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

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Medicinal Chemistry

Background:

• Ambiguines are a class of natural products with complex pentacyclic structures.
• The biological activities of ambiguines necessitate efficient synthetic routes for further investigation.
• Previous synthetic efforts have not achieved the pentacyclic core of ambiguine P.

Purpose of the Study:

• To report the first total synthesis of a pentacyclic ambiguine, specifically ambiguine P.
• To develop a synthetic strategy that allows for rapid construction of the core pentacyclic framework.
• To prepare a versatile intermediate for potential synthesis of related ambiguine analogs.

Main Methods:

• Sequential alkylation of an indole core.
• Application of the Nicholas reaction for C2 alkylation to form a seven-membered ring.
• Amide-directed functionalization at C12 to establish a quaternary center.

Main Results:

• Successful synthesis of pentacyclic ambiguine P, the first of its kind.
• Efficient construction of the characteristic fused seven-membered ring via Nicholas reaction.
• Formation of a key quaternary center using amide-directed functionalization.
• Generation of a versatile late-stage intermediate.

Conclusions:

• The developed synthetic strategy provides a robust method for accessing pentacyclic ambiguines.
• The synthesis highlights the utility of Nicholas reaction and amide-directed functionalization in complex molecule assembly.
• The late-stage intermediate offers potential for synthesizing other pentacyclic ambiguine natural products.