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Browsing by Author "Chatterjee, Delphi, committee member"

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    Development of asymmetric N-heterocyclic carbene-catalyzed reactions
    (Colorado State University. Libraries, 2017) Flanigan, Darrin Miles, author; Rovis, Tomislav, advisor; Chen, Eugene, committee member; Shi, Yian, committee member; Chatterjee, Delphi, committee member
    N-Heterocyclic carbenes (NHCs) are ubiquitous organocatalysts in a variety of asymmetric transformations. The benzoin and Stetter reactions, which couple aldehydes to other aldehydes or Michael acceptors, respectively are the most commonly reported reactivity manifold employing NHC catalysts. However, other umpolung reactivity pathways exist, for example, when α,β-unsaturated aldehydes are reacted with NHCs, the Breslow intermediate can react through the double bond of the aldehyde to functionalize at the beta position of the carbonyl. A process that has come to be known has homoenolate reactivity. A range of reactivity manifolds were investigated, including the asymmetric intermolecular Stetter reaction and an enantioselective NHC-catalyzed nucleophilic dearomatization of pyridiniums. In the dearomatization chemistry, a homoenolate equivalent is first generated from an enal and an NHC, which then adds to the pyridinium to generate 1,4-dihydropyridines with high enantioselectivity. This is a rare example of catalytic, asymmetric addition of a nucleophile to the activated pyridinium that prefers C-4 functionalization leading to the 1,4-dihydropyridine product. The asymmetric intermolecular Stetter reaction was also investigated in an attempt to broaden the scope of the reaction to include less activated Michael acceptors, specifically, α,β-unsaturated ketones. The coupling of heteroaryl aldehydes to enones could be achieved with appreciable levels of enantioselectivity (up to 80% ee), but reactivity remains a major challenge with this methodology.
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    Expanding the medicinal chemistry toolbox: development of new pyridine and piperidine functionalization strategies
    (Colorado State University. Libraries, 2022) Greenwood, Jacob W., author; McNally, Andrew, advisor; Bandar, Jeffrey, committee member; Sambur, Justin, committee member; Chatterjee, Delphi, committee member
    Nitrogen-containing heterocycles, such as pyridine, are ubiquitous in pharmaceuticals, agrochemicals, ligands, and materials. Therefore, robust methods for their direct functionalization are highly desired. Chapter one focuses on the importance of pyridine-containing molecules, the reactivity of pyridine, and challenges associated with functionalization of such compounds. In chapter two, a method for bipyridine synthesis is discussed that uses pyridylphosphonium salts as radical precursors. Other radical precursors failed to provide the desired products, highlighting the unique reactivity imparted by the phosphonium group. In chapter three, pyridylphosphonium salts are explored as alternatives to cyanopyridines in photoredox-catalyzed radical coupling reactions. This work expands the scope of the reaction manifold to complex pyridine substrates where installation of the cyano group can be challenging. Chapter four introduces the value of piperidines and challenges associated with their synthesis. A strategy is described to address these limitations using isolable, cyclic iminium salts as a general platform to elaborate the piperidine scaffold with several medicinally relevant functional groups. An alternative piperidine synthesis is presented in chapter five, where the mild transformation of a range of pyridines into pyridinium salts is achieved, followed by mild hydrogenation to the desired piperidine products. This method operates under mild conditions and can tolerate substitution at the 2-position of the pyridine substrate. As a result, a large amount of pyridine starting materials can now be engaged to form piperidines that are challenging to make with other technologies.
