Browsing by Author "Wang, Qiu"

Alkene difunctionalization is a powerful synthetic method that introduces two distinct functional groups simultaneously, which can transform simple alkenes feedstock into richly functionalized valuable skeletons. With the well-known importance of nitrogen containing molecules in organic synthesis, pharmaceuticals, and materials, great efforts have been devoted to developing alkene amination functionalization strategies, including diamination, aminooxygenation and aminohalogenation. Despite extensive progress in this area, the aminocarbonation of alkenes remains underdeveloped. Moreover, the ubiquity of carbon–carbon and carbon–nitrogen bonds in nature makes it highly desirable to develop efficient methods for concurrent formation of these two valuable bonds. In this dissertation, novel copper-catalyzed 1,2-aminocarbonation strategies have been established using O-benzoylhydroxylamines as an electron-rich amine radical precursor and oxidant. (1) First, 1,2-aminoheteroarylation via heteroaryl group migration was developed, which can furnish diverse heteroarylethylamine core. Distinctive from previous migratory strategies requiring a hydroxyl moiety as a starting material, this method is widely effective on alcohol-, amide-, and even ether-containing alkenes. This reaction was also proved to be a viable strategy for the synthesis of cyclic ketone systems. (2) Furthermore, the development of Minisci-type 1,2-aminoheteroarylation is in progress based on the discovery that a carbon-centered radical intermediate generated by addition of O-benzoylhydroxylamine to alkenes can couple with an electron-deficient aromatic moiety to easily synthesize azaheteroarene-fused cyclic skeleton. (3) Finally, a copper-catalyzed aminocyanation of alkenes was achieved through distal cyano migration using O-benzoylhydroxylamines and N-fluorobenzenesulfonimides as a rapid approach to generate diverse β-amino and β-sulfonimido nitriles, demonstrating the wide utility of this amine-initiated migration strategy as a general aminocarbonation synthetic tool.

Heterocycles represent an important class of motifs found in many bioactive molecules, pharmaceuticals, and agrochemicals. The ability to rapidly construct a diverse set of these compounds remains an important endeavor in the field of synthetic chemistry. In this thesis, an intramolecular 1,3-difunctionalization of cyclopropanes is reported using a copper-NFSI catalyzed system. Direct oxidation of the substrate by a nitrogen centered radical activates the cyclopropane which then undergoes a ring-opening cascade to produce a variety of lactones, cyclic ethers, pyrrolidines, and oximes containing γ-amino functionalization. Further product derivatization can produce various protected amines and alkyl-sulfonamides.

Nitrogen-containing compounds, specifically the 1,2-oxyamino moiety, are of vital importance to modern pharmaceuticals, natural products, and agrochemicals. 1,2-Difunctionalization of alkenes offers an efficient approach to assemble these scaffolds in a single step from readily available starting materials. In this dissertation, a novel copper-catalyzed amino oxygenation strategy of alkenes has been established using O-benzoylhydroxylamines as an electron-rich amine precursor and oxidant. First, copper-catalyzed amino lactonization was achieved starting with carboxylic acid-tethered alkenes. This intramolecular transformation is also applicable to alcohols, amides, 1,3-diones, oximes, and thioic acids as nucleophilic trapping partners. These reactions proceed in a facile manner, producing good yields and tolerance of a wide range of functional groups with excellent chemo- and regioselectivity. Mechanistic studies explicitly distinguish between a novel, electrophilic amination-initiation event and previously observed nucleophilic oxygenation-initiation events. Furthermore, the procedure can be adapted to carry out the reaction from the free amine as an O-benzoylhydroxylamine precursor. Finally, the intermolecular, three-component amino oxygenation reaction of alkenes was successfully developed using untethered carboxylic acids and O-benzoylhydroxylamines. The analogous three-component amino oxygenation reaction of dienes was also found to proceed effectively in a chemo-, regio-, and site-selective fashion.

The wide presence of C-N bonds in biologically and pharmaceutically important compounds continues to drive the development of new C-N bond-forming transformations. Among the different strategies, electrophilic amination is an important synthetic approach for the direct formation of C-N bonds. Compared to electrophilic amination of organometallic reagents, direct amination of C-H bonds will provide a potentially more effective route towards C-N bond formation. Towards this, we proposed an electrophilic amination of C-H bonds via their reactive organometallic surrogate intermediates. Specifically, we are interested in organozinc intermediates and their in situ formation from C-H bonds.

