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Synthetic studies toward the total synthesis of naturally occurring alkaloid

Title
Synthetic studies toward the total synthesis of naturally occurring alkaloid
Authors
김영아
Issue Date
1999
Department/Major
대학원 화학과
Publisher
이화여자대학교 대학원
Degree
Master
Abstract
Cyclopeptide alkaloid containing plants, in general, have long been used as a fold medicine in and around the tropical region. Not only the synthetic challenge of the molecule but also the demand of the large quantities of the compound for detailed biological evaluation. We attempted the total synthesis of a 14-membered cyclopeptide alkaloid, mauritine D, which was isolated from Zizyphus nummularia by Tschesche in 1974. In Part A, we reviewed the advances of peptide coupling reagents in regard to their structural differences. The reagents were classified as phosphonium regents, uronium regents, carbodiimides, chloroformates, imidazolium regents, organophosphorus regents, acid halides, and other active esters. In the case of the formation of secondary amides, it was cincluded that carbokiimide such DCC/HOBt, phosphonium regent such as BOP, or uronium reagent such as HBTU was the best of the choice. For tertiary amides, both phosphonium and uronium reagent, such as PyBroP, HBTU, were the most efficient peptide coupling reagents. Since many natural compounds containing peptide bonds usually exhibit some interesting biological activities, it is very important to successfully synthesizing the natural products. The knowledge on new peptide coupling regents obtained from this study will serve as the key tool in completing the total synthesis of the cyclopeptide alkaloid, mauritine D. In Part B, we carried out synthetic studies toward the total synthesis of mauritine D. The study was devided into three sessions. First enantiomerically pure 2,3-cis phrrolidine was synthesized from unnatural amino acid, D-serine, by Boc-protection, selective O-silylation, coupling with meldrum s acid followed by decarboxylation, and stereospecific reduction. Secondly, the livear precursor of the macrolactam was synthesized by Mitsunobu inversion, Swern-Masamune Oxidation, methyl esterification, Henry reaction, reduction, and coupling with Z-isoleucine of the resulting amine moiety. After saponification, the active ester was introduced with pentafluorophenol. Thus, the active ester was efficiently synthesized in overall 17 steps and total 16% yield from D-serine. Thirdly, the synthesis of N,N-dimethylated dipeptide was completed, starting from L-leucine methyl ester and Z-isoleucine in 4 steps and overall 68% yield. Even though we are able to cyclize the 14-membered macrolactam, coupling the pyrrolidine nitrogen with the side-chain dipeptide remains to be solved. In Part C, we studied the effect of two different coupling regents in peptide coupling reaction in order to find out the best to fit in our synthetic pathways. Thus, we perfomed the coupling reaction between primary or secondary amine with sterically hindered acids using BOP-Cl and cyanuric fluoride as the carboxy activator. From our results, the acid fluoride obtained from cyanuric fluoride was proved to be superior than active ester formed by BOP-Cl in sterically-hindered peptide coupling reactions. ; 본 연구에서는 시클로펩티드 알칼로이드의 일종인 Mauritine D를 전합성하고자 시도하였다. 시클로펩티드 알칼로이드는 여러 식물체에서 발견되어지며 예로부터 열대, 아열대 지방을 중심으로 민간요법에 쓰여져 왔다. 따라서 이들이 잠재적으로 지니고 있을 생리적 활성에 대한 관심이 고조되었고 시클로펩티드 알칼로이드에 대한 연구 분야가 중요시 되어졌다. Mauritine D는 14-membered ring으로 이루어진 시클로펩티드 알칼로이드로 fungi와 gram-positive bacteria에 항생활성을 나타낸다고 알려진 메틸화된 아미노기 를 포함하고 있으므로 이에 대한 전합성 시도는 매우 흥미로운 연구 과제가 아닐 수 없다. Part A에서는 다양한 peptide coupling reagent들을 구조적 특성에 따라 분류하여 이들의 변천과정과 함께 특징적인 장단점들을 살펴보았다. 일반적으로 peptide bond를 포함하는 천연물들이 흥미로운 생리적 활성을 보이므로써 coupling reagent에 대한 꾸준한 연구가 이루어졌다. 역으로 다양한 구조를 가지는 천연물의 효과적인 합성은 이러한 기본적 지식을 바탕으로 이루어질 수 있으며 peptide bond를 포함하고 있는 Mauritine D 전합성의 중요한 밑받침이 되리라 사료된다. Part B에서는 이전에 이루어진 연구를 기본으로 하여 D-Serine에서 부터 거대고리를 형성하기 위한 precursor를 17 단계에 걸쳐 총 16%의 수득률로 합성하였다. 이후 두가지 synthetic rute로 거대고리 형성 및 side-chain과의 coupling 반응을 시도해 보고자 진행 중에 있으며 앞으로 이에 대한 심도 있는 연구는 계속되어질 계획이다. 또한 side-chain인 N,N-dimethylated dipeptide를 4단계에 걸쳐 총 68%의 수득률로 합성하였다. Part C에서는 Mauritine D의 중간체에 해당하는 2,3-disubstituted pyrrolidine 유도체와 N-Boc-O-TBDMS amino acid간의 coupling 반응을 BOP-Cl와 Cyanuric fluoride를 사용하여 비교 연구하였다.
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