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    New base-catalyzed processes enable new approaches to C–H functionalization reactions
    (Colorado State University. Libraries, 2022) Puleo, Thomas R., author; Bandar, Jeffrey, advisor; McNally, Andy, committee member; Zadrozny, Joseph, committee member; Chatterjee, Delphi, committee member
    Brønsted bases are ubiquitous, inexpensive, and widely available reagents used in synthetic chemistry due to their well-studied and predictable activation mode. This thesis details the discovery and incorporation of new Brønsted base-catalyzed processes into fundamental proton transfer equilibria to enable new approaches to C–H functionalization reactions. The direct functionalization of C–H bonds represents a streamlined and attractive approach to access valuable synthetic targets, and this utility will be highlighted throughout the discussion of each method.Chapter one describes the discovery and development of a base-catalyzed α-selective styrene deuteration reaction. The mechanistic studies that led to the conceptualization and optimization of this reaction will be highlighted. α-Deuterated styrenes are compounds frequently utilized in the mechanistic studies of alkene functionalization reactions and this work represents the first method to achieve α-selective hydrogen isotope exchange on styrene derivatives. Chapter two provides an overview of existing approaches to catalytic aryl halide isomerization reactions. A particular focus on base-catalyzed aryl halide isomerization reactions will be provided, as these reports serve as the mechanistic foundation for the reactions developed throughout the remainder of the thesis. Chapter three describes our discovery and application of a general approach to base-catalyzed aryl halide isomerization. Aryl halides are valuable compounds in synthetic chemistry, and this new catalytic isomerization process unlocks a new mode of reactivity for these compounds. The scope of this process is demonstrated on several simple aryl bromides and iodides. The second part of this chapter will highlight an application of this process to enable the 4-selective nucleophilic substitution of 3-bromopyridines. Chapter four describes our approach to achieve nucleophilic C–H etherification of electron-deficient N-heteroarenes via a base-catalyzed halogen transfer mechanism. 2-Halogenated thiophenes efficiently transfer halogens to N-heteroaryl anions to generate N-heteroaryl halide intermediates that undergo nucleophilic aromatic substitution with alkoxide nucleophiles. Additionally, C–H etherification can be sequenced with a cascade base-promoted elimination to enable N-heteroarene C–H hydroxylation. The scope of process is highly general, and regioselective C–H etherification and hydroxylation is demonstrated on thiazoles, oxazoles, imidazoles, pyridines, pyrimidines, pyridazines, and polyazines. Chapter five briefly highlights two new C–H functionalization reactions currently being developed that are enabled by base-catalyzed halogen transfer. First, use of this approach to enable the C–H hydroxylation of benzenes will be described. Second, the monoselective and site-selective benzylic C–H etherification of toluenes and polyalkyl benzenes will be detailed. In the final part of the chapter, I will summarize my contributions and discuss the future outlooks on this chemistry.
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    Selective functionalization of azines via phosphonium salts
    (Colorado State University. Libraries, 2020) Koniarczyk, J. Luke, author; McNally, Andrew, advisor; Chen, Eugene, committee member; Barisas, George, committee member; Chatterjee, Delphi, committee member
    Pyridines and diazines are ubiquitous in pharmaceuticals, agrochemicals, and materials. Therefore, methods to functionalize these structural motifs are increasingly valuable. We have shown that phosphonium salts can be formed on a range of azines, including complex biologicallyactive compounds. Additionally, these azinyl phosphonium salts serve as a general functional handle to facilitate a variety of bond formations. Chapter 2 focuses on a method to incorporate deuterium and tritium atoms onto azines and pharmaceuticals using azinyl phosphonium salts. Deuteration is commonly used as a means to deter unwanted oxidative metabolism on drugs, and tritium is installed as a radiolabel for metabolic studies in the pharmaceutical industry. The protocol of the reaction is simple, and it functions on a wide range of building blocks and complex molecules. Additionally, the tritiation protocol was effectively applied on a selection of drug molecules through a collaborative effort with Merck. In chapter 3, a pyridine-pyridine coupling reaction is discussed using azinyl phosphonium salts as radical precursors. The reaction functions through a radical-radical coupling mechanism using B2pin2 and 4-cyanopyridine as an electron-transfer reagent for reduction of the phosphonium salt. Azinyl phosphonium salts were found to be the only radical precursor amenable to the reaction, and the process functions as an alternative to the Minisci reaction to form bipyridine products.
