Enantioselective synthesis of protected L-4-[sulfonamido(difluoromethyl)]phenylalanine and L-4-[sulfonamido(methyl)]phenylalanine and an examination of hexa- and tripeptide platforms for evaluating pTyr mimics for PTP1B inhibition

The first enantioselective syntheses of L-4-(sulfonamidomethyl)phenylalanine and L-sulfonamido(difluoromethyl)]phenylalanine suitably protected for peptide syntheses are described. A key step in the synthesis of L-(sulfonamidomethyl)phenylalanine was an oxidative chlorination on Ac-L-Phe(4-CH2SCOCH3)-OEt to give crude Ac-L-Phe(4-CH2SO2Cl)-OEt, which could be reacted with amines to give the corresponding sulfonamides. Key to the preparation of L-sulfonamido(difluoromethyl)]phenylalanine was a highly enantioselective reaction involving William's auxiliary and a benzylic bromide intermediate. These amino acids were incorporated into two peptide sequences, DADE-X-LNH2 and FmocGlu(OBn)-X-LNH2, which have previously been employed as platforms for assessing pTyr mimics for inhibition of protein tyrosine phosphatase 1B (PTP1B). Inhibition studies with these and other peptides and PTP1B revealed that good inhibition could be obtained using the tripeptide platform, although the presence of a pTyr mimic was not required for good inhibition. These results suggest that the FmocGlu(OBn)-X-LNH2 tripeptide platform is not suitable for assessing pTyr mimics for PTP1B inhibition.