Electroreductive Access to 1,2-Aminoalcohols via Cross Aza-Pinacol Coupling of N-Acyl Diarylketimines and Aldehydes.

We present highly efficient and operationally simple synthetic methods for 1,2-aminoalcohols via electroreductive cross aza-pinacol coupling between N-acyl diarylketimines and aldehydes. Preliminary mechanistic studies including cyclic voltammetry and density functional theory (DFT) calculations suggest that the reaction is instigated by selective electrochemical single electron transfer (SET) of N-acylketimines. The developed electrochemical protocol is compatible to biorelevant functional groups, enabling late-stage functionalization of pharmacophores.

Enantioselective Friedel-Crafts Reaction of Heteroaromatic Compounds with Glyoxals Catalyzed by Chiral Oxazaborolidinium Ion Catalyst.

A catalytic enantioselective Friedel-Crafts reaction of various heteroaromatic compounds with glyoxals has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction provided chiral α-hydroxyketones in high yield (up to 96%) with excellent enantioselectivity (up to >99% ee). The synthetic utility of this method was illustrated by conversion of the products to various derivatives such as 1,2-diol and ß-amino alcohol.

N-Cyano sulfilimine functional group as a nonclassical amide bond bioisostere in the design of a potent analogue to anthranilic diamide insecticide.

To explore the potential of the N-cyano sulfilimine group as an amide bond isostere, a derivative of the blockbuster anthranilic diamide, chlorantramiliprole, was synthesized and evaluated with regard to its physicochemical properties, permeability, and biological activity. Given the combination of N-cyano sulfilimine chlorantraniliprole 1 and its strong hydrogen bond acceptor character, high permeability, and excellent insecticidal activity, the N-cyano sulfilimine functional group could be considered as an amide bond isostere.

Enantio- and Diastereoselective Michael Addition of Cyclic Ketones/Aldehydes to Nitroolefins in Water as Catalyzed by Proline-Derived Bifunctional Organocatalysts.

New l-proline-derived bifunctional secondary amine organocatalysts were synthesized for enantioselective Michael reactions in water as a solvent. Application of these catalysts in Michael additions provided high yield (up to 97%) with high stereoselectivity (dr up to 99:1 and ee up to 99%). The effect of phenyl group at (R)-C6 in the catalyst was investigated and played a key role in successful catalysis by density functional theory computational calculations. The synthetic utility of this reaction was demonstrated by the formal synthesis of Sch 50971, which is a novel histamine H3 receptor agonist.

Visible Light-Mediated Enantioselective Addition of α-Aminoalkyl Radicals to Ketones Catalyzed by Chiral Oxazaborolidinium Ion.

The development of a visible light-mediated synthetic method for chiral 1,2-amino tertiary alcohols is described. In the presence of a chiral oxazaborolidinium ion catalyst and photosensitizer, the enantioselective addition of an α-aminoalkyl radical to aryl methyl ketones under visible light provides chiral 1,2-amino tertiary alcohol derivatives in high yields (up to 88%) with excellent enantioselectivities (up to 98% ee). With mechanistic studies such as radical trapping analysis, radical clock analysis, and the measurement of quantum yield, a plausible catalytic cycle is proposed.

Integrated metagenomics and metabolomics analysis illustrates the systemic impact of the gut microbiota on host metabolism after bariatric surgery.

AIM: To explore how bariatric surgery (BS) modified the obesity-associated gut microbiome, the host metabolome, and their interactions in obese Korean patients. MATERIALS AND METHODS: Stool and fasting blood samples were obtained before and 1, 3, 6, and 12 months after BS from 52 patients enrolled in the Korean Obesity Surgical Treatment Study. We analysed the gut microbiome by 16S rRNA gene sequencing and the serum metabolome, including bile acids, by nuclear magnetic resonance spectroscopy and ultrahigh-performance liquid chromatography/triple quadrupole mass spectrometry. RESULTS: Stool metagenomics showed that 27 microbiota were enriched and 14 microbiota were reduced after BS, whereas the abundances and diversity of observed features were increased. The levels of branched-chain amino acids and metabolites of energy metabolism in serum were decreased after surgery, whereas the levels of metabolites related to microbial metabolism, including dimethyl sulphone, glycine, and secondary bile acids, were increased in the serum samples. In addition, we found notable mutual associations among metabolites and gut microbiome changes attributed to BS. CONCLUSIONS: Changes in the gut microbiome community and systemic levels of amino acids and sugars were directly derived from anatomical changes in the gastrointestinal tract after BS. We hypothesized that the observed increases in microbiome-related serum metabolites were a result of complex and indirect changes derived from BS. Ethnic-specific environmental or genetic factors could affect Korean-specific postmetabolic modification in obese patients who undergo BS.

