Application of the Noyori annulation reaction to the cephalotaxine spirocycle.

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dc.contributor.advisor Gravestock, David.
dc.contributor.advisor Robinson, Ross S.
dc.creator McKenzie, Jean Mary-Anne.
dc.date.accessioned 2011-06-08T07:15:56Z
dc.date.available 2011-06-08T07:15:56Z
dc.date.created 2001
dc.date.issued 2001
dc.identifier.uri http://hdl.handle.net/10413/3008
dc.description Thesis (M.Sc.)-University of Natal Pietermaritzburg, 2001. en_ZA
dc.description.abstract Cephalotaxine is a naturally occurring alkaloid which is the structural motif of a number of compounds which have shown promising anti-cancer properties. This fact together with its relatively complex pentacyclic structure, which incorporates an azaspirocycle annular to a benzazepine moiety, has resulted in its popularity as a synthetic target. The aim of this project was to synthesise the azaspirocycle of cephalotaxine using a Noyori annulation method involving the reaction of an enamine and an a,a' -dibromo ketone in the presence of Fe2{CO)9. In the first attempt the reaction of l-benzyl-2-methylenepyrrolidine (117) with methyl 2,4-dibromo-3-oxobutanoate (116) proved to be unsuccessful, the electron withdrawing ester functionality of methyl 2,4-dibromo-3-oxobutanoate (116) being unable to stabilise the intermediates formed during the reaction and thus resulting in its failure. Reaction of l-benzyl-2-methylenepyrrolidine (117) and 2,4-dibromo-3-pentanone (114) resulted in the formation of an azaspirocycle though in an extremely poor yield and the reaction was deemed inefficient for the synthesis of the cephalotaxine spirocycle. Finally, reaction of 2-(l-benzyl-2-pyrrolidinylidene)acetonitrile (129) and 2,4-dibromo-3-pentanone (114) resulted in the successful synthesis of a novel azaspirocycle. The product, l-benzyl-7,9-dimethyl-8-oxo-1-azaspiro[4.4]nonane-6-carbonitrile (130), contained four stereogenic centres and one of the diastereomers was successfully crystallised out. The X-ray structure in conjunction with NOESY NMR experiments showed the relative stereochemistry to be 5s', 6s', 7s', 9s'. Significant progress was made in the application of this methodology to the construction of the cephalotaxine pentacyclic skeleton with the synthesis of a novel lactam, 1-[2-(6-iodo-I,3-benzodioxol- 5-yl)ethyl]-2-pyrrolidinone, being achieved. In the course of this work a novel compound, 2-(6-Iodo-1 ,3-benzodioxol-5-yl)ethyl 4-methylbenzenesulfonate (98), was also synthesised and its X-ray structure revealed it to be conformationally interesting. As a result a conformation analysis study was carried out on this compound as well as 2-(6-Iodo-I,3-benzodioxol- 5-yl)ethyI 4-nitrobenzenesulfonate (15a). The Noyori annulation reaction was not implemented in the route to the basic pentacyclic structure of cephalotaxine due to time constraints, however synthesis of analogues of cephalotaxine and other alkaloids possessing azaspirocycles should now be possible based on the methodology developed in this project. en_ZA
dc.language.iso en en_US
dc.subject Cephalotaxine. en_US
dc.subject Alkaloids. en_US
dc.subject Theses--Chemistry. en_US
dc.title Application of the Noyori annulation reaction to the cephalotaxine spirocycle. en_US
dc.type Thesis en_US

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