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.

Two practical entries to arylomycin antibiotics core structures are investigated. In route A, the activation of L-Hpg for the key macrolactamization step is achieved in 89% yield in the presence of unprotected phenol and amine functionalities. Alternatively, a propanephosphonic acid anhydride (T3P)-promoted coupling between theL-Tyr and L-Ala moieties in route B led to a facile macrolactamization in 68% yield with a marked reduction in competing oligomerization.

The synthesis of a unique class of highly functionalized 3,4-thienoisoquinolines via an efficient palladium-catalyzed one-pot, regioselective double C-H activation is presented. This class of biologically relevant compounds has been prepared in five steps from commercially available starting materials with overall yields ranging from 27 to 62%. A masked carboxylic acid was used to direct C-H activation to the typically less reactive C4 position. Additionally, the carboxylic acid provides a synthetically useful handle for further functionalization.

Two experimental approaches to the synthesis of a scarcely reported biologically active thienoisoquinoline system are demonstrated. A 5‐step linear synthesis employing a palladium‐catalyzed decarboxylative cross‐coupling and functionalization sequence allowed for the preparation of a diverse range of substituted thienoisoquinoline systems. Alternatively the palladium‐catalyzed decarboxylative cross‐coupling and CH activation steps can be telescoped to produce a one‐pot reaction sequence that provides efficient access to aryl‐substituted thienoisoquinolines.magnified image