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

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.