Solid-phase Synthesis of 2,3,5-Triketopiperadine

The synthesis of 2,3,5-triketopiperadines on solid-support has been achieved for the first time. Cyclization of 4 using oxalyl diimidazole proceeded excellently with N-methyl amino acids except for Sarcosine (Sar). On theother hand, this cyclization did not proceed well when amino acids without N-methyl substitution were used. This can be explained by the lower energy difference between the trans and cis configurations of oxalyl amide 5 by the introduction of N-methyl substitution, because cis conformation is necessary for the cyclization to proceed. This cyclization also worked well with amino acids with a six-membered ring such as tetrahydroisoquinoline-3-carboxylic acid (Tic) and piperidine-2-carboxylic acid (Pic), which are N-alkylated amino acids. Although the purity of the target compounds was found to be low in the case of Sar and amino acids with a five-membered ring such as proline (Pro) and thiazolidine-4-carboxylic acid (Thz) under the same cyclization conditions, we were able to successfully optimize the reaction conditions to give the target compounds with good purity. Furthermore, it was demonstrated that 2,3,5-triketopiperadines with three points diversity could be prepared on solid-support with high purity. showing the generality of this method.