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Amine-rich carbon dots (NCDs) have become promising nano-aminocatalytic platforms in organic synthesis. These nanomaterials can be effectively produced through straightforward bottom-up approaches using inexpensive nitrogen-containing molecular precursors as a starting material. However, to date, there is still a limited understanding of how the molecular features of these precursors affect the catalytic activity of the resulting nanoparticles. This study concerns the production of a new family of NCDs, which use l-arginine and different alkyl diamines as starting materials. The surface amines of all these NCDs were comprehensively characterized, thus allowing us to provide a correlation between the structural features of the nanoparticles and their catalytic performance with a selected amino-catalyzed organic transformation. Importantly, the most active nano-aminocatalysts, namely, NCDs-3, were then used as a basis for the formation of a wide variety of functionalized organic compounds in water under mild reaction conditions.

We report the first catalytic enantioselective conjugate addition of allyl groups to α,β-unsaturated aldehydes. The chemistry exploits the visible-light-excitation of chiral iminium ions to activate allyl silanes towards the formation of allylic radicals, which are then intercepted stereoselectively. The underlying radical mechanism of this process overcomes the poor regio- and chemoselectivity that traditionally affects the conjugate allylation of enals proceeding via polar pathways. We also demonstrate how this organocatalytic strategy could selectively install a valuable prenyl fragment at the β-carbon of enals.

The development of novel and effective metal-free catalytic systems, which can drive value-added organic transformations in environmentally benign solvents (for instance, water), is highly desirable. Moreover, these new catalysts need to be harmless, easy-to-prepare, and potentially recyclable. In this context, amine-rich carbon dots (CDs) have recently emerged as promising nano-catalytic platforms. These nitrogen-doped nanoparticles, which show dimensions smaller than 10 nm, generally consist of carbon cores that are surrounded by shells containing numerous amino groups. In recent years, organic chemists have used these surface amines to guide the design of several synthetic methodologies under mild operative conditions. This Concept highlights the recent advances in the synthesis of amine-rich carbon dots and their applications in organic catalysis, including forward-looking opportunities within this research field.

The first catalytic enantioselective and diastereoselective synthesis of atropisomeric hydrazides was achieved using a sequential catalysis protocol. This strategy is based on a one-pot sequence of two organocatalytic cycles featuring the enamine amination of branched aldehydes followed by nitrogen alkylation under phase-transfer conditions. The resulting axially chiral hydrazides were obtained directly from commercially available reagents in high yields and with good stereocontrol. The permutation of organocatalysts allowed easy access to all stereoisomers, enabling a stereodivergent approach to enantioenriched atropisomeric hydrazides.

Currently, conventional reductive catalytic methodologies do not guarantee general access to enantioenriched β-branched β-trifluoromethyl α-amino acid derivatives. Herein, a one-pot approach to these important α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, is presented. The configurations of the two chirality centers of the products are established during each of the two catalytic steps, enabling a stereodivergent process., A one-pot approach to β-branched β-trifluoromethyl α-amino acids, grounded on the reduction – ring opening of Erlenmeyer–Plöchl azlactones, and complementary to conventional catalytic asymmetric hydrogenation, is presented.

Herein, we report a general iminium ion‐based catalytic method for the enantioselective conjugate addition of carbon‐centered radicals to aliphatic and aromatic enals. The process uses an organic photoredox catalyst, which absorbs blue light to generate radicals from stable precursors, in combination with a chiral amine catalyst, which secures a consistently high level of stereoselectivity. The generality of this catalytic platform is demonstrated by the stereoselective interception of a wide variety of radicals, including non‐stabilized primary ones which are generally difficult to engage in asymmetric processes. The system also served to develop organocatalytic cascade reactions that combine an iminium‐ion‐based radical trap with an enamine‐mediated step, affording stereochemically dense chiral products in one‐step., An organocatalytic method for the enantioselective conjugate addition of carbon radicals to aliphatic and aromatic enals is reported. The system imparts consistently high stereoselectivity for the interception of a wide variety of radicals, including highly reactive primary radicals. The protocol also serves to develop radical cascade processes leading to stereochemically dense chiral products in one‐step.

Enantioselective organocatalysis has quickly established itself as the third pillar of asymmetric catalysis. It is a powerful technology platform, and it has a tremendous impact in both academic and industrial settings. By focusing on pregabalin, as a case study, this Perspective aims to show how a process amenable to industry of a simple chiral molecule can be tackled in several different ways using organocatalysis.

