Intramolecular Cascade Reaction Research Articles

Sonoinduced Tumor Therapy and Metastasis Inhibition by a Ruthenium Complex with Dual Action: Superoxide Anion Sensitization and Ligand Fracture.

Photoresponsive ruthenium(II) complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology, as well as for antimicrobial applications. However, the limited penetration power of photons prevents the treatment of deep-seated lesions. In this study, we introduce a sonoresponsive ruthenium complex capable of generating superoxide anion (O2•-) via type I process and initiating a ligand fracture process upon ultrasound triggering. Attaching hydroxyflavone (HF) as an "electron reservoir" to the octahedral-polypyridyl-ruthenium complex resulted in decreased highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps and triplet-state metal to ligand charge transfer (3MLCT) state energy (0.89 eV). This modification enhanced the generation of O2•- under therapeutic ultrasound irradiation at a frequency of 1 MHz. The produced O2•- rapidly induced an intramolecular cascade reaction and HF ligand fracture. As a proof-of-concept, we engineered the Ru complex into a metallopolymer platform (PolyRuHF), which could be activated by low-power ultrasound (1.5 W cm-2, 1.0 MHz, 50% duty cycle) within a centimeter range of tissue. This activation led to O2•- generation and the release of cytotoxic ruthenium complexes. Consequently, PolyRuHF induced cellular apoptosis and ferroptosis by causing mitochondrial dysfunction and excessive toxic lipid peroxidation. Furthermore, PolyRuHF effectively inhibited subcutaneous and orthotopic breast tumors and prevented lung metastasis by downregulating metastasis-related proteins in mice. This study introduces the first sonoresponsive ruthenium complex for sonodynamic therapy/sonoactivated chemotherapy, offering new avenues for deep tumor treatment.

Regulating interaction with surface ligands on Au25 nanoclusters by multivariate metal–organic framework hosts for boosting catalysis

ABSTRACT While atomically precise metal nanoclusters (NCs) with unique structures and reactivity are very promising in catalysis, the spatial resistance caused by the surface ligands and structural instability poses significant challenges. In this work, Au25(Cys)18 NCs are encapsulated in multivariate metal–organic frameworks (MOFs) to afford Au25@M-MOF-74 (M = Zn, Ni, Co, Mg). By the MOF confinement, the Au25 NCs showcase highly enhanced activity and stability in the intramolecular cascade reaction of 2-nitrobenzonitrile. Notably, the interaction between the metal nodes in M-MOF-74 and Au25(Cys)18 is able to suppress the free vibration of the surface ligands on the Au25 NCs and thereby improve the accessibility of Au sites; meanwhile, the stronger interactions lead to higher electron density and core expansion within Au25(Cys)18. As a result, the activity exhibits the trend of Au25@Ni-MOF-74 > Au25@Co-MOF-74 > Au25@Zn-MOF-74 > Au25@Mg-MOF-74, highlighting the crucial roles of microenvironment modulation around the Au25 NCs by interaction between the surface ligands and MOF hosts.

Copper-Catalyzed Synthesis of Furan-Tethered Benzocyclobutenes via Carbene-Mediated 1,4-Sulfinate Migration-Annulation.

A copper-catalyzed intramolecular cascade reaction of conjugated enynones has been achieved via a pivotal 1,4-sulfinate migration step. This process leverages a cost-effective and ecofriendly copper salt as catalyst, enabling the efficient construction of five- and four-membered rings in a rapid, sequential manner, producing furan-tethered benzocyclobutenes in good to excellent yields under mild conditions. The reaction is characterized by 100% atom economy, outstanding efficiency, and excellent diastereoselectivity in the cases studied. The robustness of this method is evidenced by its compatibility with air exposure and the use of undistilled, commercially available solvents, further enhancing its practicality.

