Total Syntheses of Lyconadins A–C

The total synthesis of the Lycopodium alkaloid lyconadin A was accomplished and it was applied to the
total syntheses of the related congeners, lyconadins B and C. Lyconadin
A has attracted attention as a challenging target for total synthesis
due to the unprecedented pentacyclic skeleton. Our synthesis of lyconadin
A features a facile construction of the highly fused tetracyclic skeleton
through a combination of an aza-Prins reaction and an electrocyclic
ring opening, followed by formation of a C–N bond. Transformation
of the bromoalkene moiety of the tetracycle to a key enone intermediate
was extensively investigated, and three methods via sulfide, oxime,
or azide intermediates were established. A pyridone ring was constructed
from the key enone intermediate to complete the synthesis of lyconadin
A. A dihydropyridone ring could also be formed from the same enone
intermediate, leading to a synthesis of lyconadin B. Establishment
of the conditions for an electrocyclic ring opening without formation
of the C–N bond resulted in completion of the total synthesis
of lyconadin C.