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Asymmetric organocatalytic reactions of various electron‐deficient racemic allenes with a wide variety of nucleophiles and electrophiles were reviewed. The literature on enantioselective functionalization of allenes that employs chiral phosphine, amine, phase transfer, bifunctional, and Brønsted acid catalysis is presented along with the mechanisms. In addition, the review emphasizes methods of obtaining enantioenriched allenes from racemic allenes via organocatalytic (dynamic) kinetic resolution techniques. The synthetic utility of the developed methodologies toward the target‐orientated biologically active molecules is narrated along with the examples. [ABSTRACT FROM AUTHOR]

Organocatalyzed Michael addition of N‐substituted tetramic acids to nitroalkene acceptors followed by O‐alkylation gave polyfunctionalized tetramic acid (31 examples, 59–94% ee). The enantioselectivity of the product was influenced by the N‐substituent of the substrate. Quantum chemical methods provided the mechanistic insights of the studied transformation. The preferred reaction pathway follows the model proposed by Pápai et al. Single crystal structure confirmed the absolute configuration, which was in line with the ECD measured and calculated structure. Additionally, a comparative study of the alkylation of a selected tetramic and tetronic acid with trans‐β‐nitrostyrene is disclosed. Follow‐up amidations demonstrated the applicability of this class of compounds for the incorporation into both dipeptide and depsipeptide sequences. [ABSTRACT FROM AUTHOR]

The field of organocatalysis, more specifically asymmetric organocatalysis, is continuously expanding having grown significantly over the recent years. However, despite this exponential expansion, the ability to determine with any degree of certainty the reaction mechanisms of these types of reactions fails to keep within pace. Due to increasing calculation capacity and methods accuracy, computational methodologies have been established as an essential approach in both a predictive and supportive role to aid the synthetic design of novel catalysts by enabling the prediction of catalytic behaviour. This review is focused on the computationally‐led catalyst design within asymmetric organocatalysis, discussing the different theoretical approaches most commonly utilised. This article is categorized under:Structure and Mechanism > Reaction Mechanisms and CatalysisSoftware > Quantum ChemistryQuantum Computing > Algorithms [ABSTRACT FROM AUTHOR]

It is clear that the field of organocatalysis is continuously expanding during the last decades. With increasing computational capacity and new techniques, computational methods have provided a more economic approach to explore different chemical systems. This review offers a broad yet concise overview of current state‐of‐the‐art studies that have employed novel strategies for catalyst design. The evolution of the all different theoretical approaches most commonly used within organocatalysis is discussed, from the traditional approach, manual‐driven, to the most recent one, machine‐driven. [ABSTRACT FROM AUTHOR]

A total of 24 novel organocatalysts based on (S)-quininamine as a chiral tertiary amine and on enaminone or 1,2-benzenediamine as hydrogen bond donors were synthesized. The enaminone-type catalysts were prepared by the transamination of N,N-dimethyl enaminones with (S)-quininamine (9 examples) and the 1,2-benzenediamine-type catalysts were prepared in 3 steps from (S)-quininamine and ortho-fluoronitrobenzene derivatives (15 examples). Their organocatalytic activity was evaluated in the Michael addition of acetylacetone to trans-β-nitrostyrene. Enantioselectivities of up to 72% ee were observed. [ABSTRACT FROM AUTHOR]

The catalytic atroposelective synthesis of axially chiral isochromenone-indoles has been established by the strategy of designing homophthalic anhydride-based indole derivatives as a new type of indole-based platform molecules for dynamic kinetic resolution. By this strategy, a wide range of axially chiral isochromenone-indoles were synthesized in high yields with excellent enantioselectivities (up to 98% yield, 97% ee) via the catalytic asymmetric sulfonylation reaction of homophthalic anhydride-based indole derivatives with aryl sulfonyl chlorides under the catalysis of chiral quaternary ammonium salt as a phase-transfer catalyst [ABSTRACT FROM AUTHOR]

The synthesis of bifunctional N-sulfinylureas and thioureas with an appended pyrrolidine unit is presented. These organocatalysts were evaluated in Michael additions of aldehydes to nitroalkenes both under solvent-free conditions and in solution. The N-sulfinylurea catalyst was more efficient than the corresponding thiourea. For some substrates, enantioselectivities reached 98% ee. The stereogenic center on the sulfur did not have a considerable influence on the catalytic reactions. Under ball-milling conditions, the Michael adducts were obtained in good yields but with slightly lower enantiomeric purities than in solution. DFT calculations elucidated its mode of action and confirmed a dual activation mode, which combines enamine activation of aldehydes and hydrogen-bond activation of nitroalkenes.

