Synthetic studies toward the total synthesis of naturally occurring mycotoxin, roquefortine C : the formation of diketopiperazine ring

Abstract

균류들이 성장과 대사에 필요로 하여 만들어낸 물질을 mycotoxin이라 하며 이들은 생물학적 활성을 지닌 물질들이다. 이런 mycotoxin의 일종인 Roquefortine C를 전합성 하기위해서 자연계에 풍부한 아미노산인 L-tryptophan을 출발 물질로 하였다. 반응성이 큰 아민 부분을 Z-protection하고, acid 부분을 esterification시켰다. 좋은 이탈기를 만들기 위한 첫 단계로 oxidation을 거쳐 oxy indole을 형성하고, 다시 Z group을 Boc으로 바꾼 후, thionation, methylation을 거쳐 thio-methyl indole유도체를 형성 하였다. Diketopiperazine ring을 만들기 위해서는 Boc을 떼어내고 Boc이 아민에 protection되어있는 glycine과 coupling을 하였다. 그리고 나서 다시 free아민을 형성 시킨 후, 분자내에서의 펩타이드 결합으로 이를 성공 시켰다. Prenyl 부분을 도입하기 위해서 thio-claisen rearrangement를 거쳤으며 이를 통하여 두개의 diasteromers가 생성이 되었다. Major 화합물은 quaternary carbon center가 (R) configuration 그리고, minor화합물은 (S) configuration으로 그 비율은 1.6:1이다. Reductive desulfurization을 거쳐서 cycle을 형성 하려 하였으나 retro-claisen rearrangement로 돌아가거나 아니면 출발물질이 그대로 존재하여 반응이 진행 되지 않았다. 또 aldol condensation으로 imidazole ring을 도입 하려 하였으나 반응이 진행 되지 않고 출발 물질만 존재 하였다. 결론적으로 최종 생산물은 thio-methyl indole유도체에 diketopiperazine ring과 prenyl부분이 도입된 중간체로 총 11단계이고 수득률은 8%이다. ; The fungi produces a variety of secondary metabolites including pigments, antibiotics, phytotoxins and some compounds toxic to animals. Those toxic metabolites produce in association with foods and animal feeds, which may be ingested and caused health problems to humans have traditionally been refered to as mycotoxin. Also Roquefortine C, which we have tried to synthesize is involved in mycotoxin. Analysis of blue cheese was viewed that contained neurotoxin roquefortine which was produced by penicillium roqueforti. In this study, Oxy indole derivative was made through Cbz-protection, esterification and oxidation from L-tryptophan. It was the first step for good leaving group. Through Boc-protection, thionation and methylation, thio-methyl indole derivative was formed. To introduce diketopiperazine ring, At first, thio-methyl indole derivative was converted the coupling segment into a free amine, then was coupled with glycine which was protected by Boc group. Again the coupling segment converted into a free amine and peptide bond was formed by intramolecular coupling reaction. So thio-methyl indole derivative had diketopiperazine ring. Inverted prenyl group was attatched by thio-claisen rearrangement. This reaction products were to give diasteromers. In other words, the sterochemistry of these products had R and S configuration. R configuration was only necessary. 5-Memberd cyclization reaction was tried by reductive desulfurizastion. Though it was extensively tried several times under various conditions, all of them failed out unsuccesfully. So it was necessary to be investigated in other sides. Imidazole ring was attatched by aldol condensation before the formation of diketpiperazine ring. It was tried several times under various conditions. But it was failed, too. Roquefortine D was tried which has similar structure as Roquefortine C. Imidazole ring was tried to attach by SN2 reaction. But it was failed. So it has better investigate in other sides. Biosynthesis and biological activity was more important parts in study of mycotoxin. Because it was the most related to human life. In this study of total synthesis of Roquefortine C, it may give helpful at these views.