A Radical Approach for Asymmetric α-C-H Addition of N-Sulfonyl Benzylamines to Aldehydes.

Efficient synthesis of enantioenriched amines is of great importance due to their significant synthetic and biological applications. Photoredox-mediated asymmetric α-amino C(sp3)-H functionalization offers an atom-economical and sustainable approach to access chiral amines. However, the development of analogous reactions is in its early stages, generally affording chiral amines with a single stereocenter. Herein, we present a novel synergistic triple-catalysis approach for the asymmetric α-C-H addition of readily available N-sulfonyl amines to aldehydes under mild conditions. This method allows for the efficient synthesis of a diverse array of valuable ß-amino alcohols bearing vicinal stereocenters. Unlike previous reports, our protocol employs a radical approach using earth-abundant Cr catalysis. Quinuclidine plays a dual role by facilitating highly selective hydrogen-atom transfer to generate α-amino radicals and promoting the dissociation of the Cr-O bond, which is crucial for the overall catalytic cycle as evidenced by control, NMR, and DFT experiments. Preliminary mechanistic studies, including radical trapping, nonlinear effect, Stern-Volmer plot, kinetic isotope effect, and Hammett plot, offer valuable insights into the reaction pathway.

Exploring CYP2D6 polymorphisms and angiotensin receptor blocker response in the Bai hypertensive population.

OBJECTIVE: The CYP2D6 enzyme is crucial for the metabolism and disposition of a variety of drugs. This study was conducted to examine the relationship between CYP2D6 gene polymorphisms and the response to angiotensin receptor blocker (ARB)-based treatment in patients of Chinese Bai ethnicity with hypertension. METHODS: Seventy-two hypertensive adults from the Chinese Bai ethnic group, exhibiting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, were recruited. Targeted regional sequencing was utilized to genotype single nucleotide polymorphisms in the CYP2D6 gene, aiming to assess their frequency and to evaluate their influence on the therapeutic efficacy of ARB medications. RESULTS: Our research identified nine significant CYP2D6 polymorphisms associated with the efficacy of ARB treatment in the Bai hypertensive cohort. Specifically, patients possessing certain mutant genotype at rs111564371 exhibited substantially greater reductions in SBP and DBP, with P-values of 0.021 and 0.016, respectively, compared to those carrying the wild genotype. Additionally, these mutant genotype at rs111564371 and rs112568578 were linked to approximately 20% higher overall efficacy rates and a 10% increased achievement rate relative to the wild genotype. CONCLUSION: Our research with the Bai hypertensive group shows that certain CYP2D6 polymorphisms significantly influence ARB treatment outcomes. Mutations at rs111564371 led to better blood pressure control (P-values: 0.021 for SBP, 0.016 for DBP), improving ARB efficacy by appromixately 20% and increasing treatment goal achievement by 10% over the wild-type genotype. STATEMENTS: Our investigation into CYP2D6 polymorphisms within the Bai hypertensive cohort marks a substantial advancement towards personalized healthcare, underscoring the pivotal influence of genetic constitution on the effectiveness of ARB therapy.

Catalytic enantioconvergent coupling of secondary and tertiary electrophiles with olefins.

Carbon-carbon bonds, including those between sp3-hybridized carbon atoms (alkyl-alkyl bonds), typically comprise much of the framework of organic molecules. In the case of sp3-hybridized carbon, the carbon can be stereogenic and the particular stereochemistry can have implications for structure and function1-3. As a consequence, the development of methods that simultaneously construct alkyl-alkyl bonds and control stereochemistry is important, although challenging. Here we describe a strategy for enantioselective alkyl-alkyl bond formation, in which a racemic alkyl electrophile is coupled with an olefin in the presence of a hydrosilane, rather than via a traditional electrophile-nucleophile cross-coupling, through the action of a chiral nickel catalyst. We demonstrate that families of racemic alkyl halides-including secondary and tertiary electrophiles, which have not previously been shown to be suitable for enantioconvergent coupling with alkyl metal nucleophiles-cross-couple with olefins with good enantioselectivity and yield under very mild reaction conditions. Given the ready availability of olefins, our approach opens the door to developing more general methods for enantioconvergent alkyl-alkyl coupling.

