We use stepwise [3+3] annulation to prepare the asymmetric glutarimides, and then we can build substituent group in C6 position after choosing regioselective addition reaction. And we establish a new approach to benzo[h]quinoline skeleton starting from glutarimides via ring-closing reaction. Finally, we applied this method to the synthetic studies toward benzo[h]quinoline derivatives.

A convenient method for the preparation of hydroxyl lactams via regioselective reduction of N-alkyl-3-sulfonyl glutarimides is described. The useful building block is applied to synthesize polysubstituted pyridin-2-one, tacamonine and deplancheine.

Glycosaminoglycans (GAGs), a large family of complex, unbranched polysaccharides, display a variety of essential physiological functions. The structural complexity of GAGs greatly impedes their availability, thus making it difficult to understand the biological roles of GAGs and structure-property relationships. A method that can access GAGs and their analogs with defined structure at relatively large scales will facilitate our understandings of GAG biological roles and biosynthesis modulation. Cellulose is an abundant and renewable natural polymer. Applications of cellulose and cellulose derivatives have drawn increasing attention in recent decades. Chemical modification is an efficient method to append new functionalities to the cellulose backbones. This dissertation describes chemical modification of cellulose and cellulose derivatives to prepare unsulfated and sulfated GAG analogs. Through these studies, we have also discovered novel chemical reactions to modify cellulose. Systematic study of these novel chemistries is also included in this dissertation. We first demonstrated our preparation of two unsulfated GAG analogs by chemical modification of a commercially available cellulose ester. Cellulose acetate was first brominated, followed by azide displacement to introduce azides as the GAG amine precursors. The resulting 6-N3 cellulose acetate was then saponified to liberate 6-OH groups, followed by subsequent (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) oxidation of the liberated primary hydroxyl groups to carboxyl groups. Finally, the azides were reduced to amines using a novel reducing reagent, dithiothreitol (DTT). Alternatively, another process utilized thioacetic acid to reduce azides to a mixture of amine and acetamido groups. Through pursuing these GAG analogs, we applied novel azide reductions by DTT and thioacetic acid that are new to polysaccharide chemistry. We systematically investigated the scope of DTT and thioacetic acid azide reduction chemistry under different conditions, substrates, and functional group tolerance. Selective chlorination is another interesting reaction we discovered in functionalization of cellulose esters. We applied this chlorination reaction to hydroxyethyl cellulose (HEC). We then utilized the chlorinated HEC as a substrate for displacement reactions with different types of model nucleophiles to demonstrate the scope of its utility. Overall, we have designed a novel synthetic route to two unsulfated GAG analogs by chemical modification of cellulose acetate. Through exploration of GAG analogs synthesis, we discovered novel methods to modify polysaccharide and polysaccharide derivatives, including azide reduction chemistry and selective chlorination reactions. Successful synthesis of various types of GAG analogs will have great potential biomedical applications and facilitate structure-activity relationship studies. / Doctor of Philosophy / Polysaccharides are long chains of natural sugars. Glycosaminoglycans (GAGs) are an important class of polysaccharides which have complicated chemical structures and play critical roles in many biological processes, including regulation of cell growth, promotion of cell adhesion, anticoagulation, and wound repair. Current methods to obtain these GAGs and GAG analogs are expensive, lengthy, and limited in capability. Novel methods to access these GAGs and their analogs would be promising and would facilitate understanding of biological activities of GAGs. Cellulose is an abundant polymer on earth and provides structural reinforcement in plant cell walls. Cellulose can be further chemically modified to tailor its physiochemical properties. Cellulose and cellulose derivatives have been widely used in many industries for various applications, such as textiles, plastic films, automotive coatings, and drug formulation. This dissertation focuses on modifying inexpensive, abundant cellulose and its derivatives to GAGs and GAG analogs. We start from the simple plant polysaccharide cellulose and obtain structurally complicated analogs of animal-sourced GAGs and GAG analogs. We reached our goal by designing a carefully crafted synthetic route, finally successfully obtaining two types of novel GAG analogs. During this process, we discovered two useful chemical reactions. We systematically investigated these chemical reactions and demonstrated their utility for polysaccharide chemical modification. These successful chemical syntheses of GAGs and their analogs will accelerate our understanding of their natural functions and have potential biomedical applications. The novel chemical methods we discovered will be helpful in chemical modification of polysaccharides.

Cellulose is the most abundant polysaccharide on earth and it is relatively a simple homopolymer with three hydroxyl groups, differing only subtly in reactivity. The position of substitution has a powerful influence on physical properties of cellulose derivatives. To better understand the structure and property relationships of cellulose derivatives, it is critical to have all homopolymers related to important cellulose ethers and esters available. However, regiocontrol in cellulose chemistry is still a difficult, mostly unconquered frontier. In this dissertation, the main objective is to develop novel synthetic methods to synthesize regioselectively substituted cellulose derivatives including cellulose ethers and esters, and apply advanced characterization tools to understand structure and its influence on properties, which will give us deep insights into the composition of more random commercial derivatives, maximizing the content of advantageous monosaccharides. Several strategies to regioselectively synthesize cellulose derivatives are discussed in detail. The obtained regioselective cellulose derivatives were fully characterized analytically. Structure-property relationships of these regioselectively substituted cellulose derivatives were also studied. / Ph. D.

