Cystic fibrosis is a debilitating genetic disease resulting from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), an anion channel that modulates epithelial hydration of the lungs and other organs. Treatment of this disease relies on the use of combinations of potentiator drugs which restore function to inactivated receptors and small molecule correctors that stabilize defective proteins to enable normal trafficking and prevent degradation. We have investigated a series of trisubstituted cyclopropanes that show promise as CFTR correctors. Rhodium-catalyzed reactions of donor-acceptor carbenes represent the most general approach to these stereochemically complex structures, however we encountered limitations with the existing methods when applied to heteroaryl substrates that led us to further investigate these reactions. Through a collaborative academic-industry partnership with Prof. Huw Davies lab at Emory University, we discovered surprising new conditions that enable highly enantioselective cyclopropanation reactions for a broad scope of heterocyclic substrates. The seminar will describe the discovery of a novel class of CFTR correctors and the new synthetic methods that were developed and applied to their stereoselective synthesis.
Mike Schrimpf (AbbVie)