Enantioselective Povarov Reactions: An Update of a Powerful Catalytic Synthetic Methodology

Abstract

The enantioselective Povarov reaction is one of the most powerful synthetic strategy to synthesize chiral, highly functionalized 1,2,3,4-tetrahydroquinolines. The present Minireview aims to collect the most significant successful examples of highly efficient enantioselective catalytic protocols for this reaction, since 2014. A comprehensive discussion of different catalytic strategies employed in recent years to realize the enantioselec-tive Povarov reaction is provided; the use of chiral phosphoric acids, thio(urea) and proline derivatives, as well as transition metal complexes will be presented. Additionally, this Minireview critically discusses the intriguing and yet obscure mechanistic pathways of this well-known reaction, the controversial dispute between a concerted or a polar two-step process.

Efficient one-pot synthesis of the unexpected fused multicyclic iminosugars by an aza-Diels–Alder mechanism

“…The tautomerization of A could generate intermediate B . Then, a stepwise inverse electron-demanding aza-Diels–Alder reaction 16 between A (diene) and B (dienophile) furnished the skeleton of D via intermediate C . In the process of [4 + 2] cycloaddition, two exo attacks occurred successively due to the hindrance effect of the neighboring cyclic isopropylidene, which resulted in the major product with trans conformations between both C-1/C-2 and C-1′/C-2′, respectively.…”

Enantioselective Approach for Expanding the Three‐Dimensional Space of Tetrahydroquinoline to Develop BET Bromodomain Inhibitors**

“…4,5 Examples include the natural There are many synthetic routes to access chiral THQ, 5 but the simplest and most versatile to implement with a multicomponent approach remains the asymmetric Povarov reaction. 10,11 Synthesis of highly optically pure THQs can be achieved by enantioselective Povarov reactions based on a [4+2] cycloaddition or a Mannich/Friedel-Craft sequence mechanism. 4 The seminal work by Kobayashi and co-workers showed that trisubstituted THQ can be obtained in good enantioselectivity with a cis-2,3 and cis-3,4 configuration (Scheme 1, Eq.1).…”

“…There are many synthetic routes to access chiral THQ, [5] but the simplest and most versatile to implement with a multicomponent approach remains the asymmetric Povarov reaction [10,11] . Synthesis of highly optically pure THQs can be achieved by enantioselective Povarov reactions based on a [4+2] cycloaddition or a Mannich/Friedel‐Craft sequence mechanism [4] .…”

Enantioselective Synthesis of Quinohelicenes through a Sequential Organocatalyzed Povarov Reaction/Oxidative Aromatization

“…The Povarov reaction, which is a commendable means to build ring system from simple and readily available substrates, has been demonstrated to be one of the most attractive approaches in the construction of chiral molecules containing quinoline units. [54][55][56][57][58][59][60][61][62] We speculated that chiral Bronsted acid catalyzed Povarov reaction followed with the subsequent oxidative aromatization process can synthesize chiral quinohelicenes (Fig. 1D).…”