In this work, the development of a novel efficient heterogeneous catalytic system capable of driving Knoevenagel condensation reactions between benzaldehydes and malononitrile was reported. Specifically, we explored a post-synthetic modification of graphitic carbon nitride (g-CN) through a strong oxidation treatment by acid mixture (HNO3/H2SO4). The as-prepared oxidized CN material (CNO) shows a large number of surface acidic moieties, that can be easily deprotonated through an aqueous alkaline wash with different bases (NaOH, K2CO3, t-BuOK), to introduce a high density of reactive basic sites. The best catalyst is obtained with NaOH as the base (CNO-NaOH), and displays high reactivity and good tolerance towards functional group variations of the reagents, thus emerging as a potential new recyclable carbon nitride-based structure for organic base catalysis.

We describe an efficient photocatalytic procedure for the direct iodosulfonylation of terminal olefins 3 with α-iodo phenylsulfones 4. Specifically, the process uses the simple, robust, and fully recyclable phenol derivative 6e as the precatalytic system and occurs with visible-light irradiation (450 nm). Mechanistic investigations proved the key role of the in situ generated photocatalyst, namely phenolate anion 7e, which has shown high catalytic activity and considerable stability toward the operating conditions. Importantly, this photocatalytic transformation provides a wide variety of densely functionalized alkyl iodides 5 (23 examples, up to 95% yield). Finally, the synthetic potential of this photochemical transformation was demonstrated by scaling up the process under microfluidic conditions (up to 0.67 mmol h–1) while accessing a series of relevant product manipulations.

The hexameric resorcin[4]arene capsule as a self-assembled organocatalyst promotes a series of reactions like the carbonyl–ene cyclization of (S)-citronellal preferentially to isopulegol, the water elimination from 1,1-diphenylethanol, the isomerization of α-pinene and β-pinene preferentially to limonene and minor amounts of camphene. The role of the supramolecular catalyst consists in promoting the protonation of the substrates leading to the formation of cationic intermediates that are stabilized within the cavity with consequent peculiar features in terms of acceleration and product selectivity. In all cases the catalytic activity displayed by the hexameric capsule is remarkable if compared to many other strong Brønsted or Lewis acids.

The main scientific objective of this doctoral research was to develop powerful metal-free organic (photo)catalytic systems to efficiently realize new carbon-carbon and carbon-heteroatom bond forming transformations of practical importance. These approaches had to meet the sustainability requirements for green chemical productions by using effective, non-toxic, safe, readily available from economic precursors and potentially recyclable catalysts. In doing so, the preparation of synthetically relevant organic intermediates could be promptly achieved in mild conditions, thus envisaging the potential application of the studied methodologies at preparative scale. Chapter I introduces the general concepts of organic catalysis, including both polar and radical chemistry. Moreover, it aims to illustrate the physicochemical principles underlying the operative mechanisms of the abovementioned catalytic systems. Chapter II focuses on the development of a photochemical strategy for the iodoperfluoroalkylation of alkenes triggered by a simple perylene diimide photocatalyst. Successively, this Chapter describes the translation of the established procedure into continuous flow with the aim of up-scaling the preparation of the relevant perfluorinated compounds. Chapter III discusses the use of photoactive nitrogen-doped carbon dots as catalysts for the light-driven perfluoroalkylation of electron-rich organic substrates. This approach allows the extension of the reactivity to more inert arenes and heteroarenes. Chapter IV describes the development of green polar organocatalytic methodologies in aqueous media by exploiting the surface amino functionalities of the very same nitrogen-doped carbon nanoparticles. Remarkably, this original approach has been made possible by a fine characterization of the nanomaterial at unprecedent level of detail. Chapter V shows how another carbon-based nanomaterial, namely carbon nitride, can trigger photochemical aryl amination reactions of high synthetic importance. Interestingly, this transformation is carried out under flow conditions by means of an innovative oscillatory microstructured reactor to overcome the challenges associated with handling solids in flow.

Self-assembling minimalistic peptides embedded with an organocatalytic moiety were designed. By controlling the formation of fibrils via external intervention, it was shown that the activation is accelerated when the organocatalyst is in its supramolecular state. The effect of the accelerated catalysis was demonstrated in a Michael benchmark reaction.

Herein, we present the scale up development of an innovative synthetic process to pregabalin. The process is underpinned by two enabling technologies critical to its success; continuous chemistry allowed a safe and clean production of nitroalkene, and asymmetric organocatalysis gave access to the chiral intermediate in an enantioenriched form. Crucial to the success of the process was the careful development of a continuous process to nitroalkene and optimization of the organocatalyst and of the reaction conditions to attain remarkably high turn-over frequency in the catalytic asymmetric reaction. Successful recycle of the organocatalysts was also developed in order to achieve a cost-competitive process.