Chromium Catalyzed Asymmetric Reformatsky Reaction.

This study describes an unprecedented chromium-catalyzed asymmetric Reformatsky reaction, enabling the synthesis of chiral ß-hydroxy carbonyl compounds from α-chlorinated or α-brominated esters and amides. By employing a chiral chromium/diarylamine bis(oxazoline) catalyst, we achieved relatively broad functional group tolerance. Distinct from known reports, the protocol operates under both classical and photoredox conditions, facilitated by the in-situ formation of a nucleophilic chiral chromium intermediate through a radical-polar crossover mechanism. Preliminary mechanistic insights, supported by DFT calculations, identify the nucleophilic aldehyde addition as the key stereo-determining step. This approach not only overcomes the limitations of existing Reformatsky reactions but also provides a versatile strategy for accessing complex chiral molecules.

Cr-Catalyzed Asymmetric Cross Aza-Pinacol Couplings for ß-Amino Alcohol Synthesis.

Chiral ß-amino alcohols are crucial structural motifs found in pharmaceuticals, natural products, and chiral ligands in asymmetric catalysis. Despite previous advances, the development of catalytic approaches to access ß-amino alcohols bearing vicinal stereocenters from readily available chemicals remains a prominent challenge. Herein, we describe the Cr-catalyzed asymmetric cross aza-pinacol coupling of aldehydes and N-sulfonyl imines. This protocol proceeds in a radical-polar crossover manner from the intermediacy of an α-amino radical instead of a ketyl radical. Key to the success is using a chiral chromium catalyst, which plays a triple role in the chemoselective single-electron reduction of the imine, fast radical interception to inhibit radical addition to imines, and chemo- and stereoselective addition to aldehydes instead of imines. This method provides a modular and efficient approach to accessing diverse ß-amino alcohols bearing vicinal stereocenters.

Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes.

Ketones are ubiquitous in organic synthesis. However, the general method to convert widely available carboxylic acids, unactivated esters, and amides into ketones remains elusive. Herein, we describe the Ti-catalyzed modular ketone synthesis from carboxylic derivatives and easily accessed gem-dihaloalkanes. Notably, this protocol could achieve the direct catalytic olefination of carboxylic acids. This method features a sequence of olefination and electrophilic transformation and good functional group compatibility and allows rapid access to various functionalized ketones. Preliminary mechanistic studies provide insights into the reaction pathway and support the intermediacy of plausible alkylidene titanocene and gem-bimetallic complexes.

Catalytic Diastereo- and Enantioselective Cyclopropanation of gem-Dihaloalkanes and Terminal Olefins.

Chiral cyclopropane derivatives are essential in synthetic chemistry and drug discovery. Their synthesis commonly relies on asymmetric cyclopropanation of diazo compounds, potentially explosive and needing stabilizing substituents. Thus, asymmetric catalytic transformations of non-stabilized carbenes or carbenoids remain a formidable challenge. Herein, we report the unprecedented chromium-catalyzed asymmetric cyclopropanation of readily available gem-dihaloalkanes and terminal olefins. Distinct from previous approaches, gem-dihaloalkanes serve as suitable precursors for non-stabilized carbenes or carbenoids, furnishing various functionalized chiral cyclopropanes. Mechanistic studies, including radical trapping, non-linear effect, and UV/Vis spectroscopy, provide insights into the catalytic process, featuring radical-polar crossover.

Ti-Catalyzed Diastereoselective Cyclopropanation of Carboxylic Derivatives with Terminal Olefins.

