SYNTHESIS OF MODIFIED CARBOXYL BINDING POCKETS OF VANCOMYCIN AND TEICOPLANIN

Sixteen-membered macrocycle 3 and 16+14 bicyclic compound 4, incorpora ting a terminal primary hydroxyl group in the peptide sequence, have b een designed and synthesized. The syntheses feature the use of an effi cient cycloetherification based on an intramolecular SNAr reaction for the formation of biaryl ether bonds. Cyclization of linear tetrapepti de 30, prepared via a convergent [2+2] segment coupling between 26 and 29, gave macrocycle 31 (P configuration) as a single isolable atropis omer. Removal of the Boc protecting group afforded the modified carbox yl 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 configurati on of the racemization-prone arylglycine residue was not affected. Chi ral building blocks such as D-(1R)-[2-[(tert-butyldimethylsilyl)oxy] 1 -[3-(allyloxy)phenyl]ethyl]amine 16, and L-(S)-N-Boc-[3-(isopropyloxy) phenyl]glycine (32) were synthesized employing Evans' asymmetric azida tion method, while L-(S)-4-fluoro-3-nitrophenylalanine methyl ester 23 was prepared using Schollkopf's bislactim ether as chiral glycine tem plate. Compound 3 showed interesting conformational properties compare d to vancomycin and its binding with Ac-D-Ala was studied by NMR titra tion experiments. A dissociation constant (K-d = 5 x 10(-4)) was calcu lated by a curve fitting method. Compound 4 is currently the most adva nced synthetic intermediate toward the total synthesis of teicoplanin.