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Towards the total synthesis of RP 66453: a neurotensin antagonist with a twist

Towards the total synthesis of RP 66453: a neurotensin antagonist with a twist
Towards the total synthesis of RP 66453: a neurotensin antagonist with a twist
This thesis describes the efforts made towards the total synthesis of RP 66453, a highly strained macrocyclic tetrapeptide. RP 66453 provides an interesting synthetic challenge, not only due to its potential biological activity but also owing to its unusual chemical architecture. The strained bicyclic ring system features a 15-membered macrocycle containing an aryl-aryl bond and a 14-membered meta,para-cyclophane.

Herein, several strategies towards the model A-B macrocycle of RP 66453 are presented featuring as a key step, a radical induced transannular ring contraction of a benzyl haloaryl ether and a photochemical transannular cyclisation of cis-stilbene derivatives. Synthetic efforts towards the B-O-C macrocycle are also presented, including copper-mediated and intramolecular SNAr cyclisation strategies. Finally, research into the union of these two fragments is presented followed by a discussion of a proposed end-game strategy.
Skinner, David
810451b7-f8f8-4cea-9fb3-415eeba840fb
Skinner, David
810451b7-f8f8-4cea-9fb3-415eeba840fb
Harrowven, David
bddcfab6-dbde-49df-aec2-42abbcf5d10b

(2013) Towards the total synthesis of RP 66453: a neurotensin antagonist with a twist. University of Southampton, Chemistry, Doctoral Thesis, 260pp.

Record type: Thesis (Doctoral)

Abstract

This thesis describes the efforts made towards the total synthesis of RP 66453, a highly strained macrocyclic tetrapeptide. RP 66453 provides an interesting synthetic challenge, not only due to its potential biological activity but also owing to its unusual chemical architecture. The strained bicyclic ring system features a 15-membered macrocycle containing an aryl-aryl bond and a 14-membered meta,para-cyclophane.

Herein, several strategies towards the model A-B macrocycle of RP 66453 are presented featuring as a key step, a radical induced transannular ring contraction of a benzyl haloaryl ether and a photochemical transannular cyclisation of cis-stilbene derivatives. Synthetic efforts towards the B-O-C macrocycle are also presented, including copper-mediated and intramolecular SNAr cyclisation strategies. Finally, research into the union of these two fragments is presented followed by a discussion of a proposed end-game strategy.

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Published date: 31 January 2013
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 350675
URI: http://eprints.soton.ac.uk/id/eprint/350675
PURE UUID: 5510f5cf-e9c9-4366-8ecd-0780cb30349f
ORCID for David Harrowven: ORCID iD orcid.org/0000-0001-6730-3573

Catalogue record

Date deposited: 09 Apr 2013 11:53
Last modified: 14 Jul 2018 00:36

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Contributors

Author: David Skinner
Thesis advisor: David Harrowven ORCID iD

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