Rational\nDesign and Stereodivergent Construction of\nEnantioenriched Tetrahydro-β-Carbolines Containing Multistereogenic\nCenters

Chiral\ntetrahydro-β-carbolines, as one of the most intriguing\nsubtypes of indole alkaloids, have emerged as the privileged units\nin plenty of natural products and biologically active molecules with\nan impressive range of bioactive properties. However, the stereodivergent\nconstruction of these valuable skeletons containing multistereogenic\ncenters from readily available starting materials remains very challenging,\nespecially, in view of the introduction of an axial chirality. Herein,\nwe developed an efficient method toward enantioenriched tetrahydro-β-carbolines\nwith readily available tryptophan-derived aldimine esters and allylic\ncarbonates under mild reaction conditions. The reaction proceeds in\na sequential fashion involving synergistic Cu/Ir-catalyzed stereodivergent\nallylation and the Brønsted acid-promoted stereospecific Pictet–Spengler\nreaction, affording a wide range of chiral tetrahydro-β-carbolines\nbearing up to four stereogenic centers in good yields with excellent\nstereoselectivity control. When <i>N</i>-aryl-substituted\ntryptophan-derived aldimine esters were utilized, notably, a unique\nC–N heterobiaryl axis could be simultaneously constructed with\nthe formation of the third point stereogenic center in the last cyclization\nstep through dynamic kinetic resolution (DKR). Computational mechanistic\nstudies established a plausible synergistic mechanism for dual Cu/Ir-catalyzed\nasymmetric allylation and the succeeding protonation-assisted Pictet–Spengler\ncyclization to complete the annulation. Structure–activity\nrelationship analyses unveil the origins of stereochemistry for the\nbuilding of one axis and three point stereogenic centers.