상전이 촉매 알킬화 반응을 통한 α,α-dialkylmalonate의 새로운 비대칭 합성법 개발과 그 응용으로서 (–)-horsfiline의 전합성

학위논문 (박사)-- 서울대학교 대학원 : 약학과, 2014. 2. 박형근.Malonates are one of the most fundamental starting material in organic synthesis for C-C bond formation. Notably, chiral α,α-dialkylmalonates have been quite popularly employed in the synthesis of biologically active natural products and pharmaceuticals for the following reasons: the quaternary carbon center of chiral α,α-dialkylmalonates is not racemized, and malonates can be easily modified through chemical conversion of the two esters. In spite of these advantages, chiral malonates can only be obtained by the desymmetrization of (±)-α,α-dialkylmalonates or (±)-α,α-dialkylmalonic acids through enzymatic resolution using the selective hydrolysis of malonates or the selective esterification of malonic acids, respectively. Although the construction of chiral quaternary carbon centers through the asymmetric α-alkylation of carbonyl systems and β-ketoester systems has been extensively studied, to date, the enantioselective direct α-alkylation of malonates has not been reported. Our research team investigated a novel enantioselective synthesis of α,α-dialkylmalonates via direct α-alkylation under phase-transfer catalytic condition. First, our research team attempted the α-benzylation of benzyl tert-butyl α-methylmalonate under typical phase-transfer catalytic conditions. This enantioselective phase-transfer catalytic benzylation was performed using representative chiral phase-transfer catalysts. Of them, (S,S)-3,4,5-trifluorophenyl-NAS bromide surprisingly afforded the α-benzylated product with 70% of enantioselectivity. Five additional alkyl tert-butyl α-mono-methylmalonates were tested in phase-transfer catalytic benzylation and the diphenylmethyl group gave the best enantioselectivity. This substrate was chosen for further investigation of phase-transfer catalytic alkylation with various alkyl halides, and it showed very high chemical yields (up to 99%) and stereoselectivities (up to 97% ee). Additionally, our research team expanded the substrate scope to α-mono-aryl and halo-malonates, and these substrates also showed high enantioselectivities. Notably, the direct, double α-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding α,α-dialkylmalonates without the loss of enantioselectivity. The high enantioselectivities and the mild reaction conditions could make this method very useful for the synthesis of valuable chiral building blocks. The synthetic potential of this method has been demonstrated by the preparation of α,α-dialkylamino acid and oxyindole systems. The spirooxindole structure is frequently found in biologically active oxyindoles. Their unique spiro structures have challenged many synthetic chemists to develop an efficient synthetic method. Among the various spirooxindole alkaloids, (–)-horsfiline was first isolated in 1991 from the leaves of the Horsfieldia superba plant. Our research team attempted to apply our method to the synthesis of the chiral spirooxindole alkaloid (–)-horsfiline. A new and efficient synthetic method for the preparation of (–)-horsfiline via the enantioselective phase-transfer catalytic α-allylation of malonate has been developed. (–)-Horsfiline was synthesized in 9 steps (including an in situ step) from diphenylmethyl tert-butyl malonate, and enantioselective phase-transfer catalytic alkylation was the key step (32% overall yield, >99% ee). The high enantioselectivity and