Azolium/Hydroquinone Organo-Radical Co-Catalysis: Aerobic C−C-Bond Cleavage in Ketones

Organo-radical catalysts have recently attracted great interest, and the development of this field can be expected to broaden the applications of organocatalysis. Herein, the first example of a radical-generating system is reported that does not require any photoirradiation, radical initiators, or preactivated substrates. The oxidative C−C-bond cleavage of 2-substituted cyclohexanones was achieved using an azolium salt and a hydroquinone as co-catalysts. A catalytic mechanism was proposed based on the results of diffusion-ordered spectroscopy and cyclic voltammetry measurements, as well as computational studies.     

Synergy,Compatibility, and Innovation: Merging Lewis Acids with Stereoselective Enamine Catalysis

In recent years there has been an accelerated rate of development in the field of organocatalysis, with asymmetric organocatalysis now reaching full maturity. The invention of new organocatalytic reactions and the exploration of new concepts now appear in tandem with the application of organocatalytic techniques in the synthesis of natural products and active pharmaceutical ingredients (APIs). After a “golden rush” in organocatalysis, researchers are now starting to combine different methods, thereby taking advantage of the significant benefits of synergy. Metals are used in combination with organocatalytic processes, thus reaching complexity that is found in nature, where enzymes take advantage of the presence of certain metals to increase the arsenal of organic transformations available. In this Focus review, we illustrate the possibility of a “happy marriage” between Lewis acids and organocatalytic stereoselective processes. Questions have been raised about the combination of Lewis acids and organocatalysis owing to the presence of water and/or strong bases in these processes. Some Lewis acids have been shown to be compatible with organocatalysis and concepts relating to their use will be illustrated herein. To summarize the fruitful use of Lewis acids in stereoselective organocatalytic processes, we will draw attention to the advantages and selectivity achieved using this method.     

The Mechanism of N-Heterocyclic Carbene Organocatalysis through a Magnifying Glass

The term “N-Heterocyclic carbene organocatalysis” is often invoked in organic synthesis for reactions that are catalyzed by different azolium salts in the presence of bases. Although the mechanism of these reactions is considered today evident, a closer look into the details that have been collected throughout the last century reveals that there are many open questions and even contradictions in the field. Emerging new theoretical and experimental results offer solutions to these problems, because they show that through considering alternative reaction mechanisms a more consistent picture on the catalytic process can be obtained. These novel perspectives will be able to extend the scope of the reactions that we call today N-heterocyclic carbene organocatalysis.     

Deconstructing Covalent Organocatalysis

Modern organocatalysis has rapidly evolved into an essential component of contemporary organic synthesis. One of the most distinctive aspects of organocatalytic processes is the biomimetic nature in which the catalyst engages the substrate, often forming covalently bound intermediates in a manner reminiscent of enzyme catalysis. Indeed, the process of intramolecularization is often accompanied by a conformational change of the catalyst scaffold, further accentuating this analogy with biological systems. The isolation and study of these catalytic intermediates facilitate the rapid generation of conformation and reactivity profiles to assist in organocatalytic reaction development and/or clarify reaction outcomes. Emulating the formative advances that have derived from studying reaction intermediates in mechanistic organometallic and enzymatic catalysis, the deconstruction of covalently bound organocatalysis intermediates is gaining momentum as a design strategy.     

Proline-catalyzed aldol reactions of cyclic diketones: fluorine modifies pathways as well as transition states

Proline-catalysed aldol reactions are central to the development of organocatalysis, and have been the subjects of many studies. List’s results on the effect of fluorine substitution on proline catalysts for an intramolecular aldol condensation provide a perfect test set for computational analysis, as subtle changes in the catalyst structure lead to clear changes in the product ratios. The results show that the carbon-carbon bond forming transition states for the Hajos-Parrish-Wiechart reaction do not account for the observed selectivity in all cases. However, if an analysis of post transition-state epimerization pathways is also included, together with the effect of water, it is possible to account for all of the experimental data.     

Enantioselective Synthesis of Spiro Heterocyclic Compounds Using a Combination of Organocatalysis and Transition-Metal Catalysis

Over the last ten years, the combination of organocatalysis with transition metal (TM) catalysis has become one of the most important toolboxes used for synthesizing optically pure compounds containing chiral quaternary centers, including spiro heterocyclic molecules. The dominant method in the enantioselective synthesis of spiro heterocyclic compounds based on synergistic catalysis includes chiral aminocatalysis and NHC catalysis, as already established covalent organocatalytic strategies. Another area of organocatalysis widely combined with TM catalysis producing enantiomerically enriched spiro heterocyclic compounds is non-covalent catalysis, dominated by chiral phosphoric acids, thiourea, and squaramide derivatives. This review article aims to summarize enantioselective methods used for constructing spirocyclic heterocycles based on a combination of organocatalysis and transition metal catalysis.     

