Industrial Distillation Fractions of Garlic Essential Oil, Design, Synthesis, and Antifungal Activity Evaluation of Aliphatic Substituted Trisulfide Derivatives.

Garlic oil has a wide range of biological activities, and its broad-spectrum activity against phytopathogenic fungi still has the potential to be explored. In this study, enzymatic treatment of garlic resulted in an increase of approximately 50 % in the yield of essential oil, a feasible GC-MS analytical program for garlic oil was provided. Vacuum fractionation of the volatile oil and determination of its inhibitory activity against 10 fungi demonstrated that garlic oil has good antifungal activity. The antifungal activity levels were ranked as diallyl trisulfide (S-3)>diallyl disulfide (S-2)>diallyl monosulfide (S-1), with an EC50 value of S-3 against Botrytis cinerea reached 8.16 mg/L. Following the structural modification of compound S-3, a series of derivatives, including compounds S-4~7, were synthesized and screened for their antifungal activity. The findings unequivocally demonstrated that the compound dimethyl trisulfide (S-4) exhibited exceptional antifungal activity. The EC50 of S-4 against Sclerotinia sclerotiorum reached 6.83 mg/L. SEM, In vivo experiments, and changes in mycelial nucleic acids, soluble proteins and soluble sugar leakage further confirmed its antifungal activity. The study indicated that the trisulfide bond structure was the key to good antifungal activity, which can be developed into a new type of green plant-derived fungicide for plant protection.

Diallyl Trisulfide Acts as a Soil Disinfestation Against the Ilyonectria destructans through Inducing the Burst of Reactive Oxygen Species.

Soil-borne diseases represent an impediment to the sustainable development of agriculture. A soil-borne disease caused by Ilyonectria destructans severely impacts Panax species, and soil disinfestation has proven to be an effective management approach. Here, diallyl trisulfide (DATS), derived from garlic, exhibited pronounced inhibitory effects on the growth of I. destructans in vitro tests and contributed to the alleviation of soil-borne diseases in the field. A comprehensive analysis demonstrated that DATS inhibits the growth of I. destructans by activating detoxifying enzymes, such as GSTs, disrupting the equilibrium of redox reactions. A series of antioxidant amino acids were suppressed by DATS. Particularly noteworthy is the substantial depletion of glutathione by DATS, resulting in the accumulation of ROS, ultimately culminating in the inhibition of I. destructans growth. Briefly, DATS could effectively suppress soil-borne diseases by inhibiting pathogen growth through the activation of ROS, and it holds promise as a potential environmentally friendly soil disinfestation.

Mechanism of active acetylcholinesterase inhibition by organic sulfanes in garlic: Non-covalent binding and covalent modifications.

Numerous secondary metabolites in medicinal food homology plants such as Allium inhibit the activity of acetylcholinesterase (AChE), but the current understanding of the inhibition mechanism is limited. In this study, we employed ultrafiltration, spectroscopic, molecular docking, and matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF-MS/MS) techniques to investigate the inhibition mechanism of AChE by garlic organic sulfanes, including diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS). The results of UV-spectrophotometry and ultrafiltration experiments showed the inhibition of AChE activity by DAS and DADS was reversible (competitive inhibition), but inhibition by DATS was irreversible. Molecular fluorescence and molecular docking indicated DAS and DADS changed the positions of key amino acids inside the catalytic cavity through hydrophobic interactions with AChE. By using MALDI-TOF-MS/MS, we found DATS irreversibly inhibited AChE activity by opening disulfide-bond switching of disulfide bond 1 (Cys-69 and Cys-96) and disulfide bond 2 (Cys-257 and Cys-272) in AChE, as well as by covalently modifying Cys-272 in disulfide bond 2 to generate AChE-SSA derivatives (strengthened switch). This study provides a basis for further exploration of natural AChE inhibitors using organic active substances in garlic and presents a hypothesis of U-shaped spring force arm effect based on the disulfide bond-switching reaction of DATS that can be used to evaluate the stability of disulfide bonds in proteins.

