Stereoretentive cross-coupling of chiral amino acid chlorides and hydrocarbons through mechanistically controlled Ni/Ir photoredox catalysis

Chiral alpha-amino ketones are privileged motifs in bioorganic and medicinal chemistry. Here, the authors develop an efficient method to synthesize these structures via stereoretentive direct cross-coupling of amino acid chlorides with simple aliphatic substrates. The direct modification of naturally occurring chiral amino acids to their amino ketone analogs is a significant synthetic challenge. Here, an efficient and robust cross-coupling reaction between chiral amino acid chlorides and unactivated C(sp(3))-H hydrocarbons is achieved by a mechanistically designed Ni/Ir photoredox catalysis. This reaction, which proceeds under mild conditions, enables modular access to a wide variety of chiral amino ketones that retain the stereochemistry of the starting amino acids. In-depth mechanistic analysis reveals that the strategic generation of an N-acyllutidinium intermediate is critical for the success of this reaction. The barrierless reduction of the N-acyllutidinium intermediate facilitates the delivery of chiral amino ketones with retention of stereochemistry. This pathway avoids the formation of a detrimental nickel intermediate, which could be responsible for undesirable decarbonylation and transmetalation reactions that limit the utility of previously reported methods.

Automated summary

In this study, an efficient method for the stereoretentive direct cross-coupling of chiral amino acid chlorides and unactivated C(sp(3))-H hydrocarbons was achieved via photoredox catalysis. The strategic generation of an N-acyllutidinium intermediate facilitated the synthesis of chiral amino ketones with retention of stereochemistry.