Transaminase-Catalyzed Synthesis of ß-Branched Noncanonical Amino Acids Driven by a Lysine Amine Donor.

Transaminases are choice biocatalysts for the synthesis of chiral primary amines, including amino acids bearing contiguous stereocenters. In this study, we employ lysine as a "smart" amine donor in transaminase-catalyzed dynamic kinetic resolution reactions to access ß-branched noncanonical arylalanines. Our mechanistic investigation demonstrates that, upon transamination, the lysine-derived ketone byproduct readily cyclizes to a six-membered imine, driving the equilibrium in the desired direction and thus alleviating the need to load superstoichiometric quantities of the amine donor or deploy a multienzyme cascade. Lysine also shows good overall compatibility with a panel of wild-type transaminases, a promising hint of its application as a smart donor more broadly. Indeed, by this approach, we furnished a broad scope of ß-branched arylalanines, including some bearing hitherto intractable cyclopropyl and isopropyl substituents, with high yields and excellent selectivities.

Exploration the interaction of cadmium and copper toxic effects in pakchoi (Brassica chinensis L) roots through combinatorial transcriptomic and weighted gene co-expression network analysis.

The interaction between cadmium(Cd) and copper(Cu) during combined pollution can lead to more complex toxic effects on humans and plants.However, there is still a lack of sufficient understanding regarding the types of interactions at the plant molecular level and the response strategies of plants to combined pollution. To assess this, we investigated the phenotypic and transcriptomic patterns of pakchoi (Brassica chinensis L) roots in response to individual and combined pollution of Cd and Cu. The results showed that compared to single addition, the translocation factor of heavy metals in roots significantly decreased (p < 0.05) under the combined addition, resulting in higher accumulation of Cd and Cu in the roots. Transcriptomic analysis of pakchoi roots revealed that compared to single pollution, there were 312 and 1926 differentially expressed genes (DEGs) specifically regulated in the Cd2Cu20 and Cd2Cu100 combined treatments, respectively. By comparing the expression of these DEGs among different treatments, we found that the combined pollution of Cd and Cu mainly affected the transcriptome of the roots in an antagonistic manner. Enrichment analysis indicated that pakchoi roots upregulated the expression of genes involved in glucosetransferase activity, phospholipid homeostasis, proton transport, and the biosynthesis of phenylpropanoids and flavonoids to resist Cd and Cu combined pollution. Using weighted gene co-expression network analysis (WGCNA), we identified hub genes related to the accumulation of Cd and Cu in the roots, which mainly belonged to the LBD, thaumatin-like protein, ERF, MYB, WRKY, and TCP transcription factor families. This may reflect a transcription factor-driven trade-off strategy between heavy metal accumulation and growth in pakchoi roots. Additionally, compared to single metal pollution, the expression of genes related to Nramp, cation/H+ antiporters, and some belonging to the ABC transporter family in the pakchoi roots was significantly upregulated under combined pollution. This could lead to increased accumulation of Cd and Cu in the roots. These findings provide new insights into the interactions and toxic mechanisms of multiple metal combined pollution at the molecular level in plants.

Characteristics and health risks of population exposure to phthalates via the use of face towels.

The production of face towels is growing at an annual rate of about 4% in China, reaching 1.13 million tons by 2021. Phthalates (PAEs) are widely used in textiles, and face towels, as an important household textile, may expose people to PAEs via the skin, further leading to health risks. We collected new face towels and analyzed the distribution characterization of PAEs in them. The changes of PAEs were explored in a face towel use experiment and a simulated laundry experiment. Based on the use of face towels by 24 volunteers, we calculated the estimated daily intake (EDI) and comprehensively assessed the hazard quotient (HQ), hazard index (HI), and dermal cancer risk (DCR) of PAEs exposure in the population. PAEs were present in new face towels at total concentrations of

Nickel-Catalyzed Sulfonylation of Aryl Bromides Enabled by Potassium Metabisulfite as a Uniquely Effective SO2 Surrogate.

The development and mechanistic investigation of a nickel-catalyzed sulfonylation of aryl bromides is disclosed. The reaction proceeds in good yields for a variety of substrates and utilizes an inexpensive, stench-free, inorganic sulfur salt (K2 S2 O5 ) as a uniquely effective SO2 surrogate. The active oxidative addition complex was synthesized, isolated, and fully characterized by a combination of NMR spectroscopy and X-ray crystallography analysis. The use of the isolated oxidative addition complex in both stoichiometric and catalytic reactions revealed that SO2 insertion occurs via dissolved SO2 , likely released upon thermal decomposition of K2 S2 O5 . Key to the success of the reaction is the role of K2 S2 O5 as a reservoir of SO2 that is slowly released, thus preventing catalyst poisoning.

