Scalable Synthesis of β-Lactamase Inhibitor QPX7728 by Sequential Nickel-Catalyzed Boron Insertion into a Benzofuran Substrate and Enantioselective Cyclopropanation of the Resulting Vinylboronate
Serge H. Boyer, Ángela González-de-Castro, J.A. Hubertus Dielemans, Laurent Lefort, Zuolin Zhu, Matthias Gnahn, Julia Schörghuber, Stefan Steinhofer, André H. M. de Vries, Scott J. Hecker
Abstract
We report the scalable, high-yielding, and highly selective synthesis of the β-lactamase inhibitor QPX7728 featuring two key synthetic steps: nickel-catalyzed boron insertion of benzofuran 1 followed by enantioselective cyclopropanation of the resulting cyclic vinylboronate 2. The identification of the key reagents (catalyst and chiral auxiliary) for both steps relied on the use of high-throughput experimentation. Further optimization allowed for the cost-effective and scalable production of QPX7728.
Topics & Concepts
CyclopropanationEnantioselective synthesisBenzofuranNickelCatalysisReagentCombinatorial chemistrySubstrate (aquarium)BoronChemistryOrganic chemistryBiologyEcologyCyclopropane Reaction MechanismsAsymmetric Hydrogenation and CatalysisAsymmetric Synthesis and Catalysis