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Herein, we present an organocatalyst that addresses the reactivity issue of aliphatic aldehydes with hydroxyacetone, leading to the formation of a linear product. Previous proline‐based catalysts required a significant excess of hydroxyacetone and could only be applied to aromatic aldehydes. The proposed sulphonamide containing a proline moiety effectively controls the reaction, generating a new stereogenic center dependent on the catalyst's configuration and does not require a large excess of the ketone. We demonstrated that this methodology can be effectively utilized in the synthesis of natural compounds, as confirmed by obtaining the 2‐keto‐3‐deoxy‐D‐gluconic acid (KDG) methyl ester from optically pure glyceraldehyde and protected hydroxyacetone. [ABSTRACT FROM AUTHOR]

Herein we report our observations from the study of the classical Robinson annulation reaction under solvent‐free mechanochemical activation by means of high‐speed ball milling. In particular, the enantioselective synthesis of the Wieland‐Miescher ketone was used as model reaction. (S)‐Proline was employed as chiral organocatalyst, either alone or in the presence of additives in order to determine their influence on the reaction's speed and stereoselectivity. Most interesting, among the additives that were examined, four solvate ionic liquids (SIL) afforded the desired product with significantly improved enantioselectivity relative to the mechanochemically‐activated reaction catalyzed by (S)‐proline alone. Furthermore, the required reaction time was reduced from 3 days to 90 min. The potential of other proline‐type organocatalysts was explored in this ball‐milling process. Initial attempts to increase the scope of the reaction to afford related annulation products were unsuccessful. HPLC‐MS experiments were carried out in order to detect some of the species that intervene in the mechanism of the (S)‐proline‐catalyzed Robinson cyclization reaction involving 2‐methyl‐1,3‐cyclohexanedione and methyl vinyl ketone. [ABSTRACT FROM AUTHOR]

A series of bispidine conjugates bearing monoterpene moieties and either l-proline or l-phenylalanine residues was synthesized. The synthesized bispidines can catalyze asymmetric ethylation of benzaldehydes with diethylzinc. The highest enantioselectivity of the addition reaction (ee 24%) was achieved for bispidine with (–)-α-pinene and Boc-l-proline moieties. [ABSTRACT FROM AUTHOR]

The catalytic asymmetric (3 + 3) cycloaddition between different 2-indolylmethanols has been established, in which a series of chiral indole-fused six-membered heterocycles were constructed in high yields with excellent enantioselectivities. This work not only has established the first catalytic asymmetric cycloaddition between different 2-indolylmethanols but also provided a powerful strategy for constructing enantioenriched indole-fused six-membered rings. Additionally, biological evaluation discovered some products with promising antitumor activities. Notably, theoretical calculations performed on the reaction pathway and activation mode provide an in-depth understanding of this catalytic asymmetric (3 + 3) cycloaddition among different 2-indolylmethanols, which will advance the understanding of the chemistry of indolylmethanols. [ABSTRACT FROM AUTHOR]

Pulsed ultrasonic irradiation with on‐off modulation remarkably enhances asymmetric noncovalent organocatalysis "on water", specifically for Michael addition and Diels‐Alder reactions. This approach effectively addresses challenges associated with solid reactant dispersion encountered in "on‐water" reactions and mitigates overheating issues caused by continuous ultrasound exposure, thereby significantly augmenting reaction rates and stereoselectivities. [ABSTRACT FROM AUTHOR]

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature's most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries. [ABSTRACT FROM AUTHOR]

Steric hindrance in Lewis acid (LA) and Lewis base (LB) obstruct the Lewis acid–base adduct formation, and the pair was termed as frustrated Lewis pair (FLP). In the past 16 years, the field of enantioselective catalysis by chiral FLPs has been slowly growing. It was shown that chiral LAs are significant as they are involved in the hydrogen transfer (HT) step to the imine, resulting in enantioselectivity. After H2 activation, the borohydride can exist in a number of plausible conformations and their stability is governed by the presence of noncovalent interaction through C–H····π and π····π interactions. However, LBs are not ideal for asymmetric induction as they compete with the imine substrate as a counter LB. Further, the proton transfer from chiral LB to the imine does not induce any chirality as chirality develops in the HT step. However, intramolecular FLPs with chiral scaffold are very efficient as they possess an optimum distance between LA and LB, which facilitates the H2 activation but precludes the adduct formation of the small molecules substrate with the LA component. This mini‐review summarizes computational investigation involving chiral LA and LB, and discusses intramolecular FLPs in the enantioselective catalysis. [ABSTRACT FROM AUTHOR]

