Asymmetric aza-Diels Alder Reaction Research Articles

Asymmetric Aza-Diels-Alder Reactions of in Situ Generated β,β-Disubstituted α,β-Unsaturated N-H Ketimines Catalyzed by Chiral Phosphoric Acids.

A novel asymmetric synthesis of dihydropyridinones with vicinal quaternary stereocenters has been realized by asymmetric aza-Diels-Alder reactions of 3-amido allylic alcohols with oxazolones enabled by chiral phosphoric acid catalysis. A series of aryl/alkyl- and alkyl/alkyl-disubstituted 3-amido allylic tertiary alcohols and 4-substituted oxazolones could be well tolerated in these reactions, producing dihydropyridinones with excellent diastereoselectivities and high enantioselectivities. Mechanistic study and control experiments were performed to shed light on the reaction mechanism, in which a configurationally defined β,β-disubstituted α,β-unsaturated N-H ketimine was proposed as the key intermediate.

Copper(i)-catalyzed asymmetric aza Diels–Alder reactions of azoalkenes toward fulvenes: a molecular electron density theory study

An ADA reaction between AD-2 and FU-3 was theoretically studied within two uncatalyzed as well as catalyzed pathways.

Synthesis of KAE609 via an Asymmetric aza-Diels–Alder Reaction

Synthesis of KAE609 via an Asymmetric aza-Diels–Alder Reaction

Chiral Bimetallic Catalysts Derived from Chiral Metal Phosphates: Enantioselective Three-Component Asymmetric Aza-Diels-Alder Reactions of Cyclic Ketones.

A new type of chiral bimetallic catalyst is disclosed. These chiral bimetallic catalysts are easily formed through mixing a metal Lewis acid and a metal binaphthyl phosphate (MLA/M[P]3) in solution. (1)H and (31)P NMR spectroscopy, electron paramagnetic resonance (EPR) spectroscopy, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, and X-ray crystallographic analysis reveal a bimetallic structure of the Y(Yb)(III)/Y[P]3 complexes with bridging binaphthyl phosphate ligands. The Lewis acidity of these chiral bimetallic catalysts is readily tuned by changing either the metal Lewis acid or the chiral metal phosphate. Through cooperative metal Lewis acid-enamine catalysis, asymmetric three-component aza-Diels-Alder reactions of 5-, 6-, and 7-membered cyclic ketones, unsaturated ketoesters, and arylamines were successfully achieved to afford fused bicyclic dihydropyridines in high yields (up to 94%) with high enantioselectivity (up to 99% enantiomeric excess) and excellent chemoselectivity.

ChemInform Abstract: Endo‐Benzonorbornen‐2‐ol as an Efficient Non‐natural Chiral Auxiliary in the Asymmetric aza‐Diels—Alder Reactions Between Cyclopentadiene and (1‐Phenylethyl)iminoacetates.

Exo-2-azabicyclo[2.2.1]hept-5-enes were obtained by cycloaddition reactions between cyclopentadiene and protonated (S)- and (R)-1-phenylethylimines of (1R,endo)-benzonorbornen-2-yl glyoxylate. The non-natural (1R,endo)-benzonorbornen-2-ol proved to be an efficient chiral auxiliary in these asymmetric aza-Diels–Alder reactions, which afforded only exo-cycloadducts with 1S : 1R diastereomeric ratios of 15 : 85 for (S)-(1-phenylethyl)imine and 93 : 7 for (R)-(1-phenylethyl)imine. The obtained diastereoisomers were effortlessly and efficiently isolated using a chromatographic column. The absolute configuration of all the formed adducts was unequivocally assigned through NMR, specific optical rotation and X-ray data.

