A Carbodiimide-Mediated P-C Bond-Forming Reaction: Mild Amidoalkylation of P-Nucleophiles by Boc-Aminals

The first example of a carbodiimide-mediated P-C bondforming reaction is described. The reaction involves activation of beta-carboxyethylphosphinic acids and subsequent reaction with Boc-aminals using acid-catalysis. Mechanistic experiments using P-31 NMR spectroscopy and DFT calculations support the contribution of unusually reactive cyclic phosphinic/carboxylic mixed anhydrides in a reaction pathway involving ion-pair swapping. The utility of this protocol is highlighted by the direct synthesis of Boc-protected phosphinic dipeptides, as precursors to potent Zn-aminopeptidase inhibitors.

Automated summary

This study presents a novel carbodiimide-mediated P-C bond forming reaction, involving activation of beta-carboxyethylphosphinic acids and subsequent reaction with Boc-aminals under acid-catalysis. Mechanistic experiments confirm the contribution of unusually reactive cyclic phosphinic/carboxylic mixed anhydrides in the reaction pathway.