Four bifunctional, noncovalent amine-squaramide organocatalysts were prepared from camphor in five steps. The stereochemistry of the prepared catalysts was thoroughly analyzed using various spectroscopic techniques. Their organocatalytic activity was investigated in the Michael addition of acetylacetone to trans-β-nitrostyrene. The addition product was formed in complete conversion and with an enantioselectivity of up to 77% ee. In the reactions catalyzed by the 2-exo-3-endo catalysts, the major (S)-enantiomer was formed, whereas in the presence of 2-endo-3-endo catalysts, the (R)-enantiomer was formed as the major product. [ABSTRACT FROM AUTHOR]

A four-step synthesis process of bifunctional, noncovalent organocatalysts based on the chiral (1R,2R)-cyclohexane-1,2-diamine scaffold containing a 1,2-benzenediamine H-bond donor was developed. Nucleophilic aromatic substitution of the 2-fluoronitrobenzene derivative with the commercial (1R,2R)-cyclohexane-1,2-diamine was followed by selective alkylation of the primary amino group, reduction of the aromatic nitro group and final derivatization of the primary aromatic amino group, i.e., acylation, sulfonation, reductive alkylation and arylation, leading to the four subtypes of organocatalysts. All new compounds were fully characterized. The prepared organocatalysts (32 examples) were tested in the Michael addition of acetylacetone to trans-β-nitrostyrene, yielding the addition product with incomplete conversions (up to 93%) and enantioselectivities of up to 41% ee. [ABSTRACT FROM AUTHOR]

A convenient and efficient method for the synthesis of optically active difluoro-substituted indoline derivatives starting from the corresponding 3H-indoles by chiral phosphoric acid-catalyzed transfer hydrogenation was developed. Using Hantzsch ester as the hydrogen source under mild reaction conditions, the target products can be obtained with excellent yield and enantioselectivity.

A designed chiral thiourea‐iminophosphorane catalyst was developed to afford α‐acyloxythioesters through enantioselective acyl‐transfer/protonation of α‐acyloxy‐β‐ketosulfides. The desired reaction proceeded in good yields with high enantioselectivities using a chiral thiourea‐iminophosphorane bearing a pyrrolidine scaffold. [ABSTRACT FROM AUTHOR]

A novel kinetic resolution (KR) method has been developed for 3,3-disubstituted indolines, whose catalytic asymmetric synthesis remains a significant challenge in organic synthesis. The key to the success of this KR protocol lies in the utilization of chiral phosphoric acid-catalyzed triazane formation reaction with azodicarboxylates, which enables the enantioselective synthesis of various substituted indolines bearing C3-quaternary stereocenters with good to high enantioselectivities (with s-factors up to 70). Moreover, an intriguing parallel kinetic resolution (PKR) has been developed by combining triazane formation and dehydrogenation reactions using different azodicarboxylates. Experimental studies have provided insight into the mechanism of this PKR reaction, demonstrating stereoselectivity in both triazane formation and dehydrogenation steps, favoring the opposite enantiomers. The large-scale synthesis and diverse derivatizations of the products, particularly the imine group-containing 3H-indoles, demonstrate the value of these (P)KR methods. [ABSTRACT FROM AUTHOR]

