Browsing by Subject "Organic chemistry"

The design of synthetic transformations that proceed selectively in the presence of multiple sites of similar chemical reactivity has been a long-standing challenge. Cross-coupling and C–H functionalization processes have gathered significant attention over the past few decades as a result of their ability to rapidly generate molecular complexity. Despite these advances, a chemist’s ability to judiciously, selectively, and predictably perform these synthetic transformations has not yet been fully realized. Herein disclosed are the investigations into new methods for the Suzuki-Miyaura and Hofmann-Löffler-Freytag reactions that proceed with predictable selectivity.

Tactical advances have resulted in the development of selective, serial, and exhaustive cross-coupling transformations of alkyl pinacol boronic esters with polyhalogenated (hetero)arenes. These Suzuki-Miyaura processes facilitate access to a wide variety of alkyl-substituted aromatic compounds, specifically 2-alkylpyridines, which constitute an important class of functional molecules.

Conceptual innovations have established sulfamate esters as a promising manifold for the radical-mediated functionalization of remote, aliphatic C–H bonds. New methods for the synthesis of sulfamate esters have facilitated access to these valuable functional motifs, thereby allowing their use in Hofmann-Löffler-Freytag reactions. Accordingly, the selective, sulfamate ester-guided chlorination of remote C(sp3)–H bonds has been developed. This transformation proceeds with unique site-selectivity and furnishes γ-functionalized masked alcohol derivatives.

The α-alkylation of N-sulfonyl hydrazones via in situ-derived azoalkenes provides an umpolung approach to ketone α-alkylation that has considerable potential with regard to catalysis and the direct incorporation of functionality not amenable to the use of enolate chemistry. Herein, the first Cu(I)-catalyzed addition of Grignard reagents to in situ-derived N-sulfonyl azoalkenes is described. This method is remarkable in its ability to deliver highly sterically hindered compounds that would be difficult or impossible to synthesize via traditional enolate chemistry, including those having up to three contiguous quaternary centers. This method is compatible with a wide variety of α-halo tosylhydrazones, including cyclic and acyclic α-halo tosylhydrazones as well as those derived from both ketones and aldehydes. Also, herein, the first asymmetric organocatalytic sulfenylation of in situ-derived nitrosoalkenes leading to chiral nonracemic α-sulfenylated ketones is described. The transformation proceeds in an umpolung fashion, relative to enolate/azaenolate methods, and uses simple thiols, thereby obviating the need for elecrophilic sulfur reagents. Moreover, excellent ee's were obtained starting from a variety of α-chloro oximes, including cyclic and acyclyic systems. Chiral nonracemic sulfur containing compounds are important both biologically, and in synthetic context through their use as chiral auxiliaries, ligands for metal catalysis, and organocatalysts. Also, herein, the addition of cuprates to α,β-epoxy tosylhydrazones is described. The transformation is operationally simple and efficient and has the unusual feature of giving high syn selectivity, which is opposite of that produced by a simple SN2-type epoxide opening reaction. This method compatible with α,β-epoxy tosylhydrazones with additional α-substitution, which provides access to aldol-like products that would be impossible to make using traditional enolate chemistry. Moreover, this method is compatible with a wide variety of both cyclic and acyclic α,β-epoxy tosylhydrazones, and produces dr's of >20:1.

Parkinson's disease (PD) is a debilitating neurodegenerative disease of the central nervous system characterized by loss of striatal dopaminergic projections from the substantia nigra. Although there is no known cure for PD, dopamine (DA) replacement using L-3,4-dihydroxyphenylalanine (L-DOPA) is the most common therapy used to manage PD symptoms. L-DOPA is poorly absorbed into the brain and metabolized in the periphery causing its efficacy to wane with time. Additionally, within five years of use, L-DOPA can induce its own severe motor dysfunction, including dyskinesias, which can be irreversible. This underscores the need for the discovery and development of improved anti-parkinsonian therapeutics. We have identified a class of conformationally-constrained phenylethylamines based on a tranylcypromine scaffold and demonstrated that many compounds in this structural class exhibited partial or full relief of akinesia in a DA-deficient/DA transporter knockout (DAT-KO) mouse model of PD developed in the Caron laboratory. Two highly active arylcyclopropylamines from studies in DAT-KO mice were subsequently evaluated in a 6-hydroxydopamine-lesioned rat model to confirm their anti-parkinsonian and anti-dyskinesia activities. In these rats, both compounds improved lesioned-induced motor deficits that emulate akinesia. Target identification and activity assays suggest 5-HT2B and 2A as candidate targets to begin elucidation of novel non-dopaminergic pathways to combat PD.

