Solid Phase Synthesis of Sulfonimidamide Pseudopeptides and Library Generation

Many synthetic routes have been explored to make small molecule sulfonimidamides (SIAs), however, its introduction into larger molecules such as oligopeptides has not been studied before. We herein demonstrate three alternative and complementary methods for synthesis of SIA based pseudopeptides, on solid phase, using both on and off-resin SIA-synthesis, via sulfonimidoyl chlorides from sulfonamides, in high conversion. Beside evaluation of various resins such as 2-CTC, Wang, and Rink amide-ChemMatrix, the possibilities to further N-functionalize and cyclize the SIA functionality on solid support are shown. The diastereomers of SIA containing pseudopeptides could in most cases be separated using normal reverse phase preparative HPLC. The solid phase SIA methodology has many advantages when it comes to handling and purification as compared to in solution, and will therefore enable exploration of the SIA group as isosteric substitutions and peptidomimetic building blocks in the development of drug-like pseudopeptides in many ways. Of particular note these approaches facilitate combinatorial library synthesis as demonstrated herein.