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.

Scheme 1. Limitations in ACAs of Alkylzirconium Species to Acyclic α,β-Unsaturated Ketones Bearing Branched or Aromatic Moieties and Our Approach Tackling These Limitations

Scheme 2. (A) Analysis of the Structure–Selectivity Relationship from the Initial Ligand Derivatization and (B) Ligand Design Workflow Used in This Work

Figure 1

Continuous refinement of the model with new input of data. The model correlates experimentally measured enantioselectivity and predicted enantioselectivity. The gray area represents the standard error at 95% confidence interval and ee’s were averaged from at least two reaction repeats.

Figure 2

(A) Substitution of isopropyl with methyl groups leads to an important selectivity jump, likely due to a conformational change. Global minimum conformers are optimized at the ωB97X-D/6-31G(d) level of theory. (B) Synthesized ligands ranked following their distance from the origin in a yield versus selectivity plot. Distances further from the origin indicate superior performance.

Scheme 3. Optimized Conditions and Substrate Scope of the ACA on α,β-Unsaturated Ketone Bearing Branched or Aromatic Moieties