Gardiner, John Michael (1988) New synthetic strategies towards cephalotaxus alkaloids. Doctoral thesis, Durham University.
Michael alkylation, with methyl acrylate, of nitrocyclohexenes bearing functionalized aromatic substituents at the 2-position, was found to be highly stereo selective. Subsequent dissolving metal reductive cyclization was highly efficient, and these two steps thus provided a stereo specific entry to a substituted 1-azaspirocyclic system, related to the cephalotaxine skeleton. Application of this methodology to trans-4-(3,4-dimethoxy-6-carbo- methoxyraethylphenyl)-5-nitrocyclohexene afforded spirolactam ester 6-(3,4-dimethoxy-6-carboraethoxymethylphenyl)-2-oxo-l-azaspiro[4.5]dec-8-ene. On reduction with DIBAL-H at -78ºC, this cyclized in high yield, with high stereoselectivity to the corresponding 3-benzazepine-2-ol system.Similar methodology with trans-4-(3,4-methylenedioxy-6-nitrophenyl) -5-nitrocyclohexene, allowed for a formaldehyde insertion reaction to provide a 1,3-benzodiazepine analogue. Preliminary studies hold promise for allowing modification of the cyclohexene ring to known pre-targets of cephalotaxine. These findings bring the synthetic strategy towards providing a competitive route to (±) cephalotaxine, and also a range of analogues, including the unknown 11-aza and 10-hydroxy-8-oxo systems.
|Item Type:||Thesis (Doctoral)|
|Award:||Doctor of Philosophy|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||08 Feb 2013 13:37|