Benzylic Photobromination for the Synthesis of Belzutifan: Elucidation of Reaction Mechanisms Using In Situ LED-NMR.

A detailed mechanistic understanding of a benzylic photobromination en route to belzutifan (MK-6482, a small molecule for the treatment of renal cell carcinoma associated with von Hippel-Lindau syndrome) has been achieved using in situ LED-NMR spectroscopy in conjunction with kinetic analysis. Two distinct mechanisms of overbromination, namely, the ionic and radical pathways, have been revealed by this study. The behavior of the major reaction species, including reactants, intermediates, products, and side products, has been elucidated. Comprehensive understanding of both pathways informed and enabled mitigation of a major process risk: a sudden product decomposition. Detailed knowledge of the processes occurring during the reaction and their potential liabilities enabled the development of a robust photochemical continuous flow process implemented for commercial manufacturing.

The effect of carbonization temperature on the capacity and mechanisms of Cd(II)-Pb(II) mix-ions adsorption by wood ear mushroom sticks derived biochar.

Heavy metals often coexist in contaminated environmental media, and competition between heavy metals for adsorption sites influences the absorption capacity of biochar. In this study, the adsorption mechanism of pyrolytically modified wood ear mushroom sticks (250, 450, and 650 °C) as a new bio-adsorbent for single-ion and mixed-ion solutions Cd2+ and Pb2+ Biochar adsorption experiments showed that the adsorption abilities of Cd2+ and Pb2+ increased with increasing WMBC (wood ear mushroom sticks biochar) pyrolysis temperature. According to the Langmuir model, the maximum adsorption capacity of Cd2+ and Pb2+increased with higher pyrolysis temperature, being 29.84, 39.08, 46.16 mg·g-1and 124.3, 186.8, 234.2 mg·g-1, respectively for three different pyrolysis temperatures 250, 450, and 650 °C. WMBC exhibited a stronger adsorption ability for Pb2+ than for Cd2+. Competition between the two heavy metals severely inhibited the adsorption of Cd2+. Based on X-ray diffraction (XRD), scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDS), and Fourier transform infrared spectroscopy (FTIR) analyses, the dominant interaction mechanisms were determined to be complexation, ion exchange, precipitation, and C-π interaction. The results suggest WMBC shows promise as a novel, cheap, and effective adsorbent that can be used to remove both Cd2+ and Pb2+ pollutants from environmental media.

Late-Stage Modification of Oligopeptides by Nickel-Catalyzed Stereoselective Radical Addition to Dehydroalanine.

Radical addition to dehydroalanine (Dha) represents an appealing, modular strategy to access non-canonical peptide analogues for drug discovery. Prior studies on radical addition to the Dha residue of peptides and proteins have demonstrated outstanding functional group compatibility, but the lack of stereoselectivity has limited the synthetic utility of this approach. Herein, we address this challenge by employing chiral nickel catalysts to control the stereoselectivity of radical addition to Dha on oligopeptides. The conditions accommodate a variety of primary and secondary electrophiles to introduce polyethylene glycol, biotin, halo-tag, and hydrophobic and hydrophilic side chains to the peptide. The reaction features catalyst control to largely override substrate-based control of stereochemical outcome for modification of short peptides. We anticipate that the discovery of chiral nickel complexes that confer catalyst control will allow rapid, late-stage modification of peptides featuring nonnatural sidechains.

Organocatalytic Conversion of Nucleosides to Furanoid Glycals.

A class of organocatalysts that are highly active for the conversion of 2'-deoxynucleosides to furanoid glycals have been discovered. These phosphorimides, (Ph2PS)2NH and (Ph2PSe)2NH, were shown to effectively mediate persilylation of 2'-deoxynucleosides allowing the elimination of the nucleobase giving the corresponding glycal. These mild conditions were demonstrated in the syntheses of glycals with various substitution patterns while minimizing the formation of undesired byproducts and expanding the scope of this methodology.

New Mechanism for Cinchona Alkaloid-Catalysis Allows for an Efficient Thiophosphorylation Reaction.

An efficient synthesis of nucleoside 5'-monothiophosphates under mild reaction conditions using commercially available thiophosphoryl chloride was achieved with a cinchona alkaloid catalyst. A detailed mechanistic study of the reaction was undertaken, employing a combination of reaction kinetics, NMR spectroscopy, and computational modeling, to better understand the observed reactivity. Taken collectively, the results support an unprecedented mechanism for this class of organocatalyst.