In the chemistry community, catalytic asymmetric synthesis of furan‐based compounds bearing both axial and central chirality has proven to be a significant but challenging issue owing to the importance and difficulty in constructing such frameworks. In this work, we have realized the first catalytic asymmetric synthesis of five‐five‐membered furan‐based compounds bearing both axial and central chirality via organocatalytic asymmetric (2+4) annulation of achiral furan‐indoles with 2,3‐indolyldimethanols with uncommon regioselectivity. By this strategy, furan‐indole compounds bearing both axial and central chirality were synthesized in high yields with excellent regio‐, diastereo‐, and enantioselectivities. Moreover, theoretical calculations were conducted to provide an in‐depth understanding of the reaction pathway, activation mode, and the origin of the selectivity. [ABSTRACT FROM AUTHOR]

Enantio‐ and diastereoselective dearomative [4+2]‐cycloaddition reaction between N,N‐dimethylhydrazone derived from 9‐anthracenecarboxaldehyde and α,β‐unsaturated aldehydes is reported. The developed strategy utilizes HOMO‐rising activation of diene (via hydrazone formation) and aminocatalytic LUMO‐lowering activation of dienophile (via iminium ion formation). High chemical and stereochemical efficiency have been obtained owing to the application of Jørgensen catalyst. Target cycloadducts were subjected to selected transformations aiming at unmasking the hydrazone moiety that proceeded with preservation of optical purity introduced in the organocatalytic step. [ABSTRACT FROM AUTHOR]

The presence of an aromatic additive has been seen to enhance, often significantly, the enantioselectivity and yield in asymmetric organocatalysis. Considering their success across a dizzying range of organocatalysts and organic transformations, it would seem unlikely that a common principle exists for their functioning. However, the current investigations with DFT suggest a general principle: the phenolic additive sandwiches itself, through hydrogen bonding and π⋅⋅⋅π stacking, between the organocatalyst coordinated electrophile and nucleophile. This is seen for a wide range of experimentally reported systems. That such complex formation leads to enhanced stereoselectivity is then demonstrated for two cases: the cinchona alkaloid complex (BzCPD), catalysing thiocyanation (2‐naphthol additive employed), as well as for L‐pipecolicacid catalysing the asymmetric nitroaldol reaction with a range of nitro‐substituted phenol additives. These findings, indicating that dual catalysis takes place when phenolic additives are employed, are likely to have a significant impact on the field of asymmetric organocatalysis. [ABSTRACT FROM AUTHOR]

Ring‐fused aminal is an interesting structural skeleton in biologically active and pharmaceutically relevant compounds. A novel and efficient method for synthesizing benzosulfamidate‐fused tetrahydroquinazolines is described. By employing the [4+2]‐cycloaddition of 2‐aminophenyl enones with cyclic N‐sulfimines in the presence of DMAP as a base, the desired benzosulfamidate‐fused tetrahydroquinazolines were obtained in good yields with high diastereoselectivities. Furthermore, an organocatalytic asymmetric [4+2]‐cycloaddition was successfully achieved using a squaramide‐based catalyst, enabling the enantioselective synthesis of chiral ring‐fused tetrahydroquinazolines with high yields and enantio‐ as well as diastereoselectivities (up to 89 % yield, 94 % ee, and >30 : 1 dr). [ABSTRACT FROM AUTHOR]

Over the recent years, the pharmaceutical field has been under significant pressure to adapt to the principles of green chemistry. The industry is facing the challenge of environmental protection and securing people's health while sustaining its fundamental goals of efficiency and selectivity optimization. In this work, the reaction processes optimization has been acheived through the microfluidic approach to the widely used aldol condensation reaction. In accordance with the green chemistry principles, we have found that the best conditions include aqueous ethanol solvent and easily available amino acids used as catalysts. Asymmetric aldol condensation of para -nitrobenzaldehyde with cyclohexanone catalyzed by L- tert -Leu under microfluidic conditions provided the product with high yield and diastereoselectivity (anti/syn = 28:1) and 98% enantiomeric excess. The microfluidic reactor process, compared to the classical batch method (in a flask), provides comparable product yield, while the reaction time was reduced by an order of magnitude. It should be noted that this approach allows to carry out the reactions at low (below zero) temperatures with greater enantioselectivity. [Display omitted] • A microfluidic approach has been successfully applied to optimize asymmetric aldol condensation. • The reaction conditions meet the principles of green chemistry. • The reaction mechanism was suggested to explain the regularities in the observed values of stereoselectivity. • Reaction time was reduced by an order of magnitude compared to conventional methods. • The reaction can be carried out even at temperature below zero with greater enantioselectivity. [ABSTRACT FROM AUTHOR]

