The genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed ...specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (M(pro)s), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV M(pro)s, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.
The first rhodium‐catalyzed annulation of N‐benzoylsulfonamide (1) with isocyanide (2) through CH activation is described. The transformation is broadly compatible with N‐benzoylsulfonamides as well ...as isocyanides with different electronic properties. From a practical point of view, this method provides the most straightforward approach to a series of 3‐(imino)isoindolinones (3). Ts=4‐toluenesulfonyl.
Herein, we achieved the asymmetric synthesis of (+)-vellosimine in 13 steps (longest linear sequences, LLS). This synthesis featured a sequential nucleophilic addition/cyclization process, which ...provided an efficient protocol for synthesizing a range of indole fused azabicyclo3.3.1nonane. Additionally, a SmI2-mediated reductive cyclization of ketone with an attached α,β-unsaturated ester for constructing the strained quinuclidine moiety was also highlighted.
A catalytic asymmetric nucleophilic reverse prenylation of indol-2-ones in situ generated from 3-bromooxindoles with prenyltributylstannane promoted by Ni(II)/chiral N,N′-dioxide was developed. This ...reaction provides facile access to C3 reverse-prenylated oxindoles in good to excellent enantioselectivities, which enabled the asymmetric synthesis of debromoflustramine A in five steps.
Herein, a concise asymmetric synthesis of (+)-isostrychnine is achieved in nine longest-linear steps with a 16% overall yield. The key features of this synthesis include the catalytic asymmetric ...tandem double Michael addition of a tryptamine-derived oxindole to an alkynone to facilely forge the A/B/C ring framework, a one-pot intramolecular dehydrative condensation/lactamization reaction to efficiently establish the E/G ring system, and an allylic diazene rearrangement to introduce the pivotal olefin for the subsequent intramolecular Heck reaction.
To synthesize the fundamental framework of dihydroagarofuran, a novel strategy was devised for constructing the C-ring through a dearomatization reaction using 6-methoxy-1-tetralone as the initial ...substrate. Subsequently, the dihydroagarofuran skeleton was assembled via two consecutive Michael addition reactions. The conjugated diene and trans-dihydroagarofuran skeleton were modified. The insecticidal activities of 33 compounds against Mythimna separata were evaluated. Compounds 11-5 exhibited an LC50 value of 0.378 mg/mL. The activity exhibited a remarkable 29-fold increase compared to positive control Celangulin V, which was widely recognized as the most renowned natural dihydroagarofuran polyol ester insecticidal active compound. Docking experiments between synthetic compounds and target proteins revealed the shared binding sites with Celangulin V. Structure-activity relationship studies indicated that methyl groups at positions C4 and C10 significantly improved insecticidal activity, while ether groups with linear chains displayed enhanced activity; in particular, the allyl ether group demonstrated optimal efficacy. Furthermore, a three-dimensional quantitative structure-activity relationship model was established to investigate the correlation between the skeletal structure and activity. These research findings provide valuable insights for discovering and developing dihydroagarofuran-like compounds.To synthesize the fundamental framework of dihydroagarofuran, a novel strategy was devised for constructing the C-ring through a dearomatization reaction using 6-methoxy-1-tetralone as the initial substrate. Subsequently, the dihydroagarofuran skeleton was assembled via two consecutive Michael addition reactions. The conjugated diene and trans-dihydroagarofuran skeleton were modified. The insecticidal activities of 33 compounds against Mythimna separata were evaluated. Compounds 11-5 exhibited an LC50 value of 0.378 mg/mL. The activity exhibited a remarkable 29-fold increase compared to positive control Celangulin V, which was widely recognized as the most renowned natural dihydroagarofuran polyol ester insecticidal active compound. Docking experiments between synthetic compounds and target proteins revealed the shared binding sites with Celangulin V. Structure-activity relationship studies indicated that methyl groups at positions C4 and C10 significantly improved insecticidal activity, while ether groups with linear chains displayed enhanced activity; in particular, the allyl ether group demonstrated optimal efficacy. Furthermore, a three-dimensional quantitative structure-activity relationship model was established to investigate the correlation between the skeletal structure and activity. These research findings provide valuable insights for discovering and developing dihydroagarofuran-like compounds.
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The asymmetric synthesis of (-)-dihydrospirotryprostatin B (3), a cytostatic spiropyrrolidine-3,3′-oxindole alkaloid, has been accomplished in 8 longest linear steps (LLS) from ...commercially available amino acids. The key step of the synthetic approach consists of the tandem Michael addition of oxindole derived from dipeptide diketopiperazine to alkynone, leading to the rapid construction of the spiropyrrolidine-3,3′-oxindole scaffold with the consecutive quaternary spiro carbon center and chiral tertiary amine being diastereoselectively established.
A nickel(II)-catalyzed asymmetric direct vinylogous Michael addition of γ-alkyl monosubstituted α,β-unsaturated butyrolactams to α,β-unsaturated carbonyl compounds has been disclosed, affording ...γ,γ-dialkyl substituted butyrolactams in good yields and satisfactory enantioselectivities. A tandem catalytic asymmetric vinylogous Michael addition/intramolecular Michael addition has also been developed based on this reaction, which enabled the construction of enantioenriched octahydroindoles with three consecutive stereogenic carbon centers.
Herein, we describe a catalytic asymmetric intramolecular vinylogous aldol reaction by taking advantage of dual organocatalysts, which enables convergent synthesis of ortho-fused tricyclic diketones ...in excellent enantioselectivities and diastereoselectivities. Noteworthy is that the reaction stereoselectively forges three consecutive stereogenic carbon centers including a quaternary one. Density functional theory calculations reveal that the enantioselectivity was facilitated by a transannular hydrogen bonding between the protonated quinuclidine moiety of the chiral aminocatalyst and the diketone fragment of the substrate.
A novel class of crystalline porous materials has been developed utilizing multilevel dynamic linkages, including covalent B−O, dative B←N and hydrogen bonds. Typically, boronic acids undergo in situ ...condensation to afford B3O3‐based units, which further extend to molecular complexes or chains via B←N bonds. The obtained superstructures are subsequently interconnected via hydrogen bonds and π–π interactions, producing crystalline porous organic frameworks (CPOFs). The CPOFs display excellent solution processability, allowing dissolution and subsequent crystallization to their original structures, independent of recrystallization conditions, possibly due to the diverse bond energies of the involved interactions. Significantly, the CPOFs can be synthesized on a gram‐scale using cost‐effective monomers. In addition, the numerous acidic sites endow the CPOFs with high NH3 capacity, surpassing most porous organic materials and commercial materials.
A novel class of crystalline porous organic frameworks (CPOFs) are prepared based on covalent B−O, dative B←N and hydrogen bonds. Furthermore, gram‐scale production can be achieved at low cost, alongside excellent solution processibility, paving the way to diverse applications. Remarkably, the CPOFs exhibit exceptionally high NH3 uptake capacities, indicating their great potential toward NH3 capture.
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