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Retooling Asymmetric Conjugate Additions for Sterically Demanding Substrates with an Iterative Data-Driven Approach

preprint
submitted on 02.05.2019 and posted on 03.05.2019 by Alexandre Brethomé, Robert Paton, Stephen P. Fletcher
The development of new catalytic enantioselective methods is routinely carried out using easily accessible and prototypical substrates. This approach to reaction development often yields asymmetric methods that perform poorly using substrates sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include new substrates is decidedly non-trivial. Here we address this challenge through the development of a systematic workflow to broaden the applicability and reliability of asymmetric conjugate additions to substrates conventionally regarded as sterically and electronically challenging. The copper-catalyzed asymmetric conjugate addition of alkylzirconium nucleophiles to form tertiary centers, although successful for linear alkyl chains, fails for more sterically demanding linear α,β-unsaturated ketones. Key to adapting this method to obtain high enantioselectivity was the discovery of new phosphoramidite ligands, designed using quantitative structure-selectivity relationships (QSSR). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of twenty chiral ligands. The copper-catalyzed asymmetric addition is now more broadly applicable, even tolerating linear enones bearing tert-butyl β-substituents. The presence of common functional groups is tolerated in both nucleophiles and electrophiles, giving up to 99% yield and 95% ee across twenty examples.

Funding

EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine (EP/L015838/1)

National Science Foundation (ACI-1532235 and ACI-1532236)

Extreme Science and Engineering Discovery Environment (XSEDE) through allocation TG-CHE180056 (Theory of New Organic Reactions). XSEDE is supported by the National Science Foundation (ACI-1548562).

History

Email Address of Submitting Author

alexandre.brethome@chem.ox.ac.uk

Institution

University of Oxford

Country

UK

ORCID For Submitting Author

0000-0002-0706-4344

Declaration of Conflict of Interest

No conflict of interest

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