Discovery of spirooxindole–ferrocene hybrids as novel MDM2 inhibitors

A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis. In vitro protein binding and cellular proliferation assays suggested that compound 5 d was the most potent mouse double minute 2 homolog(MDM2) inhibitor. In addition,mechanistic studies indicated that compound 5 d suppressed MDM2-mediated p53 degradation, induced apoptosis and promoted oxidative damage. Molecular docking studies have suggested that 5 d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53. This work can provide a basis for the development of novel multifunctional MDM2 inhibitors. The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.     

Functionalization of Carbonyl Compounds via Photoredox Organocatalysis

In recent years, a methodology merging photoredox catalysis with organocatalysis termed “photoredox organocatalysis” has emerged to allow the direct, selective and efficient functionalization of the α /β ‐C of carbonyl compounds under mild reaction condition. In this review, photophysics background of photoredox catalysis is introduced, followed by a report on recent advances in direct α ‐ and β ‐functionalization of carbonyls with photoredox organocatalysis methodology. With this different reaction modes, valuable synthetic targets including different α /β ‐functionalized carbonyls are accessible.     

Asymmetric Organocatalysis with Sulfones

Asymmetric organocatalysis has become a powerful tool for the synthesis of optically active compounds. Whereas early research mainly focused on combining simple reagents as a proof‐of‐concept for asymmetric organocatalysis, recent investigations are directed towards extending the concept to more target‐ and diversity‐oriented synthesis. As a result of the many transformation possibilities and their ability to generate both nucleophilic and electrophilic reaction partners, sulfones have become especially important substrates in the field of organocatalysis.     

丙交酯开环聚合反应的新型有机催化剂

作为生物高分子降解材料,聚乳酸具有良好的生物相容性和生物降解性,已经广泛应用于包装材料、农用薄膜等环境领域和药物控制释放体系、医用缝合线、组织工程支架等医学领域。丙交酯开环聚合是制备聚乳酸的理想之选,其催化体系目前以金属催化剂为主,但金属离子在聚合物中的痕量残留和细胞毒性限制了聚乳酸在生物医学及微电子领域的应用,而有机催化剂能够克服这些缺点,是目前聚乳酸合成领域的研究热点。本文从不同的活化机理角度,阐述了近年来有机催化剂在合成聚乳酸中的研究进展,总结了各种催化体系在活性、结构可控性及选择性方面的特点,同时展望有机催化剂在开环聚合反应中所面临的机遇与挑战。     

Hydrogel supported chiral imidazolidinone for organocatalytic enantioselective reduction of olefins in water

Chiral products play an important role particularly in the field of medicinal chemistry, where it is known that enantiomers often have very different biological properties and effects. One of the most powerful tool to obtain a product as a single enantiomer is asymmetric catalysis. Recently, organocatalysis, i.e. the use of small organic molecules to catalyze enantioselective transformations, has emerged as a prominent field in asymmetric synthesis. In this work, the use of hydrogels as a support for a chiral imidazolidinone organocatalyst (MacMillan catalyst) and its application in the reduction of activated olefins mediated by the Hantzsch ester is reported for the first time. Results showed a good activity of hydrogels in respect to both yield and enantioselection.     

N‐Heterocyclic Carbene Organocatalysis: Activation Modes and Typical Reactive Intermediates

N‐Heterocyclic carbene (NHC) organocatalysis has been developed as an important approach in modern organic synthesis. Versatile activation modes within NHC organocatalysis have been established with countless transformations being realized in both efficient and selective fashion. We would like to provide an overview on the key progresses achieved within this field in the past two decades. Since numerous excellent reviews have been documented within this area, we will mainly focus on the scientific development of this research field based on the basic reaction modes and typical reaction intermediates.      

Developing novel organocatalyzed aldol reactions for the enantioselective synthesis of biologically active molecules

Aldol reaction is one of the most important methods for the formation of carbon-carbon bonds. Because of its significance and usefulness, asymmetric versions of this reaction have been realized with different approaches in the past. Over the last decade, the area of organocatalysis has made significant progresses. As one of most studied reactions in organocatalyses, organocatalyzed aldol reaction has emerged as a powerful tool for the synthesis of a large number of useful products in optically enriched forms. In this review, we summarize our efforts on the development of novel organocatalyzed aldol reactions for the enantioselective synthesis of biological active molecules. Literatures closely related to our studies are also covered.     

Enantioselective organocatalytic fluorination using organofluoro nucleophiles

Synthetic fluorinated compounds are enormously useful in areas such as materials, agrochemicals, pharmaceuticals and fine chemicals. While methods of electrophilic fluorination have been extensively developed to stereoselectively install fluorine atoms onto molecules, nucleophilic fluorination is a much less explored approach. Recently, several organofluoro reagents have been designed and used as nucleophiles in the asymmetric synthesis of fluorinated compounds, significantly expanding the scope of enantio-enriched fluorine-containing compounds that can be synthesised. Such organofluoro nucleophiles are particularly useful in organocatalytic transformations. In this review, recent advances in the application of organofluoro nucleophiles in organocatalysis are summarised.     

