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

Abstract

The development of 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 that are sterically or electronically dissimilar to those used during the reaction optimization campaign. Consequently, expanding the scope of previously optimized catalytic asymmetric reactions to include more challenging substrates is decidedly nontrivial. 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 demanding. 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 synthesis of modified phosphoramidite ligands, designed using quantitative structure–selectivity relationships (QSSRs). Iterative rounds of model construction and ligand synthesis were executed in parallel to evaluate the performance of 20 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 20 examples.

Noncovalent CH–π and π–π Interactions in Phosphoramidite Palladium(II) Complexes with Strong Conformational Preference

“…[27,28] Following this report, interactions between the ligand and the substrates or ligands and metal (cation-p) have been proposed to be responsible for the high stereoinduction observed in many metal-catalyzed reactions. [29][30][31] A few years ago we introduced a supramolecular balance based on bis(phosphoramidite) palladium(II) complexes, which provided the principal idea how to assess the noncovalent interactions between two ligands in TM complexes. [28,32] However, later examination of the balance by computational methods and detailed chemical shift analysis revealed a conformational exchange of an amine side chain in one of the complexes, not interpreted by the previous qualitative analysis, thus reducing the accuracy of the balance.…”

A Comprehensive Discovery Platform for Organophosphorus Ligands for Catalysis

“…Unique models were averaged to provide robust predictions of which ligands would provide high selectivity. 46 Gratifyingly, trained on the results reported by the Burke group, our predictions identify the exact ligands reported by the Biscoe group as most selective. Similarly, regressing the Biscoe dataset and virtually screening VL1 revealed untested electron-poor triaryl phosphines, in particular, Buchwald and ortho-tolyl derivatives, as most selective.…”

A quantitative metric for organic radical stability and persistence using thermodynamic and kinetic features

“…4 ). 45,46 We added several charged structures known to be stable radicals ( e.g. , phenyl-viologen) to our dataset (ESI Fig.…”