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

Jessica Wahlers, Jèssica Margalef, Eric Hansen, Armita Bayesteh, Paul Helquist, Montserrat Diéguez, Oscar Pàmies, Olaf Wiest () and Per-Ola Norrby ()
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Jessica Wahlers: University of Notre Dame
Jèssica Margalef: Universitat Rovira I Virgili
Eric Hansen: University of Notre Dame
Armita Bayesteh: Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca
Paul Helquist: University of Notre Dame
Montserrat Diéguez: Universitat Rovira I Virgili
Oscar Pàmies: Universitat Rovira I Virgili
Olaf Wiest: University of Notre Dame
Per-Ola Norrby: AstraZeneca Gothenburg

Nature Communications, 2021, vol. 12, issue 1, 1-6

Abstract: Abstract 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27065-2

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DOI: 10.1038/s41467-021-27065-2

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