A naphthylimide dye-based fluorescent probe (Nap-Mem-GSH) was synthesized for the detection of Glutathione inside and outside cell membranes. This probe carried a 2-Hydroxyquinoline fragment as a recognition site on top of a naphthalimide dye, which exhibits better selective and fluorimetric response toward Glutathione in natural media. The long alkyl chain confers a cell membrane targeting role to Nap-Mem-GSH. Therefore, the detection of intra-and extracellular glutathione inside and outside the cell membrane can be realized by Nap-Mem-GSH. Meanwhile, Nap-Mem-GSH not only has a large Stokes shift (160 nm), a low detection limit and a rapid response toward GSH, but also has the advantages of low cytotoxicity and good membrane permeability to living cells, and has been successfully applied to effectively detect and image intracellular glutathione by confocal fluorescence imaging.

Enantioenriched 3-hydroxyindolenines are highly attractive scaffolds owing to their prevalence in a wide range of indole alkaloids and their utility as key intermediates for the construction of chiral 2-oxindoles. The direct C-3 selective hydroxylation of indoles represents the most straightforward approach to accessing these structures. However, catalytic asymmetric hydroxylation of indoles for the synthesis of 3-hydroxyindolenines remains underexplored, with only one successful nonenzymatic method reported to date. Herein, by developing a novel in situ-generated magnesium catalyst and introducing o-nitrobenzene as a coordinating group, we achieved the C-3 selective hydroxylation of 2,3-disubstituted indole using racemic oxaziridine as the oxidant, affording enantioenriched products that were further applied in the total synthesis of hinckdentine A. Meanwhile, the nitro group could be utilized as a handle site for further coupling transformations. Additionally, the system proved to be effective for the kinetic resolution (KR) of common oxaziridines. Control and comparative experiments were conducted to identify the key reaction intermediate. DFT calculations revealed that the Mg(II) catalyst and the indole substrate form an enzyme-like catalytic pocket, which directs the oxaziridine into a well-controlled coordination geometry. This arrangement ensures high enantioselectivity in the hydroxylation while simultaneously enabling the KR process. Furthermore, given the divergent reaction pathways between indoles and oxaziridines, DFT calculations also provide insight into how the indole substrate dictates the reaction pathways.

Iron-catalyzed ligand-to-metal charge transfer (LMCT) processes have emerged as robust strategies for diverse organic transformations. Despite this potential, their application to addition reactions of C═N unsaturated bonds remains underexplored. Herein, we report an LMCT-enabled, photoredox/iron-catalyzed radical addition to dehydroglycine derivatives. This method employs readily available aliphatic carboxylic acids as radical precursors, enabling direct decarboxylative addition for the efficient synthesis of structurally diverse amino acid derivatives in excellent yields (up to 99%) without prefunctionalization. The protocol exhibits broad scope, including successful late-stage functionalization of pharmaceutically relevant molecules.

Herein, we report the first catalytic enantioselective aza-[2+2] cyclization of simple ketoimines, thereby addressing a persistent challenge in four-membered aza-ring construction. While the aza-[2+2] cyclization represents the most straightforward approach to azetidine synthesis, previous methodologies have been strictly limited to ketoimines, all with an EWG at the central reactive carbon, and predominantly employing cyclic imine substrates. Through rational design of an in situ-generated magnesium catalytic system and systematic investigation of imine electronic effects, we have successfully developed an asymmetric protocol for simple ketoimines. This breakthrough enables efficient access to enantioenriched monocyclic azetidines with excellent stereocontrol. Moreover, a streamlined one-pot tandem oxidation readily converts these azetidines into valuable quaternary chiral β-lactams-privileged scaffolds that are prominent in numerous pharmaceuticals and bioactive agents. A combination of comparative studies, the calculation results of the HOMO and LUMO energies of different imines, relative control experiments, and a series of detailed NLE analysis revealed the coordination difference and the catalytic cycle. The catalytic protocol was used for the synthesis of a series of β-lactams containing aryl or alkyl groups, as well as for pharmaceutical active molecules' β-lactam-modifications. Importantly, the preliminary attempt to take advantage of the significant ring strain of β-lactam for peptide modifications was also achieved on tryptophan.

