Waihoensene, a tetracyclic diterpene containing an angular triquinane with a six-membered ring was isolated from the New Zealand podocarp, Podocarpus totara var waihoensis in 1997. This was the first reported metabolite of laurenene, the only natural product with C-C fenestrane ring structure and has as challenging structure as laurenene with four contiguous quaternary carbon centers of highly congested tetracyclic structure. Although it has been attractive target to synthetic organic chemists, due to this distinctive skeleton, there was only one report of construction of the ring system of waihoensene presumably due to its highly congested polycyclic structure. Recently, the intramolecular cycloaddition reaction of trimethylenemethane (TMM) diyl forming angular or linear triquinanes from linear allenyl diazo compounds was successfully utilized in construction of unique tetracyclic structures. Through the extended TMM strategy, the tetracyclic core structure of waihoensene with three contiguous quaternary carbon centers was constructed efficiently. The first total synthesis of waihoensene was accomplished pass by few steps.
In 2011, our group announced a TMM diyl mediated intramolecular cycloaddition reaction from linear allenly diazo compounds and has been applied to the total synthesis of various triquinane natural products. The intramolecular cycloaddition reaction has many advantages such as excellent stereoselectivity and regioselectivity, but is not suitable for concise synthesis. It is difficult to prepare linear substrates containing allene, diazo and olefin groups as precursors of intramolecular TMM diyl cycloaddition reaction. The intermolecular TMM diyl cycloaddition reaction could be economically the best choice for synthesizing triquinanes, because the precursors don’t require diylophiles. We have found an excellent synthetic target by optimizing the intermolecular TMM diyl cycloaddition reaction and investigating the substitution effect on the diylophiles. Through the optimized intermolecular reaction, a concise total synthesis of the triquinane natural product hirsutene was achieved in 4 steps.