Part I: Nitroalkane Transformations: Synthesis of Vicinal Diamines and Arylnitromethanes Part II: Quantification of Electrophile Lumo-Lowering via Colorimetric Probes

Part I of this dissertation focuses on the synthetic chemistry of arylnitromethanes as both products and reactants. Use of these compounds as key building blocks in the synthesis of vicinal diamines was explored via a catalytic aza-Henry strategy. These studies resulted in the identification of simple cinchonidinium acetate as an effective catalyst for the asymmetric synthesis of syn-1,2-diarylethylenediamines with excellent diastereocontrol. Difficulties in synthesizing arylnitromethanes from existing techniques provided impetus for the development of an improved method of greater generality. Ultimately, successful conditions were identified for the palladium-catalyzed cross coupling of nitromethane with readily available aryl halide partners, providing facile access to an array of functionalized arylnitromethanes. A tandem reductive Nef process was incorporated to provide a one-pot transformation directly to aryl aldehyde or oxime, thereby exploiting the use of nitromethane as a formylation equivalent. Application of the nitromethylation conditions to vinyl halides resulted in the discovery of a unique tandem cross-coupling/π-allylation nitroethylation reaction. Part II of this dissertation focuses on the use of colorimetric sensors for the quantitative measurement of catalyst strength via LUMO-lowering of electrophiles. Despite rampant growth in catalyst synthesis and application, understanding of controlling factors of catalyst activity, particularly for those functioning through hydrogen-bonding, remains limited. A simple pyrazinone chromophore was found to exhibit hypsochromic shifts upon binding to an array of known hydrogen-bond catalysts. These wavelength shifts showed high correlation to relative rate enhancement of the catalysts in Diels Alder and Friedel Crafts reactions. Acidity values, often used to estimate hydrogen-bond strength, were illustrated to be poor indicators of catalytic activity, in contrast to that of the wavelength shifts. The results establish the catalyst-sensor wavelength is a useful tool with which to gauge catalyst strength and also reveal catalyst structure-activity relationships. Current efforts for measuring stronger Brønsted and Lewis Acid catalysts with an alternate colorimetric sensor are also described

Regional Medical Campuses: Leveraging our Structure

The focus of this session presentation at the 2020 IU School of Medicine Education Day is on how the School is leveraging its regional campus model. The School is the nation’s largest by enrollment, with nine campuses, eight of which are considered regional campuses. After a review of various regional campus models, an example of scholarship that reports on how IU School of Medicine regional campus students perform in the Match compared to main (Indianapolis) campus students is shared. The session presentation also examines the unique way IU School of Medicine is leveraging a Scholarly Concentrations Program for educational enhancement, reputational focus for regional campuses, deeper community engagement, and increased student and faculty scholarship

Amino acid-dependent stability of the acyl linkage in aminoacyl-tRNA.

Aminoacyl-tRNAs are the biologically active substrates for peptide bond formation in protein synthesis. The stability of the acyl linkage in each aminoacyl-tRNA, formed through an ester bond that connects the amino acid carboxyl group with the tRNA terminal 3\u27-OH group, is thus important. While the ester linkage is the same for all aminoacyl-tRNAs, the stability of each is not well characterized, thus limiting insight into the fundamental process of peptide bond formation. Here, we show, by analysis of the half-lives of 12 of the 22 natural aminoacyl-tRNAs used in peptide bond formation, that the stability of the acyl linkage is effectively determined only by the chemical nature of the amino acid side chain. Even the chirality of the side chain exhibits little influence. Proline confers the lowest stability to the linkage, while isoleucine and valine confer the highest, whereas the nucleotide sequence in the tRNA provides negligible contribution to the stability. We find that, among the variables tested, the protein translation factor EF-Tu is the only one that can protect a weak acyl linkage from hydrolysis. These results suggest that each amino acid plays an active role in determining its own stability in the acyl linkage to tRNA, but that EF-Tu overrides this individuality and protects the acyl linkage stability for protein synthesis on the ribosome

Minimizing the Amount of Nitromethane in Palladium-Catalyzed Cross-Coupling with Aryl Halides

A method for the formation of arylnitromethanes is described that employs readily available aryl halides or triflates and small amounts of nitromethane in a dioxane solvent, thereby reducing the hazards associated with this reagent. Specifically, 2–10 equiv (1–5% v/v) of nitromethane can be employed in comparison to prior work that used nitromethane as solvent (185 equiv). The present transformation provides high yields at relatively low temperatures and tolerates an array of functionality, including heterocycles and substantial steric encumbrance

