Z Group Research Articles

Stability and reactivity of alkylidene dihydropyridines.

Alkylidene dihydropyridines (ADHPs) are electron-rich nucleophilic intermediates that can be readily prepared by dearomatization of 4-alkylpyridines using chloroformate reagents and mild base. Their stability and reactivity can be tuned with the chloroformate reagent used as evidenced by NMR chemical shifts and oxidation potentials. ADHPs prepared with ethyl, allyl and trichloroethyl chloroformate undergo decomposition under an oxygen atmosphere at different rates (ethyl > allyl > trichloroethyl), predominantly to the corresponding 4-acylpyridine. The ADHPs derived from benzyl chloroformate are stable towards oxidation, and those derived from phenyl chloroformate hydrolyze readily.

Retraction: Deoxygenative cross-electrophile coupling of benzyl chloroformates with aryl iodides.

Retraction of 'Deoxygenative cross-electrophile coupling of benzyl chloroformates with aryl iodides' by Yingying Pan et al., Org. Biomol. Chem., 2019, 17, 4230-4233, https://doi.org/10.1039/C9OB00628A.

Synthesis of N‐Cbz Amides and Their Applications in the Transamidation Reactions at Room Temperature

AbstractA wide range of aryl and alkyl N‐Cbz amides were prepared from secondary amides and benzyl chloroformate in the presence of LiHMDS. Application of N‐Cbz amides in transamidation was demonstrated with different amines at room temperature in the presence of DBU. The reactivity of N‐Cbz amides is comparable with N‐Boc and N‐Ts amides in transamidation and transesterification reactions. The optimized condition was well‐suited for the transesterification reactions with thiols and alcohols. Broad substrate scope and excellent yields are the merits of the developed methodology.

Divergent, Strain‐Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation

AbstractThe azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain‐release reactions upon N‐activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3‐substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

Divergent, Strain-Release Reactions of Azabicyclo[1.1.0]butyl Carbinols: Semipinacol or Spiroepoxy Azetidine Formation.

The azetidine moiety is a privileged motif in medicinal chemistry and new methods that access them efficiently are highly sought after. Towards this goal, we have found that azabicyclo[1.1.0]butyl carbinols, readily obtained from the highly strained azabicyclo[1.1.0]butane (ABB), can undergo divergent strain‐release reactions upon N‐activation. Treatment with trifluoroacetic anhydride or triflic anhydride triggered a semipinacol rearrangement to give keto 1,3,3‐substituted azetidines. More than 20 examples were explored, enabling us to evaluate selectivity and the migratory aptitude of different groups. Alternatively, treatment of the same alcohols with benzyl chloroformate in the presence of NaI led to iodohydrin intermediates which gave spiroepoxy azetidines upon treatment with base. The electronic nature of the activating agent dictates which pathway operates.

Amine-Catalyzed Chain Polymerization of Ethyl Glyoxylate from Alcohol and Thiol Initiators.

Polyacetals have significant potential as degradable polymers, but aldehyde polymerizations are generally difficult to control. Here we show that polymerization of ethyl glyoxylate can be initiated from alcohols or thiols by activation with triethylamine to afford poly(ethyl glyoxylate) with controllable molecular weights and relatively low dispersities (Đ = 1.3-1.4), as evidenced by MALDI-TOF mass spectrometry. Stabilization against depolymerization by chain-capping with benzyl chloroformate was found to proceed without side reactions observed from chain-capping with tolyl isocyanate. The use of the stronger base DBU leads to competing side reactions that limit polymer molecular weight.

Nickel-catalyzed reductive benzylation of tertiary alkyl halides with benzyl chlorides and chloroformates

We report a Ni-catalyzed cross-electrophile coupling of benzyl chlorides and chloroformates with unactivated tertiary alkyl halides to forge the challenging benzylated all C(sp3)-quaternary carbon centers.