chemical yield make this approach a practical route for the large-scale synthesis of spirooxindole natural products, thus enabling the systematic investigation of their biological activities.ABSTRACT 1 TABLE OF CONTENTS 3 LIST OF FIGURES 7 LIST OF TABLES 8 LIST OF SCHEMES 9 INTRODUCTION 12 1. Chiral malonate derivatives 12 1.1. Outline of chiral malonates 12 1.2. Enantioselective synthesis of dicarbonyl compounds 14 1.3. Enantioselective synthesis of malonate 15 2. Phase-transfer catalysis for asymmetric alkylation 19 2.1. Phase-transfer catalysis 19 2.2. General mechanism of phase-transfer catalysis 21 2.2.1. Interfacial mechanism by Makosza 21 2.2.2. Extraction mechanism by Stark 22 2.3. Progress of phase-transfer catalytic alkylation 24 2.3.1. Progress of phase-transfer catalysts 24 2.3.2. Progress of the substrates for phase-transfer catalytic alkylation 28 2.3.2.1. Monocarbonyl substrates for phase-transfer catalytic alkylation 28 2.3.2.2. Dicarbonyl substrates for phase-transfer catalytic alkylation 31 3. Spiro-oxindole alkaloids 34 3.1. Synthetic use of α-alkyl-α-(ortho-nitro-phenyl)-tert-butyl-malonate 34 3.2. The 3,3'-pyrrolidinyl-spirooxindole heterocycle in natural products 35 3.3. Representative synthetic methods for the 3,3'-pyrrolidinyl-spiro-oxindoles 37 3.3.1. Intramolecular Mannich reactions 37 3.3.2. Oxidative rearrangement sequences 38 3.3.3. Dipolar cycloaddition reactions 42 3.3.4. Intramolecular Heck Reactions 43 3.3.5. Magnesium iodide-catalyzed ring-expansion reactions 44 3.4. Stereoselective synthesis of (–)-horsfiline 48 3.4.1. Synthesis of (–)-horsfiline using a chiral substrate 49 3.4.2. Synthesis of (–)-horsfiline using a chiral auxiliary 51 3.4.3. Synthesis of (–)-horsfiline using a chiral reagent 54 3.4.4. Synthesis of (+)-horsfiline by asymmetric allylic alkylation 56 RESULT AND DISCUSSION 60 1. Chiral malonate derivatives 60 1.1. Design and synthesis of new malonate substrates for phase-transfer catalytic reactions 60 1.2. Optimization of phase-transfer catalytic reaction with tert-butyl-malonates 65 1.3. Scope and limitation of malonate substrates in enantioselective phase-transfer catalytic reaction 71 1.3.1. Scope of α-methylmalonates in enantioselective phase-transfer catalytic alkylation 71 1.3.2. Scope of α-arylmalonates in enantioselective phase-transfer catalytic alkylation 74 1.3.3. Scope of α-halomalonates in enantioselective phase-transfer catalytic alkylation 77 1.3.4. Limitation of α-methylmalonates in enantioselective phase-transfer catalytic Michael reaction 80 1.4. Application and confirmation of absolute configuration 83 1.4.1. Application to (R)-α-methylphenylalanine and absolute configuration of α-methyl-α-alkylmalonates 83 1.4.2. Application to oxindole derivatives and absolute configuration of α-aryl-α-alkylmalonates 84 2. Asymmetric total synthesis of (–)-horsfiline 87 2.1. Diverse attempts to synthesize the spiro-oxindole moiety 88 2.2. Total synthesis of (±)-coerulescine 95 2.3. Improvement of enantioselectivity 99 2.4. Completion of synthesis of (–)-horsfiline 102 CONCLUSION 104 EXPERIMENTAL SECTION 105 1. General methods 105 1.1. Solvents and reagents 105 1.2. Chromatography and HPLC 106 1.3. Spectra 106 2. Chiral malonate derivatives 107 2.1. General procedure for α-mono-methylmalonates 107 2.2. Preparation of α-mono-arylmalonates 110 2.3. General procedure for α-mono-halomalonates 113 2.4. General procedure for asymmetric phase-transfer catalytic reactions 114 2.5. Double