Use this URL to cite or link to this record in EThOS:
Title: Enantiopure bromonium ion-induced cation-π cyclisations
Author: Marklew, Jared Stephen
ISNI:       0000 0004 2752 8008
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2014
Availability of Full Text:
Access from EThOS:
Access from Institution:
There has been an astonishing variety of sesqui- and diterpene metabolites isolated—mainly from Laurencia species, or their predators—which possess the enantiopure α,α-dimethylcyclohexyl bromide moiety. The key step in their biogenesis is generally considered to be an enzyme-mediated formation of an asymmetric bromonium ion which initiates a cation-π cyclisation. This diverse array of terpene natural products is explored in the introduction to this thesis and their biogenesis via cation-π cyclisations analysed. Synthetic sources of electrophilic bromine such as NBS, TBCO and BDSB have been shown to initiate brominative polyene cyclisations with excellent control of relative stereochemistry albeit as necessarily racemic products. At the start of this work no asymmetric bromonium ion-induced polyene cyclisations had been demonstrated. Studies on a model system for the key in situ enantiopure bromonium ion generation and intramolecular trapping are described. Sharpless asymmetric dihydroxylation provides access to enantiopure diols of a trisubstituted alkene which can be manipulated to enantiopure bromohydrins. These are activated as 2,3,4,5-tetrafluorobenzoate esters which cyclise cleanly under the action of catalytic triflic acid to give enantiopure bromo-bicycles without racemisation from bromonium ion to alkene transfer. The mechanism of this reaction is investigated, it is practically demonstrated and shorter routes are explored. The synthesis of high purity linear terpene: homogeranyl 4-methoxybenzene is discussed, from which the synthesis of enantiopure bromo-tetrafluorobenzoate esters is carried out. The use of Lewis acid, in this case dimethylaluminium triflate, was found to successfully enact the cyclisation of these alkene containing substrates. Full conversion to cyclic products was achieved and the desired tricyclic product was isolated as a mixture of enantiopure diastereomers. Absolute and relative configuration of both diastereomers were determined by radical dehalogenation and comparison of the sign of the optical rotation of the product to literature values. Finally, the synthesis of homofarnesyl 4-methoxybenzene derived substrates is detailed. The cyclisation of which has the potential to generate tetracyclic compounds. This forms the basis of future work to be carried out.
Supervisor: Braddock, David Christopher Sponsor: AstraZeneca (Firm) ; Arrow Therapeutics Ltd ; Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral