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 of collybolide as a new non-nitrogenous, KOR-selective, potent agonist with the same clinical potential as salvinorin A seems to have been premature.

中文翻译：

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(+)- 和 (−)-Collybolide 的不对称合成能够重新评估 kappa-阿片受体激动作用

真菌代谢物 collybolide 作为一种非含氮、强效且偏向的kappa -阿片受体 (KOR) 激动剂而引起了人们的关注。在这里，我们报告了这种复杂倍半萜的 10 步不对称合成，可以轻松获得任一对映体。该合成依赖于非对映选择性 α-苯甲酰氧基化来安装埋藏的 C6 苯甲酸酯，并避免拥挤的功能密集核心发生不可逆的转内酯化。然而，两种对映体均未表现出 KOR 激动剂，这表明 collybolide 已被错误地描述为 KOR 激动剂。鉴于制药、医学和社会对 Collybolide 作为下一代止痒和镇痛药的兴趣，对 KOR 活性的反驳对正在进行的研究具有重要影响。将 collybolide 分类为一种新的非氮、KOR 选择性、强效激动剂，与 salvinorin A 具有相同的临床潜力似乎还为时过早。