Cargando…

Origin of Orthogonality of Strain-Promoted Click Reactions

Site-specific labeling of biomolecules is rapidly advancing due to the discovery of novel mutually orthogonal reactions. Quantum chemistry studies have also increased our understanding of their relative rates, although these have until now been based on highly simplified reactants. Here we examine a...

Descripción completa

Detalles Bibliográficos
Autores principales: Wagner, Johannes A, Mercadante, Davide, Nikić, Ivana, Lemke, Edward A, Gräter, Frauke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600239/
https://www.ncbi.nlm.nih.gov/pubmed/26178299
http://dx.doi.org/10.1002/chem.201501727
_version_ 1782394391378264064
author Wagner, Johannes A
Mercadante, Davide
Nikić, Ivana
Lemke, Edward A
Gräter, Frauke
author_facet Wagner, Johannes A
Mercadante, Davide
Nikić, Ivana
Lemke, Edward A
Gräter, Frauke
author_sort Wagner, Johannes A
collection PubMed
description Site-specific labeling of biomolecules is rapidly advancing due to the discovery of novel mutually orthogonal reactions. Quantum chemistry studies have also increased our understanding of their relative rates, although these have until now been based on highly simplified reactants. Here we examine a set of strain-promoted click-type cycloaddition reactions of n-propyl azide, 3-benzyl tetrazine and 3-benzyl-6-methyl tetrazine with cyclooctenes/ynes, in which we aim to address all relevant structural details of the reactants. Our calculations have included the obligatory handles used to attach the label and biomolecule as these can critically influence the stereochemistry and electron demand of the reaction. We systematically computed orbital gaps, activation and distortion energies using density functional theory and determined experimental rates for validation. Our results challenge the current paradigm of the inverse electron demand for this class of reactions. We found that the ubiquitous handles, when next to the triple bond of cyclooctynes, can switch the Diels–Alder type ligations to normal electron demand, a class we term as SPINEDAC reactions. Electron donating substituents on tetrazine can enhance normal demand but also increase distortion penalties. The presence and isomeric configuration of handles thus determine the reaction speed and regioselectivity. Our findings can be directly utilized in engineering genuine cycloaddition click chemistries for biological labeling.
format Online
Article
Text
id pubmed-4600239
institution National Center for Biotechnology Information
language English
publishDate 2015
publisher WILEY-VCH Verlag
record_format MEDLINE/PubMed
spelling pubmed-46002392015-10-14 Origin of Orthogonality of Strain-Promoted Click Reactions Wagner, Johannes A Mercadante, Davide Nikić, Ivana Lemke, Edward A Gräter, Frauke Chemistry Full Papers Site-specific labeling of biomolecules is rapidly advancing due to the discovery of novel mutually orthogonal reactions. Quantum chemistry studies have also increased our understanding of their relative rates, although these have until now been based on highly simplified reactants. Here we examine a set of strain-promoted click-type cycloaddition reactions of n-propyl azide, 3-benzyl tetrazine and 3-benzyl-6-methyl tetrazine with cyclooctenes/ynes, in which we aim to address all relevant structural details of the reactants. Our calculations have included the obligatory handles used to attach the label and biomolecule as these can critically influence the stereochemistry and electron demand of the reaction. We systematically computed orbital gaps, activation and distortion energies using density functional theory and determined experimental rates for validation. Our results challenge the current paradigm of the inverse electron demand for this class of reactions. We found that the ubiquitous handles, when next to the triple bond of cyclooctynes, can switch the Diels–Alder type ligations to normal electron demand, a class we term as SPINEDAC reactions. Electron donating substituents on tetrazine can enhance normal demand but also increase distortion penalties. The presence and isomeric configuration of handles thus determine the reaction speed and regioselectivity. Our findings can be directly utilized in engineering genuine cycloaddition click chemistries for biological labeling. WILEY-VCH Verlag 2015-08-24 2015-07-14 /pmc/articles/PMC4600239/ /pubmed/26178299 http://dx.doi.org/10.1002/chem.201501727 Text en © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. https://creativecommons.org/licenses/by/4.0/ © 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Full Papers
Wagner, Johannes A
Mercadante, Davide
Nikić, Ivana
Lemke, Edward A
Gräter, Frauke
Origin of Orthogonality of Strain-Promoted Click Reactions
title Origin of Orthogonality of Strain-Promoted Click Reactions
title_full Origin of Orthogonality of Strain-Promoted Click Reactions
title_fullStr Origin of Orthogonality of Strain-Promoted Click Reactions
title_full_unstemmed Origin of Orthogonality of Strain-Promoted Click Reactions
title_short Origin of Orthogonality of Strain-Promoted Click Reactions
title_sort origin of orthogonality of strain-promoted click reactions
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600239/
https://www.ncbi.nlm.nih.gov/pubmed/26178299
http://dx.doi.org/10.1002/chem.201501727
work_keys_str_mv AT wagnerjohannesa originoforthogonalityofstrainpromotedclickreactions
AT mercadantedavide originoforthogonalityofstrainpromotedclickreactions
AT nikicivana originoforthogonalityofstrainpromotedclickreactions
AT lemkeedwarda originoforthogonalityofstrainpromotedclickreactions
AT graterfrauke originoforthogonalityofstrainpromotedclickreactions