α-Acyloxylation of Ketones/Cyclic Ethers Mediated by Hypervalent Iodine(III) Reagents as Oxidants and Nucleophilic Sources.

This study describes a catalyst-free α-acyloxylation of ketones and a KBr-mediated α-acyloxylation of cyclic ethers. These conversions are effectively mediated by hypervalent iodine(III) reagents serving dual roles as the oxidant and nucleophilic source. Consequently, esters are produced directly in moderate to excellent yields. The proposed method features good functional group compatibility, a broad substrate scope, and high synthetic efficiency and is remarkably environmentally friendly.

Access to Chromenopyrrolidines Enabled by Organophotocatalyzed [2 + 2 + 1] Annulation of Chromones with N-Arylglycines.

A facile approach toward chromenopyrrolidines was achieved under mild conditions via organophotocatalyzed aerobic decarboxylative [2 + 2 + 1] annulation of chromones with N-arylglycines, in which N-arylglycines perform dual roles (i.e., radical precursor and methylene provider). Mechanistic studies suggested that a Giese-type radical addition and consequent Mannich pathway were likely responsible for the annulation reaction.

The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors.

The main protease (Mpro ) of SARS-CoV-2 is a well-characterized target for antiviral drug discovery. To date, most antiviral drug discovery efforts have focused on the S4-S1' pocket of Mpro ; however, it is still unclear whether the S1'-S3' pocket per se can serve as a new site for drug discovery. In this study, the S1'-S3' pocket of Mpro was found to differentially recognize viral peptidyl substrates. For instance, S3' in Mpro strongly favors Phe or Trp, and S1' favors Ala. The peptidyl inhibitor D-4-77, which possesses an α-bromoacetamide warhead, was discovered to be a promising inhibitor of Mpro , with an IC50 of 0.95 µM and an antiviral EC50 of 0.49 µM. The Mpro /inhibitor co-crystal structure confirmed the binding mode of the inhibitor to the S1'-S3' pocket and revealed a covalent mechanism. In addition, D-4-77 functions as an immune protectant and suppresses SARS-CoV-2 Mpro -induced antagonism of the host NF-κB innate immune response. These findings indicate that the S1'-S3' pocket of SARS-CoV-2 Mpro is druggable, and that inhibiting SARS-CoV-2 Mpro can simultaneously protect human innate immunity and inhibit virion assembly.

Akuammiline alkaloid derivatives: divergent synthesis and effect on the proliferation of rheumatoid arthritis fibroblast-like synoviocytes.

During the past decades, rheumatoid arthritis had become a serious problem, torturing millions of patients because of unclear pathogenesis and no ideal therapies. Natural products remain an important source of medicines to treat various major diseases such as rheumatoid arthritis (RA) given their excellent biocompatibility and structural diversity. Herein, we have developed a versatile synthetic method for constructing various skeletons of akuammiline alkaloid analogs based on our previous research on the total synthesis of the related indole alkaloids. We have also evaluated the effect of these analogs on the proliferation of RA fibroblast-like synoviocytes (FLSs) in vitro and analyzed the corresponding structure-activity relationship (SAR). Among these analogs, compounds 9 and 17c have demonstrated a promising inhibitory effect on the proliferation of RA-FLSs, with IC50 values of 3.22 ± 0.29 µM and 3.21 ± 0.31 µM, respectively. Our findings provide a solid foundation for future pharmacological studies on akuammiline alkaloid derivatives and inspiration for the development of anti-RA small molecule drugs derived from natural products.

Divergent Total Syntheses of (-)-Daphnezomines†A and B and (+)-Dapholdhamine†B.

The daphnezomine A-type subfamily of Daphniphyllum alkaloids structurally features a unique aza-adamantane core skeleton and anticipates efficient strategies for completing their syntheses to thoroughly investigate their biological activities. Herein, divergent total syntheses of (-)-daphnezomines A and B and (+)-dapholdhamine B have been accomplished in 16-20 steps from a known epoxide via rapid construction of a common core intermediate. The present work features a Ti-mediated radical cyclization to establish the azabicyclo[3.3.1]nonane ring system, an intramolecular Heck reaction to install the bridgehead all-carbon quaternary stereocenter, a tandem deprotection/reduction/keto amine-carbinolamine tautomerization to furnish the aza-adamantane backbone, and an NIS-promoted 6-endo-trig aminocyclization to assemble the (+)-dapholdhamine B backbone.

