Divergent Total Synthesis of the Lycopodium Alkaloids Huperzine A, Huperzine B, and Huperzine U

Huperzine
A, huperzine B, and huperzine U are congeners isolated
from the Chinese herb Huperzia serrata (=Lycopodium serratum) in minuscule
amounts. The most efficient total synthesis of huperzine A, the first
asymmetric total syntheses of huperzine B, and the first total synthesis
of huperzine U have been achieved efficiently in overall yields of
17%, 10%, and 9%, respectively, each spanning 10–13 steps from
(R)-pulegone. The featured steps include palladium-catalyzed
Buchwald–Hartwig coupling and Heck cyclization reactions and
an Ir-catalyzed olefin isomerization reaction. This work has established
the absolute configurations of huperzine B and huperzine U and revealed
that natural huperzine A, huperzine B, and huperzine U possess the
same set of absolute stereochemistries, thus providing support for
the potential role of huperzine B and huperzine U in the biosynthesis
of huperzine A.