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

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.

An overview of the applications of chiral phosphoric acid organocatalysts in enantioselective additions to CO and CN bonds

“…Following this strategy, in 2021, Kwon and co-workers reported a similar process using N-aryl protected tryptamine derivatives 241 and (R)-BPA3 as the catalyst (Scheme 74). 213 In this case, a highly atroposelective reaction is described using paraformaldehyde and sterically hindered N-aryl groups. The intramolecular nucleophilic addition to formaldehyde-derived imine, again, limits the free-rotation of the N-aryl group, gener- ating axially-chiral heterocycles 242 in yields up to 99% and enantiomeric excesses up to 97%.…”

A Statistical Modeling Approach to Catalyst Generality Assessment in Enantioselective Synthesis

“…Where additional comparison data is available, several other studies involving imine-type electrophiles (C=N-R) have shown the importance of including TCYP in a catalyst evaluation despite the structural similarities with TRIP. [32][33][34][35][36][37][38][39][40][41] By performing this type of analysis with similarly related electrophiles, azo compounds, [42][43][44][45][46] precedent shows TCYP to be a top performer. Continued expansion of this comparative analysis demonstrates TCYP to be effective in condensation, 47,48 halogenation [49][50][51][52] and organometallic reactions.…”

Enantioselective Access to C-N Axially Chiral Isoquinolones via Dynamic Kinetic Transformation of Carbene Reagents: Unique Chiral Induction Enabled by Dual Role of the Catalyst

“…In one category, functionalization of the peripheral groups in existing (hetero)aryl rings allows restriction of the C-N rotation by size-increasing effect. [15][16][17][18][19][20][21][22] Alternatively, de novo construction of a new (hetero)aryl ring with incorporatation of the C or N atom into it may also restrict the conformation of the C-N axis. The latter strategy is particularly important because new chiral platforms are constructed with modularity, which allows exploitation of diverse chiral structures.…”