π‐Radical Cascade to a Chiral Saddle‐Shaped Peropyrene

AbstractReactions of open‐shell molecular graphene fragments are typically thought of as undesired decomposition processes because they lead to the loss of desired features like π‐magnetism. Oxidative dimerization of phenalenyl to peropyrene shows, however, that these transformations hold promise as a synthetic tool for making complex structures via formation of multiple bonds and rings in a single step. Here, we explore the feasibility of using this “undesired” reaction of phenalenyl to build up strain and provide access to non‐planar polycyclic aromatic hydrocarbons. To this end, we designed and synthesized a biradical system with two phenalenyl units linked via a biphenylene backbone. The design facilitates an intramolecular cascade reaction to a helically twisted saddle‐shaped product, where the key transformations—ring‐closure and ring‐fusion—occur within one reaction. The negative curvature of the final peropyrene product, induced by the formed eight‐membered ring, was confirmed by single‐crystal X‐ray diffraction analysis and the helical twist was validated via resolution of the product's enantiomers that display circularly polarized luminescence and high configurational stability.

π-Radical Cascade to a Chiral Saddle-Shaped Peropyrene.

Reactions of open-shell molecular graphene fragments are typically thought of as undesired decomposition processes because they lead to the loss of desired features like π-magnetism. Oxidative dimerization of phenalenyl to peropyrene shows, however, that these transformations hold promise as a synthetic tool for making complex structures via formation of multiple bonds and rings in a single step. Here, we explore the feasibility of using this "undesired" reaction of phenalenyl to build up strain and provide access to non-planar polycyclic aromatic hydrocarbons. To this end, we designed and synthesized a biradical system with two phenalenyl units linked via a biphenylene backbone. The design facilitates an intramolecular cascade reaction to a helically twisted saddle-shaped product, where the key transformations-ring-closure and ring-fusion-occur within one reaction. The negative curvature of the final peropyrene product, induced by the formed eight-membered ring, was confirmed by single-crystal X-ray diffraction analysis and the helical twist was validated via resolution of the product's enantiomers that display circularly polarized luminescence and high configurational stability.

Advances in gold catalyzed synthesis of quinoid heteroaryls.

This review explores recent advancements in synthesizing quinoid heteroaryls, namely quinazoline and quinoline, vital in chemistry due to their prevalence in natural products and pharmaceuticals. It emphasizes the rapid, highly efficient, and economically viable synthesis achieved through gold-catalyzed cascade protocols. By investigating methodologies and reaction pathways, the review underscores exceptional yields attainable in the synthesis of quinoid heteroaryls. It offers valuable insights into accessing these complex structures through efficient synthetic routes. Various strategies, including cyclization, heteroarylation, cycloisomerization, cyclo-condensation, intermolecular and intramolecular cascade reactions, are covered, highlighting the versatility of gold-catalyzed approaches. The comprehensive compilation of different synthetic approaches and elucidation of reaction mechanisms contribute to a deeper understanding of the field. This review paves the way for future advancements in synthesizing quinoid heteroaryls and their applications in drug discovery and materials science.

Synthesis of Pyrido‐[2,1‐a]isoquinoline Derivatives via Gold(I)‐Catalyzed Intramolecular Cascade Reaction of Enamides

AbstractA gold(I)‐catalyzed intramolecular cascade reaction of tertiary enamides has been developed, which provides a method for the preparation of diverse pyrido[2,1‐a]isoquinoline derivatives with good function group tolerance. Preliminary investigation of the reaction mechanism indicate that this process comprises a nucleophilic addition of the enamide to an alkynyl group, followed by the capture of the acyliminium ion by an electron‐rich aromatic component. Additionally, scale‐up experiments and further transformations of pyrido‐[2,1‐a]isoquinolines underscore the utility of this methodology.

Superoxide Anion-Mediated Afterglow Mechanism-Based Water-Soluble Zwitterion Dye Achieving Renal-Failure Mice Detection.

