Total Synthesis of Pentacyclic (−)-Ambiguine P Using Sequential Indole Functionalizations

The
first synthesis of a pentacyclic ambiguine (ambiguine P) is
reported. The synthesis takes advantage of sequential alkylations
of an indole core to rapidly construct the pentacyclic framework of
the natural product. Key to the success of the synthesis was the use
of a Nicholas reaction to alkylate at C2, crafting a fused seven-membered
ring that is characteristic of the pentacyclic ambiguines, as well
as the use of an amide-directed functionalization at C12 to set a
requisite quaternary center. A versatile late-stage intermediate was
prepared that may be applicable to the synthesis of the other pentacyclic
ambiguines.