3 research outputs found
์์ ์ด ์ด๋งค ์ํฌํ ๋ฐ์์ ํตํ ฮฑ,ฮฑ-dialkylmalonate์ ์๋ก์ด ๋น๋์นญ ํฉ์ฑ๋ฒ ๊ฐ๋ฐ๊ณผ ๊ทธ ์์ฉ์ผ๋ก์ (โ)-horsfiline์ ์ ํฉ์ฑ
ํ์๋
ผ๋ฌธ (๋ฐ์ฌ)-- ์์ธ๋ํ๊ต ๋ํ์ : ์ฝํ๊ณผ, 2014. 2. ๋ฐํ๊ทผ.Malonates are one of the most fundamental starting material in organic synthesis for C-C bond formation. Notably, chiral ฮฑ,ฮฑ-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 ฮฑ,ฮฑ-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 (ยฑ)-ฮฑ,ฮฑ-dialkylmalonates or (ยฑ)-ฮฑ,ฮฑ-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 ฮฑ-alkylation of carbonyl systems and ฮฒ-ketoester systems has been extensively studied, to date, the enantioselective direct ฮฑ-alkylation of malonates has not been reported. Our research team investigated a novel enantioselective synthesis of ฮฑ,ฮฑ-dialkylmalonates via direct ฮฑ-alkylation under phase-transfer catalytic condition.
First, our research team attempted the ฮฑ-benzylation of benzyl tert-butyl ฮฑ-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 ฮฑ-benzylated product with 70% of enantioselectivity. Five additional alkyl tert-butyl ฮฑ-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 ฮฑ-mono-aryl and halo-malonates, and these substrates also showed high enantioselectivities. Notably, the direct, double ฮฑ-alkylations of diphenylmethyl tert-butyl malonate also provided the corresponding ฮฑ,ฮฑ-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 ฮฑ,ฮฑ-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, (โ)-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 (โ)-horsfiline. A new and efficient synthetic method for the preparation of (โ)-horsfiline via the enantioselective phase-transfer catalytic ฮฑ-allylation of malonate has been developed. (โ)-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 ฮฑ-alkyl-ฮฑ-(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 (โ)-horsfiline 48
3.4.1. Synthesis of (โ)-horsfiline using a chiral substrate 49
3.4.2. Synthesis of (โ)-horsfiline using a chiral auxiliary 51
3.4.3. Synthesis of (โ)-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 ฮฑ-methylmalonates in enantioselective phase-transfer catalytic alkylation 71
1.3.2. Scope of ฮฑ-arylmalonates in enantioselective phase-transfer catalytic alkylation 74
1.3.3. Scope of ฮฑ-halomalonates in enantioselective phase-transfer catalytic alkylation 77
1.3.4. Limitation of ฮฑ-methylmalonates in enantioselective phase-transfer catalytic Michael reaction 80
1.4. Application and confirmation of absolute configuration 83
