A Sequenced [4+3] Cycloaddition Synthesis of the Endoperoxide (+)-Jungermatrobrunin A

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This research project describes the first total synthesis of the natural products jungermatrobrunin A, diacetoxyjungermannenone C and acetoxyhydroxyjungermannenone C. Due to their low abundance and highly complex polycyclic carbon skeleton, the biological profile of these tetracyclic diterpenoids has yet to be explored. Related jungermannenones have shown promising cytotoxic activity against human leukemia cells. The endoperoxide jungermatrobrunin A is envisioned to serve as a hypoxia-activated prodrug for the treatment of solid tumors, which generally evade traditional chemotherapeutic agents.These highly oxidized jungermannenones have remained a formidable synthetic challenge. No total synthesis has been reported since their isolation in 2008. The complex framework is proposed to be rapidly established by a sequenced [4+3] cycloaddition. This process combines two powerful bond forming reactions generating a high level of structural complexity from relatively simple starting materials. The synthetic endeavor starts from commercially inexpensive carvone, which is available in both enantiomeric forms. Thus, a concise total synthesis of both natural product antipodes may be achieved.Given the efficiency of our proposed synthetic approach, the work will enable comprehensive structure-activity relationship studies by providing sufficient amounts of the natural products, eventually leading to the identification of future drug candidates.