title: First and second generation total synthesis of the teicoplanin aglycon.
abstract: Full details of studies leading to the total synthesis of the teicoplanin aglycon are provided. Key elements of the first generation approach (26 steps from constituent amino acids, 1% overall) include the coupling of an EFG tripeptide precursor to the common vancomycin/teicoplanin ABCD ring system and sequential DE macrocyclization of the 16-membered ring with formation of the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed by 14-membered FG ring closure by macrolactamization (66%). Subsequent studies have provided a second generation total synthesis which is shorter, more convergent, and highly diastereoselective (22 steps, 2% overall). This was accomplished by altering the order of ring closures such that FG macrolactamization (95%) preceded coupling of the EFG tripeptide to the ABCD ring system and subsequent DE ring closure. Notably, DE macrocyclization via diaryl ether formation on substrate 57, the key intermediate in the latter approach incorporating the intact FG ring system, occurred with exceptional diastereoselection for formation of the natural atropisomer (>10:1, 76%) without problematic C(2)(3) epimerization provided the basicity of the reaction is minimized.
authors.affiliation: Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Boger
authors.forename: S H
authors.initials: SH
authors.lastname: Kim
authors.forename: Y
authors.initials: Y
authors.lastname: Mori
authors.forename: J H
authors.initials: JH
authors.lastname: Weng
authors.forename: O
authors.initials: O
authors.lastname: Rogel
authors.forename: S L
authors.initials: SL
authors.lastname: Castle
authors.forename: J J
authors.initials: JJ
authors.lastname: McAtee
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D004352:Drug Resistance, Microbial / Q000235:genetics / Q000502:physiology; D006020:Glycopeptides / Q000737:chemistry* / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects; D017334:Teicoplanin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D014640:Vancomycin / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D006020:Glycopeptides; D017334:Teicoplanin; D014640:Vancomycin; C063101:teicoplanin aglycone