Copper-Catalyzed [4+1+1] Annulation of Ammonium Salts and Anthranils: Synthesis of 2,3-Diaroylquinolines.

A copper(I)-catalyzed protocol is developed for the synthesis of various 2,3-diaroylquinolines starting from achiral ammonium salts and anthranils through [4+1+1] annulation. Using copper(I) chloride as the sole catalyst, this reaction is featured with easily available starting materials, broad substrate scope, good yields and simple reaction conditions.

Construction of Coumarin-Based Bioorthogonal Macromolecular Probes for Photoactivation.

Photoactivatable fluorescence imaging is one of the most valuable methods for visualizing protein localization, trafficking, and interactions. Here, we designed four bioorthogonal fluorescent probes K1-K4 by installing photoactive cages and HaloTag ligands onto the different positions of the coumarin fluorophore. Although K1-K4 all exhibited rapid photostimulated responses in aqueous solution, only K3 was found to have an obvious aggregation-induced emission (AIE). Next, macromolecular fluorescent probes Kn=1/2/3/4_POIs were obtained by covalently attaching K1-K4 to HaloTag-fused proteins of interest (POIs). Kn=3/4_POIs exhibited a higher fluorescence increase than that of Kn=1/2_POIs upon photoactivation in both liquid and solid phases. Moreover, K3_GFP_Halo and K4_GFP_Halo presented the fluorescence resonance energy transfer (FRET) from photocleaved K3 and K4 to GFP in the protein complex. We further examined the fluorescence labeling ability of K1-K4 to intracellular IRE1_Halo protein and found that K3 and K4 containing the HaloTag ligand on the C4 position of coumarin could be retained in cells for long-term tracking of the IRE1_Halo protein. Hence, we established a platform of novel bioorthogonal fluorescent probes conjugating onto Halo-tagged POIs for rapid photoactivation in vitro and in cells.

Coumarin-Based Fluorescent Inhibitors for Photocontrollable Bioactivation.

Activation of the IRE-1/XBP-1 pathway is related to many human diseases. Coumarin-based derivatives acting as both IRE-1 inhibitors and bright fluorophores are highly desirable to establish an integrated fluorescent inhibitor system. Here, we take insights into the aqueous stability of a photocaged IRE-1 inhibitor PC-D-F07 through a structure activity relationship. The substituent effects indicate that the electron-withdrawing -NO2 moiety in the photocage combined with the tricyclic coumarin fluorophore contribute to the structural stability of PC-D-F07. To optimize the photocage of PC-D-F07, we incorporate a 1-ethyl-2-nitrobenzyl or 2-nitrobenzyl photolabile moiety on the hydroxyl group of the IRE-1 inhibitor to generate RF-7 and RF-8. Upon photoactivation, both RF-7 and RF-8 present an increased fluorescence response, sequentially enabling the unlocking of the ortho-1,3-dioxane acetal for the release of active IRE-1 inhibitors. Moreover, RF-7 exhibits a high repolarization ratio of converting M2-type tumor-associated macrophages (M2-TAMs) to M1-type immune-responsive macrophages. This provides a novel prodrug strategy of modulating druggable fluorophore backbones to achieve spatiotemporally controllable drug release for precise cancer treatment.

8,9-Dihydrocannabidiol, an Alternative of Cannabidiol, Its Preparation, Antibacterial and Antioxidant Ability.

Cannabidiol (CBD) from Cannabis sativa is used in cosmetics in North America due to its antibacterial and antioxidant properties, but has been prohibited in many countries except recently; so, finding a non-intoxicating CBD alternative and elucidating the structure−function relationship of CBD analogues is becoming increasingly relevant. Herein, a set of CBD analogues including 8,9-dihydrocannabidiol (H2CBD) was synthesized, and their antibacterial, bactericidal, and antioxidant activity, as well as their structure−function relationship, were studied. The results present a catalytic selectivity near 100% towards H2CBD with a production yield of 85%. Each CBD analogue presented different antibacterial and antioxidant activity. It is revealed that the phenolic hydroxyl moiety is an essential group for CBD analogues to perform antibacterial and antioxidant activities. Among them, H2CBD presented much stronger antibacterial activity than the assayed popular antibiotics. H2CBD and Compound 4 presented very similar radical scavenging activity and inhibition on lipid oxidation to vitamin C, but better thermostability. Moreover, H2CBD presented lower toxicity to human skin fibroblasts at concentrations up to 64-fold higher than its MIC value (1.25 µg/mL) against S. aureus. Above all, in all property experiments, H2CBD presented extremely similar performance to CBD (p < 0.05), including similar time−kill kinetics curves. This research finds H2CBD to be an alternative for CBD with very high potential in the aspects of antibacterial, bactericidal, and antioxidant activity, as well as lower toxicity to human skin fibroblasts.

Synthesis of 1,2-Diamines from Vinyl Sulfonium Salts and Arylamines.

A procedure for the synthesis of 1,2-diamines from vinyl sulfonium salts and arylamines under mild conditions was developed. This present synthetic protocol not only obviates the need for a transition-metal catalyst and an oxidizing reagent but also features a broad substrates scope. The practicability of this protocol is demonstrated by the one-pot synthesis, a scale-up reaction, and transformations of the products to diverse N-heterocyclic compounds. Mechanistic studies indicate that the formation of aziridine plays a key role during this diamination process.

Revealing Minor pH Changes of Mitochondria by a Highly Sensitive Molecular Fluorescent Probe.

