Enantio- and Regioselective Dihydroboration of Enals

Asymmetric hydroboration is among the most powerful and straightforward methods to construct chiral organoboron compounds, which are extensively used in natural products, bioactive molecules, and materials science. Among them, enantioselective hydroboration of a single functional group has been well-established and experienced significant advances, but the asymmetric hydroboration of multiple functional groups is rarely developed due to the extremely challenging chemo-, regio-, and enantioselectivity control. Herein, we present a Co-catalyzed enantio- and regioselective dihydroboration of enals and achieved the chemo-, regio-, and enantioselective hydroboration of both the CO bond and the CC bond. This protocol features mild reaction conditions, wide substrate scope, and good functional group tolerance and provides a highly efficient method for the preparation of highly valuable chiral 1,4-borylethers and their downstream products such as 1,4-diols and amino alcohols. Preliminary mechanistic studies suggested that this Co-catalyzed dihydroboration involved a tandem 1,2-hydroboration/dissociative isomerization/asymmetric hydroboration process

Catalytic Contra-Thermodynamic Isomerization–Asymmetric Hydroboration of Alkenyl Alcohols and Amines

Catalytic isomerization of alkenes is a powerful tool for the construction of complex synthetically valuable molecules due to their redox-neutral, atom- and step-economical nature. However, traditional catalytic asymmetric isomerization of alkenes typically required the use of a heteroatomic group such as OH or NR2 as the thermodynamic driving force (i.e., the CC double bond isomerizes along the direction of heteroatomic groups). Here, we present a contra-thermodynamic isomerization/asymmetric hydroboration of alkenyl alcohols and amines, in which the CC double bond isomerizes along the opposite direction of OR and NR2. Compared to the traditional thermal isomerizations, this reaction overcomes the unfavorable thermodynamic bias to form a contra-thermodynamic alkene intermediate, followed by an irreversible asymmetric terminal hydroboration to provide highly synthetically valuable chiral 1,n-boryl ethers and amines. This protocol shows a wide substrate scope, including allylic alcohols, homoallylic alcohols, alkenyl alcohols, protected alkenyl alcohols, and various free and protected alkenyl amines. The synthetic utilities and practicability of this method were demonstrated by gram-scale reactions, diverse product transformations, and its applications in the synthesis of bioactive molecules. Preliminary mechanistic studies show that this reaction involves dissociative alkene isomerization and an asymmetric hydroboration of 1,1-disubstituted alkene intermediates

Phosphination of Phenol Derivatives and Applications to Divergent Synthesis of Phosphine Ligands

We describe a general and efficient protocol for the synthesis of organophosphine compounds from phenols and phosphines (R2PH) via a metal-free C–O bond cleavage and C–P bond formation process. This approach exhibits broad substrate scope and excellent functional group tolerance. The synthetic utilities of this protocol were demonstrated by the synthesis of chiral ligands via the various transformations of cyano groups and their applications in asymmetric catalysis

Simultaneous Extraction of Both Basic and Non-basic N‑Compounds from Oil <i>via</i> Triethylene Glycol–Metal Complex Solvent: Performance and Behavior

Simultaneous extraction of basic and non-basic N-compounds from oil is still a big challenge. Triethylene glycol (TEG) encounters very weak Brønsted acidity. Its N-distribution coefficient [DN, (mmol·gEx–1)/(mmol·gOil–1)] for the basic was below 7.0. In this work, metals dissolved in TEG can improve the Lewis acidity of the extractant and bring about the simultaneous removal. For example, DN of TEG–Ag­(I) can increase to 40.5 for quinoline and 57.9 for pyridine, respectively. For the non-basic, it still remained higher than 70.0. The promoted performance was ascribed to the improvement of extractive behavior of the basic. From TEG to TEG–Ag­(I), first, the distribution of equilibrium N-concentrations between two phases was significantly changed from the straight line to the non-linear curve with the plateau. Second, the interaction type inside the system was optimized. The Ag­(I)-based complexation coupled with the TEG-based H-bonding was identified. Third, the interaction intensity was increased as well. Ag­(I) contributed much to reduction of Gibbs free energy change for the basic. Therefore, enhancing Lewis acidity of the extractant was a feasible way for the extraction of the N-compounds

Quantum dot nanobead immunochromatographic assay based on bispecific monoclonal antibody for the simultaneous detection of aflatoxin B₁ and amantadine

A bispecific monoclonal antibody (BsMAb) that can simultaneously recognize aflatoxin B1 (AFB1) and amantadine (AMD) was prepared. Quantum dot nanobead immunochromatographic assay (QB-ICA) based on the BsMAb was developed for the simultaneous detection of AFB1 and AMD in four feed samples (suckling pig feed, piglet feed, sow feed, and compound feed for laying ducks). Under optimal experimental conditions, the LOD values of QB-ICA for AFB1 in four feed samples were 0.188, 0.221, 0.233, and 0.306 μg/kg, respectively. The LOD values of QB-ICA for AMD in the same feed samples were 0.125, 0.187, 0.076, and 0.191 μg/kg, respectively. The recovery rates of QB-ICA for AFB1 and AMD ranged from 91.55% to 150.87% and from 91.62% to 138.42%, respectively. The variation coefficients were all less than 15%. The proposed QB-ICA had high reliability and specificity for the simultaneous detection of AFB1 and AMD, providing a platform for simultaneous detection of hazardous substances.</p

Altered activities of AMP-Kinase, acetyl-CoA carboxylase and HMG-CoA reductase in HDR islets.

