Organocatalytic Enantioselective Construction of Pyramidalized N–N Atropisomers

Comprehensive Summary The catalytic asymmetric synthesis of compounds exhibiting axial chirality has been extensively investigated over the past two decades and is now considered a mature area of research. In contrast, the construction of unplanarized atropisomeric scaffolds remains challenging due to their inherent configurational lability. Herein, we report a chiral phosphoric acid‐catalyzed atroposelective Paal−Knorr reaction of N ‐aminoindolines with 1,4‐diketones, enabling the construction of a new class of pyramidalized N–N atropisomers with high levels of stereoselectivities. A broad range of molecular motifs could be incorporated into this class of atropisomers, and the combination of scalable reaction with versatile post‐synthetic modifications demonstrates the generality and robustness of the protocol. Single‐crystal X‐ray diffraction revealed the pyramidal nitrogen adopts a geometry between sp 3 ‐ and sp 2 ‐hybridized states, while density functional theory calculations indicate that N–N axial chirality, rather than nitrogen‐centered chirality, is the predominant stereogenic element. Preliminary biological evaluations indicated that several of these N–N axially chiral N ‐pyrrolylindolines exhibit promising inhibitory activity against tumor‐cell proliferation. It is anticipated that this study will stimulate further development of novel axially chiral scaffolds.