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 Csp<sup>3</sup>-Csp<sup>2</sup> 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 O<sub>3</sub> followed by Et<sub>3</sub>N 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-Et<sub>3</sub>N strategy.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:748955 |
| Date | January 2018 |
| Creators | Fegheh-Hassanpour, Younes |
| Contributors | Hodgson, David |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:59b03e69-5fcf-46ff-a7a1-a2052622d5b7 |
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