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Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations

The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening...

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Autores principales: Wahlers, Jessica, Margalef, Jèssica, Hansen, Eric, Bayesteh, Armita, Helquist, Paul, Diéguez, Montserrat, Pàmies, Oscar, Wiest, Olaf, Norrby, Per-Ola
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602308/
https://www.ncbi.nlm.nih.gov/pubmed/34795274
http://dx.doi.org/10.1038/s41467-021-27065-2
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author Wahlers, Jessica
Margalef, Jèssica
Hansen, Eric
Bayesteh, Armita
Helquist, Paul
Diéguez, Montserrat
Pàmies, Oscar
Wiest, Olaf
Norrby, Per-Ola
author_facet Wahlers, Jessica
Margalef, Jèssica
Hansen, Eric
Bayesteh, Armita
Helquist, Paul
Diéguez, Montserrat
Pàmies, Oscar
Wiest, Olaf
Norrby, Per-Ola
author_sort Wahlers, Jessica
collection PubMed
description The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.
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spelling pubmed-86023082021-11-19 Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations Wahlers, Jessica Margalef, Jèssica Hansen, Eric Bayesteh, Armita Helquist, Paul Diéguez, Montserrat Pàmies, Oscar Wiest, Olaf Norrby, Per-Ola Nat Commun Article The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome. Nature Publishing Group UK 2021-11-18 /pmc/articles/PMC8602308/ /pubmed/34795274 http://dx.doi.org/10.1038/s41467-021-27065-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wahlers, Jessica
Margalef, Jèssica
Hansen, Eric
Bayesteh, Armita
Helquist, Paul
Diéguez, Montserrat
Pàmies, Oscar
Wiest, Olaf
Norrby, Per-Ola
Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations
title Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations
title_full Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations
title_fullStr Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations
title_full_unstemmed Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations
title_short Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations
title_sort proofreading experimentally assigned stereochemistry through q2mm predictions in pd-catalyzed allylic aminations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602308/
https://www.ncbi.nlm.nih.gov/pubmed/34795274
http://dx.doi.org/10.1038/s41467-021-27065-2
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