The Reduction of Carbonyl Compounds with Dicyclopentylzinc: A New Example of Asymmetric Amplifying Autocatalysis

A previously unknown reduction of carbonyl compounds with dicyclopentylzinc is reported. Aldehydes react in mild conditions yielding corresponding primary alcohols and cyclopentene. Although cyclohexanone and acetophenone are inert to dicyclopentylzinc, a variety of heterocyclic ketones reacted readily, yielding reasonable to high yields of corresponding secondary alcohols. When the reaction was catalyzed with (–)-(1R,2S)-ephedrine, 3-acetylpyridine (10) resulted in a high yield of (S)-1-(pyridin-3-yl)ethanol (19) with >99% ee. 5-Acetyl-2-bromopyridine (11) also provided the corresponding optically active alcohol 20, albeit with a much lower optical yield. When 10% of 19 with 92% ee was used as an autocatalyst, 55% yield of the same compound was obtained, with 95% ee and 96% ee in two independent experiments. A three-stage reaction sequence starting from “no chirality” reaction yielded 19 with 6% ee. Thus, amplifying autocatalysis was detected in the reaction of ketone 10 with dicylopentylzinc.


Introduction
The phenomenon of autocatalytic autoamplification so far has only been observed in the Soai reaction [1,2], i.e., the reaction of diisopropylzinc with pyrimidine aldehydes with a strictly defined structure.Despite the vigorous interest among researchers to investigate this unusual transformation, which, among other specific features, leads to the spontaneous generation of chirality [3][4][5][6], the extension of the reaction scope has had only very limited success.A pyridinic aldehyde with the same linker and anchor was also found to undergo an autocatalytic reaction with diisopropylzinc accompanied by the amplification of chirality [7,8].Hence, new examples of such transformations are needed for a better understanding of the intrinsic mechanisms of asymmetric autoamplification and the spontaneous generation of chirality.
So far, only diisopropylzinc has been successfully applied as an alkylating reagent in the Soai reaction.Structurally, a cyclopentyl group is close to the isopropyl group, so we decided to study dicyclopentylzinc in the Soai-type reaction.
To the best of our knowledge, dicyclopentylzinc has been previously applied in the nucleophilic alkylation of different benzyl and heteroaryl halides [9][10][11], the regioselective C-H bond functionalization of acridine [12], 1,6-conjugate addition to paraquinone methides in a microreactor [13], and the nickel-catalyzed alkylation of electron-poor cyclobutanone oximes [14].With methyllithium, dicyclopentylzinc forms mixed trialkylzincate nucleophiles, which can be further used in conjugate addition to cycloalkenones [15].Moreover, the enantioselective alkylation of cyclopropanecarboxaldehyde, furfural, and benzaldehyde with dicyclopentylzinc in the presence of a chiral catalyst was reported [16,17].We are not aware of any reactions of dicyclopentylzinc with ketones described in the literature.

Discovery of the Reducing Properties of Dicyclopentylzinc
We reckoned that since a cyclopentyl group is the closest analog of an isopropyl group, it would be worth investigating dicyclopentylzinc in the reaction with one of the most effective substrates of the Soai reaction, viz., the pyrimidinic aldehyde 1. Unexpectedly, it was found that instead of the desired alkylation product, the primary alcohol 2 formed quantitatively.Cyclopentene was identified as another reaction product (Scheme 1).This result prompted us to investigate further reducing properties of dicyclopentylzinc.
Moreover, the enantioselective alkylation of cyclopropanecarboxaldehyde, furfural, and benzaldehyde with dicyclopentylzinc in the presence of a chiral catalyst was reported [16,17].We are not aware of any reactions of dicyclopentylzinc with ketones described in the literature.