Transition metal-catalyzed asymmetric cross-electrophile coupling has emerged as a synthetically useful strategy for the stereoselective construction of a carbon-carbon bond. Herein, we report an iron-catalyzed enantioselective cross-electrophile alkylation of alpha-imino esters with unactivated alkyl halides by employing a chiral NPN ligand. This method delivers alpha-tetrasubstituted amino esters in high yields (up to 93%) and enantioselectivity (up to 97:3 er), accommodating diverse substrates, including primary, secondary, and tertiary alkyl iodides, with broad functional group tolerance. The system is extended to asymmetric benzylation using benzyl chlorides, yielding chiral phenylalanine derivatives bearing quaternary stereocenters (up to 97.5:2.5 er), including bioactive motifs. Mechanistic studies suggest alkyl radical intermediates and a low-valent iron catalytic cycle initiated by a single-electron transfer.

Magnesium catalysts are widely used in catalytic asymmetric reactions, and a series of catalytic strategies have been developed in recent years. Herein, in this review, we have tried to summarize asymmetric magnesium catalysis for the synthesis of important chiral scaffolds. Several important optically active motifs that are present in classic chiral ligands or natural products synthesized by Mg(ii) catalytic methods are briefly discussed. Moreover, the representative mechanisms for different magnesium catalytic strategies, including in situ generated magnesium catalysts, are also shown in relation to synthetic routes for obtaining these important chiral scaffolds.

It is of great research significance to construct important three-dimensional skeletons by employing abundant, inexpensive, and easily accessible elements as catalytic resources. Magnesium (Mg) is a usual, non-toxic, readily available and recyclable alkaline earth metal, which is highly stored in the earth's crust. So the investigation of the catalytic strategy by using magnesium element is highly attractive and with highly practical value, on consideration of the problem of increasingly prominent shortage of metal resources and the intrinsic demand of sustainable chemistry. In recent years, tremendous endeavors and advances have been made on the development of effective catalysts with abundant metal resources such as magnesium for construction of important three-dimensional skeletons with high level of enantioselectivities. In the context of organic synthesis, chiral compounds containing heteroatoms, such as chiral amino alcohols, chiral amides, substituted tetrazoles, indole derivatives, pyrrolidine derivatives and relative structural units, are widely found in natural products or pharmaceutical compounds, have drawn intense research interest in organic synthesis, life sciences and the discovery of drugs. The three-membered ring structure featured in strong ring tension and always resulted in low stability, so it has higher reactivity compared with other common cyclic ring systems. Important ternary cyclic compounds mainly include: Oxiranes, aziridines, and donor-acceptor cyclopropanes. The desymmetrization or asymmetric ring-opening reaction of these ring systems becomes a powerful synthetic tool for effective construction of the above important chiral skeletons. Meanwhile, it is worth noting that in recent years, the efficient construction of heteroatom-containing structural fragments and heterocyclic skeletons with high enantioselectivity through asymmetric ring-opening reactions of ternary cyclic compounds under metal-catalyzed strategies has received extensive research attention. A variety of attractive catalytic strategies were rapidly developed during the research progress. In this review paper, on the basis of our recent years work, the research progress of asymmetric ring-opening reactions of three-membered ring systems based on magnesium catalysis strategy are briefly introduced. This review includes three part: (1) The ring-opening reaction of oxiranes, which mainly include the desymmetrization reaction of oxiranes with amine compounds under in situ generated magnesium catalyst. (2) The ring-opening reaction of aziridines, several heteroatom and carbon based nucleophiles are well developed in the reaction under typical magnesium catalytic strategies. (3) The ring-opening reaction as well as asymmetric cyclization reaction of donor-acceptor cyclopropanes by employing magnesium catalysis are also discussed. These high tension compounds with different types of nucleophiles and relative magnesium catalytic methods are applied for building types of highly important chiral skeletons. Moreover, the possible catalytic mechanism is also shown in some cases, which might be useful for understanding the relative magnesium catalytic strategies. Finally, we have summarized the current stage of these asymmetric ring-opening reactions, and provided brief outlook of this research field. Novel developments are expected to arise from designing of new ligands and assembly strategies for developing novel magnesium catalysts, and thus new activation models can be established to conquer more catalytic ring-opening reactions of these high tension compounds. Furthermore, we foresee the combinational or synergistic use of magnesium catalysts with other catalytic strategies, including organocatalysts or transition metals, as well as merging with photo- or electro-catalytic protocols will arise to unlock novel methods for achieving new ring-opening reactions of oxiranes, aziridines, and donor-acceptor cyclopropanes. These endeavors will be also helpful for development of innovative and structure-creative magnesium catalysts and greatly expanding the synthetic toolbox of modern chemists.

This review summarizes the advances in the field of intramolecular kinetic resolution (KR) mediated by non-enzymatic catalysts. The relative classification of intramolecular KR is accomplished and several categories of reactions are discussed.