Endo-benzonorbornen-2-ol as an efficient non-natural chiral auxiliary in the asymmetric aza-Diels–Alder reactions between cyclopentadiene and (1-phenylethyl)iminoacetates

Exo-2-azabicyclo[2.2.1]hept-5-enes were obtained by cycloaddition reactions between cyclopentadiene and protonated (S)- and (R)-1-phenylethylimines of (1R,endo)-benzonorbornen-2-yl glyoxylate. The non-natural (1R,endo)-benzonorbornen-2-ol proved to be an efficient chiral auxiliary in these asymmetric aza-Diels–Alder reactions, which afforded only exo-cycloadducts with 1S : 1R diastereomeric ratios of 15 : 85 for (S)-(1-phenylethyl)imine and 93 : 7 for (R)-(1-phenylethyl)imine. The obtained diastereoisomers were effortlessly and efficiently isolated using a chromatographic column. The absolute configuration of all the formed adducts was unequivocally assigned through NMR, specific optical rotation and X-ray data.

Catalytic Asymmetric Aza-Diels–Alder Reactions: The Povarov Cycloaddition Reaction

The Povarov reaction provides a straightforward and modular entry to 1,2,3,4-tetrahydroquinolines (THQs). Despite its importance, it was only very recently that several highly efficient catalytic asymmetric protocols for this reaction have been developed, as summarized in this review which falls on the 50^th anniversary of Povarov’s pioneering disclosure. Furthermore, this review collects and critically discusses the interrupted versions of the reaction, often featuring intriguing and still unclear mechanicistic pathways. 1 Introduction 2 Catalytic Asymmetric Povarov Cycloaddition Reactions 2.1 Chiral Lewis Acid Catalysis 2.2 Chiral Brønsted Acid Catalysis 2.2.1 Chiral Phosphoric Acid Catalyzed Povarov Cycloaddition Reactions 2.2.2 Chiral Urea Catalyzed Povarov Cycloaddition Reactions 3 Catalytic Asymmetric Interrupted Povarov Reactions 3.1 Intermolecularly Interrupted Povarov Reactions 3.2 Intramolecularly Interrupted Povarov Reactions 3.2.1 Interrupted Povarov Reactions with Salicyaldehyde-Derived Imines 3.2.2 Interrupted Povarov Reactions with Glyoxylic Acid Derived Imines 4 Conclusion

Arylamine‐Catalyzed Enamine Formation: Cooperative Catalysis with Arylamines and Acids

