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Title: Total synthesis of (-)-6,7-dideoxysqualestatin H5 by carbonyl ylide cycloaddition and cross-electrophile coupling
Author: Fegheh-Hassanpour, Younes
ISNI:       0000 0004 7232 8398
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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The work presented in this thesis focuses on the total synthesis of (-)-6,7- Dideoxysqualestatin H5. Particular emphasis was the development of a cross- coupling strategy for direct delivery of the side chain towards the end of the synthesis. Various methods investigated to perform the key Csp3-Csp2 coupling initially led to the Fu variant of the Negishi coupling at elevated temperatures and subsequent cross- electrophile coupling at rt. Key features of the asymmetric synthesis of (-)-6,7- dideoxysqualestatin H5, include: (1) highly diastereoselective n-alkylation of a tartrate acetonide enolate and subsequent oxidation-hydrolysis to provide an asymmetric entry to a Î2-hydroxy-α-ketoester motif; (2) facilitation of Rh(II)-catalysed cyclic carbonyl ylide formation-cycloaddition by cogeneration of keto and diazo functionality through ozonolysis of an unsaturated hydrazone; and (3) stereoretentive Ni-catalysed Csp3-Csp2 cross-electrophile coupling between tricarboxylate core and unsaturated side-chain to complete the natural product. Following completion of the natural product, further work was carried out on the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyls. The scope and limitations of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems were explored. Tosylhydrazones, from tosylhydrazide condensation with readily available Î ́- and Îμ- unsaturated α-ketoesters, led in the former case to a 2-pyrazoline whereas the latter cases led to α-diazo-Îμ-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Tosylhydrazones from cyclic enones also allowed access to 1,4- and 1,5-diazocarbonyl systems using the ozonolysis-Et3N strategy.
Supervisor: Hodgson, David Sponsor: Engineering and Physical Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Organic chemistry ; total synthesis of (-)-6,7- Dideoxysqualestatin H5 ; cross-electrophile coupling ; cross-coupling ; catalysis