Scope and computational insights into enantioselective C–H amination through silver-catalyzed nitrene transfer

Chiral, non-racemic amines and amino alcohols are prevalent in drugs, bioactive natural products and ligands for transi-tion metal catalysis. Asymmetric nitrene transfer is an efficient and powerful strategy to prepare enantioenriched amines from abundant C–H bonds; however, there is a continued need for general and inexpensive transition metal catalysts sup-ported by easily tunable ligands. Herein, we report silver salts ligated to an unusual bis(oxazoline) (BOX) ligand, readily accessible through a modular synthetic approach, catalyze site- and enantioselective nitrene transfers into benzylic, al-lylic and unactivated C–H bonds of carbamate esters. The resulting 1,3-aminoalcohol building blocks are delivered in good yields and moderate-to-excellent enantioselectivities up to 99%. Computational models were employed to rational-ize the observed stereochemical outcomes and set the stage for the predictive design of second-generation silver cata-lysts. These in-depth computational investigations implicate a complex combination of features in promoting enantiose-lectivity, including substrate distortion from a square-planar geometry at silver and stabilizing C–H/π interactions be-tween ligand and substrate. Careful analyses of the enantiodetermining transition states employing diverse substrates revealed the dominant factors controlling selectivity for each substrate class, thus enabling the rational design of ligand and catalyst combinations that furnish a broader scope of chemo-, site- and enantioselective C–H bond aminations.