# Synthetic Studies Towards Darobactin A

## TL;DR

This paper describes progress in synthesizing darobactin A, an antibiotic targeting Gram-negative bacteria, and introduces new methods for making complex indole-containing molecules.

## Contribution

The paper introduces a novel synthetic strategy for darobactin A and provides insights into strained indole macrocycle synthesis.

## Key findings

- A nucleophilic aromatic substitution–Bartoli indole synthesis–Negishi coupling sequence was used to construct the tryptophan moiety.
- Larock indole synthesis was found valuable for macrocyclization but macrolactamization was unsuitable for the darobactin A scaffold.
- Two intramolecular Larock indole syntheses were used to synthesize macrocycles and study atroposelectivity.

## Abstract

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.

The urgent need for new antibiotics led us to develop a new methodology for the synthesis of the natural product darobactin A selectively targeting gram‐negative bacteria. This study provides new insights into the synthesis of strained indole‐containing macrocycles. Key steps comprise a nucleophilic aromatic substitution–Bartoli indole synthesis–Negishi coupling alkylation sequence as well as a Larock indole macrolactamization.