Academic-Industrial Collaboration in Synthesis with Real-Time Impact in Medicinal Chemistry: Discovery of Cystic Fibrosis C2 Corrector ABBV-602.

This article highlights synergistic real-time interactions between academic and industrial groups that drove innovations in both medicinal chemistry and catalysis. An AbbVie medicinal chemistry team had identified a promising series of trisubstituted cyclopropanes during a drug discovery campaign focused on developing CFTR C2 correctors for the treatment of cystic fibrosis. However, this unique chemical space was challenging to efficiently explore due to known limitations with previously established cyclopropanation reaction conditions. By expanding upon an existing precompetitive relationship with the Davies group at Emory University who are pioneers in development of methods for highly diastereo- and enantioselective cyclopropanations, a joint industry-academia team collaborated to discover a unique catalyst-additive system for this challenging transformation that had a broad and pharmaceutically relevant substrate scope. The optimized method was immediately applied to accelerate medicinal chemistry progress in the series, leading to the identification of novel CFTR corrector ABBV-602. Finally, a flow procedure was developed for generating the carbene precursor which enabled the reaction to be carried out on kilogram scale.