Catalytic and Enantioselective Control of the C-N Stereogenic Axis via the Pictet-Spengler Reaction

An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-beta-carbolines with C-N bond axial chirality are obtained via dynamic kinetic resolution. The hydrogen bond donor introduced on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is essential to achieving high enantioselectivity. A wide variety of substituents are tolerable with this transformation to provide up to 98 % ee. The application of electron-withdrawing group-substituted benzaldehydes enables the control of both axial and point stereogenicity. Biological evaluation of this new and unique scaffold shows promising antiproliferative activity and emphasizes the significance of atroposelective synthesis.

Automated summary

A novel chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles has been reported, resulting in highly enantioenriched N-aryl-tetrahydro-beta-carbolines with axial chirality. The introduction of a hydrogen bond donor on the bottom aromatic ring, forming a secondary interaction with the phosphoryl oxygen, is crucial for achieving high enantioselectivity. The transformation is tolerant to a wide variety of substituents and can provide products with up to 98% ee.