Sulfide-Directed Ir-Catalyzed Vinylic sp2 and Benzylic sp3 †C-H Activation for the Construction of Sulfur-Containing Medium-Ring System.

Ir-catalyzed transformations initiated by sulfur-directed vinylic sp2 and benzylic sp3  C-H activation are disclosed that achieve the construction of sulfur-containing seven- and eight-membered systems. Allyl 2-alkynylphenyl sulfides were transformed into dihydrobenzothiepines in 30-95 % yield, and 2-alkynylaryl 2-tolyl sulfides were converted into dibenzo[b,f]thiepines in 57-95 % yield along with double bond isomerization. In both reactions, the combination of Ir catalyst and sulfide moiety was a key to the facile cyclization.

Palladium-Catalyzed Branch- and Z-Selective Allylic C-H Amination with Aromatic Amines.

Allylamines are important building blocks in the synthesis of bioactive compounds. The direct coupling of allylic C-H bonds and commonly available amines is a major synthetic challenge. An allylic C-H amination of 1,4-dienes has been accomplished by palladium catalysis. With aromatic amines, branch-selective allylic aminations are favored to generate thermodynamically unstable Z-allylamines. In addition, more basic aliphatic cyclic amines can also engage in the reaction, but linear dienyl allylic amines are the major products.

Cooperative Catalyst-Enabled Regio- and Stereodivergent Synthesis of α-Quaternary α-Amino Acids via Asymmetric Allylic Alkylation of Aldimine Esters with Racemic Allylic Alcohols.

We describe cooperative bimetallic catalysis that enables regio-/stereodivergent asymmetric α-allylations of aldimine esters. By employing Et3 B as the key activator, racemic allylic alcohols can be directly ionized to form Pd or Ir-π-allyl species in the presence of achiral Pd or chiral Ir complexes, respectively. The less or more substituted allylic termini of the metal-π-allyl species are amenable to nucleophilic attack by the chiral Cu-azomethine ylide, the formation of which is simultaneously facilitated by Et3 B, affording α-quaternary α-amino acids with high regioselectivity and excellent stereoselectivity. The use of readily available allylic alcohols as electrophilic precursors represents an improvement from an environmental and atom/step economy perspective. Computational mechanistic studies reveal the crucial role of the Et3 B additive and the origins of stereo- and regioselectivities by analyzing steric effects, dispersion interactions, and frontier orbital population.

Metal-Free Regioselective Hydrophosphorodithioation of Spirovinylcyclopropyl Oxindoles: Rapid Access to Allyl Dialkylphosphorodithioates.

Phosphorodithioates are important substructures due to their great use in bioactive compounds and functional materials. A metal-free 1,5-addition of spirovinylcyclopropyl oxindoles have been developed by choosing P4S10 and alcohol as nucleophiles through the regioselective ring-opening of spirovinylcyclopropyl oxindoles. This method provides access to allylic organothiophosphates with high efficiency, wide functional group tolerance, good chemo- and regioselectivity, and E-selectivity. 1,3-Addition products were also prepared in high yield. Furthermore, the resulting organothiophosphates could be readily transformed into other allylic derivatives.

Enantioselective and Diastereodivergent Allylation of Propargylic C-H Bonds.

An iridium-catalyzed stereoselective coupling of allylic ethers and alkynes to generate 3,4-substituted 1,5-enynes is reported. Under optimized conditions, the coupling products are formed with excellent regio-, diastereo-, and enantioselectivities, and the protocol is functional group tolerant. Moreover, we report conditions that allow the reaction to proceed with complete reversal of diastereoselectivity. Mechanistic studies are consistent with an unprecedented dual role for the iridium catalyst, enabling the propargylic deprotonation of the alkyne through π-coordination, as well as the generation of a π-allyl species from the allylic ether starting material.

Highly diastereo- and enantioselective synthesis of multisubstituted allylic amino acid derivatives by allylic alkylation of a chiral glycine-based nickel complex and vinylethylene carbonates.

