权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Synthesis of bioactive marine natural products using intramolecular ene reaction of acylnitroso compounds

酰基亚硝基化合物分子内烯反应合成具有生物活性的海洋天然产物

基本信息

批准号：
15590024
负责人：
AOYAGI Sakae
金额：
$ 2.18万
依托单位：
Tokyo University of Pharmacy and Life Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Halichlorine and pinnaic acid are structurally related marine alkaloids isolated by Uemura and co-workers in 1996. The unusual structures of these alkaloids, coupled with the valuable biological activities, have inspired numerous synthetic investigations, culminating in several routes to the core azaspirodecane system. We have developed the synthesis of the Danishefsky key intermediates starting with the azaspirobicyclic ketone as a common precursor, which was obtained using intramolecular ene reaction of acylnitroso compounds and achieved. Upon oxidation of the hydroxamic acid with Pr_4NIO_4, intramolecular ene reaction of the in situ generated acylnitroso compound proceeded smoothly to yield the spirocyclic lactam as a single diastereomer. Subsequent hydrogenation and highly stereoselective ethynylation led to the azaspirocyclic ketone, which was converted to the 1,7-disubstituted 6-azaspiro[4.5]decane key intemediate with the proper stereochemistry established by olefin hydrogenation followed by C-methylation of the tricyclic lactam and the subsequent processes involving lactam ring-opening using methyl triflate. The spirobicyclic compound thus obtained was converted to the TBDPS-protected Danishefsky intermediate in the total synthesis of pinnaic acid via five steps involving Horner-Wadsworth-Emmons homologation. Furthermore, the ethyl ester analog of the Danishefsky key intermediate in the total synthesis of halichlorine was achieved from the azaspirobicyclic aldehyde via ring-closing metathesis of the diene with the second-generation Grubbs'catalyst.

halchlorine和pinic acid是由Uemura及其同事于1996年分离出的结构相关的海洋生物碱。这些生物碱的不同寻常的结构，加上有价值的生物活性，激发了许多合成研究，最终形成了核心的叠氮烷体系。我们开发了以氮杂环酮为共同前体的Danishefsky关键中间体的合成，该中间体采用酰基亚硝基化合物的分子内烯反应获得并实现。羟肟酸与Pr_4NIO_4氧化后，原位生成的酰基亚硝基化合物的分子内烯反应顺利进行，生成了单对映体的螺环内酰胺。随后的加氢和高度立体选择性的乙基化产生了氮杂环酮，它被转化为1,7-二取代的6-氮杂环酮[4.5]十烷键中间体，通过烯烃加氢，然后是三环内酰胺的c -甲基化，以及随后使用三氟化甲酯开环内酰胺的过程建立了适当的立体化学。通过霍纳-沃兹沃思-埃蒙斯同源化的五个步骤，将得到的螺环化合物转化为受tbdps保护的Danishefsky中间体。此外，在第二代Grubbs催化剂的催化下，以氮杂环醛为原料，通过二烯的合环复合反应，得到了类似于全氯合成中Danishefsky关键中间体的乙酯。