Modern patterning and fabrication techniques provide powerful opportunities for the preparation of micro- and nanostructured objects with applications in fields ranging from drug delivery and bioimaging to organic based electronic devices and real time biochemical sensors. In this thesis we report a systematic study focused on the development of new unconventional patterning and fabrication techniques with applications in the preparation of functional micro- and nanostructured devices.

Catalytic microcontact printing is a powerful technique that offers a simple and effective methodology for patterning chemically-functionalized surfaces with sub-100 nm accuracy. By avoiding diffusive mechanisms of pattern replication it effectively obviates the most significant limitation of traditional microcontact printing - lateral molecular ink diffusion. Moreover, catalytic microcontact printing significantly expands the diversity of patternable surfaces by using prefunctionalized substrates and gives rapid facile access to chemically discriminated surfaces that can be further functionalized with organic and biological molecules. We have developed several catalytic microcontact printing techniques that transfer pattern from an elastomeric stamp bearing an immobilized catalyst to a preformed functionalized self-assembled monolayer. By avoiding diffusive pattern transfer we were able to replicate features with sub-50 nm edge resolution. We also demonstrated that catalytic printing can be expanded to technologically important substrates not accessible through conventional soft lithography, by patterning reactive organic monolayers grafted to chemically passivated silicon.

The non-symmetric structure of Janus particles produces novel physical properties and unusual aggregation behavior that makes these materials attractive candidates for drug delivery and as nano-sensors and nano-probes, SERS and PEF imaging agents, small molecules carriers, and switchable devices. We have developed a new protocol for preparation of non-spherical inorganic Janus particles comprising metallic and semiconductor layers. The method allows for precise control over the composition, shape and size and permits fabrication of non-symmetrical particles, the opposite sides of which can be orthogonally functionalized using well-established organosilane and thiol chemistries.

When mechanical force is applied to synthetic materials, polymer chains become

highly strained, leading to bond scission and ultimately material failure. Over the last

decade or so, work in the field of polymer mechanochemistry has coupled this tension to

desired covalent chemical reactions. These functionalities, known as mechanophores,

react to unveil a new molecular structure and triggering a constructive response. This

strategy has been explored for a variety of purposes, including stress sensing, stress

strengthening, small molecule release, catalysis, and development of soft devices.

Additionally, the effect of force on a reaction coordinate, through biasing and probing

reaction pathways and trapping of transition states and intermediates, has been well–

studied experimentally and in theory. This work reports on understanding structure property

relationships for the spiropryan mechanophore and expanding our control of mechanochromism

from the single-molecule to device scale.

First, we report the effect of substituents on spiropyran derivatives substituted

with H, Br, or NO2 para to the breaking spirocyclic C− O bond using single molecule

force spectroscopy. The force required to achieve the rate constants of ~ 10 s−1 necessary

to observe transitions in the force spectroscopy experiments depends on the substituent,

with the more electron withdrawing substituent requiring less force. Rate constants at

375 pN were determined for all three derivatives, and the force coupled rate dependenc

eon substituent identity is well explained by a Hammett linear free energy relationship

with a value of ρ = 2.9, consistent with a highly polar transition state with heterolytic,

dissociative character. The methodology paves the way for further application of linear

free energy relationships and physical organic methodologies to mechanochemical

reactions.

The development and characterization of new force probes has enabled

additional, quantitative studies of force-coupled molecular behavior in polymeric

materials. The relationship between strain and color change has been measured for

these three spiropyran derivatives. The color appears at around the same strain and the

ratio of color intensities remains constant for all three derivatives. This result was not predicted by

previously reported computational work and motivates future studies of

force distribution within filled silicones.

