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. 2022 Jun 11;27(12):3780.
doi: 10.3390/molecules27123780.

Observation of Hyperpositive Non-Linear Effect in Asymmetric Organozinc Alkylation in Presence of N-Pyrrolidinyl Norephedrine

Thibault Thierry  1 , Yannick Geiger  1   2 , Stéphane Bellemin-Laponnaz  1
Affiliations

Observation of Hyperpositive Non-Linear Effect in Asymmetric Organozinc Alkylation in Presence of N-Pyrrolidinyl Norephedrine

Thibault Thierry et al. Molecules. .

Erratum in

Abstract

Phenomena related to asymmetric amplification are considered to be key to understanding the emergence of homochirality in life. In asymmetric catalysis, theoretical and experimental models have been studied to understand such chiral amplification, in particular based on non-linear effects. Three decades after the theoretical demonstration that a chiral catalyst, when not enantiopure, could be more enantioselective than its enantiopure counterpart, we show here a new experimental example of nonlinear hyperpositive effect. We report here our investigations in the enantioselective zinc-catalyzed alkylation of benzaldehyde with N-pyrrolidinyl norephedrine as partially resolved chiral ligand, which shows a significant hyperpositive non-linear effect. A study of the underlying mechanism was conducted, which allows us to confirm a mechanism that implies a monomeric and a dimeric complex both catalyzing the reaction at a steady state and giving different enantioselectivities.

Keywords: asymmetric catalysis; chiral amplification; nonlinear effect.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Product ee vs. ligand ee graphs of catalytic asymmetric reactions showing examples for (a) no NLE, (b) a positive NLE ((+)-NLE), (c) a negative NLE ((−)-NLE), (d) a hyperpositive NLE and (e) an enantiodivergent NLE.
Figure 2
Figure 2
Catalytic enantioselective addition of dialkylzincs to benzaldehyde, catalyzed by N-pyrrolidinyl norephedrine.
Figure 3
Figure 3
Optical purity of the product as a function of the enantiomeric excess of NPNE ligand (20 mol%) at different temperatures. (a) with ZnEt2 as reagent; (b) with ZnMe2 as reagent. The reaction conditions and experimental procedure are described in the Supplementary Methods. Each point is the mean of three different experiments. The vertical error bars depict standard deviations. The dashed line represents the product e.e. of the enantiopure compound; the full line is a free-hand drawing, which serves as a guideline.
Figure 3
Figure 3
Optical purity of the product as a function of the enantiomeric excess of NPNE ligand (20 mol%) at different temperatures. (a) with ZnEt2 as reagent; (b) with ZnMe2 as reagent. The reaction conditions and experimental procedure are described in the Supplementary Methods. Each point is the mean of three different experiments. The vertical error bars depict standard deviations. The dashed line represents the product e.e. of the enantiopure compound; the full line is a free-hand drawing, which serves as a guideline.
Figure 4
Figure 4
Reaction medium (ligand, substrate, diethylzinc, toluene) as function of the optical purity of the NPNE ligand. From left to right: 20% eeL, 50% eeL and 100% eeL.
Figure 5
Figure 5
Optical purity of the product as a function of the catalyst loading of NPNE ligand (enantiopure 1S-2R form) at different temperatures. (a) with ZnEt2 as reagent; (b) with ZnMe2 as reagent. The reaction conditions and experimental procedure are described in the Supplementary Methods. Each point is the mean of three different experiments. The vertical error bars depict standard deviations. The dotted trendlines are second-order polynomial fits, which serve as guidelines.
Figure 6
Figure 6
Optical purity of the product as a function of the temperature. Orange triangles correspond to the reaction with ZnEt2 as reagent; blue squares correspond to the reaction with ZnMe2 as reagent. The reaction conditions and experimental procedure are described in the Supplementary Methods. Each point is the mean of three different experiments. The horizontal error bars depict temperature variation during the reaction. The vertical error bars depict standard deviations. The dotted trendlines are second-order polynomial fits, which serve as guidelines.
Figure 7
Figure 7
Superimposition of the non-linear effect studies from Figure 2 (colored dots, triangles, and tilted quads) and the eeP vs catalyst loading data from Figure 4 (black quads) that was converted to eeP vs. simulated ligand ee, assuming a complete trapping of the racemic ligand.
Figure 8
Figure 8
Proposed enantiodivergent model with (−)-NPNE as major enantiomer.
See this image and copyright information in PMC

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