Design, selective synthesis and biological activities evaluation of novel thiazol-2-ylbenzamide and thiazole-2-ylbenzimidoyl chloride derivatives.

To promote the development and exploitation of novel antifungal agents, a series of thiazol-2-ylbenzamide derivatives (3A-3V) and thiazole-2-ylbenzimidoyl chloride derivatives (4A-4V) were designed and selective synthesis. The bioassay results showed that most of the target compounds exhibited excellent in vitro antifungal activities against five plant pathogenic fungi (Valsa mali, Sclerotinia scleotiorum, Botrytis cinerea, Rhizoctonia solani and Trichoderma viride). The antifungal effects of compounds 3B (EC50 = 0.72 mg/L) and 4B (EC50 = 0.65 mg/L) against S. scleotiorum were comparable to succinate dehydrogenase inhibitors (SDHIs) thifluzamide (EC50 = 1.08 mg/L) and boscalid (EC50 = 0.78 mg/L). Especially, compounds 3B (EC50 = 0.87 mg/L) and 4B (EC50 = 1.08 mg/L) showed higher activity against R. solani than boscalid (EC50 = 2.25 mg/L). In vivo experiments in rice leaves revealed that compounds 3B (86.8 %) and 4B (85.3 %) exhibited excellent protective activities against R. solani comparable to thifluzamide (88.5 %). Scanning electron microscopy (SEM) results exhibited that compounds 3B and 4B dramatically disrupted the typical structure and morphology of R. solani mycelium. Molecular docking demonstrated that compounds 3B and 4B had significant interactions with succinate dehydrogenase (SDH). Meanwhile, SDH inhibition assay results further proved their potential as SDHIs. In addition, acute oral toxicity tests on A. mellifera L. showed only low toxicity for compounds 3B and 4B to A. mellifera L. populations. These results suggested that these two series of compounds had merit for further investigation as potential low-risk agricultural SDHI fungicides.

Ni/Chiral Sodium Carboxylate Dual Catalyzed Asymmetric O-Propargylation.

A highly enantioselective O-propargylation catalyzed by combining a phosphine-nickel complex and an axially chiral sodium dicarboxylate has been developed. The transformation features mild reaction conditions, a broad substrate scope, and excellent functional group tolerance, offering an efficient approach to an array of enantioenriched O-propargyl hydroxylamines. Mechanistic studies support the presumed role of the chiral carboxylate as a counterion for nickel catalysis enabling the discovery of highly stereoselective transformations. The power of this reaction is illustrated by its application in the asymmetric total synthesis of potent firefly luciferase inhibitors and (S)-dihydroyashabushiketol.

Electrodimerization of N-Alkoxyamides for the Synthesis of Hydrazines.

An efficient and valuable N-N dimerization reaction of N-alkoxyamides is reported under undivided electrolytic conditions. This electrochemical strategy provides a powerful way to access a wide range of advanced, highly functionalized hydrazines. Remarkably, an N-centered radical generated from the cleavage of the N-H bond under electrolytic conditions plays a crucial role in this transformation. Furthermore, various N-alkoxyamides bearing different substituents are suitable in this transformation, furnishing the corresponding hydrazines in up to 92% yield.

Asymmetric Electrochemical Transformations.

The field of electrochemical synthesis has developed rapidly over the last decade and has provided alternative synthetic methods with the absence of stoichiometric amounts of chemical oxidants or reductants. Although sustainable electrosynthetic procedures have been developed, relatively few examples of highly enantioselective catalytic electrosynthesis have been reported to date. The development of general strategies for electrochemical enantiocontrol has thus proven to be a considerable challenge. This Minireview highlights the current knowledge and recent advances in the synthetic utility of electrochemical transformations for asymmetric synthesis. Specifically, three major types of catalytic enantioselective strategy in electrosynthesis are outlined, including electrochemical activation of chiral catalyst-bound substrates, asymmetric cascade electrochemical processes, and chemically modified chiral electrodes.

Merging Electrosynthesis and Bifunctional Squaramide Catalysis in the Asymmetric Detrifluoroacetylative Alkylation Reactions.

An enantioselective bifunctional squaramide-catalyzed detrifluoroacetylative alkylation reaction has been developed under electrochemical conditions. The unified strategy based on this key tandem methodology has been divergently explored for the asymmetric synthesis of fluorine-containing target molecules with good stereocontrol (up to 95 % ee). Furthermore, this asymmetric catalytic reaction combines the benefits of electrosynthesis and organocatalysis for the preparation of biologically relevant products containing C-F tertiary stereogenic centers.

Asymmetric Lewis Acid Catalyzed Electrochemical Alkylation.

