Synthesis of Modified Carboxyl Binding Pockets of Vancomycin and Teicoplanin

Sixteen-membered macrocycle 3 and 16+14 bicyclic compound 4, incorporating a terminal primary hydroxyl group in the peptide sequence, have been designed and synthesized. The syntheses feature the use of an efficient cycloetherification based on an intramolecular SNAr reaction for the formation of biaryl ether bonds. Cyclization of linear tetrapeptide 30, prepared via a convergent [2+2] segment coupling between 26 and 29, gave macrocycle 31 (P configuration) as a single isolable atropisomer. Removal of the Boc protecting group afforded the modified carboxyl binding pocket of vancomycin 3. A sequential 2-fold intramolecular SNAr reaction has been used to construct the model bicyclic system (i.e. 4) of the D-O-E-F-O-G ring of teicoplanin. Cyclization conditions (CsF, DMF, room temperature) are sufficiently mild that the configuration of the racemization-prone arylglycine residue was not affected. Chiral building blocks such as d-(1R)-[2-[(tert-butyldimethylsilyl)oxy]-1-[3-(allyloxy)phenyl]ethyl]amine 16, and...