Enantioselective Total Synthesis of (+)-Sieboldine A and Analogues Thereof.

An 11-step enantioselective total synthesis of (+)-sieboldine A (<b>1</b>) has been accomplished from (5<i>R</i>)-methylcyclohex-2-en-1-one (<b>16</b>), in which an intramolecular ketone/ester reductive coupling followed by one-pot acidic treatment to quickly construct the unique oxa-spiroacetal and a TsOH-catalyzed displacement to directly form the characteristic <i>N</i>-hydroxyazacyclononane ring successfully served as the key methodologies. Moreover, several full-skeleton analogues of <b>1</b> were also synthesized on the basis of the advanced intermediates, and their inhibitory effects on electric eel acetylcholinesterase were examined.