Electrochemical Synthesis of a Sitagliptin Precursor

A novel synthesis of sitagliptin based on a redox-active ester derived from the chiral pool is reported. The key step is an electrochemical nickel-catalyzed sp2-sp3 cross-coupling reaction using inexpensive nickel foam in an undivided cell. It was successfully applied to 21 examples in up to 88% yield. These sitagliptin-analogue precursors could potentially interact with the DPP4 enzyme. A full synthesis based on our new reaction pathway provided sitagliptin in an overall yield of 33%.