The synthesis of a chiral isothiourea, namely, (4aR,8aR)‐3‐phenyl‐4a,5,6,7,8,8a‐hexahydrobenzo[4,5]imidazo[2,1‐b]thiazol‐9‐ium bromide, C15H17N2S+·Br−, with potential organocatalytic and anti‐inflammatory activity is reported. The preparation of the heterocycle of interest was carried out in two high‐yielding steps. The hydrobromide salt of the isothiourea of interest provided suitable crystals for X‐ray diffraction analysis, the results of which are reported. Salient observations from this analysis are the near perpendicular arrangement of the phenyl ring and the mean plane of the heterocycle. This conformational characteristic may be relevant with regard the stereoselectivity induced by the chiral isothiourea in asymmetric reactions. Furthermore, evidence was found for the existence of an S...Br− halogen bond. [ABSTRACT FROM AUTHOR]

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature’s most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

Bifunctional thioureas and, for the first time, bifunctional thiosquaramides as organocatalysts were used in the asymmetric Betti reaction involving 1-, 2-naphthols and hydroxyquinoline with N-tosylimine and ketimine. The described methodology affords direct access to chiral aminoarylnaphthols in excellent yield (up to 98%) with high enantioselectivity (up to 80% ee) and enantioenriched 3-amino-2-oxindoles (up to 78% yield, up to 98% ee). [ABSTRACT FROM AUTHOR]

We herein report a two‐step approach for the enantioselective synthesis of novel chiral δ‐lactams. By using a cooperative chiral ITU/achiral Pd‐catalyst system, this protocol proceeds via an asymmetric α‐allylation of activated aryl esters first, followed by an acid‐mediated lactam formation. A variety of differently substituted products could be obtained with usually high levels of enantioselectivities and in reasonable yields (16 examples, up to 98 : 2 er and 73 % yield over two steps). In addition, further utilizations of the products via transformations of the exocyclic double bond were successfully carried out as well. [ABSTRACT FROM AUTHOR]

A first catalytic preparation of the popular antiplatelet drug (S)‐clopidogrel, known with the tradename of Plavix, has been developed in a one‐pot and innovative approach. The synthesis can be performed using commercially available ortho‐chlorobenzaldehyde, 1‐naphthylsulfonyl acetonitrile, tert‐butyl hydroperoxide (TBHP), 4,5,6,7‐tetrahydrothieno[3,2‐c]pyridine and 20 mol % of a quinidine derived organocatalyst in a single solvent. A Knoevenagel/asymmetric epoxidation/domino ring‐opening esterification (DROE) sequence enabled to obtain (S)‐clopidogrel in 61 % overall yield and 62 % ee. Fine optimization of the reaction conditions proved to be crucial to set up a selective and efficient process. [ABSTRACT FROM AUTHOR]

We herein report a two‐step protocol for the asymmetric synthesis of novel chiral benzofused ϵ‐lactones starting from O‐protected hydroxymethyl‐para‐quinone methides and activated aryl esters. By using chiral isothiourea Lewis base catalysts a broad variety of differently substituted products could be obtained in yields of around 50 % over both steps with high levels of enantioselectivities, albeit low diastereoselectivities only. [ABSTRACT FROM AUTHOR]

[Display omitted] New ferrocenyl-containing diastereomeric secondary alcohols derived from L-proline of (ferrocenyl)(pyrrolidin-2-yl)methanol chemotype were synthesized. Their crystal and molecular structure was explored. The prepared chiral secondary and tertiary alcohols in which hydroxy group is sterically hindered by ferrocene substituents show asymmetric induction effect in reaction between diethylzinc and benzaldehyde. [ABSTRACT FROM AUTHOR]

