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.

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