Discovery of a Photoinduced Dark Catalytic Cycle Using in Situ LED-NMR Spectroscopy.

We report the use of LED-NMR spectroscopy to study the reaction mechanism of a newly discovered photoinduced iron-catalyzed cycloisomerization of alkynols to cyclic enol ethers. By understanding on/off ligand binding to the catalyst, we were able to appropriately design reaction conditions to balance catalyst activity and stability. LED-NMR was demonstrated to be a powerful tool in elucidating reaction mechanisms of photochemical reactions. Temporal NMR spectroscopic data under visible light illumination (1) revealed the pre-catalyst activation mechanism, (2) proved that photon flux provides a unique external control of the equilibrium distribution between the pre-catalyst and active catalyst, and ultimately the rate of reaction, (3) provided information about the reaction driving forces and the turnover-limiting step, and (4) enabled both real-time structural and kinetic insights into elusive species (e.g., dissolved gases).

Asymmetric Hydrogen Bonding Catalysis for the Synthesis of Dihydroquinazoline-Containing Antiviral, Letermovir.

A weak Brønsted acid-catalyzed asymmetric guanidine aza-conjugate addition reaction has been developed. C2-symmetric, dual hydrogen-bond donating bistriflamides are shown to be highly effective in activating α,ß-unsaturated esters toward the intramolecular addition of a pendant guanidinyl nucleophile. Preliminary mechanistic investigation, including density functional theory calculations and kinetics studies, support a conjugate addition pathway as more favorable energetically than an alternative electrocyclization pathway. This methodology has been successfully applied to the synthesis of the 3,4-dihydroquinazoline-containing antiviral, Letermovir, and a series of analogues.

Oxyfunctionalization of the Remote C-H Bonds of Aliphatic Amines by Decatungstate Photocatalysis.

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H2 O2 or O2 as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value-added ketone products. Lastly, NMR spectroscopy using in situ LED-irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.

Enantioselective Synthesis of Hemiaminals via Pd-Catalyzed C-N Coupling with Chiral Bisphosphine Mono-oxides.

A novel approach to hemiaminal synthesis via palladium-catalyzed C-N coupling with chiral bisphosphine mono-oxides is described. This efficient new method exhibits a broad scope, provides a highly efficient synthesis of HCV drug candidate elbasvir, and has been applied to the synthesis of chiral N,N-acetals.

Mono-Oxidation of Bidentate Bis-phosphines in Catalyst Activation: Kinetic and Mechanistic Studies of a Pd/Xantphos-Catalyzed C-H Functionalization.

Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.

Mechanistic insights into the vanadium-catalyzed Achmatowicz rearrangement of furfurol.

The Achmatowicz rearrangement is a powerful method for the construction of pyranones from simple furan derivatives. Here, we describe the development of improved reaction conditions and an interrogation into the fate of the metal center during this interesting transformation. The reaction to form the synthetically important lactol, 6-hydroxy-2H-pyran-3(6H)-one (3), proceeds cleanly in the presence of tert-butyl hydroperoxide (TBHP, 2) using low loadings of VO(O(i)Pr)3 as catalyst. The nonaqueous conditions developed herein allow for easy isolation of product 3 and synthetically important derivatives, a key advantage of this new protocol. Detailed experimental, spectroscopic, and kinetic studies along with kinetic modeling of the catalytic cycle support a positive-order dependence in both furfurol and TBHP concentrations, first-order dependence in catalyst (VO(O(i)Pr)3), and a negative dependence on the 2-methyl-2-propanol (4) concentration. (51)V-NMR spectroscopic studies revealed that 2-methyl-2-propanol (4) competes with substrates for binding to the metal center, rationalizing its inhibitory effect.

Innate C-H trifluoromethylation of heterocycles.

Direct methods for the trifluoromethylation of heteroaromatic systems are in extremely high demand in nearly every sector of chemical industry. Here we report the discovery of a general procedure using a benchtop stable trifluoromethyl radical source that functions broadly on a variety of electron deficient and rich heteroaromatic systems and demonstrates high functional group tolerance. This C-H trifluoromethylation protocol is operationally simple (avoids gaseous CF(3)I), scalable, proceeds at ambient temperature, can be used directly on unprotected molecules, and is demonstrated to proceed at the innately reactive positions of the substrate. The unique and orthogonal reactivity of the trifluoromethyl radical relative to aryl radicals has also been investigated on both a complex natural product and a pharmaceutical agent. Finally, preliminary data suggest that the regioselectivity of C-H trifluoromethylation can be fine-tuned simply by judicious solvent choice.