On the material and device scale, we have utilized mechanochromism for soft

and stretchable electronics, which are promising for a variety of applications such as

wearable electronics, human− machine interfaces, and soft robotics. These devices,

which are often encased in elastomeric materials, maintain or adjust their functionality

during deformation, but can fail catastrophically if extended too far. Here, we report

new functional composites in which stretchable electronic properties are coupled to

molecular mechanochromic function, enabling at-a-glance visual cues that inform user

control. These properties are realized by covalently incorporating a spiropyran

mechanophore within poly(dimethylsiloxane) to indicate with a visible color change that

a strain threshold has been reached. The resulting colorimetric elastomers can be molded

and patterned so that, for example, the word “STOP” appears when a critical strain is

reached, indicating to the user that further strain risks device failure. We also show that

the strain at color onset can be programmed through the layering of silicones with

different moduli into a composite. As a demonstration, we show how color onset can be

tailored to indicate a when a specified frequency of a stretchable liquid metal antenna

has been reached. The multi-scale combination of mechanochromism and soft

electronics offers a new avenue to empower user control of strain-dependent properties

for future stretchable devices.

Through the study of the reaction that converts spiropyran into merocyanine, we

are able to teach and connect a number of standard general chemistry course topics

while also introducing students to polymer concepts. By framing a number of different

concepts including molecular orbital theory, quantum mechanics, equilibrium,

hydrogen bonding, mechanical work, and polymer chemistry with the same reaction,

our goal is to allow students to see connections in seemingly disparate sections of

general chemistry.

The reactivity of a mechanically active functional group is determined by the

activation energy of the reaction (ΔG‡) and the force-coupled change in length as the

reaction proceeds from the ground to transition state (Δx‡). Finally, we report a combination

of both principles enhances the mechanochemical reactivity of epoxides:

placing alkenes adjacent to cis-epoxide mechanophores along a polymer backbone

results in ring-opening to carbonyl ylides during sonication, whereas epoxides lacking

an adjacent alkene do not. Upon release, tension-trapped ylides preferentially close to

their trans-epoxides in accordance with the Woodward-Hoffman rules. The reactivity of

carbonyl ylides is exploited to tag the activated species with spectroscopic labels for

force-induced cross-linking through a reaction with pendant alcohols. Even with alkene

assistance, mechanochemical reactivity remains low; single molecule force spectroscopy

establishes a lower limit for ring-opening ca. 1 sec-1 at forces of ~2600 pN.

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.

Macrocycles have received growing appreciation for their potential in probing a broader biological space, and there are a significant number of bioactive macrocycles in nature. In addition, a macrocyclic scaffold provides interesting features, including high binding affinity and target selectivity due to the pre-organized conformation. Despite the therapeutic potential and valuable pharmacological characteristics, this class of scaffolds has been poorly exploited in the field of drug discovery because of synthetic challenges and incompatibility to the conventional Lipinski’s rule of five. Therefore, efficient approaches for the generation of diverse and complex macrocycles are needed to develop novel macrocyclic agents.

In an attempt to construct a diverse set of macrocycles, we designed a natural product-like macrocycle library containing a tetrahydropyran core. Our strategy for the generation of the library is based on the tandem allylic oxidation/oxa-conjugate addition for the stereoselective synthesis of a 2,6-cis-tetrahydropyran ring. The incorporation of various building blocks and the utilization of diverse macrocyclization methods were carried out to rapidly increase skeletal diversity and complexity. Appendage diversification was performed to further modulate the physicochemical properties of the macrocycles. Cheminformatic analyses demonstrated that our macrocycle library covers a distinct chemical space compared to drug-like space, while significantly overlapping

with macrocyclic natural product space.