Discovery of the Reducing Properties of Dicyclopentylzinc
We reckoned that since a cyclopentyl group is the closest analog of an isopropyl group, it would be worth investigating dicyclopentylzinc in the reaction with one of the most effective substrates of the Soai reaction, viz., the pyrimidinic aldehyde 1. Unexpectedly, it was found that instead of the desired alkylation product, the primary alcohol 2 formed quantitatively.Cyclopentene was identified as another reaction product (Scheme 1).This result prompted us to investigate further reducing properties of dicyclopentylzinc.
Scheme 1. Reduction of the pyrimidine aldehyde 1 with dicyclopentylzinc.

Reactions of Dicyclopentylzinc with Aldehydes
Reactions of aldehydes with dicyclopentylzinc were carried out at an equimolar ratio in hexane at room temperature.No alkylation products were observed, and corresponding alcohols as the exclusive products were obtained.The results of the reduction of representative aldehydes with dicyclopentylzinc are summarized in Table 1.Entries 1-4 show that the reaction is effective for various aromatic aldehydes.Both cyclopentyl groups can be used for the reduction (Entry 2), whereas in comparing the reaction conditions in Entries 4 and 5, one can conclude that an electron-acceptor substituent has an accelerating effect (Entry 5), while an electron-donating methoxy group decreases the reactivity (Entry 4).
Control experiments were performed with diisopropylzinc.With hexanal, no appreciable amount of the reduction product was obtained.In fact, the alkylation process was very slow, yielding a multispot reaction mixture.Benzaldehyde in the reaction with 1 eq. of ZnPr i 2 after 26 h at rt in hexane yielded 26% of the alkylation product, and 74% of the starting material was recovered.Scheme 1. Reduction of the pyrimidine aldehyde 1 with dicyclopentylzinc.

Reactions of Dicyclopentylzinc with Aldehydes
Reactions of aldehydes with dicyclopentylzinc were carried out at an equimolar ratio in hexane at room temperature.No alkylation products were observed, and corresponding alcohols as the exclusive products were obtained.The results of the reduction of representative aldehydes with dicyclopentylzinc are summarized in Table 1.Entries 1-4 show that the reaction is effective for various aromatic aldehydes.Both cyclopentyl groups can be used for the reduction (Entry 2), whereas in comparing the reaction conditions in Entries 4 and 5, one can conclude that an electron-acceptor substituent has an accelerating effect (Entry 5), while an electron-donating methoxy group decreases the reactivity (Entry 4).

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra. 1 eq.ZnCp 2 , rt,1 h, hexane Table 1.Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra. 1 eq.ZnCp 2 , rt, 3.5 h, hexane Table 1.Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra.Table 1.Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra. 1 eq.ZnCp 2 , rt, 0.5 h, hexane Table 1.Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra. 1 eq.ZnCp 2 , rt, 0.5 h, hexane Table 1.Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra. 1 eq.ZnCp 2 , rt, 0.5 h, hexane Table 1.Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra.Control experiments were performed with diisopropylzinc.With hexanal, no appreciable amount of the reduction product was obtained.In fact, the alkylation process was very slow, yielding a multispot reaction mixture.Benzaldehyde in the reaction with 1 eq. of ZnPr i 2 after 26 h at rt in hexane yielded 26% of the alkylation product, and 74% of the starting material was recovered.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numerous products of aldol condensation were detected in the first case.Only starting materials were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temperature as well as after heating for 7 h at 60 • C.
A series of differently substituted pyridine ketones 3-11 were involved in the reactions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic core were readily reduced to the corresponding secondary alcohols 12-20.According to the NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacted, although the organozinc reagent was used in excess (3-5 equivalents).No signals of any alkylation products were observed in NMR spectra.

