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Synthesis of the (2S, 3R)-Disubstituted Pyrrolidine from D-Serine and Its Application to the Attempted Total Synthesis of Amphibine D

Title
Synthesis of the (2S, 3R)-Disubstituted Pyrrolidine from D-Serine and Its Application to the Attempted Total Synthesis of Amphibine D
Authors
오종은
Issue Date
1994
Department/Major
대학원 화학과
Keywords
Synthesisdisubstituted pyrrolidineD-serineAmphibine D
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
한소영
Abstract
시클로펩티드 알칼로이드 Amphibine D의 전합성에 있어서 중요한 단계는 첫째, chiral pyrrolidinone의 형성, 둘째, 고리화반응의 수행, 세째 enamide의 도입이다. Amphibine D의 전합성의 중요한 중간체인 (4R, 5S)-disubstituted pyrrolidinone의 합성은 세단계로 진행되었다. 일단계는 N, O-diprotected serine 과 Meldrum's acid의 짝짓기반응으로서 염기의 존재하에서 카르복시기 활성인자로서 BOP-Cl가 이용되었다. 이단계는 고리화반응이며 이때 ethyl acetate의 환류(reflux) 조건이 요구되었다. 삼단계에서는 NaBH_(4)를 이용하여 입체 선택적 환원 반응을 진행하였다. 합성의 최적조건을 찾기위해 반응온도, 반응시간, 염기의 종류와 사용량, 출발물질의 양을 조절해가며 다양만 실험을 수행하였고, 그 결과 우리가 원하는 화합물을 높은 광학적 순도 (optical purity) 를 가지고 50% 수율로서 합성하였다. 14-멤버로 구성된 고리의 형성은 benzyloxycarbonyl 기의 제거와 분자내 고리화반응에 의해 수행되었고, 고리화반응은 pentafluorophenyl ester와 isoleucine의 아미노기의 짝짓기 반응에 의해 이루어졌다. 고리생성 이합체화 반응을 피하기위해 high dilution 조건이 요구되었으며, 온도와 용매에 따른 변화가 관찰되었다. 생성물은 부분 입체 이성질체로서 얻어졌으며, 이 두 화합물은 desilylation과 enamide를 도입하는 과정에서 상당한 반응성의 차이를 보여 주었다. Enamide는 mesylation-selenation-oxidation and elimination 단계에 의해 14-멤버로 구성된 교리에 도입되었고, trifluoroacetic acid를 이용하여 tert- butyloxycarbonyl 기를 제거 하였다. Deprotected 중간체와, Z-phenylalanine과 isoleucine methyl ester로 부터 합성된 N,N-dimethylated phenyl alanylisoleucine 의 짝짓기 반응이 DCC/HOBT 방법과 BOP-Cl 방법에 의해 시도 되었으나, 많은 부생성물이 형성 되어서 우리가 원하는 생성물을 확인 하지 못하였다.;The total synthesis of a natural product, amphibine D, involves some crucial steps. Among them are the formation of 5-membered heterocyclic compound (chiral pyrrolidinone), the 14-membered ring cyclization (macrolactamization), and the introduction of enamide moiety in the macrocyclic intermediate. (4R, 5s)-disubstituted pyrrolidinone was synthesized from D-serine in 3 step sequence and used as a key intermediate toward the total synthesis of cyclopeptide alkaloid, amphibine D. The first challenging step was the coupling reaction between N-Boc-0-TBDMS-D-serine and Meldrum's acid in the presence of DMAP and Et_(3)N as bases, and BOP-Cl as a carboxyl activator. Pyrrolidinone ring formation was then achieved by refluxing it in ethyl acetate. The third step in pyrrolidinone synthesis was the stereoselective reduction of the ketone group with NaBH_(4). Many different reaction conditions were examined in an effort to optimize the yield. It was found that the yield was largely dependent upon the scale of the experiment, the amount and kind of base used, and the reaction temperature as well as reaction period. Best yield obtained from this study was 50%. The reaction condition found also gave the highest optical purity, Cylization to the 14-membered ring was performed by intramolecular coupling reaction between pentafluorophenyl ester and carbobenzyloxy protected amine, in one step. High dilution method was required to avoid the dimerization. The diastereomeric isomers obtained from the cyclization reaction showed differences in reactivity in following desilylation and enamide formation reactions. Introduction of the enamide moiety by thermal selenoxide elimination followed by deprotection of the Boc group afforded the reactive deprotected intermediate. The final step in total synthesis of amphibine D was the coupling reaction between free amine of the 14-membered macrocycle and carboxylic acid of the dipeptide prepared. Coupling of the deprotected intermediate with N,N-dimethylated phenylalanylisoleucine was attempted by using DCC/HOBT or BOP-Cl as peptide coupling reagents. Unfortunately, the target molecule, amphibine D, could not be isolated. This is due to the formation of many side products. Study toward the completion of the total synthesis of amphibine D is under investigation.
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