The Thia-Michael Reactivity of Zerumbone and Related Cross-Conjugated Dienones: Disentangling Stoichiometry, Regiochemistry, and Addition Mode with an NMR-Spectroscopy-Based Cysteamine Assay

The cross-conjugated and electrophilic dienone system of the humulane sesquiterpene zerumbone (1a) was modified by E/Z photochem. isomerization and/or by removal of homoconjugation with the isolated endocyclic double bond of the medium-sized ring. The site (C-6/C-9), mode (transient or irreversible), stoichiometry (single or twofold), and comparative rates of thiol addn. were evaluated using an NMR-spectroscopy-based cysteamine assay. Dramatic effects were seen, and this highlights the subtleties of the reaction and the limitations of our predictive power in this field. For biol. endpoints sensitive to thiol trapping, a substantial sepn. between Michael reactivity and biol. activity was found for 1a and its analogs. This supports the view that shape complementarity plays a crit. role in the covalent binding of Michael acceptors to their macromol. target(s).