Organocatalytic Synthesis and DNA Interactive Studies of New 1,2,3-triazolyl-thiazolidines Hybrids.

An organocatalytic [3+2] cycloaddition reaction between thiazolidine-containing ß-ketoester 1 and aryl azides 2 was employed to synthesize new 1,2,3-triazolyl-thiazolidine hybrids 3. In this metal-free approach, twelve compounds were isolated in yields ranging from 23 % to 96 % by using diethylamine (10 mol%) and DMSO at 75 °C for 24 hours. DNA-binding assays were conducted through absorption, emission spectroscopy and viscosimetry analysis, to evaluate the interaction capacity of the studied derivatives with nucleic acids. All the synthesized compounds were evaluated for their interactions with a specific group of compounds containing the pharmacophoric groups triazole and thiazolidine through a molecular docking speculative study, aimed at identifying the interaction profile of these compounds with DNA. The obtained results suggest that 1,2,3-triazolyl-thiazolidine hybrids could be a promising approach in the development of novel therapeutic agents targeting DNA-related processes.

A Tandem Hydroformylation-Organocatalyzed Friedel-Crafts Reaction for the Synthesis of Diindolylmethanes.

Herein, we present an efficient and atom-economic tandem hydroformylation organocatalyzed Friedel-Crafts reaction sequence for the synthesis of diindolylmethanes. Classic syntheses have relied on (Lewis) acid activation of aldehydes, which are often not commercially available and rather sensitive in handling. In contrast, the combination of rhodium-catalyzed hydroformylation and subsequent organocatalytic activation of the in-situ formed aldehydes allows the use of readily available and stable alkenes with various functional groups while avoiding acidic conditions to expand the range of available diindolylmethanes. A broad scope of diindolylmethanes was prepared in yields up to 85 % demonstrates the utility of the presented method.

A Systematic Study of Nonionic Di- and Multiborane Catalysts for the Oligomerization and Polymerization of Epoxides.

Borane catalysis has emerged as a powerful technology in epoxide polymerization. Still, the structure-activity correlations for these catalysts are not fully understood to date, especially regarding compounds with nonionic backbones. Thus, in this work, 13 different borane catalysts of this respective type are described and investigated for their epoxide oligomerization and polymerization performance, using propylene oxide (PO), 1-butylene oxide (BO) and allyl glycidyl ether (AGE) as monomers. Structurally, special emphasis is put on catalysts with different linker lengths and linker flexibilities as well as the introduction of more than two borane functionalities. Importantly, this screening is conducted both under typical polymerization conditions as well as under the chain transfer agent (CTA)-rich conditions relevant for large-scale production. It is found that suitable preorganization of the borane groups, such as present in biphenyl derivatives, offers a simple route to high-performing catalysts and quantitative monomer conversion of the investigated epoxides. Furthermore, it is demonstrated that a diborane-catalyzed oligomerization can be kept active over weeks, whereby repeated addition of monomer batches (14 steps) constantly results in full conversion and well-defined oligoethers, underlining the practical potential of this method. The absence of co-initiating counter ions is suggested as an inherent advantage of nonionic catalysts.

Enantioselective Synthesis of α-Quaternary Isochromanes by Oxidative Aminocatalysis and Gold Catalysis.

A novel strategy that combines oxidative aminocatalysis and gold catalysis allows the preparation of chiral α-quaternary isochromanes, a motif that is prevalent in natural products and synthetic bioactive compounds. In the first step, α-branched aldehydes and propargylic alcohols are transformed into α-quaternary ethers with excellent optical purities (>90 % ee) via oxidative umpolung with DDQ and an amino acid-derived primary amine catalyst. Subsequent gold(I)-catalyzed intramolecular hydroarylation affords the isochromane products with retention of the quaternary stereocenter. A second approach explores the use of allylic alcohols as reaction partners for the oxidative coupling to furnish α-quaternary ethers with generally lower enantiopurities. Stereoretentive cyclization to isochromane products is achieved via intramolecular Friedel-Crafts type alkylation with allylic acetates as a reactive handle. A number of synthetic elaborations and a biological study on these α-quaternary isochromanes highlight the potential applicability of the presented method.

Accessing Rare α-Heterocyclic Aziridines via Brønsted Acid-catalyzed Michael Addition/Annulation: Scope, Limitations, and Mechanism.

We report an approach to the diastereoselective synthesis of 1,2-disubstituted heterocyclic aziridines. A Brønsted acid-catalyzed conjugate addition of anilines to trisubstituted heterocyclic chloroalkenes provides an intermediate 1,2-chloroamine. Diastereocontrol was found to vary significantly with solvent selection, with computational modelling confirming selective, spontaneous fragmentation in the presence of trace acids, proceeding through a pseudo-cyclic, protonated intermediate and transition state. These chloroamines can then be converted to the aziridine by treatment with LiHMDS with high stereochemical fidelity. This solvent-induced stereochemical enrichment thereby enables an efficient route to rare cis-aziridines with high dr. The scope, limitations, and mechanistic origins of selectivity are also presented.

