Working Paper
Authors
- Sophia Shevick Scripps Research Institute ,
- Stephan Freeman Scripps Research Institute ,
- Guanghu Tong Massachusetts Institute of Technology ,
- Robin Russo Scripps Research Institute ,
- Laura Bohn Scripps Research Institute ,
- Ryan Shenvi
Scripps Research Institute
Abstract
The fungal metabolite collybolide attracted attention as a non-nitrogenous, potent and biased agonist of the kappa-opioid receptor (KOR). Here we report a 10-step asymmetric synthesis of this complex sesquiterpene that enables facile access to either enantiomer. The synthesis relies on a diastereoselective α-benzoyloxylation to install the buried C6 benzoate and avoid irreversible translactonization of the congested, functionally dense core. Neither enantiomer, however, exhibited KOR agonism, raising the specter of a yet-unidentified contaminant responsible for the reported activity.
Content

Supplementary material

Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism
Supporting Information