Asymmetric Counterion Pair Catalysis: An Enantioselective Brønsted Acid‐Catalyzed Protonation

Abstract

A new asymmetric Brønsted acid-catalyzed cascade reaction involving a 1,4-addition, enantioselective protonation and 1,2-addition has been developed. This organocatalytic cascade not only provides for the first time 3-and 2,3-substituted tetrahydroquinolines and octahydroacridines in good yields with high dia-and enantioselectivities under mild reaction conditions but additionally represents the first example of a chiral Brønsted acidcatalyzed protonation reaction in an organocatalytic domino reaction. Furthermore, the new Brønsted acid-catalyzed hydride-proton-hydride transfer cascade can be applied to prepare new molecular scaffolds with up to three new stereocenters in an efficient one-pot reaction sequence.Keywords: BINOL phosphate; enantioselective isomerization; Hantzsch dihydropyridine; organocatalytic cascade reaction; transfer hydrogenationThe hydrogenation of unsaturated organic compounds, such as olefins, carbonyls, imines as well as aromatic and heteroaromatic compounds is one of the most important and utilized transformations in both academia and chemical industry.[1] Due to the constantly increasing number of optically and biologically active substances asymmetric reductions have become a central research area in enantioselective catalysis. So far, most of these enantioselective reductions rely on chiral transition metal catalysts and highly enantioselective hydrogenations of ketones, ketimines and alkenes are known.[2] However, most of these metal catalysts failed to give satisfactory results for the asymmetric hydrogenation of aromatic and heteroaromatic compounds and examples of efficient and highly selective transformations are rare. [3] Within this context, and based on our previous work on organocatalytic transfer hydrogenations [4] we recently developed new highly enantioselective partial reductions of pyridines [5] and quinolines.[6] The corresponding products are not only of great synthetic importance in the preparation of pharmaceuticals, agrochemicals, and in materials science, but additionally many interesting alkaloid natural products contain these structural key elements.With the newly developed enantioselective Brønst-ed acid-catalyzed transfer hydrogenation we were, for instance, able to reduce quinolines to the corresponding 2-or 4-substituted tetrahydroquinolines,[6] which we isolated in good yields and with excellent enantioselectivities [Scheme 1, Eq. (1)].In this first organocatalytic transfer hydrogenation, the activation of the quinolines is achieved by a catalytic protonation through a chiral Brønsted acid which subsequently allows a cascade hydrogenation involving a 1,4-hydride addition, proton transfer and Scheme 1. Brønsted acid-catalyzed enantioselective transfer hydrogenation of quinolines using Hantzsch dihydropyridine as the hydride source.

Hydrogenation of Quinolines Using a Recyclable Phosphine‐Free Chiral Cationic Ruthenium Catalyst: Enhancement of Catalyst Stability and Selectivity in an Ionic Liquid

“…Similarly, 5 is activated by protonation to form an iminium cation, [17,18] which is susceptible to 1,2-hydride transfer, to give the final product 3 a and 1 a. Recently, Ru-catalyzed ionic hydrogenation [19] of iminium cations has been proposed by Norton and coworkers [8d] where the iminium ions were reduced through a stepwise H + /H À transfer process.…”

Adventure in Asymmetric Hydrogenation: Synthesis of Chiral Phosphorus Ligands and Asymmetric Hydrogenation of Heteroaromatics

“…Based on the theoretical and experimental results mentioned above, together with suggestions of Zhang and Rueping group, [55][56][57] reported by Rueping [57]. Imine intermediate G could coordinate with Ir(III)-H species B to form the intermediate H, followed by the insertion and sigma-bond metathesis to release the product 1,2,3,4-tetrahydroquinolines P and regenerate B to complete the catalytic cycle [39].…”

“…Subsequent, isomerization and 1,2-hydride addition gave the desirable tetrahydroquinolines. Subsequently, they extended this strategy to 3-substituted quinolines with up to 86% enantioselectivity [57]. In 2008, Du and coworkers [58] designed and synthesized novel double axially chiral phosphoric acid catalysts based on BINOL (70c), and applied these catalysts to asymmetric transfer hydrogenation of 2-substitued and 2,3-disubstituted quinolines with excellent enantioselectivities and diastereoselectivities.…”

A Catalytic Asymmetric Electrocyclization‐Protonation Reaction

“…These experiments showed that the reactivities and selectivities are strongly dependent on the solvent. While reactions in polar solvents gave almost no selectivities (Table 1, entries [8][9][10][11], both better reactivities and selectivities were observed if aromatic and halogenated solvents were employed (entries 1-7). This tendency Figure 1.…”

“…[4,[10][11][12] Given the importance of cyclopentenones in organic synthesis together with our recently developed enantioselective organocatalytic Nazarov reaction [5] and carbonyl activations, [8] we decided to examine a Brønsted acid-catalyzed enantioselective cyclizationprotonation reaction. This would not only be the first organocatalytic enantioselective protonation within the Nazarov reaction but, more importantly, would provide direct and fast access to optically active 2-substituted cyclopentenones (Scheme 2 b).…”