Carbodiimide and Isocyanate Hydroboration by a Cyclic Carbodiphosphorane Catalyst.

We report hydroboration of carbodiimide and isocyanate substrates catalyzed by a cyclic carbodiphosphorane catalyst. The cyclic carbodiphosphorane outperformed the other Lewis basic carbon species tested, including other zerovalent carbon compounds, phosphorus ylides, an N-heterocyclic carbene, and an N-heterocyclic olefin. Hydroborations of seven carbodiimides and nine isocyanates were performed at room temperature to form N-boryl formamidine and N-boryl formamide products. Intermolecular competition experiments demonstrated the selective hydroboration of alkyl isocyanates over carbodiimide and ketone substrates. DFT calculations support a proposed mechanism involving activation of pinacolborane by the carbodiphosphorane catalyst, followed by hydride transfer and B-N bond formation.

Chiral 4-MeO-Pyridine (MOPY) Catalyst for Enantioselective Cyclopropanation: Attenuation of Lewis Basicity Leads to Improved Catalytic Efficiency.

The design of pyridine-derived organocatalysts aims at the increase of their Lewis basicity, however such an approach is not always efficient. For example, strongly Lewis basic DMAP is completely inefficient as catalyst in the cyclopropanation reaction. Herein we disclose an alternative approach that relies on attenuation of DMAP Lewis basicity. Specifically, the replacement of 4-dimethylamino substituent in DMAP for 4-MeO group delivered a highly efficient catalyst for cyclopropanation of electron-deficient olefins with α-bromoketones. Kinetic studies provide compelling evidence that the superior catalytic efficiency of 4-MeO pyridine (MOPY) is to be attributed to the favorable balance between Lewis basicity and leaving group ability. The use of chiral, enantiomerically pure MOPY catalyst has helped to achieve high enantioselectivities (up to 91 : 9 er) in the previously unreported pyridine-catalyzed cyclopropanation reaction.

Chalcogen Atom Size: A Key Parameter in Modulating Carbonyl Compound Properties.

Exchanging oxygen in the functional group C=O (i. e., carbonyl) for the less electronegative Group 16 elements, sulfur or selenium, unexpectedly enhances the electronegativity of the C=X group in π-conjugated molecules and reduces the molecular π HOMO-LUMO energy gap. Quantum-chemical analyses revealed that the steric size of the chalcogen atom X is at the origin of this seemingly counterintuitive behavior. This tuning of the chemical properties of carbonyl compounds by varying the chalcogen atom size in the C=X bond can be applied in many fields of chemistry. This concept article delineates several useful applications in the fields of organocatalysis, supramolecular chemistry, and photo(electro)chemistry.

Phosphine-Catalyzed 1,2-cis-Diboration of 1,3-Butadiynes.

Trialkyl phosphines PMe3 and PEt3 catalyze the 1,2-cis-diboration of 1,3-butadiynes to give 1,2-diboryl enynes. The products were utilized to synthesize 1,1,2,4-tetraaryl enynes using a Suzuki-Miyaura protocol and can readily undergo proto-deborylation.

Elucidating the Binding Mode of Sulfur- and Selenium-Based Cationic Chalcogen-Bond Donors.

For a comparison of the interaction modes of various chalcogen-bond donors, 2-chalcogeno-imidazolium salts have been designed, synthesized, and studied by single crystal X-ray diffraction, solution NMR and DFT as well as for their ability to act as activators in an SN1-type substitution reaction. Their interaction modes in solution were elucidated based on NMR diffusion and chemical shift perturbation experiments, which were supported by DFT-calculations. Our finding is that going from lighter to the heavier chalcogens, hydrogen bonding plays a less, while chalcogen bonding an increasingly important role for the coordination of anions. Anion-π interactions also show importance, especially for the sulfur and selenium derivatives.

An Enantioselective Aminocatalytic Cascade Reaction Affording Bioactive Hexahydroazulene Scaffolds.

A novel cascade reaction initiated by an enantioselective aminocatalysed 1,3-dipolar [6+4] cycloaddition between catalytically generated trienamines and 3-oxidopyridinium betaines is presented. The [6+4] cycloadduct spontaneously undergoes an intramolecular enamine-mediated aldol, hydrolysis, and E1cb sequence, which ultimately affords a chiral hexahydroazulene framework. In this process, three new C-C bonds and three new stereocenters are formed, enabled by a formal unfolding of the pyridine moiety from the dipolar reagent. The hexahydroazulenes are formed with excellent diastereo-, regio- and periselectivity (>20 : 1), up to 96 % ee, and yields up to 52 %. Synthetic elaborations of this scaffold were performed, providing access to a variety of functionalised hydroazulene compounds, of which some were found to display biological activity in U-2OS osteosarcoma cells in cell painting assays.

