Synthetic Studies toward the Total Synthesis of a Natural Product, Roquefortine C

Abstract

Fungi produce poisonous metabolites against human race. These poisonous compound are called mycotoxins which represent the second largest group of biologically active substance of microbial orgin, next to antibiotics, They display toxic-pharmacological action such as liver degradation, hemorrhags and are partially responsible for cancer. In this study, oxyindole derivative was synthesized by protection, esterification, and subsequent oxidation of L-trptophan in the course of the total synthesis of a natural product, roquefortine, which is known as the mycotoxin. The thionation reaction was studied using several reagents, because the selective conversion of amide group to thioamide in the presence of ester and carbamate was rather tricky. A model study using appropriately protected dipeptide to perform selective thionation of amide functionality was carried out with some thionating reagents such as Lawesson's, Belleau's, or P_(4)S_(10) reagent. After success of the model study, the thionation of oxyindole was also carried out under various conditions. The optimum condition found was the use of 0.6 equivalent of Lawesson's reagent under benzene reflux in 30 min stirring. After sulfur methylation using methyl iodide, inverted prenyl substituent was introduced at C3 by thio-Claisen rearragement reaction. The following 5-membered cyclization reaction of the indole ring C2 with the nitrogen of the carbamate moiety was not successful. Therefore, an alternative route was investigated. After coupling of the free amine moiety of glycine and the acid portion which was produced by hydrolysis of methyl ester of the indole ring, the formation of diketopiperazine was expected via intramolecular coupling reaction. Then, the anion of amide of diketopiperazine could attack the C2 of the indole ring to produce the desired 5-membered ring. But diketopiperazine could not be synthesized because the intramolecular cyclization reaction did not proceed at all. After additional experiments of converting the coupling segment into a free amine, and coupling this with the acid portion of glycine, the desired diketopiperazine will probably be produced. In conclusion, the investigation of the formation of the compound 26 which is an essential intermediate in mycotoxin synthesis, and has an inverted prenyl group introduced at C3, was successfully accomplished via asymmetric synthesis resulting in an overall 7 step reactions and a 26% yield.;곰팡이들이 만들어 내는 유독한 대사 물질인 mycotoxin은 미세생물에 생물학적인 활성을 갖는 물질로 항생제 (antibiotics) 다음으로 자연계에 대량 존재하는 그룹이다. Mycotoxin은 간 분해, 뇌출혈등을 발생시키며 암을 유발하기도 한다. 본 연구에서는 mycotoxin의 일종인 roquefortine 전합성의 일환으로 L-tryptophan을 출발 물질로 하여 Protection, esterification, oxidation 반응을 통해 oxyindole 유도체를 만들었다. Amide, ester, carbamate의 세 종류 carbonyl 기를 가진 화합물에서 선택적으로 amide의 carbonyl 기만을 thiocarbonyl 기로 바꾸는 반응은 매우 까다로운 반응이기때문에 여러 가지 reagent들을 사용하여 실험하였다. 먼저 thionating reagent들을 사용하여 모델 화합물인 dipeptide를 thiodipeptide로 바꾸는 반응을 해본 후, 본 연구 시스템인 oxyindole의 lactam moiety를 thiolactam으로 바꾸는 반응을 여러 가지 조건에서 시도해 보았다. 최적의 조건은 0.6 당량의 Lawesson's reagent를 사용하고 benzene을 용매로 하여 30 분간 reflux하는 것으로 관찰되었다. Methyl iodide로 sulfur에 methylation 시킨 후 thio-Claisen rearragement를 통해 C3 위치에 inverted prenyl 치환체를 도입하였다. 다음 단계인 고리화 반응은 Indole ring의 C2를 carbamate의 nitrogen과 연결시킴으로써 고리를 형성하고자 하였으나 반응이 진행되지 않았다. 따라서 methyl ester를 가수분해하여 생긴 acid 부분과 glycine의 free amine 부분을 coupling 시킨 후, 다시 분자 내 coupling을 시켜 diketopiperazine을 형성하고 diketopiperazine의 amide에서 proton을 제거하여 생긴 음이온으로 indole ring의 C2를 공격하여 고리를 형성하고자 하였다. 그러나 분자내 coupling이 이루어지지 않아서 diketopiperazine을 형성하지 못하였다. 앞으로 coupling하는 부분을 free amine으로 만든 후에 glycine의 acid 부분과 coupling시키면 원하는 diketopiperazine이 형성되리라 예상된다. 결론적으로 mycotoxin 합성에 있어 중요한 중간체인 inverted prenyl기가 C3 위치에 도입된 중간체를 형성하는 연구는 asymmetric synthesis로 전체 7단계, 26% 수율로 성공적으로 이루어졌다.