The Asymmetric Synthesis of Amines via Nickel-Catalyzed Enantioconvergent Substitution Reactions

Abstract

Chiral dialkyl carbinamines are important in fields such as organic chemistry, pharmaceutical chemistry, and biochemistry, serving for example as bioactive molecules, chiral ligands, and chiral catalysts. Unfortunately, most catalytic asymmetric methods for synthesizing dialkyl carbinamines do not provide general access to amines wherein the two alkyl groups are of similar size (e.g., CH₂R versus CH₂R¹). Herein, we report two mild methods for the catalytic enantioconvergent synthesis of protected dialkyl carbinamines, both of which use a chiral nickel catalyst to couple an alkylzinc reagent (1.1–1.2 equiv) with a racemic partner, specifically, an α-phthalimido alkyl chloride or an N-hydroxyphthalimide (NHP) ester of a protected α-amino acid. The methods are versatile, providing dialkyl carbinamine derivatives that bear an array of functional groups. For couplings of NHP esters, we further describe a one-pot variant wherein the NHP ester is generated in situ, allowing the generation of enantioenriched protected dialkyl carbinamines in one step from commercially available amino acid derivatives; we demonstrate the utility of this method by applying it to the efficient catalytic enantioselective synthesis of a range of interesting target molecules.