1,721,053 research outputs found
Dopaminergic Control of Striatal Cholinergic Interneurons Underlies Cocaine-Induced Psychostimulation
Get PDFCocaine drastically elevates dopamine (DA) levels in the striatum, a brain region that is critical to the psychomotor and rewarding properties of the drug. DA signaling regulates intrastriatal circuits connecting medium spiny neurons (MSNs) with afferent fibers and interneurons. While the cocaine-mediated increase in DA signaling on MSNs is well documented, that on cholinergic interneurons (ChIs) has been more difficult to assess. Using combined pharmacological, chemogenetic, and cell-specific ablation approaches, we reveal that the D2R-dependent inhibition of acetylcholine (ACh) signaling is fundamental to cocaine-induced changes in behavior and the striatal genomic response. We show that the D2R-dependent control of striatal ChIs enables the motor, sensitized, and reinforcing properties of cocaine. This study highlights the importance of the DA- and D2R-mediated inhibitory control of ChIs activity in the normal functioning of striatal networks
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Radical/Polar Crossover: New Methodologies and Applications in Total Synthesis & Studies Towards a Synthesis of Asperterpenoid A
No full textThis dissertation describes work completed in several areas of ongoing research in the Vanderwal Lab. Chapter 1 describes the family of natural products known as the abietane diterpenoids, the structural anomaly plebeianiol A, and our synthetic endeavor to elucidate the authentic structure of this natural product. Chapter 2 describes the development of a new radical/polar crossover annulation method using metal-hydride hydrogen atom transfer (MHAT) catalysis. Finally, Chapter 3 details our investigation into a synthetic route towards the sesterterpenoid natural product, asperterpenoid A
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A Direct Synthesis of Highly Substituted π-Rich Aromatic Heterocycles from Oxetanes & Synthesis of the AB-Core of the Dihydro-β-agarofurans & Methodology and Strategy Development Inspired by the Agarofurans
Get PDFThe research described herein focuses on the development of novel methods and synthetic sequences to solve problems in organic synthesis. Chapter 1 details our work on an operationally simple method to synthesize furans and pyrroles in high yield from keto-oxetanes, a non-obvious, easily accessible 1,4-dicarbonyl surrogate.Chapter 2 moves away from synthetic methodologies and is focused on the dihydro-β- agarofuran family of sesquiterpenoid natural products. This chapter begins by detailing the structural features that make this family unique and the diverse array of biological activity that has generated considerable interest in their study. It concludes by discussing the significant amount of synthetic efforts towards the agarofurans, focusing mainly on the most recent examples. Chapter 3 details four strategies towards the synthesis of an easily diversifiable core that could be used to synthesize several agarofurans and related analogs. Key contributions include the first use of an ester chiral auxiliary in a diastereoselective Birch reduction/alkylation reaction of substituted benzenes, an expedient route towards a fully oxidized A-ring fragment, and the synthesis of the AB-core of the agarofurans using an intramolecular 1,3-dipolar cycloaddition reaction.
