of chirality remains a significant challenge, particularly when the known synthetic routes to the target compounds are very few and use harsh conditions. Medium-sized rings which display inherent chirality often exhibit attractive properties for drug development;2-5 yet, they suffer from synthetic limitations due to challenging cyclization steps that form the strained ring. In fact, no enantioselective cyclization method is known for inherently chiral seven-membered rings which lack local stereogenic elements. In this work, we present an enantioselective organocatalytic strategy to construct seven- and eight-membered rings featuring inherent chirality under mild conditions and with high levels of stereocontrol. Notably, the same iminophosphorane chiral catalyst orchestrates the cyclization of substrates of two different ring sizes, and under two different mechanistic paradigms. Our results provide an entry into enantioenriched, congested medium-sized rings that feature high configurational stability. We believe that the strategy of this work, relying on catalyst control for enantioselective cyclization, could be adapted to other ring-forming reactions that are presently challenging or unattainable. The ring size versatility and mechanistic generality of the catalysis offer an important precedent to further study the features that may enable broad success of these catalysis concepts to broader cyclization platforms.