Cp∗Rh(III)-catalyzed enantioselective C(sp3)–H amidation of azine-linked cyclobutanes

Abstract

The highly enantioselective desymmetrizing C(sp³)–H amidation of azine-linked cyclobutanes with dioxazolones to afford enantioenriched cis-configured amido-substituted pyrimidylcyclobutane scaffolds is described. The reaction is catalyzed by an electron-deficient Cp∗Rh(III) complex in combination with a novel axially chiral carboxylic acid that was found to be key to obtaining high levels of enantiocontrol. Computational studies using density functional theory calculations revealed the presence of multiple non-covalent interactions, including inter- and intramolecular n-π∗ interactions and CH-π interactions, and that enhanced steric repulsion in the transition state structure leading to the minor enantiomer controls the enantioselectivity. The methodology was found to be broad in scope with respect to the dioxazolone and could be further extended to larger cycloalkyl ring systems as well as bis-amidated pyrimidylcyclobutane derivatives.