Mitochondrial pH is an important factor associated with cellular metabolism and pathological states. Thus, sensitively monitoring its minor change was essential. However, it was challengeable due to the lack of suitable probes. Here, a mitochondria-targeted probe (NIR-OH-1) was synthesized. Based on the protonation/deprotonation of the hydroxy group and the assistance of carboxyl group on NIR-OH-1 molecular structure, a dramatic NIR activated signal was generated for sensing pH. Probe NIR-OH-1 displayed a good photo-stability and reversibility and could detect pH change without interference by other biologically active species. Importantly, NIR-OH-1 had an appropriate pKa value (7.77) and tiny acid-base transition range, which was allowed to map the small pH changes of cellular mitochondrial. Moreover, NIR-OH-1 was also successfully applied in real-time monitoring mitochondrial pH-related pathological events in living cells under different stimulation, demonstrating the prospect of its clinical application in accurate mitochondrial pH detection under related physiological and pathological conditions.

Copper-Catalyzed Annulation or Homocoupling of Sulfoxonium Ylides: Synthesis of 2,3-Diaroylquinolines or α,α,ß-Tricarbonyl Sulfoxonium Ylides.

An unprecedented copper-catalyzed reaction of sulfoxonium ylides and anthranils is reported that enables an easy access to 2,3-diaroylquinolines through a [4+1+1] annulation. Copper-catalyzed homocoupling of sulfoxonium ylides provided α,α,ß-tricarbonyl sulfoxonium ylides, which provides a strategy to extend the carbon chain through C-C bond formation. The utility of the products as well as the mechanistic details of the process are presented.

Copper-Catalyzed Ring-Opening/Reconstruction of Anthranils with Oxo-Compounds: Synthesis of Quinoline Derivatives.

A copper-catalyzed protocol for the construction of various 2-aryl(alkyl)-3-acylquinolines or 3-arylquinolines using readily available anthranils and 1,3-diketones or aldehydes as starting materials is reported herein. Dioxygen as the sole oxidant and hexafluoroisopropanol as the solvent play an important role in both procedures. This ring-opening/reconstruction strategy involving N-O bond cleavage and C-N/C-C bond formation features high yields and broad substrate scope.

Copper-catalyzed coupling of anthranils and α-keto acids: direct synthesis of α-ketoamides.

Copper-catalyzed coupling of α-keto acids with anthranils is reported for the synthesis of α-ketoamides. This process involves N-O/C-O bond cleavages and C-N bond formation. Furthermore, the decarboxylation of α-keto acids can be successfully suppressed under redox-neutral conditions.

The complete mitochondrial genome of Propsilocerus akamusi (Diptera, Chironomidae).

Propsilocerus akamusi is one of the most important genera of Chironomidae. However, the systemically classification and taxonomic studies have so far been limited. In this study, we report the complete mitochondrial genome sequence of P. akamusi. The mitogenome has 15,632 base pairs (77.58% A + T content) and made up of total of 37 genes (13 protein-coding, 22 transfer RNAs, and 2 ribosomal RNAs). This study will provide useful genetic information for future phylogenetic and taxonomic classification of Chironomidae.

Transition-Metal-Free C-S Bond Formation: Synthesis of Polysubstituted Diaryl Sulfides and α-Thioarylcarbonyl Compounds.

A transition-metal-free protocol for the construction of C-S bonds has been developed. Acetylacetone acts as a new and green aryl source for the synthesis of polysubstituted diarylsulfides bearing a free hydroxy group and a ketone group, which provides a new access to a series of flavonoids containing a thioaryl group. In addition, a series of α-thioarylcarbonyl compounds are obtained in good to excellent yields.

Asymmetric synthesis of fully substituted cyclopentane-oxindoles through an organocatalytic triple Michael domino reaction.

An efficient, highly stereoselective asymmetric synthesis of fully functionalized cyclopentanes bearing an oxindole moiety and several other functional groups in one pot has been developed. Key step is an organocatalytic triple Michael domino reaction forming three C-C bonds and six stereocenters, including a quaternary one. Starting from equimolar amounts of simple substrates, a high molecular complexity can be reached after a Wittig olefination in one pot. The new protocol can easily be scaled up to gram amounts.

Mechanistic insights into copper-catalyzed Sonogashira-Hagihara-type cross-coupling reactions: sub-mol% catalyst loadings and ligand effects.

An efficient catalytic system for Sonogashira-Hagihara-type reactions displaying ligand acceleration in the copper-catalyzed formation of C(sp²)-C(sp) bonds is described. The structure of the ligand plays a key role for the coupling efficiency. Various copper sources show excellent catalytic activity, even in sub-mol% quantities. A wide variety of substituents is tolerated in the substrates. Mechanistic details have been revealed by kinetic measurements and DFT calculations.

Mild copper-mediated direct oxidative cross-coupling of 1,3,4-oxadiazoles with polyfluoroarenes by using dioxygen as oxidant.

CH(3)CN and O(2) do the trick! A copper-mediated direct oxidative cross-coupling of 2-(het)aryl-1,3,4-oxadiazoles with polyhaloarenes under mild reaction conditions has been developed (see scheme). The process provides a concise access to biaryl structures containing polyhaloarenes, which are of interest in the fields of pharmaceuticals and functional materials. Acetonitrile and oxygen play crucial roles.

Transition metal-free direct C-H bond thiolation of 1,3,4-oxadiazoles and related heteroarenes.

A convenient transition metal-free procedure for the direct thiolation of 1,3,4-oxadiazole C-H bonds using diaryl disulfides has been developed. Other substrates including indole, benzothiazole, N-phenylbenzimidazole, and caffeine were also thiolated in this manner, providing the corresponding products in good to excellent yields.