Vancomycin CD and DE macrocyclization and atropisomerism studies

Academic Article
uri icon

related to degree

publication date

  • January 1999

abstract

  • Continued studies on the synthesis and atropisomerism of the vancomycin CD and DE ring systems based on aromatic nucleophilic substitution macrocyclization reactions for formation of the biaryl ethers are detailed in efforts that further define substituent effects, explore the impact of protecting groups, and establish the stereochemical integrity of peripheral substituents. These have led to the identification of a previously unrecognized site of epimerization within our original approach to the DE ring system and the introduction of significant improvements in the approach that will find utilization in syntheses of the vancomycin CDE ring system and of the natural product itself. The preparation of a complete set of DE ring system isomers bearing the unnatural stereochemistry at the labile C8, C11, and C14 sites was accomplished for comparison and established that C8 is prone to epimerization to the more stable, unnatural S versus R absolute stereochemistry if it bears an ester, but not a carboxamide, substituent. Additionally, an improved synthesis of the CD ring system, enlisting a C14 carboxamide versus ester substituent, is disclosed and establishes the stereochemical integrity of our prior approach which incorporated a C14 ester. A set of fully functionalized CD and DE ring systems were prepared and include the development of conditions for the final deprotections required for incorporation into efforts on the natural product. The examination of the antimicrobial activity of these key substructures of vancomycin is detailed.