Synthesis of six- and seven-membered cyclic ethers by ring-closing metathesis and synthesis of the A-D fragment of gambieric acid A

Sieng, Bora (2011) Synthesis of six- and seven-membered cyclic ethers by ring-closing metathesis and synthesis of the A-D fragment of gambieric acid A. PhD thesis, University of Glasgow.

Abstract

Over the past thirty years, numerous fused polycyclic ether natural products have been isolated from small marine organisms. These compounds revealed a variety of interesting biological properties, which has attracted the interest of many synthetic groups. The common structural characteristic of these compounds is an array of trans-fused ether rings. Several iterative strategies have been reported to build six- and seven-membered cyclic ethers, which are the two most common units in these natural products.

The objective of work described in the first part of this thesis was to develop new synthetic methodology to access these motifs. Each unit must be built in the minimum number of steps and the new methodology must be flexible enough to obtain both six- and seven-membered rings from a common precursor. They key reaction of the strategy will be ring-closing metathesis, as previous work in our group showed that this is a powerful reaction to create cyclic ethers.

The second part of this thesis focus on the total synthesis of one of the marine polyether natural products, gambieric acid A. This compound was isolated in 1992 and has so far eluded total synthesis.
First, the synthesis of the tricyclic B-D core, which has been developed in our group, was optimised and performed on a large scale. The synthetic route relies on the ring-closing metathesis reaction to construct two of the cyclic ethers from a commercially available glucose derivative.
Several strategies for the coupling with the tetrahydrofuran A ring were then investigated. The initial method envisioned for the fragment coupling was a nucleophilic substitution of an alkyl iodide by a lithiated dithiane.
However, this strategy revealed unsuccessful. Instead, a more converging approach using a diastereoselective Tsuji reaction was developed, which allowed the formation of the complete carbon skeleton of the A-D fragment.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: RCM, enol ether, total synthesis, gambieric acid A
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Clark, Prof. J. Stephen
• Date of Award: 2011
• Depositing User: Mr Bora Sieng
• Unique ID: glathesis:2011-2523
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 05 Aug 2011
• Last Modified: 10 Dec 2012 13:56
• URI: https://theses.gla.ac.uk/id/eprint/2523