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Shape-Conserving Atom Replacements
Mikus Puriņš1, Cecile Elgindy1, Mark D Levin1
1Department of Chemistry, University of Chicago, Chicago, Illinois 60637, United States.
Skeletal editing reactions enable atom replacement in molecules, accelerating molecular optimization for drug discovery. This review categorizes these reactions and discusses strategies for shape-conserving transformations.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Synthetic Chemistry
Background:
- Recent advances allow precise atom replacement within molecular structures.
- Skeletal editing reactions are crucial for molecular optimization.
- These reactions mirror structure-activity-relationship (SAR) study tactics.
Purpose of the Study:
- To introduce a framework for categorizing atom replacement reactions in aromatic systems.
- To delineate strategies enabling these transformations.
- To discuss heuristics for shape-conservation in skeletal editing.
Main Methods:
- Categorization of atom replacement reactions.
- Analysis of strategies for skeletal transformations.
- Discussion of shape-conservation principles (skeletal rotation, vestigial substituents, retrosynthetic simplicity).
Main Results:
- A comprehensive framework for classifying atom replacement reactions is presented.
- Strategies for executing shape-conserving skeletal edits are delineated.
- Examples of C-to-N replacement (e.g., benzene to pyridine) and other aromatic/aliphatic replacements are analyzed.
Conclusions:
- Skeletal editing reactions offer powerful tools for accelerating discovery chemistry.
- Understanding shape-conservation heuristics is key for effective molecular design.
- This review provides a guide to atom replacement strategies in organic synthesis.
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