Orthogonal Inverse-Electron-Demand Cycloaddition Reactions Controlled by Frontier Molecular Orbital Interactions

  • Org Lett. 2023 Sep 1;25(34):6340-6345. doi: 10.1021/acs.orglett.3c02265.
Dennis Svatunek  1  2 ,  Konrad Chojnacki  3 ,  Titas Deb  3 ,  Hannah Eckvahl  1 ,  K N Houk  1 ,  Raphael M Franzini  3  4
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, California 90095, United States.
  • 2. Institute of Applied Synthetic Chemistry, TU Wien, 1060 Vienna, Austria.
  • 3. Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States.
  • 4. Huntsman Cancer Institute, Salt Lake City, Utah 84112, United States.
PMID: 37591496 DOI: 10.1021/acs.orglett.3c02265
Abstract

Chemoselective pairs of bioorthogonal reactants enable the simultaneous labeling of several biomolecules. Here, we access orthogonal click reactions by exploiting differences in frontier molecular orbital interaction energies in transition states. We establish that five-membered cyclic dienes are inert to isonitriles but readily react with strained Alkynes, while tetrazines with bulky substituents readily react with isonitriles. Strained Alkynes show an opposite reactivity pattern. The approach was demonstrated by orthogonally labeling two proteins with different fluorophores.

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