Stabilised sulfur ylides are synthetically appealing compounds, which reactivity under Brønsted acid catalysis has been poorly explored. Herein, we report a new catalyst- and substrate- dependent chemodivergent reaction between stabilised sulfur ylides and salicylaldehydes, leading to the (suprising) formation of 2H-chromenes or dihydrobenzofurans products. Particular attention was set on the unusual mechanisms involved. Two unique reaction routes including two ylide units in the reactions are proposed. These pathways were validated by performing a selectivity switch in some cases, enabled by the modulation of the nucleophilicity of the sulfur ylide, and by the loading of the Brønsted acid catalyst in the reaction.

This chapter covers the emerging utilization of organocatalytic methodologies in industrial settings directed at the large-scale preparation of enantioenriched amines and N-heterocycles. First, some selected manufacturing processes, based on organocatalytic stereodetermining steps, are commented concisely. Despite the generally high catalyst loadings required, these examples show that the relatively low cost of organic catalysts makes the development of cost-effective industrial routes possible. Then, three case studies (pregabalin, the bicyclic core of telaprevir, and 5-(trifluoromethyl)-2-isoxazolines) are discussed. These chiral targets have been approached through a variety of enantioselective strategies, among which the organocatalytic ones stand out for their versatility and potential for scale-up. Recent applications of organocatalysis in industrial settings are not restricted to a single activation mode or a class of catalysts. They encompass the whole catalyst and reaction repertoire typical of this relatively novel catalytic approach to asymmetric synthesis. Asymmetric organocatalysis proves to be, therefore, a useful and versatile synthetic tool for the industrial preparation of chiral compounds.

Over the last decades, organic chemistry has taken a resolute step toward green catalytic synthesis. This tries to ensure efficient and sustainable base chemical production, while also safeguarding human health and the environment. To this end, the development of novel, nontoxic, and effective catalytic systems that are capable of driving value-added chemical transformations in environmentally benign solvents (e.g., water) is highly desirable. Moreover, these new catalysts need to be metal-free, easy-to-prepare, and potentially recyclable. Carbon dots, which are relatively new carbon-based nanoparticles, fulfill all these requirements because of their outstanding physicochemical features and thus have emerged as promising nanocatalytic platforms. This Perspective highlights the recent advances in synthesis of carbon dots and their applications in organic catalysis and photocatalysis, with particular attention to green nonmetal-doped systems. Finally, forward-looking opportunities within this field are mentioned here.

Graphical Abstract Application of small chiral organic molecules in catalysis has been dominated by formation of chiral enamines or iminium ions. Nucleophiles – electrophiles reactivity has been exploited in many papers. Now, the possibility to combine organocatalysis with photochemistry open new “exciting” possibilities and opportunities, in reactions that are mediated by radicals.

This minireview covers the literature of the last decade related to the stereochemistry of axially chiral molecules. The first section reviews the use of dynamic NMR and dynamic HPLC for the ranking of the steric size of common organic moieties. The second and third sections describe the recent advances in the preparation of new atropisomeric scaffolds, and in the asymmetric synthesis of stereogenic axes by means of atroposelective organocatalysis.

A novel strategy for the direct enantioselective oxidative homocoupling of α-branched aldehydes is presented. The methodology employs open-shell intermediates for the construction of chiral 1,4-dialdehydes by forming a carbon–carbon bond connecting two quaternary stereogenic centers in good yields and excellent stereoselectivities for electron-rich aromatic aldehydes. The 1,4-dialdehydes were transformed into synthetically valuable chiral pyrrolidines. Experimental mechanistic investigations based on competition experiments combined with computational studies indicate that the reaction proceeds through a radical cation intermediate and that reactivity and stereoselectivity follow different trends.

Despite the broad interest in ferrocene containing compounds, ferrocenyl substrates have been employed in catalytic asymmetric settings only sporadically. Herein, catalytic asymmetric Povarov reactions with ferrocenecarbaldehyde-derived N-aryl imines are presented. This study demonstrates that the stereoelectronic properties of ferrocenyl imines do not preclude their engagement in enantioselective phosphoric acid catalysis: cycloadducts derived from benzyl N-vinylcarbamate were obtained in good yields and nearly enantiopure form using 0.1mol% of a standard Bronsted acid catalyst. Furthermore, it is shown that specific optimisation with some substrates allowed to lower the catalyst loading up to 10-20 parts-per-million, an unprecedented value for phosphoric acid catalysts. Such low loading protocol could be applied to a preparative scale reaction, and to imines derived from arylaldehydes.

