Discovery of Pesticide Candidates from Natural Plant Products: Semisynthesis and Characterization of Andrographolide-Based Esters and Study of Their Pesticidal Properties and Toxicology.

To explore the use of nonfood plant-derived secondary metabolites for plant protection, a series of ester derivatives for controlling the major migratory agricultural pests were obtained by structural modification of andrographolide, a labdane diterpenoid isolated from Andrographis paniculata. Compound Id showed good insecticidal activity against the fall armyworm Spodoptera frugiperda Smith. Compounds IIa (LC50: 0.382 mg/mL) and IIIc (LC50: 0.563 mg/mL), the acaricidal activities of which were, respectively, 13.1 and 8.9 times that of andrographolide (LC50: 4.996 mg/mL), exhibited strong acaricidal and control effects against Tetranychus cinnabarinus Boisduval. Against Aphis citricola Van der Goot, compounds IIIc and IVb displayed 3.9- and 3.7-fold pronounced aphicidal activity of andrographolide. Effects of compound Id on three protective enzymes (superoxide dismutase, peroxidase, and catalase) of S. frugiperda were also observed. The obvious differences of epidermal cuticle structures of mites treated with compound IIa were determined by scanning electron microscopy. Structure-activity relationships indicated that 14-ester derivatives of andrographolide showed potential insecticidal/acaricidal activities and can be further utilized as lead compounds.

Sucrose ester embedded lipid carrier for DNA delivery.

Sucrose esters (SEs) have great potential in the field of nucleic acid delivery due to their unique physical and chemical properties and good biosafety. However, the mechanism of the effect of SEs structure on delivery efficiency has not been studied. The liposomes containing peptide lipids and SEs were constructed, and the effects of SEs on the interaction between the liposomes and DNA were studied. The addition of SEs affects the binding rate of liposomes to DNA, and the binding rate gradually decreases with the increase of SEs' carbon chain length. SEs also affect the binding site and affinity of liposomes to DNA, promoting the aggregation of lipids to form liposomes, where DNA wraps around or compresses inside the liposomes, allowing it to compress DNA without damaging the DNA structure. COL-6, which is composed of sucrose laurate, exhibits the optimal affinity for DNA, and SE promotes the formation of ordered membrane structure and enhances membrane stability, so that COL-6 exhibits a balance between rigidity and flexibility, and thus exhibits the highest delivery efficiency of DNA among these formulations. This work provides theoretical foundations for the application of SE in gene delivery and guides for the rational design of delivery systems.

Cellulose esters: Synthesis for further formation of films with magnetite nanoparticles incorporated.

This study investigated the homogeneous synthesis of cellulose acetate (CA) and propionate (CP) with varying degrees of substitution (DS) from sisal cellulose in a N, N-dimethylacetamide/lithium chloride (DMAc/LiCl) solvent system. These esters were used to prepare neat (CADSF/CPDSF) and nanocomposite films (CADSFFe/CPDSFFe) from prior synthesized magnetite nanoparticles (NPs, Fe3O4, 5.1 ± 0.5 nm). Among the CA and CP series, the composite CA0.7FFe and the neat CP0.7F films exhibited the highest modulus of elasticity, 2105 MPa and 2768 MPa, respectively, probably a consequence of the continuous fibrous structures present on the surface of these films. Microsphere formation on the film's surface was observed in scanning electron microscopy micrographs. This points to applications in the controlled release of targeted substances. The VSM analysis showed that the cellulosic matrices preserved the superparamagnetic characteristics of the NPs. This study suggested a reduced coupling effect between nanoparticles inside polymeric films due to magnetic saturation at low fields. CA0.7FFe and CA1.3FFe composite films reached a saturation magnetization (MSAT) of 46 emu/g around 7 kOe field. Hosting magnetite nanoparticles in cellulose ester matrices may be an interesting way to develop new functional cellulose-based materials, which have the potential for diverse applications, including microelectromechanical systems and microsensors.

Insight into the Feasibility of Fatty Acyl Chlorides with 10-18 Carbons for the Ball-Milling Synthesis of Thermoplastic Cellulose Esters.

