Peptide thioacids and thioesters are an integral part of protein ligation strategies. The vast majority of these protein ligation strategies use thioesters or thioacids as the C-terminal reacting site. All of the reported solid-phase syntheses of peptide thioacids and thioesters use the Boc/Benzyl strategy (Boc, t-butyloxycarbonyl). This method is susceptible to problems arising from repeated exposure to acidic conditions. The milder Fmoc/t-butyl (Fmoc, 9-fluorenymethyloxycarbonyl) strategy was developed to overcome some of the difficulties associated with the Box/Benzyl strategy. I propose the development of methods for the solid- phase synthesis of thioacids and thioesters using the Fmoc/t-butyl strategy and their application in the synthesis of bovine pancreatic trypsin inhibitor (BPTI). The approach for the development of these methods will be threefold. First, the backbone amide linker strategy will be adapted to the synthesis of thioacids and thioesters by exploiting the unbound C-terminus of the peptide. The second approach uses a benzotriazole based linker to form the desired thiocarbonyl compound via a thioamide intermediate. Finally, a linker is designed which uses an O>S acyl transfer to form the thioacid. The most effective methods found will be used to form protein segments for the synthesis of BPTI. These methods will ultimately expand the number of proteins available through chemical synthesis.
