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. 2024 Mar 8;9(11):12657–12664. doi: 10.1021/acsomega.3c07948

New Strategy for the Synthesis of Some Valuable Chiral 1,3-Diols with High Enantiomeric Purity: New Organocatalyst, Asymmetric Aldol Reaction, and Reduction

Tülay Yıldız 1,*, Belma Hasdemir 1, Hasniye Yaşa 1, Hatice Başpınar Küçük 1
PMCID: PMC10955598  PMID: 38524485

Abstract

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Chiral 1,3-diols are highly valuable molecules used in industries such as pharmaceuticals, cosmetics, and agriculture. Therefore, in this study, a new strategy was developed to synthesize enantiomerically pure (>99% ee) 1,3-diols. New chiral 1,3-diols (5a–5q) with high enantiomeric purity were synthesized from aldol products chiral 1,3-keto alcohols (4a–4q), which are aldol products with different structures. Chiral 1,3-keto alcohols (4a–4q) were synthesized by a new asymmetric aldol method in the first step. This method was developed using a new proline-derived organocatalyst (3g) and Cu(OTf)2 as an additive in DMSO–H2O for the first time. Almost >99% ee was obtained using our developed aldol procedure. In the second step, original chiral diols (5a–5q) of high enantiomeric purity were obtained by asymmetric reduction of chiral keto alcohols with chiral oxazaborolidine reagents. In this way, a two-step asymmetric reaction was developed for chiral 1,3-diol enantiomers with high enantiomeric purity. The structures of all the original chiral compounds obtained were elucidated by infrared and nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis methods. Their enantiomeric excesses were determined by the chiral high-performance liquid chromatography method. Both keto alcohols and their corresponding chiral diols synthesized can be used as chiral starting materials and chiral source materials or intermediates in the synthesis of many biologically active molecules, or they can be used as chiral ligands in asymmetric synthesis, serving as organocatalysts.

Introduction

Chiral diols, commonly found in various significant natural products, have proven to be valuable as chiral ligands and auxiliaries in stereoselective organic synthesis. Serving as crucial building blocks, chiral diols play a pivotal role in the preparation of diverse chiral chemicals (Figure 1).1−3 Widely utilized in pharmaceuticals, cosmetics, and agriculture, particularly in the synthesis of natural and biologically active products, chiral diols and their derivatives find applications as starting or intermediate products.4−7 Notably, natural products such as carbohydrates, with multiple hydroxy groups in their structure, predominantly exist as a single enantiomer. However, synthesizing a single enantiomer of alcohols with more than one hydroxy group is exceptionally challenging due to the prevalent formation of diastereoisomers and enantiomers in general synthesis methods.

Figure 1.

Figure 1

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Some important applications of chiral 1,3-diols.

Recent research has focused on the enantioselective synthesis of 1,3-diols containing two stereogenic centers. A key method for achieving this synthesis involves the enantioselective catalytic reduction of 1,3-hydroxy ketones, derived from corresponding dicarbonyl compounds. Various asymmetric reduction methods, including asymmetric heterogeneous and homogeneous hydrogenation, as well as diastereoselective induction, have been employed to obtain chiral diols.8−14 Biochemical methods, such as enzymatic reduction of 1,3-diketones and enzymatic kinetic resolution, are also essential for synthesizing enantioselective diols.15 Another important method of obtaining 1,3-diols is the reduction of aldol products. Especially, biocatalytic reduction of aldol products obtained by organocatalytic aldol reaction of an aldehyde and ketone is used very frequently and is among the most important methods.16−19 Enzymatic reduction of 1,3-diketones20−22 and enzymatic kinetic resolution23−26 are also useful methods to synthesize enantioselective diols. Additionally, chiral poly alcohols can be synthesized using stereoselective aldol-Tishchenko reactions.27,28

Numerous organocatalytic enantioselective aldol reactions have successfully yielded chiral hydroxy ketones, utilizing small amino acids such as proline or its derivatives.29−34 Organocatalytic asymmetric cross-aldol reactions remain widely employed as a crucial tool in carbon–carbon bond formation reactions.35,36 In our previous studies, we reported the use of various lipase enzymes in aldol reactions between different ketone and aldehyde species, achieving antiproducts with enantioselectivity ranging from 80 to 99% ee. Additionally, we described the enzymatic kinetic resolution of racemic 1,3-keto alcohols and biocatalytic hydrolysis of racemic 1,3-keto acetates, obtaining (S)-β-hydroxy ketones with high enantioselectivities.37−39 The results of these works lead us to develop a new two-step asymmetric synthesis by the combined use of organocatalytic aldol reaction and asymmetric reduction. Although many studies achieved in multistep synthetic methodologies, only a few works have been made by combining a two-step organocatalytic process in order to synthesize chiral 1,3-diols. For example, Sonoike et al. synthesized 1,3-diol enantiomers by one-pot chemoenzymatic reaction in a water/acetone system at room temperature by a combination of enzymatic aldol reactions.17 In another study, using a combination of enantioselective chemo- and biocatalytic reactions, the structures of both stereogenic centers of 1,3-diols were obtained.16

In this study, we introduce a novel aldol reaction procedure utilizing a new amino acid-derived catalyst (3g) in the presence of copper triflate (Cu(OTf)2) as an additive in a DMSO–water mixture. While previous studies employed l-proline with various Lewis acids as additives for aldol reactions, the Cu(OTf)2 compound, yielding optimal results in our study, has not been utilized before.40,41 In the subsequent step, we achieved the asymmetric reduction of the keto group to alcohol using organoborane catalysts. Unlike previous studies using conventional reduction reagents or biocatalysts for reduction, we employed CBS-oxazaborolidine complexes for the first time, introducing a new aspect to the reduction of chiral hydroxy ketones and the formation of a second stereogenic center.13,16

