Preparation of icetexane diterpenoids: synthesis of breast cancer cell growth inhibitors
Date
2016
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
University of Delaware
Abstract
Breast cancer is one of the most common cancers among women worldwide.
Late stage treatment for breast cancer involves a chemotherapeutic, doxorubicin,
which has earned the nickname “the red death” due to the detrimental side effects
associated with this drug. Therefore, it is urgent that we identify and study recently
discovered breast cancer drugs capable of treating cancer patients. Premnalatifolin A,
an icetexane diterpene dimer, was recently isolated and evaluated against multiple
cancer cell lines, in particular MCF-7 breast cancer cells (IC50 = 1.77 μM),
outperforming doxorubicin (IC50 = 3.68 μM). The monomeric unit was also found to
be selectively cytotoxic against MCF-7 cell line (IC50 = 3.53 μM). ☐ Given that both the dimer and monomer exhibited anti-cancer activity, our goal
was to develop synthetic pathways for the tricyclic backbone of the monomer. We
have developed two synthesis pathways to forming the 3-vinyl siloxybenzyl halide and
a one-step synthesis of both the unsubstituted and 4,4-dimethyl-substituted vinylated
silyl enol ether, and during the course of our work we developed optimized conditions
for the Suzuki-Miyaura coupling of an aryl chloride. We attempted utilizing the
enolate–ortho-quinone methide Michael addition, a reaction sequence notable in our
group, to join the two cyclic fragments. Due to complications resulting from an
unproductive hemiacetal formation, we revised the synthesis by diverting to a classic
alkylation reaction sequence. The classical enolate alkylation was highly
diastereoselective, giving the desired 1,2-trans alkylation product, which was followed
by a ring-closing metathesis reaction to construct the 7-membered ring and complete
the core structure of these important natural products. Furthermore, we explored the
hydrogenation of the cycloheptene ring, opening up the synthesis to generate a small
library of icetexane model compounds.