Asymmetric modular synthesis of semi-rigid Pro-Gly dipeptide mimetic, as beta turn inducer

Asymmetric modular synthesis of semi-rigid Pro-Gly dipeptide mimetic, as β turn inducer. Sara Pellegrino, Alessandro Contini, Maria Luisa Gelmi and Emanuela Erba An important challenge for chemical biology and medicinal chemistry is the development small synthetic molecules able to selective perturb protein–protein interactions (PPI). Researches in this field have been intensively carried out in the early 21th century, allowing the design and preparation of peptidomimetics, molecules that mimic peptides and protein-fragments. The most prevalent non repetitive motif observed in protein is the four residue β turn, in which proline and glycine residues are generally found in the i+1 and i+2 positions. Many rigid scaffold mimicking this structural motif have been developed during the years, while the sequence Pro-D-pro or D-pro-Pro has been demonstrated an effective semi-rigid reverse turn nucleator. During our long time researches on multicomponent reaction between sulfonylazides and amidines, we recently developed the click reaction between the morpholino enamine of N-alkyl piperidone and tosyl azide, affording azacycloalkene monosulfonyl diamine 1, through a 5-amino-1,2,3-triazoline decomposition rearrangement. Fig 1 Fig 1 Considering the biological importance of proline and its involvement in β turn induction, we studied the possibility to apply our synthetic methodology for the preparation of compound 2. The multicomponent reaction was carried out using proline as the secondary amine and in order to obtain compound 2 in enantiopure form, we studied the selective reduction of the obtained double bond. Finally, we evaluated the possibility to use 2 as a semi-rigid β turn inducer in peptide models.