Propellane Alkaloid Biosynthesis and Total Synthesis via Interrupted Reaction Pathways

Area of Science:

• Natural Product Biosynthesis
• Organic Synthesis
• Chemical Biology

Background:

• Interrupted reactions offer novel strategies for complex natural product synthesis.
• Microbial natural products often possess unique and complex chemical scaffolds.
• Pyrrolidinoindoline alkaloids represent a class of compounds with diverse biological activities.

Purpose of the Study:

• To elucidate the biosynthesis of the newly discovered subrubine alkaloid family.
• To achieve the total synthesis of pensubrubine, a representative subrubine.
• To explore the utility of interrupted reaction pathways in natural product assembly.

Main Methods:

• High-resolution genome mining to identify novel natural product pathways.
• Complete pathway reconstitution to confirm enzyme function.
• Concise total synthesis employing interrupted Fischer indolization.

Main Results:

• Discovery and characterization of the subrubine alkaloid family, featuring microbial diaza[3.3.3]-propellane pyrrolidinoindolines.
• Identification of SubF as a propellane synthase directing biosynthesis via intramolecular Mannich cyclization.
• Development of a 7-step total synthesis of pensubrubine, establishing its absolute configuration.

Conclusions:

• Interrupted pathways are valuable for constructing complex molecular architectures like subrubines.
• The findings expand the known chemical diversity of microbial alkaloids.
• This work provides a foundation for accessing and studying subrubine natural products.