Asymmetric Aminocatalysis Research Articles

Enantioselective Cascade Reactions of Aminocatalytic Dienamines and Trienamines Initiated by a Cycloaddition Reaction.

Cycloadditions are widely accepted as a group of reactions that rapidly generate molecular complexity. Being highly atom economic and often predictable, these reactions can generate up to four stereogenic centers and two C-C (or C-X) bonds in one reaction step. During the last two decades, asymmetric aminocatalysis has shown to be a successful strategy for controlling stereoselectivity and enabling reactivity of cycloaddition reactions. By increasing the conjugation of the carbonyl species employed, dienamines and trienamines can be catalytically formed. Not only can these facilitate the cycloaddition, often accompanied by high levels of stereocontrol, but they also leave a residual enamine or carbonyl (by hydrolysis) in the cycloadduct. This residual functionality can engage in further intramolecular reactions generating complex cyclic systems in a one-pot cascade manner. In this regard, asymmetric aminocatalysis can add another layer of complexity to the already complex nature of cycloadditions. In this review, we will present the general concept of such reactivity patterns of dienamines and trienamines, and hereafter showcase examples in the literature. We aspire that the chemical community can use these concepts to design new enantioselective aminocatalytic cascade reactions to access enantioenriched, complex compounds, and perhaps use these in complex molecule synthesis.

Blossoming of Polyenamine Catalysis in Asymmetric Synthesis: Scope and Future Applications.

After the emergence of organocatalysis, the field of asymmetric synthesis has reached an exceptional level in this century. Asymmetric aminocatalysis, among other organocatalytic strategies, proceeded through LUMO-lowering iminium ion and HOMO-raising enamine ion activation has appeared as a powerful synthetic approach for realizing potential chiral building blocks from unmodified carbonyl compounds. Consequently, the concept of HOMO-raising activation strategy for a plethora of asymmetric transformations based on enamine, dienamine, and most recently trienamine, tetraenamine, and pentaenamine catalysis has been devised. In this mini-review article, we disclosed the recent progress accomplished in asymmetric aminocatalysis through polyenamine activation strategies for the functionalization of carbonyl compounds, and we covered the reports from 2014 to till date.

Accelerating Amine‐Catalyzed Asymmetric Reactions by Intermolecular Cooperative Thiourea/Oxime Hydrogen‐Bond Catalysis

AbstractThe ability of intermolecular cooperative thiourea/oxime hydrogen‐bond catalysis for improving and accelerating asymmetric aminocatalysis is presented. The two readily available hydrogen‐bond‐donating catalysts operates in synergy with a chiral amine catalyst to accomplish highly stereoselective transformations. The synergistic catalyst systems simultaneously activate both electrophiles and nucleophiles, and make the transformations more chemo‐ and stereoselective. This was exemplified by performing co‐catalytic enantioselective direct intermolecular α‐alkylation reactions of aldehydes, direct aldol reactions, and asymmetric conjugate reactions, which gave the corresponding products in high yields and enantiomeric ratios.

New Amines and Activation Modes in Asymmetric Aminocatalysis

AbstractAsymmetric aminocatalysis has become one of the most powerful strategies for the transformations of carbonyl substances over the past two decades. Here, we describe the research from our laboratory that significantly expands the horizon of aminocatalysis. It includes the development and application of cinchona‐based primary amines, fruitful reactions based on HOMO‐raising strategy, and the disclosure of amine/thiol double activation catalysis. What is the most favorite and original chemistry developed in your research group?Cinchona‐based primary amine catalysts and trienamine activation mode.How do you get into this specific field? Could you please share some experiences with our readers?I got to know asymmetric catalysis when I began to pursue my PhD study, and realized the importance and beauty of chiral substances. My key experiences in research are: try something different, and be sensitive to the difference.How do you supervise your students?Always keep honest, and try to understand what you are doing.What are your hobbies?Gardening and badminton.How do you keep balance between research and family?Keep communicating with family members.Who influences you mostly in your life?My PhD director Prof. Yao‐Zhong Jiang.

α-Keto hydrazones in asymmetric aminocatalysis: reactivity through β-amino aza-dienamine intermediates

α-keto hydrazones activated by a bifunctional amino-thiourea catalyst generate β-amino aza-dienamine intermediates which react with nitroalkenes in highly enantioselective fashion.

Enantioselective Organocatalytic Enamine C−H Oxidation/Diels‐ Alder Reaction

Abstractα,β‐unsaturated aldehydes have been traditionally used in LUMO lowering asymmetric aminocatalysis (iminium catalysis), while the use of saturated aldehydes as substrates in this type of catalysis has been elusive, until recently. Herein, we demonstrate that organic, single‐electron oxidants in the presence of diarylprolinol silylether type catalysts serve as effective tools for the transformation of electron rich enamines to iminium ions which partake in a subsequent Diels‐Alder reaction. This enantioselective one‐pot transformation represents the first example of saturated aldehydes being used in domino Diels‐Alder reaction processes and demonstrates the power of this protocol for construction of stereo‐defined chiral compounds and building blocks.magnified image

Asymmetric Aminocatalysis in the Synthesis of δ‐Lactone Derivatives

AbstractIn this manuscript, a novel approach to 3,4‐dihydrocoumarins is presented. It utilizes the aminocatalytic, trienamine‐mediated cycloaddition reaction between 2,4‐dienals and ethyl coumarincarboxylates. The reaction is promoted by a bifunctional aminocatalyst bearing a hydrogen‐bonding squaramide structural unit. As a consequence, the stereochemical outcome is governed through the double hydrogen‐bonding interactions between the hydrogen‐bonding moiety of the catalyst and the dienophile. The transformation of the obtained cycloadducts into 3,4‐dihydrocoumarins bearing a bislactone structural motif is presented.

