Rh-Catalyzed Solvent-Controlled Carboamidation for Divergent Synthesis of α- and β-Amino Acids

Abstract Divergent synthesis aims to build different molecules from the same starting materials using small changes in the reaction conditions. It is a valuable yet challenging goal in synthesis. Here, we share how simply switching between two solvents—hexafluoroisopropanol and tetrahydrofuran—can steer a rhodium-catalyzed reaction toward making either α- or β-amino acids from the same starting materials. This method works with many functional groups, avoids protecting-group steps, and has been used to quickly prepare bioactive compounds, such as N-Ac sitagliptin. DFT calculations show that the two reaction paths have different energy barriers, which explains why the solvent choice controls the product structure.