Factors influencing the performance of organocatalysts immobilised on solid supports: A review.

Organocatalysis has become a powerful tool in synthetic chemistry, providing a cost-effective alternative to traditional catalytic methods. The immobilisation of organocatalysts offers the potential to increase catalyst reusability and efficiency in organic reactions. This article reviews the key parameters that influence the effectiveness of immobilised organocatalysts, including the type of support, immobilisation techniques and the resulting interactions. In addition, the influence of these factors on catalytic activity, selectivity and recyclability is discussed, providing an insight into optimising the performance of immobilised organocatalysts for practical applications in organic chemistry.

Stereoselective mechanochemical synthesis of thiomalonate Michael adducts via iminium catalysis by chiral primary amines.

The study presents a novel approach utilizing iminium salt activation and mild enolization of thioesters, offering an efficient and rapid synthesis of Michael adducts with promising stereoselectivity and marking a significant advancement in mechanocatalysis. The stereoselective addition of bisthiomalonates 1-4 to cyclic enones and 4-chlorobenzylideneacetone proceeds stereoselectively under iminium activation conditions secured by chiral primary amines, in contrast to oxo-esters as observed in dibenzyl malonate addition. Mild enolization of thioesters allows for the generation of Michael adducts with good yields and stereoselectivities. Reactions in a ball mill afford product formation with similar efficacy to solution-phase reactions but with slightly reduced enantioselectivity, yet they yield products in just one hour compared to 24 or even 168 hours in solution-based reactions. It is noteworthy that this represents one of the early reports on the application of iminium catalysis using first-generation chiral amines under mechanochemical conditions, along with the utilization of easily enolizable thioesters as nucleophiles in this transformation.

Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis.

Organocatalysis has established itself as a third pillar of homogeneous catalysis, besides transition metal catalysis and biocatalysis, as its use for enantioselective reactions has gathered significant interest over the last decades. Concurrent to this development, machine learning (ML) has been increasingly applied in the chemical domain to efficiently uncover hidden patterns in data and accelerate scientific discovery. While the uptake of ML in organocatalysis has been comparably slow, the last two decades have showed an increased interest from the community. This review gives an overview of the work in the field of ML in organocatalysis. The review starts by giving a short primer on ML for experimental chemists, before discussing its application for predicting the selectivity of organocatalytic transformations. Subsequently, we review ML employed for privileged catalysts, before focusing on its application for catalyst and reaction design. Concluding, we give our view on current challenges and future directions for this field, drawing inspiration from the application of ML to other scientific domains.

Peptide Catalyzed Conjugate Additions to ß-Nitroacrylates - Steric Bulk Increases the Reaction Rate.

The organocatalytic conjugate addition of aldehydes to ß-nitroacrylates provides direct access to ß-ester-γ-nitroaldehydes and, thereby, common structural motifs of many bioactive compounds. However, the deactivation of amine-based catalysts by alkylation with the highly electrophilic nitroacrylates hampers this reaction. Here, we show that the peptide H-Mep-dPro-dGlu-NH2, which is reluctant to under alkylation, catalyzes this reaction at low catalyst loading (0.5-1 mol%) within short reaction times (15-60 min) to yield a broad range of ß-ester-γ-nitroaldehydes with high stereoselectivity. Kinetic studies revealed that increased steric bulk on the ß-nitroacrylate enhances the reaction rate by hindering catalyst alkylation.

Catalytic Performance of Chiral Tetraaza-Bridged Calix[4]arene[2]triazine Derivatives for Enantioselective Michael Reactions.

Novel chiral tetraaza-bridged calix[4]arene[2]triazine-based organocatalysts were synthesized and used for catalytic asymmetric Michael reaction of acetylacetone to various aromatic nitrostyrenes. Chiral subunits (R)- and (S)-1,2,3,4-tetrahydro-1-naphthylamine were attached to the tetraaza-bridged calix[4]arene[2]triazine platform in both enantiomeric forms. The R configuration of the major enantiomer of the Michael product was obtained when 3a was used as catalyst, and the S configuration was obtained when 3b was used as catalyst. This indicated that the configuration of the Michael product was controlled by the chiral calixarene moiety. The Michael adducts were obtained in excellent yields (91%) and enantioselectivities (98%).

Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions.

A new eco-friendly method for the synthesis of mono- and multifunctional organosulfur compounds, based on the process between ynals and thiols, catalyzed by bulky N-heterocyclic carbene (NHC), was designed and optimized. The proposed organocatalytic approach allows the straightforward formation of a broad range of thioesters and sulfenyl-substituted aldehydes in yields above 86%, in mild and metal-free conditions. In this study, thirty-six sulfur-based derivatives were obtained and characterized by spectroscopic methods.

Enantioselective Synthesis of Benzodihydrofurans Bearing Axial and Central Stereogenic Elements.