Asymmetric Total Synthesis of (+)-Alstonlarsine A.

The first asymmetric total synthesis of (+)-alstonlarsine A has been realized. The prominent features of the current synthesis include the following: (i) a Pd/self-adaptable ligand complex-catalyzed asymmetric allylic alkylation of 2-methyl-2-cyclopentenyl carbonate with 2-indolylsubstituted dimethyl malonate to establish the key stereocenter of C15, (ii) an intramolecular nitrile oxide-alkene [3 + 2] cycloaddition (INOC [3 + 2]) to construct the cyclohepta[b]indole backbone with the installment of the requisite stereochemistry of the all-carbon quaternary center of C20, and (iii) a late-stage interrupted Pictet-Spengler reaction (IPSR) to rapidly assemble the core structure of (+)-alstonlarsine A.

Asymmetric Total Syntheses of Cephalotane-Type Diterpenoids Cephanolides A-D.

Cephanolides A-D are cephalotane-type diterpenoids featuring a novel 6/6/6/5 tetracyclic core embedded with a bridged δ-lactone. The asymmetric and divergent total syntheses of cephanolides A-D have been accomplished, proceeding in 11-14 steps from a known alcohol. The salient features of the present work include (i) a substrate-controlled diastereoselective intermolecular Diels-Alder reaction to form the 6-6 cis-fused rings, (ii) a palladium-catalyzed formal bimolecular [2 + 2 + 2] cycloaddition reaction via a partially intermolecular cascade reaction sequence involving multiple carbometalations to rapidly install the key tetracyclic skeleton, and (iii) lactonization and late-stage oxidative diversification to complete total syntheses of the four benzenoid cephanolides.

Comparative bioactivity profile of phospholipids from three marine byproducts based on the zebrafish model.

Phospholipids (PLs) are important components of physiological metabolism in animals and plants, and they have been widely used in clinical treatment, cosmetics, and industry. With the development of marine resources, marine PLs rich in polyunsaturated fatty acids have attracted increasing attention. As important marine resources, shrimp heads (SH), codfish roe (CR), and squid gonads (SG) contain a high PL content. The antithrombotic, antistroke, anti-inflammatory, pro-angiogenic, and cardioprotective activities of PLs from SH, CR, and SG were evaluated and compared using the in vivo zebrafish model. The results showed that the PL extracts of SH, CR, and SG had significant biological activities, which lays a theoretical foundation for the development and utilization of PLs in marine byproducts in the future, providing a new choice for the prevention of inflammatory and cardiovascular diseases. PRACTICAL APPLICATIONS: In this experiment, phospholipids in seafood from different sources were extracted, and their biological activities were comprehensively evaluated and compared using the zebrafish model to lay a foundation for the development of cardiovascular drugs, health food, special medicinal food, and other effective components. The utilization of marine byproducts not only makes full use of resources, but it also protects the environment.

A Boronated Derivative of Temozolomide Showing Enhanced Efficacy in Boron Neutron Capture Therapy of Glioblastoma.

