Catalytic Enantioselective Construction of an α-Thio-Substituted α-Aminonitriles-Bearing Tetrasubstituted Carbon Center

Abstract

Chiral unnatural amino acids (UAAs) are important structural units that are commonly found in a wide range of natural products and bioactive molecules. Chiral α-aminonitriles, which are one of the most important precursors for chiral α-amino acid synthesis, are widely accessible via the asymmetric Strecker reaction. However, the construction of α-heteroatom-substituted α-aminonitriles presents a challenge due to the lack of reactivity of electrophiles (ester, amide, thioamide, etc.) and their ability as leaving groups. Therefore, a practical and robust approach to their enantioselective synthesis is highly desirable. We herein describe an efficient method for the preparation of chiral α-heteroatom-substituted α-aminonitriles containing a tetrasubstituted stereogenic carbon center. This protocol displayed a broad substrate scope for both reactants in high yield and with high enantioselectivity. Several mechanistic studies revealed that the presence of nitrile is crucial for enhancing the reactivity and controlling the selectivity of the reaction. This work not only provides N,S-and N,Se-ketal motifs but also a powerful strategy for overcoming the limitation of synthesizable α-aminonitriles.