Project description:Herein, we report a multistep one-pot reaction of substituted pyridines leading to N-protected tetrahydropyridines with outstanding enantioselectivity (up to 97% ee). An iridium(I)-catalyzed dearomative 1,2-hydrosilylation of pyridines enables the use of N-silyl enamines as a new type of nucleophile in a subsequent palladium-catalyzed asymmetric allylic alkylation. This telescoped process overcomes the intrinsic nucleophilic selectivity of pyridines to synthesize enantioenriched, C-3-substituted tetrahydropyridine products that have been otherwise challenging to access.
Project description:Developing efficient strategies for the deoxygenative functionalization of carbonyl compounds is crucial for enhancing the effective utilization of biomass and the upgrading of chemical feedstocks. In this study, we present an elegant cathodic reduction strategy that enables a tandem alkylation/dearomatization reaction between quinoline derivatives and aryl aldehydes/ketones in a one-pot process. Our approach can be executed via two distinct paths: the aluminum (Al)-facilitated spin-center shift (SCS) path and the Al-facilitated direct deoxygenation path. Both paths are theoretically substantiated by DFT calculations. The crux of this protocol is the in-situ activation of the alcohol intermediates by Al salts, which substantially lowers the activation energy necessary for the formation of key transition states, thereby effectively facilitating the deoxygenation process. Control experiments have not only successfully identified the intermediates but also established that the hydrogen source for the reaction is derived from water and tetrabutylammonium salt. Notably, this method is transition metal-free and compatible with water and oxygen.
Project description:The catalytic asymmetric dearomatization (CADA) reaction has proved to be a powerful protocol for rapid assembly of valuable three-dimensional cyclic compounds from readily available planar aromatics. In contrast to the well-studied indoles and naphthols, phenols have been considered challenging substrates for intermolecular CADA reactions due to the combination of strong aromaticity and potential regioselectivity issue over the multiple nucleophilic sites (O, C2 as well as C4). Reported herein are the chiral phosphoric acid-catalyzed divergent intermolecular CADA reactions of common phenols with azoalkenes, which deliver the tetrahydroindolone and cyclohexadienone products bearing an all-carbon quaternary stereogenic center in good yields with excellent ee values. Notably, simply adjusting the reaction temperature leads to the chemo-divergent intermolecular (3 + 2) and alkylation dearomatization reactions. Moreover, the stereo-divergent synthesis of four possible stereoisomers in a kind has been achieved via changing the sequence of catalyst enantiomers.
Project description:A simple method for the C-4 alkylation of isoquinolines is described using benzoic acid as a nucleophilic reagent and vinyl ketones as an electrophile. The reaction shows tolerance for substitution at C-3, and C-5-C-8 positions as well as allowing some variation of the vinyl ketone electrophiles. The products contain a carbonyl that can act as a synthetic handle for further manipulations giving esters, amines, or simple alkyl products.
Project description:Beta adrenergic receptors (βARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds β1AR and β2AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately tenfold selective for the β1AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human β1AR bound to an antagonist carazolol and different agonists including norepinephrine, epinephrine and BI-167107. Structural comparison revealed that the catecholamine-binding pockets are identical between β1AR and β2AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities.
Project description:A comprehensive understanding of signalling downstream of GPCRs requires a broad approach to capture novel signalling modalities in addition to established pathways. Here, using an array of sixteen validated BRET-based biosensors, we analyzed the ability of seven different β-adrenergic ligands to engage five distinct signalling pathways downstream of the β1-adrenergic receptor (β1AR). In addition to generating signalling signatures and capturing functional selectivity for the different ligands toward these pathways, we also revealed coupling to signalling pathways that have not previously been ascribed to the βAR. These include coupling to Gz and G12 pathways. The signalling cascade linking the β1AR to calcium mobilization was also characterized using a combination of BRET-based biosensors and CRISPR-engineered HEK 293 cells lacking the Gαs subunit or with pharmacological or genetically engineered pathway inhibitors. We show that both Gs and G12 are required for the full calcium response. Our work highlights the power of combining signal profiling with genome editing approaches to capture the full complement of GPCR signalling activities in a given cell type and to probe their underlying mechanisms.
