A catalytic process enables efficient and programmable access to precisely altered indole alkaloid scaffolds

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Molecular shape is critical for biological activity, necessitating access to diverse molecular architectures.
• Modifying natural products is challenging due to scarcity and limited functional groups.

Purpose of the Study:

• To develop a programmable strategy for synthesizing altered scaffolds of scarce bridged polycyclic alkaloids.
• To create diverse analogues of a natural product with expanded, contracted, or distorted frameworks.

Main Methods:

• A scalable catalytic multi-component reaction to produce tertiary homoallylic alcohols.
• Divergent synthesis pathways initiated from a common intermediate.
• In vitro cytotoxicity assays against cancer cell lines.

Main Results:

• Successfully synthesized a range of precisely altered alkaloid scaffolds.
• Identified a modified alkaloid with potent cytotoxicity against four cancer cell lines.
• Uncovered novel selectivity trends through mechanistic and computational studies.

Conclusions:

• The developed strategy enables efficient access to structurally diverse alkaloids.
• Altered alkaloid frameworks hold potential as cytotoxic agents for cancer therapy.
• Mechanistic insights provide a foundation for future drug design.