Influence of Base and Structure in the Reversible Covalent Conjugate Addition of Thiol to Polycyclic Enone Scaffolds

The energetics of thiol addition and elimination reactions to bicyclic enones derived from an indole core structure were explored using 1H NMR and density functional theory (DFT) calculations. The agreement between experiment and theory is excellent, and the combined results reveal that even minor changes in the conformation of the enone, substituents on the scaffold, and the use of different bases have a signficant influence on product distribution. A potential application of these principles is in the rational design of new reversible covalent enzyme inhibitors.