Construction of C-N Atropisomers by Aminocatalytic Enantioselective Addition of Indole-2-carboxaldehydes to o-Quinone Derivatives

The first atroposelective aminocatalytic methodology for the construction of C-N atropisomers is presented. The synthesis of this class of axially chiral molecules typically encompasses substrates in which the C-N bond is pre-formed. In contrast, this work presents the direct coupling of indole-2-carboxaldehydes to ortho-quinones, to form the stereogenic C-N axis in an atroposelective way. Application of typical secondary amine catalysts furnished the desired product, however, in low yields and as a complex mixture arising from poor regiocontrol among the C-3- and N-1-sites of the indole core. A new aminocatalyst was designed and synthesized with increased outer-sphere steric bulk to address these challenges thereby providing good levels of regio- and enantioselectivity. A novel library of functionalized and enantioenriched C-N atropisomers was obtained and their synthetic utility was demonstrated by various transformations.

Automated summary

The first atroposelective aminocatalytic methodology for the construction of C-N atropisomers is described. By directly coupling indole-2-carboxaldehydes to ortho-quinones, a new library of functionalized and enantioenriched C-N atropisomers was obtained using a designed and synthesized aminocatalyst. The synthetic utility of these atropisomers was demonstrated through various transformations.