psi-Pelletierine → (E)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole

Participants

Reaction Steps

The synthesis of arylethenyl-substituted 8-azabicyclo[3.2.1]octanes and arylethynyl-substituted 8-azabicyclo[3.2.1]octanes are accomplished in a manner similar to that described for arylethenyl-substituted 7-azabicyclo[2.2.1]heptanes and arylethynyl-substituted 7-azabicyclo[2.2.1]heptanes. Treatment of pseudopelletierine (N-methyl-9-azabicyclo[3.3.1]nonan-3-one) as described earlier for tropinone (Daly et al. Eur. J. Pharmacol. 321:189-194 (1997)) will generate ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate. Pseudopelletierine is made according to Howell et al., Org. Syn. Coll. Vol IV: 816-819 (1963). Reduction of ethyl 8-aza-6-(ethoxycarbonyl)bicyclo[3.2.1]octane-8-carboxylate with diisobutylaluminum hydride and subsequent reaction of the 6-formyl derivative with diethyl (5-isoxazolylmethyl)phosphonate and n-butylithium will provide mixture of ethyl (E)- and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole-8-carboxylate. Separation of the isomers followed by deprotection will provide (E)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole and (Z)-5-(2-(8-azabicyclo[3.2.1]oct-6-yl)ethenyl)isoxazole. The other methods described previously for the preparation of five-membered heterocycle analogues of ethenyl-substituted 7-azabicyclo[2.2.1]heptanes may be applied similarly.

Provenance & Evidence