Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego Electronic Theses and Dissertations

Taming Carbene Copper(I)-Hydride Complexes

(2019)

Although initially reported in 1844, copper(I)-hydrides were not widely studied until the isolation of “Stryker’s reagent” in 1971. Following this development, researchers reported a myriad of chemical transformations employing other transient copper-hydride complexes as highly stereo-, regio-, and enantioselective catalysts. Each of these processes, however, rely on the ability of Cu-H bonds to insert into substrate π-bonds. By focusing on reactions involving this mechanistic step, chemists have limited the potential applications of copper-hydrides to reactions within this niche.

The first part of this manuscript discusses the ability of CAAC copper complexes to affect dehydrogenative borylation reactions of terminal acetylenes under mild conditions. Moreover, during this study, we uncovered convincing evidence that points to the surprising involvement of a copper-hydride complex in the key dihydrogen extrusion step of the mechanistic cycle. We further show that more basic anions on copper switch the selectivity of the catalyst to favor formation of traditional anti-Markovnikov hydroboration products. Lastly, the active catalysts for both reactions were shown to tolerate a wide range of synthetically useful functional groups.

The second part of this manuscript describes our attempts to utilize extremely sterically encumbering NHC ligands to stabilize and characterize the first monomeric, monoligated copper(I)-hydride complex. Although this species exists as a dimer in the solid state, we confirmed the presence of an equilibrium in solution through variable temperature 1H NMR experiments and extracted the kinetic and thermodynamic parameters for this dimerization process. We then applied our synthetic strategy to the isolation and crystallographic characterization of the first neutral monoligated silver(I)-hydride. Preliminary experiments indicate that its reactivity mirrors that of copper-hydrides as opposed to gold-hydrides. Refocusing on copper, we employed borane stabilized copper-hydride complexes as benchtop stable surrogates for their highly reactive LCu-H counterparts in the hydrogenation of CO2 with H2. Excitingly, we found that this process is enhanced by an in situ generated amino-borane co-catalyst, thereby affording a rare example of tandem catalysis involving both a transition-metal complex and a classical Lewis pair.

The final chapter discusses the uncatalyzed dehydrogenative coupling of alcohols, amines and thiols with pinacolborane and 9-borabicyclononane, a result which contrasts with literature precedent.

Cover page of Time and Again: Repetition and Fixation in Boléro, Barraqué, and Moellenberg

Time and Again: Repetition and Fixation in Boléro, Barraqué, and Moellenberg

(2019)

This dissertation serves as an investigative attempt to connect musical thought to my work in performance art as well as poetry, drawing from Maurice Ravel’s Boléro and Jean Barraqué’s Sonata for piano. Using my performance Only Time, I trace how my early work embeds repetition within its structure, taking inspiration from Boléro’s formal design. Using my poem SIS TER, I show how repetitive elements become objects of fixation when presented as surface features of the work, taking inspiration from Barraqué’s use of recurrent pitches in his Sonata. This paper will trace this trajectory in chronological fashion, as I accumulate techniques through these musical influences.

Cover page of The MAPU-Lautaro Then and Now: The Chilean Struggle to Spark Revolution Through the Creation of Revolutionary Subjects

The MAPU-Lautaro Then and Now: The Chilean Struggle to Spark Revolution Through the Creation of Revolutionary Subjects

(2018)

This thesis is a narrative and analysis of the MAPU-Lautaro, a Chilean Marxist-Leninist organization active from 1983-1994. The group fought to replace socioeconomic inequality and the brutality of the Pinochet dictatorship with a Socialist vision for Chilean society. Through direct action the group aimed to alter the mindset of the Chilean population and thereby spark revolutionary consciousness within the working class. Members of the Lautaro, as they preferred to be called, recuperated basic goods and redistributed them in Santiago's poorest neighborhoods. They later became increasingly involved in more violent actions and confrontations with Chilean security forces, eventually leading to the dismemberment of the group. Interviews with former members were conducted to gauge their levels of engagement in politics and social movements and to determine the forms of resistance they are currently engaged in.

Cover page of New Insights into the Assembly Mechanism of an RNA Polymerase III-Specific Transcription Complex on a Drosophila U6 snRNA Gene Promoter

New Insights into the Assembly Mechanism of an RNA Polymerase III-Specific Transcription Complex on a Drosophila U6 snRNA Gene Promoter

(2018)