New methods were developed for the regioselective synthesis of new classes of cellulose derivatives with properties that could help improve the delivery of pharmaceutical drugs within the human body. The specific synthetic targets of this research were regioselectively carboxylated and regioselectively aminated cellulose derivatives. While different avenues to the carboxylated cellulose were ultimately explored without success, a new method for the synthesis of selectively <i>O</i>-acylated 6-amino-6-deoxy-cellulose esters was devised. A key reaction that enabled the synthesis of the new cellulose derivatives described in this dissertation was the one-pot conversion of microcrystalline cellulose to 6-bromo-6-deoxy-cellulose esters. This reaction resulted in the highly selective displacement of the primary hydroxyl groups attached to the 6-carbon (<i>C</i>-6) on each anhydroglucose unit (AGU) in cellulose with bromide, with little or no bromination occurring at carbons 2 and 3 (<i>C</i>-2 and <i>C</i>-3). The brominated cellulose was then completely esterified by adding acetic, propionoic, or butyric acid anhydride to the reaction solution. The reaction products were readily soluble in many common organic solvents, including acetone, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and chloroform. It was shown that the bromides could be converted to iodides under Finkelstein reaction conditions. The presence of halides at <i>C</i>-6 allows a variety of new functional groups to be regioselectively introduced to cellulose via nucleophilic substitution. In one case, the 6-bromo-6-deoxy-cellulose esters were reacted with sodium cyanide to produce regioselectively synthesized cellulose nitriles. These compounds were synthesized with the idea that they could be converted to regioselectively carboxylated cellulose derivatives as an alternative pathway to the rhodium-catalyzed carbonyl insertion reactions also attempted in this research. However, the cellulose nitriles were highly susceptible to alkaline degradation, and conversion to the carboxylated cellulose was not achieved. The 6-bromo-6-deoxy-cellulose esters were also reacted with sodium azide to successfully produce 6-azido-6-deoxy-cellulose esters. The azide groups were then reduced to amines using the Staudinger reaction. This very mild and selective reaction allowed the conversion of the azides to amines in the presence of the ester groups still attached to the cellulose backbone. Such derivatives could have properties useful for a range of biomedical applications, including the delivery of anionic drugs. / Ph. D.

Polysaccharides are one of the most abundant and diverse families of natural polymers, and have an incredibly wide range of natural functions including structural reinforcement, energy storage, aqueous rheology modification, and communication and identity. Application of native polysaccharides like cellulose as sustainable materials is limited by some inherent drawbacks such as insolubility in common solvents including water, and poor dimensional stability. To increase their functionality and utility, researchers have sought to tailor the chemical and physical properties of cellulose and other polysaccharides using a variety of chemical modification techniques, resulting in a number of important, useful commercial derivatives. Because of their greater biocompatibility and biodegradability, and low immunogenicity, naturally derived cationic polymers including cationic polysaccharide derivatives are very attractive candidates for biomedical applications, due to the fact that they are capable of binding with anionic biomolecules, such as nucleic acids and certain proteins, via electrostatic interactions. However, there are relatively few practical synthetic methods reported for their preparation. We demonstrated a useful and efficient strategy for cationic polysaccharide salt preparation by reaction of 6-bromo-6-deoxypolysaccharides such as 6-bromo-6-deoxycellulose esters with pyridine or 1-methylimidazole exclusively at the C-6 position, resulting in high degrees of substitution (DSs). These permanently cationic polysaccharide derivatives have been demonstrated to dissolve readily in water, and bind strongly with a hydrophilic and anionic surface. Availability of these cationic polysaccharides will facilitate structure-property relationship studies for biomedical uses including drug delivery and bioelectronics applications. We also extended the chemistry, reacting 6-imidazolo-6-deoxycellulose with propane sultone, leading to a new synthetic pathway to zwitterionic cellulose derivatives. In addition to cationic and zwitterionic derivatives, we found a simple, efficient route to carboxyl-containing polysaccharide derivatives from curdlan esters via regioselective ring-opening reactions catalyzed by triphenylphosphine (Ph3P) under mild conditions. Curdlan, a polysaccharide used by the food industry and in biomedical applications, was employed as starting material for preparing these carboxyl-containing derivatives by a reaction sequence of bromination, azide displacement and ring-opening reaction with cyclic anhydrides, affording high conversions. These modification techniques have been demonstrated to display essentially complete regio- and chemo-selectivity at C-6. These novel polysaccharide-based materials starting from abundant and inexpensive curdlan are promising for some applications such as amorphous solid dispersion (ASD) oral drug delivery. / Ph. D.