Using 4-(Carbazole-9-yl)-benzyl Chloroformate as a Derivatization Reagent for the Measurement of Amino Acids in Tea Samples by High-Performance Liquid Chromatography with Fluorescence Detection

An effective method for the determination of 20 free amino acids in tea samples using 4-(carbazole-9-yl)-benzyl chloroformate (CBBC-Cl) as a derivatization reagent by high-performance liquid chromatography combined with fluorescence detection (HPLC-FLD) has been established. CBBC-Cl quickly derivatized amino acids within 6 min in basic solution (pH 9.0) at room temperature (ca. 25 °C). The maximum excitation and emission wavelengths of the stable derivatives were 290 nm and 370 nm, respectively. The separation of 20 amino acids, including the theanine (THE) derivative, was optimized on a Hypersil BDS-C18 column. Identification of these derivatives was performed via liquid chromatography/electrospray ionization mass spectrometry (LC/ESI/MS) in positive-ion detection mode. Under optimal conditions, excellent linearity for all the amino acids was obtained, with determination coefficients of r2 > 0.9986. The detection limits (LODs) and quantitation limits (LOQs) ranged from 0.13 to 1.5 μg·kg−1 and 0.43 to 4.95 μg·kg−1, respectively. Satisfactory recoveries, ranging from 86.7 to 106.4%, were obtained for all the amino acids in the tea samples. The developed method has been successfully applied to the quantification of 20 amino acids in tea samples.

A sensitive method for the quantification of short-chain fatty acids by benzyl chloroformate derivatization combined with GC-MS.

Short-chain fatty acids (SCFAs) were identified as critical markers in the diagnosis of chronic and metabolic diseases, but a sensitive and stable method to determine SCFAs in feces is a challenge for analysts due to the high volatility. Herein, a sensitive and accurate method to determine SCFAs adopting precolumn derivatization coupled with gas chromatography-mass spectrometry (GC-MS) has been developed. Benzyl chloroformate (BCF) was chosen as the reaction reagent and emulsified derivatization was applied to homogenize the reaction system. Higher sensitivity, wider application and satisfactory derivatization efficiency were obtained using the developed method. An excellent method validation showed a good linearity ranging from 0.9947 to 0.9998. At the same time, the intra-day and inter-day precision were achieved in the range of 0.56% to 13.07%. The lower limits of detection of all target analytes varied from 0.1 to 5 pg. The recovery ranged from 80.87% to 119.03%, and storage stability under three different conditions was also determined. This method was also successfully applied to the analysis of SCFAs in mice fecal samples to illustrate the significant differences between normal and type 2 diabetes mellitus mice.

Role of hippocampal nNOS-PSD95 coupling in short-term memory retrieval disorder induced by sevoflurane in mice

Objective To evaluate the role of hippocampal neuronal nitric oxide synthase (nNOS)-postsynaptic dense protein 95 (PSD95) coupling in short-term memory retrieval disorder induced by sevoflurane in mice. Methods Sixteen clean-grade healthy Kunming mice of both sexes, aged 2-3 months, weighing 30-35 g, were divided into 2 groups (n=8 each) according to the random number table method: sevoflurane group (S group) and nNOS-PSD95 uncoupling agent ZL006 group (Z group). After successful establishment of dark avoidance memory, 3.3% sevoflurane and 40% O2 were inhaled for 2 h in both groups, and normal saline 1.5 ml was intraperitoneally injected in group S and ZL006 1 mg/kg in group Z at 30 min before anesthesia.The step-through latency and error times were recorded before anesthesia and at 12 h after the end of anesthesia.The mice were then sacrificed, and hippocampal tissues were taken for determination of the expression of nNOS and PSD95 (by Western blot) and co-expression of nNOS and PSD95 (by immunoprecipitation). Results Compared with that before anesthesia, the step-through latency was significantly shortened, and the error times were increased at 12 h after anesthesia in group S (P 0.05). Compared with group S, the step-through latency was significantly prolonged, error times were decreased, the co-expression of nNOS and PSD95 was down-regulated (P 0.05). Conclusion The mechanism by which sevoflurane induces short-term memory retrieval disorder may be related to promoting the coupling of nNOS to PSD95 in the hippocampus of mice. Key words: Anesthetics, inhalation; Memory disorders; Nitric oxide synthase typeⅠ; Membrane proteins

Chemical constituents of thermal stress induced Ganoderma applantum (Per.) secondary metabolites on larvae of Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus and histopathological effects in mosquito larvae

