Activation of a Metal‐Halogen Bond by Halogen Bonding

In recent years, the non‐covalent interaction of halogen bonding (XB) has found increasing application in organocatalysis. However, reports of the activation of metal‐ligand bonds by XB have so far been limited to a few reactions with elemental iodine or bromine. Herein, we present the activation of metal‐halogen bonds by two classes of inert halogen bond donors and the use of the resulting activated complexes in homogenous gold catalysis. The only recently explored class of iodolium derivatives were shown to be effective activators in two test reactions and their activity could be modulated by blocking of the Lewis acidic sites. Bis(benzimidazolium)‐based halogen bonding activators provided even more rapid conversion, while the non‐iodinated reference compound showed little activity. The role of halogen bonding in the activation of metal‐halogen bonds was further investigated by NMR experiments and DFT calculations, which support the mode of activation occurring via halogen bonding.     

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.     

Oxazolones in Organocatalysis,New Tricks for an Old Reagent

Oxazolones or azlactones are among the most‐common starting materials for the synthesis of quaternary amino acids. Since the seminal works of Steglich and co‐workers until the recent examples from Ooi and co‐workers, azlactones have been the focus of intense research. Oxazolones are also widely used in organometallic chemistry; however, with the “renaissance” of organocatalysis, this reagent has emerged as an important starting material for a broad range of new organocatalytic asymmetric methodologies. In this Focus Review, we aim to cover all of these new organocatalytic methodologies. We begin by discussing the dynamic kinetic resolution reactions developed with azlactones. Then, we disclose the organocatalytic rearrangements. Finally, we focus on the use of oxazolones as nucleophiles in organocatalytic processes.     

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.     

Recent advances in enantioselective organocatalyzed anhydride desymmetrization and its application to the synthesis of valuable enantiopure compounds

Recent years have witnessed increasing interest in the field of asymmetric organocatalysis. In particular, efforts in this field have been devoted to the use of small organic molecules in asymmetric processes based on enantiotopic face discrimination and, only recently, efforts have also been devoted to asymmetric organocatalytic desymmetrization of prochiral substrates-a process based on enantiotopic group discrimination. This critical review documents the advances in the use of organocatalysis for the enantioselective desymmetrization of achiral and meso anhydrides and its application to the synthesis of valuable compounds as reported until 2010 (134 references).     

Fundamentals of green chemistry: efficiency in reaction design

In this tutorial review, the fundamental concepts underlying the principles of green and sustainable chemistry--atom and step economy and the E factor--are presented, within the general context of efficiency in organic synthesis. The importance of waste minimisation through the widespread application of catalysis in all its forms--homogeneous, heterogeneous, organocatalysis and biocatalysis--is discussed. These general principles are illustrated with simple practical examples, such as alcohol oxidation and carbonylation and the asymmetric reduction of ketones. The latter reaction is exemplified by a three enzyme process for the production of a key intermediate in the synthesis of the cholesterol lowering agent, atorvastatin. The immobilisation of enzymes as cross-linked enzyme aggregates (CLEAs) as a means of optimizing operational performance is presented. The use of immobilised enzymes in catalytic cascade processes is illustrated with a trienzymatic process for the conversion of benzaldehyde to (S)-mandelic acid using a combi-CLEA containing three enzymes. Finally, the transition from fossil-based chemicals manufacture to a more sustainable biomass-based production is discussed.     

"Nonsolvent" applications of ionic liquids in biotransformations and organocatalysis

The application of room-temperature ionic liquids (RTILs) as (co)solvents and/or reagents is well documented. However, RTILS also have "nonsolvent" applications in biotransformations and organocatalysis. Examples are the anchoring of substrates to RTILs; ionic-liquid-coated enzymes (ILCE) and enzyme-IL colyophilization; the construction of biocatalytic ternary reaction systems; the combination of enzymes, RTILs, membranes, and (bio)electrochemistry; and ionic-liquid-supported organocatalysts. These strategies provide more robust, more efficient, and more enantioselective bio- and organocatalysts with many practical applications. As shown herein, RTILs offer a wide range of promising alternatives to conventional chemistry.     

