Catalytic and Enantioselective Control of the C–N Stereogenic Axis via the Pictet–Spengler Reaction
Ahreum Kim, Aram Kim, Sunjung Park, Sangji Kim, Hongil Jo, Kang Min Ok, Sang Kook Lee, Jayoung Song, Yongseok Kwon
Abstract
An unprecedented example of a chiral phosphoric acid-catalyzed atroposelective Pictet-Spengler reaction of N-arylindoles is reported. Highly enantioenriched N-aryl-tetrahydro-β-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.