N-Heterocyclic Carbene Enabled Functionalization of Inert C(Sp3)-H Bonds via Hydrogen Atom Transfer (HAT) Processes.

Developing methods to directly transform C(sp3) -H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp3) -H bonds for cross C-C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp3) -H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp3)-H substrates, such as ethers, amines, and alkanes. This mini-review summarizes the progress in carbene organocatalytic functionalization of inert C(sp3)-H bonds enabled by HAT processes, categorizing them into two sections: 1) C-H functionalization involving acyl azolium intermediates; and 2) functionalization of C-H bonds via reductive Breslow intermediates.

Chemodivergent Parallel Kinetic Resolution of Paracyclophanes: Enantiomer Fishing with Different Substrates.

An unprecedented chemodivergent strategy for parallel kinetic resolution (PKR) is disclosed through which two planar chiral products bearing different structures were simultaneously afforded with opposite stereoselectivities. Two achiral esters are activated by one single chiral N-heterocyclic carbene (NHC) catalyst to react with the different enantiomers of the racemic imine substrate in a parallel fashion. Two products bearing distinct structures and opposite stereoselectivities are respectively afforded from the same reaction system in good to excellent yields, enantio- and diastereoselectivities. Control experiments and kinetic studies are carried out to probe the kinetic and dynamic properties during the reaction progress. The planar chiral pyridine and lactam products show interesting applications in both asymmetric synthesis and pesticide development.

Photocatalytic Direct para-selective C-H Amination of Benzyl Alcohols: Selectivity Independent of Side Substituents.

Aminoarenes are important molecules for broad applications in nearly all modern industries that involve chemicals. Direct and site-selective C-H bond amination of arenes provides the most efficient and convenient method to prepare aminoarenes. A main challenge is to selectively install the amino group (or other functional groups) to the distal para-carbon of arenes (especially multi-substituted arenes) during the C-H bond functionalization events. Herein, we address this problem by designing a new strategy via a sequential radical dearomatization/radical amination/rearomatization process for para-selective amination of benzyl alcohols. The para-selectivity of our reaction is completely independent of the electronic and steric properties of the other substituents of the arene substrates. Aminoarenes with many substituents (up to full substitution) and diverse substitution patterns, including those difficult to synthesize previously, could be readily prepared using our protocols. Further exploration of the current strategy shall lead to other challenging C-H functionalization of arenes.

Regio- and stereoselective access to highly substituted vinylphosphine oxides via metal-free electrophilic phosphonoiodination of alkynes.

In general, the P-centered ring-opening of quaternary phosphirenium salts (QPrS) predominantly leads to hydrophosphorylated products, while the C-centered ring-opening is primarily confined to intramolecular nucleophilic reactions, resulting in the formation of phosphorus-containing cyclization products instead of difunctionalized products generated through intermolecular nucleophilic processes. Here, through the promotion of ring-opening of three-member rings by iodine anions and the quenching of electronegative carbon atoms by iodine cations, we successfully synthesize ß-functionalized vinylphosphine oxides by the P-addition of QPrS intermediates generated in situ. Multiple ß-iodo-substituted vinylphosphine oxides can be obtained with exceptional regio- and stereo-selectivity by reacting secondary phosphine oxides with unactivated alkynes. In addition, a variety of ß-functionalized vinylphosphine oxides converted from C-I bonds, especially the rapid construction of benzo[b]phospholes oxides, demonstrates the significance of this strategy.

Discovery of novel piperidine-containing thymol derivatives as potent antifungal agents for crop protection.

