Cyclization Process Research Articles

Organocatalytic Enantioselective Synthesis of Nitrocyclopropanes Bearing a Thioester Group and Three Stereogenic Centers

A two‐stage protocol was developed for accessing nitrocyclopropanes that bear a thioester group and three stereogenic centers. This protocol achieves practical overall yields ranging from 54% to 75%, along with high levels of stereoselectivity (single diastereomer with up to 98% ee). Brominated monothiomalonate (Br‐MTM) is used as an α‐bromo thioacetate equivalent, which reacts efficiently with nitroolefins in the presence of a low catalyst loading (0.5 mol%) of cinchona alkaloid squaramide under both "on water" and organic homogeneous conditions. The obtained α‐bromo‐γ‐nitrothioesters undergo an anti‐selective decarboxylation and intramolecular SN2 cyclization process, leading to the formation of desired cyclopropanes. Control experiments were conducted alongside computational studies in order to gain insights into the observed stereoselectivities.

Facile synthesis of dihydroisobenzofuran derivatives via a one-pot sequential Passerini-azide/Ag(I)-catalyzed cyclization process

A facile one-pot synthesis of dihydroisobenzofuran derivatives by Passerini-azide/Ag(I)-catalyzed cyclization sequence has been developed. The Passerini-azide reactions of 2-(alkynyl)benzaldehydes, trimethylsilyl azide, and isocyanides gave tetrazole intermediates, which were transformed to the dihydroisobenzofurans in moderate to good yields via Ag(I)-catalyzed 5-exo-dig cyclization reaction.

(n+3)-Cyclization for the Formation of Benzo[7]annulene Derivatives via a [1,4]-Hydride Shift: A Novel Cyclization Mode Involving an Internal Redox Reaction

AbstractWe report a unique synthetic route to benzo[7]annulene derivatives. When benzylidene malonates having a 1-(N,N-dialkylamino)alkyl group at the ortho-position are treated with a stoichiometric amount of M(OTf)3 (M = Sc, Yb, Gd), three transformations ([1,4]-hydride shift/isomerization into an enamine/intramolecular Stork enamine acylation) proceed sequentially to afford various benzo[7]annulene derivatives in moderate chemical yields. To our knowledge, the present reaction is the first example of an internal redox reaction involving a [1,n]-hydride shift/(n+3)-cyclization process.

Analysis of the non-ideal crosslinking process in thiol-X “click” thermosets

Thiol-click reactions are widely used in the preparation of thermosets. The network build-up process follows step-wise polymerization behavior, which is commonly analyzed assuming ideal step-wise behavior using well-known expressions such as the Flory-Stockmayer equation for the prediction of the gel point conversion. However, a number of factors contributing to departures from the expected ideal behavior can be identified: a) impurity of the reagents, b) complexity of the reaction mechanism and c) internal cyclization processes. In order to maximize the accuracy of predictions about the expected crosslinking behavior and therefore fine-tune the design of thermosets designed as dual-curing systems or covalent adaptable networks (CANs), it is necessary to take into consideration all these sources of non-ideality. In this work, we aim to describe the effects of such factors on the network build-up process of thiol-click thermosets, making use of the recursive methodology of Miller and Macosko. The contribution of each factor is analyzed separately and their overall combined effect is discussed in relation with real data reported in the literature and experimental results.

Določanje obstojnosti funkcionaliziranih tekstilij na osnovi kopolimerov akrilonitrila na toplotno in toplotno-oksidativno razgradnjo