Abstract Entomopathogenic fungus contains variety of secondary metabolites, which are known to have pharmacological and insecticidal properties. Stress plays an important role in production of toxic secondary metabolites. Thermal stress plays major role in production of toxic compounds. In the present study the toxicity of thermal temperatures induced G. applantum secondary metabolites were tested for larvicidal activities on Anopheles stephensi, Aedes aegypti and Culex quinquefasciatus. Our results show that after 24 h post treatment, stress induced G. applantum ethyl acetate extract produce strong larvicidal activity in An. stephensi (LC50: 53.035 mg/l),Cx. quinquefasciatus (LC50: 85.618 mg/l), and Ae. aegypti (LC50: 90.018 mg/l). G. applantum secondary metabolites were characterized using TLC and FT-IR. FT-IR shows two major functional groups which are, OH stretch and carboxylic groups. GC-MS analysis shows presence of two major compounds namely, Benzyl Chloroformates and hexyl nitro cyclohexene. Histopathological study shows that G.applantum extract, produce vacuolation in epithelial cells of midgut, far body and muscle tissues in mosquito larvae. Our overall findings suggest that thermal stress induced G. applantum culture, can produce virulent metabolites are toxic to mosquito larvae. These secondary metabolites can be used for effective, green pesticides for future mosquito control programs.

A sensitive quantification approach for detection of HETE-CP adduct after benzyl chloroformate derivatization using ultra-high-pressure liquid chromatography tandem mass spectrometry.

Sulfur mustard (HD) reacts with human serum albumin (HSA) at Cys34 and produces a long-term biomarker of HD exposure. Here, we present a novel, sensitive, and convenient method for quantification of HD exposure by detection of HD-HSA adducts using pronase digestion, benzyl chloroformate (Cbz-Cl) derivatization, and ultra-high-pressure liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). The HSA in HD-exposed plasma in vitro was precipitated with acetone and digested (2h, 50°C) with pronase to form the alkylated dipeptide, S-hydroxyethylthioethyl-CysPro (HETE-CP). The HETE-CP adduct was derivatized with Cbz-Cl to generate N-carbobenzoxy HETE-CP (HETE-C(Cbz)P). The derivatized product was analyzed by UHPLC-MS/MS. HD surrogate, 2-chloroethyl ethyl sulfide (2-CEES), was introduced as a non-isotope internal standard (ISTD) instead of traditional d8-HD for quantification. The method was found to be linear between 1.00 and 200ng/mL HD exposure (R2 > 0.998) with precision of ≤ 9.0% relative standard deviation (RSD) and accuracy ranged between 97.1 and 111%. The limit of detection (LOD) is 0.500ng/mL (S/N~5), over 15 times lower than that of the previous method (7.95ng/mL). Time-consuming affinity purification or solid phase extraction (SPE) is not needed in the experiment and the operation takes less than 5h. This study provides a new strategy and useful tool for retrospective analysis of HD exposure by HETE-CP biomarker detection. Graphical abstract Flow diagram for quantification of sulfur mustard exposure by detection of HETE-CP dipeptide adduct after benzyl chloroformate derivatization using ultra-high-pressure liquid chromatography tandem mass spectrometry.

HPLC determination of γ-aminobutyric acid and its analogs in human serum using precolumn fluorescence labeling with 4-(carbazole-9-yl)-benzyl chloroformate.

In this study, a simple analytical method for the determination of γ-aminobutyric acid, gabapentin, and baclofen by using high-performance liquid chromatography with fluorescence detection was developed. An amidogen-reactive fluorescence labeling reagent, 4-(carbazole-9-yl)-benzyl chloroformate was first used to sensitively label these analytes. The completed labeling of these analytes can be finished rapidly only within 5min at the room temperature (25°C) to form 4-(carbazole-9-yl)-benzyl chloroformate labeled fluorescence derivatives. These labeled derivatives expressed strong fluorescence property with the maximum excitation and emission wavelengths of 280 and 380nm, respectively. The labeled derivatives were analyzed using a reversed-phase Eclipse SB-C18 column within 10min with satisfactory shapes. Excellent linearity (R2 >0.995) for all analytes was achieved with the limits of detection and the limits of quantitation in the range of 0.25-0.35 and 0.70-1.10μg/L, respectively. The proposed method was used for the simultaneous determination of γ-aminobutyric acid and its analogs in human serum with satisfactory recoveries in the range of 94.5-97.5%.

Deoxygenative cross-electrophile coupling of benzyl chloroformates with aryl iodides.

