The aim of this study was to investigate the transition from non-covalent reversible over covalent reversible to covalent irreversible inhibition of cysteine proteases by making delicate structural changes to the warhead scaffold. To this end, dipeptidic rhodesain inhibitors with different N-terminal electrophilic arenes as warheads relying on the S_NAr mechanism were synthesized and investigated. Strong structure–activity relationships of the inhibition potency, the degree of covalency, and the reversibility of binding on the arene substitution pattern were found. The studies were complemented and substantiated by molecular docking and quantum-mechanical calculations of model systems. Furthermore, the improvement in the membrane permeability of peptide esters in comparison to their corresponding carboxylic acids was exemplified.

A short synthesis of the ergot alkaloid lysergene and a formal total synthesis of lysergic acid diethylamide (LSD) under avoidance of palladium and including two nickel-catalyzed steps instead has been developed. A key intermediate of this approach has already been reported by Hendrickson et al. in 2004, yet the spectral data do not match, adding to doubts on the course of their route. While the final steps of the Hendrickson synthesis could not be reproduced, we were able to leverage the elusive intermediate