Stereocontrolled Synthesis of Arylomycin-Based Gram-Negative Antibiotic GDC-5338
Nicholas Wong1, Filip Petronijević1, Allen Y Hong1
1Department of Small Molecule Process Chemistry , Genentech, Inc. , 1 DNA Way , South San Francisco , California 94080 , United States.
Abstract:
We report herein an efficient, stereocontrolled, and chromatography-free synthesis of the novel broad spectrum antibiotic GDC-5338. The route features the construction of a functionalized tripeptide backbone, a high-yielding macrocyclization via a Pd-catalyzed Suzuki-Miyaura reaction, and the late-stage elaboration of key amide bonds with minimal stereochemical erosion. Through extensive reaction development and analytical understanding, these key advancements allowed the preparation of GDC-5338 in 17 steps, 15% overall yield, >99 A % HPLC, and >99:1 dr.
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