ABSTRACT
The mechanisms and regio-, chemo-, and stereoselectivity were theoretically investigated in the Rh(III)-catalyzed [5 + 1] annulation of 2-alkenylanilides and 2-alkylphenols with allenyl acetates. Two different reactants, 2-alkenylanilides and 2-alkylphenols, were selected as model systems in the density functional theory calculations. The obtained theoretical results show that both these reactants exhibit similar steps, namely, (1) N-H/O-H deprotonation and C-H activation, (2) allenyl acetate migratory insertion, (3) ß-oxygen elimination, (4) intramolecular nucleophilic addition of the nitrogen/oxygen-rhodium bond resulting in [5 + 1]-annulation, and (5) protonation with the formation of the desired product and regeneration of the Rh(III) catalyst. The theoretical evidence suggests that the selectivity is determined at the step of allenyl acetate's migratory insertion. Moreover, the regioselectivity is driven by electronic effects, while the interaction energies (C-H···π and C-H···O interactions) play a more imperative role in controlling the stereoselectivity. The obtained theoretical results not only well rationalize the experimental observations but also provide important mechanistic insights for related types of [5 + 1]-annulation reactions.
ABSTRACT
The mechanism, enantioselectivity, and effect of chiral phosphoric acid (CPA) cocatalyst were investigated by the density functional theory (DFT) for the three-component asymmetric aminohydroxylation between two diazo compounds and a hydroxylamine derivative. This type of cascade process is cooperatively catalyzed by Rh2(OAc)4 and CPA. The obtained results clearly indicate that the first step of the global reaction involves a nucleophilic attack at the nitrogen center of N-hydroxyaniline by rhodium-carbene intermediates producing imines. Subsequently, an enolate intermediate was recognized as the key species generated from the second diazo compound and the leaving benzyl alcohol (BnOH) fragment of the first step and in the presence of the same dirhodium catalyst. Then, the reaction is terminated by the asymmetric Mannich-type addition, delivering the aminohydroxylation products of an S-R conformation with the assistance of chiral phosphoric acid. The distortion/interaction analysis shows that the relative distortions of CPA and the enol play a vital role in the energy ordering of the stereocontrolling transition states (TSs). Furthermore, the influence of different substituents in CPA was fully rationalized by distortion/interaction analysis. This study opens up novel synthetic possibilities and improves the reaction predictability when exploring the related types of cooperatively catalyzed organic transformations.
ABSTRACT
Dairy goats experience metabolic stress during the peripartal period, and their ability to navigate this stage of lactation is related to the occurrence and development of metabolic diseases. Unlike dairy cows, there is a lack of comprehensive analysis of changes in the plasma profiles of peripartal dairy goats, particularly using high-throughput techniques. A subset of 9 clinically-healthy dairy goats were used from a cohort of 96 primiparous Guanzhong dairy goats (BCS, 2.75 ± 0.15). Blood samples were collected at seven time points around parturition (d 21, 14, 7 before parturition, the day of kidding, and d 7, 14, 21 postpartum), were analyzed using untargeted metabolomics and targeted lipidomics. The orthogonal partial least squares discriminant analysis model revealed a total of 31 differential metabolites including p-cresol sulfate, pyruvic acid, cholic acid, and oxoglutaric acid. The pathway enrichment analysis identified phenylalanine metabolism, aminoacyl-tRNA biosynthesis, and citrate cycle as the top three significantly-altered pathways. The Limma package identified a total of 123 differentially expressed lipids. Phosphatidylserine (PS), free fatty acids (FFA), and acylcarnitines (ACs) were significantly increased on the day of kidding, while diacylglycerols (DAG) and triacylglycerols (TAG) decreased. Ceramides (Cer) and lyso-phosphatidylinositols (LPI) were significantly increased during postpartum period, while PS, FFA, and ACs decreased postpartum and gradually returned to antepartum levels. Individual species of FFA and phosphatidylcholines (PC) were segregated based on the differences in the saturation and length of the carbon chain. Overall, this work generated the largest repository of the plasma lipidome and metabolome in dairy goats across the peripartal period, which contributed to our understanding of the multifaceted adaptations of transition dairy goats.
ABSTRACT
Subclinical hyperketonemia (SCHK) is the major metabolic disease observed during the transition period in dairy goats, and is characterized by high plasma levels of nonesterified fatty acids (NEFA) and ß-hydroxybutyrate (BHB). However, no prior study has comprehensively assessed metabolomic profiles of dairy goats with SCHK. Plasma samples were collected within 1 h after kidding from SCHK goats (BHB concentration >0.8 mM, n = 7) and clinically healthy goats (BHB concentration <0.8 mM, n = 7) with similar body condition score (2.75 ± 0.15, mean ± standard error of the mean) and parity (primiparous). A combination of targeted and untargeted mass spectrometric approaches was employed for analyzing the various changes in the plasma lipidome and metabolome. Statistical analyses were performed using the GraphPad Prism 8.0, SIMCA-P software (version 14.1), and R packages (version 4.1.3). Plasma aminotransferase, nonesterified fatty acids, and BHB concentrations were greater in the SCHK group, but plasma glucose concentrations were lower. A total of 156 metabolites and 466 lipids were identified. The analysis of untargeted metabolomics data by principal component analysis and orthogonal partial least squares discriminant analysis revealed a separation between SCHK and clinically healthy goats. According to the screening criteria (unpaired t-test, P < 0.05), 30 differentially altered metabolites and 115 differentially altered lipids were detected. Pathway enrichment analysis identified citrate cycle, alanine, aspartate and glutamate metabolism, glyoxylate and dicarboxylate metabolism, and phenylalanine metabolism as significantly altered pathways. A greater concentration of plasma isocitric acid and cis-aconitic acid levels was observed in SCHK goats. In addition, AA such as lysine and isoleucine were greater, whereas alanine and phenylacetylglycine were lower in SCHK dairy goats. Dairy goats with SCHK also exhibited greater oleic acid, acylcarnitine, and phosphatidylcholine and lower choline and sphingomyelins. Acylcarnitines, oleic acid, and tridecanoic acid displayed positive correlations with several lipid species. Alanine, hippuric acid, and histidinyl-phenylalanine were negatively correlated with several lipids. Overall, altered metabolites in SCHK dairy goats indicated a more severe degree of negative energy balance. Data also indicated an imbalance in the tricarboxylic acid (TCA) cycle, lipid metabolism, and AA metabolism. The findings provide a more comprehensive understanding of the pathogenesis of SCHK in dairy goats.
