Direct And Facile Synthesis Of Phosphonopeptides Via Mannich-Type Reaction

Both phosphonopeptides and sulfonopeptides are important analogs of naturally occurring pep tides. They show a range of biological activities such as enzyme inhibitors since the transition states in enzyme hydrolysis can be replaced by tetrahedral phosphonamidate structures in phosphonopeptides and the sulfonamide functional group in sulfonopeptides. In addition, they are also used as herbicide in the agriculture field. In recent years, they show some potential in pharmaceutical area.In the previous methods, N-protected aminoalkylphosphonic acids were or their derivates (eg. phosphonic chloride) should be synthesized first as starting materials and then coupling with amino acids or peptides via multistep procedures generally in low overall yields. There are some limitations in the prevous modified Mannich-type reaciton, such as they could not react in one-pot. Our group has developed new methods to synthesize phosphonopeptides, phosphinopeptides, and hybrid sulfonophosphinopeptides in one-pot reactions.Herein, according to the previous studies, we applied the Mannich-type reaction successfully to synthesize phosphonopeptides. Starting from N-Cbz-aminoalkanesulfonamides and 2-(N-benzoxycarbonylamino)alkanamides and then reacting with aldehydes, and phosphorus trichloride via the Mannich-type reaction followed by hydrolysis to get hybrid sulfonophosphonodipeptides and phosphonodipeptides respectively. In this research, we proofed that the low activity starting metarials and phosphorus trichloride with low nucleophilicity can also undergo Mannich-type reaction smoothly, what’s more, the sequential hydrolysis is beneficial to improve the yield. Meanwhile, the 31P NMR was used to trace the reaction process and to verify the reasonable mechanism. In this method, the amide bond or sulfamide bond and phsophonamide bond are generated at the same time. This is the most facile and practical way to synthesize phosphonopeptides.