Chapter 4 describes the history of the diastereoselective Birch reduction/alkylation reaction and its use in the synthesis of natural products. Chapter 5 details the development of using ester chiral auxiliaries to effect a diastereoselective Birch reduction/alkylation reaction. This method generates quaternary carbons directly from salicylic acid derivatives with good diastereoselectivity using an easily removable (−)-8-phenylmenthol chiral auxiliary
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Progress Towards the Total Synthesis of Steroidal Natural Products Clionastatins A and B
Get PDFA total synthesis of naturally occurring polychlorinated steroids, clionastatins A and B, was undertaken. Efforts were first directed at the synthesis of a truncated tricyclic steroid core and multiple synthetic routes were developed, many of which featured a Diels–Alder reaction. Ultimately, these efforts culminated in the successful synthesis of the clionastatin core. Efforts then focused on development of a bicyclic diene that would allow us to apply the successful Diels–Alder route to the synthesis of a tetracycle, which could be elaborated into clionastatin A. While a suitable diene was made and a tetracyclic cycloadduct was synthesized, the undesired stereochemistry of that cycloadduct suggests that an alternative route to the clionastatins may be necessary
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Concise Total Syntheses of Helifolenals A–D and Progress Towards Illihenin A
No full textThe research described in this dissertation encompasses our work on total syntheses of helifolenals A–D and progress towards illihenin A. Chapter 1 provides a review on total syntheses of illicium sesquiterpenes with diverse polycyclic scaffolds and complex oxygenation patterns. Selected total syntheses of illicium sesquiterpenes from the 1992 to 2024 are reviewed in this chapter with a particular focus on strategies employed to construct the densely functionalized ring systems.Chapter 2 examines our synthetic and computational studies to illihenin A and helifolenals A–D. Illihenin A is a sesquiterpenoid with an unprecedented tricyclic ring system and six contiguous stereocenters. As our initial retrosynthesis involving a stepwise construction of the 5- 6-7 tricycle faced setbacks, we pivoted our strategy to an intramolecular Diels–Alder cycloaddition then a biomimetic ring expansion to synthesize illihenin A. In pursuit, we successfully employed an IMDA reaction and achieved 5-step enantiospecific syntheses of helifolenals A–D. We also discovered an unusual rearrangement of helifolenal A in the presence of a Lewis acid. With the help of Professor Dean Tantillo (UC Davis), computational insights on the potential mechanism of this rearrangement and proposed biosynthesis of illihenin A are discussed.This thesis covers approximately 10% of the work that I completed at UC Irvine over five years. Some strategies to illihenin A (i.e. enamine spiroMichael addition or [2+2]) or other projects I had worked on (i.e. diterpene alkaloids, Eschenmoser hydrazone functionalization, agarofurans or chlorosulfolipids) were not mentioned due to time constraints regarding the thesis submission
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Part I: Ring-Rearrangement Metathesis of Himbert Arene-Allene Cycloadducts for the Rapid, Modular Construction of Complex Molecular Scaffolds. Part II: Application of Zincke Aldehydes Toward the Synthesis of Gelsemine
Get PDFDeveloping new synthetic methods and strategies is an important area of research in organic chemistry. Especially useful are transformations that rapidly and rationally generate complex molecular architectures, with multiple new bonds and new stereocenters, from simple, achiral and modular precursors. This dissertation discusses the synthetic investigation and exploitation of two such reactions. In PART I, the intramolecular Diels–Alder (IMDA) reaction of aromatic dienes and allene dienophiles, utilized in conjunction with ring-rearrangement metathesis (RRM) to prepare angularly-fused polycyclic lactams, is discussed. The mechanism of the IMDA reaction was investigated with the aid of computational molecular modeling. The reaction was determined to proceed through a concerted mechanism; however, competing radical pathways accounted for stereochemical infidelity and fragmentation observed for some substrates. An improved, modular synthesis of the precursors was developed to directly couple aromatic amines with the allene fragment precursor, which allowed for the preparation of a small library of heterocyclic compounds. This two-step protocol generates topologically interesting structures, containing two or more new rings, and two new sp3 stereocenters. Computational modeling also guided the development of the unknown analogous reaction for allenyl ketone substrates, which yield carbocyclic products. Unexpected stereoselectivity and reactivity observations were made in the alkene metathesis reaction, which could not be readily explained. Computational studies were able to elucidate a subtle yet fundamental relationship between reaction mechanism and length of alkene tether in these types of substrates. In PART