Cyclopropanols and cyclopropylamines not only serve as important structural motifs in medicinal chemistry but also show diverse reactivities in organic synthesis. Owing to the high ring strain energy, the development of a general protocol from stable and readily available starting materials to afford these cyclopropyl derivatives remains a compelling challenge. Herein, we describe that a Ti-based catalyst can effectively promote the diastereoselective syntheses of cyclopropanols and cyclopropylamines from widely accessible carboxylic derivatives (acids, esters, amides) with terminal olefins. To the best of our knowledge, this method represents the first example of direct converting alkyl carboxylic acids into cyclopropanols. Distinct from conventional studies in Ti-mediated cyclopropanations with reactive alkyl Grignard reagents as nucleophiles or reductants, this protocol utilizes Mg and Me2SiCl2 to turn over the Ti catalyst. Our method exhibits broad substrate scope with good functional group compatibility and is amenable to late-stage synthetic manipulations of natural products and biologically active molecules.

Characterisation of Flavour Attributes in Egg White Protein Using HS-GC-IMS Combined with E-Nose and E-Tongue: Effect of High-Voltage Cold Plasma Treatment Time.

Egg white protein (EWP) is susceptible to denaturation and coagulation when exposed to high temperatures, adversely affecting its flavour, thereby influencing consumers' decisions. Here, we employ high-voltage cold plasma (HVCP) as a novel nonthermal technique to investigate its influence on the EWP's flavour attributes using E-nose, E-tongue, and headspace gas-chromatography-ion-mobilisation spectrometry (HS-GC-IMS) due to their rapidness and high sensitivity in identifying flavour fingerprints in foods. The EWP was investigated at 0, 60, 120, 180, 240, and 300 s of HVCP treatment time. The results revealed that HVCP significantly influences the odour and taste attributes of the EWP across all treatments, with a more significant influence at 60 and 120 s of HVCP treatment. Principal component analyses of the E-nose and E-tongue clearly distinguish the odour and taste sensors' responses. The HS-GC-IMS analysis identified 65 volatile compounds across the treatments. The volatile compounds' concentrations increased as the HVCP treatment time was increased from 0 to 300 s. The significant compounds contributing to EWP characterisation include heptanal, ethylbenzene, ethanol, acetic acid, nonanal, heptacosane, 5-octadecanal, decanal, p-xylene, and octanal. Thus, this study shows that HVCP could be utilised to modify and improve the EWP flavour attributes.

Catalytic Enantioconvergent Allenylation of Aldehydes with Propargyl Halides.

α-Allenol is a versatile synthon in organic synthesis. The catalytic asymmetric synthesis of α-allenols from readily available starting materials remains a prominent challenge, especially when simultaneous control over axial and central chirality is required. Herein, we describe the Cr-catalyzed enantioconvergent allenylation of aldehydes with racemic propargyl halides to rapidly access a wide range of chiral α-allenols with adjacent axial and central chiralities. This method features excellent regio-, diastereo- and enantioselectivity control with broad substrate scope, and provides facile access to all four stereoisomers when allied with a Mitsunobu reaction. Preliminary mechanistic studies support radical-based reaction pathways. The synthetic utility is demonstrated by the application in late-stage functionalization and the formal total synthesis of (+)-varitriol.

Effects of oral monosodium glutamate administration on serum metabolomics of suckling piglets.

