1. Development of a novel ruthenium catalyzed radical reaction and application 2. Total synthesis of ceratopicanol

Abstract

A new radical cyclization catalyzed by photolytic ruthenium dimer and tributyltin hydride was successfully accomplished on various radical precursors. The reaction using ruthenium catalyst with $nBu_3SnH$ in the presence of light generates the tin radical and ruthenium hydride species that donates hydrogen to the radical intermediate much faster over $nBu_3SnH$ to form the novel catalytic cycle. This system showed outstanding selectivity and yield in vinyl radical cyclization over the conventional reaction conditions. Furthermore, with xanthate derivatives, the interesting outcome was observed depending on the substituents of forming radical. We believe that this novel catalytic radical system affords very useful tool to overcome the limitation of conventional radical system and to be applied in organic synthesis in various ways.

The tricyclic diterpene fungal metabolite (+)-Pleuromutilin was isolated in 1951 by Kavanagh and co-workers from several species of basidiomycetes and has been found noteworthy for antibacterial activity through a novel mode of action involving binding to the prokaryotic ribosome. With the promising effect against the resistant bacteria to antibiotics due to its unique mechanism of action, its intricate skeleton including rare 8-membered ring of tricyclo-[5.4.3.01,8]-tetradecane has intrigued the synthetic chemistry community. To construct the interesting tricyclic framework of pleuromutilin, there have been various approaches. We envisioned that the core structure of pleuromutilin would be obtained in one-pot by tandem radical cyclization from cyclooctene with requisite dibutyne tethers. Along the way, we observed unusual ring closure by radical rearrangement derived from steric and conformational factors. Eventually, the framework of pleuromutilin consisting of tricyclo-[5.4.3.$0^{1,8}$]-tetradecane was elaborated through ruthenium catalyzed radical reaction.

Ceratopicanol, which was first isolated by Hanssen and Abraham from the fungus Ceratosystis Piceae Ha 4/82, is ceratopicane sesquiterpene natural product. Its highly congested structural feature with the cis/anti/cis-linearly fused triquinane structure that has five contiguous chiral carbon atoms, with two consecutive quaternary carbon centers, has challenged the synthetic chemistry community. Furthermore, recent reports have indicated that terpenes including ceratopicanol could be useful as prophylaxis or the treatment of pain. We tried to solve the problematic step in Clive’s synthesis with our radical system using ruthenium catalyst, and prepared two isomeric precursors. However, it was showed that tow isomeric precursors was transformed toward different resultant, and DFT calculation was also carried out to explain the result. Finally, the desired triquinane frameworks was afforded by palladium (0) catalyst with silyl hydride instead of radical reaction, and (±)-Ceratopicanol was synthesized via two different palladium catalyzed reactions over 16 steps.