Fatty acid cellulose esters (FACE) are common cellulose-based thermoplastics, and their thermoplasticity is determined by both the contents and the lengths of the side chains. Herein, various FACE were synthesized by the ball-milling esterification of cellulose and fatty acyl chlorides containing 10-18 carbons, and their structures and thermoplasticity were thoroughly studied. The results showed that FACE with high degrees of substitution (DS) and low melting flow temperatures (Tf) were achieved as the chain lengths of the fatty acyl chlorides were reduced. In particular, a cellulose decanoate with a DS of 1.85 and a Tf of 186 °C was achieved by feeding 3 mol of decanoyl chloride per mole anhydroglucose units of cellulose. However, cellulose stearate (DS = 1.53) synthesized by the same protocols cannot melt even at 250 °C. More interestingly, the fatty acyl chlorides with 10 and 12 carbons resulted in FACE with superior toughness (elongation at break up to 94.4%). In contrast, due to their potential crystallization of the fatty acyl groups with 14-18 carbons, the corresponding FACE showed higher tensile strength and Young's modulus than the others. This study provides some theoretical basis for the mechanochemical synthesis of thermoplastic FACE with designated properties.

Determination of the binding affinities of OPEs to integrin αvß3 and elucidation of the underlying mechanisms via a competitive binding assay, pharmacophore modeling, molecular docking and QSAR modeling.

Organophosphate esters (OPEs) can cause adverse biological effects through binding to integrin αvß3. However, few studies have focused on the binding activity and mechanism of OPEs to integrin αvß3. Herein, a comprehensive investigation of the mechanisms by which OPEs bind to integrin αvß3 and determination of the binding affinity were conducted by in vitro and in silico approaches: competitive binding assay as well as pharmacophore, molecular docking and QSAR modeling. The results showed that all 18 OPEs exhibited binding activities to integrin αvß3; moreover, hydrogen bonds were identified as crucial intermolecular interactions. In addition, essential factors, including the -P = O structure of OPEs, key amino acid residues and suitable cavity volume of integrin αvß3, were identified to contribute to the formation of hydrogen bonds. Moreover, aryl-OPEs exhibited a lower binding activity with integrin αvß3 than halogenated- and alkyl-OPEs. Ultimately, the QSAR model constructed in this study was effectively used to predict the binding affinity of OPEs to integrin αvß3, and the results suggest that some OPEs might pose potential risks in aquatic environments. The results of this study comprehensively elucidated the binding mechanism of OPEs to integrin αvß3, and supported the environmental risk management of these emerging pollutants.

Ring Opening Polymerization of Six- and Eight-Membered Racemic Cyclic Esters for Biodegradable Materials.

The low percentage of recyclability of the polymeric materials obtained by olefin transition metal (TM) polymerization catalysis has increased the interest in their substitution with more eco-friendly materials with reliable physical and mechanical properties. Among the variety of known biodegradable polymers, linear aliphatic polyesters produced by ring-opening polymerization (ROP) of cyclic esters occupy a prominent position. The polymer properties are highly dependent on the macromolecule microstructure, and the control of stereoselectivity is necessary for providing materials with precise and finely tuned properties. In this review, we aim to outline the main synthetic routes, the physical properties and also the applications of three commercially available biodegradable materials: Polylactic acid (PLA), Poly(Lactic-co-Glycolic Acid) (PLGA), and Poly(3-hydroxybutyrate) (P3HB), all of three easily accessible via ROP. In this framework, understanding the origin of enantioselectivity and the factors that determine it is then crucial for the development of materials with suitable thermal and mechanical properties.

Synthesis and biodegradation testing of some synthetic oils based on ester.