<p>Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(<i>t</i>-Bu)₃-liberating salt [(<i>t</i>-Bu)₃PH]BF₄. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent.</p><p>For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(<i>t</i>-Bu)₃PH]BF₄ as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of <i>para</i>-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(<i>t</i>-Bu)₃ ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol.</p><p>Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(<i>t</i>-Bu)₃-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing <i>para</i>-cyano substituent under cationic conditions increased the preparative usefulness of the methodology.</p><p>Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de).</p><p>Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.</p>

The first part of this thesis describes a synthetic strategythat provides all eight possible isomers of a given vic-aminoalcohol starting from vinylepoxides. The value of a generalroute is evident, as several isomers are needed ininvestigations of structure-activity relationships forpharmacologically active derivatives, and for optimizing theperformance of chiral ligands containing the amino alcoholmoiety. Vinylepoxides, obtained in high enantiomeric excess, werering-opened both with inversion and retention ofstereochemistry, delivering two diastereomeric amino alcoholswith high regio- and stereoselectivity. Via ring-closure toaziridines and subsequent regioselective ring-opening withsuitable oxygen nucleophiles, the two remaining amino alcoholswere selectively achieved. Within this study, two efficient protocols for theregioselective and stereospecific aminolysis of vinylepoxideshave been presented. Comparedto previous methods, theseprocedures use milder reaction conditions, shorter reactiontimes, generally give higher yields and are applicable to alarger set of substrates. Furthermore, the ring-closure ofvic-amino alcohols to the corresponding N-H vinylaziridines hasbeen investigated. Three routes have been found useful, whichone is preferred depends on substrate and scale. In the second part of the thesis, the synthetic strategy isapplied on the synthesis of Sphingosine and its regio- andstereoisomers. Moreover, a rapid way of determining relativeconfiguration of vic-amino alcohols is described, which shouldbe of substantial use when amino alcohols are formed bydiastereoselective reactions. amino alcohols, vinylepoxides, vinylaziridines, oxazolines,oxazolidinones, ring-opening, regioselective,diastereoselective, sphingosine, configuration, NMRspectroscopy.

Homogeneous palladium-catalyzed Heck vinylation of aryl chlorides was investigated under air using Herrmann’s palladacycle and the P(t-Bu)3-liberating salt [(t-Bu)3PH]BF4. Based on the results, controlled microwave heating was utilized to accelerate model Heck reactions with aryl chlorides down to 30 min employing an electron-poor olefin and a mixture of an ionic liquid and 1,4-dioxane as solvent. For the first time, a highly regioselective general protocol has been developed for palladium-catalyzed terminal (β-) arylation of acyclic vinyl ethers using inexpensive aryl chlorides as starting materials and the preligand [(t-Bu)3PH]BF4 as the key additive. This swift and straightforward protocol exploits non-inert conditions and controlled microwave heating to reduce handling and processing times, and aqueous DMF or environmentally friendly PEG-200 as the reaction medium. Somewhat higher selectivity for the linear β-product was observed in PEG-200. DFT calculations were performed at the B3LYP level of theory for the regioselectivity-determining insertion step in the Heck reaction following the neutral pathway. A series of para-substituted phenylpalladium(II) complexes was investigated in the computational study. The calculations support a ligand-driven selectivity rationale, where the electronic and steric influence of the bulky P(t-Bu)3 ligand provides improved β-selectivity. The preparative methodology was used to synthesize the β-adrenergic blocking agent Betaxolol. Highly stereoselective Pd(0)-catalyzed β-arylation and β-vinylation of a tetra-substituted cyclopentenyl ether have been accomplished using a chiral, pyrrolidine-based and substrate-bound palladium(II)-directing group under neutral reaction conditions. To the best of the author’s knowledge, this P(t-Bu)3-mediated method represents the first examples of the successful utilization of aryl and vinyl chlorides in asymmetric Heck reactions. The Heck arylation products formed were hydrolyzed and isolated as the corresponding quaternary 2-aryl-2-methyl cyclopentanones in good to moderate two-step yields with excellent stereoselectivity (90-96% ee). Inclusion of vinyl triflates under neutral reaction conditions and one aryl triflate equipped with a strongly electron-withdrawing para-cyano substituent under cationic conditions increased the preparative usefulness of the methodology. Furthermore, diastereoselective Heck arylation of both five- and six-membered cyclic vinyl ethers with aryl bromides, using the identical chiral auxiliary and suitable Pd sources, was performed. Arylated products from the tetra-substituted cyclopentenyl ether were also in this case hydrolyzed to the corresponding 2-aryl-2-methyl cyclopentanones with high to excellent enantioselectivity (85-94% ee). Despite low reaction rates and relatively modest yields, arylation reactions with the tri-substituted cyclohexenyl ether were found to be highly diastereoselective (94-98% de). Thus, an attractive supplement to direct Pd(0)-catalyzed α-arylation protocols, particularly when the use of organic chlorides, aryl bromides, and milder reaction conditions are of great importance, have been developed.

We can construct asymmetric glutarimide while using [3+3] annulation.Then we can build substituent group in C6 position after choosing regioselective addition reaction, and then apply it to synthetic studies toward polysubstituted pyridin-2-ones and Vitamin B6 derivatives.