A mechanochemical approach to access the proline–proline diketopiperazine framework

Nicolas Pétry (1) , Hafid Benakki (2) , Eric Clot (3) , Pascal Retailleau (1) , Farhate Guenoun (4) , Fatima Asserar , Chakib Sekkat , Thomas-Xavier Metro (2) , Jean Martinez (2) , Frédéric Lamaty (2)

1 ICSN - Institut de Chimie des Substances Naturelles
2 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]
3 ICGM - Institut Charles Gerhardt Montpellier - Institut de Chimie Moléculaire et des Matériaux de Montpellier
4 UMI - Université My Ismail

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. 2169

Mots clés: ball mill; DFT calculations; diketopiperazine; mechanochemistry; pyrrolidine

Domaines: Chimie-Physique [physics.chem-ph]

Nicolas Pétry, Hafid Benakki, Eric Clot, Pascal Retailleau, Farhate Guenoun, et al.. A mechanochemical approach to access the proline–proline diketopiperazine framework. Beilstein Journal of Organic Chemistry, 2017, 13, pp.2169 - 2178. ⟨10.3762/bjoc.13.217⟩. ⟨hal-01619861⟩