Synthesis of trisubstituted olefins by RCM using an O-Si-C tether: application to the total synthesis of dolabelide C

Wittmann, Stephane (2015) Synthesis of trisubstituted olefins by RCM using an O-Si-C tether: application to the total synthesis of dolabelide C. PhD thesis, University of Glasgow.

Abstract

Dolabelide C is a macrolide, part of the dolablide family, isolated in 1997 from the Japanese sea hare, Dolabella auricularia. Dolabelide C contains a polyhydroxylated macrocycle structure with eleven stereogenic centers and two trisubstituted olefins. It exhibits cytotoxicity against cervical cancer HeLa-S3 cells. Dolabelide C and the other members of the dolabelide family have been the object of several studies in several groups.

The approach envisaged in the Prunet group towards the synthesis of dolabelide C consists in disconnecting the molecule into two fragments of similar lengths, the C1-15 and the C16-30 fragments. Previously within the group, both fragments had been successfully synthesised. However, new routes have been envisaged in order to improve these syntheses.

For the synthesis of the C16-30 fragment, the fragment had been previously synthesised by cross metathesis, but this reaction led to an E/Z ratio to 4:1 at best. The new route consists in employing a temporary silicon-tethered ringclosing metathesis reaction in order to obtain a single isomer. This method was investigated on model substrates and was then employed for the synthesis of the C16-30 fragment of dolabelide C.

Finally, the use of a new route for the synthesis of the C1-15 fragment is discussed. The C1-15 fragment had been synthesised previously using a Mukaiyama aldol as the key step. However, as the ketone is not present in the natural product, several steps were required in order to remove it. The use of a cross metathesis between two fragments was investigated for the synthesis of this fragment in a more concise manner.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Subjects: Q Science > QD Chemistry
• Colleges/Schools: College of Science and Engineering > School of Chemistry
• Supervisor's Name: Prunet, Dr Joëlle
• Date of Award: 2015
• Depositing User: Mr Stephane Wittmann
• Unique ID: glathesis:2015-7068
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 05 Feb 2016 16:17
• Last Modified: 18 Feb 2016 09:11
• URI: https://theses.gla.ac.uk/id/eprint/7068