Studies Toward the Total Synthesis of Macrocalyxoformin E.

摘要

Macrocalyxoformin E is a complex polycyclic diterpene isolated from the the Chinese medicinal herb Isodon macrocalyx. Its structure was published in 1989 and revealed a complex, highly congested polycyclic framework, but has yet to have any comprehensive biological testing performed on its cytotoxicity. Its skeleton consists of five interwoven carbocyclic rings and eight stereogenic centers, two of which are quaternary centers. This mixture of stereochemical complexity and challenging topology could harness the potential of being a highly selective inhibitor for any range of cell lines, which should not be ignored.;We initially developed an asymmetric route to an advanced tricyclic intermediate from the synthesis of two enantiopure coupling fragments. By pairing a Nozaki-Hiyama-Kishi coupling with a Nazarov cyclization, access to the tricyclic intermediate as a single diastereomer was accomplished. We originally wanted to construct the crucial [3.2.1] core of the natural product by means of a metal-mediated cyclization from a 'east-to-west' fashion. Unfortunately, we were unable to achieve the desired C-C bond via gold(I)-catalyzed cyclization or palladium-mediated cyclization.;A second generation strategy was developed that constructed the [3.2.1] bicyclic ring system from an intramolecular Heck reaction from a 'west-to-east' direction. Key to the success of the [3.2.1] core formation relied on the reversible nature of olefin metathesis to afford a thermodynamically favored precursor to the Heck cyclization. Our next challenge was the construction of the highly oxygenated central core of the natural product. Unusual, and undesired side reactivity has prevented the completion of the natural product and ongoing efforts are focused on completing the synthesis. Thesis Advisor: Dr. Regan J. Thomson.