Electronic Control on Linear versus Branched Alkylation of 2-/3-Aroylbenzofurans with Acrylates: Combined DFT and Synthetic Studies.

Investigations on the factors that govern unusual branched alkylation of 2-aroylbenzofurans with acrylates by Ru-catalyzed carbonyl-directed C-H activation has been carried out by calculating the kinetics associated with the two key steps-the coordination of the acrylate with the intermediate ruthenacycle and the subsequent migratory insertion reaction-studied with the help of DFT calculations. Eight possible orientations for each mode of alkylation have been considered for the calculations. From these calculations, it has been understood that there is a synergistic operation of the steric and electronic effects favoring the branched alkylation. Further DFT investigations on the alkylation of the isomeric 3-aroylbenzofurans indicated a preference for the linear alkylation and this has been verified experimentally. Overall, the observed/calculated complementary selectivity in the alkylation of 2-/3-aroylbenzofurans with acrylates reveals that the substrate-dependent charge distribution of the Ru-C bond in the intermediate ruthenacycle is an important determining factor and thus the current work opens up a new domain of substrate design for controlling regioselectivity.

The NEU1-selective sialidase inhibitor, C9-butyl-amide-DANA, blocks sialidase activity and NEU1-mediated bioactivities in human lung in vitro and murine lung in vivo.

Neuraminidase-1 (NEU1) is the predominant sialidase expressed in human airway epithelia and lung microvascular endothelia where it mediates multiple biological processes. We tested whether the NEU1-selective sialidase inhibitor, C9-butyl-amide-2-deoxy-2,3-dehydro-N-acetylneuraminic acid (C9-BA-DANA), inhibits one or more established NEU1-mediated bioactivities in human lung cells. We established the IC50 values of C9-BA-DANA for total sialidase activity in human airway epithelia, lung microvascular endothelia and lung fibroblasts to be 3.74 µM, 13.0 µM and 4.82 µM, respectively. In human airway epithelia, C9-BA-DANA dose-dependently inhibited flagellin-induced, NEU1-mediated mucin-1 ectodomain desialylation, adhesiveness for Pseudomonas aeruginosa and shedding. In lung microvascular endothelia, C9-BA-DANA reversed NEU1-driven restraint of cell migration into a wound and disruption of capillary-like tube formation. NEU1 and its chaperone/transport protein, protective protein/cathepsin A (PPCA), were differentially expressed in these same cells. Normalized NEU1 protein expression correlated with total sialidase activity whereas PPCA expression did not. In contrast to eukaryotic sialidases, C9-BA-DANA exerted far less inhibitory activity for three selected bacterial neuraminidases (IC50 > 800 µM). Structural modeling of the four human sialidases and three bacterial neuraminidases revealed a loop between the seventh and eighth strands of the ß-propeller fold, that in NEU1, was substantially shorter than that seen in the six other enzymes. Predicted steric hindrance between this loop and C9-BA-DANA could explain its selectivity for NEU1. Finally, pretreatment of mice with C9-BA-DANA completely protected against flagellin-induced increases in lung sialidase activity. Our combined data indicate that C9-BA-DANA inhibits endogenous and ectopically expressed sialidase activity and established NEU1-mediated bioactivities in human airway epithelia, lung microvascular endothelia, and fibroblasts in vitro and murine lungs in vivo.

Ru-catalyzed branched versus linear selective C3-alkylation of 2-aroylbenzofurans with acrylates via C-H activation.

The carbonyl-directed C3-H activation and alkylation of 2-aroylbenzo[b]furans with acrylates occurs selectively either in a linear or branched fashion, depending on the catalyst employed; [Ru(p-cymene)Cl2]2 or Ru(PPh3)3Cl2, respectively. Two alternate pathways--funded upon the differences in steric and electronic preferences of these two complexes--is proposed for the selectivity of linear versus branched products.

Rh(III)-Catalyzed Reaction of α-Carbonyl Sulfoxonium Ylides and Alkenes: Synthesis of Indanones via [4 + 1] Cycloaddition.

The synthesis of indanone derivatives by the Rh(III)-catalyzed reaction of α-carbonyl sulfoxonium ylides with activated alkenes is reported. The reaction shows a high tolerance for functional groups and furnishes a variety of substituted indanone derivatives via a formal [4 + 1] cycloaddition. Highly stable sulfoxonium ylides were used as substrates in this C-H functionalization, and their bifunctional character could be effectively exploited using Rh(III) catalysis via sequential double C-C bond formation. Based on mechanistic studies including deuterium-labeling experiments, the reaction is proposed to proceed as follows: Rh(III)-catalyzed C-H oxidative alkenylation via ß-hydride elimination, readdition of H-Rh species, a 1,2-carbon shift with the elimination of DMSO, and protonation.

Cobalt-Catalyzed C-H Iodination of Aromatic Amides with Molecular Iodine through the Use of a 2-Aminophenyloxazoline-Based Bidentate-Chelation System.

The cobalt-catalyzed chelation-assisted C-H iodination of aromatic amides using molecular iodine as an iodinating reagent is reported. The reaction is carried out in an atmosphere of air and uses Co(OAc)2·4H2O as an efficient catalyst and 4-chloro-2-(4,5-dihydrooxazol-2-yl)aniline as a directing group. The reaction shows a wide functional group tolerance. Mechanistic studies suggest that the reaction proceeds through a different mechanism from that of our previously reported transformation in which a Co(II) catalyst/8-amino-5-choloroquinoline chelation system was used.

Cobalt(ii)-catalyzed chelation-assisted C-H iodination of aromatic amides with I2.

The cobalt-catalyzed chelation-assisted iodination of aromatic amides using molecular I2 as an iodinating reagent is reported. 8-Amino-5-chloroquinoline functions as an efficient directing group. This mild and air stable catalytic system shows a wide functional group tolerance and improved synthetic accessibility.

Cobalt-catalyzed chelation assisted C-H allylation of aromatic amides with unactivated olefins.

The cobalt-catalyzed chelation assisted ortho C-H allylation of aromatic amides with unactivated aliphatic alkenes is reported. The reaction proceeds in air under mild reaction conditions, providing allylated products in good to excellent yields with high E-selectivities. This operationally simple method shows a high functional group tolerance.

Optimization of the anti-cancer activity of phosphatidylinositol-3 kinase pathway inhibitor PITENIN-1: switching a thiourea with 1,2,3-triazole.

We previously reported encouraging in vitro and in vivoanti-cancer activity of N-((3-chloro-2-hydroxy-5-nitrophenyl)carbamothioyl)benzamide (termed PITENIN-1). In the current work, we describe the structure-activity relationship study of PIT-1 series, based on the replacement of central thiourea unit with a 1,2,3-triazole, which leads to increased liver microsomal stability, drug likeness and toxicity towards cancer cells.