The asymmetric synthesis of multisubstituted allylic amino acid derivatives was accomplished by the allylic alkylation of a chiral glycine-based nickel complex with vinylethylene carbonates. High enantioselectivities and diastereoselectivities were obtained under mild reaction conditions. The gram-scale synthesis was carried out with a good yield and high enantioselectivity, indicating that the method is a highly efficient route to chiral multisubstituted allylic amino acid derivatives.

Palladium-Catalyzed Regiodivergent Synthesis of 1,3-Dienyl and Allyl Esters from Propargyl Esters.

Catalyst-controlled regiodivergent catalysis is a vital chemical tool that allows efficient access to large collections of structurally diverse molecules from a common precursor but remains a challenge. We report a catalyst-controlled, tunable, and predictable regiodivergency in transforming the internal aliphatic propargyl esters into diverse libraries of highly substituted 1,3-dienyl and allyl products by Pd-catalysis. Depending on the ligand employed, the palladium catalyst can involve two typical approaches: electrophilic palladium catalysis and a sequential oxidative addition-reductive elimination pathway. This regiodivergent protocol endows facile access to four regioisomers with high regio- and stereoselectivity from the common propargyl esters. In terms of synthetic utility, a notable feature of this protocol is amenable to structural diversification of bioactive relevant molecules, enabling rapid assembly of many useful structural analogs of pharmaceutical candidates.

Iridium-catalyzed asymmetric double allylic alkylation of azlactone: efficient access to chiral α-amino acid derivatives.

An unprecedented Ir-catalyzed enantioselective double allylic alkylation of less bulky cyclic imine glycinate (azlactone) was rationally designed and developed, providing various bisallylated chiral amino acid derivatives. Control experiments revealed that this transformation proceeds in a sequential manner featuring quasi-dynamic kinetic resolution of the initially-formed monoallylation intermediates.

Enzyme-like catalysis by single chain nanoparticles that use transition metal cofactors.

We report a modular approach in which a noncovalently cross-linked single chain nanoparticle (SCNP) selectively binds catalyst "cofactors" and substrates to increase both the catalytic activity of a Cu-catalyzed alkyne-azide cycloaddition reaction and the Ru-catalyzed cleavage of allylcarbamate groups compared to the free catalysts.

Diallyl Trisulfide, the Antifungal Component of Garlic Essential Oil and the Bioactivity of Its Nanoemulsions Formed by Spontaneous Emulsification.

The aim of this study was to evaluate the chemical compounds of garlic essential oil (EO), and determine the antifungal efficacy of garlic EO and its major components, diallyl trisulfide and its nanoemulsions against wood-rotting fungi, Trametes hirsuta and Laetiporus sulphureus. GC-MS analysis revealed that the major constituents of garlic EO were diallyl trisulfide (39.79%), diallyl disulfide (32.91%), and diallyl sulfide (7.02%). In antifungal activity, the IC50 value of garlic EO against T. hirsuta and L. sulphureus were 137.3 and 44.6 µg/mL, respectively. Results from the antifungal tests demonstrated that the three major constituents were shown to have good antifungal activity, in which, diallyl trisulfide was the most effective against T. hirsuta and L. sulphureus, with the IC50 values of 56.1 and 31.6 µg/mL, respectively. The diallyl trisulfide nanoemulsions showed high antifungal efficacy against the examined wood-rotting fungi, and as the amount of diallyl trisulfide in the lipid phase increases, the antifungal efficacy of the nanoemulsions increases. These results showed that the nanoemulsions and normal emulsion of diallyl trisulfide have potential to develop into a natural wood preservative.

Overhauser Dynamic Nuclear Polarization with Selectively Deuterated BDPA Radicals.

