An internal -Pro-ΔAA- motif enables catalyst-controlled reduction of dehydropeptides with H₂

Catalyst-controlled asymmetric hydrogenation of dehydroamino acids (ΔAA) in peptides is a straightforward way to access both (L)- and (D)-diastereomers from a single progenitor peptide. While this approach works well for peptides terminated with ΔAAs, catalyst-controlled reduction of internal ΔAAs is more challenging. They are flanked by neighboring amino acids, greatly reducing their accessibility to metal-based hydrogenation catalysts. Their reactions are also heavily influenced by the innate chirality and shape of the peptide, pitting the stereo-inducing effect of the chiral ligand against the unyielding preference of the peptide. For these reasons, finding a single pair of catalysts that can reliably produce either (L)- or (D)-products by simply changing the ligands stereochemistry is a daunting endeavour. Herein, we show that positioning the ΔAA next to a proline residue enables catalyst-controlled hydrogenation with Rh(*DuanPhos). The origin of this control stems from the unique ability of the -Pro-ΔAA- motif to induce a β turn-like structure that orients the ΔAA away from the peptide, such that catalyst approach can occur from either side of the enamide, unimpeded. This effect can be extended to dehydropeptides with a variety of ΔAA chemotypes, e.g., aliphatic, aromatic, and heteroaromatic. Removing the proline residue diminishes the effect, eroding diastereoselectivity.