Binary Catalytic Hydrogen/Deuterium Exchange of Free α-Amino Acids and Derivatives.

The increasing demand for deuterium-labeled amino acids and derivatives has heightened interest in direct hydrogen/deuterium exchange reactions of free amino acids. Existing methods, including biocatalysis and metal catalysis, typically require expensive deuterium sources or excessive use of deuterium reagents and often struggle with site selectivity. In contrast, our pioneering binary catalysis system, employing benzaldehyde and Cs2CO3 in the presence of inexpensive D2O with minimal stoichiometric quantities, facilitates efficient hydrogen/deuterium exchange at the α-position of amino acids without the need for protecting groups in the polar aprotic solvent DMSO. The process is highly compatible with most natural and non-natural α-amino acids and derivatives, even those with potentially reactive functionalities. This advancement not only addresses the cost and efficiency concerns of existing methods but also significantly broadens the applicability and precision of deuterium labeling in biochemical research.

Halogen and Chalcogen Activation by Nucleophilic Catalysis.

The high utility of halogenated organic compounds has prompted the development of numerous transformations that install the carbon-halogen motif. Halogen functionalities, deemed as "functional and functionalizable" molecules due to their capacity to modulate diverse internal properties, constitute a pivotal strategy in drug discovery and development. Traditional routes to these building blocks have commonly involved multiple steps, harsh reaction conditions, and the use of stoichiometric and/or toxic reagents. With the emergence of solid halogen carriers such as N-halosuccinimides, and halohydantoins as popular sources of halonium ions, the past decade has witnessed enormous growth in the development of new catalytic strategies for halofunctionalization. This review aims to provide a nuanced perspective on nucleophilic activators and their roles in halogen activation. It will highlight critical discoveries in effecting racemic and asymmetric variants of these reactions, driven by the development of new catalysts, activation modes, and improved understanding of chemical reactivity and reaction kinetics.

Chiral Diselenophosphoric Acids for Ion Pair Catalysis: A Novel Approach to Enhance Both Proton Donating and Proton Accepting Properties.

The activation of poorly reactive substrates via strong chiral acids is a central topic in asymmetric ion pair catalysis these days. Despite highly successful scaffolds such as N-triflylphosphoramides, these catalysts either lack C2-symmetry or provide multiple H-bond acceptor sites, leading to lower ee values for certain reactions. We present BINOL-based diselenophosphoric acids (DSA) as an extremely promising alternative. Using an intertwined approach of synthesis and NMR studies, we developed a synthetic approach to DSA with up to 98 % NMR yield. The obtained acids provide both very high proton donor and proton acceptor properties, a bifunctionality, which is key to catalytic applications. Indeed, first reactivity test proved the much higher acidity of DSA and its ability to initiate Mukaiyama-Mannich reaction and protodesilylation of silyl ethers. Together with their C2-symmetry, the single donor and single acceptor situation, the decreased tendency of self-association, and the straightforward synthesis with potential 3,3'-substitution, the DSA provide all features ideal for the further development of ion pair catalysis.

Is the E/Z Iminium Ratio a Good Enantioselectivity Predictor in Iminium Catalysis?

Developing new enantioselective reactions is an important part of chemical discovery but requires time and resources to test large arrays of potential reaction conditions. New techniques are required to analyse many different reactions quickly and efficiently. Mass spectrometry is a high-throughput method; when combined with ion-mobility spectrometry, this technique can monitor diastereomeric reaction intermediates and thus be a handle to study enantioselective reactions. Through this technique and others, it was noted before that in the organocatalytic 1,4-addition to α,ß-unsaturated aldehydes, the abundance of initial diastereomeric intermediates correlates strongly to that of the final enantiomeric products. This work determines isomeric abundance for various catalysts and aldehydes and uses it to predict the enantiomeric excess of two control reactions. The prediction matches well for one reaction but does not predict the obtained results for the second. This finding confirms that the E/Z ratio of the iminium intermediates can be used as a predictor for some reactions, but the kinetics of the following steps can dramatically change the true enantioselectivity.

Carbonylation as a Key Step in New Tandem Reactions - A Route to BODIPYs.

Herein, a highly efficient five-step reaction sequence to BODIPYs is presented. The key step is the combination of transition metal-catalyzed in-situ generation of aldehydes and their subsequent organocatalytic activation to yield dipyrromethanes, which are further converted to the corresponding BODIPY. Classic syntheses towards BODIPYs have relied on aldehydes or acid chlorides, which are often not commercially available and rather sensitive to handle. The presented approach starts from readily available and stable alkenes or aryl-bromides, which allows to extend the range of readily available BODIPYs that can be tailored for their specific use. The synthesis of 55 derivatives with overall yields of up to 78 % demonstrates the wide applicability and advantages of the presented method.

