Synthesis of Modified Carboxyl Binding Pockets of Vancomycin and Teicoplanin

• Published in: Journal of organic chemistry Vol. 61; no. 26; pp. 9309 - 9322
• Main Authors: Bois-Choussy, Michèle, Neuville, Luc, Beugelmans, René, Zhu, Jieping
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.12.1996; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; O-G RING; ASYMMETRIC-SYNTHESIS; ALANYL-D-ALANINE; REDUCTIVE DEPROTECTION; BIPHENYL ETHER; FLUORIDE-ION; BIOMIMETIC APPROACH; ARENE-RUTHENIUM CHEMISTRY; PEPTIDE-SYNTHESIS; CYCLIC-PEPTIDES
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo961412m

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 l-(S)-N-Boc-[3-(isopropyloxy)phenyl]glycine (32) were synthesized employing Evans' asymmetric azidation method, while l-(S)-4-fluoro-3-nitrophenylalanine methyl ester 23 was prepared using Schöllkopf's bislactim ether as chiral glycine template. Compound 3 showed interesting conformational properties compared to vancomycin and its binding with Ac-d-Ala was studied by NMR titration experiments. A dissociation constant (K d = 5 × 10-4) was calculated by a curve fitting method. Compound 4 is currently the most advanced synthetic intermediate toward the total synthesis of teicoplanin.