Probes for narcotic receptor mediated phenomena. 9. Synthesis of (.+-.)-(3.alpha.,6a.alpha.,11a.beta.)-1,3,4,5,6,11a-hexahydro-2-methyl-2H-3,6a-methanobenzofuro[2,3-c]azocin-10-ol, and oxide-bridged 5-(m-hydroxyphenyl)morphan

• Published in: Journal of medicinal chemistry Vol. 29; no. 5; pp. 748 - 751
• Main Authors: Burke, Terrence R, Jacobson, Arthur E, Rice, Kenner C, Weissman, Ben Avi, Huang, Hsueh Cheng, Silverton, J. V
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.05.1986
• Subjects: Animals; Azocines - chemical synthesis; Benzofurans - chemical synthesis; Models, Molecular; Rats; Receptors, Opioid - metabolism; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00155a026

The synthesis of racemic (3 alpha,6a alpha,11a beta)-1,3,4,5,6,11a- hexahydro-2-methyl-2H-3,6a-methanobenzofuro[2,3-c]azocin -10-ol (2d) is described. The route used acid-catalyzed ring closure of enamine 5 to yield the unsaturated phenylmorphan 6. Conversion of 6 to oxide-bridged 2d was accomplished in a multistep fashion that utilized the introduction of a bromine atom, followed by O-demethylation of the phenolic methyl ethers and base-catalyzed intramolecular phenoxide displacement of the bromine. Compound (+/-)-2d represents an oxide-bridged derivative of the potent 5-(m-hydroxyphenyl)morphan class of opioid analgesics 1. Unlike the 5-(m-hydroxyphenyl)morphans that have a freely rotating phenyl group, 2d has the phenyl ring conformationally restricted at an angle of 49 degrees relative to atoms 1, 3, 11a, and 12 of 2d. The low binding of (+/-)-2d to rat brain homogenate receptor preparations [IC50 = 1000 nM] may indicate that the phenyl angle of 49 degrees is not suitable for binding to opioid receptors.