N-하이드록시 메틸기를 갖는 α-아미노 알데하이드를 활용한 threo-β-아미노-α-하이드록 카복실산의 입체선택적 합성과 아세트아미노펜의 구리 촉매화 단일단계 공정개발

학위논문 (박사)-- 서울대학교 대학원 : 화학생물공학부, 2015. 2. 김영규.This thesis comprises part A and part B. Part A is about the stereoselective synthesis of β-amino-α-hydroxy acids from the N-hydroxymethyl protected α-amino aldehydes. threo-β-Amino-α-hydroxy acids, frequently found in naturally occurring bioactive compounds, have been synthesized via the stereoselective intramolecular conjugate addition of N-hydroxymethyl group, which configurationally stabilizes an α-amino aldehyde by forming the hemiacetal. In this study, the stable α-amino aldehyde was reacted with phenylsulfonylnitromethane (PhSO2CH2NO2) to afford stereoselective trans-oxazolidine, which was a precursor for threo-β-amino-α-hydroxy. The three tandem reactions between phenylsulfonylnitromethane and the α-amino aldehydes and the followed in-situ ozonolysis affored trans-oxazolidine methyl esters (A23) in 65% to 69% yields with more than 20 to 1 stereoselectivity. Bestatin, a well-known aminopeptidase inhibitor, was stereoselectively synthesized in 83% yield from trans-oxazolidine methyl ester A23-Phe, which was derivated from D-Phe-OH. Leucinal and valinal derivatives (A23-Leu, and A23-Val) were successfully applied for the synthesis of the corresponding threo-vicinal amino alcohol embeded dipeptides at N-terminus, which were the first synthesized isobutyl and isopropyl substituted bestatin analogs. Moreover, two stereoselective dipeptides, containing (2S,3R), or (2R,3S)-3-amino-2-hydroxy-4-methylpentanoic acid at N-terminus, were synthesized to elucidate the stereochemistry of naturally occurring another aminopeptidase inhibitor lapstatin from the commercially available Boc-D-Val-OH or Boc-L-Val-OH. trans-Oxazolidine methyl ester from D-Ser-OH (A23-Ser) was stereoselectively converted to the glutamate transporter blocker L-threo-β-benzyloxy aspartic acid (L-TBOA) via the simple functionalization of hydroxymethyl of the oxazolidine A23-Ser and following selective benzyl protection of hydroxyl group. In part B, a new process development for acetaminophen has been presented. In the new proces, two copper catalyzed reactions were applied with p-dihalobenzenes for practical and efficient synthesis of acetaminophen. N-Acetylamidomethyl and hydroxyl group on acetaminophen were regioselectively introduced via Goldberg reaction with acetamide and Ullmann type condensation reactions in the presence of copper catalysts and diamine ligands. Furthermore, the suggested efficient two-step process was successfully simplified as one-pot process by excluding the purification of the intermediate, N-acetyl-p-haloaniline. Under the optimized one-pot process, acetaminophen was obtained in 74% yield from the commercially available p-bromoiodobenzeneAbstract i List of Figures vi List of Schemes viii List of Table ix List of Abbreviations xi Part A : Appications of N-hydroxymethyl protected α-amino aldehydes for stereoselective synthesis of threo-β-amino-α-hydroxy acids 1 Introduction 1 1. Introduction of stable α-amino aldehydes 1 2. The application of N-hydroxymethyl group in the stereoselective syntheses of β-amino-α-hydroxy acids 3 3. The application of N-hydroxymethyl group in the stereoselective syntheses of β-amino-α-hydroxy acids 9 Results and Discussions 16 1. The stereoselective synthesis of threo-β-amino-α-hydroxy acids 16 2. Appliation of the stereoselective synthetic method for β-amino-α-hydroxy acids : bestatin and its derivatives 28 3. Appliation of the stereoselective synthetic method for β-amino-α-hydroxy acids : threo-β-benzyloxyaspartate 36 4. Appliation of the stereoselective synthetic method for β-amino-α-hydroxy acids : lapstatin and its derivatives 43 Conclusion 50 Experimental Details 51 Part B : Cu-Catalyzed one-pot process for acetaminophen 67 Introduction 67 1. Acetaminophen 67 2. Conventional process for acetaminophen 72 3. Regioselective halogenation for p-dihalobenzene 79 4. Goldberg and Ullmann type condensation reactions 86 Results and Discussion 92 1. The development of a new efficient process for acetaminophen 92 2. Acetaminophen synthesis from p-diiodobenzene 94 3. Acetaminophen synthesis from p-dihalobenzenes 107 4. A New one pot process for acetaminophen 118 5. Acetaminophen production via the Cu-catalyzed process 120 Conclusion 122 Experimental Details 123 References 128 Appendices 142 1. List of 1H NMR Spectra of Selected Compounds 143 2. List of 13C NMR Spectra of Selected Compounds 176 Abstract in Korean 209Docto