The explosive growth of organocatalysis has had a huge impact on asymmetric catalysis in the past decade. Transition-metal catalysis, on the other hand, has been established for a long time as one of the most powerful methods in organic synthesis. Aminocatalysis is a major field in organocatalysis. The combination of organocatalysis with the more traditional metal Lewis acid catalysis has emerged, aiming to achieve organic transformations that cannot be accomplished by organocatalysis or metal catalysis independently. Although it promises huge potential, this research area has grown only slowly. The major challenge lies in the incompatibility of the catalysts, in particular, the combination of enamine catalysis with harder metal Lewis acid is very difficult. The circumvention of this problem would represent an important breakthrough, given the huge number of substrates that can be activated by the large variety of metal Lewis acids. Herein, we present the solution to this longstanding problem by using arylamines as the catalysts in enamine catalysis. Very importantly, we demonstrate that arylamines can serve as efficient amine catalysts in direct asymmetric aldol reactions. Furthermore, we have developed a highly chemoand enantioselective three-component azaDiels–Alder reaction by combining arylamines with metal Lewis acids. The combination of enamine catalysis with metal Lewis acid catalysis was first reported by Ibrahem and Codava in 2006. Since then, considerable progress has been made in this area, leading to a series of exciting discoveries. However, these combinations were limited to soft metals, such as Cu, Ag, Au, Ir, and Pd or Pd, activating either p-allyl electrophiles or alkynes (Scheme 1,A and B). Combining enamine catalysis with harder metal Lewis acid (Scheme 1, C) turned out to be very challenging because of acid–base self-quenching reactions, which render the catalysts inactive. In asymmetric aminocatalysis involving either an enamine or an iminium intermediate, a chiral aliphatic secondary or primary amine serves as the catalyst. Aliphatic amines are hard bases, and thus likely to be compatible with softer metals based on the soft/hard approach, but less likely to be compatible with harder metals. We hoped to find an amine catalyst that is compatible with a large variety of metal Lewis acids to significantly extend the scope of enamine/ metal Lewis acid catalysis, and to facilitate the development of a new research area of iminium/metal Lewis acid catalysis. We considered to use arylamines, such as aniline, because they have a much lower pKa value (4–6) than aliphatic amines (9–11), and should be much softer because of the delocalization of the lone pair to the aromatic p system. It appeared to us that arylamines are ideal candidates for combination with harder metal Lewis acids. Despite their ubiquity in organic chemistry, arylamines have never been used in enamine catalysis. This may be mainly due to the general understanding that the nucleophilicity of arylamines is much lower compared to aliphatic amines. However, List and co-workers suggested the formation of enamine intermediates from arylamines as a step in organocatalytic cascade reactions. In a recent report, Gong and co-workers also suggested that an achiral arylamine played a crucial role in controlling the stereochemistry of a Friedl nder condensation by forming an enamine intermediate. We speculate that arylamines might be suitable to serve as an efficient amine catalyst in enamine catalysis in conjunction with a stronger metal Lewis acid. The lower nucleophilicity of enamines can be compensated by the following factors: 1) facilitated formation of enamine in the presence of a metal Lewis acid; 2) higher activation of the electrophiles by a metal Lewis acid. The asymmetric aza-Diels–Alder reaction (ADAR) is the most convenient and powerful method to form nitrogencontaining heterocycles, which are one of the most important structural motifs in natural products, pharmaceuticals, and biosystems. While the recent progress on normal-electrondemand ADARs based on dienamines and imine dienophiles Scheme 1. Combination of enamine catalysis with metal catalysis.

Enantioselective aza-Diels–Alder reaction of Brassard’s diene with aldimines catalyzed by chiral N,N′-dioxide–Yb(OTf)3 complex

The chiral N , N′ -dioxide–Yb(OTf) 3 complex-catalyzed enantioselective aza-Diels–Alder reaction of Brassard’s diene with aldimines has been developed, giving the corresponding α,β-unsaturated δ-lactam derivatives in moderate yields with good enantioselectivities (up to 81% ee and up to 99% ee by single recrystallization) under mild conditions. Isolation of the reaction intermediate indicates that this asymmetric aza-Diels–Alder reaction proceeds through a stepwise Mannich-type pathway.

Direct asymmetric aza Diels–Alder reaction catalyzed by chiral 2-pyrrolidinecarboxylic acid ionic liquid

Abstract The utility of [EMIm][Pro] as an efficient catalyst for the one-pot direct asymmetric aza Diels–Alder reaction has been developed. A set of cyclic α,β-unsaturated ketones have been explored in up to 93% yield with up to >99/1 dr and >99% ee. Moreover, the catalytic system can be recycled and reused for six times without any significant loss of catalytic activity.

ChemInform Abstract: Synthesis of Novel Chiral Imidazolium‐Based Ionic Liquids Derived from Isosorbide and Their Applications in Asymmetric Aza Diels—Alder Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Synthesis of novel chiral imidazolium-based ionic liquids derived from isosorbide and their applications in asymmetric aza Diels–Alder reaction

A novel family of chiral imidazolium-based ionic liquids containing a chiral moiety and a free hydroxyl function has been designed and synthesized using isosorbide as a biorenewable substrate. These chiral ionic liquids were found to catalyze the aza Diels–Alder reaction to give good yields and moderate diastereoselectivities. Chiral ionic liquids are recycled while their efficiency is preserved.