This dissertation reports our development of direct amination of various C-H bonds using a H-Zn exchange/electrophilic amination strategy as a rapid and powerful way to access a variety of functionalized amines. We were able to achieve C-H zincation using strong and non-nucleophilic bases Zn(tmp)2 or tmpZnCl*LiCl and subsequent electrophilic amination of the corresponding zinc carbanions with copper as a catalyst and O-benzoylhydroxylamines as the electrophilic nitrogen source. With such a one-pot procedure, the synthesis of various amines from C-H bonds has been achieved, including alpha-amination of esters, amides, and phosphonates. Direct amination of heteroaromatic and aromatic C-H bonds has also been developed in good to high yields. It is important to note that mild reactivity of organozinc reagents offers a good compatibility with different functional groups, such as esters, amides, and halides.

Success in developing direct and efficient syntheses of these various amines is highly valuable. These new amination methods will greatly expand the chemical diversity and space of available amine skeletons, and will contribute to future advances in material science, medicinal chemistry and drug discovery.

Poly-substituted arenes are valuable skeletons and widespread in pharmaceuticals, agrochemicals, and functional materials. In the design and development of novel functional arenes, the major bottleneck lies in their synthetic access due to the requirement of multi-step syntheses. To tackle such challenges, functionalization directly from abundant C–H bonds offer greater flexibility and efficiency in the synthesis of diverse poly-substituted arenes. In this context, a deprotonative C–H zincation strategy is appealing for two distinct reasons. First, this strategy allows regioselective C–H activation of a variety of arenes and heteroarenes directly. Moreover, generated organozinc intermediates as nucleophiles are capable of performing effective functionalizations. Therefore, we developed several synthetic transformations toward efficient access to poly-substituted arenes using deprotonative C–H zincation. (1) The regioselective azidation of diversely substituted arenes and heteroarenes was achieved through deprotonative C–H zincation and subsequent copper-catalyzed azidation. (2) To achieve multi-bond formation in a single step, we envisioned arene 1,2-difunctionalization methods using aryne intermediates generated from aryl triflates mediated by deprotonative zincation. Both intra- and intermolecular difunctionalization of arenes were developed, providing numerous difunctionalized arenes with diverse functionalities such as carbon, nitrogen, oxygen, sulfur, and halogens. (3) The difunctionalization strategy was extended to cyclohexenes, which are prevalent fundamental structure motifs. Through generation of cyclohexynes via deprotonative zincation of cyclohexenyl triflates, three-component cyclohexyne 1,2-difunctionalization was accomplished with formation of structurally complex and diversely functionalized cyclohexenes.

Hyperpolarized magnetic resonance spectroscopic imaging (HP-MRSI) enables non-invasive visualization of metabolism and physiological activities in real-time. Hyperpolarized agents developed to date are primarily 13C-labeled metabolites with short polarization lifetimes of less than a minute, limiting the imaging assay to fast metabolic pathways. To expand on the applications of HP-MRSI, we proposed the use of a versatile 15N-molecular tagging strategy.

This dissertation reports our exploration and application of highly adaptable 15N-molecular handles for development of hyperpolarized molecular imaging probes. Towards this goal, we have investigated 15N2-diazirines and 15N3-azides as biocompatible HP tags with long polarization lifetimes. Several 15N-tagged biological molecules were prepared, including amino acid, glucose, and drug molecules. Hyperpolarization with a d-DNP method demonstrated high signal enhancements (over 400,000-fold) and long 15N relaxation lifetimes (T1) of average 3–4 minutes in aqueous solutions, which warrants a long MR imaging window.

Moreover, we have rationally designed and synthesized novel 15N-labeled reaction-based probes for sensing hydrogen peroxide (H2O2) and nitric oxide (NO) as biomarkers for oxidative stress. We were able to observe the 15N-signal from our 15N-labeled H2O2 sensing probe in vivo using an animal model, which presents exciting progress in the field. Additionally, we explored various molecular probe designs to pursue the most practical 15N-labeled gamma-glutamyl transferase (GGT) sensor. These reaction-based redox and enzyme sensing probes showed favorable hyperpolarization and bioimaging properties. Our work on innovative de novo chemical probes highlights the unprecedented HP-MRSI applications for imaging disease biomarkers.