A representative Lewis base organic catalyst (9-amino-9-deoxy epi-quinine, QNA) can be adsorbed in high yields onto acidic alginate gels (AGs) using a very simple and straightforward protocol. The resulting solvogel beads (QNA@AGs) are active as heterogeneous catalysts in the addition of aldehydes to nitroalkenes, affording the corresponding adducts in good yields and moderate to excellent diastereo- and enantio-selectivities. In these reactions, the carboxylic functions of the biopolymer act as both acidic co-catalyst and non-covalent anchoring site for the tertiary amine catalyst (as observed by IR spectroscopy). Use of heterocationic gels, derived from alkaline earth metal gels by proton exchange, provided materials with better mechanical properties and higher porosities, ultimately resulting in higher catalytic activities. This work represents the first utilization of alginates, abundant and renewable biopolymers, as gel supports/media for asymmetric organocatalytic processes.

Catalysis is, often, the preferred approach to access chiral molecules in enantioenriched form both in academia and in industry; nowadays, organocatalysis is recognised as the third pillar in asymmetric catalysis, along with bio- and metal-catalysis. Despite enormous advancements in academic research, there is a common belief that organocatalysis is not developed enough to be applicable in industry. In this review, we describe a selection of industrial routes and their R&D process for the manufacture of active pharmaceutical ingredients, highlighting how asymmetric organocatalysis brings added value to an industrial process. The thorough study of the steps, driven by economic stimuli, developed and improved chemistry that was, otherwise, believed to not be applicable in an industrial setting. The knowledge discussed in the reviewed papers will be an invaluable resource for the whole research community.

We employed the membrane of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) liposomes suspended in water as a microenvironment for carrying out the organocatalytic epoxidation of an α-alkylidene oxindole. The reaction proceeds smoothly and displays diastereo- and enantio-selectivity that differs from what is achieved under bulk solution conditions. The potential of organocatalytic approaches for synthetic transformations in aqueous phase in the presence of dispersed membranes is briefly discussed.

Diastereoisomeric pyrazolone-fused spirocyclohexenimines, bearing contiguous all-carbon quaternary and tertiary stereocenters, are readily synthesized for the first time in good to excellent yield (up to 98%) and high enantioselectivity (up to 97% ee) via vinylogous Michael reaction/cyclization cascade reaction of α-arylidene pyrazolones and α,α-dicyanoalkylidenes. The formal [4+2] atom-economical annulation proceeds with commercially available Takemoto's catalyst under mild reaction conditions. Scale-up reaction and post-transformation of the products were also demonstrated. (Figure presented.).

The catalytic enantioselective dearomatization of pyridines with nucleophiles represents a direct and convenient access to highly valuable dihydropyridines. Available methods, mostly based on N-acylpyridinium salts, give addition to the C-2/C-6 of the pyridine nucleus, rendering 1,2-/1,6-dihydropyridines. Herein, we present an alternative approach to this type of dearomatization reaction, employing activated N-benzylpyridinium salts in combination with a bifunctional organic catalyst. Optically active 1,4-dihydropyridines resulting from the addition of the nucleophile (indole) to the C-4 of the pyridine nucleus are obtained as major products, rendering this method for nucleophilic dearomatization of pyridines complementary to previous approaches.

The efficient desymmetrization of N -(2- tert -butylphenyl)maleimides was realized by means of a Michael addition reaction of a series of carbon nucleophiles generating the corresponding axially chiral succinimides in high yields. The use of (DHQD) 2 Pyr as catalyst was fundamental to achieve the remote control of the stereogenic chiral axis with the concurrent construction of adjacent quaternary and tertiary stereocenters.

The proline-catalysed asymmetric aldol reaction is usually carried out in highly dipolar aprotic solvents (dimethylsulfoxide, dimethylformamide, acetonitrile) where proline presents an acceptable solubility. Protic solvents are generally characterized by poor stereocontrol (e.g., methanol) or poor reactivity (e.g., water). Here, we report that water/methanol mixtures are exceptionally simple and effective reaction media for the intermolecular organocatalytic aldol reaction using the simple proline as the catalyst.

