A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

Palladium-catalyzed (Z)-selective allylation of phosphine oxides with vinylethylene carbonates to construct phosphorus allyl alcohols.

Allylphosphine oxide compounds are important building blocks with broad applications in organic synthesis and pharmaceutical science. Herein, we report an unprecedented palladium-catalyzed allylation of phosphine oxides with vinylethylene carbonates, producing various phosphorus allyl alcohols in excellent yields with high Z-selectivity. In addition, gram-scale synthesis and further functional group transformations demonstrate the practical utility of this synthetic method.

A straightforward access to trifluoromethylated natural products through late-stage functionalization.

Covering: 2011 to 2021Trifluoromethyl (CF3)-modified natural products have attracted increasing interest due to their magical effect in binding affinity and/or drug metabolism and pharmacokinetic properties. However, the chemo and regioselective construction of natural products (NPs) bearing a CF3 group still remains a long-standing challenge due to the complex chemical scaffolds and diverse reactive sites of NPs. In recent years, the development of late-stage functionalization strategies, including metal catalysis, organocatalysis, light-driven reactions, and electrochemical synthesis, has paved the way for direct trifluoromethylation process. In this review, we summarize the applications of these strategies in the late-stage trifluoromethylation of natural products in the past ten years with particular emphasis on the reaction model of each method. We also discuss the challenges, limitations, and future prospects of this approach.

Base-Promoted Formal (3 + 2) Cycloaddition of α-Halohydroxamates with Electron-Deficient Alkenyl-iminoindolines To Synthesize Spiro-indolinepyrrolidinones.

Construction of pyrrolidinyl-spiroindoles with easily available starting materials has attracted considerable attention from the synthesis community and is in great demand. Here, we describe a base-promoted formal (3 + 2) cycloaddition of α-halohydroxamates with alkenyl-iminoindolines. The present methodology features mild reaction conditions and a broad substrate scope with up to 99% yield and excellent diastereoselectivity. The versatility of this approach is demonstrated through valuable synthetic transformations. Preliminary mechanistic studies shed light on the mechanism of this cycloaddition process.

Direct Acylation of Unactivated Alkyl Halides with Aldehydes through N-Heterocyclic Carbene Organocatalysis.

Catalytic acylation of organohalides with aldehydes is an ideal strategy for the direct synthesis of ketones. However, the utilization of unactivated alkyl halides in such a transformation remains a formidable challenge. In this study, we developed a cross-coupling reaction of aldehydes with unactivated alkyl halides through N-heterocyclic carbene catalysis. With this protocol, various ketones could be rapidly synthesized from readily available starting materials under mild conditions. This organocatalytic system was successfully applied in the late-stage functionalization of pharmaceutical derivatives. Mechanistic investigations suggest a closed-shell nucleophilic substitution mechanism for this reaction.

Radical Acylalkylation of 1,3-Enynes To Access Allenic Ketones via N-Heterocyclic Carbene Organocatalysis.

An N-heterocyclic carbene organocatalytic 1,4-difunctionalization of 1,3-enynes was developed. This organocatalytic strategy was suitable for a broad spectrum of substrates to efficiently synthesize allenic ketones bearing diverse substituents. Preliminary mechanistic studies suggest a radical reaction pathway for this organocatalytic acylalkylation process.

Sulphur ylide-mediated cyclopropanation and subsequent spirocyclopropane rearrangement reactions.

The efficient construction of cyclopropyl spiroindoline skeletons and the exploration of related follow-up synthetic transformations have elicited considerable interest amongst members of the chemistry community. Here, we describe a formal (2 + 1) annulation and three-component (1 + 1 + 1) cascade cyclisation via sulphur ylide cyclopropanation under mild conditions. The spiro-cyclopropyl iminoindoline moiety can be readily transformed into another medicinally interesting pyrrolo[3,4-c]quinoline framework through a novel rearrangement process.

Asymmetric organocatalysis: an enabling technology for medicinal chemistry.

The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.

Remote C(sp3 )-H Acylation of Amides and Cascade Cyclization via N-Heterocyclic Carbene Organocatalysis.

The direct functionalization of inert C(sp3 )-H bonds under environmentally benign catalytic conditions remains a challenging task in synthetic chemistry. Here, we report an organocatalytic remote C(sp3 )-H acylation of amides and cascade cyclization through a radical-mediated 1,5-hydrogen atom transfer mechanism using N-heterocyclic carbene as the catalyst. Notably, a diversity of nitrogen-containing substrates, including simple linear aliphatic carbamates and ortho-alkyl benzamides, can be successfully applied to this organocatalytic system. With the established protocol, over 120 examples of functionalized δ-amino ketones and isoquinolinones with diverse substituents were easily synthesized in up to 99 % yield under mild conditions. The robustness and generality of the organocatalytic strategy were further highlighted by the successful acylation of unactivated C(sp3 )-H bonds and late-stage modification of pharmaceutical molecules. Then, the asymmetric control of the radical reaction was attempted and proven feasible by using a newly designed chiral thiazolium catalyst, and moderate enantioselectivity was obtained at the current stage. Preliminary mechanistic investigations including several control reactions, KIE experiments, and computational studies shed light on the organocatalytic radical reaction mechanism.

