Total Synthesis of the Vancomycin Aglycon

Abstract

Full details of a diastereoselective total synthesis of the vancomycin aglycon are described. Two key aromatic nucleophilic substitution macrocyclizations with formation of the 16-membered diaryl ethers were enlisted for sequential CD and DE ring formations, an effective macrolactamization was developed for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures permitted selective thermal atropisomerism of the newly formed ring systems or their immediate precursors. This indirect control of the atropisomer stereochemistry allowed all synthetic material to be funneled into the one of eight atropdiastereomers characterizing the natural product.