Studies Toward the Total Synthesis of Maoecrystal V

Maoecrystal V is a cytotoxic diterpene natural product isolated form the Chinese medicinal herb Isodon eriocalyx. Its structure was published in the 2004 and it is unique amongst all previously isolated terpenes. Preliminary biological studies performed on maoecrystal V discovered nanomolar cytotoxic activity selectively against HeLa cells (cervical tumor cells). In spite of this interesting biological activity, it has been maoecrystal V's fascinating structure which has garnered much interest from the scientific community. Its skeleton consists of five interwoven carbocyclic rings and six stereogenic centers, two of which are vicinal quaternary centers. This mixture of stereochemical complexity and challenging three-dimensional structure has driven organic chemists to use maoecrystal V as a testing ground for new chemical tactics and synthetic strategies.;We developed a strategy that combines efficient carbon-carbon bond forming reactions to rapidly assemble the carbon framework of the natural product. By pairing a Nazarov cyclization with a Diels--Alder cycloaddition, both of the vicinal quaternary stereocenters are constructed in high yield and with excellent selectivity. Our first generation strategy then attempted a challenging remote functionalization reaction to install the central ether ring. Unfortunately, both advanced synthetic intermediates and simplified models systems were unable to achieve the desired transformation.;We then developed a second generation strategy that planned to install the central ether ring by means of an intramolecular conjugate addition reaction. After some promising results were obtained in a model system, we attempted to translate this approach to the actual synthesis. Because of functional group incompatibility observed in the Nazarov cyclization, we were forced to investigate new strategies to construct the bicyclo[2.2.2]octane ring system of the natural product in lieu of the Diels-Alder cycloaddition. To this end, we developed a synthetic route that used an intramolecular cyclopropanation reaction to build the target ring system. Future efforts are focused on combining the conjugate addition strategy for ether formation with the cyclopropanation strategy for ring system building.