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Title: Rapid synthesis of the Taxol core
Author: Thomas, Palacin
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2020
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This thesis describes the combination of prochiral/racemic electrophiles and non-stabilised nucleophiles in transition metal catalysed asymmetric transformations. The first part of the thesis focuses on the synthetic approach towards the Taxol core, Taxadiene. The key steps involve a Cu-catalysed asymmetric conjugate addition (ACA) of alkylzirconocenes to enones and cyclisations. Three different routes towards the synthesis of Taxadiene were explored and investigations into the Cu-catalysed ACA led to the discovery of a novel domino hydrozirconation/conjugate addition/enolate trapping reaction. The second part of this thesis builds on the Rh-catalysed asymmetric coupling of boronic acids (vinyls, benzenes and heteroaromatics) and cyclic allyl chlorides, developed in the Fletcher group. Here, the main point is to couple a similar library of boronic acids to a more challenging electrophile, a racemic tetrahydropyridine (or N-heterocyclic piperidene) chloride, in order to access new chiral building blocks that can be found in a variety of natural products and their derivatives. The utility of this method is demonstrated by the total and formal asymmetric synthesis of the antipsychotic drug (-)-Preclamol. The last chapter builds on the Cu-catalysed asymmetric allylic alkylation of alkylzirconocenes to cyclic allyl chlorides, also developed in our group. The main goal of this work is once again to apply this methodology to the racemic N-heterocyclic piperidene chloride. Investigations led to the discovery of a kinetic resolution process which afforded novel 3-alkyl substituted tetrahydropyridines and enantioenriched 3-chloro-1,2,3,6-tetrahydropyridines in high enantioselectivities.
Supervisor: Stephen, Fletcher Sponsor: People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Total synthesis ; Enantioselective catalysis