Straightforward, racemization-free synthesis of peptides with fairly to very bulky di- and trisubstituted glycines

Several fully protected tri- and pentapeptides containing a central symmetrical α,α-dialkyl glycine residue, with the alkyl group varying from methyl or ethyl to benzyl, were synthesized in good yields by a strategy based on the Ugi-Passerini reaction. Each Ugi-Passerini adduct was selectively cleaved and the product submitted to an assisted N,N′-dicyclohehylcarbodiimide coupling to an amino acid or dipeptide ester, respectively. Tripeptides as the above but containing a 4-methoxybenzyl group at the nitrogen atom of the central residue were also synthesized in fair to good yields by N-[(1H-benzotriazol-1-yl)-(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide assisted couplings. The results reported here show that our strategy is appropriate for routine synthesis of peptides incorporating these moieties.

Graphical abstractDownload full-size imageTri and pentapeptides incorporating a central α,α-dialkylglycine or N,α,α-trialkylglycine residue by oxazolone, DCC/HOBt or HBTU couplings of the peptide acids obtained by total or partial acidolysis of Ugi-Passerini aducts.