BACKGROUND: Plant fungal diseases pose a significant threat to crop production. The extensive use of chemical pesticides has led to growing environmental safety risks and pesticide resistance of various plant pathogens. Therefore, it is an urgent task to explore novel eco-friendly fungicidal agents with high efficacy to combat fungal infection. RESULTS: In this study, we rationally designed a series of novel thymol derivatives by incorporation of the sulfonamide moiety and evaluated their biological activities against plant pathogenic fungi. The bioassay results underscored the remarkable in vitro antifungal activity of compounds 5m and 5t against Phytophthora capsici (P. capsici), with EC50 values of 8.420 and 8.414 µg/mL, respectively. Their efficacies were superior to that of widely used commercial fungicides azoxystrobin (AZO, 20.649 µg/mL) and cabendazim (CAB, 251.625 µg/mL). Furthermore, compound 5v exhibited excellent in vitro antifungal activity against Sclerotinia sclerotiorum (S. sclerotiorum), with an EC50 value of 12.829 µg/mL, significantly outperforming AZO (63.629 µg/mL). In vivo bioassays demonstrated the impactful activity of compound 5v against S. sclerotiorum, achieving over 98% curative and protective efficacies at the concentration of 200 µg/mL. Further mechanistic investigations unveiled that compound 5v induced mycelial shrinkage and collapse in S. sclerotiorum, resulting in organelle damage and the accumulation of antioxidant enzyme activity. CONCLUSION: The significant antifungal efficacy of the prepared thymol derivatives shall encourage further exploration of compound 5v as a promising candidate to develop novel fungicides for crop protection. © 2024 Society of Chemical Industry.

Synthesis of Planar Chiral Compounds Containing α-Amino Phosphonates for Antiplant Virus Applications against Potato Virus Y.

An unprecedented study of the application of planar chiral compounds in antiviral pesticide development is reported. A class of multifunctional planar chiral ferrocene derivatives bearing α-amino phosphonate moieties was synthesized. These compounds, exhibiting superior optical purities, were subsequently subjected to antiviral evaluations against the notable plant pathogen potato virus Y (PVY). The influence of the absolute configurations of the planar chiral compounds on their antiviral bioactivities was significant. A number of these enantiomerically enriched planar chiral molecules demonstrated superior anti-PVY activities. Specifically, compound (Sp, R)-9n displayed extraordinary curative activities against PVY, with a 50% maximal effective concentration (EC50) of 216.11 µg/mL, surpassing the efficacy of ningnanmycin (NNM, 272.74 µg/mL). The protective activities of compound (Sp, R)-9n had an EC50 value of 152.78 µg/mL, which was better than that of NNM (413.22 µg/mL). The molecular docking and defense enzyme activity tests were carried out using the planar chiral molecules bearing different absolute configurations to investigate the mechanism of their antiviral activities against PVY. (Sp, R)-9n, (Sp, R)-9o, and NMM all showed stronger affinities to the PVY-CP than the (Rp, S)-9n. Investigations into the mechanisms revealed that the planar chiral configurations of the compounds played pivotal roles in the interactions between the PVY-CP molecules and could augment the activities of the defense enzymes. This study contributes substantial insights into the role of planar chirality in defending plants against viral infections.

Ionic Hydrogen Bond-Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols.

The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S-, P-, Si- and B-stereocenters over the past decades, the catalyst-controlled strategies to govern the formation of N-stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen-stereogenic compounds through a desymmetrization approach. Intriguingly, the pro-chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene-bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N-oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N-oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Design, Synthesis, and Antifungal Activity of Acrylamide Derivatives Containing Trifluoromethylpyridine and Piperazine.

In this study, a series of acrylamide derivatives containing trifluoromethylpyridine or piperazine fragments were rationally designed and synthesized. Subsequently, the in vitro antifungal activities of all of the synthesized compounds were evaluated. The findings revealed that compounds 6b, 6c, and 7e exhibited >80% antifungal activity against Phomopsis sp. (Ps) at the concentration of 50 µg/mL. Furthermore, the EC50 values for compounds 6b, 6c, and 7e against Ps were determined to be 4.49, 6.47, and 8.68 µg/mL, respectively, which were better than the positive control with azoxystrobin (24.83 µg/mL). At the concentration of 200 µg/mL, the protective activity of compound 6b against Ps reached 65%, which was comparable to that of azoxystrobin (60.9%). Comprehensive mechanistic studies, including morphological studies with fluorescence microscopy (FM), cytoplasmic leakage, and enzyme activity assays, indicated that compound 6b disrupts cell membrane integrity and induces the accumulation of defense enzyme activity, thereby inhibiting mycelial growth. Therefore, compound 6b serves as a valuable candidate for the development of novel fungicides for plant protection.

Carbene-Catalyzed Enantioselective Addition of Sulfinate to Ketones.