Acrylonitrile is widely used to produce carbon fibres, household textiles, artificial fur, etc. The modification of polyacrylonitrile fibres in an alkaline medium is extended in the production of textile sorbents. The scientific direction of fibre modification through surface activation using hydrogen peroxide is of scientific interest. However, the thermal and thermophysical properties of the samples are not examined. Therefore, interest arises when analysing the effect of polyacrylonitrile textile material functionalization on the resistance of fibres to thermal oxidation and thermal degradation. The study of thermogravimetry and differential thermogravimetry thermooxide of polyacrylonitrile – modified fibres is carried out using thermogravimetric analysis to research the thermal oxidation and thermal degradation of modified polyacrylonitrile fibre samples. A change in the rate of thermal oxidative-degradation in the process of functionalization was identified in this research. A change in the loss of mass of the sample under different conditions of functionalization was also identified. The total glass transition of the polyacrylonitrile was achieved by heating the polymer to 130 °C. The intensification self-regulation of the structure of the polymeric material through the formation of the mesophase was released at the temperature of around 100 °C. During the heating of the initial polyacrylonitrile textile material to the temperature of 70‒80 °C, a weakening of intermolecular contacts was observed, which led to an increase in the mobility of macromolecular segments. The temperature of 78 °С was considered to be the initial glass transition temperature Tg,t1 and Tg,t2 – 121 °С as the final temperature for the original sample. However, if the temperature exceeded 130 °C, chemical changes in the polymer occurred, in particular, the process of cyclization. The analysis of the thermogravimetry data of thermally oxidized samples resulted in the retention of the complex stepwise nature of decomposition inherent in the initial fibrous material based on acrylonitrile copolymers. The conducted analysis showed the absence of significant changes in the reasonable conditions of chemical modification and practical operation of textile materials. The physical and mechanical properties of functionalized textile materials based on acrylonitrile copolymers were studied. As a result of surface functionalization, an insignificant strength reduction of functionalized textile materials occurred.

Catalytic Mechanism and Heterologous Biosynthesis Application of Sesquiterpene Synthases.

Sesquiterpenes comprise a diverse group of natural products with a wide range of applications in cosmetics, food, medicine, agriculture, and biofuels. Heterologous biosynthesis is increasingly employed for sesquiterpene production, aiming to overcome the limitations associated with chemical synthesis and natural extraction. Sesquiterpene synthases (STSs) play a crucial role in the heterologous biosynthesis of sesquiterpene. Under the catalysis of STSs, over 300 skeletons are produced through various cyclization processes (C1-C10 closure, C1-C11 closure, C1-C6 closure, and C1-C7 closure), which are responsible for the diversity of sesquiterpenes. According to the cyclization types, we gave an overview of advances in understanding the mechanism of STSs cyclization from the aspects of protein crystal structures and site-directed mutagenesis. We also summarized the applications of engineering STSs in the heterologous biosynthesis of sesquiterpene. Finally, the bottlenecks and potential research directions related to the STSs cyclization mechanism and application of modified STSs were presented.

A ChemoEnzymatic Approach for the Preparation of “Linear‐Shaped” Diaryl Pyrazines as Potential Antiprotozoal Agents

Nitrogenous heterocyclic rings are present in a wide range of drugs, natural compounds, and fine chemicals and are considered privileged scaffolds in medicinal chemistry. Seeking novel antiprotozoal drugs acting on new targets or by novel mechanisms of action, we focused on a preliminary evaluation of the potential of “linear‐shaped” diaryl pyrazines. To this purpose, a two‐enzyme chemoenzymatic synthesis of this heteroaromatic core was proposed. Specifically, starting from simple, commercially available aromatic aldehydes, the target pyrazines were obtained through a sequence of biocatalytic benzoin condensation, chemical oxidation, and a transaminase‐mediated tandem process of transamination and cyclization. The profiles of the compounds as antiprotozoal agents were evaluated in vitro against cultures of Leishmania and Plasmodium and using the human cell line HepG2.

Asymmetric Synthesis of 3,4‐Dihydroquinolin‐2‐ones via Organocatalytic [4+2]‐Cyclization of 2‐Amino‐β‐nitrostyrenes with Azlactones

AbstractDihydroquinolin‐2‐ones, recognized for their bioactive properties, feature a six‐membered structure with nitrogen‐containing heterocycles. A method has been developed for synthesizing enantioenriched 3,4‐dihydroquinoline‐2‐one derivatives. This approach utilizes an asymmetric [4+2]‐cyclization process, combining 2‐amino‐β‐nitrostyrenes with azlactones, and is facilitated by a bifunctional squaramide‐based organocatalyst. This process has enabled the creation of chiral 3,4‐dihydroquinoline‐2‐ones with complex structures, including chiral tetrasubstituted carbon stereocenters, delivering corresponding products in 26–95% yield with a diastereomeric ratio of 1.2:1–19:1 and 52–97 ee.