We also explored a modular strategy for the synthesis of a macrocycle from nature, forazoline A, polyketide natural product. Forazoline A exhibits potent in vivo efficacy against the fungal pathogen Candida albicans displaying a synergistic effect with amphotericin B. Our approach towards the synthesis of forazoline A relied on the construction of three major fragments with the desired stereochemistry and the assembly of those fragments. In the dissertation, the synthetic studies of cyclohexane, thiazolidine, and alkyl chain fragments were introduced. Construction of the highly functionalized cyclohexane moiety was efficiently accomplished utilizing Mukaiyama aldol, Bayer–Villeger reaction, and addition of lithium dimethyl cuprate. Synthesis of the thiazolidine fragment was investigated via oxa-conjugate addition and Pummerer-type rearrangements. Finally, the alkyl chain fragment was synthesized through epoxidation, regioselective ring opening, and β-ketoester formation.

!Drug discovery typically involves structure-based drug design based on three-dimensional protein structures and hit/lead compound identification and optimization. Herein, this technique was used to overcome several obstacles associated with the developing of antibiotics, anticancer agents, and antifungals and reveal critical insights into the corresponding structure-activity relationships (SARs).Phospho-N-acetyl-muramyl-pentapeptide translocase (MraY) is an important membrane enzyme involved in the early-stage biosynthesis of bacterial peptidoglycans. As the inhibition of MraY leads to bacterial cell lysis, such MraY inhibitors (e.g., muraymycin) hold great promise for antibiotic development. However, the structural complexity of muraymycin makes its synthesis and practical applications challenging. Hence, we synthesized several muraymycin analogs with reduced structural complexity and better synthetic tractability and identified the moieties responsible for their biological activity to facilitate the development of muraymycin-derived antibiotics. Translesion synthesis (TLS) is a major mechanism that enables bypass replication over DNA lesions and promotes the formation of mutagenic DNA. Rev1/Pol ζ–mediated TLS plays an important role in cisplatin-induced mutations, and thus, the Rev1/Pol ζ interface is an attractive target for small-molecule TLS inhibitors. Herein, we aimed to develop TLS inhibitors as potential anticancer agents based on the recently reported inhibitor of the Rev1-Rev7 interaction, JH-RE-06. Despite its high potency, JH-RE-06 is poorly soluble in aqueous media and is therefore a limitation for further development. To overcome this limitation and identify novel anticancer agents, we prepared various JH-RE-06 analogs and studied the related SARs, to determine the critical functional groups for improving the biological activity improvement and aqueous solubility. Currently, fungal infections, which are particularly dangerous to immunocompromised patients, are a frequent cause of a death. However, the similarities between the eukaryotic physiologies of fungal pathogens and their hosts render targeting of the pathogen without causing side effects in the host challenging. Calcineurin (CN) plays a major role in invasive fungal diseases and is therefore a promising target for antifungal drug development. FK506, which is an approved CN inhibitor, exhibits promising activity but an insufficient selectivity because of its strong immunosuppressive effect. Therefore, in developing antifungal agents, we exploited the major structural differences between the CN-FK506-FKBP12 ternary complexes of humans and fungi and developed FK506/520 analogs targeting these complexes. The synthesized analogs retained the parent antifungal efficacy while exhibiting lower immunosuppressive activities and improved therapeutic efficacies both in vivo and in vitro.

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.

The direct addition of enolizable aldehydes and sulfonyl imines to α-halo thioesters to produce β-hydroxy/amino thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced for the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that not only contain acidic α-protons, but also towards electrophiles containing other acidic protons and base-sensitive functional groups. Moreover, excellent diastereoselectivity is achieved when a chiral non-racemic α-hydroxy aldehyde derivative is used. Using MgI₂ and Ph₃P, this method gives a wide range of aldol and Mannich products in good yields with high syn-diastereoselectivity. The products obtained from the reductive aldol and Mannich reactions are synthetically important intermediates in both polyketide and β-lactam synthesis, respectively, and can be readily derivatized to form many carbonyl derivatives through known manipulation of the thioester moiety.

Also, herein the asymmetric synthesis of (+)-mefloquine, a potent anti-malarial compound, is described. The synthesis is based on a key enantioselective Darzens reaction between a chiral α-chloro-N-amino cyclic carbamate (ACC) hydrazone and a quinoline-based aldehyde. This is a novel methodology developed by our lab, which gives a highly enantioenriched epoxide that can be further functionalized to give both enantiomers of mefloquine.

