<i>N</i>-Acetyl-<span style="font-variant: small-caps">l</span>-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(<i>N</i>-Acetyl)-<span style="font-variant: small-caps">l</span>-phenylalanylamido-2-deoxy-<span style="font-variant: small-caps">d</span>-glucose (NAPA)
Elisa Sturabotti,
Fabrizio Vetica,
Giorgia Toscano,
Andrea Calcaterra,
Andrea Martinelli,
Luisa Maria Migneco,
Francesca Leonelli
Affiliations
Elisa Sturabotti
Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Fabrizio Vetica
Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Giorgia Toscano
Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Andrea Calcaterra
Department of Chemistry and Technology of Drugs, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Andrea Martinelli
Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Luisa Maria Migneco
Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Francesca Leonelli
Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
A thorough study on the amidation conditions of N-acetyl-l-phenylalanine using TBTU and various bases is reported for the synthesis of 2-(N-acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA), a promising drug for the treatment of joints diseases. TBTU-mediated diastereoselective amidation reaction with 1,3,4,6-tetra-O-acetyl-β-d-glucosamine always gave racemization of N-acetyl-l-phenylalanine. The stereochemical retention under amidation conditions was studied in detail in the presence of difference bases and via other control experiments, evidencing the possibility to reduce racemization using pyridine as base.