[Display omitted] Syntheses of new ferrocenyl-containing tertiary alcohols derived from l-proline were developed. In these alcohols,two ferrocenyl groups are bonded at prolinol moiety directly or through p -phenylene spacer. Specific features for the ferrocene Grignard reagents were discovered. [ABSTRACT FROM AUTHOR]

A chiral sulfonamide-phosphine catalyzed regio- and enantioselective (3 + 3)-annulation of 2-(4H-benzo[d][1,3]oxazin-4-yl)acrylates with 2,4-dihydro-3H-pyrazol-3-ones has been established, affording a wide range of such 1,4,5,6-tetrahydropyrano [2,3-c]pyrazole-containing carboxylates in generally high yields (61–96%) with high diastereo- and enantioselectivities (8:1->20:1 dr, 85–95% ee). Based on several control experiments, a reaction mechanism was proposed. Importantly, the work represents the first example of using benzoxazinyl acrylates as three-atom synthons, which enriches the chemistry of benzoxazinyl acrylates.

Direct enantioselective synthesis of 2‐substituted chromen‐4‐ones, bearing the amino group at α‐stereogenic center with respect to the heterocycle is developed. It is based on Mannich‐type asymmetric addition of 3‐hydroxychromen‐4‐one and its analogues to N‐protected imines in the presence of available alkaloid dihydrocuprein. α‐Stereogenic chromenone amino derivatives were formed in this reactions in 81–95% yield with up to 98% ee. The chiral adducts were transformed to diverse enantiomerically enriched chromen‐4‐one functional derivatives. [ABSTRACT FROM AUTHOR]

Catalytic asymmetric construction of chiral indole‐fused rings has become an important issue in the chemical community because of the significance of such scaffolds. In this work, we have accomplished the first catalytic asymmetric (4+2) and (4+3) cycloadditions of 2,3‐indolyldimethanols by using indoles and 2‐naphthols as suitable reaction partners under the catalysis of chiral phosphoric acids, constructing enantioenriched indole‐fused six‐membered and seven‐membered rings in high yields with excellent enantioselectivities. In addition, this approach is used to realize the first enantioselective construction of challenging tetrahydroindolocarbazole scaffolds, which are found to show promising anticancer activity. More importantly, theoretical calculations of the reaction pathways and activation mode offer an in‐depth understanding of this class of indolylmethanols. This work not only settles the challenges in realizing catalytic asymmetric cycloadditions of indolyldimethanols but also provides a powerful strategy for the construction of enantioenriched indole‐fused rings. [ABSTRACT FROM AUTHOR]

We have developed an efficient modular asymmetric synthesis of azahelicenes through an organocatalyzed asymmetric multicomponent reaction from readily available polycyclic aromatic amines, aldehydes, and (di)enamides, by employing a central‐to‐helical chirality conversion strategy. A series of aza[5]‐ and aza[4]helicenes bearing various substituents were readily afforded through this one‐pot sequential enantioselective Povarov reaction/oxidative aromatization process, with good yields and high enantioselectivities. The fruitful and diverse derivatizations of the chiral azahelicene products demonstrated the potential of this method, and a preliminary application of the azahelicene derivative as a chiral organocatalyst was showcased. The photophysical and chiroptical properties of these azahelicenes, particularly the acid/base‐triggered switching of these properties, were also well studied, which may find potential applications in the development of novel organic optoelectronic materials. [ABSTRACT FROM AUTHOR]

Chiral porous organic frameworks have emerged in the last decade as candidates for heterogeneous asymmetric organocatalysis. This review aims to provide a summary of the synthetic strategies towards the design of chiral organic materials, the characterization techniques used to evaluate their chirality, and their applications in asymmetric organocatalysis. We briefly describe the types of porous organic frameworks, including crystalline (covalent organic frameworks, COFs) and amorphous (conjugated microporous polymers, CMPs; covalent triazine frameworks, CTFs and porous aromatic frameworks, PAFs) materials. Furthermore, the strategies reported to incorporate chirality in porous organic materials are presented. We finally focus on the applications of chiral porous organic frameworks in asymmetric organocatalytic reactions, summarizing and categorizing all the available literature in the field. [ABSTRACT FROM AUTHOR]