Il focus di questo dottorato è stato lo sviluppo di due reazioni organocatalitiche e stereoselettive: le addizioni di sulfa-Michael e le condensazioni di Darzens poiché rappresentano degli approcci sintetici interessanti per la sintesi di farmaci chirali e, nell’ambito farmaceutico, ci sono pochi principi attivi (API) sintetizzati con reazioni di SMAs e/o di Darzens organocatalitiche e stereoselettive. Nell’ambito delle addizioni di sulfa-Michael (SMAs), la catalisi mediata da molecole bifunzionali donatrici di legami ad idrogeno (HBD) rappresenta un approccio interessante per l'attivazione sia della componente nucleofila che di quella elettrofila di una reazione. Gli esempi di SMA stereoselettive catalizzate da HBD bifunzionali e aventi il trans-chalcone come accettore di Michael sono pochi. Con l’obiettivo di ottimizzare l’attivitá dei catalizzatori HBD, la letteratura suggerisce come l'aumento dell'acidità dei protoni tioureici NH abbia effetti positivi sulle velocità di alcune reazioni. Spinto da queste informazioni, si è deciso di eseguire un'analisi comparativa di alcuni catalizzatori HBD in SMA stereoselettive aventi il trans-calcone come accettore di Michael. All’inizio, abbiamo studiato l'effetto della quantitá di catalizzatore, del solvente e della temperatura nella reazione modello: l'addizione del fenilmetantiolo al trans-calcone. Successivamente, con le condizioni di reazione ottimizzate, abbiamo valutato la capacità di indurre stereoselezione da parte di alcuni catalizzatori HBDs nelle SMAs stereoselettive del benzentiolo, fenilmetantiolo e 2-feniletantiolo al trans-calcone. L'aumento dell'acidità di Brønsted nella porzione donatrice di legami ad idrogeno ha dato, in alcuni casi, reazioni più rapide ma, in generale, ha avuto un impatto negativo sulla stereoselettività. Inoltre, il prodotto ottenuto dall’addizione del benzentiolo al trans-calcone è risultato stereochimicamente instabile, poiché subisce una reazione di retro-Michael quando lasciato in presenza di catalizzatori, come nel caso di un ritardato work-up della reazione. Per quanto riguarda le condensazioni di Darzens, generalmente, sono condotte in presenza di basi forti come idrossidi o alcossidi di metalli alcalini, sodio ammide, LDA, LiHMDS o n-butil-litio. In letteratura, non ci sono esempi di reazioni di Darzens condotte in presenza di basi organiche neutre. Quindi, si è deciso di studiare la reazione di Darzens in presenza di basi organiche neutre aventi una diversa pKBH+. La reazione, in presenza di una quantità stechiometrica di fosfazene P1-t-Bu, genera gli epossidi cis e trans con una buona resa e con un breve tempo di reazione. Tuttavia, sia i problemi di stabilità che le difficoltà di preparazione delle basi fosfazeniche, rendono importante l’obiettivo di identificare nuove superbasi. A tal fine, è stata valutata la ciclopropenimmina, con una pKBH+ simile a quella di P1-t-Bu. Con l’impiego di una quantità stechiometrica di ciclopropenimmina, l'epossido è stato ottenuto con una resa fino al 34% e 1/0.85 d.r. cis/trans. Usando una quantità catalitica di ciclopropenimmina (30 mol%), i composti α,β-epossicarbonilici sono stati ottenuti con una resa fino all'86% e 1/0.6 d.r. cis/trans; dimostrando di essere tollerante sia alle variazioni strutturali che alle proprietà elettroniche delle aldeidi aromatiche e dei composti carbonilici impiegati.

Taking into account the postulated reaction mechanism for the organocatalytic epoxidation of electron-poor olefins developed by our laboratory, we have investigated the key factors able to positively influence the H-bond network installed inside the substrate/catalyst/oxidizing agent. With this aim, we have: (i) tested a few catalysts displaying various effects that noticeably differ in terms of steric hindrance and electron demand; (ii) employed alpha-alkylidene oxindoles decorated with different substituents on the aromatic ring (11a-“g), the exocyclic double bond (11h-l), and the amide moiety (11m-“v). The observed results suggest that the modification of the electron-withdrawing group (EWG) weakly conditions the overall outcomes, and conversely a strong influence is unambiguously ascribable to either the N-protected or N-protected lactam framework. Specifically, when the NH free substrates (11m-“u) are employed, an inversion of the stereochemical control is observed, while the introduction of a Boc protecting group affords the desired product 12v in excellent enantioselectivity (97:3 er).