Reactions of Dicyclopentylzinc with Ketones
Acetophenone and cyclohexanone do not react with dicyclopentylzinc.Numero products of aldol condensation were detected in the first case.Only starting materi were observed in the reaction of 3-acetylindole with dicyclopentylzinc at room temp ature as well as after heating for 7 h at 60 °C.
A series of differently substituted pyridine ketones 3-11 were involved in the re tions with dicyclopentylzinc (Schemes 2 and 3, Table 2).Ketones 3-11 with pyridinic co were readily reduced to the corresponding secondary alcohols 12-20.According to t NMR spectra of crude reaction mixtures, 4-15% of starting ketones remained unreacte although the organozinc reagent was used in excess (3-5 equivalents).No signals of a alkylation products were observed in NMR spectra.Since an asymmetric carbon atom is generated in this transformation, we decided to check the possibility of the catalytic asymmetric reduction using (1R,2S)-ephedrine ( 21) as a catalyst.The analysis of the obtained data led us to conclude that the asymmetric reaction was possible, but solely for 3-acetylpyridines 10 and 11, which showed enantiomeric excess (Table 2) since the secondary alcohols obtained from 2-acetylpyridines 3-7 and 4-acetylpyridines 8 and 9 were not optically active.It was previously reported that the enantioselective reduction of isomeric acetylpyridines 3, 8, and 10 can be achieved using chiral lithium borohydride modified with N,N′-dibenzoylcystine and ethanol [18].
The best ee was obtained in the case of 3-acetylpyridine (10) (Entries 2 and 3, Table 2), which prompted us to study the asymmetric reduction of ketone 10 in more detail.Two independent experiments under similar reaction conditions reproduced the high ee value.

Computational Studies of the Reduction of Pyridinic Ketones with Dicyclopentylzinc
In order to study distinctive features of the reaction of dicyclopentylzinc with ketones, we located the transition states for the reduction of the ketones 3, 8, and 10 (Scheme 4).
Computations attest to a synchronous transformation through a six-membered transition state.The lowest activation barrier was computed for the reduction of 3-acetylpyridine 10.Although we are unaware of the synthetically meaningful reactions of this type, similar transformations are frequently observed as side processes in the reactions of hindered Grignard reagents with carbonyl compounds [19,20].Since an asymmetric carbon atom is generated in this transformation, we decided to check the possibility of the catalytic asymmetric reduction using (1R,2S)-ephedrine ( 21) as a catalyst.The analysis of the obtained data led us to conclude that the asymmetric reaction was possible, but solely for 3-acetylpyridines 10 and 11, which showed enantiomeric excess (Table 2) since the secondary alcohols obtained from 2-acetylpyridines 3-7 and 4-acetylpyridines 8 and 9 were not optically active.It was previously reported that the enantioselective reduction of isomeric acetylpyridines 3, 8, and 10 can be achieved using chiral lithium borohydride modified with N,N′-dibenzoylcystine and ethanol [18].
The best ee was obtained in the case of 3-acetylpyridine (10) (Entries 2 and 3, Table 2), which prompted us to study the asymmetric reduction of ketone 10 in more detail.Two independent experiments under similar reaction conditions reproduced the high ee value.

Computational Studies of the Reduction of Pyridinic Ketones with Dicyclopentylzinc
In order to study distinctive features of the reaction of dicyclopentylzinc with ketones, we located the transition states for the reduction of the ketones 3, 8, and 10 (Scheme 4).
Computations attest to a synchronous transformation through a six-membered transition state.The lowest activation barrier was computed for the reduction of 3-acetylpyridine 10.Although we are unaware of the synthetically meaningful reactions of this type, similar transformations are frequently observed as side processes in the reactions of hindered Grignard reagents with carbonyl compounds [19,20].Since an asymmetric carbon atom is generated in this transformation, we decided to check the possibility of the catalytic asymmetric reduction using (1R,2S)-ephedrine ( 21) as a catalyst.The analysis of the obtained data led us to conclude that the asymmetric reaction was possible, but solely for 3-acetylpyridines 10 and 11, which showed enantiomeric excess (Table 2) since the secondary alcohols obtained from 2-acetylpyridines 3-7 and 4-acetylpyridines 8 and 9 were not optically active.It was previously reported that the enantioselective reduction of isomeric acetylpyridines 3, 8, and 10 can be achieved using chiral lithium borohydride modified with N,N′-dibenzoylcystine and ethanol [18].
The best ee was obtained in the case of 3-acetylpyridine (10) (Entries 2 and 3, Table 2), which prompted us to study the asymmetric reduction of ketone 10 in more detail.Two independent experiments under similar reaction conditions reproduced the high ee value.