Synthetic ester oils are widely used in many applications due to their ideal cleaning properties, lubricating performance and assured polarity. The majority of esters oils are more biodegradable. than any other base stock. For instance, oil soluble polyalkyleneglycols (PAGs) or polyalphaolephins (PAOs), are only biodegradable in the lower viscosity grades. The goal of this study is to create some synthetic base oils by two major protocols; the first is esterifying valeric acid with various glycols (ethylene glycol, propylene glycol, butylene glycol and poly (ethylene glycol 400). The second involves esterification of propanoic acid, heptanoic acid, or octanoic acid with ethylene glycol. The reaction yield varies between 85 and 94%. The chemical composition of the prepared esters was examined using various spectroscopic methods (Fourier-transform infrared (FT-IR) and proton nuclear magnetic resonance (1H-NMR) spectroscopy. The thermal properties investigation by thermo gravimetric analysis (TGA) showed pronounced thermal stability of the prepared esters. The biodegradability was verified versus two bacterial isolates (B1, B2). The results showed that percentage of degradation of the lube oil was in the range of 34% to 84% after 3 days of incubation. Moreover, the rheological study revealed that the prepared esters exhibited Newtonian rheological behaviours. Viscosity examination displayed that the esters based on ethylene glycol, such as (A), had the highest VI: 179 values when compared to those based on higher glycols. Viscosity and viscosity index results showed slight increase as the number of carbon atoms in the acid chain increases. At last, most of the synthesized esters possessed pour points ≤ - 32 °C: ≤ - 40 except in case of using higher acids like heptanoic acid and octanoic acid in preparation the pour point increases to - 9 °C and - 15 °C.

Gas-Phase Ion/Ion Reactions to Enable Radical-Directed Dissociation of Fatty Acid Ions: Application to Localization of Methyl Branching.

Methyl branching on the carbon chains of fatty acids and fatty esters is among the structural variations encountered with fatty acids and fatty esters. Branching in fatty acid/ester chains is particularly prominent in bacterial species and, for example, in vernix caseosa and sebum. The distinction of branched chains from isomeric straight-chain species and the localization of branching can be challenging to determine by mass spectrometry (MS). Condensed-phase derivatization strategies, often used in conjunction with separations, are most commonly used to address the identification and characterization of branched fatty acids. In this work, a gas-phase ion/ion strategy is presented that obviates condensed-phase derivatization and introduces a radical site into fatty acid ions to facilitate radical-directed dissociation (RDD). The gas-phase approach is also directly amenable to fatty acid anions generated via collision-induced dissociation from lipid classes that contain fatty esters. Specifically, divalent magnesium complexes bound to two terpyridine ligands that each incorporate a ((2,2,6,6-tetramethyl-1-piperidine-1-yl)oxy) (TEMPO) moiety are used to charge-invert fatty acid anions. Following the facile loss of one of the ligands and the TEMPO group of the remaining ligand, a radical site is introduced into the complex. Subsequent collision-induced dissociation (CID) of the complex exhibits preferred cleavages that localize the site(s) of branching. The approach is illustrated with iso-, anteiso-, and isoprenoid branched-chain fatty acids and an intact glycerophospholipid and is applied to a mixture of branched- and straight-chain fatty acids derived from Bacillus subtilis.

Optimizing the enzymatic production of biolubricants by the Taguchi method: Esterification of the free fatty acids from castor oil with 2-ethyl-1-hexanol catalyzed by Eversa Transform 2.0.

The solvent-free esterification of the free fatty acids (FFAs) obtained by the hydrolysis of castor oil (a non-edible vegetable oil) with 2-ethyl-1-hexanol (a branched fatty alcohol) was catalyzed by different free lipases. Eversa Transform 2.0 (ETL) features surpassed most commercial lipases. Some process parameters were optimized by the Taguchi method (L16'). As a result, a conversion over 95% of the FFAs of castor oil into esters with lubricants properties was achieved under optimized reaction conditions (15 wt% of biocatalyst content, 1:4 molar ratio (FFAs/alcohol), 30 °C, 180 rpm, 96 h). The substrates molar ratio had the highest influence on the dependent variable (conversion at 24 h). FFAs/2-ethyl-1-hexanol esters were characterized regarding the physicochemical and tribological properties. Interestingly, the modification of the FFAs with 2-ethyl-1-hexanol by ETL increased the oxidative stability of the FFAs feedstock from 0.18 h to 16.83 h. The biolubricants presented a lower friction coefficient than the reference commercial mineral lubricant (0.052 ± 0.07 against 0.078 ± 0.04). Under these conditions, ETL catalyzed the oligomerization of ricinoleic acid (a hydroxyl fatty acid) into estolides, reaching a conversion of 25.15% of the initial FFAs (for the first time).

