Phosphonopeptides and sulfonopeptides are important phosphorus and sulfur analogues of naturally occurring peptides. They have been widely used as stable mimetics of tetrahedral transition states for the hydrolysis of peptides and proteins in recent years. The phosphonopeptides and sulfonopeptides as transition state analogues have also been exploited as enzyme inhibitors and as haptens for catalytic antibody research.
Recently, we developed a new and effective one-pot approach to synthesizing phosphonopeptides, phosphonodepsipeptides, phosphinopeptides, and phosphinodepsipeptides using the Mannich-type pseudo four component condensation reaction of carbamates/amino amides, aldehydes, and dichlorophosphite/aryldichlorophosphines, followed by aminolysis, alcoholysis, and hydrolysis. This is an economic and convergent synthesis of phosphonopeptides.
For synthesis of sulfonopeptides with various functionalized side-chains, an efficient and convenient method was developed. We synthesized O-ethyl S-(2-N-protected aminoalkyl) xanthates via the radical addition of various xanthates to N-allylphthalimide. The synthesis of N-protected α-substituted β-aminoalkanesulfonopeptides was realized via NCS/HCl oxidative chlorination of xanthates or thioacetates to the corresponding sulfonyl chlorides followed by reaction with amino esters. It is a useful and efficient strategy for the synthesis of sulfonopeptides with diverse functionalized side-chains.
In summary, efficient strategies for synthesis of phosphonopeptides and ulfonopeptides have been provided.