Development of Oxime Palladacycle Resin, Ionic Liquid Resin, and CoreShell-Type Resin Designed for Efficient C-C Coupling and Peptide Synthesis

학위논문 (박사)-- 서울대학교 대학원 : 화학생물공학부, 2013. 2. 이윤식.Polymer support is a very useful tool for organic synthesis and chemical process. A polymer support on which metal or organic catalyst are immobilized has been used as a heterogeneous catalyst and a functionalized polymer support with linker has been used in SPPS and SPOS. Because the polymer support is mostly insoluble in solvents, it can be easily isolated from the reaction media by simple filtration and reused many times. Furthermore, it is possible to design simple chemical processes through repeating reaction and filtration. Despite these advantages, there are several limitations in using polymer support because the reaction occurs between a solid and a liquid interface. Therefore, the development of highly efficient polymer supports still remains a challenge in SPPS and heterogeneous catalyst fields. In this thesis, three different types of polymer supports were developed for efficient Suzuki coupling reaction and SPPS: palladated oxime resins, ionic liquid resins, and coreshell-type resin. In the first part, various oxime derived palladacycle resins were prepared as a heterogeneous catalyst for Suzuki coupling reaction of aryl halide with arylboronic acid. Unlike Kaiser oxime resin, electron-rich oxime resins afforded efficient and stable environment to form a palladium complex. The electron-richness of oxime ligand could be controlled by the number of methoxy group. The electronic effect of oxime ligand on C-C coupling reactions of activated and deactivated aryl halide (Cl, Br, I) with arylboronic acid were studied with the oxime palladacycle resins. The most electron-rich oxime resin catalyzed Suzuki coupling reaction in high yield and displayed high turnover number without severe leaching of palladium. In reusability test, two methoxy substituted oxime palladacycle resin could be reused during 5 cycles maintaining good catalytic activity for C-C coupling. In the second part, ionic liquid (IL) resins with an ionic liquid environment on polymer support were prepared by immobilizing ionic liquid spacers on polystyrene (PS) resin. The properties of IL resins were dramatically changed as the anions of IL were exchanged. The performance of IL resins for solid-phase peptide synthesis (SPPS) was evaluated by measuring coupling kinetics of the first amino acid and synthesizing several peptides on IL resins. Initial loading of amino acids were performed very efficiently on IL resins with PF6- and TFSI- anions. They also achieved higher purity in the synthesis of difficult sequences peptide than that of AM PS resin. In the third part, a simple, mild and inexpensive bi-phasic functionalization approach is attempted for preparing an ideal coreshell-type resin. The coreshell-type architecture was constructed by coupling Fmoc-OSu to the amino groups on the shell layer of an aminomethyl polystyrene (AM PS) resin. The shell layer thickness of the resin could be easily controlled under mild conditions. The efficiency of coreshell-type resin for solid-phase peptide synthesis (SPPS) was demonstrated by the synthesis of various peptides, and compared with commercially available non-coreshell-type resins, such as AM PS and poly(ethylene glycol)-based resins. The coreshell-type resin provided effective performance during the synthesis of hydrophobic peptide sequences, a disulfide-bridged cyclic peptide and a difficult PNA sequence. Furthermore, a highly aggregative peptide fragment, MoPrP 105–125, was synthesized more efficiently on the coreshell-type resin under microwave condition than AM PS and ChemMatrix resins.Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . x List of Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii List of Schemes . . . . . . . . . . . . . . . . . . . . . . . . . . xv List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvi Chapter I. General Introduction 1. Solid-Phase Peptide Synthesis . . . . . . . . . . . . . . . 1 2. Core-Shell-Type Resin . . . . . . . . . . . . . . . . . . . . 4 2.1. Core-Shell Structure on Polymer . . . . . . . . . . . . 4 2.2. Core-Shell-Type Resin for Peptide Synthesis . . 9 3. Ionic Liquid Resin . . . . . . . . . . . . . . . . . . . . . . . . 14 3.1. Ionic Liquid . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 3.2. Characteristics Properties of Ionic Liquid . . . . . . 17 3.3. Supported Ionic Liquid . . . . . . . . . . . . . . . . . . . 23 4. Oxime Palladacycle Resin . . . . . . . . . . . . . . . . . . 26 4.1. Oxime Palladacycle . . . . . . . . . . . . . . . . . . . . . 26 4.2. Supported Oxime-Derived Palladacycle . . . . . . . 29 5. General Experimental Methods . . . . . . . . . . . . . . 33 Chapter II. Polymer-Supported Electron-Rich Oxime Palladacycles as an Efficient Catalyst for C-C Coupling 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 2. Experimental Section . . . . . . . . . . . . . . . . . . . . . 