(S)-(1-Pyrrolidin-2-ylmethyl)quinuclidine-1-ium bromide was synthesized in a six-step reaction process starting from l-proline and spectroscopically and thermally characterized.

Asymmetric Michael additions of carbonyl compounds to N-substituted maleimides are among the most convenient reactions to prepare optically pure succinimide building blocks. Although a few β-amino acids were found to be highly efficient organocatalysts in the addition of α-branched aldehydes, the effect of their structure on the results of these reactions has not yet been investigated. In the present study, we disclose several unexpected and interesting structural effects of aliphatic and cycloaliphatic β-amino acids obtained in the enantioselective conjugate addition of isobutyraldehyde to N-benzylmaleimide. The dependence of the sense of the enantioselectivity on the bulkiness of the substituent on the β-carbon atom, the beneficial spatial arrangements of the functional groups in cis isomers with cyclohexane scaffold and the inversion of the enantioselectivity depending on the absence of a base additive observed with some trans isomers are unprecedented findings. The minor influence of the nitrogen substituent of the maleimide ring on both the reaction rate and the enantioselectivity was also evidenced using alicyclic β-amino acid prepared from an easily available terpene derivative. [ABSTRACT FROM AUTHOR]

The synthesis of chiral proline-derived squaramide and thiosquaramide organocatalysts, which are capable of the dual activation in asymmetric reactions is reported. The (thio)squaramide moiety can form hydrogen bonds to activate the substrates and to stereocontrol the reaction, while the pyrrolidine unit can form enamines to activate carbonyl compounds via aminocatalysis. Comparing the performance of thiosquaramide to squaramide, the Diels–Alder reaction of (anthracen-9-yl)acetaldehyde and trans -β-nitrostyrene was examined, which has been investigated in the literature using quantum chemical calculations. Both squaramide and thiosquaramide gave excellent yields (up to 99%) and enantiomeric excess values (up to 98%). Moreover, their catalytic performance was compared in conjugate addition of lawsone to β,γ-unsaturated α-keto ester. [ABSTRACT FROM AUTHOR]

In an interview with Benjamin List, winner of the 2021 Nobel Prize in Chemistry, members of the Young Chemists' Network (JCF) of the German Chemical Society (GDCh) asked him about his science, his career, and the academic system. Benjamin List, Director at the Max‐Planck‐Institut für Kohlenforschung in Germany, was awarded the Nobel Prize together with David W. C. MacMillan (Princeton University, USA) for the development of asymmetric organocatalysis. After studying chemistry at the Free University of Berlin, he received his doctorate from Goethe University in Frankfurt. He discovered the amino acid proline to be an efficient catalyst and thus co‐founded the field of organocatalysis. In 2016, he received the Gottfried Wilhelm Leibniz Prize, which is considered the most important research award in Germany. [ABSTRACT FROM AUTHOR]

A series of chiral enantiomerically pure aziridines containing a phosphine moiety were synthesized and successfully applied as organocatalysts in asymmetric intramolecular Rauhut–Currier reactions of p-quinone derivatives. The desired chiral phenols were achieved in high chemical yields and with satisfactory values of enantiomeric excess (up to 98% ee, in some cases). The stereochemical course of the title reaction may be controlled by the use of an appropriate enantiomer of the catalyst. The individual enantiomers of the organocatalyst led to the formation of specific enantiomers of the chiral product. [ABSTRACT FROM AUTHOR]

