Scalable Solid-Phase Synthesis of Orberryamides A–D via a Late-Stage Transformation Strategy

Orberryamides A–D (1–4) represent a unique class of 27-membered macrocyclic nonapeptide exhibiting potent inhibition of TH17 cell differentiation. Herein, we describe the scalable synthesis of these natural products, based on an integrated strategy that couples solid-phase peptide synthesis for macrocycle assembly with late-stage transformation. Compounds 2 and 3 were efficiently derived from 4 via a streamlined two-step modification, whereas compound 1 was synthesized through pre-installation of the C-4 ester functionality, circumventing challenges associated with the Baeyer–Villiger oxidation of 2. This approach enhanced synthetic efficiency and atom economy, achieving overall yields of 3–22%.