VANCOMYCIN AND RISTOCETIN MODELS - SYNTHESIS VIA THE ULLMANN MACROCYCLIZATION REACTION

The preparations of 2 and 3, the parent skeletons of the CD and DE diphenyl ether 16-membered ring systems of vancomycin and ristocetin, based on the implementation of an intramolecular Ullmann macrocyclization reaction are detailed. Additional studies which define the scope of substrates suitable for use in the Ullmann macrocyclization reaction are described including a limited study of those bearing centers capable of racemization. Within the limited series of agents examined, Ullmann macrocyclization closure of the DE ring system was found to occur at a faster rate and in higher overall yields than those providing the CD ring system. N-Methylation of the amide linking chain decelerates or inhibits Ullmann macrocyclization and a-substitution of the central amino acid of the linking chain significantly increases the cyclization conversions. Racemization of the central amino acid of the linking amide chain was found to be minimal (5%) under reaction conditions where the secondary amides are deliberately deprotonated prior to exposure of the substrate to the thermal, basic reaction conditions.