Gold-Catalyzed Intramolecular Aminoarylation of Alkenes: C-C Bond Formation through Bimolecular Reductive Elimination

Gold-ilocks and the 3 mol % catalyst: Bimetallic gold bromides allow the room temperature aminoarylation of unactivated terminal olefins with aryl boronic acids using Selectfluor as an oxidant. A catalytic cycle involving gold(I)/gold(III) and a bimolecular reductive elimination for the key CC bond-forming step is proposed. dppm= bis(diphenylphosphanyl)methane

Enantiomerically selective vapochromic sensing

a b s t r a c t The double salt materials platinum(II)tetrakis-R-␤-methylphenethylisocyanide tetracyanoplatinate(II) (R-1) and platinum(II)tetrakis-S-␤-methylphenethylisocyanide tetracyanoplatinate(II) (S-1) have been synthesized with highly enantiomerically pure isocyanide ligands. The vapochromic behavior of R-1 and S-1 has been studied in the presence of a chiral probe vapor to determine if enantiomerically selective sensing is possible with these materials. The wavelength of maximum emission values ( max ) for solidstate vapoluminescence spectra of R-1 and S-1 in the presence of enriched R-and S-2-butanol vapor differ by approximately 10 nm while the max values for R-1 and S-1 under nitrogen are nearly identical. Principal component analysis has been performed on datasets that consist of a series of vapoluminescence spectra of R-1 and S-1 as a function of the R/S-2-butanol ratio. Plots of principal component one versus R/S-2-butanol ratio show mirror image trends for R-1 relative to S-1. While care must be taken to control water vapor and monitor R-1 and S-1 for possible decomposition, the reported results nevertheless show that R-1 and S-1 are capable of enantiomerically selective vapochromic sensing

Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis

Alcoholic hepatitis (AH) is a life-threatening condition characterized by profound hepatocellular dysfunction for which targeted treatments are urgently needed. Identification of molecular drivers is hampered by the lack of suitable animal models. By performing RNA sequencing in livers from patients with different phenotypes of alcohol-related liver disease (ALD), we show that development of AH is characterized by defective activity of liver-enriched transcription factors (LETFs). TGFβ1 is a key upstream transcriptome regulator in AH and induces the use of HNF4α P2 promoter in hepatocytes, which results in defective metabolic and synthetic functions. Gene polymorphisms in LETFs including HNF4α are not associated with the development of AH. In contrast, epigenetic studies show that AH livers have profound changes in DNA methylation state and chromatin remodeling, affecting HNF4α-dependent gene expression. We conclude that targeting TGFβ1 and epigenetic drivers that modulate HNF4α-dependent gene expression could be beneficial to improve hepatocellular function in patients with AH

RANTES/CCL5 and risk for coronary events: Results from the MONICA/KORA Augsburg case-cohort, Athero-express and CARDIoGRAM studies

Background: The chemokine RANTES (regulated on activation, normal T-cell expressed and secreted)/CCL5 is involved in the pathogenesis of cardiovascular disease in mice, whereas less is known in humans. We hypothesised that its relevance for atherosclerosis should be reflected by associations between CCL5 gene variants, RANTES serum concentrations and protein levels in atherosclerotic plaques and risk for coronary events. Methods and Findings: We conducted a case-cohort study within the population-based MONICA/KORA Augsburg studies. Baseline RANTES serum levels were measured in 363 individuals with incident coronary events and 1,908 non-cases (mean follow-up: 10.2±

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies

Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Development of Gold-Catalyzed Oxidative Alkene Heteroarylation and of Enantioselective Reactions Enabled by Phase Separation

AbstractDevelopment of Gold-Catalyzed Oxidative Alkene Heteroarylation and of Enantioselective Reactions Enabled by Phase SeparationbyAaron Daniel LacknerDoctor of Philosophy in ChemistryUniversity of California, BerkeleyProf. F. Dean Toste, ChairAs with many bodies of research compiled through the course of a graduate career, this thesis reflects an uneven progression of aim based on the accumulation of unexpected results. Three main topics will be discussed in this thesis' chapters that may appear somewhat disparate. In particular, a significant conceptual gap exists between the first topic, oxidative gold catalysis, and the second topic, chiral anion phase-transfer catalysis. However, these fields are united by the realization that the characteristics of a reagent integral to the former might also be uniquely suitable for implementation in the latter. Chapter 1 discusses the development of a redox-active Au(I)-Au(III) catalytic system for the functionalization of alkenes. Based on early precedent, we hoped to show that the strong dicationic oxidant Selectfluor could generate a catalytically active cationic Au(III) center that enables reactivity that cannot be achieved through Au(I) catalysis, terminating in an arylation rather than protonation to return the catalyst. Methods for the intra- and intermolecular heteroarylation of alkenes were developed and experiments were performed suggesting an unusual reaction mechanism. Attempts to expand the types of transformations that could be accomplished under this mode of reactivity unexpectedly led us to consider instead the properties of Selectfluor and how it could be effectively employed as a reagent in enantioselective transformations.Chapter 2 addresses this very topic. The dicationic nature of the electrophilic fluorination reagent Selectfluor imparts on it many favorable qualities, but solubility in organic solvents is not one of them. Using a concept developed earlier within our laboratories, we hoped to show that this insolubility could be used to suppress racemic background reaction in enantioselective fluorination reactions, a class of transformation that remains largely underdeveloped in the literature. Lipophilic chiral phosphate anions, which can undergo anion exchange with the reagent salt, serve to solubilize the cationic fluorinating agent, rendering it both chiral and available for reaction with a suitable substrate. This mode of reactivity, chiral anion phase-transfer catalysis, was used to develop the enantioselective fluorocyclization of alkenes. Studies in the use of another type of cationic electrophile for the enantioselective oxidation of alcohols will also be discussed.An extension of the concept of phase-separation for suppression of unwanted reactivity was applied to the deracemization of chiral amines, which is presented in Chapter 3. Single-operation deracemization, in which a racemic substrate is dynamically resolved to its enantioenriched form, generally employs an oxidant to destroy a stereocenter and a reductant to reform it, as well as a chiral element to impart enantioselectivity on at least one of these steps. The highly reactive nature of oxidants and reductants towards one another has thus far precluded the development of such a deracemization by purely chemical means. We hypothesized that by separating the oxidant, substrate, and reductant into different phases, we could use a single catalyst to promote both the oxidation and subsequent enantioselective reduction of chiral substrates. This concept was used in the development of a deracemization protocol for 3H indolines and other chiral amine substrates

Single-Operation Deracemization of 3H-Indolines and Tetrahydroquinolines Enabled by Phase Separation

The single-operation deracemization of 3H indolines and tetrahydroquinolines is described. An asymmetric redox approach was employed, in which a phosphoric acid catalyst, oxidant, and reductant are present in the reaction mixture. The simultaneous presence of both oxidant and reductant was enabled by phase separation and resulted in the isolation of highly enantioenriched starting materials in high yields