The Overhauser effect (OE), commonly observed in NMR spectra of liquids and conducting solids, was recently discovered in insulating solids doped with the radical 1,3-bisdiphenylene-2-phenylallyl (BDPA). However, the mechanism of polarization transfer in OE-DNP in insulators is yet to be established, but hyperfine coupling of the radical to protons in BDPA has been proposed. In this paper we present a study that addresses the role of hyperfine couplings via the EPR and DNP measurements on some selectively deuterated BDPA radicals synthesized for this purpose. Newly developed synthetic routes enable selective deuteration at orthogonal positions or perdeuteration of the fluorene moieties with 2H incorporation of >93%. The fluorene moieties were subsequently used to synthesize two octadeuterated BDPA radicals, 1,3-[α,γ-d8]-BDPA and 1,3-[ß,δ-d8]-BDPA, and a BDPA radical with perdeuterated fluorene moieties, 1,3-[α,ß,γ,δ-d16]-BDPA. In contrast to the strong positive OE enhancement observed in degassed samples of fully protonated h21-BDPA (ε ∼ +70), perdeuteration of the fluorenes results in a negative enhancement (ε ∼ -13), while selective deuteration of α- and γ-positions (aiso ∼ 5.4 MHz) in BDPA results in a weak negative OE enhancement (ε ∼ -1). Furthermore, deuteration of ß- and δ-positions (aiso ∼ 1.2 MHz) results in a positive OE enhancement (ε ∼ +36), albeit with a reduced magnitude relative to that observed in fully protonated BDPA. Our results clearly show the role of the hyperfine coupled α and γ 1H spins in the BDPA radical in determining the dominance of the zero and double-quantum cross-relaxation pathways and the polarization-transfer mechanism to the bulk matrix.

Synthesis of mixed chitin esters with long fatty and bulky acyl substituents in ionic liquid.

This study revealed that mixed chitin esters with long fatty and bulky acyl substituents were efficiently synthesized by acylation using acyl chlorides in the presence of pyridine and N,N-dimethyl-4-aminopyridine in an ionic liquid, 1-allyl-3-methylimidazolium bromide (AMIMBr), at 100 °C for 24 h. A stearoyl group was selected as the first substituent, which was combined with different long fatty and bulky acyl groups as the second substituents. In addition to IR analysis of the products, which suggested progress of the acylation, 1H NMR measurement was allowed for structural confirmation for high degrees of substitution (DSs) of the desired derivatives in CDCl3/CF3CO2H solvents. Crystalline structures and thermal property of the products were evaluated by powder X-ray diffraction and differential scanning calorimetry measurements, respectively. All the products showed film formability by casting from solutions in chloroform or chloroform/trifluoroacetic acid solvents. The occurrence of halogen exchange between acyl chlorides and AMIMBr in the present system was speculated to produce highly reactive acyl bromides in situ, which efficiently reacted with hydroxy groups in chitin to obtain high DS products.

Direct access to spirocycles by Pd/WingPhos-catalyzed enantioselective cycloaddition of 1,3-enynes.

Spirocycles play an important role in drug discovery and development. The direct, catalytic, and enantioselective synthesis of spirocycles from readily available starting materials and in an atom economic manner remains a highly sought-after task in organic synthesis. Herein, an enantioselective Pd-hydride-catalyzed cycloaddition method for the synthesis of spirocyclic compounds directly from two classes of commonly available starting materials, 1,3-enynes and cyclic carbon-hydrogen (C-H) bonds, is reported. The reactions employ a chiral Pd/WingPhos catalyst to both suppress the formation of bis-allenyl by-products and control the stereoselectivity. 1,3-Enynes are used as dielectrophilic four-carbon units in the cycloaddition reactions, which also enables an enyne substrate-directed enantioselectivity switch with good levels of stereocontrol. The present spirocycle synthesis tolerates a broad range of functional groups of 1,3-enyne substrates, including alcohols, esters, nitriles, halides, and olefins. A variety of diverse cyclic nucleophiles, including pharmaceutically important heterocycles and carbocycles, can be flexibly incorporated with spiro scaffolds.

A convenient synthesis of branched-chain nucleoside isothiocyanates via aza-Claisen rearrangement.

