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

Author

Listed:
  • 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
    University of Gothenburg)

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.

Suggested Citation

  • Jessica Wahlers & Jèssica Margalef & Eric Hansen & Armita Bayesteh & Paul Helquist & Montserrat Diéguez & Oscar Pàmies & Olaf Wiest & Per-Ola Norrby, 2021. "Proofreading experimentally assigned stereochemistry through Q2MM predictions in Pd-catalyzed allylic aminations," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27065-2
    DOI: 10.1038/s41467-021-27065-2
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