Publications
Detailed Information
Studies on rhe total synthesis of (-)-Incarvilline, (+)-Incarvine C, (-)-Incarvillateine : (-)-Incarvilline, (+)-Incarvine C, (-)-Incarvillateine의 전합성에 관한 연구
DC Field | Value | Language |
---|---|---|
dc.contributor.advisor | 서영거 | - |
dc.contributor.author | 서효원 | - |
dc.date.accessioned | 2017-07-19T11:14:27Z | - |
dc.date.available | 2017-07-19T11:14:27Z | - |
dc.date.issued | 2013-08 | - |
dc.identifier.other | 000000013047 | - |
dc.identifier.uri | https://hdl.handle.net/10371/133483 | - |
dc.description | 학위논문 (석사)-- 서울대학교 대학원 : 약학과, 2013. 8. 서영거. | - |
dc.description.abstract | 중국 북동부에 서식하는 식물 Incarvillea sinensis의 지상부에서 1990년 새로운 종류의 monoterpene alkaloids인 (-)-Incarvillateine의 분리 보고를 필두로, 1992년, 1995년에 각각 (-)-incarvilline과 (-)-incarvines A-C가 잇달아 분리 보고 되었다. Incarvillea sinensis는 중국에서 전통적으로 Jiaohao라는 이름으로 류마티즘과 통증 경감을 목적으로 민간약으로 사용되어 왔다. 이 식물에서 분리 보고 된 천연물 중 (-)-incarvilline과 (-)-incarvillateine이 강력한 진통효과를 가짐이 보고되어 있다. 특히 morphine에 필적할만한 강력한 진통효과를 보이는 (-)-incarvillateine의 활성기전이 κ, μ, δ -opiate receptor mechanism을 거치는 morphine과는 달리 κ, μ-opiate receptor와 adenosine receptor mechanism을 거치는 것으로 생각되어지기 때문에 새로운 활성 경로를 가지는 진통제의 개발이 가능할 것으로 보여 주목을 받고 있다.
(-)-Incarvillateine은 생합성적으로 (+)-incarvine C의 dimer로 여겨지고 있다. 이는 cis-anti cis-4원환을 중심으로 알칼로이드와 방향족 환이 C2 대칭으로 연결되어 있다. 특히, 알칼로이드 모핵인 (-)-incarvilline은 5개의 연속된 입체탄소가 bicyclic piperidine 골격에 밀집되어 있다. 본 논문에서는 (-)-incarvilline, (+)-incarvine C, (-)-incarvillateine의 핵심 합성 중간체인 7-epi-Incarvilline을 입체선택적으로 합성하였다. 본 합성에서는 (1) 입체 선택적 Pd(0)-catalyzed allylic alkylation, (2) [2.1.2] bridged bicyclic lactone의 cis-fused 5,6-bicyclic lactam으로의 효율적인 전환, (3) 반응 기질에 의해 입체 선택성이 조절되는 수소화 반응과 1,4-첨가 반응을 핵심 반응으로 이용하였다. 나아가 (-)-incarvillateine의 전합성을 목표로 cis-anti cis-4원환을 입체 선택적으로 합성하고자 하였다. 고리 내부에 두 개의 lactone과 두 개의 olefin을 갖는 12원환의 전구체를 double Ireland-Claisen 전이반응을 통해 고리를 축소시켜 원하는 입체탄소를 갖는 4원환을 합성하고자 하였다. | - |
dc.description.abstract | In 1990, a new class of monoterpene alkaloid, (-)-incarvillateine, was isolated from the aerial part of Chinese plant Incarvillea sinensis. (-)-Incarvilline and (+)-incarvines A-C were isolated from the same plant. Incarvillea sinensis has been used as a Chinese folk medicine as "Jiaohao" for rheumatism or relieving pain. (-)-Incarvilline and (-)-incarvillateine showed strong analgesic effects. Especially, significant antinociceptive property of (-)-incarvillateine has received the attention due to its different mechanism compared to morphine. While morphine has κ, μ, δ-opiate receptor mechanism, (-)-incarvillateine is considered interacting with κ, μ-opiate receptor and adenosine receptor mechanism.
