Total Synthesis of Darobactin A

• DOI: 10.1021/jacs.2c05891
• Publication Date: 2022-07-28T13:49:01Z
• Authors: Marko Nesic; 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 Cam...; Niki R. Patel; David A. Petrone; David Sarlah
• Keywords: Aldehydes; Phenylpropionates; Cyclization; Stereoisomerism; Amino Acids; 01 natural sciences; 0104 chemical sciences

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.