Oxidative Radical NHC Catalysis: Divergent Difunctionalization of Olefins through Intermolecular Hydrogen Atom Transfer.

Oxidative N-heterocyclic carbene (NHC) organocatalysis, typically leading to the formation of acyl azolium reactive intermediates, constitutes one of the most important activation strategies for the NHC-catalyzed chemical transformations. Here, we report an unprecedented oxidative radical NHC catalysis by using peroxyester as the external single-electron oxidant to realize divergent difunctionalization of olefins. The key to success of this chemistry is the catalytic generation of oxygen radicals that could trigger an intermolecular hydrogen atom transfer to activate the inert C-H bonds, thereby enabling the productive radical relay process. With this protocol, commonly used general chemicals could serve as radical precursors to allow efficient synthesis of value-added products in a straightforward and cost-effective manner. Preliminary mechanistic investigations, including control experiments and DFT calculations, shed light on the NHC organocatalytic radical reaction mechanism.

Single-Electron Transfer Reactions Enabled by N-Heterocyclic Carbene Organocatalysis.

Over the past decades, N-heterocyclic carbene (NHC) organocatalysis has undergone a flourish of development on the basis of closed-shell reaction paths. By contrast, the emerging area of single-electron transfer (SET) reactions enabled by NHC catalysis still remain underdeveloped, but offer plenty of opportunities to develop new catalytic modes and useful synthetic methods. A number of interesting transformations were triggered by the SET process from the electron-rich Breslow intermediates to various single-electron acceptors. In additions, recent studies revealed that the Breslow radical cations could also be generated by single-electron reduction of the electron-deficient acyl azolium intermediates. These discoveries open a new avenue for NHC organocatalysis to harness radical reactions. The present review will focus on the exciting advancements in the dynamic area of radical NHC organocatalysis.

Highly Chemoselective [2+1] Annulation of α-Alkylidene Pyrazolones with α-Bromonitroalkenes: Synthesis of Pyrazolone-Based Vinylcyclopropanes and Computational Studies.

A highly chemoselective [2+1] annulation of α-alkylidene pyrazolones with α-bromonitroalkenes has been achieved under mild conditions. α-Alkylidene pyrazolones were unprecedentedly used as a C1 synthon to participate in annulation reactions, providing access to diverse vinylcyclopropane-based pyrazolone products. In addition, a spectrum of pharmaceutically interesting pyrazole-fused pyranone oximes could be rapidly obtained through a [2+1] annulation/rearrangement sequential process. Computational studies disclosed the origin of the observed chemoselectivity of the [2+1] cycloaddition.

Bifunctional Brønsted Base Catalyzed [3 + 3] Annulations of Indolin-2-imines and α,ß-Unsaturated Imides: An Enantioselective Approach to α-Carbolinones.

Asymmetric construction of α-carbolinones with easily available starting materials has recently attracted considerable attention from the synthesis community, and the development of effective catalysis for this target is in great demand. Here, a bifunctional Brønsted base catalyzed asymmetric [3 + 3] cyclization of indolin-2-imines and α,ß-unsaturated N-acylated succinimides was developed by using the strategy of noncovalent bonding catalysis. With this organocatalytic protocol, a variety of tetrahydro-α-carbolinones bearing different substituents were synthesized with up to 99% yield and up to 96:4 er.

Palladium-catalysed decarboxylative annulations of vinylethylene carbonates leading to diverse functionalised heterocycles.

Heterocycles are the fundamental structural motifs found in natural products and biologically active compounds. The construction of these structures is therefore an important task in organic chemistry. Vinylethylene carbonates (VECs) are versatile building blocks that can undergo transition metal catalysed decarboxylation to enable various kinds of interesting transformations. This review provides an overview of the significant achievements of VECs in palladium-catalysed annulations over the past five years. The flexible reactivity of VECs is demonstrated by various [3 + 2], [5 + n] and other types of annulations, which could offer powerful protocols for accessing diverse functionalised heterocycles.

Erxian decoction, a famous Chinese medicine formula, antagonizes corticosterone-induced injury in PC12 cells, and improves depression-like behaviours in mice.

