ORGN 645 |
| The powerful analgesic epibatidine (1) is found on the skin of the Ecuadorian poison frog Epipedobates tricolor. It shows exceptionally high activity at nicotinic acetylcholine receptors and has stimulated global interest in the synthesis of analog molecules with higher receptor subtype selectivity and improved pharmacological properties. We report the synthesis of the novel epibatidine isomers isoepiboxidine (4) and isoepibatidine (7), the first epibatidine analogs based on 7-substituted 2-azabicyclo[2.2.1]heptane. Development of literature procedures allows the key intermediate 2 to be accessed. Nucleophilic substitution of the 7-Br substituent in 2 been achieved but occurs with retention of configuration, consistent with neighbouring group participation by the 2-nitrogen. Base-induced epimerisation of anti-3 provides syn-3. Conversion of the ester group into the methylisoxazole heterocycle gives syn-isoepiboxidine (4). Isoepibatidine (7) was accessed via a Suzuki-type coupling reaction, the conditions used gave anti-6 and syn-6 (ratio: 25:75). Deprotection of syn-6 afforded syn-isoepibatidine (7).
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Asymmetric Reactions, Heterocycles, Aromatics, Combinatorial, and Physical Organic Chemistry
8:00 PM-10:00 PM, Wednesday, 31 August 2005 Washington DC Convention Center -- Hall A, Poster
Division of Organic Chemistry |
