Organic Chemistry

Total Synthesis of Darobactin A

Authors

  • Marko Nesic University of Illinois Urbana-Champaign ,
  • David B. Ryffel University of Illinois Urbana-Champaign ,
  • Jonathan Maturano University of Illinois Urbana-Champaign ,
  • Michael Shevlin Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • Scott R. Pollack Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • Donald R. Gauthier Jr. Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • Pablo Trigo-Mouriño Analytical Research & Development, Merck & Co., Inc., Rahway, NJ 07065, United States ,
  • Li-Kang Zhang Analytical Research & Development, Merck & Co., Inc., Rahway, NJ 07065, United States ,
  • Danielle Schultz Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • Jamie M. McCabe Dunn Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • Louis-Charles Campeau Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • Niki R. Patel Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • David A. Petrone Department of Process Research & Development, Merck & Co., Inc., MRL, Rahway, NJ 07065, United States ,
  • David Sarlah University of Illinois Urbana-Champaign

Abstract

The 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 ᴅ-Garner’s aldehyde and ʟ-serine. Scalable routes towards 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.

Content

Thumbnail image of Darobactin Manuscript.pdf

Supplementary material

Thumbnail image of Darobactin SI.pdf
Supporting Information
Description of protocols and characterization data