A mechanochemical approach to access the proline–proline diketopiperazine framework (Beilstein Journal of Organic Chemistry)

Abstract Ball milling was exploited to prepare a substituted proline building block by mechanochemical nucleophilic substitution. Subsequently, the mechanocoupling of hindered proline amino acid derivatives was developed to provide proline–proline dipeptides under solvent-free conditions. A deprotection–cyclization sequence yielded the corresponding diketopiperazines that were obtained with a high stereoselectivity which could be explained by DFT calculations. Using this method, an enantiopure disubstituted Pro–Pro diketopiperazine was synthesized in 4 steps, making 5 new bonds using a ball mill. Beilstein J. Org. Chem. 2017, 13, 2169–2178. doi:10.3762/bjoc.13.217