New synthetic methods in an approach to taxinine.
thesisposted on 19.11.2015, 08:48 by Roger Victor. Bonnert
A series of studies were undertaken directed towards the synthesis of taxinine. As part of these studies the need arose for a stepwise synthesis of a highly substituted butadiene from an aldehyde. The initial approach used the Peterson elimination to control the regio-chemistry in the formation of tri- and tetra-substituted dienes. The generality of this method appeared to be hampered by the basicity of 2-lithio-2-trimethylsilyl propane, which was required to undergo nucleophilic attack at an aldehyde. A study of the Diels-Alder reactions of a 3-alkyl-2,4-penta-l,3-diene and a 3-alkyl-4-methyl-penta-1,3-diene showed the former to react more efficiently. A deuterium labelling experiment eliminated the degeneracy of this diene in a 1,5-hydrogen shift as a reason for its increased reactivity. A more reliable route to the preparation of highly substituted butadienes was attained using the highly nucleophilic 2-lithio-2-phenyl- seleno-propane reagent. This route was used to prepare a triene system which underwent an intramolecular Diels-Alder reaction to enable the preparation of the taxane model compound 8,12,15,15-tetra- metllyltricyclo[9. 3. 1 .03,8] pentadec-ll-en-2-one which has the same stereochemistry and methyl group substitution as the naturally occurring taxanes. Attempts were then made to prepare taxinine using a carbohydrate derivative. A key step in the route to taxinine involved a Robinson annulation of a carbohydrate derived ketone. Alkylations of a carbohydrate derived enolate were studied initially. The Robinson annulation was then carried out using 3-trimethylsilyl-3-buten-2-ol and the enolate derived from methyl 4,6-O-benzylidene-3-deoxy-3-C- methyl-D-arabino-hexapyranosid-2-ulose.