A carbene-catalyzed enantioselective addition of sulfinate to ketones between 2-benzoylbenzaldehyde and sulfonyl chloride is disclosed. Up to now, the carbon and heteroatom nucleophiles have effectively undergone catalytic enantioselective addition to carbonyl molecules to introduce functionalities and chirality. Sulfone, as an important class of sulfur-containing functional groups, represents highly valuable motifs in medicines and natural products. It remains undeveloped for the catalytic asymmetric addition of sulfinate to carbonyls. Herein we disclosed the first catalytic enantioselective addition of sulfinate to ketones for the synthesis of sulfones via N-heterocyclic carbene (NHC) catalysis. The sulfonyl chloride behaves both as an oxidant and as a nucleophilic substrate in this carbene-catalyzed process. Experimental studies suggested that the Breslow intermediate can be SET oxidized by sulfonyl chloride to generate the sulfonyl radical. This novel synthetic approach for the asymmetric addition of sulfinate to carbonyls can also be used to modify the commercially available functional molecules.

Carbene-Catalyzed and Pnictogen Bond-Assisted Access to PIII-Stereogenic Compounds.

Intermolecular pnictogen bonding (PnB) catalysis has received increased interest in non-covalent organocatalysis. It has been demonstrated that organic electron-deficient pnictogen atoms can act as prospective Lewis acids. Here, we present a catalytic approach for the asymmetric synthesis of chiral PIII compounds by combining intramolecular PnB interactions and carbene catalysis. Our design features a pre-chiral phosphorus molecule bearing two electron-withdrawing benzoyl groups, resulting in the formation of a σ-hole at the P atom. X-ray and non-covalent interaction (NCI) analysis indicate that the model substrates exhibit intrinsic PnB interaction between the oxygen atom of the formyl group and the phosphorus atom. This induces a conformational locking effect, leading to the crystallization of the phosphorus substrate in a preferred conformation (P212121 chiral group). Under the catalysis of N-heterocyclic carbene, the aldehyde moiety activated by the pnictogen bond selectively reacts with an alcohol to yield the corresponding chiral monoester/phosphorus product with excellent enantioselectivity. This Lewis acidic phosphorus center, aroused by the non-polarized intramolecular pnictogen bond interaction, assists in conformational and selective regulations, providing unique opportunities for catalysis and beyond.

Discovery of Pyridyl-Benzothiazol Hybrids as Novel Protoporphyrinogen Oxidase Inhibitors via Scaffold Hopping.

In order to discover novel protoporphyrinogen oxidase (PPO) inhibitors with excellent herbicidal activity, a series of structurally novel 6-(pyridin-2-yl) benzothiazole derivatives were designed based on the scaffold hopping strategy. The in vitro experiments demonstrated that the newly synthesized compounds exhibited noteworthy inhibitory activity against Arabidopsis thaliana PPO (AtPPO), with IC50 values ranging from 0.06 to 1.36 µM. Preliminary postemergence herbicidal activity tests and crop safety studies indicated that some of our compounds exhibited excellent herbicidal activity and crop safety. For instance, compound (rac)-7as exhibited superior herbicidal activities to commercially available flumioxazin (FLU) and saflufenacil (SAF) at all the tested concentrations and showed effective herbicidal activities even at a dosage as low as 18.75 g ai/ha. Meanwhile, compound (rac)-7as showed good crop safety for wheat at a dosage as high as 150 g of ai/ha. Although the absolute configuration of compound 7as has no obvious effect on its herbicidal activity, compound (R)-7as showed a slightly higher crop safety than compound (S)-7as. Molecular simulation studies of Nicotiana tabacum PPO (NtPPO) and our candidate compounds showed that the benzothiazole moiety of compounds (R)-7as or (S)-7as formed multiple π-π stacking interactions with FAD, and the pyridine ring generated π-π stacking with Phe-392. Our finding proved that the pyridyl-benzothiazol hybrids are promising scaffolds for the development of PPO-inhibiting herbicides.

Design, synthesis and Anti-PVY activity of planar chiral thiourea derivatives incorporated with [2.2]Paracyclophane.