A catalytic asymmetric vinylogous Mannich/annulation/acylation reaction of 2‐ethylidene 1,3‐indandiones with isatin N‐Boc ketimines has been developed, which furnished a series of chiral spiro‐oxindole piperidine derivatives with polyaromatic scaffolds in 30–67% yield and 93–98% ee. The DFT computational calculation is used to probe and explain the origin of the enantioselectivity and observed formation of O‐acetylated products. [ABSTRACT FROM AUTHOR]

An unprecedented Cinchona alkaloid catalyzed atropoenantioselective transamination of biaryl aldehydes with 2,2-diphenylglycine via a cascade decarboxylation and dynamic kinetic resolution strategy is described. This protocol features broad substrate scope and good functional group tolerance and allows the rapid assembly of axially chiral biaryls in high yields with acceptable to good enantioselectivities. In addition, such structural motifs may have potential applications in enantioselective catalysis as chiral ligands or catalysts. [ABSTRACT FROM AUTHOR]

Abstract Inspired by Mother Nature, the use of chiral covalent organic frameworks as heterogeneous asymmetric organocatalysts has arisen over the last decade as a new method in enantioselective synthesis. In this Short Review, sophisticated design of these polymeric materials and their application in asymmetric organocatalysis will be discussed.

The present Tetrahedron Report highlights salient contributions accomplished by the author's research group during the past decade in three relevant areas of organic chemistry: (1) reexamination and interpretation of conformational effects such as the anomeric and α-effect in terms of potential stereoelectronic interactions, (2) development of strategies seeking to improve the efficiency of the emblematic chiral organocatalyst (S)-proline in asymmetric organocatalysis, and (3) the successful combination of enzymatic catalysis and mechanochemical activation in the mechanoenzymatic kinetic resolution of relevant biologically active compounds. As it happens, several of these contributions were inspired by seminal contributions of Ernest L. Eliel, Dieter Seebach, Benjamin List, Tomislav Friščić, Carsten Bolm and others, and accordingly this Tetrahedron Report provides relevant examples that cover beyond the 2015–2024 decade. [Display omitted] [ABSTRACT FROM AUTHOR]

A general and efficient organocatalytic asymmetric polymerization approach for the synthesis of chiral covalent organic frameworks (CCOFs) has been developed. With a chiral 2‐methylpyrrolidine catalyst, a series of tris(N‐salicylideneamine)‐derived β‐ketoenamine‐CCOFs are directly constructed from prochiral aldehyde‐ and primary amine‐monomers. The adopted aminocatalytic asymmetric Schiff‐base condensation herein is performed under ambient conditions with clear green synthetic advantages over the conventional acid‐catalysed solvothermal methods. The obtained β‐ketoenamine‐CCOFs can be further metalated by a solid‐state coordination approach, and the resulting CuII@CCOFs can highly promote an asymmetric A3‐coupling reaction. Specifically, a CuII@CCOF@chitosan aerogel was fabricated as a highly efficient fixed‐bed model reactor for scaled‐up catalysis. The concept of aminocatalytic asymmetric polymerization might open a new way for constructing the CCOFs via asymmetric organocatalysis. [ABSTRACT FROM AUTHOR]

With increasing demand for customized commodities and the greater insight and understanding of olfaction, the synthesis of fragrances with diverse structures and odor characters has become a core task. Recent progress in organic synthesis and catalysis enables the rapid construction of carbocycles and heterocycles from readily available unsaturated molecular building blocks, with increased selectivity, atom economy, sustainability and product diversity. In this review, synthetic methods for creating cyclic fragrances, including both natural and synthetic ones, will be discussed, with a focus on the key transformations of alkenes, alkynes, dienes and enynes. Several strategies will be discussed, including cycloaddition, catalytic cyclization, ring-closing metathesis, intramolecular addition, and rearrangement reactions. Representative examples and the featured olfactory investigations will be highlighted, along with some perspectives on future developments in this area. [ABSTRACT FROM AUTHOR]