Lewis-acid catalysis and electrochemistry represent two powerful fields that have found widespread application in organic chemistry. Reported herein is an asymmetric electrosynthesis in combination with a chiral Ni catalyst leading to an intermolecular alkylation reaction in good yields with excellent enantioselectivities (up to 97 % ee). Mechanistic studies suggest that the Lewis-acid-bound radical intermediate from a single-electron anodic oxidation selectively reacts with the benzylic radical species to generate the desired adducts.

Palladium(II)-catalyzed direct alkenylation of dihydropyranones.

A palladium(II)-catalyzed direct alkenylation reaction of dihydropyranones was developed. Various substituted dihydropyranones could afford the desired products in reasonable yields. And different acrylates were found to be good coupling partners in this coupling reaction. A Pd(0)/Pd(II) catalytic pathway was proposed to be involved in this coupling reaction.

Design, Synthesis, and Evaluation of Antifungal Bioactivity of Novel Pyrazole Carboxamide Thiazole Derivatives as SDH Inhibitors.

Agricultural production is seriously threatened by plant pathogens. The development of new fungicides with high efficacy and low toxicity is urgently needed. In this study, a series of pyrazole carboxamide thiazole derivatives were designed, synthesized, and evaluated for their antifungal activities against nine plant pathogens in vitro. Bioassay results showed that most compounds (3i, 5i, 6i, 7i, 9i, 12i, 16i, 19i, and 23i) exhibited good antifungal activities against Valsa mali. In particular, compounds 6i and 19i exhibited better antifungal activities against Valsa mali with EC50 values of 1.77 and 1.97 mg/L, respectively, than the control drug boscalid (EC50 = 9.19 mg/L). Additionally, compound 23i exhibited excellent inhibitory activity against Rhizoctonia solani, with an EC50 value of 3.79 mg/L. Compound 6i at 40 mg/L showed a satisfactory in vivo protective effect against Valsa mali. Scanning electron microscopy analyses revealed that compound 6i could significantly damage the surface morphology to interfere with the growth of Valsa mali. In molecular docking, the results showed that compound 6i interacts with TRP O: 173, SER P: 39, TYR Q: 58, and ARG P: 43 of succinate dehydrogenase (SDH) through hydrogen bonding and σ-π interaction, and its binding mode is similar to that of boscalid and SDH. The enzyme activity experiment also further verified its action mode. Our studies suggested that pyrazole carboxamide thiazole derivative 6i provided a valuable reference for the further development of succinate dehydrogenase inhibitors.

Discovery of Pyrazole-5-yl-amide Derivatives Containing Cinnamamide Structural Fragments as Potential Succinate Dehydrogenase Inhibitors.

To promote the development of novel agricultural succinate dehydrogenase inhibitor (SDHI) fungicides, we introduced cinnamamide and nicotinamide structural fragments into the structure of pyrazol-5-yl-amide by carbon chain extension and scaffold hopping, respectively, and synthesized a series of derivatives. The results of the biological activity assays indicated that most of the target compounds exhibited varying degrees of inhibitory activity against the tested fungi. Notably, compounds G22, G28, G34, G38, and G39 exhibited excellent in vitro antifungal activities against Valsa mali with EC50 values of 0.48, 0.86, 0.57, 0.73, and 0.87 mg/L, respectively, and this result was significantly more potent than boscalid (EC50 = 2.80 mg/L) and closer to the specialty control drug tebuconazole (EC50 = 0.30 mg/L). Compounds G22 and G34 also exhibited excellent in vivo protective and curative effects against V. mali at 40 mg/L. The SEM and TEM observations indicated that compounds G22 and G34 may affect normal V. mali mycelial morphology as well as the cellular ultrastructure. Molecular docking analysis results indicated that G22 and boscalid possessed a similar binding mode to that of SDH, and detailed SDH inhibition assays validated the feasibility of the designed compounds as potential SDH inhibitors. Compounds G22 and G3 were selected for theoretical calculations, and the terminal carboxylic acid group of this series of compounds may be a key region influencing the antifungal activity. Furthermore, toxicity tests on Apis mellifera l. revealed that compounds G22 and G34 exhibited low toxicity to A. mellifera l. populations. The above results demonstrated that these series of pyrazole-5-yl-amide derivatives are promising for development as potential low-risk drug-resistance agricultural SDHI fungicides.

Design, Synthesis, and Biological Evaluation of Novel Pyrazol-5-yl-benzamide Derivatives Containing Oxazole Group as Potential Succinate Dehydrogenase Inhibitors.