Enantioselective Friedel-Crafts Alkylation of Furans with o-Quinone Methide Using a Chiral Oxazaborolidinium Ion Catalyst.

A chiral Lewis acid-catalyzed enantioselective Friedel-Crafts furan alkylation with in situ-generated o-quinone methides has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99%) with excellent enantioselectivity (up to >99% ee).

Catalytic Asymmetric Darzens-Type Epoxidation of Diazoesters: Highly Enantioselective Synthesis of Trisubstituted Epoxides.

Highly enantioselective Darzens-type epoxidation of diazoesters with glyoxal derivatives was accomplished using a chiral boron-Lewis acid catalyst, which facilitated asymmetric synthesis of trisubstituted α,ß-epoxy esters. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99 %) with excellent enantio- and diastereoselectivity (up to >99 % ee and >20:1 dr, respectively). The synthetic potential of this method was illustrated by conversion of the products to various compounds such as epoxy γ-butyrolactone, tertiary ß-hydroxy ketone and epoxy diester.

Bifunctional Urea/Hg(OAc)2-Mediated Synthesis of 4-Aryl-6-oxycarbonyl-2-pyrones and 2-Pyridones from Dithiomalonate and ß,γ-Unsaturated α-Keto Esters.

Disubstituted 2-pyrones and 2-pyridones were obtained by bifunctional urea-catalyzed Michael addition/lactonization or lactamization followed by a Hg(OAc)2- or Hg(OAc)2/DBU-mediated hydrolysis/decarboxylation/dehydrogenation process. This one-pot two-stage protocol enabled the rapid synthesis of 4,6-disubstituted 2-pyrones and 2-pyridones from dithiomalonate and ß,γ-unsaturated α-keto esters in practical yields under mild reaction conditions. Additionally, the obtained 2-pyridones were facilely transformed to 2,4,6-trisubstituted pyridines in excellent yields.

Enantioselective Acyloin Rearrangement of Acyclic Aldehydes Catalyzed by Chiral Oxazaborolidinium Ion.

A catalytic enantioselective acyloin rearrangement of acyclic aldehydes to synthesize highly optically active acyloin derivatives is described. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction provided chiral α-hydroxy aryl ketones in high yield (up to 95%) and enantioselectivity (up to 98% ee). In addition, the enantioselective acyloin rearrangement of α,α-dialkyl-α-siloxy aldehydes produced chiral α-siloxy alkyl ketones in high yield (up to 92%) with good enantioselectivity (up to 89% ee).

Enantioselective Cyclopropanation/[1,5]-Hydrogen Shift to Access Rauhut-Currier Product.

A Michael addition initiated cyclopropanation/[1,5]-hydrogen shift has been developed for the enantioselective synthesis of Rauhut-Currier products. The reaction of α-alkyl diazoesters and in situ generated o-quinone methides proceeds in the presence of chiral oxazaborolidinium ion, providing Z-stereocontrolled Rauhut-Currier products in high yields (up to 96%) with excellent Z/E selectivities (>20:1) and enantioselectivities (up to >99% ee). The synthetic utility was illustrated by conversion of the product to 3,4-dihydrocoumarins with two adjacent chiral stereocenters.

Comparable Plasma Lipid Changes in Patients with High-Grade Cervical Intraepithelial Neoplasia and Patients with Cervical Cancer.

Cervical cancer is the fourth most prevalent cancer among women worldwide and usually develops from cervical intraepithelial neoplasia (CIN). In the present study, we compared alterations in lipids associated with high-grade CIN and cervical cancer with those associated with a normal status and low-grade CIN by performing global lipid profiling on plasma (66 healthy controls and 55 patients with CIN1, 44 with CIN2/3, and 60 with cervical cancer) using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry. We identified 246 lipids and found 31 lipids with similar alterations in both high-grade CIN and cervical cancer. Among these 31 lipids, four lipid classes (phosphatidylcholine, phosphatidylethanolamine, diglyceride, and free fatty acids) were identified as the major lipid classes with significant differences in the patients with CIN2/3 and cervical cancer compared to the healthy controls and the patients with CIN1. Lipid metabolites belonging to the same classes were positively correlated with each other. High-grade CIN and cervical cancer induce comparable changes in lipid levels, which are closely related to the development of cervical tumors. These results suggest that lipid profiling is a useful method for monitoring progression to cervical cancer.