Asymmetric organocatalysis is a robust methodology providing access to numerous valuable compounds while having green chemistry principles in mind. The realization of organocatalytic transformation under solvent‐free mechanochemical conditions brings additional benefits in terms of yields, selectivities, and, last but not least overall improved sustainability. This overview describes developments in the use of mechanochemistry as a vehicle for asymmetric organocatalytic transformations. The material is organized according to main catalytic activation modes, starting with covalent activation and proceeding to non‐covalent activation modes. The advantages of mechanochemical organocatalytic reactions are particularly highlighted, but in some cases also, limitations are mentioned. Possibilities for target compound synthesis are also discussed. [ABSTRACT FROM AUTHOR]

The sulfa‐Michael addition reaction is a crucial subset of the Michael addition reaction, and aroused the interest of numerous synthetic biologists and chemists. In particular, sulfa‐Michael addition triggered cascade reaction has developed quickly in recent years because it offers an efficient method to construct C−S bonds and other bonds in one approach, which is widely applicable for building chiral pharmaceuticals, their intermediates, and natural compounds. This review emphasizes the recent advancements in sulfa‐Michael addition‐triggered cascade reactions for the stereoselective synthesis of sulfur‐containing compounds, including sulfa‐Michael/aldol, sulfa‐Michael/Henry, sulfa‐Michael/Michael, sulfa‐Michael/Mannich and some sulfa‐Michael triggered multi‐step processes. Moreover, some reaction mechanisms and derivatization experiments are introduced appropriately. [ABSTRACT FROM AUTHOR]

(Thio)‐urea‐containing bifunctional quaternary ammonium salts emerged as powerful non‐covalently interacting organocatalysts over the course of the last decade. The most commonly employed catalysts in this field are either based on Cinchona alkaloids, α‐amino acids, or trans‐cyclohexane‐1,2‐diamine. Our group has been heavily engaged in the design and use of such catalysts, i. e. trans‐cyclohexane‐1,2‐diamine‐based ones for around 10 years now, and it is therefore the intention of this short personal account to provide an overview of the, at least in our opinion, most significant and pioneering achievements in this field by looking on catalyst design and asymmetric method development, with a special focus on our own contributions. [ABSTRACT FROM AUTHOR]

The catalytic asymmetric construction of axially chiral indole-based frameworks is an important area of research due to the unique characteristics of such frameworks. Nevertheless, research in this area is still in its infancy and has some challenges, such as designing and constructing new classes of axially chiral indole-based scaffolds and developing their applications in chiral catalysts, ligands, etc. To overcome these challenges, we present herein the design and atroposelective synthesis of aryl-pyrroloindoles as a new class of axially chiral indole-based scaffolds via the strategy of organocatalytic asymmetric (2 + 3) cyclization between 3-arylindoles and propargylic alcohols. More importantly, this new class of axially chiral scaffolds was derived into phosphines, which served as efficient chiral ligands in palladium-catalyzed asymmetric reactions. Moreover, theoretical calculations provided an in-depth understanding of the reaction mechanism. This work offers a new strategy for constructing axially chiral indole-based scaffolds, which are promising for finding more applications in asymmetric catalysis.

Chiral phosphoric acids (CPAs) and their salts are the privileged catalysts in a plethora of asymmetric transformations. All of the scaffolds of efficient CPAs rely on C2‐symmetry and axial chirality, while the only examples of punctually chiral CPAs are TADDOL derivatives. Herein, we present the design and the synthesis of C2‐symmetric cycloglycerophosphates (cGPAs) and their application throughout the addition of trimethylsilyl cyanide (TMSCN) to aldehydes and ketones, to obtain the corresponding cyanohydrins in yields between 77 and 99% and ee between 84.2 and 99.5% (27 examples). A DFT computational model is moreover performed to rationalize the reaction mechanism and its stereochemical outcome. [ABSTRACT FROM AUTHOR]