Commonly, an elusive intermediate is generated from a precursor and then trapped and consumed in a reaction. Vinylidene ortho‐quinone methides (VQMs) have been demonstrated as transient axially chiral intermediates in asymmetric catalysis due to their orthogonal π‐bonds forming an allene motif. The current understanding of VQMs is primarily based on time‐resolved absorption, trapping experiments and computational studies. Herein, we report the first isolation and comprehensive characterization of a VQM, including crystallographic analysis. The disturbed aromaticity of the VQM led to its high reactivity as an electrophile or a 4π‐component capable of asymmetric dearomatization of an electron‐deficient phenyl group. Notably, the VQM could be isolated in enantiomerically enriched form, and the subsequent transformation was stereospecific, indicating that the generation of the VQM was involved in the enantiodetermining step. This study paves the way for the direct application of VQMs as starting materials. [ABSTRACT FROM AUTHOR]

In this personal account, we describe our recent developments on the four types of amino Tf‐amide catalysts in asymmetric transformations. Firstly, axially chiral biaryl‐based secondary‐amino Tf‐amide catalyzed various stereoselective reactions via enamine intermediates. Secondly, pyrrolidine‐based secondary‐amino aliphatic Tf‐amide catalyzed asymmetric direct Mannich reaction. Thirdly, chiral primary‐amino aliphatic Tf‐amide catalyzed asymmetric direct aldol reaction and conjugate addition. Finally, modified chiral amino aromatic Tf‐amide catalyzed asymmetric transformations. These four different strategies are illustrated by using various organocatalyzed asymmetric transformations. [ABSTRACT FROM AUTHOR]

The development of an enantioselective enamine‐catalysed addition of masked acetaldehyde to nitroalkenes via a rational approach helped to move away from the use of chloroform. The presented research allows the use of water as a reaction medium, therefore improving the industrial relevance of a protocol to access very important pharmaceutical intermediates. Critical to the success is the use of chemometrics‐assisted 'Design of Experiments' (DoE) optimisation during the development of the presented new synthetic approach, which allows to investigate the chemical space in a rational way. [ABSTRACT FROM AUTHOR]

The first highly atroposelective construction of N−N axially chiral indole scaffolds was established via a new strategy of de novo ring formation. This strategy makes use of the organocatalytic asymmetric Paal–Knorr reaction of well‐designed N‐aminoindoles with 1,4‐diketones, thus affording N‐pyrrolylindoles in high yields and with excellent atroposelectivities (up to 98 % yield, 96 % ee). In addition, this strategy is applicable for the atroposelective synthesis of N−N axially chiral bispyrroles (up to 98 % yield, 97 % ee). More importantly, such N−N axially chiral heterocycles can be converted into chiral organocatalysts with applications in asymmetric catalysis, and some molecules display potent anticancer activity. This work not only provides a new strategy for the atroposelective synthesis of N−N axially chiral molecules but also offers new members of the N−N atropisomer family with promising applications in synthetic and medicinal chemistry. [ABSTRACT FROM AUTHOR]

Organocatalyzed and metal complex‐catalyzed asymmetric decarboxylative aldol reactions of malonic acid half thioesters (MAHTs), malonic acid half oxyester (MAHOs), and β‐ketoacids with different carbonyl compounds are transformations of high synthetic value. These reactions, which are heavily inspired by nature's synthesis strategies, represent important methods for the direct synthesis of valuable enantio‐enriched β‐hydroxy esters and ketones. Within this short review we wish to give an overview about the recent progress in this field by discussing the leading strategies to carry out decarboxylative aldol reactions using organocatalytic methods as well as metal catalysis. [ABSTRACT FROM AUTHOR]

Continuing our research on the use of organophosphorus derivatives of aziridines in asymmetric synthesis and expanding the scope of their applicability, chiral aziridine-phosphines obtained earlier in our laboratory were used as chiral catalysts in the asymmetric Morita–Baylis–Hillman reaction of methyl vinyl ketone and methyl acrylate with various aromatic aldehydes. The desired chiral products were formed in moderate to high chemical yields and with enantiomeric excess reaching value of 98% ee in some cases. The use of catalysts being pairs of enantiomers led to the desired products with opposite absolute configurations. [ABSTRACT FROM AUTHOR]