Synthetic Studies toward Pseudolaric Acids: Radical Cyclization to Form Bridged Scaffold

Comprehensive SummaryPseudolaric acids are a family of diterpenoid natural products that exhibit a broad spectrum of biological activities. The main structural feature of their framework is a trans‐fused perhydroazulene bearing a bridged lactone positioned at the junction of the rings. Herein, we have developed a radical cyclization strategy that allows flexible tuning of the cyclization process through diverse silicon substitutions on the substrates. This strategy can assist in constructing a series of skeletons with structural resemblance to pseudolaric acids and expedites the construction of the bridged lactone. Finally, it facilitates the synthesis of the entire skeletal structure of the pseudolaric acid family of natural products, excluding the B‐ring functionalization.

Gold-catalyzed synthesis of small-sized carbo- and heterocyclic compounds: A review

Abstract Research on gold catalysis has flourished over the last 20 years, and gold catalysts are now acknowledged as the “best choice” for a range of organic transformations. Gold complexes have emerged as promising candidates for this use in recent years because of their high reactivity, which enables them to induce a broad range of transformations under mild conditions. Extensive demonstrations have showcased the extraordinary efficiency of synthesizing complex organic compounds from the basic starting components. In addition to its traditional applications in catalysis, gold catalysis has expanded to include the total synthesis of natural compounds, which is a complex and demanding undertaking. The class of molecules known as carbo- and heterocycles, which is arguably the most important, has a significant impact on the synthesis of agrochemicals and pharmaceuticals among the numerous additional products made possible by the novel procedures pioneered. The main topic of this review is how to use Au salts in homogeneous catalysis to create cyclization processes for small heterocyclic and carbocyclic systems. This study gives an overview of most of the books and articles written after 2013 that discuss making three- and four-membered carbo- and heterocyclic rings with gold as a catalyst. We have made every effort to include all outstanding reports on this subject; nonetheless, we apologize for any omissions.

Synthesis of hydantoins from N‐Boc protected amino acid derived amides using polymer‐supported PPh3/CBr4 as a reagent

AbstractHydantoin derivatives are versatile structural motifs found in natural products and various compounds with different biological or other properties. Due to their importance in both organic and medicinal chemistry, a number of synthetic procedures have been developed. In this article, a novel methodology utilizing N‐Boc protected amino acid amides for their preparation has been described. The cyclisation process was accomplished using solid supported PPh3 and CBr4 as reagents affording substituted hydantoins in moderate to good yields (40%–77%).

Intramolecular Catalytic Hydrogen Atom Transfer (CHAT).

Intramolecular catalysis (IntraCat) is the acceleration of a process at one site of a molecule catalyzed by a functional group in the same molecule; an external agent such as a solvent typically facilitates it. Here, we report a general first-principles-based IntraCat mechanism, which strictly occurs within a single molecule with no coreagent being involved─we call it intramolecular catalytic transfer of hydrogen atoms (CHAT). A reactive part of a molecule (chat catalyst moiety or chat agent, represented by -OOH, -COOH, -SH, -CH2OH, -HPO4, or another bifunctional H-donor/acceptor group) catalyzes an interconversion process, such as keto-enol or amino-imino tautomerization, and cyclization in the same molecule, while being regenerated in the process. It can thus be regarded as an intramolecular version of the intermolecular H atom transfer processes mediated by an external molecular catalyst, e.g., dihydrogen, water, or a carboxylic acid. Earlier, we proposed a general mechanistic systematization of intermolecular processes, illustrated in the simplest case of the H2-mediated reactions classified as dihydrogen catalysis [Asatryan, R.; et al. Catal. Rev.: Sci. Eng., 2014, 56, 403-475]. Following this systematization, the CHAT catalysis belongs to the category of relay transfer of H atoms, albeit in an intramolecular manner. A broader class of intramolecular processes includes all types of H-transfer reactions stimulated by an H-migration, which we call self-catalyzed H atom transfer (SC-HAT). The CHAT mechanism comprises a subset of SC-HAT in which the catalytic moiety is regenerated (i.e., acts as a true catalyst and not a reagent). We provide several characteristic examples of CHAT mechanism based on detailed analysis of the corresponding potential energy surfaces. All such cases showed a dramatically reduced activation barrier relative to the corresponding uncatalyzed H-transfer reactions. For example, we show that CHAT can facilitate long-range H-migration in larger molecules and can occur multiple times in one molecule with multiple interconverting groups. It also facilitates amino-imino tautomerization of unsaturated GABA-analogues and peptides, as well as intramolecular cyclization processes to form heterocycles, e.g., oxygenated rings. CHAT pathways may also explain the pH-dependent increase of mutarotation rate of glucose-6-phosphate demonstrated in pioneering experiments that introduced the classical IntraCat concept. In addition, we identify a ground electronic state CHAT pathway as an alternative to the UV-promoted long-range molecular crane keto-enol conversion with a remarkably low activation energy. To initially assess the possible impact of the new keto-enol conversion pathway on combustion of n-alkanes, we present a detailed kinetic analysis of isomerization and decomposition of pentane-2,4-ketohydroperoxide (2,4-KHP). The results are compared with key alternative reactions, including direct dissociation and Korcek channels (for which a new alkyl group migration channel is also identified), revealing the competitiveness of the CHAT pathway across a range of conditions. Taken together, this work provides insight into a general class of reaction pathways that has not previously being systematically considered and that may occur in a broad range of contexts from combustion to atmospheric chemistry to biochemistry.

