Asymmetric syntheses of (+)- and (–)-collybolide enable reevaluation of kappa-opioid receptor agonism
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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, indicating that collybolide has been mischaracterized as a KOR agonist and leaving open the basis for antipruritic effects in mice.
2021 ◽
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2017 ◽
Vol 60
(7)
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pp. 3070-3081
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2020 ◽
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