An umpolung-enabled copper-catalysed regioselective hydroamination approach to α-amino acids

A copper-catalysed regio- and stereoselective hydroamination of acrylates with hydrosilanes and hydroxylamines has been developed to afford the corresponding alpha-amino acids in good yields. The key to regioselectivity control is the use of hydroxylamine as an umpolung, electrophilic amination reagent. Additionally, a judicious choice of conditions involving the CsOPiv base and DTBM-dppbz ligand of remote steric hindrance enables the otherwise challenging C-N bond formation at the alpha position to the carbonyl. The point chirality at the beta-position is successfully controlled by the Xyl-BINAP or DTBM-SEGPHOS chiral ligand with similarly remote steric bulkiness. The combination with the chiral auxiliary, (-)-8-phenylmenthol, also induces stereoselectivity at the alpha-position to form the optically active unnatural alpha-amino acids with two adjacent stereocentres.

Automated summary

This study established a copper-catalysed hydroamination method for the regio- and stereoselective synthesis of alpha-amino acids from acrylates using hydrosilanes and hydroxylamines. Regioselectivity control was achieved by utilizing hydroxylamine as an electrophilic amination reagent. The use of CsOPiv base and DTBM-dppbz ligand facilitated the challenging C-N bond formation at the alpha position, while the chiral ligands Xyl-BINAP and DTBM-SEGPHOS controlled the stereochemistry at the beta-position. Additionally, the chiral auxiliary (-)-8-phenylmenthol induced stereoselectivity at the alpha-position to produce optically active unnatural alpha-amino acids with adjacent stereocentres.