Construction of Diverse Pyrrolidine-Based Skeletons through the Ag-Catalyzed Stereoselective Addition-Elimination Reaction of Azomethine Ylides with Nitroallyl Acetates.

Because scaffold diversity has a pronounced impact on biological screening, the efficient and expedient construction of skeletally diverse compound collections is a fundamental demand in drug discovery. In this regard, we report here an asymmetric tandem conjugate addition-elimination reaction of pyrroline esters with nitroallyl acetates and its application to the construction of various types of fused or spirocyclic pyrrolidines. A AgOAc/(R,Sp)-ThioClickFerrophos (TCF) catalyst efficiently promotes the addition-elimination reaction, setting vicinal chiral stereocenters featuring a tetrasubstituted carbon with excellent enantio- and diastereoselectivity while leaving the versatile nitroolefin moiety. The broad substrate scope of this reaction and the transformability of the resulting nitroolefin, imine, and ester moieties allow for the construction of diverse pyrrolidine-based fused or spiro bicyclic skeletons in optically active forms by various intramolecular cyclization processes.

Synthesis of 1‐(4‐hydroxybutyl)‐2‐benzoyl indoles from 2‐pyrrolidine benzaldehydes and α‐bromoacetophenones in deep eutectic solvent

AbstractA novel and highly efficient method for the synthesis of 1‐(4‐hydroxybutyl)‐2‐benzoyl indoles from 2‐pyrrolidine benzaldehyde and α‐bromoacetophenone in a choline chloride (ChCl)/ZnCl2 eutectic mixture was developed. This method, which does not require any catalyst, additive, or alkali, is useful for realizing tandem cyclization reactions. Several indoles were produced after cyclization and ring opening processes. Not all the compounds obtained are reported in the literature. This synthetic strategy proves that deep eutectic solvents can replace catalysts and organic solvents. Consequently, this is an environmentally friendly strategy that has significant potential in the development of green and sustainable chemistry.

Sp3 -Rich Heterocycle Synthesis on DNA: Application to DNA-Encoded Library Production.

DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2 -rich molecules. Herein, we show that sp3 -rich mono- and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space.

Sp3‐Rich Heterocycle Synthesis on DNA: Application to DNA‐Encoded Library Production

AbstractDNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2‐rich molecules. Herein, we show that sp3‐rich mono‐ and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space.

Catalytic Intermolecular Deoxygenative Coupling of Carbonyl Compounds with Alkynes by a Cp*Mo(II)-Catalyst.

Carbonyl is highly accessible and acts as an essential functional group in chemical synthesis. However, the direct catalytic deoxygenative functionalization of carbonyl compounds via a putative metal carbene intermediate is a formidable challenge due to the requirement of a high activation energy for the cleavage of strong C═O double bonds. Here, we report a class of bench stable and readily available Cp*Mo(II)-complexes as efficient deoxygenation catalysts that could catalyze the direct intermolecular deoxygenative coupling of carbonyl compounds with alkynes. Enabled by this powerful Cp*Mo(II)-catalyst, various valuable heteroarenes (10 different classes) were obtained in generally good yields and remarkable chemo- and regioselectivities. Mechanistic studies suggested that this reaction might proceed via a sequence of C═O double bonds cleavage, carbene-alkyne metathesis, cyclization, and aromatization processes. This strategy not only provided a general catalytic platform for the rapid preparation of heteroarenes but also opened a new window for the applications of Cp*Mo(II)-catalysts in organic synthesis.