Computational Studies of the Reduction of Pyridinic Ketones with Dicyclopentylzinc
In order to study distinctive features of the reaction of dicyclopentylzinc with ketones, we located the transition states for the reduction of the ketones 3, 8, and 10 (Scheme 4).
Computations attest to a synchronous transformation through a six-membered transition state.The lowest activation barrier was computed for the reduction of 3-acetylpyridine 10.Although we are unaware of the synthetically meaningful reactions of this type, similar transformations are frequently observed as side processes in the reactions of hindered Grignard reagents with carbonyl compounds [19,20] Since an asymmetric carbon atom is generated in this transformation, we decided to check the possibility of the catalytic asymmetric reduction using (1R,2S)-ephedrine ( 21) as a catalyst.The analysis of the obtained data led us to conclude that the asymmetric reaction was possible, but solely for 3-acetylpyridines 10 and 11, which showed enantiomeric excess (Table 2) since the secondary alcohols obtained from 2-acetylpyridines 3-7 and 4-acetylpyridines 8 and 9 were not optically active.It was previously reported that the enantioselective reduction of isomeric acetylpyridines 3, 8, and 10 can be achieved using chiral lithium borohydride modified with N,N′-dibenzoylcystine and ethanol [18].
The best ee was obtained in the case of 3-acetylpyridine (10) (Entries 2 and 3, Table 2), which prompted us to study the asymmetric reduction of ketone 10 in more detail.Two independent experiments under similar reaction conditions reproduced the high ee value.

Computational Studies of the Reduction of Pyridinic Ketones with Dicyclopentylzinc
In order to study distinctive features of the reaction of dicyclopentylzinc with ketones, we located the transition states for the reduction of the ketones 3, 8, and 10 (Scheme 4).
Computations attest to a synchronous transformation through a six-membered transition state.The lowest activation barrier was computed for the reduction of 3-acetylpyridine 10.Although we are unaware of the synthetically meaningful reactions of this type, similar transformations are frequently observed as side processes in the reactions of hindered Grignard reagents with carbonyl compounds [19,20].
Since an asymmetric carbon atom is generated in this transformation, we decided to check the possibility of the catalytic asymmetric reduction using (1R,2S)-ephedrine ( 21) as a catalyst.The analysis of the obtained data led us to conclude that the asymmetric reaction was possible, but solely for 3-acetylpyridines 10 and 11, which showed enantiomeric excess (Table 2) since the secondary alcohols obtained from 2-acetylpyridines 3-7 and 4-acetylpyridines 8 and 9 were not optically active.It was previously reported that the enantioselective reduction of isomeric acetylpyridines 3, 8, and 10 can be achieved using chiral lithium borohydride modified with N,N′-dibenzoylcystine and ethanol [18].
The best ee was obtained in the case of 3-acetylpyridine (10) (Entries 2 and 3, Table 2), which prompted us to study the asymmetric reduction of ketone 10 in more detail.Two independent experiments under similar reaction conditions reproduced the high ee value.