Recent applications of mechanochemistry in enantioselective synthesis

In recent years, sustainable organocatalysis has become a relevant target in asymmetric organic synthesis. Among the most successful strategies to achieve “greener” organocatalyzed processes are (1) the elimination of solvent from reaction media, and (2) the use of alternative activation energies such as solvent-free mechanochemistry in high speed ball mills. In recent years we have stepped up efforts in the pursuit of organocatalysts and biocatalysts that allow reactions to take place in the absence of solvent and under mechanochemical activation. In this article we present the application of small dipeptides as chiral organocatalysts under solvent-free and high-speed ball milling conditions, with focus on the asymmetric aldol addition reaction. Finally, we report on recent results using supported enzymes for the resolution of racemic β-amino acids and amines, under mechanochemical conditions.     

Halogen Bonding in Organic Synthesis and Organocatalysis

Halogen bonding is a noncovalent interaction similar to hydrogen bonding, which is based on electrophilic halogen substituents. Hydrogen‐bonding‐based organocatalysis is a well‐established strategy which has found numerous applications in recent years. In light of this, halogen bonding has recently been introduced as a key interaction for the design of activators or organocatalysts that is complementary to hydrogen bonding. This Concept features a discussion on the history and electronic origin of halogen bonding, summarizes all relevant examples of its application in organocatalysis, and provides an overview on the use of cationic or polyfluorinated halogen‐bond donors in halide abstraction reactions or in the activation of neutral organic substrates.     

Enantioselective methodologies for the synthesis of spiro compounds

The enantioselective synthesis of spirocycles has been a long time pursued dream for organic chemists. Since the first pioneering efforts of Tamao and coworkers in the enantioselective construction of spirosilanes, many efforts have been devoted to the development of new and promising asymmetric methodologies. Remarkably, with the advent of organocatalysis the number of methodologies has been highly increased. The aim of this tutorial review is to summarize the last trends and developments reported in the literature in the enantioselective synthesis of spirocompounds.     

Organocatalytic Asymmetric Synthesis of Organophosphorus Compounds

240 Years have passed since the discovery of elemental phosphorus. During that time organophosphorus chemistry has emerged as an interesting and exciting field of research. Recently organophosphorus chemistry has been raised to a new level. Organophosphorus compounds have found applications in asymmetric organocatalysis for the synthesis of optically active compounds of synthetic or biological importance. The aim of this review article is to present recent contributions to this developing field of chemistry and to point out synthetic advantages of methodologies developed so far.     

Synergistic Photoredox Catalysis and Organocatalysis for Inverse Hydroboration of Imines

The first catalytic inverse hydroboration of imines with N‐heterocyclic carbene (NHC) boranes has been realized by means of cooperative organocatalysis and photocatalysis. This catalytic combination provides a promising platform for promoting NHC‐boryl radical chemistry under sustainable and radical‐initiator‐free conditions. The highly important functional‐group compatibility and possible application in late‐stage hydroborations represent an important step forward to an enhanced α‐amino organoboron library.     

Synthesis of Heterocycles by isothiourea organocatalysis

Isothiourea was first employed as catalyst by Birman in 2006 for the enantioselective acyl transfer reaction. The catalyst was then well explored in the course of kinetic resolution and desymmetrization studies. A few years later, Romo and Smith applied isothiourea catalysis in enantioselective cascade reactions to prepare carbocycles and heterocycles acessing new reactivities of isothiourea. Several research groups were then attracted toward this new field of organocatalysis, and applied isothioureas as nucleophilic catalysts in executing cascade methodologies to synthesize various intresteting molecular scaffolds including heterocycles. The present review documents a summary on the construction of heterocyclic molecules by isothiourea organocatalysis. Heterocycles are of prime interest to organic chemists due to their omnipresence in natural products and bioactive molecules. The Lewis basic nucleophilic catalyst isothioureas play a pivotal role in the cascades to generate either α,β-unsaturated acyl isothiouronium ion or isothiouronium enolate as the prime reaction intermediate. We have covered the reactions involving two intermediates of opposite reactivities affording various heterocycles.     