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    Selective functionalization of pyridines and diazines via nucleophilic addition to heterocyclic phosphonium salts
    (Colorado State University. Libraries, 2018) Anderson, Ryan Gerald, author; McNally, Andrew, advisor; Paton, Robert S., committee member; Chatterjee, Delphi, committee member
    Nitrogen heterocycles, specifically pyridines and pyrimidines, are common motifs found in pharmaceuticals, agrochemicals and materials. Site-selective functionalization of these azines are highly sought after for medicinal chemistry purposes. It has previously been found in our lab that heterocyclic phosphonium salts can potentially serve as a useful functional handle to selectively functionalize these valuable scaffolds. This work describes the utility of heterocyclic phosphonium salts as electrophiles to selectively form C-O, C-S, C-N and C-Se bonds in a diverse range of pyridines and diazines. First, the addition of thiolate nucleophiles to heterocyclic phosphonium salts to selectively form heteroaryl thioethers is described. This coupling reaction proceeds through deprotonation of the alkyl thiol followed by addition of the heterocyclic phosphonium salt under mild conditions. The reaction scope was tested for a variety of alkyl thiol nucleophiles as well as different pyridine phosphonium salts. The extent of the method's utility was demonstrated through late-stage functionalization of some complex pharmaceuticals. Additionally, initial results on the reactivity of sulfinate nucleophiles with heterocyclic phosphonium salts is communicated. Second, aromatic heteronucleophiles were explored for reactivity with heterocyclic phosphonium salts. Aromatic heteronucleophiles can be classified as either exocyclic or endocyclic. Exocyclic aromatic heteronucleophiles, such as phenols, thiophenols and anilines, were able to be selectively coupled to azines and pharmaceuticals. Endocyclic aromatic heteronucleophiles, such as pyrroles, pyrazoles and imidazoles, also proved to be compatible. All these nucleophiles were able to be coupled to complex drug-like fragments as well as other bioactive molecules via the phosphonium ion. The method also enabled a convergent coupling reaction between two elaborate coupling partners to form a novel tyrosine kinase inhibitor that would be difficult to access using conventional methods.
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    The development and application of metal-catalyzed diamination reactions
    (Colorado State University. Libraries, 2014) Cornwall, Richard G., author; Shi, Yian, advisor; Kennan, Alan, committee member; McNaughton, Brian, committee member; Henry, Charles, committee member; Chatterjee, Delphi, committee member
    Nitrogen-rich molecules are of great interest in chemistry and incorporation of nitrogen into molecules is an on-going active field of study. In particular, vicinal diamines are important functional moieties that are found throughout biologically active molecules and natural products as well as highly effective chiral control agents in organic synthesis. There has been much effort directed toward the efficient synthesis of vicinal diamines; however the development of a direct route has proven to be challenging. This dissertation discusses the application of diamination products from existing methods to synthesize biologically active motifs, as well as the development of new metal-catalyzed diamination methods for the synthesis of biologically interesting motifs from readily available starting materials. The β, γ-diamino acid motif is an area of active research because of its prevalence in biologically active molecules and its use in peptide library syntheses. Cyclization of β, γ-diamino acids give the closely related 4-aminopyrrolidinones. These five-membered amino lactams have been reported to potentiate insulin activity when incorporated into hypoglycemic peptide analogues and made the analogues more stable towards physiological degradation. Current methods for the synthesis of these compounds require multi-step procedures and rely heavily on commercially available amino acids as starting materials, thus limiting the structural variability for biological studies. Using a diamination method discovered in our lab, 4-aminopyrrolidinones were efficiently synthesized in 40% overall yield, over five steps from readily available terminal olefins or conjugated dienes, providing a comparable process in the synthesis of these compounds. As part of our ongoing efforts to study the mechanism of metal-catalyzed diaminations using diaziridinone as nitrogen source, it was found that regioselectivity in the diamination of conjugated dienes could be controlled using Cu(I) as catalyst and varying reaction conditions. An alternative nitrogen source, thiadiaziridine 1,1-dioxide, which has shown to display interesting reactivity, was chosen to further investigate the Cu(I)-catalyzed regioselective diamination. Upon varying reaction conditions with Cu(I) catalysts, regioselective diamination occurred for various conjugated dienes and allowed direct access to a range of diverse cyclic sulfamides which have interesting biological potential. With the racemic synthesis of cyclic sulfamides, it was of interest to obtain these compounds asymmetrically, as their biological properties are of value and current methods for their asymmetric synthesis do not allow much variation in substitution patterns. Using Pd2(dba)3 and a chiral phosphoramidite ligand, a variety of chiral cyclic sulfamides were synthesized in moderate to high yields and with ee's greater than 90%, providing direct access to these valuable compounds in one step from readily available conjugated diene substrates. Lastly, N,N-Di-tert-butyl thiadiaziridine 1,1-dioxide has been found to be a versatile reagent for interesting reactivity. Other uses of this reagent include the Pd(II)-catalyzed terminal diamination of conjugated dienes, diamination of allenes, and the Pd-catalyzed oxidation of alcohols to form α, β-unsaturated compounds.
