2004 Alkaloids

AlkaloidsU 0600 Synthesis and Nicotinic Acetylcholine Receptor Binding Affinities of 2- and

3-Isoxazolyl-8-azabicyclo[3.2.1]octanes. — The 7-azabicyclo[2.2.1]heptane ring sys-tem of epibatidine, a highly potent nicotinic acetylcholine receptor agonist at neuronal receptor subtypes, is replaced by a 8-azabicyclo[3.2.1]octane ring system and the chlo-ropyridyl ring is substituted with an isoxazole ring to afford 2- and 3-substituted epi-batidine homologues. The 2-substituted homologue (V) is prepared from anhydroecgo-nine methyl ester (I) by stereoselective reduction of (I), subsequent formation of the isoxazole ring and final demethylation of (IV), while the isoxazole ring formation of (VIII) is achieved following a more simple procedure. This procedure avoids the iso-lation of the β-ketone oxime intermediate since concomitant cyclodehydration can be carried out in situ. 2β-Homologue (V), the most potent compound, displays a binding affinity twice that of nicotine. 3β-Homologue (X) shows moderate affinity. — (CHENG, J.; IZENWASSER, S.; ZHANG, C.; ZHANG, S.; WADE, D.; TRUDELL*, M. L.; Bioorg. Med. Chem. Lett. 14 (2004) 7, 1775-1778; Dep. Chem., Univ. New Orleans, New Orleans, LA 70148, USA; Eng.) — H. Hoennerscheid

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2004 Alkaloids