Accessing Trans-Substituted Azetidines through Diastereoselective Metalation

A diastereoselective metalation of 3-substituted azetidines is reported, providing efficient access to a variety of 2,3-trans-disubstituted azetidines. This transformation complements our previously developed cis-selective hydrogenation of azetines, which delivers the corresponding 2,3-cis-disubstituted analogues. Together, these two methodologies establish a stereodivergent strategy for the preparation of functionalized azetidines with precise control over relative configuration. The newly developed trans-selective protocol further enables the synthesis of non-natural amino acid derivatives bearing a trans-relationship between substituents—structural motifs that are otherwise difficult to access by conventional means.