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Title: The development and application of magnesium base-mediated transformations
Author: Weber, Tina
Awarding Body: University of Strathclyde
Current Institution: University of Strathclyde
Date of Award: 2013
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Abstract:
The exploration of magnesium bases has been the focus of this programme. Utilising the readily prepared Mes2Mg as a base reagent in a slight excess of 1.5 mol, efficient mediation of the Shapiro reaction has been achieved. A range of easily accessible aryl tosylhydrazones, bearing electron-neutral or -donating substituents, delivered excellent levels of selectivity in electrophilic quench, up to 97:3 (E:H), in conjunction with yields up to 90 % of the corresponding disubstituted alkenes. With only 1.05 equivalents of Weinreb amides as electrophiles, yields as high as 77% could be obtained. Efforts to utilise more demanding dialkyl tosylhydrazones were of limited success. Mechanistic investigations and attempts to trap key intermediates revealed a substantial lack of reactivity of the carbon-centred base at ambient temperatures and below. Further utilisation of the in situ generated vinyl magnesium species within Kumada-type cross-coupling reactions was also briefly explor ed. Preliminary studies, employing iron(III) chloride as a catalyst and TMEDA as an additive, delivered up to 32% yield of the desired alkylated product. Initial investigations into the efficacy of Mes2Mg in Wittig reactions were focused on the formation of a non-stabilised phosphonium ylide and subsequent reaction with acetophenone. These studies furnished an unusually high E-selectivity of 4:1 (E:Z), albeit in low yields of the alkene product. The conversion of phosphonium salts bearing electron-withdrawing groups delivered yields of up to 93%. Extension of the methodology studies utilising magnesium base reagents within the synthesis of the natural product (-)-mucosin was targeted. Efficient preparation of two main fragments, the bicyclic core and the allylic side chain, furnished the desired compounds in 51 % and 41 % yield, respectively. In the key step, enantioselective deprotonation of the meso-ketone using a chiral magnesium bisamide produced the enol silane in exc ellent 92:8 selectivity and up to 87% yield. Reaction of the silylenol ether with the allylic bromide delivered the desired keto ester in a 70 % yield. As an alternative for the alkylation step, utilisation of Tsuji-Trost allylation chemistry was explored. Completion of the natural product focused at first on the reduction of the ketone moiety and subsequent installation of a bromide leaving group. Extensive 1H-NMR studies on the alcohol intermediate validated the proposed route towards (-)mucosin. Introduction of the final nbutyl side chain was attempted using a range of stoichiometric and catalytic organocuprate-based protocols. A second strategy towards (-)mucosin was devised, concentrating on alkylation of the ketone moiety instead of hydride reduction. However, the hindered position within the molecule prevented the nbutyl group introduction and the completion of the natural product in both routes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.576464  DOI: Not available
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