Christopher Bemis
UIUC
The sesquiterpene-tropolones are fungal metabolites that have been recognized for their compelling biological activities against multiple cancer cell lines and pathogens. Natural products in this class are comprised of a hydroxylated α–humulene-derived core fused to one or two tropolone units by dihydropyran rings. While precise mechanisms of action remain unknown, structural comparisons suggest that the bis tropolone structure is required for enhanced biological activities. A general synthesis of sesquiterpene-tropolones has not yet been achieved despite the necessity for a thorough evaluation of their promising medicinal potential through derivatization. We have completed the total synthesis of mono tropolone epolone B featuring a biomimetic hetero Diels–Alder reaction between the oxygenated α–humulene core and tropolone o-quinone methide fragments. The core is synthesized in racemic form via Nozaki-Hiyama-Kishi macrocyclization and in enantiopure form via hydrogen atom transfer isomerization of a (–)-caryophyllene oxide derivative. The tropolone o-quinone methide precursor is prepared through a Lewis acid mediated de Mayo-type fragmentation. Conditions to affect a challenging second hetero-Diels–Alder reaction and complete the synthesis of bis tropolone pycnidione and phenol-tropolone epolone A are currently under investigation. Additionally, access to the tropolone has enabled the synthesis of deoxygenated analogs of pycnidione, epolone A, and epolone B, which will be subject to biological studies intent on revealing the dependence of activity on oxygenation of the core of the natural products.