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Cephalotaxus Alkaloids의 전합성을 위해 Sequential Chirality Transfer를 통한 Cα-Substituted Proline 유도체의 효과적인 비대칭 합성 : Effective Asymmetric Synthesis of Cα-Substituted Proline Derivatives via Sequential Chirality Transfer toward the Total Synthesis of Cephalotaxus Alkaloids
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- Authors
- Advisor
- 김상희
- Issue Date
- 2021-02
- Publisher
- 서울대학교 대학원
- Keywords
- Asymmetric Synthesis ; Cα-Substituted Proline ; Chirality Transfer ; Friedel-Crafts 반응 ; Cephalotaxus Alkaloids
- Description
- 학위논문 (석사) -- 서울대학교 대학원 : 약학대학 약학과, 2021. 2. 김상희.
- Abstract
- 본 논문에서는 bicyclic system에서의 C-N-C chirality transfer 개념을 [5,6]-bicyclic system에 적용하여 이를 항백혈병 및 항암 활성을 지닌 Cephalotaxus alkaloids의 전합성에 도입하고자 하였다. Chiral proline으로부터 N-quaternization과 [2,3]-sigmatropic rearrangement를 통해 입체선택적 Cα-Substituted Proline 유도체를 합성하였다. 또한 bicyclic proline 유도체에서 anomeric 위치의 입체선택성이 rearrangement 통해 새롭게 형성되는 Cβ-위치의 입체 선택성에 영향을 미침을 실험을 통해 확인하였고, 이상적인 부분입체 이성질체를 효율적으로 합성하기 위한 조건을 최적화하였다. bicyclic proline 유도체의 두 chiral 중심이 Cα-위치와 Cβ-위치에 선택성을 부여하므로 이는 C-N-C chiral transfer의 연장선으로 볼 수 있으며, 외부 chiral source의 도움 없이 연속적인 chiral transfer를 효율적으로 수행했다는 점에서 주목할 만하다. 또한 얻어진 Cα-Substituted Proline 유도체에 Friedel-Crafts 반응을 수행함으로써 7-membered azepine ring을 포함한 3개의 ring 구축하였으며 azaspiranic tetracyclic backbone을 합성하는 새로운 route를 제시하였다.
In this paper, we apply the concept of C-N-C chirality transfer in bicyclic systems to [5,6]-bicyclic systems to introduce them to the synthesis of Cephalotaxus alkaloids with anti-leukemia and anticancer activity. We synthesize Cα-substituted proline derivatives stereoselectively via N-quaternization and [2,3]-sigmatropic rearrangement from chiral proline. Experiments have shown that the stereochemistry of anomeric position in bicyclic proline derivatives influences the stereoselectivity of the newly formed Cβ-position through rearrangement, and we optimize the conditions for efficient synthesis of ideal diastereomer. Since the two chiral centers of bicyclic proline derivative give stereoselectivity to the Cα- and Cβ-centers, this can be seen as an extension of the C-N-C chiral transfer and is noteworthy in that sequential chiral transfer was performed efficiently without the help of external chiral sources. We also constructed three rings, including 7-membersized azepine ring, by performing Friedel-Crafts reaction with the obtained Cα-Substructed Proline derivative, and presented a new route to synthesize azaspiranic tetracyclic backbones.
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