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    The development of novel N-heterocyclic carbenes for asymmetric C-C bond forming reactions
    (Colorado State University. Libraries, 2012) DiRocco, Daniel A., author; Rovis, Tomislav, advisor; Williams, Robert M., committee member; Finke, Richard G., committee member; Bailey, Travis S., committee member; Chatterjee, Delphi, committee member
    A variety of novel N-heterocyclic carbenes have been developed as organocatalysts for highly efficient and selective intermolecular C-C bond forming reactions. Problems associated with attaining high selectivity while retaining high efficiency in asymmetric intermolecular acyl anion pathways have been resolved through non-traditional manipulation of the catalyst architecture. In the context of the asymmetric intermolecular Stetter reaction, a new series of fluorinated triazolium salt pre-catalysts have been developed that catalyze the highly enantioselective coupling of hetaryl aldehydes and nitroalkenes. Stereoelectronic effects in the ground state suggest that conformation of the catalyst plays a role in determining selectivity. DFT calculations provide evidence for an electrostatic interaction between the fluorine-induced dipole and the electrophiles as the source of increased selectivity. The scope of the asymmetric intermolecular Stetter reaction of nitroalkenes has been further expanded to incorporate α,β-unsaturated aldehydes as partners. Mechanistic studies point to the initial proton-transfer event leading to generation of the acyl-anion equivalent as being turnover limiting. With this knowledge, an additive has been introduced that effectively increases the rate of proton transfer leading to substantially shorter reaction times and dramatically lower catalyst loadings. Further catalyst development has led to the realization of another mode of catalyst control, using the C-F bond as an additional source of substrate differentiation. This complementary fluorinated catalyst architecture substantially increases the reactivity of enolizable aldehydes in the asymmetric intermolecular Stetter reaction of nitrostyrenes, and for the first time allows for their inclusion in this transformation. An asymmetric aza-benzoin reaction of aliphatic aldehydes and N-Boc imines has been developed after identifying an extremely selective amino-indanol derived catalyst scaffold and mild reaction conditions. The direct enantioselective acylation of amines has been realized using a dual catalysis manifold, incorporating a photoactive metal complex as a catalyst to activate amines toward acyl-anion addition and a chiral NHC catalyst. This methodology has led to the isolation and full characterization of a series of aza-Breslow intermediates by X-ray crystallography. Studies of these intermediates provide crucial information about the fundamental reactivity of the Breslow intermediate and show that it is not only a catalyst resting state in these transformation but its generation is also reversible in the presence of a weak acid.
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    Understanding Mycobacterium abscessus in cystic fibrosis mice
    (Colorado State University. Libraries, 2019) Vongtongsalee, Kridakorn, author; Ordway, Diane, advisor; Schenkel, Alan, committee member; Chatterjee, Delphi, committee member; Kirby, Michael, committee member
    Cystic fibrosis (CF) is caused by mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which normally encodes an ABC transporter-class ion channel protein that allows chloride and thiocyanate ions transport across epithelial cell membranes. Thus, CFTR plays an important role in airway homeostasis. Mutations of CFTR in patients with CF leads to a defect in transport of chloride and thiocyanate ions by epithelial cells, resulting in a multi-system disorder that affects the respiratory tract, gastrointestinal tract, the endocrine system, among others. The epithelial cell dysfunction in the lungs of CF patients also leads to an impaired pulmonary defense mechanism, resulting in decreased bacterial clearance and chronic inflammation. In CF patients, lung disease due to non-tuberculous mycobacteria (NTM) — an environmental organisms found in soil, water, and biofilms — is one of the most feared complications. Among the NTM, the rapidly-growing Mycobacterium abscessus is particularly notorious given its intrinsic resistance to many antibiotics. The transmission of M. abscessus to humans occurs by wound contamination, airborne transmission, or ingestion. Despite the fact that M. abscessus infection is increasing worldwide, little is known about how M. abscessus causes disease. To improve our understanding of M. abscessus in CF patients, we set out to investigate the progression of M. abscessus infection in a CF mouse model by developing a reinfection mouse model using three different strains of "CF mouse" — Beta-ENaC mice, Cftrtm1UNCTgN(FABPCFTR) mice and CFTRtm1UNC/ CFTRtm1UNC mice — to track the bacterial burden and organ pathology. Our results support the hypothesis that repeated infection with M. abscessus is more likely to result in disease progression and increased pathogenesis of the disease in CF mouse models. The high bacterial burden persisted in the lung after four infections in β-ENaC transgenic mice and CFTRtm1UNC/CFTRtm1UNC mice and maintained in the organs by day 30. Cftrtm1UNCTgN(FABPCFTR) mice tended to show slowly increasing bacterial burden in all organs. In summary, we demonstrate that reinfection of the CF mouse models with M. abscessus is more likely to result in a sustained infection in the lungs associated with increased pulmonary pathology.
