# Autoinductive Effects in Zinc-Catalyzed Alkylations of Benzaldehyde Mediated by Simple Chiral *β*-Amino Alcohol Ligands

Joseph El Khoury, Thibault Thierry, Yannick Geiger, Stéphane

Bellemin-Laponnaz

► To cite this version:

Joseph El Khoury, Thibault Thierry, Yannick Geiger, Stéphane Bellemin-Laponnaz. Autoinductive Effects in Zinc-Catalyzed Alkylations of Benzaldehyde Mediated by Simple Chiral *β*-Amino Alcohol Ligands. ChemistryEurope, 2025, 3 (4), 10.1002/ceur.202500067. hal-05339962

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# Autoinductive Effects in Zinc-Catalyzed Alkylations of Benzaldehyde Mediated by Simple Chiral β-Amino Alcohol Ligands

Joseph El Khoury, Thibault Thierry, Yannick Geiger, and Stéphane Bellemin-Laponnaz*

The first report on enantioselective zinc-catalyzed aldehyde alkyl-
ation mediated by a chiral auxiliary has been revisited in the con-
text of recent advances in the field. The enantioselectivity of the
alcohol formed as a function of the progress of the reaction has
been studied with four different amino alcohols. During the
course of the reaction, the enantiomeric ratio, in which the
product is formed, is inverted, giving rise to enantiodivergence,

a phenomenon that is also dependent on the catalyst loading. By
combining these results with studies on nonlinear effects as well
as other mechanistic studies, a model that accounts for the enan-
tiodivergence is derived. It turns out that it is a case of catalytic
autoinduction in which an active species with better enantiose-
lectivity than the native catalyst is generated.

**1. Introduction**

Asymmetric catalysis provides access to a wide range of enantioen-
riched compounds and underlies pivotal research domains such as
the development of novel pharmaceuticals.[1] The design of chiral
catalysts represents a significant challenge, with difficulties that can
be attributed in some cases to the existence of disparate catalytic
pathways that give rise to parallel reactions. Such competitive reac-
tion sequences can impact not only the yield of the synthetic
reaction but also the enantioselectivity of the desired product.
Therefore, achieving close to perfect enantiopurity ideally requires
the presence of a single, efficient and enantioselective catalytic spe-
cies that remains unaltered throughout the course of the reaction.

Within mechanistic studies of catalytic systems, the enantio-
selectivity of a reaction as a function of the overall conversion is
very rarely studied. Notably, this type of experiment enables the
acquisition of information that would otherwise be inaccessible
through the analysis of the final reaction outcome alone. For
example, in some cases, the product itself affects the perfor-
mance of the catalyst in terms of activity and enantioselectivity,

giving an asymmetric autoinduction.[2] Nevertheless, a review of
the literature reveals a number of interesting examples where
autoinduction was observed. These examples include cases of
organocatalysis[3,4] or metal catalysis with titanium,[5–7] manga-
nese,[8,9] or palladium[10] and others.[11] There are also several
examples involving zinc, such as in the aldol reaction[12] and,
especially, the addition of ZnR<sub>2</sub> to ketones or aldehydes.[13] It
is important to note the distinction between autoinduction
and autocatalysis, where the catalyst and product are the same
species, as exemplified by the Soai reaction.[14–16]

In order to gain further insight into the field, we revisited the
pioneering work published by Oguni and Omi in 1984 on the
zinc-catalyzed asymmetric alkylation reaction, which represented
a significant advancement at the time.[17] The evolution of the
enantioselectivity of the reaction as a function of conversion
has been investigated with four different β-amino alcohols,
and they all display a signature consistent with asymmetric auto-
induction. In addition, the autoinduction phenomenon is comple-
mented by enantiodivergence. In all these systems, the product
interacts with the chiral active complex, improving its perfor-
mance in terms of enantioselectivity.