40 2.1. Preparation of Palladated Oxime Resins . . . . . . . 40 2.1.1. Immobilization of 4′-Hydroxyacetophenone Derivatives on CM PS . . . . . . . . . . . . . . . . . . . . . . . 40 2.1.2. Preparation of Oxime Resins . . . . . . . . . . . . . 40 2.1.3. Preparation of Palladated Oxime Resins . . . . . . 41 2.2. Suzuki Coupling Reaction Catalyzed by Palladated Oxime Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 2.2.1. Optimization of Suzuki Coupling Reaction . . . . . 42 2.2.2. General Experimental Procedure for Suzuki Coupling Reaction of Aryl Halides with Phenylboronic Acid . . . . 43 2.2.3. Reusability Test of Palladated-Oxime Resins . . 43 3. Results and Discussion . . . . . . . . . . . . . . . . . . . . 45 3.1. Preparation and Characterization of Palladated Oxime Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 3.1.1. Preparation of Oxime Resins . . . . . . . . . . . . . . 45 3.1.2. Preparation of Palladated Oxime Resins . . . . . . 48 3.2. Suzuki Coupling Reaction Catalyzed by Palladated Oxime Resins . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.2.1. Effects of Solvents and Bases on Suzuki Coupling Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.2.2. Suzuki Coupling Reaction of Various Aryl Halides with Phenylboronic Acid . . . . . . . . . . . . . . . . . . . . . 55 3.2.3. Reusability Test of Palladated-Oxime Resins for Suzuki Coupling Reaction . . . . . . . . . . . . . . . . . . . . 59 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 Chapter III. Ionic Liquid Resin for Solid-Phase Peptide Synthesis 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 2. Experimental Section . . . . . . . . . . . . . . . . . . . . . 64 2.1. Preparation of Ionic Liquid Resin . . . . . . . . . . . . . 64 2.1.1. Synthesis of Boc Protected 1-(3-Aminopropyl)imidazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.1.2. Immobilization of Boc-API on CM PS . . . . . . . . 64 2.1.3. Anion Exchange on IL Resin . . . . . . . . . . . . . . 65 2.1.4. Coupling Kinetics of the First Amino Acid . . . . . 65 2.2. Peptides Synthesis . . . . . . . . . . . . . . . . . . . . . 67 2.2.1. Leu-enkephalin (H-YGGFL-NH2) . . . . . . . . . . . . 67 2.2.2. JR 10-mer (H-WFTTLISTIM-NH2) . . . . . . . . . . . 67 2.2.3. β2M(59–71) (Ac-LDWSFYLLYYTE-NH2) . . . . . . . 68 3. Results and Discussion . . . . . . . . . . . . . . . . . . . . 69 3.1. Preparation and Characterization of IL Resin . . . . 69 3.1.1. Preparation of IL Resins . . . . . . . . . . . . . . . . . 69 3.1.2. Preparation of IL Resin with Different Anions by Anion Exchange . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 3.1.3. Swelling Properties . . . . . . . . . . . . . . . . . . . . 73 3.1.4. Coupling Kinetics . . . . . . . . . . . . . . . . . . . . . 75 3.2. Synthesis of Peptides on IL resins . . . . . . . . . . . 77 3.2.1. Synthesis of Leu-enkephalin . . . . . . . . . . . . . . 77 3.2.2. Synthesis of β2M(59–71) . . . . . . . . . . . . . . . . . 79 3.2.3. Synthesis of JR 10-mer . . . . . . . . . . . . . . . . . 81 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 Chapter IV. Core-Shell-Type Resin for Solid-Phase Peptide Synthesis 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 2. Experimental Section . . . . . . . . . . . . . . . . . . . . . 89 2.1. Preparation of Solid Support . . . . . . . . . . . . . . . 89 2.1.1. Preparation of Core-Shell-Type Resin . . . . . . . 89 2.1.2. Coupling FITC on Core-Shell-Type Resin for CLSM Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 2.2. Peptides Synthesis . . . . . . . . . . . . . . . . . . . . . 91 2.2.1. ACP(65–74) (H-VQAAIDYING-NH2) . . . . . . . . . 91 2.2.2. JR 10-mer (H-WFTTLISTIM-NH2) . . . . . . . . . . 92 2.2.3. iRGD (Fmoc-c(CRGDRGPDC)-TEG-K-NH2) . . . 92 2.2.4. PNA Probe for HPV 31 (Bts-ctgcaattgcaaacagtg) 93 2.2.5. MoPrP 105–125 (H-KTNLKHVAGAAAAGAVVGGLG-NH2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 3. Results and Discussion . . . . . . . . . . . . . . . . . . . . 96 3.1. Preparation and Characterization of Core-Shell-Type Resin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 3.1.1. Preparation of Core-Shell-Type Resin . . . . . . . 96 3.1.2. Swelling Properties . . . . . . . . . . . . . . . . . . . . 98 3.1.3. Core-Shell Structure . . . . . . . . . . . . . . . . . . . 99 3.1.4. Control of Shell Layer Thickness . . . . . . . . . . 100 3.2. Synthesis of Peptides on Core-Shell-Type Resin . 102 3.2.1. Synthesis of ACP(65-74) and JR 10-mer . . . . . 102 3.2.2. Synthesis of Cyclic Peptide (iRGD) . . . . . . . . . 104 3.2.3. Synthesis of PNA . . . . . . . . . . . . . . . . . . . . . 106 3.2.4. Synthesis of MoPrP(105–125) under Microwave Condition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107 4. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Abstract in Korean . . . . . . . . . . . . . . . . . . . . . . . . . 133Docto