By development of ProPhenol/Ti(IV) catalysts, a catalytic enantioselective hydroxylative dearomatization of naphthols is achieved by using TBHP as a simple oxidative reagent. The side coordinative chain equipped on the C1-position of β-naphthols plays an important role for initiating this asymmetric hydroxylative reaction, which might be a result of the proper cocoordination effects to the titanium center in the catalyst. A reasonable catalytic cycle is proposed, the catalytic system is applied to a reasonable range of this type of phenolic compound, and related concise transformations are carried out.

Imines, or Schiff bases are basic and important synthons in modern chemical synthesis, which are widely used in methodological studies, synthesis of natural products or pharmaceutical agents, construction of organic porous materials and relative late‐stage modifications. In most cases, the imines often act as “electrophilic reagents” in reactions on the basis of their C‐electrophilicity owing to the dipole effect of the C=N bond. However, on the other hand, reactions initiated by the N‐nucleophilicity of imine, draw relatively less attentions. In this concept article, we try to give a concise summary of the reactions, especially the cyclization reaction that are initiated by the N‐nucleophilicity of imine. The basic measurement data and discussions of the N‐nucleophilicity of different imines, relative possible mechanisms, catalytic strategies, and reaction types in this context are briefly discussed. We hope the imines, as one of the basic chemical synthons in organic synthesis, will be utilized in broader scope in the future by taking advantage of their N‐nucleophilicity.

Dpp-imines are classic model substrates for synthetic method studies. Here, we disclose their powerful use as achiral coligands in metal-catalyzed reactions. It is highly interesting to find that the Dpp-imine can not only act as powerful ligand to create excellent chiral pockets with magnesium complexes but also, more importantly, this coligand can dramatically enhance the catalytic ability of the metal catalyst. The underlying reaction mechanism was extensively explored by conducting a series of experiments, including P-31 NMR studies of the coordination complex between the Dpp-imine coligand and magnesium complexes, ESI capture results, multiple control experiments, studies and comparison of different coligands, H-1 NMR studies on the relationship between the substrate and Dpp-imine coligand, as well as the relationship between the substrate and the full complexes. Furthermore, DFT calculation provided valuable insights in the role of the imine additive and demonstrated that adding the Dpp-imine coligand in the magnesium catalyst can switch the deprotonation/nucleophilic addition steps from a stepwise mechanism to a concerted process during the oxa-cyclization reaction. The crucial factors responsible for the excellent enantioselectivity and enhanced reaction efficiency brought by Dpp-imine have been extracted from the calculation model. These mechanistic experiments and DFT calculation data clearly disclose and prove the powerful and interesting functions of the Dpp-imine coligand, which also direct a novel application of this type of active imine as useful ligands in metal-catalyzed asymmetric reactions.

Enantioselective [2 + 2] cyclization between an imine and a carbon-carbon double bond is a versatile strategy to build chiral azetidines. However, α-branched allenoates have never been successfully applied in [2 + 2] cyclization reactions with imines, as they always undergo Kwon's [4 + 2] annulation in previous catalytic methods. Herein, a simple in situ generated magnesium catalyst was employed to successfully achieve the enantioselective [2 + 2] cyclization reaction of DPP-imines and α-branched allenoates for the first time. Insightful experiments including KIE experiments, controlled experiments, Hammett plot analysis, and 31P NMR studies of initial intermediates indicate that the current [2 + 2] cyclization of imine most likely involves an asynchronous concerted transition state. Further mechanistic investigations by combining kinetic studies, ESI experiments, 31P NMR studies of coordination complexes, and controlled experiments on reaction rates under different catalyst loading amounts provided the coordination details for this [2 + 2] cyclization reaction between DPP-imines and α-branched allenoates. This new approach was applied to the synthesis of various chiral aza-heterocycles, including the enantioselective synthesis of the key intermediate of a lipid-lowering agent Ezetimibe.

A catalytic asymmetric hydroxylative dearomatization reaction has been disclosed, and the products can smoothly transform into spiroannulation adducts by simply treated with a base under mild conditions.Novel in-situ generated magnesium catalytic methods are developed by application of combinational ligands. Related concise transformaitons of the spiroannulation adducts have been carried out.

Conjugated ynones are easily accessible feedstock and the existence of an alkyne bond endows ynones with different attractive reactivities, thus making them unique substrates for catalytic asymmetric reactions. Their compatibility under organocatalytic, metal-catalyzed as well as cooperative catalytic conditions has resulted in numerous enantioselective transformations. Importantly, conjugated ynones can act as nucleophiles or electrophiles, and serve as easily accessed synthons for different cyclization pathways. This review summarizes the recent literature examples of the catalytic reactions of conjugated ynones and related compounds such as alkyne conjugated α-ketoesters, and classifies these reaction types alongside mechanistic insights whenever possible. We aim to trigger more intensive research in the future to render the asymmetric transformation of ynones as a common and reliable tool for asymmetric synthesis.