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.     

Superhydrophobic surfaces from sustainable colloidal systems

In recent decades, sustainable superhydrophobic surfaces from natural materials and sustainable processes have attracted increased interest due to their lower environmental footprint and potential applications in self-cleaning surfaces and biomedical devices. Although there is significant progress on selecting suitable nano and micro particles to prepare superhydrophobic surfaces, a comprehensive review on the direct use of sustainable colloidal particles (SCPs) is lacking. In this review, we highlight the recent advances on sustainable superhydrophobic surfaces using SCPs. The composition and properties, extraction methods, and chemical modifications are described, including cellulose nanocrystals, chitin/chitosan nanoparticles, and lignin nanoparticles. In addition to the physico–chemical properties and tunable dimensionality, the fabrication methodologies of superhydrophobic surfaces using modified colloids are described. Finally, the potential applications of these sustainable superhydrophobic surfaces ranging from oil/water separation, biomedical, water harvesting, biofabrication, microfluidic reactor, and food packaging are discussed together with a future perspective on the advances made.     

Aromatic Aminocatalysis

Aromatic aminocatalysis refers to transformations that employ aromatic amines, such as anilines or aminopyridines, as catalysts. Owing to the conjugation of the amine moiety with the aromatic ring, aromatic amines demonstrate distinctive features in aminocatalysis compared with their aliphatic counterparts. For example, aromatic aminocatalysis typically proceeds with slower turnover, but is more active and conformationally rigid as a result of the stabilized aromatic imine or iminium species. In fact, the advent of aromatic aminocatalysis can be traced back to before the renaissance of organocatalysis in the early 2000s. So far, aromatic aminocatalysis has been widely applied in bioconjugation reactions through transamination; in asymmetric organocatalysis through imine/enamine tautomerization; and in cooperative catalysis with transition metals through C?H/C?C activation and functionalization. This Focus Review summarizes the advent of and major advances in the use of aromatic aminocatalysis in bioconjugation reactions and organic synthesis.     

Direct Asymmetric Alkylation of Ketones: Still Unconquered

The alkylation of ketones is taught at basic undergraduate level. In many cases this transformation leads to the formation of a new stereogenic center. However, the apparent simplicity of the transformation is belied by a number of problems. So much so, that a general method for the direct asymmetric alkylation of ketones remains an unmet target. Despite the advancement of organocatalysis and transition‐metal catalysis, neither field has provided an adequate solution. Indeed, even use of an efficient and general stoichiometric chiral reagent has yet to be reported. Herein we describe the state‐of‐the‐art in terms of direct alkylation reactions of some carbonyl groups. We outline the limited progress that has been made with ketones, and potential routes towards ultimately achieving a widely applicable methodology for the asymmetric alkylation of ketones.     

In the golden age of organocatalysis

The term "organocatalysis" describes the acceleration of chemical reactions through the addition of a substoichiometric quantity of an organic compound. The interest in this field has increased spectacularly in the last few years as result of both the novelty of the concept and, more importantly, the fact that the efficiency and selectivity of many organocatalytic reactions meet the standards of established organic reactions. Organocatalytic reactions are becoming powerful tools in the construction of complex molecular skeletons. The diverse examples show that in recent years organocatalysis has developed within organic chemistry into its own subdiscipline, whose "Golden Age" has already dawned.     

γ-Valerolactone (GVL) as a green and efficient dipolar aprotic reaction medium

The great challenge for modern research is to define the most efficient tools to make more sustainable the industrial production and manufacturing. Among the different aspects that require attention the replacement of toxic and/or non-renewable solvents it is certainly playing a crucial role. Dealing with widely used dipolar aprotic solvents, among the different alternatives proposed in the literature γ-valerolactone (GVL) plays a pivotal role covering different application area. In this contribution, the benefits derived from the use of GVL as a circular, safe, biomass-derived reaction medium are highlighted covering most recent publications (2021). The presentation has been divided into three major sections: (i) biomass valorization, (ii) materials synthesis, manufacturing and recycle and (iii) new synthetic methodologies.     

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.