Organocatalytic Enantioselective Construction of Pyramidalized N–N Atropisomers

Abstract

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 sp³- and sp²-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.