Biocatalytic Regioselective O-acylation of Sesquiterpene Lactones from Chicory: A Pathway to Novel Ester Derivatives.

We report the first biocatalytic modification of sesquiterpene lactones (STLs) found in the chicory plants, specifically lactucin (Lc), 11ß,13-dihydrolactucin (DHLc), lactucopicrin (Lp), and 11ß,13-dihydrolactucopicrin (DHLp). The selective O-acylation of their primary alcohol group was carried out by the lipase B from Candida antarctica (CAL-B) using various aliphatic vinyl esters as acyl donors. Perillyl alcohol, a simpler monoterpenoid, served as a model to set up the desired O-acetylation reaction by comparing the use of acetic acid and vinyl acetate as acyl donors. Similar conditions were then applied to DHLc, where five novel ester chains were selectively introduced onto the primary alcohol group, with conversions going from >99 % (acetate and propionate) to 69 % (octanoate). The synthesis of the corresponding O-acetyl esters of Lc, Lp, and DHLp was also successfully achieved with near-quantitative conversion. Molecular docking simulations were then performed to elucidate the preferred enzyme-substrate binding modes in the acylation reactions with STLs, as well as to understand their interactions with crucial amino acid residues at the active site. Our methodology enables the selective O-acylation of the primary alcohol group in four different STLs, offering possibilities for synthesizing novel derivatives with significant potential applications in pharmaceuticals or as biocontrol agents.

Enhanced gene transfection and induction of apoptosis in melanoma cells by branched poly(ß-amino ester)s with uniformly distributed branching units.

Melanoma, one of the most devastating forms of skin cancer, currently lacks effective clinical treatments. Delivery of functional genes to modulate specific protein expression to induce melanoma cell apoptosis could be a promising therapeutic approach. However, transfecting melanoma cells using non-viral methods, particularly with cationic polymers, presents significant challenges. In this study, we synthesized three branched poly(ß-amino ester)s (HPAEs) with evenly distributed branching units but varying space lengths through a two-step "oligomer combination" strategy. The unique topological structure enables HPAEs to condense DNA to form nano-sized polyplexes with favorable physiochemical properties. Notably, HPAEs, especially HPAE-2 with intermediate branching unit space length, demonstrated significantly higher gene transfection efficiency than the leading commercial gene transfection reagent, jetPRIME, in human melanoma cells. Furthermore, HPAE-2 efficiently delivered the Bax-encoding plasmid into melanoma cells, leading to a pronounced pro-apoptotic effect without causing noticeable cytotoxicity. This study establishes a potent non-viral platform for gene transfection of melanoma cells by harnessing the distribution of branching units, paving the way for potential clinical applications of gene therapy in melanoma treatment.

Comparative study on the enzymatic degradation of phenolic esters: The HPLC-UV quantification of tyrosol and gallic acid liberated from tyrosol acyl esters and alkyl gallates by hydrolytic enzymes.

HPLC-UV analysis was used to evaluate the enzymatic degradation characteristics of tyrosol acyl esters (TYr-Es) and alkyl gallates (A-GAs). Among various hydrolytic enzymes, TYr-Es can be hydrolyzed by pancrelipase, while A-GAs cannot be hydrolyzed by pancrelipase. Interestingly, carboxylesterase-1b (CES-1b), carboxylesterase-1c (CES-1c) and carboxylesterase-2 (CES-2) are able to hydrolyze TYr-Es and A-GAs, and thus to liberate tyrosol (TYr) and gallic acid (GA). By contrast, the degrees of hydrolysis (DHs) of TYr-Es and A-GAs by CES-1b and CES-1c were significantly higher than those by CES-2. Meanwhile, the DHs of TYr-Es were much higher than those of A-GAs. Especially, the DHs firstly increased and then decreased with the increasing alkyl chain length. Besides, DHs positively correlated with the unsaturation degree at the same chain length. Through regulating carbon length, unsaturation degree and the ester bond structure, controlled-release of phenolic compounds and fatty acids (or fatty alcohols) from phenolic esters will be easily achieved.