We introduce 3-(alkoxycarbonyl-2-alkyliden)-2-oxindoles as pronucleophilic donors in the direct, vinylogous Michael addition to nitroolefins orchestrated by a chiral, bifunctional cinchona-thiourea organocatalyst. This reaction displays excellent levels of γ-site-, diastereo- and enantioselectivity delivering valuable enantioenriched functionalized oxindoles. Of note, the C-γ enolization of these pronucleophiles by the organocatalyst generates a multidentate, captodative dienolate that delivers vinylogous adducts with an unprecedented Z-selectivity through a peculiar interaction with the catalyst and the nitroolefin. The optimized procedure is operatively simple: the reaction is conducted in air, at room temperature, with low catalyst loading (up to 1 mol%). The synthetic versatility of these Michael adducts is demonstrated by several transformations leading to a valuable quaternary oxindolyl proline analogue and a chiral spirocyclic furoindolone structure. Finally, a mechanistic rationale and a suitable transition state accounting for the observed selectivities are proposed, which are supported by DFT calculations. (Figure presented.).

A novel concept for catalytic asymmetric coupling reactions is presented. Merging organocatalysis with single-electron oxidation by using a catalytic amount of a copper(II) salt and air as the terminal oxidant, we have developed a highly stereoselective carbon–carbon oxidative coupling reaction of α,β-unsaturated aldehydes. The concept relies on the generation of a dienamine intermediate, which is oxidized to an open-shell activated species that undergoes highly selective γ-homo- and γ-heterocoupling reactions. In the majority of examples presented, only a single stereoisomer was formed.

Activated 3-substituted isoindolinones have been investigated as nucleophiles in the organocatalytic asymmetric cross-aldol reaction with formaldehyde for the synthesis of derivatives with tetrasubstituted stereocenters. Among the tested catalysts, bifunctional chiral tertiary amines led to the target products in high yields and moderate enantioselectivity, while chiral ammonium salts, tested under phase-transfer conditions, were less effective. Graphical abstract: [Figure not available: see fulltext.]

In recent years, the field of organocatalysis has extensively explored the use of carbenium ions for practical C−C bond forming reactions. In order to control the formation of new stereocenters, the generation of carbenium ions was investigated by exploring asymmetric Brønsted acid catalysis. Oxocarbenium ions, iminium ions, and other carbenium ions stabilized by heteroatoms could also be generated by Brønsted acid catalysis, through the departure of suitable leaving groups. The aforementioned reactivity has recently been exploited leading to remarkable achievements. The application of chiral Brønsted acids in the generation of heteroatom stabilized carbenium ions has recently been investigated, with the demonstration of important results. Although diverse architectural arrays of Brønsted acid catalysts were conceived, BINOL-derived phosphoric acids have played a dominant role in this area of research. Their low pKa values combined with the possibility to alter their architecture, and their ability to assemble ordered transition states was exploited in different SN1-type reactions allowing the formation of a variety of products with high enantiomeric excesses. In addition, the generation of highly stabilized chiral counter anions allowed the exploitation of counterion asymmetric catalysis with various nucleophiles.

In the context of a programme directed at the manufacture of telaprevir, eight possible approaches to its bicyclic α-amino acid core, based on organocatalytic enantioselective conjugate additions to cyclopent-1-enecarbaldehyde, were identified and preliminarily explored. Four reactions, delivering advanced intermediates en route to the target amino acid, were selected for a thorough optimisation. Three of this reactions involved iminium ion catalysis with a prolinol catalyst (addition of nitromethane, nitroacetate and acetamidomalonate) and one was based on a Cinchona-derived phase-transfer catalyst (addition of glycine imines). A careful choice of additives allowed lowering of the catalyst loading to 0.5 mol% in some cases. The preparation of intermediates that would give access to the core of telaprevir in good yields and enantioselectivities by exploiting readily available substrates and catalysts, highlights the potential of organocatalytic technology for a cost-effective preparation of pharmaceuticals.

Quinone methides (QMs) are highly reactive compounds that have been defined as “elusive” intermediates, or even as a “synthetic enigma” in organic chemistry. Indeed, there were just a handful of examples of their utilization in catalytic asymmetric settings until some years ago. This review collects organocatalytic asymmetric reactions that employ QMs as substrates and intermediates, from the early examples, mostly based on stabilized QMs bearing specific substitution patterns, to more recent contributions, which have dramatically expanded the scope of QM chemistry. In fact, it was only very recently that the generation of QMs in situ through strategies compatible with organocatalytic methodologies has been realized. This tactic has finally opened the gate to the full exploitation of these unstable intermediates, leading to a series of remarkable disclosures. Several types of synthetically powerful asymmetric addition and cycloaddition reactions, applicable to a broad range of QMs, are now available.