Synthesis of Novel Chiral Ammonium‐Based Ionic Liquids Derived from Isosorbide and Their Applications in an Asymmetric Aza Diels—Alder Reaction.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Asymmetric aza-Diels–Alder reactions of an N- tert-butanesulfinyl α-imino ester

Diastereoselective aza-Diels–Alder (aza-DA) reactions of an N- tert-butanesulfinyl α-imino ester with different dienes including activated and non-activated dienes in the presence of BF 3·OEt 2 are described. Diastereoselectivities up to 99% were observed for acyclic unactivated dienes. The absolute configurations of two aza-DA products have been solved by X-ray analysis.

Synthesis of Novel Chiral Ammonium-Based Ionic Liquids Derived from Isosorbide and their Applications in an Asymmetric Aza Diels-Alder Reaction

A novel family of chiral ammonium-based ionic liquids containing a chiral moiety and a free hydroxyl function has been designed and synthesized from isosorbide. The synthesis of these ionic liquids is easy and practical owing to the commercially available starting materials. These new chiral ionic liquids can be used as chiral reaction media as well as catalysts in asymmetric synthesis, which are currently being investigated in our laboratory. Keywords: Ionic liquid, chirality, isosorbide, asymmetric synthesis, aza Diels-Alder reaction, Danishefsky's diene

The use of (−)-8-phenylisoneomenthol and (−)-8-phenylmenthol in the enantioselective synthesis of 3-functionalized 2-azabicyclo[2.2.1]heptane derivatives via aza-Diels–Alder reaction

The asymmetric aza-Diels–Alder reaction of the (1 R)-8-phenylmenthyl or (1 R)-8-phenylisoneomenthyl glyoxylate-derived N-benzylimine with cyclopentadiene resulted in the enantioselective synthesis of the corresponding pure [(1 S,3- exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-ene]-3-carboxylates (80 or 69% yield, respectively). Reduction of these cycloadducts with LiAlH 4 afforded pure (−)-[(1 S,3- exo)-2-benzyl-2-azabicyclo[2.2.1]hept-5-en-3-yl]methanol. Furthermore, a reaction sequence based on Barbier–Wieland degradation of both (1 S,3- exo)-adducts afforded pure (+)-(1 R)-2-benzoyl-2-azabicyclo[2.2.1]heptan-3-one. In the course of the two transformation sequences referred, the chiral auxiliaries were recovered in a virtually quantitative way.

Catalytic Asymmetric Aza Diels—Alder Reactions of Hydrazones Using a Chiral Zirconium Catalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Catalytic asymmetric aza Diels–Alder reactions of hydrazones using a chiral zirconium catalyst

Catalytic asymmetric aza Diels–Alder reactions of acylhydrazones with Danishefsky’s dienes have been developed. A chiral zirconium complex derived from zirconium propoxide and 3,3′,6,6′-I 4BINOL was found to be effective in this reaction, and the desired optically active 2,3-dihydro-4-pyridone derivatives were obtained with high enantioselectivities. Asymmetric formal synthesis of a natural product, coniine, was conducted using this catalytic asymmetric reaction as a key step.

Corrigendum to “A parallel combinatorial approach to locating homochiral Lewis acid catalysts for the asymmetric aza-Diels–Alder reaction of an imino dienophile”

Corrigendum to “A parallel combinatorial approach to locating homochiral Lewis acid catalysts for the asymmetric aza-Diels–Alder reaction of an imino dienophile”

The exo-selectivity of the new non-natural chiral auxiliary (+)-(1 R, endo)-2-benzonorbornenol in an asymmetric aza-Diels–Alder reaction

The recently reported compound (+)-(1 R, endo)-2-benzonorbornenol ( 2 ) proved to be an efficient chiral auxiliary in the asymmetric aza-Diels–Alder reaction between cyclopentadiene and the N-benzyl imine of its glyoxylate, which afforded a virtually all- exo mixture of cycloaducts with a 1 S:1 R diastereomeric ratio of 63:37.