This work describes Ni-catalyzed cross-electrophile coupling of benzyl chloroformate derivatives with aryl iodides that generates a wide range of diaryl methane products. The mild reaction conditions merit the C-O bond radical fragmentation of benzyl chloroformates via halide abstraction or a single electron reduction by a Ni catalyst. This work offers a new substrate type for cross-electrophile couplings.

Novel fluorescence labeling reagent 4-(carbazole-9-yl)-benzyl chloroformate and its application in the determination of nitrofuran metabolites compounds in foodstuffs by high performance liquid chromatography with fluorescence detection

The goal of the presented work is to develop a simple and sensitive high-performance liquid chromatography in combination with fluorescence detection (HPLC-FLD) method for the determination of four nitrofurans (NFs) metabolites compounds (semicarbazide (SEM), 1-aminohydantoin (AH), 3-amino-2-oxazolidinone (AOZ) and 3-amino-morpholinomethyl-2-oxazolidinone (AMOZ)) in foodstuffs. For this goal, we synthesized a novel fluorescence labeling reagent, 4-(carbazole-9-yl)-benzyl chloroformate (CBBC) to label NFs metabolites compounds. NFs metabolites compounds can be labeled rapidly only within 5 min at the room temperature (25 °C). The labeled derivatives showed excellent fluorescence property with maximum excitation and emission wavelengths of 375 nm and 410 nm, respectively. The labeled derivatives were analyzed on a reversed-phase Eclipse XDB-C18 column within 10 min. Excellent linearity (R2 > 0.995) of all NFs metabolites compounds was achieved with the limits of detection (LODs) and the limits of quantitations (LOQs) in the low micrograms per kilogram range of 0.20–0.30 μg·kg−1 and 0.70–1.00 μg·kg−1, respectively. Satisfactory recoveries in the range of 92.5–98.0% were obtained for all NFs metabolites compounds. Using the proposed HPLC-FLD method, we successfully determined four NFs metabolites compounds in different foodstuffs. As promising, this highly sensitive and reliable method would also be extended for the quantitation of NFs metabolites compounds in other samples.

Efficacy of domestic electronic vaporizer when used for sevoflurane anesthesia in rabbits

Objective To evaluate the efficacy of domestic electronic vaporizer when used for sevoflurane anesthesia in rabbits. Methods Ninety healthy pathogen-free New Zealand rabbits of both sexes, aged 4-5 months, weighing 2.5-3.5 kg, were divided into 3 groups(n=30 each)using a random number table: mechanical vaporizer group(group M), domestic electronic vaporizer group(group E)and Zeus electronic vaporizer group(group Z). In group M, the mechanical vaporizer was used, the sevoflurane vaporizer dial was adjusted to 2%, with the fresh air flow set at 2 L/min.In E and Z groups, BR850 domestic electronic vaporizer and Zeus electronic vaporizer were used, respectively, and the concentration of sevoflurane inhaled was 2%.Sevoflurane was inhaled for 2 h in each group.The formula method and weighing method were used to calculate the consumption of sevoflurane in group M. The electronic calculation method and weighing method were used to calculate the consumption of sevoflurane in Z and E groups.The stable value of end-tidal sevoflurane concentration(ETCsev)and time for ETCsev reaching the stable value were recorded.ETCsev was recorded every 10 min after reaching the stable value(T1-T12). Results Compared with group M, the consumption of sevoflurane(weighing method)was significantly reduced, and the time for ETCsev reaching the stable value was shortened in Z and E groups(P 0.05). Compared with the consumption of sevoflurane(weighing method), no significant change was found in the consumption of sevoflurane(electronic method)in group Z(P>0.05), and the consumption of sevoflurane(electronic method)was significantly increased in group E(P 0.05). Conclusion The domestic electronic vaporizer achieves automatic and precise control of volatile concentrations of inhalation anesthetics and can be effectively used for sevoflurane anesthesia in rabbits.When compared with Zeus electronic vaporizer, the precision of the domestic electronic vaporizer needs further improvement, but the cost is obviously low, the compatibility is strong, and it has clinical application value. Key words: Anesthesia, Inhalation; Nebulizers and vaporizers

Efficacy of transforaminal endoscopic spine system technique in treating lumbar disc herniation complicated withI degree stability of lumbar spondylolisthesis