Circulating lipidomic alterations in obese and non-obese subjects with non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) affects obese and non-obese individuals. However, mechanisms underlying non-obese non-alcoholic steatohepatitis (NASH) remain unclear. AIMS: To attempt to identify metabolic perturbations associated with non-obese and obese NAFLD using a lipidomics approach. METHODS: A cross-sectional analysis of 361 subjects with biopsy-proven NAFLD (157 NAFL and 138 NASH) and healthy controls (n = 66) was performed. Individuals were categorised as obese or non-obese based on the Asian cut-off for body mass index. Circulating lipidomic profiling of sera was performed based on the histological severity of NAFLD. Circulating lipidomic alterations were validated with an independent validation set (154 NAFLD subjects [93 NAFL and 61 NASH] and 21 healthy controls). RESULTS: Saturated sphingomyelin (SM) species were significantly associated with visceral adiposity in non-obese NAFLD (SM d38:0; P < 0.001) but not in obese NAFLD. Additionally, SM levels were significantly associated with systemic and adipose tissue insulin resistance (SM d38:0; P = 0.002 and <0.001, respectively). Five potential lipid metabolites for non-obese subjects and seven potential lipids for obese subjects were selected to predict NAFLD and NASH. These lipid combinations showed good diagnostic performance for non-obese (area under the curve [AUC] for NAFLD/NASH = 0.916/0.813) and obese (AUC for NAFLD/NASH = 0.967/0.812) subjects. Moreover, distinctly altered patterns of diacylglycerol (DAG), triacylglycerol (TAG) and SM levels were confirmed in the validation set depending on the histological severity of NAFLD. CONCLUSION: Non-obese and obese NAFLD subjects exhibit unique circulating lipidomic signatures, including DAGs, TAGs and SMs. These lipid combinations may be useful biomarkers for non-obese and obese NAFLD patients.

Highly Enantioselective Allylation Reactions of Aldehydes with Allyltrimethylsilane Catalyzed by a Chiral Oxazaborolidinium Ion.

A highly enantioselective allylation reaction of aldehydes with silyl reagents was developed for the synthesis of a variety of chiral homoallylic alcohols. In the presence of a chiral oxazaborolidinium ion (COBI) catalyst, the reaction proceeded in high yield (up to 99%) with excellent asymmetric induction (up to 99% ee).

Urinary Metabolomic Profiling Analysis and Evaluation of the Effect of Ecklonia cava Extract Intake.

Metabolomics is a powerful tool for the investigation of interactions between diet, nutrients, and human metabolism. Ecklonia cava is an edible brown alga that is abundantly found in Korea and Japan and contains unique polyphenols referred to as phlorotannins. However, there are few metabolomics studies related to the effects of polyphenols in humans. In this study, we performed a mass spectrometry-based metabolomics analysis of urine samples from participants with a body mass index (BMI) higher than 25 kg/m2 and lower than 30 kg/m2 to investigate the effects of the intake of seapolynol isolated from E. cava. Metabolomic profiling showed that the levels of riboflavin, urocanic acid, 5-hydroxy-6-methoxyindole glucuronide, and guanidino valeric acid were significantly increased in the seapolynol intake group compared with the placebo group. A correlation analysis was performed to identify the association between the metabolites' levels and clinical characteristics related to body fat. Among the metabolites whose concentrations changed in the seapolynol intake group, riboflavin was associated with BMI, body weight, fat mass, and percent body fat. These findings suggest that the decreased body fat induced by the intake of seapolynol is related to an increase in the antioxidant effect of riboflavin.

Enantioselective Strecker and Allylation Reactions with Aldimines Catalyzed by Chiral Oxazaborolidinium Ions.

Chiral oxazaborolidinium ion (COBI)-catalyzed enantioselective nucleophilic addition reactions of aldimines using tributyltin cyanide and allyltributylstannane have been developed. Various α-aminonitriles and homoallylic amines were synthesized in high yield (up to 98%) with high to excellent enantioselectivity (up to 99% ee). A rational mechanistic model for the complex of COBI and aldimine is provided to account for these enantioselective reactions.

