Catalytic Atroposelective aza-Grob Fragmentation: An Approach toward Axially Chiral Biarylnitriles

Abstract

Grob fragmentation is a powerful synthetic tool for cleaving C–C bonds, which was particularly useful in the construction of seven- to nine-membered carbocycles or heterocycles. This reaction typically breaks one C–C bond and one C–X bond and forms two unsaturated functional groups. As no stereogenic centers are generated, catalytic asymmetric Grob fragmentation has remained unexplored. In this study, we have successfully developed a catalytic asymmetric aza-Grob fragmentation of α-keto oxime esters, achieving atroposelective C–C bond cleavage to construct axially chiral biarylnitriles. Single-crystal X-ray diffraction analysis of oxime esters elucidated the structure–reactivity relationship, highlighting the role of torsional strain. These studies also revealed the unique role of the 2-phenyl benzoyl group in controlling the substrate conformation, tuning reactivity, and stereoselectivity. The ¹H NMR titration experiments provided brief insights into the activation mode of the catalyst with the substrate, suggesting a multi-hydrogen-bonding interaction model.