Orthogonal Regioselective Synthesis of Folic Acid γ-Conjugates

Abstract

γ-Folic acid conjugates are valuable tools for targeting the folate receptor, an important cancer biomarker, but direct conjugation of folic acid is hampered by poor regioselectivity and challenging purification. We report an orthogonal protection strategy that enables controlled regioselective access to γ-folic acid conjugates from readily available building blocks. This approach permits site-selective installation of a range of functional modalities, including an amphiphilic ligand, a fluorescent probe, and a bioorthogonal handle, followed by global deprotection to afford γ-conjugates without the need for reversed phase chromatography.