Rules of Macrocycle Topology: A [13]-Macrodilactone Case Study
Anniefer N Magpusao1, Kelli Rutledge1, Trevor A Hamlin1,2
1Department of Chemistry, University of Connecticut, 55 N. Eagleville Road, U3060, Storrs, CT, 06269-3060, USA.
Chemistry (Weinheim an Der Bergstrasse, Germany)
|March 23, 2016
Summary
Molecular shape governs interactions, but macrocycle conformation rules are basic. This study develops general rules for macrocycle shape using [13]-macrodilactones, aiding in designing molecules with specific properties.
Area of Science:
- Organic Chemistry
- Structural Chemistry
- Computational Chemistry
Background:
- Molecular shape is critical for molecular interactions and biological activity.
- Macrocyclic compounds, particularly large-ring systems, exhibit unique conformational properties influencing their function.
- Existing rules linking macrocycle structure to conformation are limited, hindering rational design.
Purpose of the Study:
- To establish general rules for predicting macrocycle conformation based on structural parameters.
- To investigate the conformational behavior of [13]-macrodilactones as a model system.
- To apply these rules to understand the structure of natural products like migrastatin.
Main Methods:
- X-ray crystallography and NMR spectroscopy were used for structural investigations.
- Systematic modification of [13]-macrodilactone structures to probe conformational changes.
- Application of derived conformational rules to analyze known natural product structures.
Main Results:
- [13]-macrodilactones adopt a characteristic "ribbon" shape in the absence of stereogenic centers, displaying planar chirality.
- The presence and configuration of stereogenic centers dictate or influence the macrocycle's overall shape.
- Established rules successfully predicted and explained the conformation of the natural product migrastatin.
Conclusions:
- Developed generalizable rules for predicting macrocycle conformation based on structural features and stereochemistry.
- These rules provide a foundation for understanding macrocycle-biomolecule interactions.
- Enables the rational design and synthesis of macrocycles with tailored properties and biological activities.
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