A chiral Brønsted acid‐catalysed asymmetric hydrophosphinylation of 2‐vinylazaarenes by secondary phosphine oxides is described. A variety of P‐chiral 2‐azaaryl‐ethylphosphine oxides are synthesized with high yields and ees, of which both the substituents of phosphines and azaarenes can be flexibly modulated, underscoring an exceptionally broad scope of substrates. These adducts are valuable to asymmetric metal catalysis since the resultant P‐chiral tertiary phosphines from the reduction of them are verified as a kind of effective C1‐symmetric chiral 1,5‐hybrid P,N‐ligands. Importantly, this catalysis platform enables the generic and efficient kinetic resolution of P‐chiral secondary phosphine oxides. It thus provides an expedient approach to access the enantiomers of the P‐chiral tertiary phosphine oxides derived from asymmetric hydrophosphinylation, further improving the utility of the method. [ABSTRACT FROM AUTHOR]

Thiourea‐based iminophosphorane (BIMP) organocatalysts featuring SPhos‐ or BIDIME phosphine units have been developed and successfully applied in the asymmetric addition of nitromethane to N‐Boc‐protected trifluoromethyl aryl ketimines. α‐Trifluoromethyl β‐nitroamines were obtained in 40–82% isolated yields and 80–95% enantioselectivities. A careful evaluation of the catalytic activity of BIMPs indicates that the catalysts derived from the combination via Staudinger reaction of a chiral 1,2‐amino alcohol‐derived thiourea‐organoazide with electron‐rich phosphines, promote the aza‐Henry reaction on fluorinated ketimines with the highest enantioselectivity, leading to the amine featuring a tetrasubstituted stereocenter in up to 95% ee. The reaction was performed also on gram scale, without loss of enantioselectivity. [ABSTRACT FROM AUTHOR]

The inclusion of achievements in science awarded with the Nobel prize in chemistry can give students in chemistry lessons inspiring and, above all, motivating insights into current researches. The awarded researches give an important basis for the conception of experimental teaching courses and are fundamental for the design of chemistry lessons according to the principle of scientific accuracy and topicality. Based on Benjamin List′s work, the following article presents an experimental and theoretical approach to asymmetric organocatalysis for pupils in accordance with the principle of exemplary teaching. Due to the low hazard potential of the reactants and products as well as the simplicity of the procedure, pupils can carry out the experiment and derive the reaction mechanisms using their technical competences acquired during their school career and thus they can understand the basic concepts of asymmetric organocatalysis. In addition, classical reactions to detect functional groups of organic molecules and analyses for the characterisation of the products are used, which, in comparison with the base‐catalysed aldol reaction, allow access to the concept of enantioselectivity. The comparison of the base‐catalyzed with the L‐Proline‐catalyzed aldol reaction enables the discussion of ecological and economic aspects of both reaction methods and promotes communication and evaluation skills as well as reflection in scientific contexts. [ABSTRACT FROM AUTHOR]

Asymmetric Brønsted acid catalysis has been recognized as a powerful concept for asymmetric synthesis. In the process of pursuing more robust and highly effective chiral Brønsted acid catalysts, chiral bisphosphoric acids have received much attention in the last two decades. Their unique catalytic properties are mainly attributed to the inherent intramolecular hydrogen bonding interactions that could increase the overall acidity and tune the conformation property. Integrating hydrogen bonding into the catalyst design, quite a few structurally unique and effective bisphosphoric acids have been synthesized, which frequently exhibited superior selectivity in a broad range of asymmetric transformations. This review summarizes the status quo of chiral bisphosphoric acid catalysts and their applications in catalyzing asymmetric transformations. [ABSTRACT FROM AUTHOR]