**2. Results and Discussion**

**2.1. Enantiodivergence in the Oguni-Omi Reaction**

In 1984, Oguni and Omi reported the first example of enantiose-
lective addition of dialkylzinc to an aldehyde, who showed
that a small amount of chiral β-amino alcohols (2 mol%) can
give the alkylation product in high yield and enantiomeric
excesses up to 49%.[17] We studied the reaction under the same
conditions (i.e., at 20 °C in toluene, **Figure 1**) in presence of four
different β-amino alcohols, namely (S)-valinol, (S)-leucinol,
(S)-phenylalaninol, and (S)-phenylglycinol. With the first three
β-amino alcohols that had been already used by Oguni et al.

J. El Khoury, T. Thierry, S. Bellemin-Laponnaz

IPCMS

Institut de Physique et Chimie des Matériaux de Strasbourg

Université de Strasbourg-CNRS UMR 7504

23 rue du Loess, 67034 Strasbourg Cedex 2, France

E-mail: bellemin@unistra.fr

Y. Geiger

Laboratory of Systems Chemistry

Chimie de la Matière Complexe (CMC)

Université de Strasbourg-CNRS UMR7140

4 rue Blaise Pascal, 67081 Strasbourg, France

<figure><img src="image_3.png" /></figure>

Supporting information for this article is available on the WWW under https://
doi.org/10.1002/ceur.202500067

<figure><img src="image_4.png" /></figure>

© 2025 The Author(s). ChemistryEurope published by Chemistry Europe and Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>**Figure 1.** The chiral β-amino alcohol-catalyzed addition of ZnEt₂ to benzaldehyde (R = iPr-, valinol; iPrCH₂-, leucinol; PhCH₂-, phenylalaninol; Ph-, phenylglycinol).</figcaption></figure>

the published results proved to be reproducible provided that low catalytic loadings were used. Notably, a significant drop in the enantioselectivity of the product (*ee*<sub>P</sub>) was observed when the amount of the chiral auxiliary was increased, which appeared counter-intuitive. We then monitored the enantioselectivity of the reaction as a function of overall conversion, employing different loadings of the enantiopure auxiliary (Figure 2; ligand *ee* (*ee*<sub>L</sub>) = 100%).

We observed that whatever the amount of chiral auxiliary, the reaction product had a different *ee*<sub>P</sub> at the start and the end of the reaction. With (S)-valinol (Figure 2a), the reaction appeared to start

with a negative enantiomeric excess (i.e., the (S)-alcohol as major product). However, at the end of the reaction performed with a 1 mol% catalyst loading an *ee* of 64% in favor of the (R)-product was obtained, whereas the same reaction with a 20 mol% loading of catalyst only gave rise to an *ee* of 21% (R). Monitoring of the reaction during the course of the conversion showed that with a high catalyst loading, the enantioselectivity evolved slowly and progressively with a moderate gradient. The *ee* change was much faster when the amount of catalyst was reduced. Thus, the lower the catalyst loading, the earlier and more pronounced the increase in *ee* over time, with the initial *ee* remaining virtually unchanged. The same feature was observed with leucinol or phenylalaninol (Figure 2b,c): At high catalyst loadings, initially the (S)-enantiomer of the alcohol was generated with an even more pronounced negative *ee*<sub>P</sub>. Finally, with phenylglycinol (Figure 2d), the variation of the *ee*<sub>P</sub> between the beginning and end of the reaction was the most pronounced ranging from -65% to +55% *ee*.

## 2.2. NLEs

A practical consequence of the dynamic behavior of the catalysts is that the *ee*<sub>P</sub>/*ee*<sub>L</sub> relationships, as established in studies on

<figure><img src="image_7.png" /><figcaption>(c) Phenylalaninol</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 2.** The a) (S)-valinol, b) (S)-leucinol, c) (S)-phenylalaninol, and d) (S)-phenylglycinol-catalyzed addition of ZnEt₂ to benzaldehyde: enantiomeric excess of the product as function of the advancement of the reaction at different catalyst loading (20 °C in toluene). The full lines are a free-hand drawing, which serves as a guideline.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>(d) Phenylglycinol</figcaption></figure>

