Synthesis and Structure of Preorganized, C3-Symmetric Trilactam Scaffolds with Convergently Oriented (S)-Acetylthiomethyl Appendages

Abstract
Efficient modular synthesis of conformationally preorganized, C3-symmetric trilactams is reported. The allyl acetate cyclization substrate was synthesized in five steps from Garner's l-serine-derived aldehyde. After chiral ligand-mediated palladium cyclization, the resulting vinyl hydropyran was transformed into the orthogonally protected amino acids for iterative coupling. The final macrolactamization was accomplished using EDCI/HOBt or HATU/HOAt under high dilution conditions.