Computational Approach to Diarylprolinol-Silyl Ethers in Aminocatalysis.

Asymmetric organocatalysis has witnessed a remarkable development since its "re-birth" in the beginning of the millenium. In this rapidly growing field, computational investigations have proven to be an important contribution for the elucidation of mechanisms and rationalizations of the stereochemical outcomes of many of the reaction concepts developed. The improved understanding of mechanistic details has facilitated the further advancement of the field. The diarylprolinol-silyl ethers have since their introduction been one of the most applied catalysts in asymmetric aminocatalysis due to their robustness and generality. Although aminocatalytic methods at first glance appear to follow relatively simple mechanistic principles, more comprehensive computational studies have shown that this notion in some cases is deceiving and that more complex pathways might be operating. In this Account, the application of density functional theory (DFT) and other computational methods on systems catalyzed by the diarylprolinol-silyl ethers is described. It will be illustrated how computational investigations have shed light on the structure and reactivity of important intermediates in aminocatalysis, such as enamines and iminium ions formed from aldehydes and α,β-unsaturated aldehydes, respectively. Enamine and iminium ion catalysis can be classified as HOMO-raising and LUMO-lowering activation modes. In these systems, the exclusive reactivity through one of the possible intermediates is often a requisite for achieving high stereoselectivity; therefore, the appreciation of subtle energy differences has been vital for the efficient development of new stereoselective reactions. The diarylprolinol-silyl ethers have also allowed for novel activation modes for unsaturated aldehydes, which have opened up avenues for the development of new remote functionalization reactions of poly-unsaturated carbonyl compounds via di-, tri-, and tetraenamine intermediates and vinylogous iminium ions. Computational studies have played a pivotal role in the elucidation of the regioselectivities observed for such systems because these pose a challenge due to the presence of multiple reactive sites in these intermediates. Charge distribution and π-orbital coefficient calculations have been applied to explain the observed regioselectivity of the given reactions. The calculation of more elaborate energetic pathways has allowed for in silico identification of high-energy intermediates, such as zwitterions, and transition-state structures, which have also provided information on the driving force controlling the reaction course and outcome.

ChemInform Abstract: Explaining Anomalies in Enamine Catalysis: “Downstream Species” as a New Paradigm for Stereocontrol

AbstractReview: 25 refs.

Explaining Anomalies in Enamine Catalysis: "Downstream Species" as a New Paradigm for Stereocontrol.

Enantioselective organocatalysis by diarylprolinol ethers is remarkably selective and efficient for a wide range of transformations involving a number of different activation modes, including HOMO activation via enamines. A simple steric model based on facial discrimination in the attack of an enamine on an electrophile has been invoked to rationalize high enantioselectivity. In a number of reactions, however, experimental observations have persistently left us with mechanistic puzzles that fail to fit neatly into this simple picture. Further studies involving both kinetic profiling of reaction networks and NMR spectroscopic characterization of the structures of intermediate species helped us to address these puzzles. This work led to the proposal of a new paradigm for stereocontrol in asymmetric aminocatalysis, demonstrating that the ultimate stereochemical outcome may not, in fact, be determined solely in the stereogenic bond-forming step between enamine and electrophile. The identification of stable species occurring downstream from the addition of an electrophile to an enamine, and the discovery of kinetic features that are diagnostic of the presence of such species, allows development of a new mechanistic framework that reveals a hierarchical selection. Both kinetic and thermodynamic processes associated with downstream intermediates can exert an influence on the ultimate enantioselectivity. Interestingly, the role of these species may be either to enhance or to erode selectivity established at the enamine-electrophile step. The reversibility of steps preceding and subsequent to the stereogenic bond-forming step is an important factor, as are reaction parameters that may stabilize or destabilize intermediates, including the nature of the electrophile counterion and the solvent. These concepts hold implications for the future design and optimization of asymmetric catalytic processes, because such design does not necessarily feature the same parameters at the second hierarchical level as it does at the first. Examples presented to highlight these issues include the conjugate addition of aldehydes to nitroalkenes and the α-chlorination and α-selenylation of aldehdyes using diarylprolinol ether catalysts commonly assumed to follow a steric model for enantioselectivity. While the new paradigm for stereocontrol involving downstream intermediates is developed here for enamine catalysis, the same concepts may hold for other organocatalytic modes of activation.

ChemInform Abstract: Combined Asymmetric Aminocatalysis and Carbene Catalysis

AbstractReview: [33 refs.

