Bioactivities of Triazolium-Based N-Heterocyclic Carbene Salts.

1,2,4-Triazolium salts are precursors of N-heterocyclic carbenes (NHCs), which have been extensively used as effective catalysts and ligands for both asymmetric and non-enantioselective reactions. Nevertheless, they are also a kind of quaternary ammonium compounds (QACs) that possess amphipathic properties. The unique chemical and physical properties of 1,2,4-triazolium salts have received significant attention from scientists focusing on the development of novel bioactive molecules as pesticides and medicines. It is timely and meaningful to summarize the bioactivities of 1,2,4-triazolium salt derivatives against various bacteria, fungi, cancer cells, and other pathogens in the past 30 years. Meanwhile, the structure-activity relationship (SAR) of 1,2,4-triazolium salts was also summarized. Finally, our perspective on the future development and applications of triazolium salts as agrichemicals or human drugs is presented.

Carbene-Catalyzed Enantioselective Sulfonylation of Enone Aryl Aldehydes: A New Mode of Breslow Intermediate Oxidation.

A carbene-catalyzed sulfonylation reaction between enone aryl aldehydes and sulfonyl chlorides is disclosed. The reaction effectively installs sulfone moieties in a highly enantioselective manner to afford sulfone-containing bicyclic lactones. The sulfonyl chloride behaves both as an oxidant and a nucleophilic substrate (via its reduced form) in this N-heterocyclic carbene (NHC)-catalyzed process. The NHC catalyst provides both activation and stereoselectivity control on a very remote site of enone aryl aldehyde substrates. Water plays an important role in modulating catalyst deactivation and reactivation routes that involve reactions between NHC and sulfonyl chloride. Experimental studies and DFT calculations suggest that an unprecedented intermediate and a new oxidation mode of the NHC-derived Breslow intermediate are involved in the new asymmetric sulfonylation reaction.

N-Heterocyclic Carbene-Catalyzed Atroposelective Annulation for Access to Thiazine Derivatives with C-N Axial Chirality.

A catalytic atroposelective cycloaddition reaction between thioureas and ynals is developed. This reaction features the first NHC-catalyzed addition of thioureas to acetylenic acylazolium intermediates to eventually set up C-N axial chirality with excellent optical purities. The obtained axially chiral thiazine derivative products bear multiple functional groups and are feasible for further transformations.

Gold and Carbene Relay Catalytic Enantioselective Cycloisomerization/Cyclization Reactions of Ynamides and Enals.

The combined use of gold as transition metal catalyst and N-heterocyclic carbene (NHC) as organic catalyst in the same solution for relay catalytic reactions was disclosed. The ynamide substrate was activated by gold catalyst to form unsaturated ketimine intermediate that subsequently reacted with the enals (via azolium enolate intermediate generated with NHC) effectively to form bicyclic lactam products with excellent diastereo- and enantio-selectivities. The gold and NHC coordination and dissociation can be dynamic and tunable events, and thus allow the co-existence of both active metal and carbene organic catalysts in appreciable concentrations, for the dual catalytic reaction to proceed.

Carbene-Catalyzed Dynamic Kinetic Resolution and Asymmetric Acylation of Hydroxyphthalides and Related Natural Products.

A catalytic dynamic kinetic resolution and asymmetric acylation reaction of hydroxyphthalides is developed. The reaction involves formation of a carbene catalyst derived chiral acyl azolium intermediate that effectively differentiates the two enantiomers of racemic hydroxyphthalides. The method allows quick access to enantiomerically enriched phthalidyl esters with proven applications in medicine. It also enables asymmetric modification of natural products and other functional molecules that contain acetal/ketal groups, such as corollosporine and fimbricalyxlactone C.

Hydrodehalogenation of Aryl Halides through Direct Electrolysis.

A catalyst- and metal-free electrochemical hydrodehalogenation of aryl halides is disclosed. Our reaction by a flexible protocol is operated in an undivided cell equipped with an inexpensive graphite rod anode and cathode. Trialkylamines nBu3 N/Et3 N behave as effective reductants and hydrogen atom donors for this electrochemical reductive reaction. Various aryl and heteroaryl bromides worked effectively. The typically less reactive aryl chlorides and fluorides can also be smoothly converted. The utility of our method is demonstrated by detoxification of harmful pesticides and hydrodebromination of a dibrominated biphenyl (analogues of flame-retardants) in gram scale.