The conceptually designed imidodiphosphorimidates (IDPis) have emerged as one of the most potent classes of chiral acid catalysts. They are characterized by enzyme‐like, highly confined active site and high acidity, which underlie their wide‐reaching applications as Brønsted acid catalysts and as precatalysts for silylium Lewis acids. Many carbon‐carbon and carbon‐heteroatom bond formation reactions that were deemed intractable could now be attained with spectacular reactivity and selectivity. Substrates that are small, unbiased and/or possess insufficient reactivity such as simple alkenes could now be engaged. The high structural confinement is particularly invaluable to control stereo‐ and chemoselectivity. The well‐defined steric environment offers unique opportunity to control high‐energy but structurally unbiased cation intermediates such as the norbonyl cations. Beyond practical appeals such as good scalability as well as ease and modularity of preparation, the extremely low pre‐catalyst loadings required to achieve high turnover and stereoselectivity have also come to define a new frontier in organocatalysis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Efficient synthetic methods that avoid the extensive use of hazardous reagents and solvents, as well as harsh reaction conditions, have become paramount in the field of organic synthesis. Organocatalysis is notably one of the best tools in building chemical bonds between carbons and carbon-heteroatoms; however, most examples still employ toxic volatile organic solvents. Although a portfolio of greener solvents is now commercially available, only ethyl alcohol, ethyl acetate, 2-methyltetrahydrofuran, supercritical carbon dioxide, ethyl lactate, and diethyl carbonate have been explored with chiral organocatalysts. In this review, the application of these bio-based solvents in asymmetric organocatalytic methods reported in the last decade is discussed, highlighting the proposed mechanism pathway for the transformations. [ABSTRACT FROM AUTHOR]

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. [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. [ABSTRACT FROM AUTHOR]

[Display omitted] Phosphine-mediated reactions driven by the formation of phosphine oxide have long been recognized as an intriguing approach in forming C C, C N, and C–X (where X represents O, N, S etc.) bonds. In the field of P(III)/P(V)=O redox catalysis, the asymmetric version is still in its infancy. In the past decade, several noteworthy works on asymmetric P(III)/P(V)=O redox catalysis processes revealed their application in various chemically valuable transformations. These achievements also elucidated unique features of catalyst structures for catalyst design. In this review, we will delve into these advances, with a specific emphasis on the phosphine skeletons used and the reduction conditions employed, providing future directions in the development of asymmetric P(III)/P(V)=O redox catalysis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Theoretical solid–liquid equilibrium curves and experimental studies have been used to identified new chiral DES. • A chiral choline chloride surrogate is an ideal chiral hydrogen bond acceptor for the preparation of new chiral DES. • The chiral DES have been thermally and structural characterized and used as reaction media in asymmetric organocatalysis. The present investigation centers on synthesizing, characterizing, and exploring the organocatalytic potential of a novel series of chiral deep eutectic solvents based on chiral (ammoniummethyl)pyrrolidine derivatives 1 – 3. Using the theoretical solid–liquid equilibrium curves, we have been able to identify three chiral deep eutectic solvents (CDESs) that have been thermally and structurally characterized and used as reaction medium in the conjugate addition of cyclohexanone to trans -β-nitrostyrene. Among these chiral deep eutectic solvents, the mixture 2 /EG: 1/3, where a chiral choline bromide surrogate is employed as the HBA, has shown good organocatalytic activity and recyclability in the studied model organocatalyzed process. Notably, this CDES exhibited higher activity and selectivity compared to organocatalyst 2 , and at the same level as that exhibited by the 2 /TFA catalyst under neat conditions. [ABSTRACT FROM AUTHOR]

Bifunctional thioureas and, for the first time, bifunctional thiosquaramides as organocatalysts were used in the asymmetric Betti reaction involving 1-, 2-naphthols and hydroxyquinoline with N-tosylimine and ketimine. The described methodology affords direct access to chiral aminoarylnaphthols in excellent yield (up to 98%) with high enantioselectivity (up to 80% ee) and enantioenriched 3-amino-2-oxindoles (up to 78% yield, up to 98% ee).

This perspective intends to cover the vast field of asymmetric organocatalysis and its evolution during the last ten years. This work has evaluated the corresponding timeline of the progression of the field concerning the main synthetic approaches as well as the ground-breaking synergetic approach between experimental and computational methods. With the combination of an evolutionary trend and the expansion of computing technology, further advancements in the field of asymmetric organocatalysis are undeniable.

(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. [ABSTRACT FROM AUTHOR]