An organocatalytic construction of axially chiral tetrasubstituted allenes featuring indole skeletons has been established. With the aid of chiral phosphoric acid, alkynyl indole imine methides were formed in situ from α‐(3‐indolyl) propargylic alcohols, followed by the asymmetric 1,6‐conjugate addition with 2‐substituted indoles, furnishing axially chiral indole‐containing tetrasubstituted allenes in generally high yields and enantioselectivities. [ABSTRACT FROM AUTHOR]

An organocatalytic asymmetric construction of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted allene scaffolds bearing both axial chirality and central chirality has been established via a cascade 1,8-addition/dearomatization-cyclization reaction of para-aminophenyl propargylic alcohols with tryptamines in the presence of chiral phosphoric acid (CPA), thus affording a wide range of such tetrasubstituted allenes bearing multiple chiral elements in generally good yields (up to 94%) with high diastereo- and enantioselectivities (up to 95:5 dr, 95% ee). In addition, the evaluation on the cytotoxicity of some selected products indicated that this class of chiral tetrasubstituted allenes could inhibit the growth of the pancreatic cancer cells to some extent. This work not only solved the challenging issues in enantioselective construction of tetrasubstituted allenes via alkynyl (aza)-para-quinone methides, but also represents the first example of using alkyne derivatives as electrophiles in organocatalytic asymmetric dearomatizations of tryptamines.

In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos–Parrish–Eder–Sauer–Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels–Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.

Ten novel bifunctional quaternary ammonium salt phase-transfer organocatalysts were synthesized in four steps from (+)-camphor-derived 1,3-diamines. These quaternary ammonium salts contained either (thio)urea or squaramide hydrogen bond donor groups in combination with either trifluoroacetate or iodide as the counteranion. Their organocatalytic activity was evaluated in electrophilic heterofunctionalizations of β-keto esters and in the Michael addition of a glycine Schiff base with methyl acrylate. α-Fluorination and chlorination of β-keto esters proceeded with full conversion and low enantioselectivities (up to 29% ee). Similarly, the Michael addition of a glycine Schiff base with methyl acrylate proceeded with full conversion and up to 11% ee. The new catalysts have been fully characterized; the stereochemistry at the C-2 chiral center was unambiguously determined.

An organocatalytic 1,6-addition using 4-(alk-1-en-1-yl)-3-cyanocoumarins as acceptors has been developed. Dienolates derived from 5-substituted-furan-2(3H)-ones have been employed as pronucleophiles, therefore, enabling the synthesis of hybrid molecules bearing two biologically relevant units. Appropriate design of substrates and the application of quinine-derived catalyst resulted in very good site-selectivity as well as chemical and stereochemical efficiency of the process. [ABSTRACT FROM AUTHOR]

The first catalytic asymmetric Mannich reaction of 5‐substituted oxazolidine‐2,4‐diones is reported. By using an L‐tert‐leucine‐derived thiourea‐tertiary amine as catalyst, a variety of valuable oxazolidine‐2,4‐ones bearing a quaternary stereocenter at the 5‐position and an adjacent aza‐tertiary stereocenter at the α‐position of the heterocycles were obtained in high enantio‐ and diastereoselectivities. Meanwhile, exploiting an L‐tert‐leucine‐derived dipeptide‐based thiourea‐amide‐tertiary amine catalyst could switch diastereoselectivity, delivering the corresponding diastereomers with good to excellent enantioselectivities. [ABSTRACT FROM AUTHOR]

Majority of drugs act by interacting with chiral counterparts, e.g., proteins, and we are, unfortunately, well-aware of how chirality can negatively impact the outcome of a therapeutic regime. The number of chiral, non-racemic drugs on the market is increasing, and it is becoming ever more important to prepare these compounds in a safe, economic, and environmentally sustainable fashion. Asymmetric organocatalysis has a long history, but it began its renaissance era only during the first years of the millennium. Since then, this field has reached an extraordinary level, as confirmed by the awarding of the 2021 Chemistry Nobel Prize. In the present review, we wish to highlight the application of organocatalysis in the synthesis of enantio-enriched molecules that may be of interest to the pharmaceutical industry and the medicinal chemistry community. We aim to discuss the different activation modes observed for organocatalysts, examining, for each of them, the generally accepted mechanisms and the most important and developed reactions, that may be useful to medicinal chemists. For each of these types of organocatalytic activations, select examples from academic and industrial applications will be disclosed during the synthesis of drugs and natural products.