Three methodology studies and two total synthesis endeavors are presented. First, a study of Lewis acid and hydrogen bond mediated soft enolization of thioesters and their addition to imines in the Mannich reaction is reported. MgBr2*OEt2 and Hunig's base are used in concert with bulky thioesters and aromatic aldehydes to generate syn-b-aminothioesters with moderate diastereoselectivity and yield. Next, a biomimetic organocatalytic Mannich reaction is presented using a chiral cinchona alkaloid to effect the enantioselective addition of an imines to thioesters with high yield and diastereoselectivity and enantioselectivities up to 88:12.

The direct addition of enolizable aldehydes to a-iodo thioesters to produce b-hydroxy thioesters enabled by reductive soft enolization is reported. The transformation is operationally simple and efficient and has the unusual feature of giving high syn-selectivity, which is the opposite of that produced in the aldol addition with (thio)esters under conventional conditions. This method is tolerant to aldehydes and imines that contain acidic a-protons, as well as electrophiles containing other acidic protons and base-sensitive functional groups.

The development of a strategy for the asymmetric synthesis of a large portion of the polycyclic polyprenylated acyl phloroglucinols via N-amino cyclic carbamate hydrazones, and its application to the first asymmetric total synthesis of both (+)- and (-)-clusianone is discussed. The clusianones are synthesized with an er of 99:1 and their anti-HIV activity is found to be 1.53 and 1.13 M, respectively. A library of clusianone-like compounds is synthesized and their biological activity has been probed.

Finally, efforts towards the total synthesis of brasilicardin A are reported. An appropriate model system was synthesized, and conditions were established using a pinene-based aldol reaction to synthesize the b-methoxy-a-amino ester side chain of the molecule. Next, efforts toward the synthesis of the anti-syn-anti- perhydro-phenanthrene core are discussed.

RNA is a critical macromolecule in many biological processes by encoding both structural and genetic information. It can serve as the physical template for ribosome read-through during protein synthesis and the intermediary interfering gene expression. For example, messenger RNA encodes specific gene sequence, microRNA regulates expression level of the gene, riboswitch controls translation level and RNA splicing, non-coding RNA provides molecular scaffolding for protein recruitment. Undoubtedly, malfunction of cellular RNAs lead to multiple diseases and targeting disease related RNAs has emerged as the new strategy in many drug development campaigns. Indeed, ribosomal RNA has been utilized as the drug target for a long history and fruitful studies on naturally occurred or synthetic ligands were brought to elucidate the mechanism of translation inhibition. It was the past two decades that witnessed growing research on using small-molecule probes to interrogate non-ribosomal RNAs in various disease pathways.RNA molecules bear distinct chemical properties from proteins that make the design of selective and potent chemical probes challenging. The poor chemical diversity of four building units, immensely charged phosphate backbone, shallow and highly hydrophilic binding pocket, dynamic conformations, all combined render a mysterious ligand space to RNA-targeted small molecules that needs further exploration. A deep understanding of privileged chemotypes or physicochemical properties of RNA-targeting ligands will definitely benefit a broad-scope developing novel chemical entities with desired RNA-interfering outcome. In my thesis work, I first applied the computational approach by building the quantitative structure-activity relationship (QSAR) model to predict the binding profiles of a set of biased ligands scaffolding an amiloride core structure against HIV viral RNA elements. The well-performed model predicted the binding parameters of a set of untested molecules and selected the top-ranked one during lead optimization. The study showed the potential of this computational tool in decision-making during synthesis of RNA-targeted ligands. In the following study, we extended the scope of the QSAR study and leveraged the workflow to cater for the context with diverse structures as substrates. We applied explicit algorithms to build the baseline models to allow easy interpretation of binding behaviors of structurally distinct ligands to HIV-1 TAR. The model first time demonstrated molecular factors that contribute to RNA: small molecule recognition, both kinetically and thermodynamically. The general workflow we described will serve as a powerful computational tool to effectively assess underexplored chemical space and guide decision-making for synthesizing RNA-targeted chemical probes. We then bridged our QSAR approach with the generative deep learning model to pursue de novo ligand design to target SARS-CoV-2 frameshifting pseudoknot. The QSAR model that built on the experimentally validated data provided label annotation of the large training sample for deep learning model. A tree graph-based variational auto-encoder was trained to learn the molecular generation process. Annotated label of each training sample was encoded into the continuous latent space where molecules were reduced their dimensionality and projected. Conditions were applied when sampling new entities from the latent space, leading to the new compounds with desired binding properties. The method mentioned here constitutes the first deep learning practice for automatic chemical design against an RNA target and the first-time application of conditional molecular generation via a junction tree-based variational auto-encoder. Overall, the work presented in this thesis explored possibility of data-driven methods such as QSAR studies and deep learning in accelerating ligand discovery for RNA targets. It is anticipated that these workflows will benefit a wide-range studies in understanding and pursuing RNA-centric drug development, yet slight modifications might be needed for tuning into larger data size.

