Assembly of Four Diverse Heterocyclic Libraries Enabled by Prins Cyclization, Au-Catalyzed Enyne Cycloisomerization, and Automated Amide Synthesis
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- 作者：Jiayue Cui ; David I. Chai ; Christopher Miller ; Jason Hao ; Christopher Thomas ; JingQi Wang ; Karl A. Scheidt ; Sergey A. Kozmin
- 刊名：The Journal of Organic Chemistry
- 出版年：2012
- 出版时间：September 7, 2012
- 年：2012
- 卷：77
- 期：17
- 页码：7435-7470
- 全文大小：1069K
- 年卷期：v.77,no.17(September 7, 2012)
- ISSN：1520-6904
文摘
We describe a unified synthetic strategy for efficient assembly of four new heterocyclic libraries. The synthesis began by creating a range of structurally diverse pyrrolidinones or piperidinones. Such compounds were obtained in a simple one-flask operation starting with readily available amines, ketoesters, and unsaturated anhydrides. The use of tetrahydropyran-containing ketoesters, which were rapidly assembled by our Prins cyclization protocol, enabled efficient fusion of pyran and piperidinone cores. A newly developed Au(I)-catalyzed cycloisomerization of alkyne-containing enamides further expanded heterocyclic diversity by providing rapid entry into a wide range of bicyclic and tricyclic dienamides. The final stage of the process entailed diversification of each of the initially produced carboxylic acids using a fully automated platform for amide synthesis, which delivered 1872 compounds in high diastereomeric and chemical purity.