Towards the total synthesis of nakadomarin A

Xu, Chao (2015) Towards the total synthesis of nakadomarin A. PhD thesis, University of Glasgow.

Abstract

Nakadomarin A was first isolated from the sponge Amphimedon sp. by Kobayashi
and co-workers in 1997. The structure showed a unique hexacyclic skeleton
consisting of 5-, 6-, 8- and 13-membered rings. This natural
product shows cytotoxicity, antimicrobial and inhibitory activities.
The challenging structure, as well as the promising biological
activity and limited availability make nakadomarin A an attractive
target for total synthesis. The aim of the project was to design a
synthesis of a common late-stage intermediate that could be used to prepare not
only nakadomarin A, but also other members of the manzamine natural product
family.
The concise preparation of the common intermediate ABCD tetracyclic core was
achieved in only 7 steps (longest linear sequence). The key features of the
synthetic route are asymmetric construction of the AB ring using an asymmetric
Pauson-Khand reaction; installation of the azocine D ring through metathesis
reactions (CM, RCM) and Overman rearrangement; and introduction of the C ring
by N-alkylation. Finally, several side chains were prepared and evaluated to find
the optimum method for installation of the furan. This resulted in two advanced
intermediates which could be malipulated to form nakadomarin A in only 3 steps.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Total Synthesis, Nakadomarin A, Furan synthesis, Natural Product
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Clark, Professor Stephen
• Date of Award: 2015
• Depositing User: Dr Chao Xu
• Unique ID: glathesis:2015-6905
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 01 Dec 2015 11:23
• Last Modified: 28 Nov 2018 14:28
• URI: https://theses.gla.ac.uk/id/eprint/6905