The enantioselective synthesis of chiral compounds containing multiple stereogenic elements via a single catalytic step is a challenging process. In the presence of α-chloronitrostyrenes and a chiral squaramide catalyst, C-C or C-N pro-axially chiral 2-naphthol substrates, featuring low barriers to enantiomerization, underwent a remote diastereo- and enantioselective domino Michael/O-alkylation. It provided the desired benzodihydrofurans bearing two stereogenic carbon atoms and a configurationally stable C-C or a C-N bond, thanks to a high increase of the barrier to rotation upon dihydrofurannulation.

Development of Organocatalytic Darzens Reactions Exploiting the Cyclopropenimine Superbase.

A truly organocatalytic approach to the Darzens reaction affording α,ß-epoxy carbonyl compounds in good yields was developed taking advantage of the high basic strength and low nucleophilicity of cyclopropenimine superbases. The catalytic active free base can easily be generated in situ from its hydrochloride salt and maintained in the active deprotonated form by performing the reactions in a heterogeneous reaction system in the presence of excess potassium carbonate as a sacrificial base.

L-Cysteine-Catalysed Hydration of Activated Alkynes.

Hydration reactions consist of the introduction of a molecule of water into a chemical compound and are particularly useful to transform alkynes into carbonyls, which are strategic intermediates in the synthesis of a plethora of compounds. Herein we demonstrate that L-cysteine can catalyse the hydration of activated alkynes in a very effective and fully regioselective manner to access important building blocks in synthetic chemistry such as ß-ketosulfones, amides and esters, in aqueous media. The mild reaction conditions facilitated the integration with enzyme catalysis to access chiral ß-hydroxy sulfones from the corresponding alkynes in a one-pot cascade process in good yields and excellent enantiomeric ratios. These findings pave the way towards establishing a general method for metal-free, cost-effective, and more sustainable alkyne hydration processes.

One-Pot Access to Functionalised Malamides via Organocatalytic Enantioselective Formation of Spirocyclic ß-Lactone-Oxindoles and Double Ring-Opening.

Malamides (diamide derivatives of malic acid) are prevalent in nature and of significant biological interest, yet only limited synthetic methods to access functionalised enantiopure derivatives have been established to date. Herein, an effective synthetic method to generate this molecular class is developed through in situ formation of spirocyclic ß-lactone-oxindoles (employing a known enantioselective isothiourea-catalysed formal [2+2] cycloaddition of C(1)-ammonium enolates and isatin derivatives) followed by a subsequent dual ring-opening protocol (of the ß-lactone and oxindole) with amine nucleophiles. The application of this protocol is demonstrated across twelve examples to give densely functionalised malamide derivatives with high enantio- and diastereo-selectivity (up to >95:5 dr and >99:1 er).

N-Heterocyclic Carbene Enabled Functionalization of Inert C(Sp3)-H Bonds via Hydrogen Atom Transfer (HAT) Processes.

Developing methods to directly transform C(sp3) -H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp3) -H bonds for cross C-C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp3) -H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp3)-H substrates, such as ethers, amines, and alkanes. This mini-review summarizes the progress in carbene organocatalytic functionalization of inert C(sp3)-H bonds enabled by HAT processes, categorizing them into two sections: 1) C-H functionalization involving acyl azolium intermediates; and 2) functionalization of C-H bonds via reductive Breslow intermediates.

Chiral bifunctional sulfide-catalyzed enantioselective bromolactonizations of α- and ß-substituted 5-hexenoic acids.

Enantioselective halolactonizations of sterically less hindered alkenoic acid substrates without substituents on the carbon-carbon double bond have remained a formidable challenge. To address this limitation, we report herein the asymmetric bromolactonization of 5-hexenoic acid derivatives catalyzed by a BINOL-derived chiral bifunctional sulfide.

Homogeneous Catalysis in N-formylation/N-methylation Utilizing Carbon Dioxide as the C1 Source.

The growing emphasis on sustainable chemistry has driven research into utilizing carbon dioxide (CO2) as a nontoxic, abundant, and cost-effective C1 building block. CO2 offers a promising avenue for direct conversion into valuable chemicals ranging from fuels to pharmaceuticals. This review focuses on the utilization of CO2 for reductive N-formylation/N-methylation reactions of various amines, providing advantages over conventional methods involving toxic CO and other methylating reagents. The approach employs readily available reductants such as silane, borane reagents, and hydrogen (H2). The discussion encompasses recent developments in transition metal and organocatalyst systems for these reactions, highlighting mechanistic interpretations and factors influencing product selectivity.

Collective Asymmetric Synthesis of Thiosilvatins.

Thiosilvatins are a family of biologically active sulfenylated diketopiperazine natural products. The first members were reported over 40 years ago, but total synthesis of a thiosilvatin has remained elusive. Here, we describe the first, collective, synthesis of the parent epidithiodiketopiperazine (-)-dithiosilvatin and ten related thiosilvatins. Several of the targets are structurally revised. A catalytic asymmetric sulfenylation of triketopiperazines efficiently controls absolute configuration at the thioaminal units. Further synthetic highlights include a diastereoconvergent installation of the requisite cis-orientation of the sulfur atoms and a tandem epidisulfide formation/O-prenylation under mild Mitsunobu conditions. The described methods for late-stage diversification of sensitive bis(methylthio)diketopiperazines offer a blueprint for systematically exploring this interesting 3D-pharmacophore in stereochemically pure form.

