Towards the total synthesis of nakadomarin A

QD Chemistry

Xu, Chao ; Clark, Stephen

University:University of Glasgow

Department:School of Chemistry

关键词: Total Synthesis, Nakadomarin A, Furan synthesis, Natural Product;   

Others  :  http://theses.gla.ac.uk/6905/1/2015XuPhD.pdf

来源: University of Glasgow

【 摘 要 】

Nakadomarin A was first isolated from the sponge Amphimedon sp. by Kobayashiand co-workers in 1997. The structure showed a unique hexacyclic skeletonconsisting of 5-, 6-, 8- and 13-membered rings. This naturalproduct shows cytotoxicity, antimicrobial and inhibitory activities.The challenging structure, as well as the promising biologicalactivity and limited availability make nakadomarin A an attractivetarget for total synthesis. The aim of the project was to design asynthesis of a common late-stage intermediate that could be used to prepare notonly nakadomarin A, but also other members of the manzamine natural productfamily.The concise preparation of the common intermediate ABCD tetracyclic core wasachieved in only 7 steps (longest linear sequence). The key features of thesynthetic route are asymmetric construction of the AB ring using an asymmetricPauson-Khand reaction; installation of the azocine D ring through metathesisreactions (CM, RCM) and Overman rearrangement; and introduction of the C ringby N-alkylation. Finally, several side chains were prepared and evaluated to findthe optimum method for installation of the furan. This resulted in two advancedintermediates which could be malipulated to form nakadomarin A in only 3 steps.