Total Synthesis of Darobactin A

Marko  Nesic; David B. Ryffel; Jonathan Maturano; Michael  Shevlin; Scott R.  Pollack; Donald R.  Gauthier Jr.; Pablo  Trigo-Mouriño; Li-Kang  Zhang; Danielle  Schultz; Jamie M.  McCabe Dunn; Louis-Charles  Campeau; Niki R.  Patel; David A.  Petrone; David Sarlah

doi:10.26434/chemrxiv-2022-c4mz6

Organic Chemistry

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Total Synthesis of Darobactin A

Working Paper

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

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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.