Regiodivergent Access to α- and β-Amino Acids via Solvent-Controlled Rh-Catalyzed Carboamidation of β,γ-Unsaturated Carboxylic Acids

Non-natural α- and β-amino acids are pivotal building blocks in medicinal chemistry and bioactive molecule discovery. Herein, we report a rhodium-catalyzed, solvent-directed, regiodivergent carboamidation of β,γ-unsaturated alkenyl carboxylic acid for the programmable synthesis of both α- and β-amino acids. This strategy leverages β,γ-unsaturated alkenyl carboxylic acids, organoboronic acids, and dioxazolones as readily available substrates, achieving broad substrate scope with high efficiency (average yield 60%) and excellent functional group tolerance. The solvent system (HFIP vs THF) serves as a simple switch to precisely control regioselectivity (α:β up to >20:1 or β:α up to >20:1), bypassing traditional protecting-group manipulations. Notably, this protocol enables concise two-step synthesis of N-Ac sitagliptin and rapid access to diverse peptidomimetics, showcasing its potential in streamlining the development of pharmaceuticals and bioactive probes. DFT calculations reveal distinct energy barriers for the rate-determining steps of the two pathways in HFIP and THF, rationalizing the solvent-controlled selectivity.