II, efforts toward the synthesis of the alkaloid natural product gelsemine are discussed. The synthetic strategy employs a Zincke aldehyde rearrangement/IMDA cascade previously developed by the Vanderwal lab. Using 4-phenylpyridine as a model system, the expected transformation successfully gives an advanced synthetic intermediate lacking only the oxindole substructure, and the key C3–O4 and C5–C16 bonds present in the target. Elaboration of this intermediate toward the target is detailed. A number of protected 4-(2-aminophenyl)pyridine analogues were prepared to facilitate oxindole formation and circumvent later stage complications that arose in the model system. These compounds all either failed to undergo Zincke salt formation, pyridinium ring-opening, or subsequent rearrangement/IMDA, thus delineating the synthetic boundaries of this type of chemistry
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Part 1: Total Syntheses of Pyrroloiminoquinone Alkaloids Part 2: A Synthesis of Alstonlarsine A via Alstolucines B and F Demonstrates the Chemical Feasibility of a Proposed Biogenesis. Part 3: Development of a Hydrogen-Atom-Transfer-Initiated Radical/Polar Crossover Annulation Cascade for Expedient Access to Complex Tetralins
No full textThis dissertation describes four research aims involving natural products total synthesis or synthetic methods development. Chapter 1 reviews the isolation, proposed biosynthesis, biological activity, and prior syntheses of pyrroloiminoquinone (PIQ) alkaloids. Chapter 2 describes our efforts towards a synthesis of aleutianamine, a PIQ alkaloid that is structurally distinct from other PIQs and possesses selective anticancer properties. While an aleutianamine synthesis has yet to be accomplished in our laboratory after several synthesis approaches (discussed herein), we discovered novel reactivity of PIQ intermediates en route to aleutianamine, which will aid in our ongoing synthesis efforts. Chapter 3 describes syntheses of numerous simpler PIQ alkaloids, fueled by an efficient synthesis of a versatile PIQ building block en route to aleutianamine. These studies were motivated by a preliminary discovery that some simpler PIQs possess antimalarial properties. By collaborating with the Ben Mamoun and Le Roch groups at Yale and UC Riverside, respectively, we discovered that many of our synthetic PIQs are promising inhibitors of human disease-causing parasites Plasmodium falciparum and Babesia divergens. Chapter 4 describes our synthesis of a monoterpene indole alkaloid alstonlarsine A from alstolucines B and F, which are all isolated from plants of genus Alstonia. The success of our synthesis supports the chemical feasibility of a new biosynthetic proposal for alstonlarsine A. Chapter 5 describes our development of a novel cascade annulation reaction inspired by a bicyclization reaction discovered previously in our lab. In this work, we use similar conditions to react allylbenzenes and electron-deficient alkenes to make functionalized tetralin products
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Synthesis and Translation Inhibition of the Lissoclimides
Get PDFThis dissertation describes the development of synthesis strategies for the lissoclimide natural product syntheses starting from either sclareolide or geranyl acetate. Chapter 1 focuses on the isolation and biological activity of lissoclimide terpenoid natural products. Previous synthesis efforts from the Vanderwal lab and other groups are described. Chapter 2 focuses on the semi-synthesis of chlorolissoclimide, haterumaimide N, and haterumaimide Q from sclareolide. Development of a reliable Evans auxiliary based aldol approach to the hydroxysuccinimide moiety common to all lissoclimide natural products is described. The C–H chlorination of sclareolide is vastly improved with the use of a new chlorinating protocol co-developed with the Alexanian lab, enabling the first synthesis of chlorolissoclimide in 9 steps and 14% overall yield. Chapter 3 focuses on a fully synthetic route towards the lissoclimides from geranyl acetate featuring an epoxide-initiated bicyclization. This strategy provides access to a readily diversifiable intermediate that is converted to haterumaimide Q and key analogues. A key finding was that the preference for Fürst–Plattner addition of chlorine across an alkene on a rigid decalin system is partially reversed in the presence of a homoallylic trifluoroacetate. The resulting diequatorial dichlorides are found in several of the most potent lissoclimides. Chapter 4 focuses on four key biological investigations our syntheses have enabled: (1) the Yusupov group elucidated the biological mode of action via a co-crystal structure of chlorolissoclimide in the E-site of the eukaryotic large ribosomal subunit (2); our synthetic lissoclimide natural products and analogues were screened against several cell lines to determine structure activity relationships (SAR); (3) the structural information was used to computationally rationalize the observed SAR; and (4) these compounds were evaluated for their ability to eradicate several viral infections, including Ebola, exhibiting EC50 values of 20 nM. Chapter 5 focuses on the exploration of 2,2-disubstituted epoxide-initiated bicyclizations to access haterumaimide J. A Ti(III) radical cyclization strategy is first explored using several cyclization precursors. Lewis-acid-catalyzed bicyclizations are described for our efforts towards both haterumaimide J and hydroxytotarol
