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Synthetic Studies Toward The Total Synthesis of 14-Membered Cyclopeptide Alkaloid

Title
Synthetic Studies Toward The Total Synthesis of 14-Membered Cyclopeptide Alkaloid
Authors
김호정
Issue Date
1994
Department/Major
대학원 화학과
Keywords
Synthetic studiestotal synthesis14-memberedcyclopeptide alkaloid
Publisher
이화여자대학교 대학원
Degree
Master
Advisors
한소엽
Abstract
시콜로펩티드 알칼로이드는 식물체에서 추출되는 염기성의 고리형 폴리아미드이다. 그것들은 trans-β-히드록시-α-아미노산, 스티릴 아민 록은 그 유도체, 고리내 결합된 아미노산과 N,N-dimethylated amino acid 혹은 dipeptide로 구성된다. 여기서는 β-히드록시-α-아미노산으로 β-히드록시-α-프롤린 (β-hydroxy-α-proline)을 사용했고 스티릴 아민 (styryl a'mine)은 Mitsunobu 반응에 의해 도입된 p-cyanophenol 과 Henry 반응에 의해 도입된 nitromethane이 전구체로 사용되었다. 고리내 결합된 아미노산은 L-isoleucine이었으며 N,N-dimethylated dipeptide는 L-leucine methylester와 L-isoleucine으로부터 합성되었다. 2치환된 pyrrolidine을 출발물질로하여 p-cyanophenol이 Mitsunobu 반응에 의해 입체 선택적으로 3번 위치에 트랜스로 도입되었으며 니트릴기는 Raney Ni을 촉매로 하여 formyl기로 전환되고 이것은 다시 nitromethane 음이온과 Henry reaction하고 환원되어 스티릴 아민의 전구체가 되었다. Styryl amine 전구체는 고리를 구성하는 아미노산, L-isoleucine과 짝짓기 반응하였고 여기서 도입된 아민은 고리화 형성 부위가 되었다. β-히드록시 -α-아미노산의 카르복시기는 히드록시기로부터 Swern oxidation, 산 촉매 KMn0_(4) Oxidation을 거쳐 형성될 수 있었고 반응 중 메틸 에스테르로 존재하다가 고리화 반응 전 가수 분해하여 pentafluorophenolate로 활성화 되었다. 활성화된 카르복시기는 Z-protected 아민과 묽은 농도의 용액에서 짝짓기 반응하며 이때 Z-기가 제거됨과 동시에 입체 선택적으로 14-멤버로 구성된 고리가 형성되었다. 출발 물질인 2치환된 pyrrolidine으로부터 고리화 반응까지 13단계의 반응을 거치며 총 15%의 수득률로 마지막 생성물을 얻을 수 있었다. 시클로펩티드 알칼로이드의 생리적 활성에 중요 역할을 할 수 있는 N,N-dimethylated dipeptide의 합성은 L-leucine methyl ester와 L-isoleucine 의 짝짓기 및 N,N-dimethylation 등을 통하여 이루어 졌다. 시클로펩티드 알칼로이드, mauritine D의 전합성은 위에서 형성된 고리 화합물을 몇 단계 더 반응시킨 후 합성한 N,N-dimethylated peptide와 결합시켜 이루어 질 수 있을 것이다.;Cyclopeptide alkaloids are basic cyclicpolyamides of plant origin. They are composed of trans-β-hydroxy-α-amino acids, styrylamine or derivatives, ring bound amino acids, and N, N-dimethylated amino acids or dipeptides. The general structure of the target 14-membered cyclopeptide alkaloide constitutes β- hydroxy-a-proline derivative as the β-hydroxy-α-amino acid unit, β-amino alcohol derivative (obtained from Mitsunobu reaction, followed by Henry reaction) as the styrylamine precursor, L-isoleucine as the ring bound amino acid, and N,N-dimethylated leucyl isoleucine as the dipeptide. Formation of the p-cyanophenyl ether derivative started from (2S, 3R)-disubsti tuted pyrrol idine by Mi tsunobu inversion with p-cyanophenol in the presence of PPh_(3) and DEAD. Thus the streochemistry of C3-hydroxyl center was inverted and the desired trans relationship between C2 and C3 of the pyrrolidine ring was well established. We envisioned the macrocyclization (14-membered ring formation) at the amine portion of the ring bound amino acid and carboxylic acid portion of the pyrrolidine derivative. First, the synthesis of amine moiety started from conversion of the cyano group to formyl group using Raney Ni, followed by Henry reaction of the aldehyde with nitromethane in the presence of sodium methoxide as base and reduction of the corresponding nitro group, The ring bound amino acid, Z-L-leucine, was then coupled with the styryl amine derivative using DCC/HOBT as coupling reagent. The synthesized terminal amino unit was thought to be used in the macrocyclization (macrolactamization) step. Second, the synthesis of carboxylic moiety was achieved by sequential oxidation of the C2-hydroxyl substituent of the pyrrolidine ring by Swern reaction followed by aqueous KMnO_(4) oxidation (Masamune condition). Treatment of the resulting carboxylic acid with methanol in the presence of DCC and DMAP produced methyl ester which was later hydrolysed and activated by using pentafluorophenol to afford the active pentafluorophenyl ester. Intramolecular coupling reaction between activated ester and Z-protected amine in the presence of cyclohexene and Pd/C as catalyst resulted in 14-membered macrocycle in very dilute condition, 14-membered macrocycle was synthesized in 15% yield from 2,3-disubstituted pyrrolidine in 13 steps, overall. Finally, N,N-dimethylated dipeptide which has been known to play an important role for biological activities was synthesized from coupling reaction between L-Z-isoleucine and L-leucine methyl ester, followed by N, N-dimethylation reaction. After confirmation of the structure of N, N-dimethylated dipeptide, the final coupling reaction between the dipeptide and the properly transformed macrocycle will complete the total synthesis of the natural product, mauritine D.
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