This short review focuses on enantiopure planar chiral [2.2]paracyclophanes (pCps), a fascinating class of molecules that possess an unusual three‐dimensional core and intriguing physicochemical properties. In the first part of the review, different synthetic strategies for preparing optically active pCps are described. Although classical resolution methods based on the synthesis and separation of diastereoisomeric products still dominate the field, recent advances involving the kinetic resolution of racemic compounds and the desymmetrization of meso derivatives open up new possibilities to access enantiopure key intermediates on synthetically useful scales. Due to their advantageous properties including high configurational and chemical stability, [2.2]paracyclophanes are increasingly employed in various research fields, ranging from stereoselective synthesis to material sciences. The applications of [2.2]paracyclophanes in asymmetric organocatalysis are described in the second part of the review. While historically enantiopure pCps have been mainly employed by organic chemists as chiral ligands in transition‐metal catalysis, these compounds can also be used as efficient catalysts in metal‐free reactions and may inspire the development of new transformations in the near future. [ABSTRACT FROM AUTHOR]

The recent advances in asymmetric organocatalysis using eutectic mixtures as a reaction medium are revised in this mini‐review. In addition, the first enantioselective transformations using chiral eutectic solvents, which play the role of a green medium and organocatalyst, are described. In this minireview we intend to deepen not only in the synthetic aspects of asymmetric organocatalysis in eutectic mixtures, but also in the fundamental issues that seem to be essential for a successful development of this promising, and at the same time challenging, methodology. [ABSTRACT FROM AUTHOR]

[Display omitted] Chiral β-amino carbonyl compounds serve as a useful building block in synthesizing diverse molecules. Organocatalytic Mannich-type reactions of glyoxylate imines provide efficient access to compounds with additional ester functionality. This article overviews recent advances in Mannich-type reactions using iminoester acceptor derivatives. In the first part, organocatalysts operating via covalent activation are discussed. The focus is on enamine-forming organocatalysts such as pyrrolidine-derived catalysts as well as catalysts based on other structural motifs. The second part deals with non-covalent organocatalysts, such as thioureas, squaramides, and more acidic chiral Brønsted acids. The new catalysts or their combinations allow for achieving high enantioselectivities and desired diastereoselectivities. Applications in the synthesis of target compounds are also demonstrated. [ABSTRACT FROM AUTHOR]

New chiral atropisomeric biphenyl diols 3, 4 and 6 containing additional peripheral chiral centers with different steric bulkiness and/or electronic properties were synthesized. The X-ray crystal structure of 3 shows the formation of a supramolecular structure whereas that of 6, containing additional CF3 substituents, shows the formation of a monomeric structure. Diols 1–6 were found to be active organocatalysts in oxo-Diels–Alder reactions in which 2 recorded a 72% ee with trimethylacetaldehyde as a substrate.

A series of chiral enantiomerically pure aziridines containing a phosphine moiety were synthesized and successfully applied as organocatalysts in asymmetric intramolecular Rauhut–Currier reactions of p-quinone derivatives. The desired chiral phenols were achieved in high chemical yields and with satisfactory values of enantiomeric excess (up to 98% ee, in some cases). The stereochemical course of the title reaction may be controlled by the use of an appropriate enantiomer of the catalyst. The individual enantiomers of the organocatalyst led to the formation of specific enantiomers of the chiral product.

Chiral analogues of squaramides have been fruitful in organocatalyzed asymmetric reactions over last decade. Alongside other H‐bonding catalysts like ureas, thioureas: squaramides have been proved to be efficient asymmetric catalysts for the formation of acyclic and cyclic chiral molecules. A wide range of cyclic molecules bearing multiple functionalities and stereocenters have been synthesized by using several bifunctional squaramides as catalysts. These catalysts perform as base utilizing basic N atom in their chiral extension and help in stereoinduction by forming H‐bonds with suitable H‐bond acceptors. The present review focuses on assembling recent progresses of asymmetric synthesis of five and six membered rings promoted by squaramides. A handful of articles have been published by several research groups documenting asymmetric construction of five‐ and six‐membered rings as part of interesting and complex molecular architectures. Different methodologies like conventional and formal cycloadditions or cascade reactions have been engineered through the assistance of chiral squaramides to fabricate the carbo‐ and heterocycles. This review also includes dual and cooperative catalytic system in which squaramide is one of the catalysts. [ABSTRACT FROM AUTHOR]

