Total Synthesis Highlights

The last challenge was the establishment of the (Z) alkene of the side chain. This was
accomplished using the Toru protocol. Coupling of the secondary bromide with the Cs salt 12
proceeded with inversion of absolute configuration, to give 13. The carboxylates of stronger acids
were not sufficiently nucleophilic to displace the bromide. Aldol condensation of 13 with the
aldehyde 14 gave a mixture of diastereomers, exposure of which to MsCl in pyridine delivered the
requisite (Z) alkene 4.
35. The Smith Synthesis of (+)-Lyconadin A
The pentacyclic alkaloid (+)-lyconadin A (3), isolated from the club moss Lycopodium
complanatum, showed modest in vitro cytotoxicity. A key step in the first reported (J. Am. Chem.
Soc. 2007, 129, 4148.) total synthesis of 3, by Amos B. Smith III of the University of
Pennsylvania, was the cyclization of 1 to 2.
The pentacyclic skeleton of 3 was constructed around a central organizing piperidine ring 9. This
was prepared from the known (and commercial) enantiomerically-pure lactone 4. The akylated
stereogenic center of 9 was assembled by diastereoselective hydroxy methylation of the acyl
oxazolidinone 5 with s-trioxane, followed by protection. Reduction of the imide to the alcohol led
to the mesylate 7, which on reduction of the azide spontaneously cyclized to give, after protection,
the piperidine 8. Selective desilylation of the primary alcohol then enabled the preparation of 9.