<figure><img src="image_10.png" /></figure>
<figure><img src="image_11.png" /></figure>

nonlinear effects (NLEs), will be impacted by changes in the reac-
tion environment as the reaction progresses. In this context, and
by setting the catalyst loading at 2.5 mol%, we studied the
dependency of ee~p~ on the overall conversion in presence of
the aminoalcohols at various ee~L~ (see Figure S4, Supporting info-
mation). This allowed a probe into NLEs at various stages of the
reaction as displayed in **Figure 3**. With valinol, a linear ee~p~/ee~L~
correlation was observed whatever the conversion (Figure 3a).
With leucinol as the ligand, a positive NLE was observed, which
appeared to be slightly less marked at the end of the reaction, a
trend that was also the case in presence of phenylalaninol as
ligand (Figure 3b,c). The most interesting observation was made
with phenylglycinol, for which a negative NLE was observed at
the start of the reaction, which gradually converged to a linear
relationship at the end of the reaction (Figure 3d). Such phenom-
enon is directly linked to the fact that the active catalytic species
undergoes a change during the course of the reaction. The grad-
ual disappearance of the NLE suggests that the increasing pres-
ence of the product appears to disfavor the formation of catalyst
aggregates, which usually are at the origin of the NLE.[18,19] A lin-
ear correlation between product ee and ligand ee is generally
accepted as an indication of the absence of catalyst aggregation,

even though this can be misleading in some cases.[20] In this case,
it is clear that the observed linearity at the end of the reaction
appears to hide a much more complex catalyst behavior.

**2.3. Autoinduction in the Catalytic Transformation**

Given the observations represented in Figure 3, there are several scenarios to be considered. The first involves a system with multiple active species in equilibrium. If the product formed an inactive adduct with one of the catalytically active species (i.e., product inhibition), then the interplay of such equilibria might favor another active species, resulting in a change in ee<sub>p</sub> with progressive conversion. This phenomenon was observed in a ZnMe<sub>2</sub> addition involving an N-benzyl ephedrine ligand (NBE), where monomeric and dimeric catalysts were found to be active. Progressive product inhibition was found to decrease the effective catalyst concentration, thereby favoring the more enantioselective monomer.[18] Such scenario may apply to (S)-valinol, whose ee<sub>p</sub> versus conversion profiles (Figure 2a) are similar to those of NBE. However, the change of curve shape observed for the other three ligands (Figure 2b–d) is incompatible with that scenario.

<figure><img src="image_12.png" /><figcaption>**Figure 3.** Nonlinear behavior in presence of 2.5 mol% of aminoalcohol at different stages of the reaction; from bottom to top 5% (purple), 15, 30, 50, and 100% conversion (green) (20 °C, toluene as solvent). a) (S)-valinol, b) (S)-leucinol, c) (S)-phenylalaninol, and d) (S)-phenylglycinol.</figcaption></figure>
<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /><figcaption>**Figure 4.** Schematic representation of a autocatalytic model which consists of a monomeric catalyst [ML] in equilibrium with a dimeric catalyst [ML]₂ and with a catalyst that includes *n* equivalents of product P, i.e., [ML][P]n. The catalysts are issued from the reaction of a metal salt (M) with a chiral, enantiomeric ligand (L) and promote the reaction of a substrate and a reactant to form the chiral product, with the overall enantiomeric excess eeP.</figcaption></figure>

For the case at hand, the most reasonable interpretation involves asymmetric autoinduction, which is based on the combination of a catalyst and a product to form a new catalytically active species with a different enantioselectivity.[21] As an additional experiment to test for such a possibility, we investigated the effect of adding the product prior to the start of the reaction and compared the result with reaction involving the “undoped” catalyst(s). In our case, this led to a slight increase in the ee<sub>P</sub>, the dopant being racemic or enantiopure (S), which made no difference (see ESI). Additionally, we conducted ¹H diffusion-ordered spectroscopy (DOSY) NMR experiments with enantiopure valinol and phenylglycinol as ligands. Before the addition of the aldehyde, the reaction of aminoalcohol and diethylzinc gave rise to a tetrameric species [LZnEt]<sub>4</sub> with valinol and a pentameric species [LZnEt]<sub>5</sub> with phenylglycinol, both of which can be considered the precatalysts. Similar experiments carried out after completion of the catalytic reaction revealed the presence of even higher aggregates made up of zinc complexes, either from the [EtZnOR] product or from the [LZnEt] catalyst, giving the general formula [EtZnOR]<sub>n</sub>[LZnEt]<sub>m</sub> with n + m = 3 to 9. This proves that the catalyst can, in principle, co-aggregate with the product. However, it is important to note that the aggregation state during ongoing reaction can differ during the course of the reaction, as seen in a ZnEt<sub>2</sub>-addition involving N-methyl ephedrine.[20]