Objective To evaluate the efficacy of transforanminal endoscopic spine system(TESSYS)technique in treating lumbar disc herniation complicated with Ⅰ degree stability of lumbar spondylolisthesis. Methods Thirty-two patients with lumbar disc herniation, aged 51-82 yr, weighing 52-93 kg, of American Society of Anesthesiologists physical statusⅠ or Ⅱ, were randomly divided into 2 groups(n=16 each)according to whether patients had lumbar spondylolisthesis: lumbar disc herniation group(Y group)and lumbar disc herniation combined with I degree stability of lumbar spondylolisthesis group(Y+ Z group). Extirpated protrusion, plasty ligamenum flavum and posterior longitudinal ligament and nerve root decompression were carried out using TESSYS technique in two groups, and in addition excision of osseous neoplasias and retro-positioned posterior margin of lumbar vertebral body was done in group Y+ Z.Pain was assessed using Visual Analogue Scale(VAS)score at 1 day before surgery and 3 days and 1, 3, 6 and 12 months after surgery.Patient′s function was assessed by using the Oswestry Disability Index(ODI)at 1 day before surgery and 12 months after surgery.The therapeutic effect was evaluated using modified Macnab criteria at 12 months after surgery. Results Compared with the baseline at 1 day before surgery, VAS scores were significantly decreased at each time point after surgery, and ODI was decreased at 12 months after surgery in two groups(P 0.05). Conclusion TESSYS technique can be used to treat lumbar disc herniation complicated with Ⅰ degree stability of lumbar spondylolisthesis. Key words: Intervertebral disk displacement; Endoscopes; Surgery, minimally invasive

Highly Luminescent Folate-Functionalized Au22 Nanoclusters for Bioimaging.

Gold nanoclusters are emerging as new materials for biomedical applications because of promises offered by their ultrasmall size and excellent biocompatibility. Here, the synthesis and optical and biological characterizations of a highly luminescent folate-functionalized Au22 cluster (Au22 -FA) are reported. The Au22 -FA clusters are synthesized by functionalizing the surface of Au22 (SG)18 clusters, where SG is glutathione, with benzyl chloroformate and folate. The functionalized clusters are highly water-soluble and exhibit remarkably bright luminescence with a quantum yield of 42%, significantly higher than any other water-soluble gold clusters protected with thiolate ligands. The folate groups conjugated to the gold cluster give rise to additional luminescence enhancement by energy transfer sensitization. The brightness of Au22 -FA is found to be 4.77 mM-1 cm-1 , nearly 8-fold brighter than that of Au22 (SG)18 . Further biological characterizations have revealed that the Au22 -FA clusters are well-suited for bioimaging. The Au22 -FA clusters exhibit excellent photostability and low toxicity; nearly 80% cell viability at 1000 ppm of the cluster. Additionally, the Au22 -FA clusters show target specificity to folate-receptor positive cells. Finally, the time-course in vivo luminescence images of intravenous-injected mice show that the Au22 -FA clusters are renal-clearable, leaving only 8% of them remained in the body after 24 h post-injection.

Practical and Efficient Synthesis of α-Aminophosphonic Acids Containing 1,2,3,4-Tetrahydroquinoline or 1,2,3,4-Tetrahydroisoquinoline Heterocycles.

We report here a practical and efficient synthesis of α-aminophosphonic acid incorporated into 1,2,3,4-tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline heterocycles, which could be considered to be conformationally constrained analogues of pipecolic acid. The principal contribution of this synthesis is the introduction of the phosphonate group in the N-acyliminium ion intermediates, obtained from activation of the quinoline and isoquinoline heterocycles or from the appropriate δ-lactam with benzyl chloroformate. Finally, the hydrolysis of phosphonate moiety with simultaneous cleavage of the carbamate afforded the target compounds.

Synthesis of 4,8-dioxa-1-azabicyclo[4.3.0]nonane-3,9-dione

A new bicyclic aziridino lactone 1 was synthesized from methyl 2,3-dibromopropionate and 2-amino-2-methylpropane-1,3-diol (AMPD). The reaction of compound 1 with benzyl chloroformate and subsequent treatment of the intermediate compound with 1,8-diazabicyclo[5.4.0]undec-7-ene gave a bicyclic lactone, 4,8-dioxa-1-azabicyclo[4.3.0]nonane-3,9dione.