Combined Asymmetric Aminocatalysis and Carbene Catalysis

The use of multiple catalytic systems for cascade reactions has found widespread application in recent years. The combination of two important organocatalysts, chiral amines and N-heterocyclic carbenes (NHCs), is of extraordinary interest since they can both potentially mediate a variety of reactions with aldehyde derivatives. In this short review, we discuss the successful combination of asymmetric aminocatalysis and carbene catalysis in the efficient construction of complex chiral architectures, either in a relay or sequential manner. 1 Introduction 2 NHC-Catalyzed Redox Reaction Combined with Aminocatalysis 3 NHC-Catalyzed Benzoin Condensation Combined with Aminocatalysis 4 NHC-Catalyzed Stetter reaction Combined with Aminocatalysis 5 Miscellaneous NHC Catalysis Combined with Aminocatalysis 6 Summary

ChemInform Abstract: One‐Pot Enantioselective Synthesis of 1,4‐Naphthoquinone‐Derived Polycycles Through Oxidative Dearomatization and Aminocatalysis.

AbstractAn enantioselective process involving dearomatization and asymmetric aminocatalysis is developed for the synthesis of polycyclic and/or bridged products (III), (V), and (VII).

ChemInform Abstract: Asymmetric Enamine Catalysis with β‐Ketoesters by Chiral Primary Amine: Divergent Stereocontrol Modes.

AbstractThis describes different methods for the conversion of α‐substituted β‐ketoesters via asymmetric aminocatalysis.

Redox Tuning of a Direct Asymmetric Aldol Reaction

Presented herein is a redox tuning strategy for asymmetric aminocatalysis with a designed chiral ferrocenophane. Under redox control, the ferrocenophane catalyst efficiently catalyzes the asymmetric aldol reaction at room temperature with excellent yield and good stereoselectivity. Moreover, the redox-active ferrocene moiety also served as phase-tag to facilitate catalyst recovery and reuse. The catalyst can be reused for five cycles without much loss of activity. Ferrocenium of the oxidized ferrocenophane was proposed to serve as Lewis acidic site, thus accounting for the stereo control.

Redox Tuning of a Direct Asymmetric Aldol Reaction

AbstractPresented herein is a redox tuning strategy for asymmetric aminocatalysis with a designed chiral ferrocenophane. Under redox control, the ferrocenophane catalyst efficiently catalyzes the asymmetric aldol reaction at room temperature with excellent yield and good stereoselectivity. Moreover, the redox‐active ferrocene moiety also served as phase‐tag to facilitate catalyst recovery and reuse. The catalyst can be reused for five cycles without much loss of activity. Ferrocenium of the oxidized ferrocenophane was proposed to serve as Lewis acidic site, thus accounting for the stereo control.

One‐Pot Enantioselective Synthesis of 1,4‐Naphthoquinone‐Derived Polycycles through Oxidative Dearomatization and Aminocatalysis

AbstractA synthetic process merging oxidative dearomatization and asymmetric aminocatalysis in a single vessel is reported. The PhI(OAc)2‐mediated oxidation of 1,4‐dihydroxynaphthalene is followed by a trienamine‐mediated Diels–Alder cycloaddition/aldol reaction or a trienamine‐mediated Diels–Alder cycloaddition/oxidation sequence depending on the dienal substitution pattern. The polycyclic compounds are obtained in good yields with enantiomeric excesses up to 99 %. Additionally, these polycyclic architectures can be synthesized with similar enantioselectivities through an unprecedented one‐pot marriage of bodipy‐photocatalyzed oxidative dearomatization of 1‐naphthol and asymmetric aminocatalysis. A catalytic cycle is suggested to explain the reaction outcome.

Asymmetric enamine catalysis with β-ketoesters by chiral primary amine: divergent stereocontrol modes.

α-Branched ketones remain a challenging type of substrates in aminocatalysis due to their congested structures as well as the associated difficulties in controlling chemo- and stereoselectivity. In this work, we have explored asymmetric aminocatalysis with α-substituted β-ketoesters. A simple chiral primary amine catalyst was identified to enable unprecedentedly effective catalysis of β-ketoesters in α-hydrazination and Robinson annulation reaction with good yields and high enantioselectivities. Stoichiometric experiments with preformed enamine ester intermediates revealed their enamine-catalytic nature as well as the critical roles of acidic additives in facilitating catalytic turnovers and in tuning the chemo- and stereoselectivity. With the identical catalytic system, the two reactions demonstrated opposite chiral inductions in terms of the absolute configurations of the newly formed stereogenic centers. Investigations into this intriguing issue by DFT have revealed divergent stereocontrol modes. For α-hydrazination, H-bonding-directed facial attack determines the stereoselectivity, whereas a steric model is applied to the Robinson annulation where dual activations of both β-ketoester and vinyl ketone/aldehyde are involved.

Oxidative Cross-Coupling in Asymmetric Aminocatalysis

Oxidative Cross-Coupling in Asymmetric Aminocatalysis

ChemInform Abstract: When Asymmetric Aminocatalysis Meets the Vinylogy Principle

AbstractReview: <60 refs.