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

• Published in: Chemistry : a European journal 2022-10, Vol.28 (60), p.e202202395-n/a
• Main Authors: Corti, Vasco, Thøgersen, Mathias Kirk, Enemærke, Valdemar Juel, Rezayee, Nomaan M., Barløse, Casper L., Anker Jørgensen, Karl
• Format: Article
• Language: English
• Subjects: asymmetric catalysis; atropisomerism; Catalysts; Coupling (molecular); Enantiomers; heterocycles; Indoles; organocatalysis; Quinones; Substrates
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202202395

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 C3‐ and N1‐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. You (don't) spin me right ‘round, baby, right ‘round. A new organocatalytic atroposelective method for the construction of C−N atropisomers is presented. The newly developed F‐substituted aminocatalyst, with an increased outer‐sphere steric control, enables the atroposelective formation of the desired product, which feature interesting biological motifs.