Asymmetric Total Synthesis and Biological Evaluation of (+)-Cycloclavine

Abstract

The first total synthesis of natural (+)-cycloclavine uses a catalytic asymmetric cyclopropanation of allene, a regiospecific Pd-catalyzed enone formation, and two intramolecular Diels-Alder reactions for indole/indoline annulations. The binding properties of natural (+)- and unnatural (-)-cycloclavine on 16 CNS receptors revealed significant stereospecificity and unique binding profiles in comparison to LSD, psilocin, and DMT. Differential 5-HT affinities, as well as novel sigma1 receptor properties bode well for potential therapeutic developments of clavine alkaloid scaffolds.