BACKGROUND: Potato virus Y (PVY) is a prominent representative of plant viruses. It can inflict severe damage upon Solanaceae plants, leading to global dissemination and substantial economic losses. To discover new antiviral agents, a class of planar chiral thiourea molecules through the key step of N-heterocyclic carbene-catalyzed nitrile formation reaction was synthesized with excellent optical purities for antiviral evaluations against plant virus PVY. RESULTS: The absolute configurations of the planar chiral compounds exhibited obvious distinctions in the anti-PVY activities. Notability, compound (S)-4u exhibited remarkable curative activities against PVY, with a half maximal effective concentration (EC50) of 349.3 µg mL-1, which was lower than that of the ningnanmycin (NNM) (EC50 = 400.8 µg mL-1). Additionally, The EC50 value for the protective effects of (S)-4u was 146.2 µg mL-1, which was superior to that of NNM (276.4 µg mL-1). Furthermore, the mechanism-of-action of enantiomers of planar chiral compound 4u was investigated through molecular docking, defensive enzyme activity tests and chlorophyll content tests. CONCLUSION: Biological mechanism studies have demonstrated that the configuration of planar chiral target compounds plays a crucial role in the molecular interaction with PVY-CP, enhancing the activity of defense enzymes and affecting chlorophyll content. The current study has provided significant insights into the roles played by planar chiralities in plant protection against viruses. This paves the way for the development of novel green pesticides bearing planar chiralities with excellent optical purities. © 2024 Society of Chemical Industry.

Design, Synthesis, and Herbicidal Evaluation of Pyrrolidinone-Containing 2-Phenylpyridine Derivatives as Novel Protoporphyrinogen Oxidase Inhibitors.

In this work, a series of pyrrolidinone-containing 2-phenylpyridine derivatives were synthesized and evaluated as novel protoporphyrinogen IX oxidase (PPO, EC 1.3.3.4) inhibitors for herbicide development. At 150 g ai/ha, compounds 4d, 4f, and 4l can inhibit the grassy weeds of Echinochloa crus-galli (EC), Digitaria sanguinalis (DS), and Lolium perenne (LP) with a range of 60 to 90%. Remarkably, at 9.375 g ai/ha, these compounds showed 100% inhibition effects against broadleaf weeds of Amaranthus retroflexus (AR) and Abutilon theophrasti (AT), which were comparable to the performance of the commercial herbicides flumioxazin (FLU) and saflufenacil (SAF) and better than that of acifluorfen (ACI). Molecular docking analyses revealed significant hydrogen bonding and π-π stacking interactions between compounds 4d and 4l with Arg98, Asn67, and Phe392, respectively. Additionally, representative compounds were chosen for in vivo assessment of PPO inhibitory activity, with compounds 4d, 4f, and 4l demonstrating excellent inhibitory effects. Notably, compounds 4d and 4l induced the accumulation of reactive oxygen species (ROS) and a reduction in the chlorophyll (Chl) content. Consequently, compounds 4d, 4f, and 4l are promising lead candidates for the development of novel PPO herbicides.

Access to Axially Chiral Aryl Aldehydes via Carbene-Catalyzed Nitrile Formation and Desymmetrization Reaction.

An approach utilizing N-heterocyclic carbene for nitrile formation and desymmetrization reaction is developed. The process involves kinetic resolution, with the axially chiral aryl monoaldehydes obtained in moderate yields with excellent optical purities. These axially chiral aryl monoaldehydes can be conveniently transformed into functionalized molecules, showing great potential as catalysts in organic chemistry.

Discovery of Novel Chiral Indole Derivatives Containing the Oxazoline Moiety as Potential Antiviral Agents for Plants.

Potato virus Y (PVY) is an important plant virus that has spread worldwide, causing significant economic losses. To search for novel structures as potent antiviral agents, a series of chiral indole derivatives containing oxazoline moieties were designed and synthesized and their anti-PVY activities were evaluated. Biological activity tests demonstrated that many chiral compounds exhibited promising anti-PVY activities and that their absolute configurations exhibited obvious distinctions in antiviral bioactivities. Notably, compound (S)-4v displayed excellent curative and protective efficacy against PVY, with EC50 values of 328.6 and 256.1 µg/mL, respectively, which were superior to those of commercial virucide ningnanmycin (NNM, 437.4 and 397.4 µg/mL, respectively). The preliminary antiviral mechanism was investigated to determine the difference in antiviral activity between the two enantiomers of 4v chiral compounds. Molecular docking indicated a stronger binding affinity between the coating proteins of PVY (PVY-CP) and (S)-4v (-6.5 kcal/mol) compared to (R)-4v (-6.2 kcal/mol). Additionally, compound (S)-4v can increase the chlorophyll content and defense-related enzyme activities more effectively than its enantiomer. Therefore, this study provides an important basis for the development of chiral indole derivatives containing oxazoline moieties as novel agricultural chemicals.