Afterglow materials-based biological imaging has promising application prospects, due to negligible background. However, currently available afterglow materials mainly include inorganic materials as well as some organic nanoparticles, which are difficult to translate to the clinic, resulting from non-negligible metabolic toxicity and even leakage risk of inorganic heavy metals. Although building small organic molecules could solve such obstacles, organic small molecules with afterglow ability are extremely scarce, especially with a sufficient renal metabolic capacity. To address these issues, herein, we designed water-soluble zwitterion Cy5-NF with renal metabolic capacity and afterglow luminescence, which relied on an intramolecular cascade reaction between superoxide anion (O2•-, instead of 1O2) and Cy5-NF to release afterglow luminescence. Of note, compared with different reference contrast agents, zwitterion Cy5-NF not only had excellent afterglow properties but also had a rapid renal metabolism rate (half-life period, t1/2, around 10 min) and good biocompatibility. Unlike prior afterglow nanosystems possessing a large size, for the first time, zwitterion Cy5-NF has achieved the construction of water-soluble renal metabolic afterglow contrast agents, which showed higher sensitivity and signal-to-background ratio in afterglow imaging than fluorescence imaging for the kidney. Moreover, zwitterion Cy5-NF had a longer kidney retention time in renal-failure mice (t1/2 more than 15 min). More importantly, zwitterion Cy5-NF can be metabolized very quickly even in severe renal-failure mice (t1/2 around 25-30 min), which greatly improved biosecurity. Therefore, we are optimistic that the O2•--mediated afterglow mechanism-based water-soluble zwitterion Cy5-NF is very promising for clinical application, especially rapid detection of kidney failure.

Intramolecular cascade reaction sensing platform for rapid, specific and ultrasensitive detection of nitrite

Nitrite is a carcinogenic substance in food. Excessive consumption of nitrite severely endangers human health. However, rapid and accurate quantification of nitrite by a simple tool is still very challenging. In this work, we designed a practical sensing platform based on 8-(o-phenylenediamine)-boron dipyrromethene (BDP-OPD) to determine nitrite in food. BDP-OPD can take a specific diazotization-cyclization cascade reaction with nitrite to form boron dipyrromethene (BODIPY), giving rise to a remarkable chromogenic reaction along with high contrast fluorescence turn-on response towards nitrite. BDP-OPD has high sensitivity, rapid response, and good selectivity. Furthermore, a portable smartphone-based fluorescence device integrated with a self-programmed Python program was fabricated, which has been successfully used to determine nitrite in food with the advantages of rapid response, low cost, ease of operation, portability, and satisfactory recoveries (92–112%). The good sensing performance rendered BDP-OPD a promising fluorescence platform for on-site visual detection of nitrite.

Visible-light-induced oxidant/additive-free atom-economic synthesis of multifunctionalized cyclopropanes via energy transfer.

Herein we describe intramolecular cascade reactions enabling the synthesis of bridged cyclopropanes, via the photoinduced energy-transfer catalysis of tethered conjugated dienes. Photocatalysis affords the efficient synthesis of complex tricyclic compounds that exhibit multiple stereocenters from readily accessible starting materials that would otherwise be difficult to obtain. This single-step reaction is characterized by its broad substrate scope, atom-economy, excellent selectivity, and satisfactory yield, which includes a facile scale-up synthesis and synthetic transformation. An in-depth mechanistic study reveals that the reaction proceeds via an energy-transfer pathway.

Advancements in Gold-Catalyzed Cascade Reactions to Access Carbocycles and Heterocycles: An Overview.

This review summarizes recent developments (from 2006 to 2022) in numerous important and efficient carbo- and heterocycle generations using gold-catalyzed cascade protocols. Herein, methodologies involve selectivity, cost-effectiveness, and ease of product formation being controlled by the ligand as well as the counter anion, catalyst, substrate, and reaction conditions. Gold-catalyzed cascade reactions covered different strategies through the compilation of various approaches such as cyclization, hydroarylation, intermolecular and intramolecular cascade reactions, etc. This entitled reaction is also useful for the synthesis of spiro, fused, bridged carbo- and heterocycles.