Constructing a Stable Integrated Silicon Electrode with Efficient Lithium Storage Performance through Multidimensional Structural Design.

Silicon (Si) stands out as a highly promising anode material for next-generation lithium-ion batteries. However, its low intrinsic conductivity and the severe volume changes during the lithiation/delithiation process adversely affect cycling stability and hinder commercial viability. Rational design of electrode architecture to enhance charge transfer and optimize stress distribution of Si is a transformative way to enhance cycling stability, which still remains a great challenge. In this work, we fabricated a stable integrated Si electrode by combining two-dimensional graphene sheets (G), one-dimensional Si nanowires (SiNW), and carbon nanotubes (CNT) through the cyclization process of polyacrylonitrile (PAN). The integrated electrode features a G/SiNW framework enveloped by a conformal coating consisting of cyclized PAN (cPAN) and CNT. This configuration establishes interconnected electron and lithium-ion transport channels, coupled with a rigid-flexible encapsulated coating, ensuring both high conductivity and resistance against the substantial volume changes in the electrode. The unique multidimensional structural design enhances the rate performance, cyclability, and structural stability of the integrated electrode, yielding a gravimetric capacity (based on the total mass of the electrode) of 650 mAh g-1 after 1000 cycles at 3.0 A g-1. When paired with a commercial LiNi0.5Co0.2Mn0.3O2 cathode, the resulting full cell retains 84.8% of its capacity after 160 cycles at 2.0 C and achieves an impressive energy density of 435 Wh kg-1 at 0.5 C, indicating significant potential for practical applications. This study offers valuable insights into comprehensive electrode structure design at the electrode level for Si-based materials.

Design, synthesis, and anticancer evaluation of alkynylated pyrrole derivatives.

A series of alkynylated pyrrole derivatives were meticulously designed, drawing inspiration from the structure of 3-alkynylpyrrole-2,4-dicarboxylates, which were synthesized via a cyclization process involving methylene isocyanides and propiolaldehydes under mild conditions. These derivatives were subsequently subjected to evaluation for their anticancer properties against a panel of cell lines, including U251, A549, 769-P, HepG2, and HCT-116. According to the detailed analysis of structure-activity relationship, compound 12l emerged as the most promising molecule, with IC50 values of 2.29 ± 0.18 and 3.49 ± 0.30 μM toward U251 and A549 cells, respectively. Subsequent mechanistic investigations revealed that compound 12l exerts its effects by arresting the cell cycle in the G0/G1 phase and inducing apoptosis specifically in A549 cells. These innovative alkynylated pyrrole derivatives hold the potential to serve as a valuable template for the discovery of novel anticancer molecules.

Trifluoroacetyl‐Containing Scaffolds Assisted in Total Synthesis of Oxostephanine and Thailandine and Their Antimicrobial Activity

AbstractThis study is the first to fully synthesize oxostephanine (1) and thailandine (2), two aporphine alkaloids that were originally found in Stephania venosa (Blume) Spreng. The synthesis described in this study utilized commercially available starting materials, namely 2‐bromo‐6‐methoxybenzaldehyde and 3,4‐dihydroxybenzaldehyde. The B‐ring moiety of aporphines was successfully synthesized through the utilization of the Bischler‐Napieralski cyclization process. The synthesis of the C ring in oxoaporphine was accomplished using an order of crucial steps, namely biaryl coupling, incorporation of trifluoroacetyl‐containing scaffolds, and palladium coupling, followed by oxidation using Fremy's salt. The synthesis of oxostephanine (1) and thailandine (2) was successfully achieved in 11 and 12 steps, respectively, resulting in equivalent overall yields of 11.7 %. This study aimed to increase amount of interested compounds and explore the biological activity of those compounds. In this study, both compounds were subjected to testing for antibacterial activity using the CLSI standard M100 guideline. Oxostephanine (1) has shown significant antibacterial efficacy against gram‐positive bacteria and bacterial biofilms, as seen by minimum inhibitory concentration (MIC) values ranging from 7.8 to 125 μg/mL. Conversely, higher MIC values of 250 μg/mL indicated that thailandine (2) exhibited limited antimicrobial activity.