1.AgOAc-mediated Pyrrole Synthesis And Its Application In The Total Syntheses Of Lamellarins D,H,R And Ningalin B 2.Synthetic Studies Toward Marine Natural Product Halichomycin

第二部分:海洋天然产物Halichomycin的合成研究Halichomycin是一个结构新颖的含有一个三元内酰胺环的大环内酯类化合物,具有很好的细胞毒活性,吸引了很多化学和药物学家的兴趣。由于Halichomycin新颖独特的化学骨架在化学合成上的挑战性,到目前为止还没有该分子的全合成报道。我们课题组从R-Roche出发,通过催化控制合成了内酯片段；从S-丝氨酸出发,通过底物引入手性中心完成了烯丙基溴片段的合成；最后,以底物控制的不对称烷基化反应及后续的官能团转化,完成了Halichomycin的C5-C18片段的合成。整个途径最长线性路线20步,8.8%的总收率。虽然没有完成整个分子的合成,但为完成该分子的合成提供了宝贵的经验。 The thesis describes a new method for AgOAc-mediated polysubstituted pyrrolessynthesis and its application in the total synthesis of marine natural productlamellarins. In addition, the stereoselective synthesis of the C5-C18 fragment ofmarine natural product Halichomycin is also studied. It consists of the following twoparts:Part 1: AgOAc-mediated pyrroles synthesis and its application in the totalsynthesis of lamellarins D, H, R and ningalin BThis part involves the first two chapters. Firstly, a simple and efficient methodfor the synthesis of 1,3,4-trisubstituted or 3,4-disubstituted pyrroles has beendeveloped. The reaction represents the first time that pyrroles are synthesized directlyform simple, readily available aldehydes and amines (anilines) as starting materialsusing AgOAc-mediated oxidative coupling reactionin in a one-pot manner. Themethod is not only simple and efficient but also general for substrate scopes.From the biosynthesis point of view, using AgOAc-mediated pyrrole synthesis asthe key reaction, we have successfully achieved the total synthesis of lamellarins D (7steps), H (7 steps), R (5 steps), and ningalin B (5 steps) from the corresponding aldehydes and amines. The synthesis features three oxidative coupling reactions,involving an AgOAc-mediated oxidative coupling reaction to form the1,3,4-trisubstituted pyrrole, a Pb(OAc)4-induced oxidative cyclization to form thelactone, and Kita's oxidation reaction to form the pyrrole-arene C-C bond.Part 2: Synthetic studies toward marine natural product HalichomycinHalichomycin, a structurally unique tricyclic macrolactam, exhibits potentcytotoxicity and attracts lots of chemists'interest. Halichomycin represents asignificant challenge to chemical synthesis owing to its extraordinary moleculararchitecture, and no total synthesis has been accomplished up to now. Butanolidefragment was readily prepared stereoselectively from (R)-Roche ester through catalystcontrol; dienylic bromide domain was synthesized from (S)-serine by substratecontrol. C5 C18fragment was rapidly assembled through a stereoselective alkylationof the butanolide with the dienylic bromide, followed by functional grouptransformations. The longest linear sequence is 20 steps, and the overall yield is animpressive 8.8%. This study gives valuable experience for the further study of thismolecule, even though the total synthesis of Halichomycin is not completed.