Thiol “click” chromene mediated cascade reaction forming coumarin for in-situ imaging of thiol flux in drug-induced liver injury

Drug-induced organ damage has long been considered as a serious public health concern. Drug-induced liver injury (DILI) is one of the common clinical side effects of drugs and the main cause of acute liver failure. Previous evidence showed that there is a potential relationship between thiols and DILI. Many studies have reported that oxidative stress is involved in many drug-induced liver injury mechanisms. APAP, as the most representative drug for clinical DILI, is considered to cause large amounts of intracellular reactive oxygen species. However, thiols as the effective antioxidant maintain the normal redox balance of organisms and play a vital role in the liver injury and other diseases. Therefore, a new NIR fluorescent probe DCI-Ac-HMPC was developed based on thiol-chromene “click” reaction, which triggered the intramolecular cascade reaction to in-situ generate NIR coumarin fluorophore. In addition, we found that thiols levels in the liver of mice with DILI were significantly reduced, revealing a negative correlation between thiols and DILI. Furthermore, the therapeutic effects of three kinds of liver-protecting drugs on hepatotoxicity induced by acetaminophen (APAP) in vivo based on thiols fluctuations. This work provides a new idea for the in-situ synthesis strategy of NIR coumarin dyes, which is helpful for the diagnosis of DILI and the further study of the role of thiols in related diseases.

Synthesis of Diverse Pentasubstituted Pyrroles by a Gold(I)-Catalyzed Cascade Rearrangement-Cyclization of Tertiary Enamide.

An efficient Au(I)-catalyzed intramolecular cascade reaction of tertiary enamides tethered an alkynyl group has been developed. The process is composed of a propargyl-claisen rearrangement and 5-exo-dig cyclization. This protocol provided a powerful method for the preparation of a variety of pentasubstituted pyrroles derivatives with excellent functional group tolerance in excellent yields. Scale-up experiment and chemical transformations of products exhibited the versatility of tertiary enamides in organic synthesis again.

Gold-Catalyzed [3 + 2] Annulation, Carbenoid Transfer, and C–H Insertion Cascade: Elucidation of Annulation Mechanisms via Benzopyrylium Intermediates

It has been established that a cationic gold(I)/PCy3 complex catalyzes the intramolecular cascade reaction of enediyne-carbonyls via benzopyrylium intermediates giving pentacyclic compounds, bearin...

Development of Silver Nanoparticles Decorated on Functional Glass Slide as Highly Efficient and Recyclable Dip Catalyst

AbstractThe development of a highly reusable and extremely efficient catalyst is still a fundamental as well as technological problem. Here, we report on the preparation and catalytic applications of Silver nanoparticles (AgNPs) immobilized on amine terminated glass slide as a dip catalyst for the transformation of nitrophenol, intramolecular cascade reaction and synthesis of 5‐Phenyl‐1H‐tetrazole. The dip catalyst system consists of AgNPs stabilized on microscopic glass slide as the support. AgNPs were decorated on the glass slide by modifying the glass surface with (3‐Aminopropyl)triethoxysilane (APTES). The dip catalyst was characterized using SEM, EDX, FTIR, and TEM, and AFM. This system is found to be stable in both organic and aquous solvents and exhibits excellent recyclability even at high temperatures. The catalyst was used for 20 cycles of nitrophenol reduction reaction and 5 cycles for other reactions in this study to test its efficiency. No any significant decrease was observed in the activity of the catalyst. We have also investigated the applicability of the AgNPs immobilized on functional glass slide as surface enhanced Raman scattering (SERS) substrate to understand the catalytic reduction reaction mechanism.