## 2.4. A Systems Model of the Active Catalytic Species

We have recently proposed a kinetic model to elucidate the type of behavior described in the previous sections[22] as summarized in **Figure 4**. It is based on a system of coupled equilibria in which the enantiopure ligand reacts with the metal precursor species to give monomeric and dimeric homochiral complexes ([ML] and [ML]₂). The monomeric species is in equilibrium with *n* molecule(s) of product P to generate a catalytically active complex of the general type [ML][P]n. Such a model allows simulations of product enantiopurity (ee<sub>P</sub>) which represent interesting tendencies of catalyst behavior. For instance, the dependence of the ee<sub>P</sub> vs conversion curve on the initial catalyst loading (cf. Figure 2a–d) suggests that the active species at the beginning has a degree of aggregation greater than one, a feature that was confirmed by our simulations.

<figure><img src="image_15.png" /><figcaption>**Figure 5.** Enantioselectivity versus Conversion simulations according to the model described in Figure 4 with the catalyst loading as varying parameter (20 to 0.1 mol%). Fixed parameters: K<sub>2</sub><sup>Homo</sup> = K<sub>RP</sub> = 100, k<sub>2</sub> = 1, k<sub>RP</sub> = 0.01, k<sub>1</sub> = 0, ee<sub>2</sub> = -75%, ee<sub>RP</sub> = +55% ee, and [S]<sub>0</sub> = 0.2 M.</figcaption></figure>

As a representative result illustrating this point, **Figure 5** shows the evolution of the instantaneous enantioselectivity of the reaction as a function of reaction progress, assuming a [ML]₂ dimer that generates the product (S) with an enantioselectivity of -65% and a competing monomer-product [ML][P] catalyst aggregate generating the other enantiomer (R) with an ee of +55%. This model emulates the experimental results in the presence of phenylglycinol as a chiral auxiliary.

Another feature observed in these model studies concerns the difficulty in achieving complete conversion, with kinetics slowing down more markedly than expected, a sign of catalyst poisoning. This phenomenon is unsurprising, given the catalyst's favorable interaction with its own product. In light with the DOSY experiments, it is thus conceivable that the catalyst is increasingly trapped in aggregates with the reaction product of the type [R'Zn-OR]<sub>n</sub>[LZnR']<sub>m</sub>.

## 3. Conclusion

By using a low catalytic loading of chiral auxiliary, Oguni and Omi employed ideal conditions for achieving a significant enantiomeric
<figure><img src="image_16.png" /></figure>

excess, without acquiring a detailed understanding of all the rele-
vant factors involved. However, this study of the alkylation reaction
with organozincs using these first enantioselective systems shows a
much more complicated behavior than previously thought.[23] It
demonstrates that the aggregated catalyst react rapidly with the
product, thereby generating a new catalyst that gives rise to the
observed enantiodivergence in the reaction. It also shows that
the enantioselectivity of the catalytic process may thus depend both
on its progress (i.e., conversion) and the shifts in the composition of
the reaction mixture involved as well as NLEs based on catalyst
aggregation phenomena. The studies carried out here provide cru-
cial information for a better understanding of the mechanism and
consequently for improving the enantioselective process. This work
also points out that the "systems-chemical" approach to an enan-
tioselective catalytic reaction may be encountered more often than
previously thought.

Acknowledgements

This research was funded by the French National Research
Agency (ANR) under project ANR-23-CE07-0023. This research
was supported in part by the Interdisciplinary Thematic
Institute ITI-CSC via the IdEx Unistra (ANR-10-IDEX-0002) within
the programme Investissement d'Avenir.

Conflict of Interest

The authors declare no conflict of interest.

Data Availability Statement

The data that support the findings of this study are available in
the supplementary material of this article.

**Keywords:** asymmetric catalysis · autoinduction · enantiodivergence · nonlinear effects · zinc

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