Asymmetric Synthesis of Planar Chiral Carbonitriles and Amines via Carbene-Catalyzed Kinetic Resolution.

We have developed a catalytic method using chiral N-heterocyclic carbene (NHC) as the sole organic catalyst to synthesize planar chiral carbonitriles asymmetrically, resulting in optically pure, multifunctional compounds. The method demonstrates remarkable tolerance toward diverse substituents and substitution patterns through kinetic resolution (KR) or desymmetrization processes. The resulting optically pure planar chiral products hold significant potential for applications in asymmetric synthesis and antibacterial pesticide development.

NHC-Catalyzed Reaction of Carboxylic Acids Using Allene Ketones as Substrates and Activating Reagents.

We present a new reaction between carboxylic acids and allene ketones mediated by N-heterocyclic carbene (NHC) catalysts, which exhibit, in principle, nearly perfect atom economy. In this new approach, allene ketones act as both an activating reagent and a reactant. All atoms in the substrates end up in the product without the need for coupling reagents. The present study aims to encourage further explorations of NHC catalytic reactions with alternative activation strategies and better atom economy.

Carbene-Catalyzed Direct O-Functionalization of Ketone: Atroposelective Access to Non-C2-Symmetric Binaphthyls.

Disclosed here is NHC-catalyzed direct intermolecular trapping of the ketone oxygen atom with the acyl azolium intermediate. The overall reaction is a dynamic kinetic resolution process that converts ketone to the corresponding enol ester with well-controlled axial chirality. Our reaction eventually affords non-C2-symmetric binaphthyl derivatives with important applications, such as in the area of asymmetric catalysis.

Facile access to benzofuran derivatives through radical reactions with heteroatom-centered super-electron-donors.

The development of suitable electron donors is critical to single-electron-transfer (SET) processes. The use of heteroatom-centered anions as super-electron-donors (SEDs) for direct SET reactions has rarely been studied. Here we show that heteroatom anions can be applied as SEDs to initiate radical reactions for facile synthesis of 3-substituted benzofurans. Phosphines, thiols and anilines bearing different substitution patterns work well in this inter-molecular radical coupling reaction and the 3-functionalized benzofuran products bearing heteroatomic functionalities are given in moderate to excellent yields. The reaction mechanism is elucidated via control experiments and computational methods. The afforded products show promising applications in both organic synthesis and pesticide development.

NHC-catalyzed enantioselective access to ß-cyano carboxylic esters via in situ substrate alternation and release.

A carbene-catalyzed asymmetric access to chiral ß-cyano carboxylic esters is disclosed. The reaction proceeds between ß,ß-disubstituted enals and aromatic thiols involving enantioselective protonation of enal ß-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched ß-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.

Carbene-Catalyzed Access to Thiochromene Derivatives: Control of Reaction Pathways via Slow Release of Thiols from Disulfides.

Substrates containing disulfide bonds, which are more stable and less smelling, could be used as thiophenol precursors in organic synthesis. Herein, an N-heterocyclic carbene (NHC)-catalyzed reaction between α-bromoenals and 2,2'-dithiodibenzaldehydes was developed. Through the sustained release strategy, the side reaction can be effectively inhibited, and the chiral thiochromene derivatives can be obtained with good yields and high optical purities. Application studies showed encouraging results when the desired products were explored for antimicrobial utilities in pesticide development.

NHC-catalyzed [12+2] reaction of polycyclic arylaldehydes for access to indole derivatives.

An N-heterocyclic carbene (NHC) catalyzed enantio- and diastereoselective [12+2] cycloaddition is disclosed to rapidly construct sophisticated molecules bearing a tricyclic core and morpholine moiety. The success of our reaction relies on the NHC-catalyzed remote sp3 (C-H) bond activation of a 5H-benzo[a]pyrrolizine-3-carbaldehyde under oxidative conditions. Preliminary studies revealed that our products exhibit superior in vitro bioactivities against two plant pathogens to commercial Bismerthiazol (BT) and Thiodiazole Copper (TC).

Development of axially chiral urazole scaffolds for antiplant virus applications against potato virus Y.