There is an incontestable need for improved treatment modality for glioblastoma due to its extraordinary resistance to traditional chemoradiation therapy. Boron neutron capture therapy (BNCT) may play a role in the future. We designed and synthesized a 10B-boronated derivative of temozolomide, TMZB. BNCT was carried out with a total neutron radiation fluence of 2.4 ± 0.3 × 1011 n/cm2. The effects of TMZB in BNCT were measured with a clonogenic cell survival assay in vitro and PET/CT imaging in vivo. Then, 10B-boronated phenylalanine (BPA) was tested in parallel with TMZB for comparison. The IC50 of TMZB for the cytotoxicity of clonogenic cells in HS683 was 0.208 mM, which is comparable to the IC50 of temozolomide at 0.213 mM. In BNCT treatment, 0.243 mM TMZB caused 91.2% ± 6.4% of clonogenic cell death, while 0.239 mM BPA eliminated 63.7% ± 6.3% of clonogenic cells. TMZB had a tumor-to-normal brain ratio of 2.9 ± 1.1 and a tumor-to-blood ratio of 3.8 ± 0.2 in a mouse glioblastoma model. BNCT with TMZB in this model caused 58.2% tumor shrinkage at 31 days after neutron irradiation, while the number for BPA was 35.2%. Therefore, by combining the effects of chemotherapy from temozolomide and radiotherapy with heavy charged particles from BNCT, TMZB-based BNCT exhibited promising potential for therapeutic applications in glioblastoma treatment.

Synthesis of Chromeno[2,3-d]pyrimidin-5-one Derivatives from 1,3,5-Triazinanes via Two Different Reaction Pathways.

1,3,5-Triazinanes, as a kind of versatile building block, are applied in the synthesis of chromeno[2,3-d]pyrimidin-5-one derivatives via two different reaction modes, which perfectly exhibits the powerful function of 1,3,5-triazinane as a three-atom synthon along with the structure variation of another substrate. The two annulation reactions proceed under mild conditions and bear broad substrate scope and high yield.

Lipid Profiles of the Heads of Four Shrimp Species by UPLC-Q-Exactive Orbitrap/MS and Their Cardiovascular Activities.

Lipids are key factors in nutrition, structural function, metabolic features, and other biological functions. In this study, the lipids from the heads of four species of shrimp (Fenneropenaeus chinensis (FC), Penaeus japonicus (PJ), Penaeus vannamei (PV), and Procambarus clarkia (PCC)) were compared and characterized based on UPLC-Q-Exactive Orbitrap/MS. We compared the differences in lipid composition of four kinds of shrimp head using multivariate analysis. In addition, a zebrafish model was used to evaluate pro-angiogenic, anti-inflammatory, anti-thrombotic, and cardioprotective activities of the shrimp head lipids. The lipids from the four kinds of shrimp head had different degrees of pro-angiogenic activities, and the activities of PCC and PJ shrimp lipids were more significant than those of the other two species. Four lipid groups displayed strong anti-inflammatory activities. For antithrombotic activity, only PCC (25 µg/mL) and PV (100 µg/mL) groups showed obvious activity. In terms of cardioprotective activity, the four kinds of lipid groups significantly increased the zebrafish heart rhythms. The heart distances were shortened, except for those of the FC (100 µg/mL) and PJ (25 µg/mL) groups. Our comprehensive lipidomics analysis and bioactivity study of lipids from different sources could provide a basis for the better utilization of shrimp.

Synthesis of 5H-Chromeno[2,3-d]pyrimidin-5-one Derivatives via Microwave-Promoted Multicomponent Reaction.

A microwave-promoted multicomponent reaction of 3-formylchromones, amines, and paraformaldehyde was achieved under catalyst-free and solvent-free conditions, delivering 5H-chromeno[2,3-d]pyrimidin-5-one derivatives in good to excellent yields via an unexpected annulation pathway, which further expanded the synthetic application of paraformaldehyde as a C1 building block.

Palladium-Catalyzed Arylation of C(sp2)-H Bonds with 2-(1-Methylhydrazinyl)pyridine as the Bidentate Directing Group.

Palladium-catalyzed C(sp2)-H arylation of ortho C-H bonds involving 2-(1-methylhydrazinyl)pyridine (MHP) as the directing group has been investigated. The reaction proceeds smoothly under an air atmosphere to generate biaryl derivatives in an environmentally friendly manner while tolerating a wide range of functional groups. Notably, the directing group present in the product could be easily removed under mild reductive conditions.

Cobalt-Catalyzed 2-(1-Methylhydrazinyl)pyridine-Assisted C-H Alkylation/Annulation: Mechanistic Insights and Rapid Access to Cyclopenta[c]isoquinolinone Derivatives.