The intricate interplay of biomolecules acting together, rather than alone, provides insight into the most basic of cellular functions, such as cell signaling, metabolism, defense, and, ultimately, the creation of life. Inherent in each of these processes is an evolutionary tendency towards increased efficiency by means of biolgocial synergy-- the ability of individual elements of a system to produce a combined effect that is different and often greater than the sum of the effects of the parts. Modern biochemists are challenged to find model systems to characterize biological synergy.

We discuss the multicomponent, enzyme complex the cellulosome as a model system of biological synergy. Native cellulosomes comprise numerous carbohydrate-active binding proteins and enzymes designed for the efficient degradation of plant cell wall matrix polysaccharides, namely cellulose. Cellulosomes are modular enzyme complexes, comparable to enzyme "legos" that may be readily constructed into multiple geometries by synthetic design. Cellulosomal enzymes provide means to measure protein efficiency with altered complex geometry through assay of enzymatic activity as a function of geometry.

Cellulosomes are known to be highly efficient at cellulose depolymerization, and current debates on the molecular origins of this efficiency suggest two related effects provide this efficiency: i) substrate targeting, which argues that the localization of the enzyme complex at the interface of insoluble cell wall polysaccharides facilitates substrate depolymerization; and ii) proximity effects, which describe the implicit benefit for co-localizing multiple enzymes with divergent substrate preferences on the activity of the whole complex.

Substrate targeting can be traced to the activity of a single protein, the cellulosomal scaffoldin cellulose binding module CBM3a that is thought to uniquely bind highly crystalline, insoluble cellulose. We introduce methods to develop a molecular understanding of the substrate preferences for CBM3a on soluble and insoluble cellulosic substrates. Using pivaloylysis of cellulose triacetate, we obtain multiple soluble cello-oligosaccharides with increasing degree of glucose polymerization (DP) from glucose (DP1) to cellodecaose (DP10) in high yield. Using calorimetry and centrifugal titrations, cello-oligosacharides were shown to not bind Clostridial cellulolyticum CMB3a. We developed AFM cantilever functionalization protocols to immobilize CBM3a and then probe the interfacial binding between CBM3a and a cellulose nanocrystal thin film using force spectroscopy. Specific binding at the interface was demonstrated in reference to a control protein that does not bind cellulose. The results indicate that i) CBM3a specifically binds nanocrystalline cellulose and ii) specific interfacial binding may be probed by force spectroscopy with the proper introduction of controls and blocking agents.

The question of enzyme proximity effects in the cellulosome must be answered by assaying the activity of cellulosomal cellulases in response to cellulosome geometry. The kinetic characterization of cellulases requires robust and reproducible assays to quantify functional cellulase content of from recombinant enzyme preparations. To facilitate the real-time routine assay of cellulase activity, we developed a custom synthesis of a fluorogenic cellulase substrate based on the cellohexaoside of Driguez and co-workers (vide infra). Two routes to synthesize a key thiophenyl glycoside building block were presented, with the more concise route providing the disaccharide in four steps from a commercial starting material. The disaccharide building blocks were coupled by chemical activation to yield the fully protected cellohexaoside over additional six steps. Future work will include the elaboration of this compound into an underivatized FRET-paired hexasaccharide and its subsequent use in cellulase activity assays.

