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.