Total Synthesis of Darobactin A
Marko Nešić, David B. Ryffel, Jonathan Maturano, Michael Shevlin, Scott R. Pollack, Donald R. Gauthier, Pablo Trigo‐Mouriño, Li‐Kang Zhang, Danielle M. Schultz, Jamie M. McCabe Dunn, Louis‐Charles Campeau, Niki R. Patel, David A. Petrone, David Šarlah
Abstract
The collaborative total synthesis of darobactin A, a recently isolated antibiotic that selectively targets Gram-negative bacteria, has been accomplished in a convergent fashion with a longest linear sequence of 16 steps from d-Garner's aldehyde and l-serine. Scalable routes toward three non-canonical amino acids were developed to enable the synthesis. The closure of the bismacrocycle was realized through sequential, halogen-selective Larock indole syntheses, where the proper order of cyclizations proved crucial for the formation of the desired atropisomer of the natural product.