A directed enolization strategy enables by-product-free construction of contiguous stereocentres en route to complex amino acids

Homochiral alpha-amino acids are widely used in pharmaceutical design as key subunits in chiral catalyst synthesis or as building blocks in synthetic biology. Many synthetic methods have been developed to access rare or unnatural variants by controlling the installation of the alpha-stereocentre. By contrast, and despite their importance, alpha-amino acids possessing beta-stereocentres are much harder to synthesize. Here we demonstrate an iridium-catalysed protocol that allows the direct upconversion of simple alkenes and glycine derivatives to give beta-substituted alpha-amino acids with exceptional levels of regio- and stereocontrol. Our method exploits the native directing ability of a glycine-derived N-H unit to facilitate Ir-catalysed enolization of the adjacent carbonyl. The resulting stereodefined enolate cross-couples with a styrene or alpha-olefin to install two contiguous stereocentres. The process offers very high levels of regio- and stereocontrol and occurs with complete atom economy. In broader terms, our reaction design offers a unique directing-group-controlled strategy for the direct stereocontrolled alpha-alkylation of carbonyl compounds, and provides a powerful approach for the synthesis of challenging contiguous stereocentres. alpha-Amino acids possessing beta-stereocentres are difficult to synthesize. Now, an iridium-catalysed protocol allows the direct upconversion of simple alkenes and glycine derivatives to give beta-substituted alpha-amino acids with exceptional levels of regio- and stereocontrol. The reaction design is based on exploiting the native directing ability of a glycine-derived N-H unit to facilitate enolization of the adjacent carbonyl.