1.4.1. Application to (R)-ฮฑ-methylphenylalanine and absolute configuration of ฮฑ-methyl-ฮฑ-alkylmalonates 83
1.4.2. Application to oxindole derivatives and absolute configuration of ฮฑ-aryl-ฮฑ-alkylmalonates 84
2. Asymmetric total synthesis of (โ)-horsfiline 87
2.1. Diverse attempts to synthesize the spiro-oxindole moiety 88
2.2. Total synthesis of (ยฑ)-coerulescine 95
2.3. Improvement of enantioselectivity 99
2.4. Completion of synthesis of (โ)-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 ฮฑ-mono-methylmalonates 107
2.2. Preparation of ฮฑ-mono-arylmalonates 110
2.3. General procedure for ฮฑ-mono-halomalonates 113
2.4. General procedure for asymmetric phase-transfer catalytic reactions 114
2.5. Double asymmetric phase-transfer catalytic ฮฑ-alkylation 136
2.6. Application to the synthesis of (R)-ฮฑ-methylphenylalanine 138
2.7. Application to the synthesis of chiral oxindole derivative 140
3. Asymmetric total synthesis of (โ)-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 (โ)-horsfiline 148
3.4. Synthesis of (ยฑ)-coerulescine 155
3.5. Synthesis of (โ)-horsfiline 159
REFERENCES 164
APPENDIX 172
๊ตญ๋ฌธ์ด๋ก 203Docto
๋ฎ์ ์ ์น์ฑ ๋ฐ์ดํฐ์ ๋น์ ํ ํ๋ ๋ฐฉ์ ์์ ์ฝ์ ๋ฌธ์
ํ์๋
ผ๋ฌธ(๋ฐ์ฌ) -- ์์ธ๋ํ๊ต๋ํ์ : ์์ฐ๊ณผํ๋ํ ์๋ฆฌ๊ณผํ๋ถ, 2022.2. ์ด์ํ.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 . Secondly, we establish global well-posedness and scattering of the Hartree-type nonlinear Dirac equations on 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.์ด ํ์ ๋
ผ๋ฌธ์์๋ ๋ฎ์ ์ ์น์ฑ์ ๊ฐ์ง๋ ๋ฐ์ดํฐ์ ๊ดํ ๋น์ ํ ํ๋ ๋ฐฉ์ ์์ ์ฝ์ ๋ฌธ์ ๋ฅผ ์ฐ๊ตฌํ์๋ค. ์ฒซ๋ฒ์งธ๋ก 2์ฐจ์ ์ ํด๋ฆฌ๋ ๊ณต๊ฐ ์์์์ ํ๋ ๋ฐฉ์ ์์ผ๋ก ๋ํ๋๋ ๋ก๋ ์ฏ ๊ฒ์ด์ง ์์์์ ๋น๊ฐํ ์ฒ-์ฌ์ด๋จผ-ํ์ค ๋ฐฉ์ ์์ ๊ดํ ๋ฎ์ ์ ์น์ฑ์ ๊ฐ์ง๋ ํด์ ๊ตญ์์ ์ฑ์ง์ ๊ด์ฐฐํ๊ณ , ๋๋ฒ์งธ๋ก ์ ์นด์ ํผํ
์
์ ๊ฐ์ง๋ ํํธ๋ฆฌ ํ์
๋น์ ํ ๋๋ฝ ๋ฐฉ์ ์์ ๋ํ์ฌ ๊ฐ์ ๋ํ ์ ์น์ฑ์ ํ์ฉํ ์ํฉ์์ ์๊ณ ์ ์น์ฑ์ ํด์ ๋ํ ๋์ญ์ ์ฑ์ง์ ์ฐ๊ตฌํ์๋ค. ์ฃผ์ด์ง ๋ฐฉ์ ์์ ๋ํ ๋ฎ์ ์ ์น์ฑ ๋ฌธ์ ๋ฅผ ํด๊ฒฐํ ๋ ์ฃผ์ ๋ฌธ์ ๋ ๋น์ ํํญ์ด ๊ฐ์ง๋ ๊ณต๋ช
์ํธ์์ฉ์ธ๋ฐ, ์ด๋ฅผ ํด๊ฒฐํ๊ธฐ ์ํด ๋ฐฉ์ ์์ ์ ํ์์ผ๋ก ์ฃผ์ด์ง๋ ์์ ํ์์ ์ด์ฉํ์๋ค. ํ์ง๋ง ์ ํด๋ฆฌ๋ ๊ณต๊ฐ์ ์ฐจ์์ด ๋ฎ์์ง์๋ก ๊ณต๋ช
์ํธ์์ฉ์ด ๊ฐํด์ง๊ธฐ ๋๋ฌธ์ ์ ํ์์ ์ฌ์ฉํ๋๋ผ๋ ์๊ณ ์ ์น์ฑ ๋ฐ์ดํฐ์ ๊ดํ ํด์ ์ฑ์ง์ ์ฐ๊ตฌํ๋ ๊ฒ์ ์ฝ์ง ์์ ์ผ์ธ๋ฐ, ์ด๋ฅผ ์ํด ํ์ ์ฐ์ฐ์๋ฅผ ๋์
ํ๋ค. ์ด ์ฐ์ฐ์๊ฐ ๋น์ ํํญ์ ๊ณต๋ช
์ํธ์์ฉ์ ์ํํ๋ ์ญํ ์ ํ๊ธฐ ๋๋ฌธ์ด๋ค. ์ด์ ๊ฐ์ ๋ฐฉ๋ฒ์ผ๋ก, ๋ฐฉ์ ์์ ๋์ญ์ ํด์, ๊ทธ ํด์ ์ฐ๋์ฑ์ ์ป์ ์ ์๋ค.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 dโAlembertian 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(ฯ, ฯ:) 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 86๋ฐ