Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

This article describes synthetic studies that culminated
in the
first total synthesis of the Lycopodium alkaloid
sieboldine A. During this study, a number of pinacol-terminated cationic
cyclizations were examined to form the cis-hydrindanone
core of sieboldine A. Of these, a mild Au­(I)-promoted 1,6-enyne cyclization
that was terminated by a semipinacol rearrangement proved to be most
efficient. Fashioning the unprecedented N-hydroxyazacyclononane
ring embedded within the bicyclo[5.2.1]­decane-N,O-acetal moiety of sieboldine A was a formidable challenge.
Ultimately, the enantioselective total synthesis of (+)-sieboldine
A was completed by forming this ring in good yield by cyclization
of a protected-hydroxylamine thioglycoside precursor.