Synthetic Studies on Bielschowskysin
Hudlicky, Jason Reed
Natural products have a long history of serving as therapeutic leads (e.g. taxol and compactin) and biological tools (e.g. rapamycin and oligomycin). Bielschowskysin is a rare and structurally complex marine diterpene, isolated in 2004 from the Gorgonian coral, Pseudopterogorgia kallos. Bielschowskysin displays potent and selective cytotoxic activity against EKVC non-small cell lung cancer (GI50 < 0.01 µM) and CAKI-1 renal cancer (GI50 = 0.51 µM) as well as modest anti-malarial activity (IC50 = 10 µg/mL). Although at least nine research groups around the world have published synthetic approaches to bielschowskysin, the natural product has yet to be prepared by total synthesis. Herein is described the efforts toward the total synthesis of bielschowskysin. Ten synthetic generations are explored, with varying success, in order to reach the key cycloaddition step. The final, tenth, generation consists of a 16-step synthesis of an advanced tetracyclic intermediate, utilizing a photochemical [2+2] cycloaddition between a γ-alkylidene butenolide and a butenolide to furnish the fully substituted cyclobutane core of the natural product. This reaction was accomplished in continuous flow, which enabled the synthesis of multigram quantities of the advanced tetracycle. Additional efforts to convert the tetracyclic intermediate into bielschowskysin are also described. Although the total synthesis is not reported, in its entirety, a synthetic route consisting of a total of 24 steps to the natural product is proposed. The synthesis, as developed, is a robust and reproducible route by which large quantities of key, advanced intermediates may be prepared in a relatively short period of time.