Overcoming Product Inhibition in a Nucleophilic Aromatic Substitution Reaction.

The development of a nucleophilic aromatic substitution (SNAr) reaction for the synthesis of belzutifan and related analogues is disclosed. This classical transformation suffered from reaction stalling, despite prolonged reaction times. Through experimental and mechanistic studies, product inhibition was revealed and rationalized. Herein, we describe our efforts to overcome this synthetic challenge and demonstrate the importance of the judicious choice of the solvent to achieve reactivity.

Comprehensive assessment of phthalates in indoor dust across China between 2007 and 2019: Benefits from regulatory restrictions.

China is the largest producer and consumer of phthalates in the world. However, it remains unclear whether China's phthalate restrictions have alleviated indoor phthalate pollution. We extracted the concentrations of dimethyl phthalate (DMP), diethyl phthalate (DEP), dibutyl phthalate (DBP), diisobutyl phthalate (DIBP), benzyl butyl phthalate (BBP), and bis(2-ethylhexyl) phthalate (DEHP) in indoor dust at 2762 sites throughout China between 2007 and 2019 from the published literature. Based on these data, we investigated the effects of phthalate restrictions and environmental factors on the temporal-spatial distribution and sources of phthalates and estimated human exposure and risk of phthalates. The results revealed that the mean concentrations of phthalates in indoor dust throughout China decreased in the following order: DEHP > DBP > DIBP > DMP > DEP > BBP. The concentrations of six phthalates were generally higher in northern and central-western China than in southern regions. BBP and DEHP concentrations decreased by 73.5% and 17.9%, respectively, from 2007 to 2019. Sunshine was a critical environmental factor in reducing phthalate levels in indoor dust. Polyvinyl chloride materials, personal care products, building materials, and furniture were the primary sources of phthalates in indoor dust. The phthalates in indoor dust posed the most significant threat to children and older adults. This study provides a picture of phthalate pollution, thus supporting timely and effective policies and legislation.

Filtration of polystyrene nanoplastics with different functional groups by natural mineral materials: Performance and mechanisms.

Optimizing nanoplastics (NPs) removal performance of rapid sand filter (RSF) in water treatment plants is significant for NP pollution prevention and remediation. This study investigated the application prospect of natural granular manganese sand, zeolite and limestone in RSF for NP removal through column experiments. Pristine, amino-modified, and carboxyl-modified polystyrene NPs (100 nm) were selected as experimental subjects. Quartz sand filter showed negligible NP removal, zeolite and manganese sand showed no obvious optimization on NP filtration. Limestone amended RSF significantly enhanced the removal of three NPs, the removal efficiency increased with decreasing size and increasing limestone grains dosage. The excellent performance of limestone was attributed to its special physicochemical properties in terms of synthetical action of electrostatic interaction, cationic bridging and especially the surface roughness morphology, and the mechanisms overcame the influence of functional groups of NPs. The results indicate the prospective applications of granular limestone in RSF for NP filtration.

Distribution and major driving elements of antibiotic resistance genes in the soil-vegetable system under microplastic stress.

Microplastics (MPs) and antibiotic resistance genes (ARGs) are both enriched in soil-vegetable systems as a consequence of the prolonged use of agricultural mulches. MPs can form unique bacterial communities and provide potential hosts for ARGs. Therefore, MPs stress may promote the spread of ARGs from soil to crops. Increasing ARGs pollution in soil-vegetable system. In our research, we investigated the distribution and major driving elements of antibiotic resistance genes in the soil-vegetable system under microplastic stress. The results showed that MPs treatment decreased the relative abundance of ARGs in non-rhizosphere soil. High concentrations of MPs promoted the enrichment of tetracycline antibiotic resistance genes in rhizosphere soil. MPs treatment promoted the enrichment of ARGs and mobile genetic elements (MGEs) in lettuce tissues, and the overall abundance of ARGs in root after 0.5 %, 1 %, and 2 % (w/w, dry weight) polyethylene (PE) administration was considerably higher compared to that in the untreated group (p < 0.05). At the same time, high PE concentrations promoted the spread of sulfa ARGs from root to leaf. MPs also impacted the bacterial communities in the soil-plant system, and the changes in ARGs as well as MGEs in each part of the soil-vegetable system were significantly correlated with the bacterial diversity index (p < 0.05). Correlation analysis and network analysis showed that bacterial communities and MGEs were the main drivers of ARGs variation in soil-lettuce systems.