This dissertation also covers an experimental system for the evaluation of methonium desolvation thermodynamics. Methonium (-N+Me3, Am) is an organic cation widely distributed in biological systems. The appearance of methonium in biological transmitters and receptors seems at odds with the large unfavorable desolvation free energy reported for tetramethylammonium (TMA+), a frequently utilized surrogate of methonium. We report an experimental system that facilitates incremental internalization of methonium within the molecular cavity of cucurbit[7]uril (CB[7]).

Using a combination of experimental and computational studies we show that the transfer of methonium from bulk water to the CB[7] cavity is accompanied by a remarkably small desolvation enthalpy of just 0.5±0.3 kcal*mol-1, a value significantly less endothermic than those values suggested from gas-phase model studies (+49.3 kcal*mol-1). More surprisingly, the incremental withdrawal of methonium surface from water produces a non- monotonic response in desolvation enthalpy. A partially desolvated state exists, in which a portion of the methonium group remains exposed to solvent. This structure incurs an increased enthalpic penalty of ~3 kcal*mol-1 compared to other solvation states. We attribute this observation to the pre- encapsulation de-wetting of the methonium surface. Together, our results offer a rationale for the wide biological distribution of methonium and suggest limitations to computational estimates of binding affinities based on simple parameterization of solvent-accessible surface area.

Numerous methodologies for efficient formation of carbon-nitrogen bonds have been developed over the decades due to the widespread importance of nitrogen containing compounds in pharmaceuticals and bulk commercial chemicals. Among many methods, hydroamination, especially, has attracted enormous attention because of its atom-economical characteristic to synthesize amine moieties. As a result, numerous publications have been reported relating the hydroamination reaction using various metal catalysts. However, the hydroamination of unactivated alkenes still remains a challenge task because of the low reactivity of the CC double bond. Recent development of superior gold(I) catalysis in many organic transformations stimulated us to develop efficient gold(I)-catalyzed methods for enantioselective intra- and intermolecular hydroamination of unactivated alkenes.

A gold(I)-catalyzed system for enantioselective intramolecular hydroamination of unactivated alkenes has been developed. For the effective gold(I)-catalyzed method, various gold(I)-catalysts have been synthesized and tested. Among the catalysts, bis(gold) complexes containing an axially chiral bis(phosphine) ligand catalyze the enantioselective intramolecular hydroamination of unactivated alkenes with carboxamide derivatives, most effectively. The method was effective for both carbamates and ureas to form pyrrolidine derivatives with up to 85 % ee.

The first enantioselective intermolecular hydroamination of unactivated alkenes was realized by a gold(I)-catalyzed method. The gold(I) catalyst system adds cyclic ureas to unactivated 1-alkenes to produce corresponding enantiomerically enriched hydroamination product in good yield with enantioselectivity up to 78 % ee.

Polymer-embedded ligands have been synthesized to demonstrate proofs of concepts for fluxional mechanocatalysis. We applied a certain shear stress using a rheometer in the course of palladium-catalyzed asymmetric allylic alkylation to examine catalytic reactivity change under the mechanical force.

Advancements in photocatalysis have enabled access to previously inaccessible intermediates, and have allowed for the development of innovative strategies for bond-formation. By employing a series of metal polypyridyl complexes, chemists have been able to tune reaction conditions to favor productive methodologies for the synthesis of challenging molecular targets. In recent years, photochemically-mediated strategies utilizing this series of privileged metal polypyridal complexes, have overcome significant hurdles when applied to C–H functionalization reactions. C–H functionalization processes take inspiration from the precision of enzymatic reactions in Nature, which are able to transform otherwise indistinguishable and unreactive C(sp3)–H bonds into high value functional groups. A typical strategy employed by chemists for selectively engaging strong C(sp3)–H bonds (BDE = 90 – 105 kcal/mol) involves the use of directing groups that are geometrically disposed to guide reactions at one C–H bond in preference to others. Photoredox-catalyzed platforms have enabled the controlled access to reactive radical intermediates capable of acting as directing groups for the transformation of unreactive C–H bonds under mild conditions.