Context: In folk medicine, erxian decoction (EXD) is used to treat perimenopausal syndrome in women. It is also used clinically to treat depression, but the mechanism remains unknown.Objectives: To investigate the neuroprotective effect of EXD, and its antidepressant potential.Materials and methods: ICR mice were treated with EXD (0.5, 1.5 and 4.5 g/kg i.g.) and fluoxetine (6.0 mg/kg i.g.) for 10 days. On day 10 of the treatment, depression-like behaviour was induced by reserpine (2.5 mg/kg injected i.p.), and after 24 h of reserpine administration, it was assessed using the tail suspension and forced swimming tests. MTT assay, lactate dehydrogenase test, flow cytometry analysis, Hoechst staining and western blotting were used to assess the apoptosis of PC12 cells. Apoptosis proteins and neurotransmitter were tested in vitro and in vivo, respectively.Results: MTT assay results showed corticosterone prevented cell growth, but EXD at concentrations of 100, 200 and 400 µg/mL restored cell viability (EC50: 204.016 µg/mL). EXD decreased lactate dehydrogenase leakage from 63.48 to 43.60 U/L, and upregulated expression of Bcl-2 while the expression of Bax, caspase-3 and caspase-8 were decreased in vivo and in vitro. Moreover, EXD improved depression-like behaviour in mice, and 4.5 g/kg EXD treatment increased the secretion of serotonin, dopamine and norepinephrine by 67.44, 28.12 and 42.12 pg/mg, respectively, in hypothalamus compared to that of reserpine group.Discussion and conclusions: EXD demonstrated neuroprotective effects and improved depression-like behaviour in mice. Further research should be focussed on the mechanism of the active components in EXD.

Radical Acylfluoroalkylation of Olefins through N-Heterocyclic Carbene Organocatalysis.

Fluorinated ketones are widely prevalent in numerous biologically interesting molecules, and the development of novel transformations to access these structures is an important task in organic synthesis. Herein, we report the multicomponent radical acylfluoroalkylation of a variety of olefins in the presence of various commercially available aromatic aldehydes and fluoroalkyl reagents through N-heterocyclic carbene organocatalysis. With this protocol, over 120 examples of functionalized ketones with diverse fluorine substituents have been synthesized in up to 99 % yield with complete regioselectivity. The generality of this catalytic strategy was further highlighted by its successful application in the late-stage functionalization of pharmaceutical skeletons. Excellent diastereoselectivity could be achieved in the reactions forging multiple stereocenters. In addition, preliminary results have been achieved on the catalytic asymmetric variant of the olefin difunctionalization process.

Direct Sulfide-Catalyzed Diastereoselective [4+1] Annulations of ortho-Quinone Methides and Bromides.

Direct sulfide organocatalysis is an emerging topic in research on synthetic chemistry. Here, an unprecedented sulfide-catalyzed diastereoselective [4+1] annulation of (in situ generated) ortho-quinone methides and bromides is reported. Notably, the robustness of such sulfide organocatalysis was demonstrated by performing the catalytic reaction under oxidative conditions without significantly affecting the reaction outcome. Various dihydrobenzofurans with diverse substituents were obtained with high isolated yields of up to 98% and remarkable diastereoselectivity (>19:1 dr in general).

Highly diastereoselective synthesis of cyclopropane-fused spiro-pseudoindoxyl derivatives through [2 + 1] annulation of 2-ylideneoxindoles and sulfonium bromides.

Compared with the intensively studied C3 spirooxindoles, limited reliable approaches are reported for synthesizing structurally analogous C2-spiropseudoindoxyl derivatives. Here, we developed an efficient method for highly diastereoselective synthesis of cyclopropane-fused spiropseudoindoxyl derivatives (up to 88% yield and >20 : 1 dr in all cases) through [2 + 1] annulation of (Z)-2-ylideneoxindoles with sulfur ylides.

Stereoselective Construction of Halogenated Quaternary Carbon Centers by Brønsted Base Catalyzed [4+2] Cycloaddition of α-Haloaldehydes.

Asymmetric construction of halogenated quaternary carbon centers under mild reaction conditions remains challenging. Reported here is an unprecedented and highly stereoselective Brønsted base catalyzed [4+2] cycloaddition between either α-chloro- or α-bromoaldehydes and cyclic enones. The key intermediate, an α-halogenated enolate, is susceptible to dehalogenation and can be stabilized and stereochemically controlled using bifunctional tertiary amines. This method provides facile access to a collection of optically pure bicyclic dihydropyrans having three contiguous stereocenters, including a halogen-bearing quaternary carbon center. Of note, the product can be transformed in situ into densely functionalized spirocyclopropanes in a highly efficient and stereoselective manner.

Diastereoselective Synthesis of Spirocyclopropanes under Mild Conditions via Formal [2 + 1] Cycloadditions Using 2,3-Dioxo-4-benzylidene-pyrrolidines.

A highly diastereoselective cyclopropanation of cyclic enones with sulfur ylides was developed under catalyst-free conditions, producing multifunctional spirocyclopropanes in generally excellent yields (up to 99% yield and >99:1 d.r.). The asymmetric version of this method was realized by using an easily available chiral sulfur ylide, affording products with moderate to good stereoselectivity.