This study was conducted to determine the effects of oral administration with glutamate on metabolism of suckling piglets based on 1 H-Nuclear magnetic resonance (1 H NMR) spectroscopy through the level of metabolism. Forty-eight healthy [(Yorkshire × Landrace) × Duroc] piglets born on the same day with a similar birth bodyweight (1.55 ± 0.20 kg) were obtained from six sows (8 piglets per sow). The piglets from each sow were randomly assigned into four treatments (2 piglets per treatment). The piglets were given 0.09 g/kg body weight (BW) of sodium chloride (CN group), 0.03 g/kg BW monosodium glutamate (LMG group), 0.25 g/kg BW monosodium glutamate (MMG group) and 0.50 g/kg BW monosodium glutamate (HMG group) twice a day respectively. An 1 H NMR-based metabolomics' study found that the addition of monosodium glutamate (MSG) significantly reduced serum citrate content in 7-day-old piglets, while HMG significantly increased serum trimethylamine content and significantly reduced unsaturated fat content in 7-day-old piglets (p < .05). The content of glutamine, trimethylamine, albumin, choline and urea nitrogen was significantly increased and the creatinine content decreased significantly in the 21-day-old HMG (p < .05). Analysis of serum hormones revealed that glucagon-like peptide-1 (GLP-1) content in the 21-day-old HMG was highest (p < .05). The cholecystokinin (CCK) content in the HMG of 7-day-old piglets was lower than that in the LMG (p < .05), and the CCK content in the serum of the 21-day-old MMG was highest (p < .05). The serum leptin levels in the 21-day-old HMG were the lowest (p < .05). The serum insulin content in the 7-day-old MMG was highest (p < .05). This study suggests that MSG plays an important role in the metabolism of sugar, fat and protein (amino acids). These results provide a theoretical basis for designing piglet feed formulations.

Protective effect of chicken egg yolk immunoglobulins (IgY) against enterotoxigenic Escherichia coli K88 adhesion in weaned piglets.

BACKGROUND: Enterotoxigenic Escherichia coli K88 (E. coli K88) are considered as a major cause of diarrhea and death in newly weaned piglets. Oral passive immunization with chicken egg yolk immunoglobulins (IgY) have attracted considerable attention for treatment of gastrointestinal infection due to its high specificity. In this study it was estimated the protective effect of anti-K88 fimbriae IgY against E. coli K88 adhesion to piglet intestinal mucus in vitro and to investigate the potential use of IgY for controlling E. coli-induced diarrhea in weaned piglets in vivo. RESULTS: E. coli K88 was incubated with IgY for 24 h, and the bacterial growth profiles showed that specific IgY with a concentration higher than 5 mg/mL was observed to significantly inhibit the growth of E. coli K88 compared to nonspecific yolk powder in a liquid medium. Moreover, pretreatment with 50 mg/mL of IgY was found to significantly decrease the adhesion ability of E. coli K88 to porcine jejunal and ileal mucus, further supported by the observations from our immunofluorescence microscopic analysis. In vivo, administration of IgY successfully protected piglets from diarrhea caused by E. coli K88 challenge. Additionally, IgY treatment efficiently alleviated E. coli-induced intestinal inflammation in piglets as the gene expression levels of inflammatory cytokines TNF-α, IL-22, IL-6 and IL-1ß in IgY-treated piglets remained unchanged after E. coli K88 infection. Furthermore, IgY significantly prevented E. coli K88 adhering to the jejunal and ileal mucosa of piglets with E. coli infection and significantly decreased E. coli and enterotoxin expression in colonic contents. CONCLUSION: Outcome of the study demonstrated that IgY against the fimbrial antigen K88 was able to significantly inhibit the growth of E. coli K88, block the binding of E. coli to small intestinal mucus, and protect piglets from E. coli-induced diarrhea. These results indicate that passive immunization with IgY may be useful to prevent bacterial colonization and to control enteric diseases due to E. coli infection. The study has great clinical implication to provide alternative therapy to antibiotics in E coli induced diarrhea.

Nickel-Catalyzed Enantioconvergent Borylation of Racemic Secondary Benzylic Electrophiles.

Nickel-catalyzed cross-coupling has emerged as the most versatile approach to date for achieving enantioconvergent carbon-carbon bond formation using racemic alkyl halides as electrophiles. In contrast, there have not yet been reports of the application of chiral nickel catalysts to the corresponding reactions with heteroatom nucleophiles to produce carbon-heteroatom bonds with good enantioselectivity. Herein, we establish that a chiral nickel/pybox catalyst can borylate racemic secondary benzylic chlorides to provide enantioenriched benzylic boronic esters, a highly useful family of compounds in organic synthesis. The method displays good functional group compatibility (e.g., being unimpeded by the presence of an indole, a ketone, a tertiary amine, or an unactivated alkyl bromide), and both of the catalyst components (NiCl2 ⋅glyme and the pybox ligand) are commercially available.