N-하이드록시메틸기의 나이트로 올레핀의 분자내 콘주게이션 첨가 반응을 통한 β-아미노-α-하이드록시산의 입체선택적 합성

학위논문 (석사)-- 서울대학교 대학원 : 화학생물공학부, 2011.2. 김영규.Maste

(An) analysis of Korean population structure by use of the stable population theorem

보건학과/석사[한글] 인구구조에 영향을 주는 기본적인 요인은 출생률과 사망률이다. 출생률과 사망률을 같은 수준에서 비교하는 가장 합리적인 방법의 하나는 안정인구이론에 의한 것이다. 안정인구란 인구의 유출입이 배제된 폐쇄인구를 전제로 연령별 사망률이 고정되었을 때 항상 같은 비율로 증가 또는 감소하는 인구이다. 안정 인구는 센서스 자료와 인구동태자료, 생명표를 이용하여 계산할 수 있다. 이 연구에서는 1960년을 기준년도로 정하여 출생률과 사망률을 각 각 고정 또는 변화시켜 안정인구를 계산하였다. 그 결과는 다음과 같다. 1. 출생률을 고정시키고 사망률을 변화시켰을 때, 출생률을 변화시키고 사망률을 고정시켰을 때, 출생률과 사망률을 동시에 변화시켰을 때 기준년도로 부터의 순인구증가율, 소년인구지수, 노년인구비율, 소년인구에 대한 노년인구의 비, 중위연령등의 차이를 보았다. 그 결과 출생률과 사망률이 동시에 변화되었을 때 변화가 가장 커 1970년, 1980년에 각각 순인구증가율이 0.817, 3.297을, 소년인구비율이 9.13, 24.60, 노년인구비율이 1.24, 2.68,소년인구에 대한 노년인구의 비 3.85, 14.27, 중위연령이 4.53, 16.99를 보였다. 인구구조가 출생률과 사망률의 영향을 동시에 받음을 의미한다. 출생률을 고정시킨 안정인구에 비해 사망률을 고정시킨 안정인구의 기준년도로 부터의 차이는 1970년 1980년에 순인구증가율이 0.579, 1.855, 소년인구비율이 7.49, 5.62, 노년 인구비율은 0.96, 3.49, 소년인구에 대한 노년인구의 비는 2.90, 11.98, 중위연령은 3.66, 9.22였다. 출생률의 변화로 인한 인구구조의 변화가 더욱 큰 것을 알 수 있다. 2. 센서스에 의한 인구구조와 안정인구에 의한 인구구조를 비교한 결과 센서스에 의한 인구구조는 1960년에서 1970년, 1980년으로 갈수록 소년인구비율이 42.3, 42.5, 34.0으로 감소하였고, 안정 인구에 의해서는 49.04, 39.91, 22.44로 감소되었다. 소년인구에 대한 노년인구의 비는 센서스 결과 6.91, 5.67, 8.26을 보였고, 안정인구 결과 3.28, 7.13, 17.55를 보였다. [영문] It is recognized that the fertility and mortality are the primary factors in affecting on changes of the structure of population. The stable population theory is recommended as one of the most acceptable procedures in comparison with the same level of the birth rate and death rate. The stable population means the population which is hypothetically counted as the increasing or decreasing population under the flexed death rate with excluded migration. Vital statistics, census and life table are usually uses in counting the stable population. In this study, stable populations are constructed from the national census data In 1960 1970 and 1980, and 1960 census data was used as the base year for applying age-specific birth rates and death rates. Indices of measurement of the changes the dependency ratio, proportion of young ages and old ages, and median ages. Comparisons of the population structures between the three censuses are as follows : 1. Birth rate and death rate were changed simultaneously onward since the 1960 base years an extreme change in the structure was observed In comparison with that of one vital rate was fixed. The intrinsic growth rate for the year of 1970 and 1980 were 2.511 and 0.131 respectively. In 1970, young population occupied 39.91 percent and old population did 2.85 respectively. In 1980, the proportions were 24.44 and 4.29 respectively. For median ages of the 1970 and 1980 stable population showed 19.50 and 31.96 respectively. 2. With fixing birth rate and death rate differently from the base of 1960 stable population, the intrinsic growth rate was observed as 3.090 in 1970 and 2.016 in 1980 and percentage of young population was 43.88 in 1970 and 37.51 in 1980. Also dependency ratio showed 4.99 in 1970 and 10.64 in 1980, and median age was 17.44 in 1970 and 21.35 in 1980. Consequently population change by birth rate was larger than that of death rate. 3. In comparison of structural changes between censuses and the stable populations, it was shown that the proportion of the old population was increased both In the national census data and the stable population.prohibitio