BACKGROUND: Potato virus Y (PVY) was first discovered by Smith in 1931 and is currently ranked as the fifth most significant plant virus. It can cause severe damage to plants from the family Solanaceae, which results in billions of dollars of economic loss worldwide every year. To discover new antiviral drugs, a class of multifunctional urazole derivatives bearing a stereogenic CN axis were synthesized with excellent optical purities for antiviral evaluations against PVY. RESULTS: The absolute configurations of the axially chiral compounds exhibited obvious distinctions in antiviral bioactivities, with several of these enantio-enriched axially chiral molecules showing excellent anti-PVY activities. In particular, compound (R)-9f exhibited remarkable curative activities against PVY with a 50% maximal effective concentration (EC50 ) of 224.9 µg mL-1 , which was better than that of ningnanmycin (NNM), which had an EC50 of 234.0 µg mL-1 . And the EC50 value of the protective activities of compound (R)-9f was 462.2 µg mL-1 , which was comparable to that of NNM (442.0 µg mL-1 ). The mechanisms of two enantiomer of the axially chiral compounds 9f were studied by both molecule docking and defensive enzyme activity tests. CONCLUSION: Mechanistic studies demonstrated that the axially chiral configurations of the compounds played significant roles in the molecule PVY-CP (PVY Coat Protein) interactions and could enhance the activities of the defense enzymes. The (S)-9f showed only one carbon-hydrogen bond and one π-cation interaction between the chiral molecule and the PVY-CP amino acid sites. In contrast, the (R)-enantiomer of 9f exhibited three hydrogen bonding interactions between the carbonyl groups and the PVY-CP active sites of ARG157 and GLN158. The current study provides significant information on the roles that axial chiralities play in plant protection against viruses, which will facilitate the development of novel green pesticides bearing axial chiralities with excellent optical purities. © 2023 Society of Chemical Industry.

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.

Enantioselective Synthesis of Pyrazolo[3,4-b]pyridone Derivatives with Antifungal Activities against Phytophthora capsici and Colletotrichum fructicola.

A chiral NHC-catalyzed [3 + 3] cycloaddition reaction is developed for the efficient synthesis of pyrazolo[3,4-b]pyridones in generally excellent yields and optical purities. The R, S, and racemic forms of these molecules are systematically studied via in vitro tests that detect antifungal activity against Phytophthora capsici and Colletotrichum fructicola. Chiral compounds (R)-3i, (R)-3j, and (R)-3p are identified to have excellent inhibitory effects against P. capsici and C. fructicola.

Direct Reaction of Nitroarenes and Thiols via Photodriven Oxygen Atom Transfer for Access to Sulfonamides.

Sulfonamide is a common motif in medicines and agrochemicals. Typically, this class of functional groups is prepared by reacting amines with sulfonyl chlorides that are presynthesized from nitro compounds and thiols, respectively. Here, we report a novel strategy that directly couples nitro compounds and thiols to form sulfonamides atom- and redox-economically. Mechanistic studies suggest our reaction proceeds via direct photoexcitation of nitroarenes that eventually transfers the oxygen atoms from the nitro group to the thiol unit.

Carbene and photocatalyst-catalyzed decarboxylative radical coupling of carboxylic acids and acyl imidazoles to form ketones.

The carbene and photocatalyst co-catalyzed radical coupling of acyl electrophile and a radical precursor is emerging as attractive method for ketone synthesis. However, previous reports mainly limited to prefunctionalized radical precursors and two-component coupling. Herein, an N-heterocyclic carbene and photocatalyst catalyzed decarboxylative radical coupling of carboxylic acids and acyl imidazoles is disclosed, in which the carboxylic acids are directly used as radical precursors. The acyl imidazoles could also be generated in situ by reaction of a carboxylic acid with CDI thus furnishing a formally decarboxylative coupling of two carboxylic acids. In addition, the reaction is successfully extended to three-component coupling by using alkene as a third coupling partner via a radical relay process. The mild conditions, operational simplicity, and use of carboxylic acids as the reacting partners make our method a powerful strategy for construction of complex ketones from readily available starting materials, and late-stage modification of natural products and medicines.

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.

Green and Facile Synthesis of Spirocyclopentanes Through NaOH-Promoted Chemo- and Diastereo-Selective (3 + 2) Cycloaddition Reactions of Activated Cyclopropanes and Enamides.

A chemo- and diastereo-selective (3 + 2) cycloaddition reacition between Donor-Acceptor (D-A) cyclopropanes and α,ß-unsaturated enamides is developed for efficient access to spiro(cyclopentane-1,3'-indoline) derivatives. Simple, inexpensive and readily available NaOH is used as the sole catalyst for this process. A broad range of D-A cyclopropanes could be used as the C-3 synthons to react with oxindole-derived α,ß-unsaturated enamides. The structurally sophisticated spiro(cyclopentane-1,3'-indoline) derivatives bearing up to 3 adjacent chiral centers are afforded in excellent yields as single diastereomers.

Carbene-Catalyzed Reaction of Indolyl Methylenemalononitriles and Enals for Access to Complex Tetrahydrocarbazoles.

A carbene-catalyzed enantioselective cascade reaction of substituted methylenemalononitriles and α-bromoenals is disclosed. Key steps of this cascade process include a formal [4 + 2] cycloaddition, aldol reaction, and intramolecular lactonization. Our reaction offers streamlined and highly stereoselective access to complex tetrahydrocarbazole derivatives, with simultaneous formation of four chemical bonds and four chiral centers.

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.

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.

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.