Characterization of Nine Compounds Isolated from the Acid Hydrolysate of Lonicera fulvotomentosa Hsu et S. C. Cheng and Evaluation of Their In Vitro Activity towards HIV Protease.

In this study, we isolated nine compounds from the acid hydrolysate of the flower buds of Lonicera fulvotomentosa Hsu et S. C. Cheng and characterized their chemical structures using 1H-NMR, 13C-NMR, and electron ionization mass spectroscopy (EI-MS). These compounds were identified as ß-sitosterol (1), 5,5'-dibutoxy-2,2'-bifuran (2), nonacosane-10-ol (3), ethyl (3ß)-3,23-dihydroxyolean-12-en-28-oate (4), oleanolic acid (5), ethyl caffeate (6), caffeic acid (7), isovanillin (8), and hederagenin (9), with 4 as a new triterpene compound. Inhibitory activity against human immunodeficiency virus (HIV) protease was also evaluated for the compounds, and only ethyl caffeate, caffeic acid, and isovanillin (6, 7, and 8) exhibited inhibitory effects, with IC50 values of 1.0 µM, 1.5 µM, and 3.5 µM, respectively. Molecular docking with energy minimization and subsequent molecular dynamic (MD) simulation showed that ethyl caffeate and caffeic acid bound to the active site of HIV protease, while isovanillin drifted out from the active site and dissociated into bulk water during MD simulations, and most of the binding residues of HIV protease have been previously identified for HIV protease inhibitors. These results suggest that caffeic acid derivatives may possess inhibitory activities towards HIV protease other than previously reported inhibitory activities against HIV integrase, and thus ethyl caffeate and caffeic acid could be used as lead compounds in developing potential HIV protease inhibitors, and possibly even dual-function inhibitors against HIV.

Access to Cyclic ß-Amino Acids by Amine-Catalyzed Enantioselective Addition of the γ-Carbon Atoms of α,ß-Unsaturated Imines to Enals.

Disclosed herein is a new catalytic approach for an efficient access to cyclic ß-amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ-carbon atoms of α,ß-unsaturated imines to enals by iminium organic catalysis. This highly chemo- and stereo-selective reaction affords cyclic ß-amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.

Sulfinate and Carbene Co-catalyzed Rauhut-Currier Reaction for Enantioselective Access to Azepino[1,2-a]indoles.

A carbene and sulfinate co-catalyzed intermolecular Rauhut-Currier reaction between enals and nitrovinyl indoles is disclosed. The carbene catalyst activates the enal and the sulfinate co-catalyst activates the nitrovinyl indole. Both activation processes are realized via the formation of covalent bonds between the catalysts and substrates to generate catalyst-bound intermediates. The dual catalytic reaction affords azepino[1,2-a]indole products with excellent stereoselectivity. Our study demonstrates the unique involvement of sulfinate as an effective nucleophilic catalyst in activating electron-deficient alkenes for asymmetric reactions. This dual catalytic approach should also encourage future explorations of both sulfinate and carbene catalysts for new reactions.

Carbene-Catalyzed Desymmetrization and Direct Construction of Arenes with All-Carbon Quaternary Chiral Center.

Multisubstituted arenes such as indanes with attached all-carbon quaternary centers are unique scaffolds in synthetic functional molecules and sophisticated natural products. A key challenge in preparing such molecules lies in the enantioselective installation of the quaternary carbon centers. Conventional methods in this direction include asymmetric substitution reactions and substrate-controlled cyclization reactions. These reactions lead to poor stereoselectivities and/or require long and tedious synthetic steps. Disclosed here is a one-step organic catalytic strategy for enantioselective access to this class of molecules. The reaction involves an N-heterocyclic carbene catalyzed process for direct benzene construction, indane formation, remote-carbon desymmetrization, and excellent chirality control. This approach will enable the concise synthesis of arene-containing molecules, including those with complex structures and challenging chiral centers.