N-Acetyl-l-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(N-Acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA)

Elisa Sturabotti; Fabrizio Vetica; Giorgia Toscano; Andrea Calcaterra; Andrea Martinelli; Luisa Maria Migneco; Francesca Leonelli

doi:10.3390/molecules28020581

N-Acetyl-l-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(N-Acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA)

Molecules. 2023 Jan 6;28(2):581. doi: 10.3390/molecules28020581.

Authors

Elisa Sturabotti¹, Fabrizio Vetica¹, Giorgia Toscano¹, Andrea Calcaterra², Andrea Martinelli¹, Luisa Maria Migneco¹, Francesca Leonelli¹

Affiliations

¹ Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
² Department of Chemistry and Technology of Drugs, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Abstract

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.

Keywords: N-acetyl amino acids; TBTU; coupling; pyridine; racemization.

MeSH terms

Anti-Inflammatory Agents
Deoxyglucose
Glucosamine*
Glucose*

Substances

Glucose
Glucosamine
Anti-Inflammatory Agents
Deoxyglucose

Grants and funding

This research was funded by University of Rome “La Sapienza” (RG11916B702B43B9 and AR11916B89334BBE).