Chiral phosphoric acid catalyzed asymmetric addition of naphthols to para-quinone methides.

An asymmetric addition of naphthols to in situ generated para-quinone methides catalyzed by a chiral phosphoric acid is described. A range of useful triarylmethanes can be generated from stable general para-hydroxybenzyl alcohols with good efficiency and enantioselectivity.

Enantioselective Oxetane Ring Opening with Chloride: Unusual Use of Wet Molecular Sieves for the Controlled Release of HCl.

An unprecedented enantioselective oxetane opening with chloride provides access to a range of highly functionalized three-carbon building blocks. The excellent enantiocontrol is enabled not only by a new catalyst, but also by the unusual use of wet molecular sieves for the controlled release of HCl.

Organocatalytic enantio- and diastereoselective synthesis of 1,2-dihydronaphthalenes from isobenzopyrylium ions.

A highly efficient asymmetric synthesis of dihydronaphthalenes is disclosed. The process represents a new addition to the limited asymmetric reactions of isobenzopyryliums, a family of versatile 10π-electron aromatic species. Excellent asymmetric induction is achieved for the first time without an anchoring group in the 4-position or a metal catalyst, both of which were required previously in these reactions. The success is attributed to the unusual chiral counteranion (meanwhile also the nucleophile) generated in situ from the chiral phosphate and the boronic acid as well as the leaving group. Preliminary control experiments provided important insight into the reaction mechanism.

Catalytic enantioselective intermolecular desymmetrization of azetidines.

The first catalytic asymmetric desymmetrization of azetidines is disclosed. Despite the low propensity of azetidine ring opening and challenging stereocontrol, smooth intermolecular reactions were realized with excellent efficiency and enantioselectivity. These were enabled by the suitable combination of catalyst, nucleophile, protective group, and reaction conditions. The highly enantioenriched densely functionalized products are versatile precursors to other useful chiral molecules. Mechanistic studies, including DFT calculations, revealed that only one catalyst molecule is involved in the key transition state, though both reactants can be activated. Also, the Curtin-Hammett principle dictates the reaction proceeds via amide nitrogen activation.

Organocatalytic asymmetric synthesis of 1,1-diarylethanes by transfer hydrogenation.

A new organocatalytic transfer hydrogenation strategy for the asymmetric synthesis of 1,1-diarylethanes is described. Under mild conditions, a range of 1,1-diarylethanes substituted with an o-hydroxyphenyl or indole unit could be obtained with excellent efficiency and enantioselectivity. We also extended the protocol to an unprecedented asymmetric hydroarylation of 1,1-diarylalkenes with indoles for the synthesis of a range of highly enantioenriched 1,1,1-triarylethanes bearing acyclic all-carbon quaternary stereocenters. These diaryl- and triarylethanes exhibit impressive cytotoxicity against a number of human cancer cell lines. Preliminary mechanistic studies combined with DFT calculations provided important insight into the reaction mechanism.

Catalytic Asymmetric 1,6-Conjugate Addition of para-Quinone Methides: Formation of All-Carbon Quaternary Stereocenters.

Described herein is a general and mild catalytic asymmetric 1,6-conjugate addition of para-quinone methides (p-QMs), a class of challenging reactions with previous limited success. Benefiting from chiral Brønsted acid catalysis, which allows in situ formation of p-QMs, our reaction expands the scope to general p-QMs with various substitution patterns. It also enables efficient intermolecular formation of all-carbon quaternary stereocenters with high enantioselectivity.

Enantioselective formation of all-carbon quaternary stereocenters from indoles and tertiary alcohols bearing a directing group.

Described is an efficient catalytic asymmetric intermolecular C-C bond-formation process to generate acyclic all-carbon quaternary stereocenters. The reactions overcome the unfavorable steric hindrance around reactive centers, and the competitive elimination (E1), to form a range of useful indole products with excellent efficiency and enantioselectivity.