Single step synthesis of ß- and γ- aryl-substituted ß- and γ-amino acid derivatives by electrochemistry.

Electrochemical transformations are a subject of increasing interest in early drug discovery due to its ability to assemble complex scaffolds under rather mild reaction conditions. In this context, we became interested in electrochemical decarboxylative cross-coupling (DCC) protocols of redox-active esters (RAEs) and halo(hetero)arenes. Starting with the one-step electrochemical synthesis of novel methylamino-substituted heterocycles we recognized the potential of this methodology to deliver a novel approach to ß- and γ- amino acids by starting from the corresponding RAEs. Our work finally resulted in the delivery of novel and highly valuable trifunctional building blocks based on ß- and γ-amino-acid scaffolds.

A facile approach for incorporating tyrosine esters to probe ion-binding sites and backbone hydrogen bonds.

Amide-to-ester substitutions are used to study the role of the amide bonds of the protein backbone in protein structure, function, and folding. An amber suppressor tRNA/synthetase pair has been reported for incorporation of p-hydroxy-phenyl-L-lactic acid (HPLA), thereby introducing ester substitution at tyrosine residues. However, the application of this approach was limited due to the low yields of the modified proteins and the high cost of HPLA. Here we report the in vivo generation of HPLA from the significantly cheaper phenyl-L-lactic acid. We also construct an optimized plasmid with the HPLA suppressor tRNA/synthetase pair that provides higher yields of the modified proteins. The combination of the new plasmid and the in-situ generation of HPLA provides a facile and economical approach for introducing tyrosine ester substitutions. We demonstrate the utility of this approach by introducing tyrosine ester substitutions into the K+ channel KcsA and the integral membrane enzyme GlpG. We introduce the tyrosine ester in the selectivity filter of the M96V mutant of the KcsA to probe the role of the second ion binding site in the conformation of the selectivity filter and the process of inactivation. We use tyrosine ester substitutions in GlpG to perturb backbone H-bonds to investigate the contribution of these H-bonds to membrane protein stability. We anticipate that the approach developed in this study will facilitate further investigations using tyrosine ester substitutions.

Reverse metabolomics for the discovery of chemical structures from humans.

Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis1,2, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4+ T cells3 and agonism of the pregnane X receptor4. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.

Modulating the hydrophobicity of cellulose by lipase-catalyzed transesterification.

The production of hydrophobic and oil resistant cellulosic fibers usually requires severe chemical treatments and generates toxic by-products. Alternative approaches such as biocatalysis use milder conditions; lipase-catalyzed methods for grafting nanocellulose with hydrophobic ester moieties have been reported. Here, we investigate the lipase-catalyzed esterification of cellulose fibers, in native form or pretreated with 1,4-ß-glucanases, and cellulose nanocrystals (CNC) in solvent-free conditions. The fibers were compared for degree of ester formation after incubation with methyl myristate and lipase at 50 °C. After washing, the grafting of fatty esters on cellulose was confirmed by ATR-FTIR and the degree of substitution determined by 13C CP/MAS NMR (from 0.04 up to DS 0.1) confirming successful esterification. Optical photothermal infrared (O-PTIR) spectroscopy showed strongly localized presence of ester moieties on cellulose. Functional properties mirrored the degree of substitution of the cellulose materials whereby cellulose esters made with glucanase-pretreatment produced the highest water contact angle of 117° ± 9 and esterified cellulose blended at 10 % w/w content in paper composites showed significant differences in hydrophobicity and lipophilicity compared to plain paper. The esterification of cellulose was completely reversed by lipase treatment in aqueous media. These ester-functionalized fibers show potential in a wide range of packaging applications.

Inhibitory effects of phthalate esters (PAEs) and phthalate monoesters towards human carboxylesterases (CESs).