Bioorthogonal chemistry is a burgeoning area of study that has innumerable applications. This dissertation describes applications of bioorthogonal chemistry to solve problems in the fields of imaging and metal uncaging. We first consider hyperpolarized magnetic resonance, a powerful tool in clinical and biochemical imaging that suffers from short signal lifetimes, which are typically less than a minute for many common molecular probes. Bioorthogonal handles such as azides and tetrazines are shown to be a viable, highly generalized approach to overcome these lifetime limitations in a variety of molecular probes. Additionally, in the field of inorganic chemistry, we hypothesize the potential use of bioorthogonal “click” reaction toward the development of a novel metal uncaging strategy. These innovative demonstrations of bioorthogonal chemistry highlight their potential in diverse areas of study.

Aminoarenes are common structural features in pharmaceuticals and biologically relevant scaffolds, motivating continued development of strategies to facilitate their synthesis. Canonical approaches to aryl amination rely upon nucleophilic N–H bond precursors. Nitrogen–heteroatom bonds possess versatile reactivity and can enable synthetically attractive approaches to functionalized aminoarenes. Towards this, we proposed the use of nitrogen–heteroatom bonds in both bond insertion by reactive aryne intermediates and as electrophilic amination reagents in the net C–H amination of arenes via zinc-amide mediated H–Zn exchange.

Herein, we describe the development of nitrogen–heteroatom bond enabled strategies to access functionally diverse aminoarene products. Aryne insertion of N-chloro, -bromo, and even -iodoamines was achieved in moderate yields and excellent regioselectivity to provide direct access to ortho-haloaminoarene motifs. This approach employs ortho-trimethylsilyl aryltriflates and simple fluoride salts as a mild platform for in situ formation of reactive arynes, affording functionally complex aminoarene products in a single transformation. Access to aminoarenes from ubiquitous heteroaryl and aryl C–H bonds was also achieved via copper-catalyzed electrophilic amination with O-benzoylhydroxylamines, mediated by initial H–Zn exchange from highly hindered amide-zinc complexes. In addition to well-established Zn(TMP)2 and Zn(TMP)Cl•LiCl, we developed LiTMP0.1Li[ZnEt2(TMP)] as part of a general ortho-directed C–H zincation/amination strategy. Using O-benzoylhydroxylamines and a copper catalyst to affect electrophilic amination, this zincate base permitted access to a broad scope of heteroarene and arene substrates with varied ortho-directing group functionalities. The improved access to aminoarene products enabled by these methods was then demonstrated through the study of functionally selective dopamine receptor ligands, which yielded valuable information on the complex SAR and SFSR of D2 and D3 receptors and their signaling pathways.

The successful development of strategies to access highly functionalized aminoarene scaffolds provides valuable tools for drug discovery. The methods presented here expand access to diverse aryl amine motifs and will contribute to the development of novel small molecule biochemical tools and therapeutics.

Dopamine receptors (D1-5R), responsible for cognition and locomotion, are involved in several neurological diseases. Parkinson’s Disease (PD) is a neurodegenerative disorder wherein patients suffer from the loss of dopaminergic neurons, resulting in both bradykinesia and tremors. Levodopa (L-DOPA) and apomorphine are both effective treatments of PD; however, they both produce severe dyskinesia with chronic use. In a PD model, a recent discovery shows the G-protein pathway is associated with dyskinesia while the beta-arrestin pathway led to locomotor improvement. As of date, there are no known beta-arrestin biased ligands at D1R. Thus, this work focuses on the derivatization of (R)-apomorphine to develop a D1- or D2R beta-arrestin biased ligand through total synthesis or through late-stage functionalization of the core. These analogs will be tested in vitro through collaboration where we will study the structure-functional-selectivity relationship to better assist us in the design of future beta-arrestin biased analogs. The long-term goal of this research is to contribute to the improvement of PD treatment through selective activation of the beta-arrestin pathway. This work is motivated by the severity of L-DOPA induced dyskinesia and the lack of proper, long-term treatment.

The Protein Arginine Methyltransferases (PRMTs) are a family of proteins that play important roles in epigenetic modification of genes. They have been found to have crucial roles in various diseases, most notably in cancer. In order to probe their functions and potentials in cancer therapy, we have undertaken efforts to design and discover small-molecule compounds that specifically target PRMT4 and PRMT6. We have also developed a series of functional assays to assess the effects of potential lead compounds on enzymatic activities of PRMT4 and PRMT6 proteins.

We took a computation-facilitated in silico approach to identify small-molecule binders of PRMT4 and an empirical facilitated structure-based design for PRMT6. From these efforts, a few lead compounds have been identified for future studies.

