Direct Mitsunobu monoesterification of N-protected tobramycin competes with intramolecular pyrrolidine formation in ester prodrug synthesis

•Selective esterification carried out on N-protected tobramycin without alcohol protection.•Tobramycin esters have the potential to serve as prodrugs and improve bioavailability.•Under high concentrations of Mitsunobu reagents, an unusual pyrrolidine forms.

Unlike the related aminoglycoside neomycin B, N-protected tobramycin can be selectively esterified at its sole, primary hydroxyl group under Mitsunobu conditions. However, depending on the reaction conditions, the reaction can take a different course with intramolecular cyclization of an N-Boc amine leading to formation of an unusual tobramycin pyrrolidine derivative as the major reaction product.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slide