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Tandem reaction sequences on a zirconocene template

Tandem reaction sequences on a zirconocene template
Tandem reaction sequences on a zirconocene template
The novel research work described in this thesis covers three areas of organozirconium chemistry.
The first area concerns the synthesis of rigid core structures containing the cis-bicyclo[3.3.0]oct-2-ene skeleton. Zirconocene mediated co-cyclisation of 1,6-enynes provides unsaturated 5-membered zirconacycles which are homologated to 6-membered zirconacycles by insertion of 1,1-dihalo-1-lithio species (dihalogenocarbenoids). Further rearrangement to a novel zirconium-alkenylidene complex driven by acetylides provided a powerful method for a rapid construction of novel bicyclic compounds with the potential for functionalization at multiple sites. Such obtained analogues provided an attractive template for structure-activity studies with respect to investigating the biological function of the human orphan nuclear receptors: LRH-1 and SF-1. Equivalent tandem insertion of 1,1-dihalo-1-lithio species and lithium acetylides into saturated zirconacycles resulted in the synthesis of novel bicyclo[3.3.0]octanes, though in many cases limited by a ?-H elimination process.
In the second area is presented research work relating to acyclic organozirconocene systems. Insertion of allenyl and propargyl carbenoids into organochlorozirconocenes and bisalkyl/-alkynyl zirconocenes led to 1,2-zirconate rearrangement with expulsion of the corresponding leaving group. Lewis acid promoted insertion of aldehydes and ketones into the resulting allenyl/propargyl zirconocene intermediate gave after hydrolysis a series of propargylic alcohols. Insertion of carbenoids derived from chiral propargyl tosylates into organochlorozirconocenes and further 1,2-metallate rearrangement gave the final alcohols as enantiomerically enriched products.
The third area was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo[4.3.0]nonane unit with four contiguous stereocentres. Zirconocene mediated co-cyclisation of the appropriate precursor provided four possible diastereoisomers. It was proved that thermodynamic equilibration of the zirconacycle gives the desired bicyclic product as a major isomer. Although the target molecule was not realised, thorough work on Zr-based total synthesis of mucosin has been achieved and a viable route for successful completion of the synthesis has also been proposed.
Stec, Jozef
c8ef34c5-6d89-453b-a8aa-86d7b54864c4
Stec, Jozef
c8ef34c5-6d89-453b-a8aa-86d7b54864c4
Whitby, Richard
45632236-ab00-4ad0-a02d-6209043e818b

Stec, Jozef (2010) Tandem reaction sequences on a zirconocene template. University of Southampton, School of Chemistry, Doctoral Thesis, 270pp.

Record type: Thesis (Doctoral)

Abstract

The novel research work described in this thesis covers three areas of organozirconium chemistry.
The first area concerns the synthesis of rigid core structures containing the cis-bicyclo[3.3.0]oct-2-ene skeleton. Zirconocene mediated co-cyclisation of 1,6-enynes provides unsaturated 5-membered zirconacycles which are homologated to 6-membered zirconacycles by insertion of 1,1-dihalo-1-lithio species (dihalogenocarbenoids). Further rearrangement to a novel zirconium-alkenylidene complex driven by acetylides provided a powerful method for a rapid construction of novel bicyclic compounds with the potential for functionalization at multiple sites. Such obtained analogues provided an attractive template for structure-activity studies with respect to investigating the biological function of the human orphan nuclear receptors: LRH-1 and SF-1. Equivalent tandem insertion of 1,1-dihalo-1-lithio species and lithium acetylides into saturated zirconacycles resulted in the synthesis of novel bicyclo[3.3.0]octanes, though in many cases limited by a ?-H elimination process.
In the second area is presented research work relating to acyclic organozirconocene systems. Insertion of allenyl and propargyl carbenoids into organochlorozirconocenes and bisalkyl/-alkynyl zirconocenes led to 1,2-zirconate rearrangement with expulsion of the corresponding leaving group. Lewis acid promoted insertion of aldehydes and ketones into the resulting allenyl/propargyl zirconocene intermediate gave after hydrolysis a series of propargylic alcohols. Insertion of carbenoids derived from chiral propargyl tosylates into organochlorozirconocenes and further 1,2-metallate rearrangement gave the final alcohols as enantiomerically enriched products.
The third area was an attempted total synthesis of the natural product mucosin, whose structure contains a bicyclo[4.3.0]nonane unit with four contiguous stereocentres. Zirconocene mediated co-cyclisation of the appropriate precursor provided four possible diastereoisomers. It was proved that thermodynamic equilibration of the zirconacycle gives the desired bicyclic product as a major isomer. Although the target molecule was not realised, thorough work on Zr-based total synthesis of mucosin has been achieved and a viable route for successful completion of the synthesis has also been proposed.

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Published date: January 2010
Organisations: University of Southampton

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Local EPrints ID: 72925
URI: http://eprints.soton.ac.uk/id/eprint/72925
PURE UUID: 948e89a9-0acd-4318-b55f-9713618db46a
ORCID for Richard Whitby: ORCID iD orcid.org/0000-0002-9891-5502

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Date deposited: 02 Mar 2010
Last modified: 30 Jan 2020 01:24

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Contributors

Author: Jozef Stec
Thesis advisor: Richard Whitby ORCID iD

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