Computational Studies of the Reduction of Pyridinic Ketones with Dicyclopentylzinc
In order to study distinctive features of the reaction of dicyclopentylzinc with ketones, we located the transition states for the reduction of the ketones 3, 8, and 10 (Scheme 4).
Computations attest to a synchronous transformation through a six-membered transition state.The lowest activation barrier was computed for the reduction of 3-acetylpyridine 10.Although we are unaware of the synthetically meaningful reactions of this type, similar transformations are frequently observed as side processes in the reactions of hindered Grignard reagents with carbonyl compounds [19,20].Since an asymmetric carbon atom is generated in this transformation, we decided to check the possibility of the catalytic asymmetric reduction using (1R,2S)-ephedrine (21) as a catalyst.The analysis of the obtained data led us to conclude that the asymmetric reaction was possible, but solely for 3-acetylpyridines 10 and 11, which showed enantiomeric excess (Table 2) since the secondary alcohols obtained from 2-acetylpyridines 3-7 and 4-acetylpyridines 8 and 9 were not optically active.It was previously reported that the enantioselective reduction of isomeric acetylpyridines 3, 8, and 10 can be achieved using chiral lithium borohydride modified with N,N -dibenzoylcystine and ethanol [18].
The best ee was obtained in the case of 3-acetylpyridine (10) (Entries 2 and 3, Table 2), which prompted us to study the asymmetric reduction of ketone 10 in more detail.Two independent experiments under similar reaction conditions reproduced the high ee value.

Computational Studies of the Reduction of Pyridinic Ketones with Dicyclopentylzinc
In order to study distinctive features of the reaction of dicyclopentylzinc with ketones, we located the transition states for the reduction of the ketones 3, 8, and 10 (Scheme 4).
Computations attest to a synchronous transformation through a six-membered transition state.The lowest activation barrier was computed for the reduction of 3-acetylpyridine 10.Although we are unaware of the synthetically meaningful reactions of this type, similar transformations are frequently observed as side processes in the reactions of hindered Grignard reagents with carbonyl compounds [19,20].
Interestingly, the same alcohol ((S)-(-)-( 19)) with 42% ee was used as an asymmetric autocatalyst in the methylation reaction between pyridine-3-carbaldehyde and dimethylzinc, resulting in the formation of product 19 with 7% ee of the same absolute configuration [21].
Searching for further support for our observation, we applied the three-stage reaction sequence developed by Soai et al. [1] (Scheme 5).Product 19′ obtained in a non-catalytic reaction was used as a catalyst in the second run, yielding 19″ of 3% ee.This was in turn used as a catalyst in the third reaction to provide (S)-19 with 6% ee.The results of two further experiments with 2% ee and 6% ee catalysts are in line with the results of the three-stage reaction sequence.Interestingly, the same alcohol ((S)-(-)-( 19)) with 42% ee was used as an asymmetric autocatalyst in the methylation reaction between pyridine-3-carbaldehyde and dimethylzinc, resulting in the formation of product 19 with 7% ee of the same absolute configuration [21].
Searching for further support for our observation, we applied the three-stage reaction sequence developed by Soai et al. [1] (Scheme 5).Product 19 obtained in a non-catalytic reaction was used as a catalyst in the second run, yielding 19 of 3% ee.This was in turn used as a catalyst in the third reaction to provide (S)-19 with 6% ee.The results of two further experiments with 2% ee and 6% ee catalysts are in line with the results of the three-stage reaction sequence.
Thus, we conclude that asymmetric amplifying autocatalysis plays a role in the reaction of 3-acetylpyridine (10) with dicyclopentylzinc, although the level of this effect is significantly lower than that in the reactions of 1 and structurally similar aldehydes.

Computational Search of the Possible Mechanism of Autoamplification
Elucidating the mechanism of asymmetric amplification is a difficult task, requiring extensive studies of the equilibria in the reaction pool and computations based on experimental evidence [22].We will pursue this task in our further studies.
Computations allowed us to predict very high enantioselectivity in favor of the formation of (S,S)-25 through the transition state TS4S since the transition state TS4R was computed to be 8.2 kcal/mol less stable.
On the other hand, the activation barrier was computed to be around 5 kcal/mol, higher than that for the reaction of ketone 10 with dicyclopentylzinc (Scheme 4).
These results correspond roughly to the experimental data: The high level of stereodiscrimination in this system is leveled by a much faster background reaction with more active dicyclopentylzinc.Further mechanistic studies may be able to help overcome this issue.Thus, we conclude that asymmetric amplifying autocatalysis plays a role in the reaction of 3-acetylpyridine (10) with dicyclopentylzinc, although the level of this effect is significantly lower than that in the reactions of 1 and structurally similar aldehydes.