In metazoans, the genes that code for the U6 small nuclear RNA (snRNA) have promoters that consist of a proximal sequence element (PSE) and a TATA box. The PSE is recognized by the multi-subunit small nuclear RNA activating protein complex (SNAPc). SNAPc forms a complex on the U6 promoter with TFIIIB, an RNA polymerase III-specific general transcription factor that includes TBP, Brf1 (Brf2 in vertebrates), and Bdp1. Here we show that, in the fruit fly Drosophila melanogaster, DmSNAPc directly recruits Bdp1 to the U6 promoter. We also demonstrate that an 87-residue region of Bdp1 is sufficient for this recruitment and is, furthermore, sufficient to recruit TBP to the TATA box. The non-conserved N-terminal tail of TBP also plays a role in stabilizing TBP incorporation into the DmSNAPc-Bdp1 complex. While Bdp1 recruitment by DmSNAPc is independent of the presence of TBP, Brf1, or a TATA box, it does require that DmSNAPc be bound to a U6 gene PSE rather than a PSE derived from a U1 gene (which is transcribed by RNA polymerase II). We also confirmed that Brf1 is present at U6 snRNA genes but not at U1 genes. These findings further develop the concept that DmSNAPc adopts different conformations upon binding U6 and U1 gene PSEs, and that these different DmSNAPc conformations lead to the subsequent recruitment of distinct general transcription factors and RNA polymerases for U6 and U1 gene transcription.

Obesity and diabetes risk variants affect chromatin and gene regulation in the human brain

(2018)

Obesity and type 2 diabetes (T2D) are complex diseases that are major public health concerns. Genetic variation contributes substantially to risk of developing obesity and T2D. Many previous studies on genetic factors influencing obesity (as measured by body mass index, or BMI) and T2D have focused on the effects of insulin resistance and glucose homeostasis in the pancreas and adipose tissue. A recent study demonstrated that genetic loci associated with BMI are enriched near genes expressed in the brain, but the effects of specific BMI variants on brain function is unknown. Furthermore, despite being a key regulator of energy intake as well as glucose homeostasis, the brain has not been a focus in the molecular genetics of T2D risk. In this work, we aimed to determine the effects of BMI and T2D variants on regulatory processes in the brain through computational analyses integrating genetic association data and brain epigenome data. We determined the enrichment of enhancers in various regions of the brain for BMI and T2D risk signals, identified BMI and T2D risk signals affecting gene expression in the brain, predicted the allelic effects of variants based on brain chromatin features, and prioritized specific BMI and T2D variants likely affecting brain regulation. These data together suggest that variants associated with BMI and T2D risk are broadly enriched for effects on regulatory processes in the brain. Together with pancreatic and adipose tissue, the brain should be considered when studying the molecular mechanisms of genetic variants affecting obesity and diabetes pathogenesis.

Cover page of Essays on Non-parametric and High-dimensional Econometrics

Essays on Non-parametric and High-dimensional Econometrics

(2018)

Chapter 1 studies the instrument validity for local average treatment effects. we provide

a testable implication for instrument validity in the local average treatment effect (LATE)

framework with multivalued treatments. Based on this testable implication, we construct a

nonparametric test of instrument validity in the multivalued treatment LATE framework. The

test is asymptotically consistent. The size of the test can be promoted to the nominal significance level over much of the null, indicating a good power property. Simulation evidence is provided

to show the good performance of the test in finite samples. Chapter 2 constructs improved

nonparametric bootstrap tests of Lorenz dominance based on preliminary estimation of a contact set. Our tests achieve the nominal rejection rate asymptotically on the boundary of the null;

that is, when Lorenz dominance is satisfied, and the Lorenz curves coincide on some interval.

Numerical simulations indicate that our tests enjoy substantially improved power compared

to existing procedures at relevant sample sizes. Chapter 3 proposes a sieve focused GMM

(SFGMM) estimator for general high-dimensional semiparametric conditional moment models

in the presence of endogeneity. Under certain conditions, the SFGMM estimator has oracle

consistency properties and converges at a desirable rate. We then establish the asymptotic

normality of the plug-in SFGMM estimator for possibly irregular functionals. Simulation

evidence illustrates the performance of the proposed estimator.

From Molecules to Genes and Back Again: Tales of Marine Microbes and their Specialized

(2018)

Nature has created elegant and efficient ways of assembling a wide variety of diverse chemical scaffolds. Microbes are prolific producers of these secondary metabolites, which can have profound bioactivities and be harnessed for use in medicine. Within their genomes, microbes possess the blueprints for making natural products, and recent advances in high-throughput DNA sequencing have revealed a much larger repertoire of specialized chemistry than what can be observed in the lab. This bacterial ‘dark matter’ has the potential to contain the instructions for making countless new chemical scaffolds and represents an untapped source for drug discovery. Connecting secondary metabolite compounds with their biosynthetic gene clusters can inform novel biosynthetic transformations, provide a renewable source of promising bioactive compounds, and inspire synthetic biology approaches to assembling new molecules. Chapter 2 of this dissertation connects two pharmaceutically relevant natural products with their corresponding biosynthetic gene clusters. The epoxyketone proteasome inhibitors epoxomicin and eponemycin are naturally produced by actinomycete bacteria, and whole genome sequencing revealed their genetic underpinnings and native resistance mechanism. This work represents the first elucidation of biosynthetic gene clusters for epoxyketone proteasome inhibitors. Chapter 3 takes a wider lens to examine an understudied group of bacteria: the rare marine actinomycetes. Whole genome sequencing of a group of rare marine actinomycetes revealed an incredible wealth of biosynthetic potential and diversity not yet represented in current sequencing databases. This study establishes rare marine actinomycetes as a group worthy of further exploration for genome mining and drug discovery. Chapter 4 investigates a more complex system with a focus on uncultivatable cyanobacterial sponge symbionts. Previous work showed that the genomes of these symbionts contained the genes necessary to produce environmentally relevant poly-brominated diphenyl ethers (PBDEs). In assembling high quality draft genomes of two symbionts of distinct sponges, their full secondary metabolite potential was revealed. Additionally, genome mining led to the identification of two novel dysinosin molecules, representing the first example of mining for gene clusters in a metagenome assembled genome leading to new chemistry.

