The acid-catalyzed [4+2] cycloaddition of N
-aryl imines and electron-rich olefins, known as the Povarov reaction,1
is a powerful method for the synthesis of tetrahydroquinolines (THQ), a commonly occurring motif in a variety of natural products and biologically active compounds ().2
Up to three contiguous stereocenters can be generated simultaneously in the Povarov reaction, and enantioselective catalytic variants of this reaction have been identified recently.3
As part of our ongoing efforts to develop new methods for producing collections of stereochemically and skeletally diverse small molecules,4,5
we were interested in applying the the chiral urea/ Brønsted acid co-catalyzed asymmetric Povarov reaction3a
() to the synthesis of a THQ-based library.
Examples of natural products and biologically active compounds featuring a tetrahydroquinoline core.
Asymmetric co-catalysis of the Povarov reaction using a Brønsted acid and a chiral urea.
At the outset of the project we faced three synthetic challenges in the production of a diverse THQ-based library: (1) adaptation of the asymmetric Povarov reaction conditions to multigram scale, (2) development of a practical strategy for accessing a matrix of stereoisomers and (3) optimization of solid-phase diversification reactions. In this paper, we describe successful solutions to these challenges in the context of the large-scale synthesis of a collection of stereoisomeric THQ scaffolds as well as the solid-phase production of a 2328-membered THQ library.