Hilton, Stephen (2002) Towards the synthesis of indole alkaloids. (PhD thesis), Kingston University, .
Abstract
Radical chemistry and, in particular, tandem radical chemistry has rarely been used in the synthesis of the 'Strychnos' and 'Aspidosperma' alkaloids. These two classes of compounds are structurally complex, possess a range of biological activity and present a synthetic challenge. Previous routes to these molecules are reviewed in the first section . of this thesis. The utility of radical chemistry, tandem radical chemistry and 1,S'I hydrogen atom abstraction towards the syntheses of complex molecules is outlined with examples that demonstrate the potential of radical chemistry. A new synthetic approach towards the spiropyrrolidinyl oxindole alkaloids is presented, which utilises tandem radical chemistry. The radical sequence involves an initial 1,5- hydrogen atom abstraction, followed by a Sew-trig cyclisation onto the indole C-3 position. This is governed by the directing effect of a cyano group at the C-2 position of indole. The tricyclic core of the oxindole alkaloids can be readily obtained following an oxidative decyanation. In the course of these studies a novel product was observed during the cyclisation of the N-isopropyl precursor. Modification of the cyclisation precursor to incorporate the N-pentenyl group resulted in the formation of the tetraeyelic core of the Strychnos and Aspidosperma alkaloids. This arose from a subsequent 6-exo¬trig cyclisation after formation of the tricyclic core. Cyclisation of the N-pentynyl radical precursor led to the expected cyclised product along with an unexpected pentaeyelic structure, which arose from an unprecedented further l,S-hydrogen atom abstraction followed by a 4-exo-dig cyclisation. The second approach involves the addition of alkyl radicals onto the indole C-3 position to generate the tricyclic core of the spiropyrrolidinyl oxindole alkaloids. This approach is directed towards a total synthesis of the oxindole alkaloids, horsfiline and coerulescine. However, this approach led instead to rearrangement before cyclisation followed by intramolecular transfer of the cyano group from the indole C-2 to C-3 position. A novel approach to the formation of 3-substituted 2-cyanoindoles is also presented which negates the need for protection of the indole nitrogen allowing for a flexible approach to the tandem radical cyclisation precursors. The experimental conditions for the synthesis of all new compounds prepared during this work along with characterisation data are presented.
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