The atroposelective desymmetrization of N-arylmaleimides was realized by means of a primary amine catalyzed Diels-Alder reaction of enones. The chiral axis as new element of chirality is generated under the remote control of the catalyst that selectively drives the formal Diels-Alder reaction through an exclusive stereochemical outcome.

A new approach to the utilization of highly reactive and unstable ortho-quinone methides (o-QMs) in catalytic asymmetric settings is presented. The enantioselective reactions are catalysed by bifunctional organocatalysts, and the o-QM intermediates are formed in situ from 2-sulfonylalkyl phenols through base-promoted elimination of sulfinic acid. The use of mild Brønsted basic conditions for transiently generating o-QMs in catalytic asymmetric processes is unprecedented, and allows engaging productively in the reactions nucleophiles such as Meldrum’s acid, malononitrile and 1,3-dicarbonyls. The catalytic transformations give new and general entries to 3,4-dihydrocoumarins, 4H-chromenes and xanthenones. These frameworks are recurring structures in natural product and medicinal chemistry, as testified by the formal syntheses of (R)-tolterodine and (S)-4-methoxydalbergione from the catalytic adducts.

A method for the synthesis of pyridine derivatives based on a triple cascade reaction catalyzed by chiral secondary amines was developed. The resulting cyclohexenes (three C–C bonds were formed) were obtained in good yields with good diastereoselectivities and excellent enantioselectivities.

Supported ionic liquids (SILs) represent a class of materials with peculiar properties and a huge potential regarding their possible applications in different fields of chemistry. Herein, we report our ongoing research about the use of SILs as support for organocatalysts, their role as catalysts themselves, and their application as support and stabilizers of palladium nanoparticles (PdNPs). The use of SILs based materials allowed achieving good results. Moreover, in some cases, after the functionalization of the catalytic species with an ion-tag moiety, a release and catch approach was employed in order to improve the catalytic activity and to facilitate the recovery of the hybrid system formed by the catalyst adsorbed onto SILs materials. All the reported examples demonstrate the versatility of such SILs materials, which can represent powerful tools able to exert a large number of functions.

1,5-Benzothiazepine frameworks are highly relevant in medicinal chemistry. Reported catalytic asymmetric approaches to these scaffolds have targeted 2,3-dihydro-1,5-benzothiazepin-4-ones but leave the corresponding amines (i.e., 2,3,4,5-tetrahydro-1,5-benzothiazepines) out of reach. Herein, we present the first entry to these important compounds in enantioenriched form. Our approach is based on the catalytic asymmetric sulfa-Michael addition of 2-aminothiophenols to trans-chalcones, followed by intramolecular reductive amination. Both reactions required careful study to solve several challenging issues. The resulting optimized two-step protocol afforded a range of 2,3,4,5-tetrahydro-1,5-benzothiazepines as single trans diastereomers in moderate to good yields and enantioselectivities.

Organocatalytic domino reactions of 4-substituted indoles are summarized in this account. Two reactions have been developed, one with enals, activated by secondary amine catalysts via iminium ions, and one with nitroethene, using a phosphoric acid catalyst. Both reactions required solving the challenge posed by the very low nucleo­philicity of the indole substrates, which bear an electron-withdrawing Michael acceptor at C4. DFT calculations were used to shed light on the unique reaction pathway followed by the phosphoric acid catalyzed transformation, wherein a bicoordinated nitronic acid intermediate was found to evolve preferentially through an intramolecular nitro-Michael reaction, instead of the common tautomerization pathway. These reactions provide new and efficient entries to 3,4-ring-fused indoles in dia­stereo- and enantioenriched form. In more detail, the structures obtained feature a 1,3,4,5-tetrahydrobenzo[cd]indole core, which is present in the structural framework of ergot alkaloids. Indeed, the preparation of an intermediate previously used in ergot alkaloid (6,7-secoagroclavine) synthesis was possible from one of the catalytic adducts.1 Introduction2 Reactions of 4-Substituted Indoles with α,β-Unsaturated Aldehydes Catalyzed by Secondary Amines3 Reactions of 4-Substituted Indoles with Nitroethene Catalyzed by Brønsted Acids4 Conclusion

Two polystyrene-supported and six homogeneous MacMillan imidazolidinone catalysts were prepared and tested for the asymmetric α-alkylation of propanal with benzodithiolylium tetrafluoroborate. The chiral imidazolidinone was linked to polystyrene through the N-3 atom or through the phenyl ring and their catalytic activity was compared with that of their unsupported precursors. This comparison has allowed us to find an unsupported catalyst that displays high catalytic activity down to 5 or 2 mol % at room temperature with a high level of enantioselectivity also when used with hexanal and 3-phenylpropanal. In addition, one of the heterogeneous materials was revealed to be highly recyclable for at least eight cycles with no loss in efficiency working at the same levels of activity and enantioselectivity as the unsupported counterpart.

