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Vancomycin CD and DE Macrocyclization and Atropisomerism Studies
Dale L. Boger1, Steven L. Castle, Susumu Miyazaki
1Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037.
The Journal of Organic Chemistry
|October 25, 2001
Summary
Researchers studied vancomycin synthesis, identifying a new epimerization site in the DE ring system. Improvements were made, showing ester substituents at C8 lead to epimerization, unlike carboxamides.
Area of Science:
- Organic Synthesis
- Medicinal Chemistry
- Stereochemistry
Background:
- Vancomycin is a crucial antibiotic requiring complex synthesis.
- Understanding the stereochemistry of its ring systems is vital for total synthesis.
- Previous synthetic routes faced challenges with stereochemical integrity.
Purpose of the Study:
- To investigate substituent and protecting group effects on vancomycin CD and DE ring system synthesis.
- To identify and address epimerization issues in the DE ring system.
- To develop improved synthetic strategies for vancomycin substructures and the natural product.
Main Methods:
- Aromatic nucleophilic substitution macrocyclization for biaryl ether formation.
- Synthesis and characterization of vancomycin DE ring system isomers.
- Comparative analysis of ester versus carboxamide substituents at C8, C11, and C14.
- Development of improved CD ring system synthesis.
Main Results:
- A previously unrecognized epimerization site in the DE ring system was identified.
- C8 epimerization occurs with ester substituents but not carboxamides.
- An improved CD ring system synthesis was developed, confirming stereochemical integrity.
- Fully functionalized CD and DE ring systems were prepared, including deprotection strategies.
Conclusions:
- The study refined vancomycin synthesis by addressing epimerization.
- Carboxamide substituents enhance stereochemical stability at C8.
- Developed methods are applicable to the synthesis of the vancomycin CDE ring system and the natural product.
- Antimicrobial activity of key substructures was evaluated.