Palladium-Catalyzed Nitromethylation of Aryl Halides: An Orthogonal Formylation Equivalent

An efficient cross-coupling reaction of aryl halides and nitromethane was developed with the use of parallel microscale experimentation. The arylnitromethane products are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl equivalent, providing a mild and convenient formylation method that is compatible with many functional groups

Nitroethylation of Vinyl Triflates and Bromides

A two-carbon homologation of vinyl triflates and bromides for the synthesis of homoallylic nitro products is described. This palladium-catalyzed double coupling of nitromethane exploits the anion stabilizing and leaving group properties of nitromethane, generating the homo allyl nitro products via a tandem cross-coupling/π-allylation sequence. The resultant process provides a mild and convenient entry to nitroethylated products, which are versatile precursors to β,γ-unsaturated carbonyls, homoallylic amines, and nitrile oxides

Quantification of Electrophilic Activation by Hydrogen-Bonding Organocatalysts

A spectrophotometric sensor is described that provides a useful assessment of the LUMO-lowering provided by catalysts in Diels–Alder and Friedel–Crafts reactions. A broad range of 33 hydrogen-bonding catalysts was assessed with the sensor, and the relative rates in the above reactions spanned 5 orders of magnitude as determined via ¹H- and ²H NMR spectroscopic measurements, respectively. The differences between the maximum wavelength shift of the sensor with and without catalyst (Δλ_max^–1) were found to correlate linearly with ln­(<i>k</i>_rel) values for both reactions, even though the substrate feature that interacts with the catalyst differs significantly (ketone vs nitro). The sensor provides an assessment of both the <i>inherent reactivity</i> of a catalyst architecture as well as the <i>sensitivity</i> of the reaction to changes within an architecture. In contrast, catalyst p<i>K</i>_a values are a poor measure of reactivity, although correlations have been identified within catalyst classes

Development of a General Aza-Cope Reaction Trigger Applied to Fluorescence Imaging of Formaldehyde in Living Cells

Formaldehyde (FA) is a reactive signaling molecule that is continuously produced through a number of central biological pathways spanning epigenetics to one-carbon metabolism. On the other hand, aberrant, elevated levels of FA are implicated in disease states ranging from asthma to neurodegenerative disorders. In this context, fluorescence-based probes for FA imaging are emerging as potentially powerful chemical tools to help disentangle the complexities of FA homeostasis and its physiological and pathological contributions. Currently available FA indicators require direct modification of the fluorophore backbone through complex synthetic considerations to enable FA detection, often limiting the generalization of designs to other fluorophore classes. To address this challenge, we now present the rational, iterative development of a general reaction-based trigger utilizing 2-aza-Cope reactivity for selective and sensitive detection of FA in living systems. Specifically, we developed a homoallylamine functionality that can undergo a subsequent self-immolative β-elimination, creating a FA-responsive trigger that is capable of masking a phenol on a fluorophore or any other potential chemical scaffold for related imaging and/or therapeutic applications. We demonstrate the utility of this trigger by creating a series of fluorescent probes for FA with excitation and emission wavelengths that span the UV to visible spectral regions through caging of a variety of dye units. In particular, Formaldehyde Probe 573 (FAP573), based on a resorufin scaffold, is the most red-shifted and FA sensitive in this series in terms of signal-to-noise responses and enables identification of alcohol dehydrogenase 5 (ADH5) as an enzyme that regulates FA metabolism in living cells. The results provide a starting point for the broader use of 2-aza-Cope reactivity for probing and manipulating FA biology.Fil: Bruemmer, Kevin J.. University of California at Berkeley; Estados UnidosFil: Walvoord, Ryan R.. University of California at Berkeley; Estados UnidosFil: Brewer, Thomas F.. University of California at Berkeley; Estados UnidosFil: Burgos Barragan, Guillermo. Medical Research Council. Laboratory of Molecular Biology; Reino UnidoFil: Wit, Niek. Medical Research Council. Laboratory of Molecular Biology; Reino UnidoFil: Pontel, Lucas Blas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina. Medical Research Council. Laboratory of Molecular Biology; Reino UnidoFil: Patel, Ketan J.. University of Cambridge; Reino Unido. Medical Research Council. Laboratory of Molecular Biology; Reino UnidoFil: Chang, Christopher J.. University of California at Berkeley; Estados Unido