(A) Total AMPKα (n = 16–23); (B,C) phospho-AMPKα (P-Thr172 n = 6–14); (D) Total ACC (n = 12–18); (E) phospho-ACC (P-Ser79) (n = 7–9); (F) Total SIRT1 (n = 19–22); (G) Total LKB1 (n = 6–11); and (H) phospho-HMGCR (P-Ser872) (n = 6–12). Tubulin or total AMPK (T-AMPK) were used for normalization. Graphs represent means ± SEM for the number of determinations per experimental conditions in parenthesis. (A,D,F,G) non-treated islets. (B,C,E,H) islets treated at 3 mM (3G) or 16 mM (16G) glucose for 30 min and data are expressed as % of ND islets at 3 mM glucose (3G). # p<0.05, ##p<0.01 vs 3G for the same islet group; * p<0.05, ** p<0.01 vs ND for the same glucose concentration; & p<0.05 for HDR vs LDR of the same glucose concentration, One-way Anova, Tukey post-hoc test. ND: white; LDR: gray; HDR: black.</p

Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression

<div><p>Diet induced obese (DIO) mice can be stratified according to their weight gain in response to high fat diet as low responders (LDR) and high responders (HDR). This allows the study of β-cell failure and the transitions to prediabetes (LDR) and early diabetes (HDR). C57BL/6N mice were fed for 8 weeks with a normal chow diet (ND) or a high fat diet and stratified as LDR and HDR. Freshly isolated islets from ND, LDR and HDR mice were studied <i>ex-vivo</i> for mitochondrial metabolism, AMPK activity and signalling, the expression and activity of key enzymes of energy metabolism, cholesterol synthesis, and mRNA profiling. Severely compromised glucose-induced insulin secretion in HDR islets, as compared to ND and LDR islets, was associated with suppressed AMP-kinase activity. HDR islets also showed reduced acetyl-CoA carboxylase activity and enhanced activity of 3-hydroxy-3-methylglutaryl-CoA reductase, which led respectively to elevated fatty acid oxidation and increased cholesterol biosynthesis. HDR islets also displayed mitochondrial membrane hyperpolarization and reduced ATP turnover in the presence of elevated glucose. Expression of protein kinase Cε, which reduces both lipolysis and production of signals for insulin secretion, was elevated in DIO islets. Genes whose expression increased or decreased by more than 1.2-fold were minor between LDR and ND islets (17 differentially expressed), but were prominent between HDR and ND islets (1508 differentially expressed). In HDR islets, particularly affected genes were related to cell cycle and proliferation, AMPK signaling, mitochondrial metabolism and cholesterol metabolism. In conclusion, chronically reduced AMPK activity, mitochondrial dysfunction, elevated cholesterol biosynthesis in islets, and substantial alterations in gene expression accompany β-cell failure in HDR islets. The β-cell compensation process in the prediabetic state (LDR) is largely independent of transcriptional adaptive changes, whereas the transition to early diabetes (HDR) is associated with major alterations in gene expression.</p></div

Defective insulin secretion and mitochondrial dysfunction in DIO islets.

<p>(A) Insulin secretion was measured in freshly isolated islets from normal diet (ND), and obese high fat diet fed low responders (LDR) and high responders (HDR) mice. Groups of 10 islets were incubated 1 h in KRBH at 3, 8, or 16 mM glucose (G) or 3 mM glucose ± 35 mM KCl. Means ± SEM of 10–12 determinations from islets of 6 animals per group in three separate experiments. ***p<0.001 versus ND for the same glucose concentration; ###p<0.001 versus 3 mM glucose; one-way ANOVA, Tukey post-hoc test. (B) Mitochondrial membrane potential (Δψmito) measured by Rhodamine123 fluorescence in dispersed islet cells from ND, LDR and HDR mice. Δψmito was initially measured at 3 mM glucose to set a baseline and then at 16 mM glucose. Data were normalized to baseline fluorescence. Means of 6 (ND) or 5 (LDR and HDR) mice. ***p<0.0001 vs ND; One-way ANOVA, repeated measures, Tukey post-hoc test. (C) Mitochondrial O₂ consumption rate (OCR) measured at 3 mM glucose and then at 16 mM glucose (16G). (D) Baseline respiration at 3 mM glucose, (E) glucose-induced respiration as the difference in OCR between 16 and 3 mM glucose, (F) ATP-turnover at 16G, (G) maximal respiration, (H) uncoupled respiration and (I) non-mitochondrial respiration were determined using mitochondrial inhibitors. Means ± SEM of 5 mice per group, each with quadruplicate observations. *p<0.05 versus ND; One-way ANOVA, Tukey post-hoc test.</p

Individual metabolic parameters of C57BL/6N mice fed with a normal or HFD for 8 weeks used for islet gene expression analysis.

<p>(A) Body weight (BW), (B) glycemia, (C) insulinemia, (D) cholesterolemia, (E) plasma fatty acids and (F) plasma triglycerides. Means ± SEM of 8 animals per group are indicated below the X- axis for each graph. LDR or HDR versus ND: *P<0.05, ***P<0.001; HDR versus LDR: & P<0.05, && P<0.01, &&& P<0.001. One-way ANOVA-Bonferroni’s multiple comparison post hoc test.</p

Model depicting the mechanisms contributing to β-cell dysfunction and failure in obese HDR mice.

Hyperglycemic and hypercholesterolemic HDR mice are characterized by major changes in islet mRNA species expression, and suppression of AMPK activity that causes HMG-CoA reductase activation and increased cholesterol synthesis and deposition in islet β-cells. Cholesterol accumulation leads to mitochondrial dysfunction and reduced exocytotic release of insulin. Reduced AMPK activity may promote β-cell growth and proliferation as a compensatory mechanism, but can also lead to altered gene expression and modify various signaling pathways for insulin secretion, causing β-cell phenotypic alterations and defective insulin secretion.</p