These are preliminary reports that have not been peer-reviewed. They should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information. For more information, please see our FAQs.
4 files

Triple, Mutually Orthogonal Cycloadditions Through the Design of Electronically Activated SNO-OCTs

submitted on 22.06.2020, 22:11 and posted on 24.06.2020, 12:29 by Yun Hu, Jessica M. Roberts, Henry R. Kilgore, Amirah Mat Lani, Ronald Raines, Jennifer Schomaker
Interest in mutually exclusive pairs of bioorthogonal labeling reagents continues to drive the design of new compounds capable of fast and predictable reactions. The ability to easily modify heterocyclic strained cyclooctynes containing sulfamate backbones (SNO-OCTs) enables electronic tuning of the relative rates of reactions of SNO-OCTs in cycloadditions with Type I–III dipoles. As opposed to optimizations based on just one specific dipole class, the electrophilicity of the alkynes in SNO-OCTs can be manipulated to achieve divergent reactivities and furnish mutually orthogonal dual ligation systems. Significant rate enhancements for reactions of a difluorinated SNO-OCT derivative compared to the parent scaffold were noted, with the second-order rate constant in cycloadditions with diazoacetamides exceeding 1 M−1 s −1 . Computational and experimental studies were employed to inform the design of triple ligation systems that encompass three orthogonal reactivities. Finally, polar SNO-OCTs are rapidly internalized by mammalian cells and remain functional in the cytosol for live-cell labeling, highlighting their potential for diverse in vitro and in vivo applications.


NIH R01 GM044783

Wisconsin Alumni Research Foundation


Email Address of Submitting Author


University of Wisconsin-Madison



ORCID For Submitting Author


Declaration of Conflict of Interest

No conflict of interest.


Logo branding