We have investigated the stereoselective formation of spiro oxindole pyrrolidines via formal [3+2] cycloaddition of oxindole imines with ketoesters and ketoamides. Bifunctional squaramide organocatalyst was able to induce enantioselectivity of up to 60 % ee, increased to 72 % ee after re‐crystallization, in the formation of spiro pyrrolidines with ketoesters. Interestingly, ketoamides provided alternative spiro oxindole pyrrole products in addition to the main product, which was formed via a different reaction pathway. Structures of spiro oxindole pyrrolidine as well as pyrrole products were confirmed by X‐ray crystallographic analysis. Two new squaramide based catalysts were synthesized and tested. DFT calculation helped elucidate the reaction course. [ABSTRACT FROM AUTHOR]

The first kinetic resolution of hydroquinoline derivatives with α,α‐disubstitution has been achieved through asymmetric remote aminations with azodicarboxylates enabled by chiral phosphoric acid catalysis. Mechanistic studies suggest a monomeric catalyst pathway proceeding through rate‐ and enantio‐determining electrophilic attack promoted by a network of attractive non‐covalent interactions between the substrate and catalyst. Facile subsequent removal and transformations of the newly introduced hydrazine moiety enable these protocols to serve as powerful tools for asymmetric synthesis of N‐heterocycles with α,α‐disubstitution. [ABSTRACT FROM AUTHOR]

In this study, the novel bifunctional homochiral thiourea‐L‐prolinamides 1–4, tertiary amino‐L‐prolinamide 5, and bis‐L‐prolinamides 6 and 7 were prepared from enantiomerically pure (11R,12R)‐11,12‐diamino‐9,10‐dihydro‐9,10‐ethanoanthracene 8 and (11S,12S)‐11,12‐diamino‐9,10‐dihydro‐9,10‐ethanoanthracene ent‐8. Highly enantioselective and diastereoselective aldolic intermolecular reactions (up to 95% enantiomeric excess, 93:7 anti/syn) between aliphatic ketones (20 equiv) and a range of aromatic aldehydes (1 equiv) were successfully carried out in the presence of water (10 equiv) and monochloroacetic acid (10 mol%), solvent‐free conditions, at room temperature over 24 h using organocatalysts 1–7 (5 mol%). Stereoselective induction using density functional theory–based methods was consistent with the experimental data. [ABSTRACT FROM AUTHOR]

A new asymmetric organocatalyzed intramolecular aza-Michael reaction by means of both a chiral auxiliary and a catalyst for stereocontrol is reported for the synthesis of optically active isoindolinones. A selected cinchoninium salt was used as phase-transfer catalyst in combination with a chiral nucleophile, a Michael acceptor and a base to provide 3-substituted isoindolinones in good yields and diastereomeric excesses. This methodology was applied to the asymmetric synthesis of a new pazinaclone analogue which is of interest in the field of benzodiazepine-receptor agonists.

H‐bond donor catalysts able to modulate the reactivity of ionic substrates for asymmetric reactions have gained great attention in the past years, leading to the development of cooperative multidentate H‐bonding supramolecular structures. However, there is still a lack of understanding of the forces driving the ion recognition and catalytic performance of these systems. Herein, insight into the cooperativity nature, anion binding strength, and folding mechanism of a model chiral triazole catalyst is presented. Our combined experimental and computational study revealed that multi‐interaction catalysts exhibiting weak binding energies (≈3–4 kcal mol−1) can effectively recognize ionic substrates and induce chirality, while strong dependencies on the temperature and solvent were quantified. These results are key for the future design of catalysts with optimal anion binding strength and catalytic activity in target reactions. [ABSTRACT FROM AUTHOR]