Nickel‐CatalyzedDicarbofunctionalization of Alkenes†

As a straightforward strategy for rapidly increasing molecular complexity, dicarbofunctionalization of alkenes has attracted substantial interests of organic synthesis, medicine chemistry, and materials science. Nickel‐catalyzed cascade dicarbofunctionalizations have been flourished in this area recently, and nickel‐mediated radical pathways particularly offer new opportunities in conjunctive cross‐couplings with alkyl coupling partners. Herein, we give a comprehensive review of nickel‐catalyzed dicarbofunctionalization of alkenes through a historical perspective, including intermolecular three‐component reactions and intramolecular cascade reactions. Among the pathways discussed in this review, the carbometallation/cross‐coupling process and the radical addition/cross‐coupling process are the two major pathways for the nickel‐catalyzed dicarbofunctionalization of alkenes. The oxidative cyclization and 1,2‐metallate shift processes are also selectively discussed. These methods overcome the limitations associated with the reactions using noble metals in the field, providing an efficient and straightforward access to structurally diversified molecules.

Intramolecular trans-Carbocarbonation of Internal Alkynes by a Cascade of Formal anti-Carbopalladation/Cyclopropanol Opening.

An intramolecular cascade reaction consisting of a formal anti-carbopalladation terminated by the ring-opening of a cyclopropanol unit is presented. The products, which involve tetrasubstituted alkene units embedded in an oligocyclic ring system, are generated in moderate to excellent yield. The opening of the cyclopropanol unit leads to a keto group in the γ-position to the emerging double bond.

Copper-Catalyzed Intramolecular Annulation of Conjugated Enynones to Substituted 1 H-Indenes and Mechanistic Studies.

Herein, a copper-catalyzed intramolecular cascade reaction of conjugated enynones to deliver substituted 1 H-indenes is reported. The inexpensive and less toxic copper salt served as the only catalyst in the transformation, affording the 3-(2-furyl)-substituted 1 H-indenes in good to excellent yields under mild reaction conditions with broad functional group tolerance and making it highly appealing for synthetic organic chemistry. Notably, detailed DFT calculations have been carried out to elucidate that the reaction undergoes a copper-mediated 5- exo-dig cyclization of enynones to afford copper-(2-furyl)-carbene intermediate, followed by diene-carbene cyclization (one step but involving 6π cyclization of Cu-carbene and reductive elimination) and 1,5-hydrogen shift to provide the 1 H-indenes.

Triggering a [2]rotaxane molecular shuttle through hydrogen sulfide

A novel chemically-controlled [2]rotaxane molecular shuttle was successfully designed and synthesized. A H2S-responsive bulk barrier was introduced between the two identical recognition stations of the [2]rotaxane to prevent dynamic shuttling of the macrocycle. Upon addition of H2S, the complete intramolecular cascade reaction occurs in a controllable manner, resulting in removal of the bulk barrier and the shuttling motion of the macrocycle between the two stations recovers.

Extended third ring is a charm for indole-annulated compounds

Fused-ring systems are special structural features of many natural product and synthetic compounds, contributing to the bioactivity that makes them useful as pharmaceuticals and agrochemicals. Chemists have numerous methods for generating small rings with six or fewer members, such as Diels-Alder and other cycloaddition reactions. They also have ways of constructing large rings with 10 or more members, including macrolactonization and ring-closing metathesis. However, the direct synthesis of medium-sized rings, especially enantioselectively, has remained a challenge because of steric constraints. Lin Huang, Li-Xin Dai, and Shu-Li You of Shanghai Institute of Organic Chemistry have now discovered a pathway around this roadblock by developing an intramolecular cascade reaction for building asymmetric seven- to nine-membered rings onto indole frameworks (J. Am. Chem. Soc. 2016, DOI: 10.1021/jacs.6b02678). As an example, the team found that a chiral iridium catalyst can drive dearomatization of an allylic carboline to form a bridged intermediate. A subsequent ring-opening