A Remarkable Influence of La(III)/<i>N,N</i>′-Dioxide Structure on Asymmetric Formal Substitution of 3-Bromo-3-substituted Oxindoles with TMSCN

Abstract

The structural elucidation of chiral rare-earth-based catalysts in asymmetric reactions holds significant importance as it is crucial for comprehending their operational mechanisms and for broadening their applications in the realm of asymmetric synthesis. Herein, a LaIII/(L3-RaMe3)2 complex was identified to be more active and enantioselective than LaIII/L3-RaMe3 in the asymmetric formal substitution of racemic 3-bromo-3-substituted oxindoles with TMSCN. The experimental studies and theoretical calculations disclosed that the partial dissociation of the chiral N,N′-dioxide ligand was involved in the catalytic process with LaIII/(L3-RaMe3)2. These insights provided a rationale for the remarkable effect of catalyst structures on the results and nonlinear effect observed in the current reaction system. This protocol offers a straightforward and efficient pathway to synthesize various chiral 3-cyano-3-substituted oxindoles (53 examples, up to 99% yield, 98% ee). In addition, the synthesis of a bioactive compound CRTH2 receptor antagonist and obvious inhibitory effect of several products on the viability of cancer cells demonstrate the potential utility of this methodology.