A series of pyrazol-5-yl-benzamide derivatives containing the oxazole group were designed and synthesized as potential SDH inhibitors. According to the results of the bioassays, most target compounds displayed moderate-to-excellent in vitro antifungal activities against Valsa mali, Sclerotinia scleotiorum, Alternaria alternata, and Botrytis cinerea. Among them, compounds C13, C14, and C16 exhibited more excellently inhibitory activities against S. sclerotiorum than boscalid (EC50 = 0.96 mg/L), with EC50 values of 0.69, 0.26, and 0.95 mg/L, respectively. In vivo experiments on rape leaves and cucumber leaves showed that compounds C13 and C14 exhibited considerable protective effects against S. sclerotiorum than boscalid. SEM analysis indicated that compounds C13 and C14 significantly destroyed the typical structure and morphology of S. scleotiorum hyphae. In the respiratory inhibition effect assays, compounds C13 (28.0%) and C14 (33.9%) exhibited a strong inhibitory effect on the respiration rate of S. sclerotiorum mycelia, which was close to boscalid (30.6%). The results of molecular docking indicated that compounds C13 and C14 could form strong interactions with the key residues TRP O:173, ARG P:43, TYR Q:58, and MET P:43 of the SDH. Furthermore, the antifungal mechanism of these derivatives was demonstrated by the SDH enzymatic inhibition assay. These results demonstrate that compounds C13 and C14 can be developed into novel SDH inhibitors for crop protection.

Nickel-catalyzed switchable 1,3-dienylation and enantioselective allenylation of phosphine oxides.

The development of general catalytic methods for the regio- and stereoselective construction of phosphoryl derivatives from identical substrates remains a formidable challenge in organic synthesis. Enabled by the newly developed BDPP-type ligands, we disclosed a nickel-catalyzed allenylation of phosphine oxides rationally and predictably, allowing the construction of versatile chiral allenylphosphoryl derivatives with high enantiopurity (up to 94% e.e.). Alternatively, using an achiral phosphine ligand dcypbz under acidic conditions, we achieved a regiochemical switch of the 1,3-dienylation to afford functionalized phosphinoyl 1,3-butadienes (up to 93% yield). The salient features of this method include switchable reactivity, broad substrate scope, readily available feedstock, single-step preparation, and high asymmetric induction.

Collective synthesis of acetylenic pharmaceuticals via enantioselective Nickel/Lewis acid-catalyzed propargylic alkylation.

Chiral acetylenic derivatives are found in many bioactive compounds and are versatile functional groups in organic chemistry. Here, we describe an enantioselective nickel/Lewis acid-catalyzed asymmetric propargylic substitution reaction from simple achiral materials under mild condition. The introduction of a Lewis acid cocatalyst is crucial to the efficiency of the transformation. Notably, we investigate this asymmetric propargylic substitution reaction for the development of a range of structurally diverse natural products. The power of this strategy is highlighted by the collective synthesis of seven biologically active compounds: (-)-Thiohexital, (+)-Thiopental, (+)-Pentobarbital, (-)-AMG 837, (+)-Phenoxanol, (+)-Citralis, and (-)-Citralis Nitrile.

Synthesis of Functionalized Vinylsilanes via Metal-Free Dehydrogenative Silylation of Enamides.

A novel method of metal-free dehydrogenative silylation of enamides has been developed. The desired functionalized vinylsilane products were obtained in moderate to good yield and with high stereoselectivities. This protocol displays good tolerance of various functionalities. Furthermore, the high chemoselectivity of this reaction enables us to introduce different unsaturated C-C moieties to the products. The ease of further derivatization of the products to other useful compounds also demonstrates the highly synthetic utility of the current methodology.

Electrochemical Reductive Smiles Rearrangement for C-N Bond Formation.

A conceptually new and synthetically valuable radical Smiles rearrangement reaction is reported under undivided electrolytic conditions. This protocol employs an entirely new strategy for the electrochemical radical Smiles rearrangement. Remarkably, an amidyl radical generated from the cleavage of the N-O bond under reductive electrolytic conditions plays a crucial role in this transformation. Various hydroxylamine derivatives bearing different substituents are suitable in this electrochemical transformation, furnishing the corresponding amides in up to 86% yield.

Switchable Smiles Rearrangement for Enantioselective O-Aryl Amination.

Asymmetric assembly of atropisomeric anilines from abundant and readily available precursors is one of the most challenging but valuable processes in organic synthesis. The use of highly efficient Smiles rearrangement to accomplish switchable enantioselective amination reactions of O-arenes provides access to nonsymmetric 2'-amino[1,1'-binaphthalen]-2-ol (i.e., NOBIN-type) and [1,1'-binaphthalene]-2,2'-diamine (i.e., BINAM-type) derivatives. This transition metal-free strategy provides a powerful way to access a wide range of advanced highly functionalized enantioenriched anilines.

Copper-catalyzed silylation reactions of propargyl epoxides: easy access to 2,3-allenols and stereodefined alkenes.

Efficient silylation reactions of propargyl epoxides catalyzed by copper catalysts have been developed. Under mild reaction conditions, tri- and tetra-substituted functionalized allenols and alkenes could be selectively obtained in moderate to high yields via tuning the bases and solvents used in the reactions. This work provides straightforward and efficient approaches to the synthesis of multifunctionalized 2,3-allenols and stereodefined alkenes from the same starting material of propargyl epoxides.