asymmetric phase-transfer catalytic α-alkylation 136 2.6. Application to the synthesis of (R)-α-methylphenylalanine 138 2.7. Application to the synthesis of chiral oxindole derivative 140 3. Asymmetric total synthesis of (–)-horsfiline 142 3.1. Preparation of phase-transfer catalytic substrate 142 3.2. General procedure for asymmetric phase-transfer catalytic allylation 144 3.3. Diverse approach to (–)-horsfiline 148 3.4. Synthesis of (±)-coerulescine 155 3.5. Synthesis of (–)-horsfiline 159 REFERENCES 164 APPENDIX 172 국문초록 203Docto

낮은 정칙성 데이터의 비선형 파동 방정식의 코시 문제

학위논문(박사) -- 서울대학교대학원 : 자연과학대학 수리과학부, 2022.2. 이상혁.This dissertation is devoted to the study of Cauchy problems for nonlinear wave equations with low regularity initial data. Firstly, the author is concerned with low regularity local well-posedness of the non-abelian Chern-Simons-Higgs system in the Lorenz gauge, which is a system of nonlinear wave equations on $\mathbf R^{1+2}$. Secondly, we establish global well-posedness and scattering of the Hartree-type nonlinear Dirac equations on $\mathbf R^{1+3}$ with Yukawa potential for small critical Sobolev data with additional angular regularity. When one deals with low regularity problems of given equations, the main obstacle is the presence of {\it resonant interaction}. To relax such a interaction, we utilse an additional cancellation typically given by {\it null structure}, which gives rises to better regularity properties. However, even though we make use of a fully null structure, it is not easy to attain the scaling critical regularity, since parallel interactions resulting in resonance in the nonlinearity grow stronger as spatial dimension lower. To overcome this difficulty, we exploit the rotation generators, which plays a distinguished role to eliminate parallel interactions in the nonlinearity. In this manner, we handle quadratic-type nonlinearity and investigate global existence and scattering for solutions to equations.이 학위 논문에서는 낮은 정칙성을 가지는 데이터에 관한 비선형 파동 방정식의 코시 문제를 연구하였다. 첫번째로 2차원 유클리드 공간 위에서의 파동 방정식으로 나타나는 로렌쯔 게이지 위에서의 비가환 천-사이먼-힉스 방정식에 관한 낮은 정칙성을 가지는 해의 국소적 성질을 관찰하고, 두번째로 유카와 퍼텐셜을 가지는 하트리 타입 비선형 디락 방정식에 대하여 각에 대한 정칙성을 허용한 상황에서 임계 정칙성의 해에 대한 대역적 성질을 연구하였다. 주어진 방정식에 대한 낮은 정칙성 문제를 해결할 때 주요 문제는 비선형항이 가지는 공명 상호작용인데, 이를 해결하기 위해 방정식의 영 형식으로 주어지는 상쇄 현상을 이용하였다. 하지만 유클리드 공간의 차원이 낮아질수록 공명 상호작용이 강해지기 때문에 영 형식을 사용하더라도 임계 정칙성 데이터에 관한 해의 성질을 연구하는 것은 쉽지 않은 일인데, 이를 위해 회전 연산자를 도입했다. 이 연산자가 비선형항의 공명 상호작용을 완화하는 역할을 하기 때문이다. 이와 같은 방법으로, 방정식의 대역적 해와, 그 해의 산란성을 얻을 수 있다.Abstract i 1 Introduction 1 1.1 Low regularity well-posedness for nonlinear wave equations 3 1.2 Main strategy in low regularity problems 10 2 Preliminaries 15 2.1 Littlewood-Paley theory 16 2.2 Half-wave decomposition of the d’Alembertian 18 2.3 Function spaces 19 2.4 Strichartz estimates 22 2.5 Auxiliary estimates 25 3 Chern-Simons-Higgs equations 31 3.1 Non-abelian Chern-Simons-Higgs equations in the Lorenz gauge 32 3.2 Null form in the Chern-Simons-Higgs equations in the Lorenz gauge 34 3.3 Proof of local well-posedness 36 3.4 Bilinear estimates 41 3.5 Trilinear estimates 48 3.6 Estimates of V(φ, φ:) 53 3.7 The failure of smoothness 53 3.8 Appendix 58 4 Dirac equations 60 4.1 Dirac equations with the Hartree-type nonlinearity 60 4.2 Preliminary on Dirac operators 66 4.3 Proof of global well-posedness and scattering 69 4.4 Trilinear estimates: Proof of Proposition 4.3.1 71 4.5 Bilinear estimates: Proof of Proposition 4.4.1 78 4.6 Non-scattering: Proof of Theorem 4.1.2 86박