Asymmetric Syntheses of (+)- and (-)-Collybolide Enable Reevaluation of kappa-Opioid Receptor Agonism.

ABSTRACT: The fungal metabolite collybolide has 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, indicating that collybolide has been mischaracterized as a KOR agonist. Given the pharmaceutical, medical, and societal interest in collybolide as a next-generation antipruritic and analgesic, this refutation of KOR activity has important ramifications for ongoing studies. Classification

SUBMITTER: Shevick SL 

PROVIDER: S-EPMC9335922 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature