Synthesis of the vancomycin CDE ring system

A first generation synthesis of 22 is described constituting the first disclosure of the preparation of an appropriately protected and fully functionalized vancomycin CDE ring system complete with the C and E ring monochloro substitution pattern. The approach, which is based on two aromatic nucleophilic substitution reactions for sequential CD and DE macrocyclization, provided the opportunity to define an indirect solution to the control of the CDE atropisomer stereochemistry through selective thermal equilibration of the DE versus unaltered CD ring system. Its success provides a rationale for a preferred order to the CD and DE ring system introductions.