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

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.

[1]  Arkajyoti Sengupta,et al.  Cycloaddition Reactivities Analyzed by Energy Decomposition Analyses and the Frontier Molecular Orbital Model. , 2022, Accounts of chemical research.

[2]  R. Bird,et al.  Bioorthogonal Chemistry and Its Applications. , 2021, Bioconjugate chemistry.

[3]  J. Schomaker,et al.  Recent Developments and Strategies for Mutually Orthogonal Bioorthogonal Reactions , 2021, Chembiochem : a European journal of chemical biology.

[4]  R. Franzini,et al.  Mechanisms and Substituent Effects of Metal-Free Bioorthogonal Reactions. , 2021, Chemical reviews.

[5]  Kimberly M. Bonger,et al.  Recent developments in bioorthogonal chemistry and the orthogonality within. , 2020, Current opinion in chemical biology.

[6]  Guilian Luchini,et al.  GoodVibes: automated thermochemistry for heterogeneous computational chemistry data , 2020, F1000Research.

[7]  Brian J. Levandowski,et al.  Differential Effects of Nitrogen-Substitution in 5- and 6-Membered Aromatic Motifs. , 2020, Chemistry.

[8]  R. Franzini,et al.  Tuning Isonitrile/Tetrazine Chemistry for Accelerated Deprotection and Formation of Stable Conjugates. , 2019, The Journal of organic chemistry.

[9]  Brian J. Levandowski,et al.  Hyperconjugative Antiaromaticity Activates 4H-Pyrazoles as Inverse-Electron-Demand Diels-Alder Dienes. , 2019, Organic letters.

[10]  Brian J. Levandowski,et al.  Stable, Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles. , 2019, Angewandte Chemie.

[11]  Kamalika Mukherjee,et al.  Site-Specific Bioconjugation and Multi-Bioorthogonal Labeling via Rapid Formation of a Boron-Nitrogen Heterocycle. , 2019, Bioconjugate chemistry.

[12]  K. Houk,et al.  autoDIAS: a python tool for an automated distortion/interaction activation strain analysis , 2019, J. Comput. Chem..

[13]  C. Biot,et al.  One, Two, Three: A Bioorthogonal Triple Labelling Strategy for Studying the Dynamics of Plant Cell Wall Formation In Vivo. , 2018, Angewandte Chemie.

[14]  F. Bickelhaupt,et al.  Chemoselectivity of Tertiary Azides in Strain‐Promoted Alkyne‐Azide Cycloadditions , 2018, Chemistry.

[15]  H. Overkleeft,et al.  Coordination‐Assisted Bioorthogonal Chemistry: Orthogonal Tetrazine Ligation with Vinylboronic Acid and a Strained Alkene , 2018, Chembiochem : a European journal of chemical biology.

[16]  R. Peterson,et al.  Bioorthogonal Removal of 3-Isocyanopropyl Groups Enables the Controlled Release of Fluorophores and Drugs in Vivo. , 2018, Journal of the American Chemical Society.

[17]  Jennifer M Murphy,et al.  Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling. , 2018, Journal of the American Chemical Society.

[18]  Haoxing Wu,et al.  Advances in Tetrazine Bioorthogonal Chemistry Driven by the Synthesis of Novel Tetrazines and Dienophiles. , 2018, Accounts of chemical research.

[19]  H. Mikula,et al.  A computational model to predict the Diels–Alder reactivity of aryl/alkyl-substituted tetrazines , 2017, Monatshefte für Chemie - Chemical Monthly.

[20]  K. Houk,et al.  Analyzing Reaction Rates with the Distortion/Interaction‐Activation Strain Model , 2017, Angewandte Chemie.

[21]  Jennifer A. Prescher,et al.  Orthogonal bioorthogonal chemistries. , 2015, Current opinion in chemical biology.

[22]  F. Bickelhaupt,et al.  Activation-strain analysis reveals unexpected origin of fast reactivity in heteroaromatic azadiene inverse-electron-demand diels-alder cycloadditions. , 2015, The Journal of organic chemistry.

[23]  J. Chin,et al.  Concerted, Rapid, Quantitative, and Site-Specific Dual Labeling of Proteins , 2014, Journal of the American Chemical Society.

[24]  Jennifer A. Prescher,et al.  Functionalized cyclopropenes as bioorthogonal chemical reporters. , 2012, Journal of the American Chemical Society.

[25]  A. Jäschke,et al.  Site-specific one-pot dual labeling of DNA by orthogonal cycloaddition chemistry. , 2012, Bioconjugate chemistry.

[26]  H. Overkleeft,et al.  Triple bioorthogonal ligation strategy for simultaneous labeling of multiple enzymatic activities. , 2012, Angewandte Chemie.

[27]  K. Houk,et al.  Computational methods to calculate accurate activation and reaction energies of 1,3-dipolar cycloadditions of 24 1,3-dipoles. , 2011, The journal of physical chemistry. A.

[28]  K. Brindle,et al.  Exploring isonitrile-based click chemistry for ligation with biomolecules. , 2011, Organic & biomolecular chemistry.

[29]  Jun Hee Lee,et al.  Origins of stereoselectivity in the trans Diels-Alder paradigm. , 2010, Journal of the American Chemical Society.

[30]  P. Imming,et al.  [4 + 1]Cycloaddition of Isocyanides to 1,2,4,5‐Tetrazines: A Novel Synthesis of Pyrazole , 1982 .