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Towards the synthesis of RP66453

Towards the synthesis of RP66453
Towards the synthesis of RP66453
This thesis details synthetic studies towards the total synthesis of RP 66453, a natural product isolated from a strain of Actinomycetes bacteria which is shown to bind to the neurotensin antagonist of guinea pigs. RP 66453 provides an attractive target as its bis-macrocyclic core contains a biaryl axis that displays atropisomerism. The natural atropisomer of RP 66453 is less stable than its diastereoatropisomer. To date there have been no reported syntheses of the natural product, and just one reported synthesis of the unnatural atropisomer. This thesis describes a new approach towards the synthesis of this challenging natural product. Model studies are described towards the formation of the biaryl macrocyclic ring via a radical induced transannular ring contraction of a halogenated benzyl aryl ether. Also described are model studies towards the formation of the biaryl linkage via phenanthrene formation, accessed in turn from a radical induced transannular ring contraction of a halogenated stilbene. Unfortunately, though short synthetic routes to these macrocyclic precursors were established, we were unable to realize either of the key steps. Synthesis of the second macrocycle (ether ring) was achieved via an SNAr ring closure. Coupling of this fragment to an advanced tetrapeptide intermediate was achieved. Further macrocyclisation is needed to advance this material to the natural product.
Nanson, Lana
45d26fc2-88f6-484a-9436-874e0c7f4d4d
Nanson, Lana
45d26fc2-88f6-484a-9436-874e0c7f4d4d
Harrowven, D. C.
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Nanson, Lana (2010) Towards the synthesis of RP66453. University of Southampton, School of Chemistry, Doctoral Thesis, 218pp.

Record type: Thesis (Doctoral)

Abstract

This thesis details synthetic studies towards the total synthesis of RP 66453, a natural product isolated from a strain of Actinomycetes bacteria which is shown to bind to the neurotensin antagonist of guinea pigs. RP 66453 provides an attractive target as its bis-macrocyclic core contains a biaryl axis that displays atropisomerism. The natural atropisomer of RP 66453 is less stable than its diastereoatropisomer. To date there have been no reported syntheses of the natural product, and just one reported synthesis of the unnatural atropisomer. This thesis describes a new approach towards the synthesis of this challenging natural product. Model studies are described towards the formation of the biaryl macrocyclic ring via a radical induced transannular ring contraction of a halogenated benzyl aryl ether. Also described are model studies towards the formation of the biaryl linkage via phenanthrene formation, accessed in turn from a radical induced transannular ring contraction of a halogenated stilbene. Unfortunately, though short synthetic routes to these macrocyclic precursors were established, we were unable to realize either of the key steps. Synthesis of the second macrocycle (ether ring) was achieved via an SNAr ring closure. Coupling of this fragment to an advanced tetrapeptide intermediate was achieved. Further macrocyclisation is needed to advance this material to the natural product.

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Published date: 10 June 2010
Organisations: University of Southampton

Identifiers

Local EPrints ID: 173859
URI: http://eprints.soton.ac.uk/id/eprint/173859
PURE UUID: 4af6dcb6-2904-4feb-9051-f30fa229315f
ORCID for D. C. Harrowven: ORCID iD orcid.org/0000-0001-6730-3573

Catalogue record

Date deposited: 19 May 2011 11:17
Last modified: 30 Jan 2020 01:27

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Contributors

Author: Lana Nanson
Thesis advisor: D. C. Harrowven ORCID iD

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