Project description:The β2-adrenergic receptor (β2AR) is a prototypical G protein-coupled receptor (GPCR) that preferentially couples to the stimulatory G protein Gs and stimulates cAMP formation. Functional studies have shown that the β2AR also couples to inhibitory G protein Gi, activation of which inhibits cAMP formation [R. P. Xiao, Sci. STKE 2001, re15 (2001)]. A crystal structure of the β2AR-Gs complex revealed the interaction interface of β2AR-Gs and structural changes upon complex formation [S. G. Rasmussen et al., Nature 477, 549-555 (2011)], yet, the dynamic process of the β2AR signaling through Gs and its preferential coupling to Gs over Gi is still not fully understood. Here, we utilize solution nuclear magnetic resonance (NMR) spectroscopy and supporting molecular dynamics (MD) simulations to monitor the conformational changes in the G protein coupling interface of the β2AR in response to the full agonist BI-167107 and Gs and Gi1 These results show that BI-167107 stabilizes conformational changes in four transmembrane segments (TM4, TM5, TM6, and TM7) prior to coupling to a G protein, and that the agonist-bound receptor conformation is different from the G protein coupled state. While most of the conformational changes observed in the β2AR are qualitatively the same for Gs and Gi1, we detected distinct differences between the β2AR-Gs and the β2AR-Gi1 complex in intracellular loop 2 (ICL2). Interactions with ICL2 are essential for activation of Gs These differences between the β2AR-Gs and β2AR-Gi1 complexes in ICL2 may be key determinants for G protein coupling selectivity.
Project description:Chiral-at-metal compounds (R Ru,S C)/(S Ru,S C)-[CyRu(1O-2N)PPh3]PF6 and (R Ru,S C)/(S Ru,S C)-[CyRu(2O-1N)PPh3]PF6 were prepared using anions 1O-2N- and 2O-1N- of the Schiff bases, derived from the hydroxynaphthaldehydes and (S)-1-phenylethylamine. The pure (R Ru,S C)-diastereomers were obtained by crystallization. In the unit cell of (R Ru,S C)-[CyRu(1O-2N)PPh3]PF6, there are three independent molecules, which differ in the propeller sense of the PPh3 ligand. Molecules [1] and [2] have (M PPh3 )-configuration and molecule [3] has (P PPh3 )-PPh3 configuration. PPh3 diastereoisomerism is discussed including other pairs of compounds, differing only in the PPh3 configuration. A conformational analysis reveals an internal stabilization inside the PPh3 ligand by a system of attractive CH/π interactions and a new bonding motif PhPPh3 face-on π-Ar, both characteristic features of [(π-Ar)LL'MPPh3] compounds. The propeller diastereomers interconvert via a low-energy pathway and a high-energy pathway, corroborated by density functional theory calculations.
Project description:Feedstock aromatic compounds are compelling low-cost starting points from which molecular complexity can be generated rapidly via oxidative dearomatization. Oxidative dearomatizations commonly rely heavily on hypervalent iodine or heavy metals to provide the requisite thermodynamic driving force for overcoming aromatic stabilization energy. This article describes oxidative dearomatizations of 2-(hydroxymethyl)phenols via their derived bis(dichloroacetates) using hydrogen peroxide as a mild oxidant that intercepts a transient quinone methide. A stereochemical study revealed that the reaction proceeds by a new mechanism relative to other phenol dearomatizations and is complementary to extant methods that rely on hypervalent iodine. Using a new chiral phase-transfer catalyst, the first asymmetric syntheses of 1-oxaspiro[2.5]octa-5,7-dien-4-ones were reported. The synthetic utility of the derived 1-oxaspiro[2.5]octadienones products is demonstrated in a downstream complexity-generating transformation.
Project description:"Chemical precompression" through introducing impurity atoms into hydrogen has been proposed as a method to facilitate metallization of hydrogen under external pressure. Here we selected Ar(H2)2, a hydrogen-rich compound with molecular hydrogen, to explore the effect of "doping" on the intermolecular interaction of H2 molecules and metallization at ultrahigh pressure. Ar(H2)2 was studied experimentally by synchrotron X-ray diffraction to 265 GPa, by Raman and optical absorption spectroscopy to 358 GPa, and theoretically using the density-functional theory. Our measurements of the optical bandgap and the vibron frequency show that Ar(H2)2 retains 2-eV bandgap and H2 molecular units up to 358 GPa. This is attributed to reduced intermolecular interactions between H2 molecules in Ar(H2)2 compared with that in solid H2 A splitting of the molecular vibron mode above 216 GPa suggests an orientational ordering transition, which is not accompanied by a change in lattice symmetry. The experimental and theoretical equations of state of Ar(H2)2 provide direct insight into the structure and bonding of this hydrogen-rich system, suggesting a negative chemical pressure on H2 molecules brought about by doping of Ar.