Enantioselective Carbonyl 1,2- or 1,4-Addition Reactions of Nucleophilic Silyl and Diazo Compounds Catalyzed by the Chiral Oxazaborolidinium Ion.

Boron Lewis acid catalysis has a long history and has become one of the most powerful methods for organic synthesis. In addition to achiral boron catalysts such as BX3 (X = F, Cl, Br) and B(C6F5)3, chiral boron catalysts are also significant synthetic tools used by organic chemists in academic laboratories and industry. Since first reported by Corey et al. in 2002 ( Corey et al. J. Am. Chem. Soc. 2002 , 124 , 3808 ), the chiral oxazaborolidinium ion (COBI), an activated form of proline-derived oxazaborolidine, has been used as a strong Lewis acid catalyst. Although the early examples of asymmetric synthesis through COBI-catalyzed nucleophilic 1,2- or 1,4-carbonyl additions were reported in 2004-2006, Diels-Alder and cycloaddition reactions of various carbonyl compounds were mostly developed over the next several years to afford enantioenriched cyclized products. The power of COBI in catalyzing carbonyl 1,2- or 1,4-addition reactions triggered our interest in developing asymmetric synthetic methodologies to generate versatile enantiomerically enriched compounds. In this Account, we summarize our recent studies on COBI-catalyzed asymmetric nucleophilic carbonyl addition and tandem reactions. Logical mechanistic explanations of asymmetric COBI catalysis are also discussed. The proton-activated COBI catalyst, which can activate various carbonyl compounds such as aldehydes, ketones, acroleins, and enones through Lewis acid-base interactions and synergistic hydrogen bonds, facilitates asymmetric 1,2- or 1,4-carbonyl additions of nucleophiles. Nucleophiles bearing trialkylsilyl groups successfully reacted with aromatic, aliphatic, and α,ß-unsaturated aldehydes through 1,2-addition reactions resulting in chiral ß-hydroxy esters. In addition, efficient asymmetric hydrosilylation of ketones was achieved with a TfOH-activated COBI catalyst. Optically active ß-keto esters and all-carbon quaternary aldehydes were synthesized successfully through asymmetric 1,2-addition of diazo compounds and tandem H- or C-migration, respectively. In some cases, epoxide products were obtained as side products via the Darzens reaction pathway. Solvent and π-π interactions played important roles in favoring C-migration over H-migration. Nucleophilic 1,4-addition of diazo compounds and chemoselective ring-closure afforded an efficient approach to cyclopropanes, and their tandem rearrangements provided four- and seven-membered cyclic compounds with excellent stereoselectivity. After a Michael addition of diazo compounds, the selective ß-hydride shift pathway afforded the ß-substituted cyclic enones with high diastereo- and enantioselectivity. The presence of π-bond(s) in the substituents at the α-position of the diazo compound hindered the ß-hydride shift pathway and, as a result, favored the cyclopropanation pathway. While there still remain challenges to be overcome, these results further understanding of COBI catalysis and open a window for future development of new asymmetric synthetic methods using carbonyl addition and tandem reactions.

Asymmetric Synthesis of Enantioenriched 2-Aryl-2,3-Dihydrobenzofurans by a Lewis Acid Catalyzed Cyclopropanation/Intramolecular Rearrangement Sequence.

A cyclopropanation/intramolecular rearrangement initiated by the Michael addition of in situ generated ortho-quinone methides (o-QMs) has been developed for the enantioselective synthesis of 2-aryl-2,3-dihydrobenzofurans containing two consecutive stereogenic centers, including a quaternary carbon atom. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in excellent yields (up to 95 %) with excellent stereoselectivity (up to >99 ee, up to >20:1 d.r.).

Multicomponent dipolar cycloadditions: efficient synthesis of polycyclic fused pyrrolizidines via azomethine ylides.

An efficient multicomponent dipolar cycloaddition for the synthesis of polycyclic fused pyrrolizidines was developed using N-aromatic zwitterions, aldehydes, and amino acids. The developed reactions proceed through azomethine ylides generated in situ from the decarboxylated reactions of aldehydes and amino acids followed by the [3 + 2] cycloaddition of N-aromatic zwitterions under mild reaction conditions.