Structurally, (-)-incarvillateine is the dimer of (+)-incarvine C. It has cis-anti cis-cyclobutane core structure and C2-symmetric alkaloid units and aromatic parts. Moreover, (-)-incarvilline as the alkaloid part of incarvillea alkaloids has five contiguous stereocenters within bicyclic piperidine system. Herein, we have accomplished the substrate-controlled asymmetric synthesis of 7-epi-incarvilline for the formal synthesis of (-)-incarvilline, (+)-incarvine C, and (-)-incarvillateine. The key features of our synthesis include (1) diastereoselective construction of the [2.1.2] bicyclic lactone using a stereoselective Pd(0)-catalyzed cyclization, (2) isomerization of the [2.1.2] bicyclic lactone to the cis-fused 5,6-bicyclic lactam and (3) elaboration of two stereocenters via stereoselective catalytic hydrogenation and Michael addition. Furthermore, we attempted to stereoselectively synthesize cis-anti cis-cyclobutane core structure of (-)-incarvillateine via double Ireland-Claisen rearrangement. We anticipated bis-ketene acetal precursor might afford cis-anti cis-cyclobutane core structure of (-)-incarvillateine through Ireland-Claisen rearrangement via double boatlike transition states. | - |
dc.description.tableofcontents | Table of Contents
국문 초록 i Table of Contents iii List of Tables vi List of Figures vii List of Schemes viii Abbreviations x I. Introduction 1 1. Biological Activities and Structural Features of Incarvillea Alkaloids 1 1.1. Isolation 1 1.2. Biological Activities 2 1.3. Structural Features 3 2. Previous Synthetic Approaches 5 2.1. Hongs Synthetic Study 6 2.2. Kibayashis Total Synthesis of (-)-Incarvilline, (+)-Incarvine C, and (-)-Incarvillateine 6 2.3. Hondas Formal Synthesis of (-)-Incarvilline 9 2.4. Bergman and Ellmans Total Synthesis of (-)-Incarvillateine 10 2.5. Jias Total Synthesis of (-)-Incarvillateine 11 3. Pd(0)-catalyzed Allylic Alkylation 12 4. Ireland-Claisen Rearrangement 13 Ⅱ. Result and Discussion 15 1. Retrosynthetic Analysis of 7-epi-Incarvilline 15 2. Total synthesis of 7-epi-Incarvilline 16 2.1. Synthesis of the Precursor of Pd(0)-catalyzed cyclization16 2.2. Pd(0)-catalyzed Cyclization 17 2.3. Synthesis of Fused Bicyclic Lactam 18 2.4. Introducing the Site Specific Michael Acceptor 20 2.5. Completion of the Synthesis of 7-epi-Incarvilline 21 3. Retrosynthetic Analysis of (-)-Incarvillateine 23 3.1. Initial Approach to cis-anti cis-Cyclobutane 23 3.2. Revised Approach to cis-anti cis-Cyclobutane 24 3.3. Plausible Transition State of Double Ireland-Claisen Rearrangement 25 4. Synthetic Approach to (-)-Incarvillateine 26 4.1. Initial Approach to the Precursor of Double Ireland-Claisen Rearrangement 26 4.2. Revised Approach to the Precursor of Double Ireland-Claisen Rearrangement 28 4.3. Computational Calculations of the Precursors of Double Ireland-Claisen Rearrangement 30 Ⅲ. Conclusion 32 Ⅳ. Experimental 33 Ⅴ. References 61 Ⅵ. Appendix 64 Ⅶ. Abstract 88 | - |
dc.format | application/pdf | - |
dc.format.extent | 29602123 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Total synthesis | - |
dc.subject | Monoterpene alkaloid | - |
dc.subject | (-)-Incarvilline | - |
dc.subject | (-)-Incarvillateine | - |
dc.subject | Pd(0)-catalyzed allylic alkylation | - |
dc.subject | Ireland-Claisen rearrangement | - |
dc.subject.ddc | 615 | - |
dc.title | Studies on rhe total synthesis of (-)-Incarvilline, (+)-Incarvine C, (-)-Incarvillateine | - |
dc.title.alternative | (-)-Incarvilline, (+)-Incarvine C, (-)-Incarvillateine의 전합성에 관한 연구 | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | Hyowon Seo | - |
dc.description.degree | Master | - |
dc.citation.pages | xii, 86 | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2013-08 | - |
- Appears in Collections:
- Files in This Item:
Item View & Download Count
Items in S-Space are protected by copyright, with all rights reserved, unless otherwise indicated.