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Synthetic Studies Towards Brasilicardin A and Preparation of a Complex Analog & Progress Towards a Synthesis of Neoamphilectane Featuring Unanticipated Polycyclizations
No full textThe research described in this dissertation encompasses our work on the synthesis of unusual terpenoid natural products. In Chapter 1, an overview of the studies conducted on the brasilicardin family of natural products are discussed while highlighting unique stereochemical challenges and impressive immunosuppressive activity. These studies detail isolation and structural determination, discovery of the gene cluster responsible for biosynthesis, details of the mechanism of action for immunosuppression, and synthetic endeavors aimed at the flagship compound within the class (brasilicardin A). Chapter 2 examines our progress towards the total synthesis of brasilicardin A centered around a transannular Diels–Alder cycloaddition reaction. Completion of two complex fragments was achieved, and a brief investigation of their unification towards a macrocyclic intermediate is described. Chapter 3 highlights our use of a cobalt metal-hydrogen-atom-transfer (MHAT) initiated radical bicyclization reaction in two distinct areas: for the synthesis and structural revision of an abietane diterpenoid, plebeianiol A, and the synthesis of a simplified brasilicardin analog (termed as a Vanderlog) featuring an unnatural, rigidified core scaffold. Both of these projects were linked by the expedient synthesis of a key cyanophosphonate fragment, which was produced in both enantiomeric series by a Sharpless dihydroxylation. Application of our MHAT radical bicyclization reaction delivered the targeted, complex analog in 17 steps in the longest linear sequence and its immunosuppressive activity was biochemically evaluated by our collaborators in the Fruman lab at UCI.
Chapter 4 provides an introduction to our studies of a rare spirocyclic isocyanoterpene (ICT) natural product, neoamphilectane. Within the ICT family, neoamphilectane is one of the only members yet to succumb to synthetic efforts and its biological activity remains unknown. Additionally, its unique spirocyclic ring system that is unlike any other amphilectane has prompted our exploration of alternative methods for its synthesis. Our enantiospecific strategy towards neoamphilectane is delineated, and a synthesis of a key spirocyclic intermediate was achieved in 7 steps from (+)-dihydrocarvone. In Chapter 5, an array of annulation methodologies for establishing the tricyclic scaffold of neoamphilectane were evaluated, which revealed numerous unexpected polycyclization reactions and rearrangements of complex intermediates. While several cyclization reactions produced the core carbon framework of neoamphilectane, manipulating the oxidation state of these carbocycles proved challenging. Future work will be aimed at a strategy involving late-stage electrophilic methylation of a secondary isocyanide-stabilized carbanion whose substrate synthesis efforts are discussed
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Unusual Natural Products: Lessons Learned in Pursuit of KS-504d and Curvulamine
Get PDFThis thesis details some of the paths taken, ideas explored, and failures met with during synthesis projects targeting two unusual natural products, neither of which has to-date succumbed to total synthesis. The first natural product, KS-504d, is a polychlorinated small molecule, possessing a chlorine-to-carbon ratio of greater-then-one. To contextualize the work and synthetic strategies, a brief background on chlorinated natural products and their synthesis is presented, followed by a discussion of KS-504d and the related family of natural products, along with similar halogenated small molecules. Initial exploratory studies—“information gathering”—are presented, followed by a discussion of a successful synthesis of a model system of KS-504d and unsuccessful attempts to translate this success to a total synthesis of the natural product. The second natural product, curvulamine, is a pyrrole-containing natural product with a caged tricyclic core and a challenging stereochemical arrangement. The synthetic work is prefaced by a discussion of the natural product and the key structural features of the natural product. Syntheses of other natural products which possess similar structural features to curvulamine are presented along with an analysis of the strategies used to access those natural products. Our work is presented in such a way as to demonstrate the growth and refinement of our synthetic strategy, with multiple failed routes and undesired stereochemical outcomes eventually giving way to a successful synthesis of the stereochemically-rich central ring of the natural product as well as a tentative synthesis of the tricyclic core structure of curvulamine
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