Mortality differentials of government officers and private school teachers by social stratification in Korea

학위논문(박사)--서울대학교 대학원 :보건학과 보건학전공,1997.Docto

Associations between the Type of Tobacco Products and Suicidal Behaviors: A Nationwide Population-Based Study among Korean Adolescents

The relationships between multiple tobacco products, such as heated tobacco products (HTPs), electronic cigarettes (ECs), and combustible cigarettes (CCs), and suicide-related behaviors among adolescents have not been extensively researched. This study examined the associations between the type of tobacco products used and suicidal thoughts, plans, and attempts among Korean adolescents. Data from the 2019 Korea Youth Risk Behavior Web-Based Survey were analyzed, and participants included 57,069 individuals aged 13-18 years. A multivariable logistic regression analysis was performed. Of the total participants, 13.0%, 4.0%, and 2.9% reported suicidal thoughts, suicidal plans, and suicidal attempts, respectively. After adjusting for confounding variables, all tobacco product users showed a greater likelihood of having suicidal behavior. However, compared with never users, dual users of CCs and HTPs were not significantly associated with having suicidal thoughts and attempts. Among tobacco product users, dual users of ECs and HTPs and triple users of CCs, ECs, and HTPs showed a greater likelihood of having suicidal behavior. Considering the prevalence of suicide and the increasing trend of using multiple tobacco products among Korean adolescents, tobacco control policies should monitor the effects of different products

Prevalence and predictors of heated tobacco product use and its relationship with attempts to quit cigarette smoking among Korean adolescents

Introduction Heated tobacco products (HTPs) have been available in the Korean market since June 2017. In this study, we examined the prevalence and predictors of HTP use among Korean adolescents and the association between HTP and electronic cigarette (EC) use and attempts to quit conventional cigarette (CC) smoking. Methods We analysed the data of a representative sample (n=60 040) of 13-18-year-old middle-school and high-school students in Korea who had participated in the 14th Korea Youth Risk Behavior Web-based Survey in 2018. Results The prevalence of ever HTP use among Korean adolescents was 2.9% (men: 4.4%, women: 1.2%), a year after the introduction of HTPs in the Korean market. Furthermore, 81.3% of the 1568 ever HTP users were triple users of HTPs, ECs and CCs. Multivariate analysis revealed that ever HTP use was greater among men, higher-grade students, current CC and/or EC users and risky alcohol drinkers. Among current CC smokers, ever users of ECs (28%-30%) and ever HTP users and current EC users (48%) were more likely to have attempted to quit CC smoking than those who had never used HTPs and ECs. However, there were fewer HTP and/or EC ever users among ever CC smokers who successfully quit smoking. Conclusions Many adolescents, especially CC and EC users, had already used HTPs shortly after the introduction of HTPs in Korea. The use of newer types of tobacco products is associated with lower odds of abstinence from CCs; therefore, it is important to protect adolescents from them

