Session: Heterocycles & Aromatics:

The synthesis of medium-sized heterocycles serves as an attractive yet challenging synthetic target in drug design. The structural rigidity and complexity of these molecules make them exceptional drug candidates; however, their synthesis often relies on precious metal catalysis or lengthy, and thereby costly, starting material preparation. Iron is the second most abundant metal in the Earth’s crust and has the potential to enjoy the high performance of traditional rhodium catalysis while incorporating greener synthetic strategies. Likewise, a cascade-based approach negates the need for long, linear synthetic strategies to target these valuable scaffolds.
To address this problem, we have developed favorable conditions to embark on the challenge of invoking iron carbenes for the synthesis of medium-sized heterocycles. This work features a carbene O–H insertion followed by an intramolecular aldol cyclization to provide substituted tetrahydrofuran intermediates. These intermediate can undergo an additional oxy-Cope rearrangement to provide functionalized 9-membered oxacycles with high distereoselectivity. This work provides access to valuable heterocyclic motifs, found abundantly in bioactive natural product cores, while incorporating three synthetic steps in one pot.

Indrajeet Sharma

Appearances