Synthesis of a new opioid ligand having the oxabicyclo[3.2.1]octane skeleton using a new rearrangement reaction

• Published in: Bioorganic & medicinal chemistry letters 2009-05, Vol.19 (9), p.2416-2419
• Main Authors: Watanabe, Akio, Fujii, Hideaki, Nakajima, Mayumi, Hasebe, Ko, Mochizuki, Hidenori, Nagase, Hiroshi
• Format: Article
• Language: English
• Subjects: Acetals - chemistry; Analgesics, Opioid - chemical synthesis; Biological and medical sciences; Chemistry, Organic - methods; Chemistry, Pharmaceutical - methods; Drug Design; Kinetics; Ligands; Medical sciences; Models, Chemical; Molecular Conformation; Morphinan; Morphinans - chemistry; Morphine - chemistry; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Opioid; Oxabicyclo[3.2.1]octane skeleton; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems; Pharmacology. Drug treatments; Rearrangement reaction; Receptors, Opioid, delta - chemistry; Receptors, Opioid, kappa - agonists; Receptors, Opioid, kappa - chemistry; Receptors, Opioid, mu - chemistry; Spiro Compounds - chemistry
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.03.068

Novel morphinan derivative having oxabicyclo[3.2.1]octane skeleton was prepared from dimethyl acetal derivative. The novel compound showed strong affinity for μ and κ opioid receptor types. An attempt to prepare a trimer having the 1,3,5-trioxazatriquinane skeleton led to discovery of a novel rearrangement reaction that afforded a compound with an oxabicyclo[3.2.1]octane skeleton whose reaction mechanism was proposed. On the basis of this mechanism, we synthesized the rearranged product from a dimethyl acetal intermediate in excellent yield. The compound with an oxabicyclo[3.2.1]octane skeleton showed high affinity for μ and κ but not δ opioid receptor types. The compound expected to be a key intermediate for novel κ selective ligands.