| The schweinfurthins are a small set of prenylated stilbenes isolated from the African plant Macaranga schweinfurthii by Beutler and co-workers at the National Cancer Institute. Three of the four natural products, schweinfurthins A, B, and D, were shown to have sub-micromolar anti-cancer activity in the NCI 60 cell line assay. More significant than the level of activity, these compounds show a pattern of activity different from any clinically used antitumor agent. Therefore, they may represent a new class of antitumor agents, functioning by an as yet untapped mechanism of action.; This work details the study of two routes towards the synthesis of these natural products. Both routes involve cationic cascade type cyclizations terminating with a phenolic capture of a carbocationic intermediate. A route from vanillin to a phenylselenide cyclization precursor via an intermediate epoxide will be described first. This route gave access to an advanced tricyclic olefin with the carbon skeleton of the ABC ring system of the schweinfurthins, and eventually to an analog bearing the full skeleton of the natural product. Initial difficulty with elaboration of the A-ring oxygenation pattern, presumably due to steric constraints, led to examination of an alternate route.; Revisiting the epoxide intermediate led to the second cyclization strategy wherein a more biomimetic type cyclization was envisioned. Cation formation would be followed by steps leading to an intermediate with one A-ring hydroxyl group already in place. This strategy allowed access to an advanced analog with the entire schweinfurthin carbon skeleton, 3-deoxyschweinfurthin B. This compound was found to have significant activity by our collaborators at the National Cancer Institute.; The activity of 3-deoxyschweifurthin B pushed this work into a new direction involving exploration of the effects of modifications in the right-half of the schweinfurthins on activity. This work will be described in the context of the synthesis of several advanced analogs and a discussion of the structure activity relationships elucidated to date. A brief quantitative assessment of structure-activity relationships will be presented because it gives further insight into the, future directions of this work. |
