Studies toward the total synthesis of artocarpol A, D, E and structurally related analogues

The work described in this thesis concerns studies toward the total synthesis of artocarpol A, D and E as well as the synthesis of structurally related analogues. The artocarpol family of natural products was isolated from the root bark of a breadfruit tree, Artocarpus rigida (Moraceae). Notably, artocarpol A has a particularly interesting molecular structure as well as potent anti-inflammatory activity and so it represents an important target for total synthesis. Artocarpol A, C, D, E, F, G and I share a common structural feature, a functionalized dibenz[b,f]oxepin ring system. Moreover, in the case of artocarpol A the dibenz[b,f]oxepin moiety is fused to a tricyclic system (a condensed 4,5,6-polycyclic system that features four contiguous stereogenic centres at the ring-junctions). Based on retrosynthetic analysis of this target compound, a novel synthetic route was devised and model studies were undertaken. The known 11 H-dibenzo[b,f]oxepin-10-one was efficiently synthesized in five steps in order to test the validity of the two key steps in the proposed route. The first key step involved a cross-aldol condensation reaction between the unsubstituted oxepinone and citral that was coupled to a subsequent electrocyclization reaction. The second key step, involved an intramolecular [2+2] photocycloaddition reaction that resulted in the construction of the complete polycyclic ring system of artocarpol A and installed the four stereogenic centres in the correct relative sense. The structure of this complex polycyclic artocarpol A analogue was elucidated by detailed NMR studies and by X-ray crystallography. A series of related 2H-chromenes and pyrans were also prepared by modification of a known synthetic procedure and were employed as additional substrates for this photocycloaddition reaction. An analogue of artocarpol D was also prepared from senecialdehyde. An alternative strategy was also developed for the synthesis of analogues of artocarpol A, D and E that employed alkylation reactions of the parent oxepinone with geranyl and prenyl bromide as key steps. The synthesis of a dimethoxy-substituted dibenzo[b,f ]oxepinone was also completed. However, this appropriately functionalized substrate proved to be unsuitable for the proposed total syntheses. Thus, the corresponding dinitro-substituted oxepinone was identified as an alternative substrate for synthesis and preliminary investigations were undertaken.