Asymmetric Syntheses of (+)- and (−)-Collybolide Enable Reevaluation of kappa -Opioid Receptor Agonism Article Swipe
YOU?
·
· 2022
· Open Access
·
· DOI: https://doi.org/10.1021/acscentsci.2c00442
· OA: W4285800360
The fungal metabolite collybolide has attracted attention as a non-nitrogenous, potent, and biased agonist of the <i>kappa</i>-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 of collybolide as a new non-nitrogenous, KOR-selective, potent agonist with the same clinical potential as salvinorin A seems to have been premature.
