Stereodivergent Truce-Smiles Rearrangement Enables Enantioselective Access to α-Heteroaryl Quaternary Amino Acid Derivatives

Increasing molecular three-dimensionality is a key strategy in drug discovery, yet α-heteroaryl α,α-disubstituted amino acids (HAAs) remain largely unexplored despite their potential to modulate peptide conformation and recognition. Here we report a stereodivergent Truce-Smiles rearrangement that converts enantioenriched heteroaryl sulfonamides into HAA derivatives with predictable control over configuration at Cα. The method exploits memory-of-chirality and cation-dependent conformational bias to deliver either inversion or retention of configuration under complementary conditions (Method A: NaHMDS/18-crown-6/LiCl; Method B: KHMDS/Cu(I)OTf). Both protocols operate under mild conditions (THF, −78 °C) and accommodate diverse heteroaryl motifs, N-substituents, and amino acid backbones, achieving high enantiomeric ratios and good yields. Downstream functionalization demonstrates compatibility with peptide coupling and reveals intrinsic limitations such as decarboxylation of free acids. This stereodivergent approach expands the toolbox for constructing quaternary stereocenters adjacent to nitrogen and provides practical access to conformationally defined scaffolds for peptide engineering and 3D chemical-space exploration.