Computational Search of the Possible Mechanism of Autoamplification
Elucidating the mechanism of asymmetric amplification is a difficult task, requiring extensive studies of the equilibria in the reaction pool and computations based on experimental evidence [22].We will pursue this task in our further studies.
Computations allowed us to predict very high enantioselectivity in favor of the formation of (S,S)-25 through the transition state TS4S since the transition state TS4R was computed to be 8.2 kcal/mol less stable.On the other hand, the activation barrier was computed to be around 5 kcal/mol, higher than that for the reaction of ketone 10 with dicyclopentylzinc (Scheme 4).
These results correspond roughly to the experimental data: The high level of stereodiscrimination in this system is leveled by a much faster background reaction with more active dicyclopentylzinc.Further mechanistic studies may be able to help overcome this issue.Scheme 6.The computed enantioselective reaction of alcoholate 19a with 3-acetylpyridine (10).Scheme 6.The computed enantioselective reaction of alcoholate 19a with 3-acetylpyridine (10).Scheme 6.The computed enantioselective reaction of alcoholate 19a with 3-acetylpyridine (10).Thus, we found a new example of asymmetric amplifying autocatalytic reaction.So far, we have obtained only (S)-19 in our experiments.Hence, currently, we cannot claim a spontaneous chirality generation until the random generation of handedness is proved as in the case of the Soai reaction [4][5][6].Further synthetic and mechanistic studies of this remarkable transformation are underway in our laboratories.

Discussion
To the best of our knowledge, the reaction of dicyclopentylzinc with 3-acetylpyridine catalyzed by its own optically active product is only the second clear example of asymmetric autoamplification ever presented since the Soai reaction was discovered 30 years ago and actively investigated thereafter [1,2].Similarly to the pioneering discovery of Soai, the newly found asymmetric amplifying autocatalytic reaction involves the participation of an organozinc reagent that is structurally similar to diisopropylzinc operating in the Soai reaction.This is an important analogy that will certainly Thus, we found a new example of asymmetric amplifying autocatalytic reaction.So far, we have obtained only (S)-19 in our experiments.Hence, currently, we cannot claim a spontaneous chirality generation until the random generation of handedness is proved as in the case of the Soai reaction [4][5][6].Further synthetic and mechanistic studies of this remarkable transformation are underway in our laboratories.

Discussion
To the best of our knowledge, the reaction of dicyclopentylzinc with 3-acetylpyridine catalyzed by its own optically active product is only the second clear example of asymmetric autoamplification ever presented since the Soai reaction was discovered 30 years ago and actively investigated thereafter [1,2].Similarly to the pioneering discovery of Soai, the newly found asymmetric amplifying autocatalytic reaction involves the participation of an organozinc reagent that is structurally similar to diisopropylzinc operating in the Soai reaction.This is an important analogy that will certainly help in further experimental and computational mechanistic investigations aimed at providing a deeper understanding of this rare phenomenon.On the other hand, these two reactions are intrinsically different in terms of the nature of chemical transformation-alkylation in the Soai reaction vs. reduction in the reaction reported here.This fact improves the prognoses for possible findings of other examples of asymmetric autoamplification.In addition, unlike the sophisticated substrates of the Soai reaction, 3-acetylpyridine is a commercially available reagent that opens the door for extensive studies and possible practical applications of asymmetric autoamplification.We are actively working according to these considerations in our laboratories.

