Synthetic Framework Evolution: A Scaffold-Centric Perspective on Iterative Chemical Space Expansion

Area of Science:

• Synthetic chemistry and chemical biology
• Natural product synthesis
• Cheminformatics

Background:

• Efficient exploration of chemical space is crucial for drug discovery.
• Current synthetic strategies often limit cumulative expansion of molecular diversity.
• Developing scalable and unbiased methods for generating molecular diversity is a key objective.

Purpose of the Study:

• To formalize Synthetic Framework Evolution (SFE) as a scaffold-centric framework for synthetic planning.
• To enable sustained, scalable, and unbiased expansion of biologically relevant molecular diversity.
• To bridge synthetic chemistry and biosynthetic organization for novel molecular discovery.

Main Methods:

• Organizing synthetic planning around scaffold persistence, connectivity, and growth.
• Utilizing information-rich intermediates as reusable nodes in an evolving synthetic network.
• Implementing SFE in sesquiterpenoid synthesis, incorporating scaffold rearrangements and oxidative transformations.
• Employing cheminformatic analysis to assess chemical space coverage and properties of SFE-derived compounds.

Main Results:

• SFE enables iterative divergence and cumulative expansion of interconnected molecular architectures from persistent scaffolds.
• Sesquiterpenoid synthesis demonstrated access to multiple carbocyclic frameworks from unified pathways.
• Oxidative transformations amplify chemical space generation through rearrangements and cascade reactions.
• SFE-derived compounds occupy broad, biologically relevant chemical space with high natural product-likeness and molecular complexity.

Conclusions:

• SFE provides a dynamic and scalable approach to chemical space exploration by focusing on framework evolution.
• The framework integrates scaffold persistence and oxidative amplification for efficient construction of complex chemical space.
• SFE facilitates the discovery of new molecular architectures and functions, moving beyond target enumeration.