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Towards the total synthesis of vibralactone and the miuraenamides

Towards the total synthesis of vibralactone and the miuraenamides
Towards the total synthesis of vibralactone and the miuraenamides
This thesis describes the efforts made towards the total synthesis of vibralactone and the miuraenamides. Initially, the attempted synthesis and derivatisation of vibralactone, a pancreatic lipase inhibiting fused bicyclic ?-lactone, will be discussed.

Vibralactone provides an interesting synthetic challenge not only because of its potent biological activity, but also due to its unique structure when compared to biologically related natural products. Herein, several ring closing metathesis (RCM) and aldol condensation strategies towards vibralactone’s cyclopentene ring are presented.

Following diastereoselective addition reactions, metathesis approaches have successfully provided two racemic ibralactone derivatives. A novel auxiliary was subsequently implemented towards a stereoselective formal synthesis of a vibralactone model compound. An alternative aldol ndensation approach was then investigated to optimise the synthesis of vibralactone intermediates.

The synthetic approach towards the miuraenamide family is then described. The miuraenamides are macrocyclic depsipeptides which have been shown to possess potent anti-fungal activity. Miuraenamide A has also been shown to stabilise actin filaments. This biological activity makes the miuraenamide family interesting synthetic targets towards the development of novel anti-fungal and anti-cancer therapeutics.

The synthesis towards miuraenamide A, via miuraenamide E, is described. The synthesis of the miuraenamide hydrocarbon fragment using stereoselective catalytic procedures was successfully achieved. The remaining peptide fragment was then synthesised using developed amino acid functionalisation and coupling techniques.

Finally, optimisation of the union of each of the fragments was investigated,consequently leading to the successful synthesis of a linear, protected, miuraenamide E derivative.
Heap, Robert
c1557a74-f91f-4a3d-8767-23abe717065c
Heap, Robert
c1557a74-f91f-4a3d-8767-23abe717065c
Brown, Richard
21ce697a-7c3a-480e-919f-429a3d8550f5

Heap, Robert (2014) Towards the total synthesis of vibralactone and the miuraenamides. University of Southampton, Chemistry, Doctoral Thesis, 258pp.

Record type: Thesis (Doctoral)

Abstract

This thesis describes the efforts made towards the total synthesis of vibralactone and the miuraenamides. Initially, the attempted synthesis and derivatisation of vibralactone, a pancreatic lipase inhibiting fused bicyclic ?-lactone, will be discussed.

Vibralactone provides an interesting synthetic challenge not only because of its potent biological activity, but also due to its unique structure when compared to biologically related natural products. Herein, several ring closing metathesis (RCM) and aldol condensation strategies towards vibralactone’s cyclopentene ring are presented.

Following diastereoselective addition reactions, metathesis approaches have successfully provided two racemic ibralactone derivatives. A novel auxiliary was subsequently implemented towards a stereoselective formal synthesis of a vibralactone model compound. An alternative aldol ndensation approach was then investigated to optimise the synthesis of vibralactone intermediates.

The synthetic approach towards the miuraenamide family is then described. The miuraenamides are macrocyclic depsipeptides which have been shown to possess potent anti-fungal activity. Miuraenamide A has also been shown to stabilise actin filaments. This biological activity makes the miuraenamide family interesting synthetic targets towards the development of novel anti-fungal and anti-cancer therapeutics.

The synthesis towards miuraenamide A, via miuraenamide E, is described. The synthesis of the miuraenamide hydrocarbon fragment using stereoselective catalytic procedures was successfully achieved. The remaining peptide fragment was then synthesised using developed amino acid functionalisation and coupling techniques.

Finally, optimisation of the union of each of the fragments was investigated,consequently leading to the successful synthesis of a linear, protected, miuraenamide E derivative.

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Published date: 17 November 2014
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 374535
URI: http://eprints.soton.ac.uk/id/eprint/374535
PURE UUID: 305ff974-7dcf-44a0-82ba-c63eeae4504a
ORCID for Richard Brown: ORCID iD orcid.org/0000-0003-0156-7087

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Date deposited: 23 Feb 2015 10:48
Last modified: 16 Jan 2019 05:01

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Contributors

Author: Robert Heap
Thesis advisor: Richard Brown ORCID iD

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