Experimental Details
Dicyclopentylzinc was prepared according to the known procedure [23].All solvents were purified and distilled using standard procedures.Analytical thin-layer chromatography (TLC) was carried out on Sorbfil PTLC-AF-A-UF plates using UV light (254 nm) as the visualizing agent.Silica gel 60A (Acros Organics, Geel, Belgium, 400-230 mesh, 0.040-0.063mm) was used for open column chromatography.Melting points were recorded with a Boëtius melting point instrument and are uncorrected.NMR spectra were measured on a Bruker Avance III 400 spectrometer at 400.17 MHz ( 1 H) and 100.62 MHz ( 13 C), and a Bruker Avance III 500 spectrometer at 500.1 MHz ( 1 H) and 125.8 MHz ( 13 C) at 20 • C in deuterated chloroform and benzene.The chemical shifts (δ) are expressed in parts per million (ppm) and are calibrated using residual undeuterated solvent peak as an internal . Mol. Sci.2023, 24, x FOR PEER REVIEW 3 of 11
Scheme 3. Reactions of acetylpyridines 3-11 with dicyclopentylzinc in the presence of catalyst.

a
Yields were not optimized; b alcohol 19, 92% ee; c yield of the newly formed product; d yield of the product purified for HPLC, the NMR of the reaction mixture contained only 10 and 19.

Figure 1 .
Figure 1.Computed structures of transition states for enantioselective reduction of 3-acetylpyridine 10 with (S)-alcoholate 19a.The greater stability of TS4S is due to a much more extensive framework of the stabilizing non-covalent interactions: lime, C-H-π; blue, C-H-N; red, C-H-O.Red ball-oxygen atom, green ball-zinc atom, blue ball-nitrogen atom.

Figure 1 .
Figure 1.Computed structures of transition states for enantioselective reduction of 3-acetylpyridine 10 with (S)-alcoholate 19a.The greater stability of TS4S is due to a much more extensive framework of the stabilizing non-covalent interactions: lime, C-H-π; blue, C-H-N; red, C-H-O.Red ball-oxygen atom, green ball-zinc atom, blue ball-nitrogen atom.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 . Cont. Entry Starting Compound Reaction Conditions Product Yield, % a 5Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.
a Yields were not optimized.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.
a Yields were not optimized.

Table 1 .
Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.
a Yields were not optimized.

Table 1 .
Int. J. Mol.Sci.2023, 24, x FOR PEER REVIEW 3 of Reduction of aldehydes with dicyclopentylzinc to the corresponding primary alcohols.
a Yields were not optimized.

Table 2 .
Reduction of 3-acetylpyridines 10 and 11 with dicyclopentylzinc to the corresponding secondary alcohols 19 and 20.
a Yields were not optimized; b alcohol 19, 92% ee; c yield of the newly formed product; d yield of the product purified for HPLC, the NMR of the reaction mixture contained only 10 and 19.

Table 2 .
Reduction of 3-acetylpyridines 10 and 11 with dicyclopentylzinc to the corresponding secondary alcohols 19 and 20.Reactions of acetylpyridines 3-11 with dicyclopentylzinc in the presence of catalyst.

Table 2 .
Reduction of 3-acetylpyridines 10 and 11 with dicyclopentylzinc to the corresponding secondary alcohols 19 and 20.
a Yields were not optimized; b alcohol 19, 92% ee; c yield of the newly formed product; d yield of the product purified for HPLC, the NMR of the reaction mixture contained only 10 and 19.

Table 2 .
Reduction of 3-acetylpyridines 10 and 11 with dicyclopentylzinc to the corresponding secondary alcohols 19 and 20.
a Yields were not optimized; b alcohol 19, 92% ee; c yield of the newly formed product; d yield of the product purified for HPLC, the NMR of the reaction mixture contained only 10 and 19.
. Reactions of acetylpyridines 3-11 with dicyclopentylzinc in the presence of catalyst.

Table 2 .
Reduction of 3-acetylpyridines 10 and 11 with dicyclopentylzinc to the corresponding secondary alcohols 19 and 20.
a Yields were not optimized; b alcohol 19, 92% ee; c yield of the newly formed product; d yield of the product purified for HPLC, the NMR of the reaction mixture contained only 10 and 19.

Table 2 .
Reduction of 3-acetylpyridines 10 and 11 with dicyclopentylzinc to the corresponding secondary alcohols 19 and 20.