Cover page of Trusted Systems for Uncertain Times

Trusted Systems for Uncertain Times

(2018)

When software is designed, even with security in mind, assumptions are made about

the details of hardware behavior. Unfortunately, the correctness of such assumptions can be

critical to the desired security properties. In this dissertation we first demonstrate how incorrect

assumptions about the hardware abstraction lead to side-channels that threaten modern software

security, and second we propose a principled method of timing channel defense for modern web

browsers.

We show how performance variations in floating-point math instructions enable the

first demonstrated instruction-data timing side-channel on commodity hardware. We use this

side-channel in two case studies to prove it’s viability. First, we redesign a previous attack on an

xivolder version of the Firefox web browser to violate the Same Origin Policy. Second, we break

the guarantees of a differentially private database designed to resist timing attacks. We show

how the timing side-channel arises from hardware optimization decisions that have been well

understood in the architecture, numerical analysis, and game-engine communities, but largely

ignored in security.

Using a detailed measurement and analysis of floating-point performance, we examine

the progress and potential of defenses against floating-point timing side-channels. We find that

all deployed defensive schemes for desktop web browsers were insufficient, and most are still

vulnerable. Using the same analysis methods, we show how a proposed defensive scheme makes

incorrect assumptions about the hardware features it leverages, negating its guarantees.

As a possible remediation to the problem of floating-point timing side-channels, we

present libfixedtimefixedpoint as an alternative to floating-point. It provides a fixed-

point implementation of most available floating-point operations and is designed to run in

constant time regardless of the input values.

Finally, we discuss structural problems in modern web browser design that make them

amenable to all timing attacks. Adapting solutions from parallel problems solved by early trusted

operating systems projects, we propose a modified browser architecture providing a provable

defensive guarantee against all timing attacks. We then demonstrate the viability of this scheme

by prototyping aspects of the architecture in a modified web browser.

CRISPR/Cas9 in Saccharomyces cerevisiae and Its Application to Promote Future Scientists

(2018)

Middle school and high school students are often confronted with the problem of textbook memorization as the singular form of biological learning, rather than acquiring knowledge by performing lab work. Middle and high school teachers may lack experience teaching biology by guiding a class through a protocol in the lab, as opposed to lecturing. This protocol uses CRISPR technology, an advanced genome editing application. This wet-lab approach not only teaches students the reality of molecular biology research, but also works through the scientific method and realistic problem based thinking researchers must apply. Most notably, this protocol’s purpose is to ignite a scientific passion in these students beginning at a young age. This exciting protocol is simple to use and can be completed in minimum time and is inexpensive. If used correctly, students may develop a life-long passion for science and one day research disease ending medicines, such as CRISPR/Cas9. Experienced researchers can also use this protocol as an introduction to CRISPR/Cas9. This protocol uses Saccharomyces cerevisiae, a medium that displays broad phenotypic change after mutation. The visual nature of this mutation allows students to see that the tiny biomolecules organisms are made of really are the cause of phenotypes.

Development of Computer Aided Drug Design Algorithms and Application to be APOBEC3 Family of Proteins

(2018)

The development of molecular dynamics (MD) simulations builds off the maturing field of structural biology to provide new insight into the mechanisms of disease on an atomic level. However, there are few established methods that use these insights to develop effective therapies. This thesis begins by discussing the creation of “POVME 3.0”, a novel method to generate drug design-relevant insights from MD simulations. POVME 3.0 takes as input a MD simulation of a binding pocket of interest, and returns a summary of how the pocket shape changes over time. We then discuss the application of POVME 3.0 and other analysis techniques to the APOBEC3 family of proteins. APOBEC3 proteins are a newly discovered driver of mutation in many cancers, and their inhibition could contribute to cancer treatments. Next, we review algorithms that could be productively used in the study of APOBEC3 enzymes, both to understand their essential dynamics and also to discover new modes of inhibition. Finally, we discuss CELPP, a community-driven analysis of computer-aided drug design algorithms, which aims to improve the quality of predictive models in drug design.