Phthalate esters (PAEs), accompanied by phthalate monoesters as hydrolysis metabolites in humans, have been widely used as plasticizers and exhibited disruptive effects on the endocrine and metabolic systems. The present study aims to investigate the inhibition behavior of PAEs and phthalate monoesters on the activity of the important hydrolytic enzymes, carboxylesterases (CESs), to elucidate the toxicity mechanism from a new perspective. The results showed significant inhibition on CES1 and CES2 by most PAEs, but not by phthalate monoesters, above which the activity of CES1 was strongly inhibited by DCHP, DEHP, DiOP, DiPP, DNP, DPP and BBZP, with inhibition ratios exceeding 80%. Kinetic analyses and in vitro-in vivo extrapolation were conducted, revealing that PAEs have the potential to disrupt the metabolism of endogenous substances catalyzed by CES1 in vivo. Molecular docking results revealed that hydrogen bonds and hydrophobic contacts formed by ester bonds contributed to the interaction of PAEs towards CES1. These findings will be beneficial for understanding the adverse effect of PAEs and phthalate monoesters.

Structural analysis of polyglycerol fatty acid ester-coenzyme Q10 aggregates in solution.

Polyglycerol fatty acid esters (PGFEs) are common food additives. PGFE-based formulations exhibit high structural stability, however, the stability mechanism of the micellar structures has not been yet elucidated. In this study, nanostructural analysis was performed using small-angle neutron and X-ray scattering (SANS and SAXS) measurements to reveal the mechanism of the structural stability of PGFE-coenzyme Q10 (CoQ10) mixtures as a CoQ10 formulation. Pure PGFE formed multilamellar vesicles, whereas PGFE-CoQ10 formed spherical micelles. Furthermore, when the amount of added water increased, the PGFE-CoQ10 micellar size and the amount of water in the micelles remained unchanged. A model-fitting analysis of the SANS results suggested that the CoQ10 molecules were introduced between the surfactants, forming a palisade-type structure. The high structural stability of the PGFE-CoQ10 micelles was attributed to two factors: proper spreading of the hydrophilic head chains and inhibition of the change of the amount of water inside the micelles by the PGFE heads and quinone ring of CoQ10. This indicates that PGFE-CoQ10 can function in water while maintaining the micellar structure formed in the storage solution. The findings of this study are important for the safety and nano-hazard aspects of PGFE-CoQ10 formulations.

A Chemo-Enzymatic Cascade Strategy for the Synthesis of Phosphatidylcholine Incorporated with Structurally Diverse FAHFAs.

Fatty acid esters of hydroxy fatty acids (FAHFAs), a newly discovered class of human endogenous complex lipids showing great promise for treating diabetes and inflammatory diseases, exist naturally in extremely low concentrations. This work reports a chemo-enzymatic approach for the comprehensive synthesis of phospholipids containing FAHFAs via sequential steps: hydratase-catalyzed hydration of unsaturated fatty acids to generate structurally diverse hydroxy fatty acids (HFAs), followed by the selective esterification of these HFAs with fatty acids mediated by secondary alcohol-specific Candida antarctica lipase A (CALA), resulting in the formation of a series of diverse FAHFA analogs. The final synthesis is completed through carbodiimide-based coupling of FAHFAs with glycerophosphatidylcholine. Optimal reaction conditions are identified for each step, and the substrate affinity of CALA, responsible for the catalytic mechanisms during FAHFA production, is evaluated through molecular docking. Compared to multistep lab-tedious chemical synthesis, this route, relying on natural building blocks and natural biocatalysts, is significantly facile, scalable, and highly selective, affording high yields (74-98 mol %) in each step for the construction of higher FAHFA-PC series (10/12/13-FAHFAs). The developed strategy aims to increase the availability of naturally occurring FAHFA species and provide the tools for the construction of versatile and novel analogs of FAHFA conjugates.

[Development of Unactivated Bond Cleavage Reactions Under Mild Conditions Based on Stabilization of Addition Intermediates].

Cleavage of unactivated bonds, such as amides, often requires challenging reaction conditions with strong acids and bases, and the tolerance of functional groups is limited. Therefore, the development of cleavage reactions for unactivated bonds under mild reaction conditions is essential. Herein, I report our recent developments in the cleavage of unactivated bonds under mild conditions. We achieved cleavage of unactivated amides, carbamates, ureas, and esters, as well as chemoselective cleavage of directing groups. Furthermore, we conducted mechanistic studies and found that these reactions proceed through the stabilization of addition intermediates.