Gender-Based Socioeconomic Inequality of Electronic Cigarettes and Heated Tobacco Products in Korea

Background: Conventional cigarettes are commonly used by adults with low educational level and lower income in South Korea. Information on socioeconomic and gender-related disparities associated with the use of electronic cigarettes (EC) and heated tobacco products (HTP) is limited. Therefore, this study aimed at investigating gender differences in relation to socioeconomic inequalities and use of EC and HTP in Korea. Methods: Data of 226,749 adults from the 2020 Community Health Survey in South Korea were analyzed. Variables associated with socioeconomic position included household income and education. Multivariable logistic regression analysis was adjusted for age, household income, education, occupation, marital status, and binge drinking. Results: Current HTP and EC users were 6,065 (5,414 men and 651 women) and 3,764 (3,432 men and 332 women), respectively. The odds of EC and HTP users were 0.33 (95% confidence interval [CI], 0.24-0.46) and 0.77 (0.63-0.95) in men, and 2.52 (1.46-4.35) and 2.56 (1.57-4.15) in women with educational levels of middle school or lower, compared with those with at least college education, respectively. Income differences were not observed among men. However, women in the first income quartile (lower income) had higher odds of using EC at 2.12 (1.14-3.93) and HTP at 2.78 (1.90-4.08) compared with those in the fourth quartile. Conclusion: Men with higher educational levels and women with lower income and educational levels were more likely to use EC and HTP. Therefore, regulatory strategies should be designed to control the use of novel tobacco products in South Korea

Trends in the Socioeconomic Inequalities Related to Second-Hand Smoke Exposure as Verified by Urine Cotinine Levels Among Nonsmoking Adults: Korea National Health and Nutrition Examination Survey 2008?2018

Introduction The expansion of smoke-free policies has reduced the prevalence of second-hand smoke (SHS) exposure; however, declines differ according to socioeconomic positions. We evaluated the trends in socioeconomic inequalities related to SHS exposure in nonsmoking Korean adults from 2008 to 2018. Methods We analyzed 30,027 nonsmoking adults from the Korea National Health and Nutrition Examination Survey 2008 to 2018. We evaluated trends in urine cotinine levels, self-reported prevalence of SHS exposure at workplaces and homes, and people exhibiting nonmeasurable urine cotinine levels between 2008 and 2018. To evaluate the yearly decline differences of urine cotinine levels according to socioeconomic positions, we calculated the interaction effects of year and education, household incomes, and occupation from linear regression analysis. Results In the last 11 years, the geometric means of urine cotinine levels decreased from 3.53 (95% CI 2.96?4.19) ng/mL to 0.60 (0.57?0.64) ng/mL in males, and from 2.36 (2.03?2.73) ng/mL to 0.53 (0.51?0.56) ng/mL in females. The prevalence of SHS exposure at workplaces and homes also declined. In the multivariate model, the interaction effects between education and years were significant; therefore, indicating a substantial yearly decline of urine cotinine levels in higher educated individuals. The interaction effects between household incomes and years were only significant among males; the interaction effects between occupations and years were not significant. Conclusions SHS exposure in nonsmoking Korean adults has consistently decreased; however, socioeconomic inequalities related to SHS exposure by education level have widened. Policies targeting socioeconomically disadvantaged populations should be implemented to decrease the disparities of SHS exposure. Implications Along with tobacco control policies, the prevalence of self-reported and urinary cotinine verified SHS exposure has decreased in the last 11 years. In contrast, the socioeconomic inequalities related to SHS exposure by education level have increased over time. This study emphasizes the need for implementing tobacco control policies to reduce disparities of SHS exposure