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    Understanding Mycobacterium abscessus pulmonary and disseminated disease
    (Colorado State University. Libraries, 2017) Layer, Emily L., author; Ordway, Diane, advisor; Orme, Ian, committee member; Chatterjee, Delphi, committee member; Kirby, Michael, committee member
    Mycobacterium abscessus is an emerging human pathogen which is difficult to treat and results in increased mortality. Moreover, the cause of increasing case rates and also the pathogenesis of M. abscessus are poorly understood. M. abscessus belongs to the family of nontuberculous mycobacteria (NTM) classified as members of the rapidly growing mycobacteria (RGM). These environmental pathogens are ubiquitous and found in shower heads, tap water, natural water sources, and soil. Humans contract pulmonary or disseminated infections with M. abscessus by breathing in the aerosolized bacteria or ingesting contaminated water. Immunocompromised individuals such as HIV or AIDS patients, are more susceptible to infection with M. abscessus as are those with cystic fibrosis, bronchiectasis, and individuals on tumor necrosis factor α (TNFα) inhibitors. Strangely, an increasing population of patients becoming infected with M. abscessus are immunocompetent, tall, slender, Caucasian, non-smoking women. To expand our understanding of M. abscessus pathogenesis we developed mouse models that maintain high levels of bacterial infection to study immune responses induced by clinical strains of M. abscessus. Our results support the hypothesis that this bacteria can only persist in our animal models that possess a deficiency in macrophages and T cell function. Clustered bacterial strains obtained from Cystic Fibrosis patients are more virulent than unclustered bacterial strains obtained from Cystic Fibrosis patients. Additionally, counts of viable mycobacterial colony forming units and histological analysis in (Severe Combined Immunodeficiency) SCID mice on a beige background infected with clustered versus unclustered M. abscessus strains which were isolated from Cystic Fibrosis patients also supported the increased virulence exhibited by the clustered strains. Lastly, we show that major human M. abscessus outbreak strains, when infecting IL-3, GM-CSF deficient mice on an IL-2, Rag2 deficient background (GM/Rag-dblKO mice), result in increased bacterial replication and organ pathology and impaired protective immunity against this pathogen.
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    Understanding the process of Mycobacterium abscessus reinfection on host immunity
    (Colorado State University. Libraries, 2020) Ohanjanyan, Tamara, author; Ordway, Diane, advisor; Schenkel, Alan, advisor; Elf, Jessica, committee member; Chatterjee, Delphi, committee member
    Mycobacterium abscessus is a bacterial pathogen emerging in humans. The bacterium is difficult to treat, and it results in increased mortality. The patient case rates of diseases associated with this bacterium are increasing. Mycobacterium abscessus pathogenesis is poorly understood which limits our understanding of M. abscessus. The bacterium is part of the diverse family of nontuberculous mycobacterial species (NTM), and it is classified as a member of rapidly growing mycobacteria (RGM). These are environmental pathogens and they are found in tap water, showerheads, natural water sources, and soil. M. abscessus can infect individuals by breathing in aerosolized water particles, contact with surface fomites and transmission from infected patients. Individuals with human immunodeficiency syndrome (HIV) and are immunocompromised are more susceptible to infection with M. abscessus. Also, individuals with cystic fibrosis, chronic obstructive pulmonary disease or using tumor necrosis factor α (TNF- α) inhibitors are also susceptible to becoming infected with M. abscessus. Surprisingly, immunocompetent, tall slender Caucasian, non-smoking women also show an increasing rate of being infected with M. abscessus. To gain a better understanding M. abscessus pathogenesis and immune modulation, we developed βENaC over-expressing mouse models (βENaC-Tg). The main goal for this study was to discover the re-infection with the bacterium to study immune responses induced by M. abscessus. This is particularly important since the M. abscessus is an environmental pathogen and from birth to death we are all suspected to it. The reinfection process can have serious consequences in immune-compromised patients causing immune exhaustion, or in other words where the immune system is unable to fight against the bacteria after several times of infection. Our M. abscessus immunological results have shown after βENaC-Tg mice that are exposed to 4 subsequent aerosols of M. abscessus intracheal infections their CD4+ T cells show increased expression of the immune exhaustion marker PD1+ and CD11b+ macrophages show increased expression of another immune exhaustion marker CTLA4+. Together, these results support the idea that repeated environmental exposure to M. abscessus through environmental sources can potentially result in immune exhaustion leading to lack of effective function of T cells and macrophages to kill M. abscessus.