We have developed cobalt-catalyzed, bidentate 2-(1-methylhydrazinyl)pyridine (MHP)-directed C(sp2)-H alkylation/annulation of benzoic hydrazides with various alkenes. Notably, diverse cyclopenta[c]isoquinolinones and dihydroisoquinolinones were obtained via this functional group-tolerant protocol. The reaction can be performed on a gram scale while maintaining an excellent yield, and the directing group can be removed efficiently under mild conditions. Furthermore, density-functional theory (DFT) calculations provide an incisive understanding of the observed regioselectivities for different olefins.

Transition-Metal-Free [3+2] Dehydration Cycloaddition of Donor-Acceptor Cyclopropanes With 2-Naphthols.

A Brønsted acid-catalyzed domino ring-opening cyclization transformation of donor-acceptor (D-A) cyclopropanes and 2-naphthols has been developed. This formal [3+2] cyclization reaction provided novel and efficient access to the naphthalene-fused cyclopentanes in the absence of any transition-metal catalysts or additives. This robust procedure was completed smoothly on a gram-scale to afford the corresponding product with comparable efficiency. Furthermore, the synthetic application of the prepared product has been demonstrated by its transformation into a variety of synthetically useful molecules.

Total Synthesis of (-)-Picrinine, (-)-Scholarisine C, and (+)-5-ß-Methoxyaspidophylline.

The first asymmetric total synthesis of three picrinine-type akuammiline alkaloids, (-)-picrinine, (-)-scholarisine C, and (+)-5-ß-methoxyaspidophylline, has been accomplished. The synthesis features an efficient acid-promoted oxo-bridge ring-opening and further carbonyl O-cyclization to assemble the furoindoline scaffold, an unusual Dauben-Michno oxidation to construct the requisite α,ß-unsaturated aldehyde functionality, and a nickel-mediated reductive Heck reaction to forge the [3.3.1]-azabicyclic core.

Diversity-oriented synthesis of benzofuro[3,2-b]pyridine derivatives from aurone-derived α,ß-unsaturated imines and activated terminal alkynes.

An efficient annulation reaction of aurone-derived α,ß-unsaturated imines and activated terminal alkynes mediated by triethylamine is described, which enables the facile synthesis of 1,4-dihydrobenzofuro[3,2-b]pyridines in high yields. When the nucleophile of triethylamine was replaced with triphenylphosphine, another class of 1,4-dihydrobenzofuro[3,2-b]pyridines tethered with an additional acrylate motif were obtained instead. These two types of 1,4-dihydrobenzofuro[3,2-b]pyridines could be aromatized in the presence of DBU to afford benzofuro[3,2-b]pyridines, which could also be accessed via a one-pot procedure.

Asymmetric Total Synthesis of (+)-Mannolide†C.

(+)-Mannolide C is a complex hexacyclic C20 cephalotane-type diterpenoid featuring a highly strained 7/6/6/5 tetracyclic core containing eight consecutive stereocenters and two bridging lactones. The first asymmetric total synthesis of (+)-mannolide C has been accomplished by lipase-mediated resolution, Ru-complex-catalyzed double ring-closing metathesis (RCM) reactions, NiII -catalyzed diastereoselective Michael addition, and MnIII -catalyzed allylic oxidation as the key transformations.

The Regioselective Functionalization Reaction of Unprotected Carbazoles with Donor-Acceptor Cyclopropanes.

The regioselective functionalization reaction of unprotected carbazoles with donor-acceptor (D-A) cyclopropanes has been demonstrated for the first time. With Sc(OTf)3 as Lewis acid catalyst, the N-H functionalization of carbazoles takes place through a highly selective nitrogen-initiated nucleophilic ring opening reaction. Significantly, by engaging TfOH as Brønsted acid catalyst, a straightforward C-H functionalization at the 3-position of the unprotected carbazole proceeds via Friedel-Crafts-type addition. This strategy facilitates the diversity-oriented synthesis of carbazole-containing heterocycles and expands the novel application of D-A cyclopropanes.