Shaping Chirality via Stereoselective, Organocatalytic [4+2] Cycloadditions involving Heterocyclic ortho-Quinodimethanes.

Polycyclic compounds bearing a complex heterocyclic core such as an aromatic heterocycle "fused" with one or more functionalized rings, are widespread leading molecules in the domain of synthetic organic chemistry and pharmaceuticals. Although many synthetic methodologies have been devised to access achiral, fused heteroaromatic scaffolds, or related chiral variants adorned with out-of-cycle stereogenic elements, equally efficient strategies to afford chiral heterocycles featuring in-cycle stereocenters, exist to a lesser extent and presently represent a growing field of investigation. The mild, organocatalytic generation of elusive ortho-quinodimethane intermediates (oQDMs), derived from suitable heteroaromatic carbonyl- or carbonyl-like pronucleophiles has recently proved successful in the synthesis of such peculiar chiral architectures via stereoselective [4+2] cycloadditions. This review provides an overview of the most important advances attained in this field over the last decade.

A Powerful P-N Connection: Preparative Approaches, Reactivity, and Applications of P-Stereogenic Aminophosphines.

For more than five decades, P-stereogenic aminophosphine chalcogenides and boranes have attracted scientific attention and are still in the focus of ongoing research. In the last years, novel transition metal-based synthesis methods have been discovered, in addition to the long-known use of chiral auxiliaries. Enantiomerically pure compounds with N-P+-X- (X=O, S, BH3) motifs served as valuable reactive building blocks to provide new classes of organophosphorus derivatives, thereby preserving the stereochemical information at the phosphorus atom. Over the years, intriguing applications in organocatalysis and transition metal catalysis have been reported for some representatives. Asymmetric reductions of C=C, C=N, and C=O double bonds were feasible with selected P-stereogenic aminophosphine oxides in the presence of hydrogen transfer reagents. P-stereogenic aminophosphine boranes could be easily deprotected and used as ligands for various transition metals to enable catalytic asymmetric hydrogenations of olefins and imines. This review traces the emergence of a synthetically and catalytically powerful functional compound class with phosphorus-centered chirality in its main lines, starting from classical approaches to modern synthesis methods to current applications.

Cationic Hypervalent Chalcogen Bond Catalysis on the Povarov Reaction: Reactivity and Stereoselectivity.

Chalcogen bond catalysis, particularly cationic hypervalent chalcogen bond catalysis, is considered to be an effective strategy for organocatalysis. In this work, the cationic hypervalent chalcogen bond catalysis for the Povarov reaction between N-benzylideneaniline and ethyl vinyl ether was investigated by density functional theory (DFT). The catalytic reaction involves the cycloaddition process and the proton transfer process, and the rate-determining step is the cycloaddition process. Cationic hypervalent tellurium derivatives bearing CF3 and F groups exhibit superior catalytic activity. For the rate-determining step, the Gibbs free energy barrier decreases as the positive electrostatic potential of the chalcogen bond catalysts increases. More importantly, the Gibbs free energy barrier has a strong linear correlation with the electrostatic energy of the chalcogen bond in the catalyst-substrate complex. Furthermore, the catalytic reactions include the endo pathway and exo pathway. The C-H⋅⋅⋅π interaction between the substituent of the ethyl vinyl ether and the aryl ring of the N-benzylideneaniline contributes to the endo-selectivity of the reaction. This research contributes to a deeper understanding of chalcogen bond catalysis, providing insights for designing chalcogen bond catalysts with high performance.

An Organocatalytic Highly Enantioselective Stereospecific Synthesis of 1,1-Disubstituted-1,3-Dihydroisobenzofurans.

Herein, we disclosed the asymmetric construction of an oxa-quaternary stereocenter via an intramolecular oxa-Michael (IOM) reaction in ß-substituted ortho-hydroxymethyl chalcone by the formation of 1,1-disubstituted-1,3-dihydroisobenzofuran using cinchona alkaloid-based chiral amino-squaramide catalyst. Both the (E- and Z)-ß-substituted ortho-hydroxymethyl chalcone provide (S)- and (R)-enantiomers of the 1,1-disubstituted-1,3-dihydroisobenzofuran with excellent stereospecificity. In general, excellent yields (up to 95 %) and enantioselectivity (up to 98 % ee) were obtained. Furthermore, the resulting 1,1-disubstituted isobenzofuran or phthalan was converted to corresponding chiral 3,3-disubstituted phthalides without losing the enantioselectivity. This methodology provides the core moiety of the (S)-citalopram drug.