First and second generation total synthesis of the teicoplanin aglycon

Full details of studies leading to the total synthesis of the teicoplanin a glycon are provided. Key elements of the first generation approach (26 step s 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 o f the diaryl ether via a phenoxide nucleophilic aromatic substitution of an o-fluoronitroaromatic (80%, 3:1 atropisomer diastereoselection) followed b y 14-membered FG ring closure by macrolactamization (66%). Subsequent studi es 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 macrolact amization (95%) preceded coupling of the EFG tripeptide to the ABCD ring sy stem and subsequent DE ring closure. Notably, DE macrocyclization via diary l ether formation on substrate 57, the key intermediate in the latter appro ach incorporating the intact FG ring system, occurred with exceptional dias tereoselection for formation of the natural atropisomer (> 10:1, 76%) witho ut problematic C-2(3) epimerization provided the basicity of the reaction i s minimized.