Development of a Solid‐Phase Approach to the Natural Product Class of Ahp‐Containing Cyclodepsipeptides

Abstract

AbstractThe 3‐amino‐6‐hydroxy‐2‐piperidone (Ahp) containing cyclodepsipeptides are an interesting class of natural products that inhibit S1 (trypsin and chymotrypsin‐like) serine protease in a reversible, noncovalent manner, turning them into potential chemical tools for protease research. Their systematic use in chemical biology is however hampered by their tedious solution‐phase chemical synthesis. To overcome this limitation, we report a solid‐phase approach to Ahp cyclodepsipeptides that is based on the use of a maskedglutamic aldehyde moiety as a general Ahp precursor molecule. As a proof‐of‐concept, we therefore recently reported the solid‐phase synthesis of Symplocamide A. Here, we want to give a full account on the development and application of the masked glutamic aldehyde moiety as well as the optimization of the solid‐phase synthesis, which allowed the successful synthesis of the natural product Symplocamide A.