posted on 2021-12-16, 22:15authored byShuang Liu, Zhe Zhuang, Jennifer X. Qiao, Kap-Sun Yeung, Shun Su, Emily C. Cherney, Zheming Ruan, William R. Ewing, Michael A. Poss, Jin-Quan Yu
γ-Lactams
form important structural cores of a range of medicinally
relevant natural products and clinical drugs, principal examples being
the new generation of immunomodulatory imide drugs (IMiDs) and the
brivaracetam family. Compared to conventional multistep synthesis,
an intramolecular γ-C–H amination of aliphatic amides
would allow for the direct construction of valuable γ-lactam
motifs from abundant amino acid precursors. Herein we report a novel
2-pyridone ligand enabled Pd(II)-catalyzed γ-C(sp3)–H lactamization of amino acid derived native amides, providing
the convenient synthesis of γ-lactams, isoindolinones, and 2-imidazolidinones.
C6-Substitution of the 2-pyridone ligand is crucial for the lactam
formation. This protocol features the use of N-acyl
amino acids, which serve as both the directing group and cyclization
partner, practical and environmentally benign tert-butyl hydrogen peroxide (TBHP) as the sole bystanding oxidant, and
a broad substrate scope. The utility of this protocol was demonstrated
through the two-step syntheses of a lenalidomide analog and brivaracetam
from readily available carboxylic acids and amino acids.