Selective Orthogonal nitroalkane-alkyne 1, 3-dipolar Cycloadditions on peptides: A versatile approach for Biomolecular Conjugation

Abstract

The mild and substrate compatible copper catalyzed 1, 3-dipolar cylcoaddition reaction between azide and alkyne (click chemistry) has been extensively used in the conjugation chemistry. Though the click chemistry has proven its wide applications in bioconjugations, however suffers with toxicity of copper in the biological systems. In addition, performing more than one cycloaddition reactions on a substrate containing two or more azide functionalities is proved to be difficult. In this context, we sought to investigate 1, 3-dipolar cycloaddition reactions orthogonal to the azide-alkyne cycloadditions. Nitroalknes have been serving as versatile intermediates in various organic transformations including 1, 3-dipolar cycloadditions with alkenes and alkynes. We hypothesized that nitroalkanes can serve attractive alternatives to azides in 1, 3-dipolar cycloadditions. Herein, we are reporting the mild 1, 3-dipolar cycloaddition reaction between alkyl nitro and alkynes. The new nitro amino acid was synthesized and introduced into the peptide sequence along with azidolysine. The reaction was found to be orthogonal to the azide-alkyne chemistry. In addition, the nitroalkane-alkyne cycloaddition reaction was compatible with both solid and solution phase chemistry. Using mild and orthogonal cycloaddition reactions, various nitroalkane-alkyne and azide-alkyne cycloaddition reactions were performed step by step in both solution as well as on solid phase. Besides the cycloaddition, the nitro group was further transformed into various other functional groups on peptides. Overall, we have demonstrated the mild functional group transformations of nitro amino acid on the peptides including orthogonal 1, 3-dipolar cycloaddition reactions.