Photoactivated 1,3-dipolar cycloaddition as a new bioorthogonal reaction
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A mild, photoactivated 1,3-dipolar cycloaddition procedure based on photolysis of 2,5-disubstituted tetrazoles was successfully developed to serve as a new bioorthogonal reaction called photoclick chemistry. This procedure involved the in situ generation of the reactive nitrile imine dipoles using a hand-held UV lamp with wavelength at 302 nm, followed by spontaneous [3+2] cycloaddition with a broad range of 1,3-dipolarophiles with excellent solvent compatibility, functional group tolerance, regioselectivity, and yield. This reaction provided a convenient method for the synthesis of polysubstituted pyrazolines as well as a powerful tool for molecular manipulations such as protein modifications and peptide stapling. By screening a series of substituted diaryltetrazoles, a few long-wavelength (365 nm) photoactivatable diaryltetrazoles were also discovered. These tetrazoles showed excellent reactivity in the photoactivated 1,3-dipolar cycloaddition reactions toward electron-deficient and conjugated alkenes. The reaction rate of this [3+2] cycloaddition can be increased by systematically tuning the HOMO energies of the nitrile imines generated in the photolysis. A dipole HOMO-lifting effect was observed in the study. Finally, unnatural amino acids containing the tetrazole motif were synthesized.