Stereocontrolled introduction of a nitrogen atom at either C-2' or C-3' positions of nucleosides derived from uridine, 4-N-benzoylcytidine and adenosine was investigated. An efficient and rapid procedure was employed for creating new chiral centers at C-2' and C-3' positions using [3,3]-sigmatropic aza-Claisen rearrangement of allyl thiocyanates under conventional and microwave conditions. Structure of isothiocyanate products was confirmed by 1-D and 2-D NMR spectral analyses including selective 1H 1-D-NOE experiments.

Characterization the structural property and degradation behavior of corn starch in KOH/thiourea aqueous solution.

Finding an efficient and eco-friendly solution for starch dissolution has attracted considerable attentions in recent years. This study investigated the structural characteristics, and degradation behavior of corn starch in KOH/thiourea aqueous solution by the comparison with DMSO/LiBr and 1-allyl-3-methylimidazolium chloride (AMIMCl). Results showed that KOH/thiourea solution was an effective solvent for corn starch dissolution (30 min with 97.01% solubility). X-ray diffraction (XRD) and 13C CP-MAS NMR spectroscopy revealed that native crystallinity of the corn starch was altered by all tested solvents, especially DMSO/LiBr and AMIMCl. Conversely, this new solvent did not change the primary molecular structure, chain-length distribution, or thermal stability of starch, compared with the native starch. Furthermore, KOH/thiourea solution was more suitable for measuring the molecular weight of corn starch, with a weight-average molecular weight (Mw) of 7.18 × 107 g/mol. Therefore, KOH/thiourea solution is a promising novel solvent for starch dissolution and structural exploration.

Interest of Homodialkyl Neamine Derivatives against Resistant P. aeruginosa, E. coli, and ß-Lactamases-Producing Bacteria-Effect of Alkyl Chain Length on the Interaction with LPS.

Development of novel therapeutics to treat antibiotic-resistant infections, especially those caused by ESKAPE pathogens, is urgent. One of the most critical pathogens is P. aeruginosa, which is able to develop a large number of factors associated with antibiotic resistance, including high level of impermeability. Gram-negative bacteria are protected from the environment by an asymmetric Outer Membrane primarily composed of lipopolysaccharides (LPS) at the outer leaflet and phospholipids in the inner leaflet. Based on a large hemi-synthesis program focusing on amphiphilic aminoglycoside derivatives, we extend the antimicrobial activity of 3',6-dinonyl neamine and its branched isomer, 3',6-di(dimethyloctyl) neamine on clinical P. aeruginosa, ESBL, and carbapenemase strains. We also investigated the capacity of 3',6-homodialkyl neamine derivatives carrying different alkyl chains (C7-C11) to interact with LPS and alter membrane permeability. 3',6-Dinonyl neamine and its branched isomer, 3',6-di(dimethyloctyl) neamine showed low MICs on clinical P. aeruginosa, ESBL, and carbapenemase strains with no MIC increase for long-duration incubation. In contrast from what was observed for membrane permeability, length of alkyl chains was critical for the capacity of 3',6-homodialkyl neamine derivatives to bind to LPS. We demonstrated the high antibacterial potential of the amphiphilic neamine derivatives in the fight against ESKAPE pathogens and pointed out some particular characteristics making the 3',6-dinonyl- and 3',6-di(dimethyloctyl)-neamine derivatives the best candidates for further development.

Enantioselective Lactonization by π-Acid-Catalyzed Allylic Substitution: A Complement to π-Allylmetal Chemistry.

Asymmetric allylic alkylation (AAA) is a powerful method for the formation of highly useful, non-racemic allylic compounds. Here we present a complementary enantioselective process that generates allylic lactones via π-acid catalysis. More specifically, a catalytic enantioselective dehydrative lactonization of allylic alcohols using a novel PdII -catalyst containing the imidazole-based P,N-ligand (S)-StackPhos is reported. The high-yielding reactions are operationally simple to perform with enantioselectivities up to 99 % ee. This strategy facilitates the replacement of a poor leaving group with what would ostensibly be a better leaving group in the product avoiding complications arising from racemization by equilibration.