Asymmetric Cobalt Catalysis for the Construction of Quaternary Stereogenic Centers with Fluorine Atoms

Abstract

The advancement of robust synthetic methodologies for generating fluorinated quaternary carbon chiral centers is highly sought after in the fields of organic and medicinal chemistry. This study successfully provides such compounds through cobalt-catalyzed asymmetric Negishi coupling reactions of α-bromo-α-fluoro ketones with aryl/alkenyl zinc reagents. The adjustment of chiral unsymmetric N,N,N-tridentate (CUT) ligands played a key role in improving reactivity and selectivity in the cobalt catalysis, preventing the formation of hydrodebromination byproducts, and accommodating sterically hindered substrates and heterocycles. Control and kinetic experiments reveal that transmetalation serves as the rate-limiting step, a mechanistic characteristic that sets the newly developed asymmetric cobalt-catalyzed cross-couplings apart from previous methodologies.