Cyclization Process Research Articles

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.

Copper(I)-Catalyzed Dearomatization of Benzofurans with 2-(Chloromethyl)anilines through Radical Addition and Cyclization Cascade.

Herein, we described a copper(I)-catalyzed dearomatization of benzofurans with 2-(chloromethyl)anilines to prepare various tetrahydrobenzofuro[3,2-b]quinolines and 2-(quinolin-2-yl)phenols in good to excellent yields through radical addition and an intramolecular cyclization process. Mechanistic studies revealed that 2-(chloromethyl)anilines served as radical precursors. The present method features broad substrate scope, good functional group tolerance, quinoline scaffold diversity, and radical addition dearomatization of benzofurans.

K2S2O8‐Mediated Access to Alkylsulfonated Spiro[4,5] Trienones from N‐Arylpropiolamides with the Insertion of Sulfur Dioxide

AbstractA four‐component reaction of N‐arylpropiolamides, Hantzsch esters, Na2S2O5 and water via a radical cascade cyclization process with the insertion of sulfur dioxide mediated by K2S2O8 is reported. A series of alkylsulfonated spiro[4,5] trienones are prepared up to 86% yield with a good functional group tolerance and substrate applicability. Preliminary mechanism experiments indicate that carbonyl oxygen of spiro[4,5] trienones originated from water.

6-Amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamides: Synthesis, Biological Activity, Quantum Chemical Studies and In Silico Docking Studies.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N'-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Glycosylation of n-pentenyl glycosides using bromodiethylsulfonium salt as an activator: interception of the glycosyl intermediate by chloride ion transfer.

Utilization of n-pentenyl glycosides (NPGs) in modern carbohydrate synthesis may be hindered by their sluggish activation, which results from reversible halogenation and cyclization processes. Bromodiethylsulfonium bromopentachloroantimonate (BDSB) has been previously shown to be a powerful brominating agent for the cation-π polyene cyclization of less reactive and electron-poor polyenes. This study demonstrates the activation of NPGs using BDSB as a powerful brominating agent. BDSB effectively activates the terminal olefins of NPGs and the reaction proceeds through 5-exo-tet cyclization, offering a rapid and mild approach for glycosylation with a wide range of glycosyl donors, including n-pentenyl mannoside, n-pentenyl galactoside, and n-pentenyl glucoside. The success of this approach derives from the chloride ion transfer from the nonnucleophilic SbCl5Br anion to the glycosyl intermediate, which disrupts the equilibrium and produces a glycosyl chloride intermediate that is smoothly converted to 22 coupling products, with yields ranging from moderate to excellent (49-100%). The β-selective glycosylation is accomplished when employing NPGs equipped with a neighboring participating group. The practicality of the BDSB-activated glycosylation is demonstrated by a gram-scale synthesis. This study showcases BDSB as a potent activator for NPG glycosylation through the interception of a glycosyl intermediate that diminishes the equilibration during halogenation and 5-exo-tet cyclization.

Cu(OTf)2/HFIP catalyzed regioselective cycloisomerization of indole-C3-functionalized alkynols to carbazoles.

We report here a simple and atom economic cycloisomerization reaction of indole-tethered alkynols for constructing diverse carbazoles using Cu(OTf)2/HFIP as the excellent promoter system. The reaction proceeds through a one-pot, domino process of spiro cyclization and 1,2-migration followed by aromatization to deliver carbazoles.

Synthesis of constrained bicycloalkanes through bibase-promoted brook rearrangement/radical-polar crossover cyclization.

Highly constrained bicyclic scaffolds are ubiquitous and attracting increasing interest in pharmaceutical and biotechnology discoveries owing to the enhanced activities. Herein, we report a protocol to access highly substituted constrained bicycloalkanes from readily accessible α-silyl alcohols and olefins through a bibase-promoted Brook rearrangement/radical-polar crossover cyclization (RPCC) process. Of note, the practical procedure features broad substrate scope and good group tolerance under mild and operationally simple conditions, using an inexpensive organic photocatalyst. Gram-scale preparation and diverse synthetic transformations demonstrate opportunities to rapidly construct molecular complexity. Mechanistic studies have indicated that the transformation involves a bibase-promoted radical transfer rearrangement addition/radical-polar crossover cyclization relay sequence, which differs from traditional solitary RPCC reactions.

Synthesis and anticancer evaluation of [d-Ala]-nocardiotide A.

Cancer is currently one of the biggest causes of death in the world. Like some microorganisms, cancer cells also develop resistance to various chemotherapy drugs and are termed multidrug resistant (MDR). In this regard, there is a need to develop new alternative anticancer agents. Anticancer peptides (ACPs) with high selectivity and high cell penetration ability are a promising candidate, as well as they are easy to modify. A cyclohexapeptide called nocardiotide A was isolated from the marine sponge Callyspongia sp., which is cytotoxic towards several cancer cells such as MM, 1S, HeLa, and CT26 cells. Previously, nocardiotide A was synthesized with a very low yield owing to its challenging cyclization process. In this study, we synthesized [d-Ala]-nocardiotide A as a derivative of nocardiotide A using a combination of solid phase peptide synthesis (SPPS) and liquid phase peptide synthesis (LPPS). The synthesis was carried out by selecting a d-alanine residue at the C-terminus to give a desired cyclic peptide product with a yield of 31% after purification. The purified [d-Ala]-nocardiotide A was characterized using HR-ToF MS and 1H and 13C-NMR spectroscopy to validate the desired product. The anticancer activity of the peptide was determined against HeLa cancer cell lines with an IC50 value of 52 μM compared to the parent nocardiotide A with an IC50 value of 59 μM. In the future, we aim to mutate various l-amino acids in nocardiotide A to d-amino acids to prepare nocardiotide A derivatives with a higher activity to kill cancer cells with higher membrane permeation. In addition, the mechanism of action of nocardiotide A and its derivatives will be evaluated.

Recent development in the synthesis of imidazo[1,5-a]indole derivatives: an in-depth overview.

In the realm of nitrogen-fused heterocycles, imidazo[1,5-a]indole and its derivatives are recognized as privileged structural patterns in various pharmaceutical drugs and biologically active natural products, emphasizing their significance. This review comprehensively explores the synthetic strategies for constructing imidazo[1,5-a]indole scaffolds, with a particular focus on transition metal-catalyzed methodologies. The primary highlighted method is [4 + 1] annulation, along with other notable approaches such as C-H activation/cyclization, enantioselective C-H annulation, intramolecular hydroamination, and double cyclization processes.