The clinical treatment of chronic postoperative pain (CPSP) remains challenging. The side effects of chronic morphine treatment limit its clinical application. MEL-0614, a novel endomorphin analogue that is highly selective and agonistic for μ opioid receptor (MOR), produces a more powerful analgesic effect than that of morphine. In this study, we explored the difference in antinociceptive tolerance and related mechanisms between MEL-0614 and morphine in CPSP induced in a skin/muscle incision and retraction (SMIR) mice model. We found that acute administration of MEL-0614 (1, 3, 5, and 10 nmol, i.t.) produced a dose-dependent analgesic effect that was superior to that of morphine in the SMIR mice model. Long-term MEL-0614 treatment (10 nmol, i.t.) did not induce tolerance compared with morphine. Notably, tolerance induced by morphine could be greatly prevented and/or inhibited via cross-administration or coadministration between MEL-0614 and morphine. In addition, MEL-0614 accelerated the recovery of postoperative pain, whereas morphine aggravated postoperative pain and prolonged its recovery time regardless of preoperative or postoperative treatment. In addition, MEL-0614 did not activate microglia and the P2X7R signaling pathway and showed reduced expression iba1 and P2X7R compared with that observed after morphine administration. Release of inflammatory factors was induced by continued administration of morphine during SMIR surgery, but MEL-0614 did not promote the activation of inflammatory factors. Our results showed that MEL-0614 has superior analgesic effects in CPSP and leads to tolerance to a lesser degree than morphine. Further, MEL-0614 may be used as a promising treatment option for the long-term treatment in CPSP.

An oxa-Michael kinetic resolution reaction is developed to efficiently construct complexed polycyclic motifs by developing novel bifunctional zinc catalysts.

Magnesium (Mg) is a cheap, non-toxic, and recyclable alkaline earth metal that constitutes about 2% weight in the Earth's crust. The use of magnesium catalysts to forge chiral moieties in molecules is highly attractive. Based on our work in recent years, we describe the current progress in the development of in situ generated magnesium catalysts and their application in asymmetric synthesis. In this perspective, a critically concise classification of in situ generated magnesium catalytic modes, with relevant examples, is presented, and representative mechanisms of each category are discussed. Building on the established diverse strategies, one can foresee that more innovative and structurally creative magnesium catalysts that are generated in situ will be developed to overcome more formidable challenges of catalytic en-antioselective reactions. 1 Introduction 2 Magnesium Catalysts Generated in Situ from Chiral Ligands Containing Dual Reactive Hydrogens 3 Magnesium Catalysts Generated in Situ from Monoanionic Chiral Ligands 4 Bimetallic and Polymetallic Magnesium Catalysts Assembled in Situ 5 Summary and Outlook

Effective treatment of inflammatory pain is a major clinical concern for both patients and physicians. Traditional analgesics such as morphine and coxibs are not effective in all patients and have various unwanted side effects. Accumulating evidence has suggested that endomorphins (EMs), particularly EM-1, possess potent anti-inflammatory effects. However, poor bioavailability and low resistance to enzymatic degradation impede their direct application in the treatment of inflammation. A series of novel peptides based on the structure of EM-1, with lower undesired effects than their parent compounds, called MEL-EMs were discovered and synthetized in our preceding studies. Here, we selected two (MEL-0614 and MEL-N1606) to further investigate their anti-inflammatory effects. This work showed that MEL analogs exerted potent analgesic effects with the inhibition of activated glial cells and macrophages in a CFA-induced inflammatory pain model. Furthermore, multiple-dose administration of MEL analogs did not prolong CFA-induced chronic inflammatory pain, in contrast to morphine. Together, our findings revealed that MEL analogs may serve as effective candidates for chronic inflammation treatment.

Kinetic resolution (KR) of racemic starting materials is a powerful and practical alternative to prepare valuable enantiomerically enriched compounds. A magnesium-catalyzed kinetic resolution based on a designed intramolecular vinylogous Michael reaction is disclosed. Here we show a synergistic catalytic strategy based on the development of chiral ligands. Substrates containing linear allylic ester structures are designed and synthesized to construct key [6.6.5]-tricyclic chiral skeletons via this kinetic resolution process. Detailed mechanistic studies reveal a rational mechanism for the current intramolecular vinylogous KR reaction. The desired direct intramolecular asymmetric vinylogous Michael reaction of linear allylic esters is realized in high efficiency and enantioselectivity with the synergistic catalytic system.