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

preprint
submitted on 22.06.2020 and posted on 24.06.2020 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.

Funding

NIH R01 GM044783

Wisconsin Alumni Research Foundation

History

Email Address of Submitting Author

schomakerj@chem.wisc.edu

Institution

University of Wisconsin-Madison

Country

USA

ORCID For Submitting Author

0000-0003-1329-950X

Declaration of Conflict of Interest

No conflict of interest.

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