Total synthesis of the vancomycin aglycon

Full details of a diastereoselective total synthesis of the vancomycin agly con are described. Two key aromatic nucleophilic substitution macrocyclizat ions with formation of the 16-membered diaryl ethers were enlisted for sequ ential CD and DE ring formations, an effective macrolactamization was devel oped for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures permitted selective thermal atropisom erism of the newly formed ring systems or their immediate precursors. This indirect control of the atropisomer stereochemistry allowed all synthetic m aterial to be funneled into the one of eight atropdiastereomers characteriz ing the natural product.