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