Asymmetric Organocatalyzed Intermolecular Functionalization of Cyclohexanone-Derived Dienones

Over the past decades, the advent of asymmetric organocatalysis has changed the way chemists think about creating or breaking chemical bonds, enabling new enantioselective strategies for functionalized molecules. The success of asymmetric organocatalysis is notably based on the existence of various activation modes, leading to countless transformations, and on the vast array of available chiral organic catalysts. Breakthroughs in this area have also been driven by selective functionalization of compounds with multiple activation sites such as cyclohexanone-derived dienones. These platforms can undergo diverse transformations such as Michael addition, Friedel-Crafts alkylation or Diels-Alder cycloaddition that offer new opportunities for reaching natural products and biologically relevant compounds. Amongst cyclohexanone-derived dienones, the 2,5-cyclohexadienone motif has received a great deal of attention due to its reactivity pattern and recently, (cross)-conjugated cyclohexanone-derived substrates have also been considered. In this review, we discuss the intermolecular functionalization of (cross)-conjugated cyclohexanone-derived compounds employing asymmetric organocatalysis.     

Recent advances in organocatalytic asymmetric synthesis of polysubstituted pyrrolidines

Chiral substituted pyrrolidines are important N-heterocyclic structural motifs, existing in many natural products, drug candidates, ligands and organocatalysts. We summarise herein the recent (between January 2010 and July 2013) developments on synthesising the chiral polysubstituted pyrrolidines through asymmetric organocatalysis. The organocatalytic strategies for constructing the pyrrolidine scaffolds can be divided into one-step and sequential approaches, respectively. The straightforward one-step approach is mainly the [3+2] cycloaddition based on the iminium activation, chiral Brønsted acid catalysis, bifunctional organocatalysis and SOMO activation. In the sequential approach (multi-step or one-pot reactions), the primary construction of chiral linear precursors is followed by the sequential cyclisation. Other important strategies, such as the organocatalytic bromoaminocyclisation were also described. These organocatalytic strategies have enriched the synthetic chemistry of chiral pyrrolidines, especially towards the target-, diversity- and application-oriented synthesis. New organocatalytic approaches are thus expected for the facile construction of polysubstituted pyrrolidines with well-controlled stereochemistry and for the practical synthesis of pyrrolidine-related natural alkaloids, drug candidates and functional proline derivatives.     

A Transient-Directing-Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes

Metal-coordinating directing groups have seen extensive use in the field of transition-metal-catalyzed alkene functionalization; however, their waste-generating installation and removal steps limit the efficiency and practicality of reactions that rely on their use. Inspired by developments in asymmetric organocatalysis, where reactions rely on reversible covalent interactions between an organic substrate and a chiral mediator, we have developed a transient-directing-group approach to reductive Heck hydroarylation of alkenyl benzaldehyde substrates that proceeds under mild conditions. Highly stereoselective migratory insertion is facilitated by in situ formation of an imine from catalytic amounts of a commercially available amino acid additive. Computational studies reveal an unusual mode of enantioinduction by the remote chiral center in the transient directing group.     

Asymmetric organocatalytic formal [2 + 2]-cycloadditions via bifunctional H-bond directing dienamine catalysis

A new concept in organocatalysis allowing for the construction of cyclobutanes with four contiguous stereocenters with complete diastereo- and enantiomeric control by a formal [2 + 2]-cycloaddition is presented. The concept is based on simultaneous dual activation of α,β-unsaturated aldehydes and nitroolefins by amino- and hydrogen-bonding catalysis, respectively. A new bifunctional squaramide-based aminocatalyst has been designed and synthesized in order to enable such an activation strategy. The potential and scope of the reaction are demonstrated, and computational studies which account for the stereochemical outcome are presented.     

Merging organocatalysis and gold catalysis-a critical evaluation of the underlying concepts

While both organocatalysis and gold catalysis have their roots deeply entrenched in the landscape of modern organic chemistry, an exciting trend in the complementary merging of organocatalysis and especially Au(I) catalysis has emerged in the last four years. This niche area has been developing rapidly and this minireview serves to pin-point the fundamental concepts guiding reaction design in these binary catalytic systems. Moreover, the proven synthetic utility of organo/Au(I) multicatalytic systems in accessing molecular frameworks, previously a challenge to single catalytic systems, has resulted in this new concept permeating numerous areas of organocatalysis, such as primary/secondary amine, Br?nsted acid, hydrogen-bonding as well as N-heterocyclic carbene (NHC) catalysis. The first detailed account of these recent developments is systematically presented.     

Catalysis with Pnictogen,Chalcogen, and Halogen Bonds

Halogen‐ and chalcogen‐based σ‐hole interactions have recently received increased interest in non‐covalent organocatalysis. However, the closely related pnictogen bonds have been neglected. In this study, we introduce conceptually simple, neutral, and monodentate pnictogen‐bonding catalysts. Solution and in silico binding studies, together with high catalytic activity in chloride abstraction reactions, yield compelling evidence for operational pnictogen bonds. The depth of the σ holes is easily varied with different substituents. Comparison with homologous halogen‐ and chalcogen‐bonding catalysts shows an increase in activity from main group VII to V and from row 3 to 5 in the periodic table. Pnictogen bonds from antimony thus emerged as by far the best among the elements covered, a finding that provides most intriguing perspectives for future applications in catalysis and beyond.