Direct Formation of Amide-Linked C-Glycosyl Amino Acids and Peptides via Photoredox/Nickel Dual Catalysis.

Glycoproteins account for numerous biological processes including those associated with diseases and infections. The advancement of glycopeptides has emerged as a promising strategy for unraveling biological pathways and discovering novel medicines. In this arena, a key challenge arises from the absence of efficient synthetic strategies to access glycopeptides and glycoproteins. Here, we present a highly concise approach to bridging saccharides with amino acids and peptides through an amide linkage. Our amide-linked C-glycosyl amino acids and peptides are synthesized through cooperative Ni-catalyzed and photoredox processes. The catalytic process generates a glycosyl radical and an amide carbonyl radical, which subsequently combine to yield the C-glycosyl products. The saccharide reaction partners encompass mono-, di-, and trisaccharides. All 20 natural amino acids, peptides, and their derivatives can efficiently undergo glycosylations with yields ranging from acceptable to high, demonstrating excellent stereoselectivities. As a substantial expansion of applications, we have shown that simple C-glycosyl amino acids can function as versatile building units for constructing C-glycopeptides with intricate spatial complexities.

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.

Design and Enantioselective Synthesis of Chiral Pyranone Fused Indole Derivatives with Antibacterial Activities against Xanthomonas oryzae pv oryzae for Protection of Rice.

A new class of chiral pyranone fused indole derivatives were prepared by means of N-heterocyclic carbene (NHC) organocatalysis and demonstrated notable antibacterial activity against Xanthomonas oryzae pv oryzae (Xoo). Bioassays showed that compounds (3S,4R)-5b, (3S,4R)-5d, and (3S,4R)-5l exhibited promising in vitro efficacy against Xoo, with EC50 values of 9.05, 9.71, and 5.84 mg/L, respectively, which were superior to that of the positive controls with commercial antibacterial agents, bismerthiazol (BT, EC50 = 27.8 mg/L) and thiodiazole copper (TC, EC50 = 70.1 mg/L). Furthermore, single enantiomer (3S,4R)-5l was identified as an optimal structure displaying 55.3% and 52.0% curative and protective activities against Xoo in vivo tests at a concentration of 200 mg/L, which slightly surpassed the positive control with TC (curative and protective activities of 47.2% and 48.8%, respectively). Mechanistic studies through molecular docking analysis revealed preliminary insights into the distinct anti-Xoo activity of the two single enantiomers (3S,4R)-5l and (3R,4S)-5l, wherein the (3S,4R)-configured stereoisomer could form a more stable interaction with XooDHPS (dihydropteroate synthase). These findings underscore the significant anti-Xoo potential of these chiral pyranone fused indole derivatives, and shall inspire further exploration as promising lead structures for a novel class of bactericides to combat bacterial infections and other plant diseases.

Carbene organic catalytic planar enantioselective macrolactonization.

Macrolactones exhibit distinct conformational and configurational properties and are widely found in natural products, medicines, and agrochemicals. Up to now, the major effort for macrolactonization is directed toward identifying suitable carboxylic acid/alcohol coupling reagents to address the challenges associated with macrocyclization, wherein the stereochemistry of products is usually controlled by the substrate's inherent chirality. It remains largely unexplored in using catalysts to govern both macrolactone formation and stereochemical control. Here, we disclose a non-enzymatic organocatalytic approach to construct macrolactones bearing chiral planes from achiral substrates. Our strategy utilizes N-heterocyclic carbene (NHC) as a potent acylation catalyst that simultaneously mediates the macrocyclization and controls planar chirality during the catalytic process. Macrolactones varying in ring sizes from sixteen to twenty members are obtained with good-to-excellent yields and enantiomeric ratios. Our study shall open new avenues in accessing macrolactones with various stereogenic elements and ring structures by using readily available small-molecule catalysts.