Quantitatively Correlating the Effect of Ligand‐Substituent Size in Asymmetric Catalysis Using Linear Free Energy Relationships

Abstract

In the past three decades, the discovery and application of effective asymmetric catalysts has flourished in both academic and industrial settings.[1] This is especially true within the recent decade where the field of asymmetric catalysis has witnessed an incredible expansion, and the benchmarks for acceptable asymmetric induction have significantly risen. However, the approach to catalyst identification remains mainly empirical, wherein evaluation of a considerable number of catalyst structures is required to develop a mature chiral catalyst. While this process has been expedited by technological advancements, [2] the understanding of the relationship between catalyst structure and the enantioselectivity of the catalyzed reaction is generally precarious. This can be attributed to the small energy differences in the activation barrier leading to the enantiomeric products and/or the complicated preequilibria in most catalytic reactions. [3] An approach to developing greater predictive power in asymmetric catalysis is based on the use of modular ligands [4] in lieu of a detailed understanding of the microscopic processes involved in asymmetric induction. We believe the ability to make systematic changes to the ligand structure not only leads to enhanced product enantiomeric excess, [5] but allows for the elucidation of structure-enantioselectivity relationships. [6] Herein, we report the use of a modular ligand set to systematically study the effect of ligand size and the first observation of a linear free energy relationship between steric parameters and enantiomeric ratio. Additionally, our analysis of several previously reported enantioselective reactions reveals similar linear free energy relationships.We have recently disclosed the use of modular oxazoline ligands [7] in enantioselective Nozaki-Hiyama-Kishi reactions of allylic halides [8,9] with both aldehydes [5a] and ketones [5c] ( Figure 1). A key observation from these studies is that the facial selectivity of the reaction is directly correlated to the absolute configuration of the proline module of the ligand. For example, in comparing ligands 1 a and 1 b, which differ only in the configuration of the proline module, a considerable difference in enantiomeric ratio is observed for allylation of both aldehydes and ketones. Most notably, the allylation of benzaldehyde is promoted in nearly 90 % ee (96:4 e.r. and 94.5:5.5 e.r.) using both ligands but with different senses of asymmetric induction. A similar effect is also found for the allylation of acetophenone. Systematic changes to the configuration of the other chiral centers in the ligand structure had only a subtle impact. These observations prompted us to explore the role of the proline module in greater detail. In order to initiate the investigation, we decided to make systematic changes to the proline module and probe the effect on the enantioselective outcome of the reaction. This was reasoned to be most easily accomplished through modification of the proline nitrogen, as proline carbamates...

Multidimensional steric parameters in the analysis of asymmetric catalytic reactions

“…2) 23,24 . Systematic optimization of the ligand scaffold revealed a pronounced effect of different carbamoyl moieties on the enantioselectivity of the reaction.…”

“…Requisite to developing steric effect-based linear free energy relationships (LFERs) was the consideration of two key challenges: (i) developing modular ligand scaffolds with which meaningful systematic perturbations could be executed 24,25 and (ii) numerically quantifying steric effects for the synthetically accessible substituents. Steric parameterization based on experimental results has been studied for over 60 years, but it has been applied to asymmetric catalysis only recently 23,[26][27][28] . However, the related discipline of quantitative structure-activity relationships (QSAR) is particularly adept in the application, refinement and development of steric parameters so as to fundamentally understand the spatial interactions of small molecules in biological systems 29 .…”

“…Steric effects are widely implicated in asymmetric induction 3,22 , so we began to examine methods by which steric effects in enantioselective reactions could be quantitatively defined 23 . Requisite to developing steric effect-based linear free energy relationships (LFERs) was the consideration of two key challenges: (i) developing modular ligand scaffolds with which meaningful systematic perturbations could be executed 24,25 and (ii) numerically quantifying steric effects for the synthetically accessible substituents.…”

Enantiodivergent Fluorination of Allylic Alcohols: Data Set Design Reveals Structural Interplay between Achiral Directing Group and Chiral Anion

“…68–77 Figure 4A depicts the enantioselective outcome of each BA-phosphate combination. It was anticipated that the general trends observed using TRIP (Figure 3) would hold across the series of catalysts (e.g., 4 -substituted BAs would display the highest propensity for one enantiomer, while 3,5-disubstituted BAs would favor the other).…”

Predicting and optimizing asymmetric catalyst performance using the principles of experimental design and steric parameters

“…We have recently disclosed the use of steric parameters originally developed by Taft and modified by to quantitatively evaluate ligand effects on enantioselectivity in several Nozaki-HiyamaKishi (NHK) carbonyl allylations (18,19). Because the product distribution of enantiomers (R vs. S) is directly related to the differences in free energy arising in the diastereomeric transition states, we were able to correlate er with the corresponding Charton steric parameter.…”