| (-)-Gelsemicine 1 is a minor alkaloid isolated from Gelsemium sempervirens. Despite efforts by several groups, the elusive (-)-gelsemicine (1) has yet to succumb to a total synthesis. The Baldwin strategy focuses on the construction of tricyclic ketone core 3 and subsequent N-methoxyspirooxindole incorporation via 3-aza-4-oxa-[3,3] sigmatropic process. The pivotal step in the construction of the tricyclic ketone 3 is an intramolecular N-acyliminium ion cyclization of 4a, 4b, 4c or 4d to yield the tricyclic ketone core 3. These cyclization substrates 4a, 4b, 4c or 4d are constructed from primary alcohol 5, respectively. Primary alcohol 5 is available from cis-1,2,3,6-tetrahydrophthalic anhydride 6. Cyclization precursors 4a, 4b, 4c or 4d have been synthesized but only vinyl ether 4d can be cyclized to give tricyclic ketone core 3.*; After the optically active tricyclic ketone core 3 of (-)-gelsemicine has been synthesized, in order to incorporate the oxindole substructure into the tricyclic ketone core 3, a new method for preparing spirocyclic oxindoles was developed. Featuring a [3,3]-sigmatropic enolate rearrangement, the three-step process converts carboxylic acid starting materials 8 to oxindole products 12 in overall yields of 52-76%. The enolate rearrangement step occurs at -78°C and provides easy access to oxindole products 12 that have previously been difficult to prepare. Thus, the progress made to date lays a firm foundation for the first total synthesis of (-)-gelsemicine 1.*; *Please refer to dissertation for diagrams. |