In addition to allowing access to unprecedented radical intermediates, photosensitizers can also overcome longstanding challenges associated with metal catalyzed cross-coupling reactions. The use of photocatalysts in nickel-catalyzed cross-coupling reactions enables more efficient reductive elimination, and has revolutionized the types of nucleophiles capable of engaging in C–C, C–O, C–S, and C–N coupling reactions. As a result, these photochemically-driven strategies potentiate access to diverse chemical structures, including many underexplored classes of small molecules.

Through this research, we apply photocatalysis to the generation of sulfamyl and sulfamidyl radicals for site-selective carbon–carbon bond formation. These guided alkylation reactions are the first of their kind to generate sulfamyl and sulfamidyl radicals from non-preoxidized or activated sulfamate esters and sulfamides. As directing groups, both sulfamate esters and sulfamides offer modified Hofmann-Löffler Freytag (HLF) position selectivity for late-stage C–H functionalization processes. Additionally, we have applied a dual photochemically driven, nickel-catalyzed reaction manifold to the N-(hetero)arylation of sulfamate esters and sulfamides. We demonstrate that both sulfamates and sulfamides are competent nucleophiles in these dual photochemical and nickel-catalyzed processes. Furthermore, these user-friendly methods improve access to underexplored arylated sulfamate ester and sulfamide small molecules.

Synthetic technologies that enable transformation of typically inert carbon–hydrogen (C–H) bonds into diverse functional groups have streamlined access to complex molecules. These processes, defined as C–H functionalization reactions, remain challenging as traditionally unreactive C–H bonds have high bond dissociation energies (90–105 kcal•mol–1), are not acidic (pKa ≥ 50), and do not incorporate more polarizable and electronically accessible π-orbitals. In addition, the ubiquity of C–H bonds within organic molecules requires methods to predictably and selectivity control the site of functionalization.

Some of the most effective strategies for controlling the position of C–H functionalization employ directing groups to guide a reaction to a particular site within a molecule. Herein disclosed are investigations into position-selective C–H halogenation reactions mediated by sulfamate ester and sulfamide directing groups. We have demonstrated that these substrates guide rare, 1,6-hydrogen-atom transfer (1,6-HAT) processes to dictate the position of halogen installation with specific focus on chlorination and fluorination reactions.

Through this research, we have developed methods to prepare sulfamate esters and sulfamides from readily available starting materials via activation of sulfamic acid salts. Additionally, we have utilized these substrates to guide position-selective chlorine- and fluorine-transfer reactions, enabling access to alkyl halide products with complementary selectivity to that achieved with other known halogenation technologies.

Synthetic technologies that enable transformation of typically inert carbon–hydrogen (C–H) bonds into diverse functional groups have streamlined access to complex molecules. These processes, defined as C–H functionalization reactions, remain challenging as traditionally unreactive C–H bonds have high bond dissociation energies (90–105 kcal•mol–1), are not acidic (pKa ≥ 50), and do not incorporate more polarizable and electronically accessible π-orbitals. In addition, the ubiquity of C–H bonds within organic molecules requires methods to predictably and selectivity control the site of functionalization.

Some of the most effective strategies for controlling the position of C–H functionalization employ directing groups to guide a reaction to a particular site within a molecule. Herein disclosed are investigations into position-selective C–H halogenation reactions mediated by sulfamate ester and sulfamide directing groups. We have demonstrated that these substrates guide rare, 1,6-hydrogen-atom transfer (1,6-HAT) processes to dictate the position of halogen installation with specific focus on chlorination and fluorination reactions.

Through this research, we have developed methods to prepare sulfamate esters and sulfamides from readily available starting materials via activation of sulfamic acid salts. Additionally, we have utilized these substrates to guide position-selective chlorine- and fluorine-transfer reactions, enabling access to alkyl halide products with complementary selectivity to that achieved with other known halogenation technologies.