The compatibility of indium(III) Lewis acids with water and amines allows their employment in synergistic and cooperative catalysis. Stereoselective organocatalytic S(N)1-type reactions, in which carbenium ions are generated, are promoted by the presence of indium salts. The peculiar properties of indium salts can be exploited in organocatalysis for the design of water-compatible, benign, green processes. The development of such indium(III)-promoted organocatalytic procedures is the focus of our recent research, a summary of which is presented in this article. The compatibility of indium(III) Lewis acids with water and amines allows their employment in synergistic and cooperative catalysis. Stereoselective organocatalytic SN1-type reactions, in which carbenium ions are generated, are promoted by the presence of indium salts. The peculiar properties of indium salts can be exploited in organocatalysis for the design of water-compatible, benign, green processes. The development of such indium(III)-promoted organocatalytic procedures is the focus of our recent research, a summary of which is presented in this article. © Georg Thieme Verlag Stuttgart.New York.

In this review, the most recent advances (2014–2016) on the synthesis of new polymer-supported catalysts are reported, focusing the attention on the synthetic strategies developed for their preparation. The polymer-supported catalysts examined will be organic-based polymers and organic-inorganic hybrids and will include, among others, polystyrenes, poly-ionic liquids, chiral ionic polymers, dendrimers, carbon nanotubes, as well as silica and halloysite-based catalysts. Selected examples will show the synthesis and application in the field of organocatalysis and metal-based catalysis both for non-asymmetric and asymmetric transformations.

What do quantum cellular automata (QCA), "on water" reactions, and SN 1-type organocatalytic transformations have in common? The link between these distant arguments is the practical access to useful intermediates and key products through the use of stabilized carbenium ions. Over 10 years, starting with a carbenium ion bearing a ferrocenyl group, to the 1,3-benzodithiolylium carbenium ion, our group has exploited the use of these intermediates in useful and practical synthetic transformations. In particular, we have applied the use of carbenium ions to stereoselective organocatalytic alkylation reactions, showing a possible solution for the "holy grail of organocatalysis". Examples of the use of these quite stabilized intermediates are now also considered in organometallic chemistry. On the other hand, the stable carbenium ions are also applied to tailored molecules adapted to quantum cellular automata, a new possible paradigm for computation. Carbenium ions are not a problem, they can be a/the solution!

Three BINOL-derived phosphoric acids exhibiting atropisomerism in the 3,3′-positions were obtained by Suzuki coupling reaction. The diastereomeric mixture was resolved by HPLC. Structural assignment was achieved by NOE-NMR analysis and by TD-DFT simulation of the electronic circular dichroism (ECD) spectra. The three atropisomeric catalysts were tested in three enantioselective reactions, comparing their ability to induce enantioselectivity with related, well-known, phosphoric acid structures. All three catalysts were competent in promoting the reactions, rendering excellent enantioselectivity (98 % ee) in one case. The atropisomeric features at the 3,3′-position were indeed found to influence the outcome of the reaction, demonstrating the potential of atropisomeric conformational control at the 3,3′-position of the BINOL core in the rationalization of catalyst performances and in the design of new efficient structures.

In this review, the most recent advances in the synthesis and catalytic applications of covalently supported ionic liquid (IL) phases will be discussed. This class of recyclable catalytic materials is based on the covalent attachment of several types of ammonium salts, usually imidazolium, but also thiazolium, triazolium, and pyrrolidinium salts, on the surface of different supports, for example, silica, periodic mesoporous organosilica, polystyrene, magnetic-based materials, carbon nanotubes (NTs), halloysite NTs, polyhedral oligomeric silsesquioxane (POSS), and fullerenes. Moreover, poly(ionic liquid) materials, in which the IL-based structure also acts as a support, will be considered. The synthetic applications of these materials will be presented, with special emphasis on their roles as catalysts, without added organocatalysts or metal-based catalysts, as supports for organocatalysts, and as supports for metal-based catalysts.

Nonquaternised Cinchona Alkaloid Derivatives as Asymmetric Organocatalysts for Carbon-Carbon Bond-Forming Reactions