A Heterogeneous Acid-Base Organocatalyst For Cascade Deacetalisation-Knoevenagel Condensations.

Multifunctional heterogeneous catalysts are an effective strategy to drive chemical cascades, with attendant time, resource and cost efficiencies by eliminating unit operations arising in normal multistep processes. Despite advances in the design of such catalysts, the fabrication of proximate, chemically antagonistic active sites remains a challenge for inorganic materials science. Hydrogen-bonded organocatalysts offer new opportunities for the molecular level design of multifunctional structures capable of stabilising antagonistic active sites. We report the catalytic application of a charge-assisted, hydrogen-bonded crystalline material, bis(melaminium)adipate (BMA), synthesised from melamine and adipic acid, which possesses proximate acid-base sites. BMA exhibits high activity for the cascade deacetalisation-Knoevenagel condensation of dimethyl acetals to form benzylidenemalononitriles under mild conditions in water; BMA is amenable to large-scale manufacture and recycling with minimal deactivation. Computational modelling of the melaminium cation in protonated BMA explains the observed catalytic reactivity, and identifies the first demethoxylation step as rate-limiting, in good agreement with time-dependent 1H NMR and kinetic experiments. A broad substrate scope for the cascade transformation of aromatic dimethyl acetals is demonstrated.

Symmetric Anion Mediated Dynamic Kinetic Asymmetric Knoevenagel Reaction for N-C and N-N Atropisomers Synthesis.

A symmetric anion mediated dynamic kinetic asymmetric Knoevenagel reaction was established as a general and efficient method for accessing both N-C and N-N atropisomers. The resulting highly enantio-pure pyridine-2,6(1H,3H)-diones exhibit diverse structures and functional groups. The key to excellent regio- and remote enantiocontrol could be owed to the hydrogen bond between the enolate anion and triflamide block of the organocatalyst. This connected the enolate anion and iminium cation by a chiral backbone. The mechanism investigation via control experiments, correlation analysis, and density functional theory calculations further revealed how the stereochemical information was transferred from the catalyst into the axially chiral pyridine-2,6(1H,3H)-diones. The synthetic applications also demonstrated the reaction's potential.

N-Heterocyclic Carbene/Transition Metal Dual Catalysis.

N-heterocyclic carbene catalysis has been developed as a versatile method for the enantioselective synthesis of complex organic molecules in organic chemistry. Merging of N-heterocyclic carbene catalysis with transition metal catalysis holds the potential to achieve unprecedented transformations with broad substrate scope and excellent stereoselectivity, which are unfeasible with individual catalyst. Thus, this dual catalysis has attracted increasing attention, and numerous elegant dual catalytic systems have been established. In this review, we summarize the recent achievements of dual NHC/transition metal catalysis, including the reaction design, mechanistic studies and practical applications.

Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic ß-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99 % ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99 % ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Primary amine-catalyzed enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones to α,ß-unsaturated ketones.

The enantioselective 1,4-addition reaction of pyrazolin-5-ones to α,ß-unsaturated ketones catalyzed by a cinchona alkaloid-derived primary amine-Brønsted acid composite is reported. Both enantiomers of the anticipated pyrazole derivatives were obtained in good to excellent yields (up to 97%) and high enantioselectivities (up to 98.5% ee) under mild reaction conditions. In addition, this protocol was further expanded to synthesize highly enantioenriched hybrid molecules bearing biologically relevant heterocycles.

Computational Design of Bidentate Hypervalent Iodine Catalysts in Halogen Bond-Mediated Organocatalysis.

In recent years, halogen bond-based organocatalysis has garnered significant attention as an alternative to hydrogen-based catalysis, capturing considerable interest within the scientific community. This transition has witnessed the evolution of catalytic scaffolds from monodentate to bidentate architectures, and from monovalent to hypervalent species. In this DFT-based study, we explored a bidentate hypervalent iodine(III)-based system that has already undergone experimental validation. Additionally, we explore various functionalisations (-CF$_3$, -CH$_3$, -tBu, -OH, -OMe, -NO$_2$, -CN) and scaffold modifications, such as sulfur oxidation, theoretically proposed for an indole-based Michael addition. The investigated systems favour bidentate O-type binding, underlining the importance of ligand coordination in catalytic activity. Electron-deficient scaffolds exhibited stronger binding and lower activation energies, indicating the pivotal role of electronic properties for $\sigma$-hole-based catalysis. Of these groups, Lewis-base-like moieties formed stabilising intramolecular interactions with hypervalent iodines when in the ortho-position. Furthermore, inductive electron withdrawal was deemed more effective than mesomeric withdrawal in enhancing catalytic efficacy for these systems. Lastly, increasing sulfur oxidation was theoretically proven to improve catalytic activity significantly.