Synthetic Studies Towards Darobactin A

We describe our efforts toward the total synthesis of darobactin A, an antibiotic that selectively targets Gram-negative bacteria. The first route comprised the preparation of two separate advanced fragments. The unusual ether-linked tryptophan moiety was constructed utilizing a nucleophilic aromatic substitution-Bartoli indole synthesis-Negishi coupling sequence, while C-H arylation was used to prepare the β-arylated lysine scaffold. Larock indole synthesis was confirmed as a valuable approach to achieve the first macrocyclization. An approach using macrolactamization for the construction of the second, western macrocycle proved to be unsuitable for the darobactin A scaffold. Thus, a second strategy focused on the synthesis of both macrocycles through two distinct intramolecular Larock indole syntheses that further brought valuable insights into the atroposelectivity of such reactions. Herein, we report our study toward the total synthesis of darobactin A, including the synthesis of advanced intermediates.