An organocatalytic enantioselective synthesis of δ‐lactone‐fused 4‐chromanones was demonstrated using 1‐(2‐hydroxyaryl)‐1,3‐butanedione and α,β‐unsaturated aldehydes in the presence of the Jørgensen‐Hayashi catalyst. The reaction proceeded through a Michael addition/cycloketalization/hemiacetalization sequence, and the resulting hemiacetals were oxidized into the corresponding lactone derivatives in a one‐pot manner. The desired fused O,O‐ketal tricyclic lactone motifs containing three contiguous chiral centers were obtained in excellent chemical yields (up to 97%) and with high stereoselectivities (up to >20:1 dr and up to 95% ee). [ABSTRACT FROM AUTHOR]

Chiral aliphatic heterocycles are important structural feature of many pharmaceutical agents. Antibiotic resistance is a serious medical problem, therefore new antibacterial compounds are urgently needed. Herein, we describe synthesis of a series of 3,4‐disubstituted pyrrolidine derivatives via organocatalytic Michael addition followed by reductive cyclization. These compounds inhibited growth of standard as well as methicillin‐resistant strains of Escherichia coli and Staphylococcus aureus. [ABSTRACT FROM AUTHOR]

An organocatalyst‐controlled site‐selectivity switchable enantioselective Friedel‐Crafts reaction of unprotected 1‐naphthols has been established for the first time via the conjugate addition of 1‐azadienes. By two chiral complementary squaramide and phosphoric acid, both ortho‐ and para‐selective Friedel‐Crafts alkylations of 1‐naphthols were independently achieved with high efficiency and enantioselectivity. With this strategy, a wide range of optically active triarylmethanes have been achieved in high yields with good to excellent enantioselectivities. [ABSTRACT FROM AUTHOR]

Catalytic asymmetric [2 + 4] cycloadditions of 3-vinylindoles with ortho-quinone methides and their precursors were carried out in the presence of chiral phosphoric acid to afford a series of indole-containing chroman derivatives with structural diversity in overall high yields (up to 98%), good diastereoselectivities (up to 93:7 dr) and moderate to excellent enantioselectivities (up to 98% ee). This approach not only enriches the chemistry of catalytic asymmetric cycloadditions involving 3-vinylindoles but is also useful for synthesizing chiral chroman derivatives.

In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural products and synthetic bioactive molecules, hence it has attracted intense interest in organic synthesis and medicinal chemistry, particularly with respect to controlling the diastereo- and enantioselectivity. To the best of our knowledge, there has been only one attempt prior to this work towards the development of a catalytic enantioselective Pinder reaction. In our approach, we designed, synthesized, and tested dual chiral organocatalysts by combining BIMAH amines, (2-(α-(alkyl)methanamine)-1H-benzimidazoles, and a Lewis acid motif, such as squaramides, ureas and thioureas. The optimum catalyst was the derivative of isopropyl BIMAH bearing a bis(3,5-trifluoromethyl) thiourea, which afforded the Pinder products from various aromatic aldehydes with diastereomeric ratio >98:2 and enatioselectivity up to 92 ee%. Interestingly, the enantioselectivity of this catalyzed process is increased at higher concentrations and exhibits an isoinversion effect, namely an inverted "U" shaped dependency with respect to the temperature. Mechanistically, these features, point to a transition state involving an entropy-favored heterodimer interaction between a catalyst/anhydride and a catalyst/aldehyde complex when all other processes leading to this are much faster in comparison above the isoinversion temperature.

This review highlights major developments in the application of green organocatalytic and enzymatic dynamic kinetic resolutions (DKRs) in the total synthesis of biorelevant scaffolds. It illustrates the diversity of useful bioactive products and intermediates that can be synthesized under greener and more economic conditions through the combination of the powerful concept of DKR, which allows the resolution of racemic compounds with up to 100% yield, with either asymmetric organocatalysis or enzymatic catalysis, avoiding the use of toxic and expensive metals. With the need for more ecologic synthetic technologies, this field will undoubtedly expand its scope in the future with the employment of other organocatalysts/enzymes to even more types of transformations, thus allowing powerful greener and more economic strategies to reach other biologically important molecules., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)