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Synthesis 2002(16): 2359-2364
DOI: 10.1055/s-2002-35237
PAPER
© Georg Thieme Verlag Stuttgart · New York

Probes for Narcotic Receptor Mediated Phenomena; 29: Synthesis of rac-(4R,6aR,11bR)-3-Methyl-2,3,4,5,6,6a-hexahydro-1H-4,11b-methanobenzo­furo[3,2-d]azocin-10-ol, the para-a Oxide-Bridged Phenylmorphan Isomer, and a New Route to rac-(4R,6aR,11bR)-3-Methyl- 2,3,4,5,6,6a-hexahydro-1H-4,11b-methanobenzofuro[3,2-d]azocin-8-ol, the ortho-a Oxide-Bridged Phenylmorphan­ Isomer

Koichiro Yamadaa, Judith L. Flippen-Andersonb, Arthur E. Jacobsona, Kenner C. Rice*a
a Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney Diseases, National­ Institutes of Health, Bethesda, Maryland, 20892-0815, USA
Fax: +1(301)4020589; e-Mail: kr21f@nih.gov;
b Laboratory for the Structure of Matter, Naval Research Laboratory, Washington D.C., 20375, USA
Further Information

Publication History

Received 24 July 2002
Publication Date:
04 November 2002 (online)

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Abstract

A six-step synthesis of the para-a oxide-bridged phenylmorphan isomer rac-(4R,6aR,11bR)-3-methyl-2,3,4,5,6,6a-hexahydro-1H-4,11b-methanobenzofuro[3,2-d]azocin-10-ol (4), was achieved using Okahara’s reagent, 3-chloro-2-methoxymethoxy­propene, to prepare the key intermediate 8. Bromination was directed at the desired carbon atom via the correctly positioned ketone moiety in 8. O-Demethylation followed by subsequent displacement of the bromine by the phenolic ion in situ gave ketone 9 that, after reduction to the alcohol and conversion to the bis-mesylate, could be reduced to obtain the desired product. The structure of 4 was unequivocally determined by an X-ray spectroscopic study. A similar sequence of reactions provided a novel, much shorter synthetic route to the known ortho-a oxide-bridged phenylmorphan isomer.

Key words

phenylmorphan - narcotic antagonist - drugs - ring closure - heterocycles

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Current Address: Tanabe Seiyaku Co., Ltd., Medicinal Chemistry Department, Discovery Research Laboratory, 2-50, Kawagishi, 2-Chome, Toda, Saitama, 335-8505, Japan.