We have established multiple-mode assays for characterizing small molecule’s effects on enzymatic activities of PRMT4 and PRMT6, including biochemical activity assays, cellular activity assay, and downstream-gene regulatory assay. The reliability of all assays has been validated. However, further validation of the downstream gene assay for PRMT4 is needed.

Our efforts also involved the development of a florescence probe for florescence polarization (FP) assay of PRMT6.

Fluorine in modern pharmaceuticals has enabled development of drugs with enhanced therapeutic value through the selective modulation of a variety of pharmacological parameters. Therefore, methods to prepare molecular scaffolds which contain the fluorine atom are of critical importance for the continued success of novel drug discovery. In this thesis, the regioselective intermolecular aminofluorination of alkenes has been achieved with N,N-dialkylhydroxylamines and nucleophilic fluorine. With this copper-catalyzed approach, a variety of pharmaceutically relevant β-fluorophenethylamines have been prepared. Additionally, through the systematic evaluation of substituted alkenes and electronically varied O-substituted-N-hydroxylmorpholines, the limitations of the method have been discovered. Mechanistic experiments have also revealed the presence of a radical intermediate, which suggests the transformation occurs through a nitrogen-initiated pathway.

N-Heterocycles are ubiquitous in biologically active natural products and pharmaceuticals. Yet, new syntheses and modifications of N-heterocycles are continually of interest for the purposes of expanding chemical space, finding quicker synthetic routes, better pharmaceuticals, and even new handles for molecular labeling. There are several iterations of molecular labeling; the decision of where to place the label is as important as of which visualization technique to emphasize.

Piperidine and indole are two of the most widely distributed N-heterocycles and thus were targeted for synthesis, functionalization, and labeling. The major functionalization of these scaffolds should include a nitrogen atom, while the inclusion of other groups will expand the utility of the method. Towards this goal, ease of synthesis and elimination of step-wise transformations are of the utmost concern. Here, the concept of electrophilic amination can be utilized as a way of introducing complex secondary and tertiary amines with minimal operations.

Molecular tags should be on or adjacent to an N-heterocycle as they are normally the motifs implicated at the binding site of enzymes and receptors. The labeling techniques should be useful to a chemical biologist, but should also in theory be useful to the medical community. The two types of labeling that are of interest to a chemist and a physician would be positron emission tomography (PET) and magnetic resonance imaging (MRI).

Coincidentally, the 3-positions of both piperidine and indole are historically difficult to access and modify. However, using electrophilic amination techniques, 3-functionalized piperidines can be synthesized in good yields from unsaturated amines. In the same manner, 3-labeled piperidines can be obtained; the piperidines can either be labeled with an azide for biochemical research or an 18F for PET imaging research. The novel electrophiles, N-benzenesulfonyloxyamides, can be reacted with indole in one of two ways: 3-amidation or 1-amidomethylation, depending on the exact reaction conditions. Lastly, a novel, hyperpolarizable 15N2-labeled diazirine has been developed as an exogenous and versatile tag for use in magnetic resonance imaging.

Carbon–hydrogen bond functionalization is a highly desirable transformation as C–H bonds are plentiful in feedstock chemicals and the direct introduction of valuable functional groups improves atom economy and efficiency. However, field of direct C–H functionalization still has many challenges including regioselectivity, directing group limitations, and often harsh reaction conditions with toxic and rare transition metal catalysts. Deprotonative zincation has been demonstrated as a useful method to achieve C–H functionalization.

The direct C–H amination of a wide scope of arenes and heteroarenes has been achieved by copper-catalyzed electrophilic amination with O-benzoyl hydroxylamines. Key to the expanded scope of substrates is the use of a lithium zincate base, Li[ZnEt2TMP] which can coordinate to a variety of common functionalities to direct zincation. The mild reaction conditions and compatibility with functional groups such as esters, nitriles and halides make this method orthogonal to many existing strategies.

Additionally, a novel lithium zincate base with inexpensive dicyclohexylamine has been developed and shown to be capable of efficient and regioselective zincation with an extensive scope of directing groups. Aryl and heteroaryl zincates can undergo direct electrophilic silylation and borylation without the need for any transition metal catalyst.

α-Functionalization of substituted amides and esters has been achieved by utilizing a tribasic lithium zincate for direct allylation and copper-catalyzed arylation and vinylation with aryl iodides and vinyl iodides. In summary, lithium zincate bases have been demonstrated to be broadly useful for diverse and regioselective C–H functionalization to introduce valuable complexity from simple starting materials.