Oxazaborolidine catalysts, particularly CBS–oxazaborolidine complexes, are vital in asymmetric reduction, playing a crucial role in obtaining chiral alcohols and diols with high enantioselectivity.42,43 Building on our prior work utilizing CBS–oxazaborolidine complexes for the synthesis of chiral alcohols and diols, we demonstrate their efficiency in achieving a single enantiomer of chiral diols by reducing chiral keto alcohols.14,44 The rationale behind employing asymmetric reduction at this stage is to ensure the highly selective formation of the secondary stereogenic center, increasing the probability of obtaining a single enantiomer.

Results and Discussion

We used cyclohexanone (1a) and p-nitrobenzaldehyde (2a) as a bench reaction in DMSO, the optimum solvent for the asymmetric aldol reaction. Various amino acid–based molecules were tried in the aldolization reaction as organocatalysts in this study. Among the catalysts used, only l-proline (3a), (R)-amino-phenyl-acetic acid (3b), and (S)-diphenyl-pyrrolidin-2-yl-methanol (3c) were purchased, while the others (3c-3i) were synthesized in our previous studies.44,45 All amino acid-derived organocatalysts, except for l-proline, were used for the first time in an aldol reaction. These organocatalysts used are given in Figure 2, and the results obtained from these catalysts are shown in Table 1.

Figure 2.

Figure 2

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Organocatalysts used for the asymmetric aldol reactions.

Table 1. Screening of Different Organocatalysts for the Asymmetric Aldol Reactionsa.

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entry catalyst yield (%)b dr (anti/syn)c ee (%)c
1 3a 83 78:22 71
2 3b 67 76:24 20
3 3c 59 63:37 26
4 3d 45 55:45 14
5 3e 63 68:32 63
6 3f 73 60:40 52
7 3g 85 78:22 78
8 3h 75 67:33 46
9 3i 64 61:39 15
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a

Conditions: Cyclohexanone (1a) (0.5 mmol), p-nitrobenzaldehyde (2a) (0.1 mmol), and catalyst (20% equiv) are stirred in DMSO (1 mL) at room temperature for 3 days.

b

Combined isolated yield of anti-4a and syn-4a.

c

ee and dr were determined by high-performance liquid chromatography (HPLC) analysis using a Chiralpac AD-H chiral column. The absolute configuration of 4a was assigned by comparison of the retention times of known compounds.

As can be seen from Table 1, it was determined that the best catalyst was our newly synthesized proline-derived catalyst 3g. As expected, proline gave a good result, while, interestingly, catalyst 3g showed slightly a better result than proline (entry 7). Other catalysts tested were observed to show moderate or low ee and dr results.

An additional screening was performed to increase the ee values by testing some organic solvents in equal reaction conditions and the same substrates (Table 2). Many apolar, polar protic, and aprotic solvents were tested as solvents. According to the results given in Table 2, methanol from polar protic solvents gave a good yield, ethanol gave a medium yield, and water gave a low yield. Very low yields were obtained with hexane and toluene from apolar solvents and acetonitrile and tetrahydrofuran from polar aprotic solvents. The best yield was obtained with an 8:2 mixture of DMSO, a polar aporotic solvent, and water, a polar protic solvent. Gratifyingly, we found that the reaction of 1a with 2a was accomplished with an improved yield (92%) and selectivity (anti/syn 91:9; 85% ee) in DMSO–H2O (8:2) (Table 2, entry 10). Especially in asymmetric aldol reactions, it is preferred together with DMSO and some water, and it has been used in many previous studies.46−49 Moreover, the reports prepared by the U.S. Environmental Protection Agency have mentioned that DMSO is a nontoxic solvent that does not harm human health.50

Table 2. Solvent Effect in Asymmetric Aldol Reactiona.

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entry solvent yield (%)b dr (anti/syn)c ee (%)c
1 DMSO 85 78:22 78
2 EtOH 48 65:34 45
3 MeOH 86 76:24 75
4 hexane 12 57:43 18
5 THF 23 59:41 19
6 toluene 15 61:39 21
7 DMF 75 75:25 74
8 cyclohexanone 84 74:26 73
9 MeCN 15 55:44 16
10 DMSO–H2O(8:2) 92 91:9 85
11 H2O 10 50:50 0
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a

Conditions: Cyclohexanone (1a) (0.5 mmol), p-nitrobenzaldehyde (2a) (0.1 mmol), and catalyst 3g (20% eq.) are stirred in solvent (1 mL) at room temperature for 3 days.

b

Combined isolated yield of anti-4a and syn-4a.

c

ee and dr were determined by HPLC analysis using a Chiralpac AD-H chiral column. The absolute configuration of 4a was assigned by comparison of the retention times of known compounds.

In our next experiments, we tested some Lewis acids and organic acids as an additive to increase the enantiomeric excess by forming a catalyst complex, and we monitored the results in Table 3.

Table 3. Effect of Lewis Acids and Organic Acids Used as Additives on the Reactiona.

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entry additive (10%) yield (%)b dr (anti/syn)c ee (%)c
1 no 92 91:9 85
2 Cu(OTf)2 99 97:3 98
3 FeCl3 95 92:8 95
4 MnCl2 64 78:22 76
5 CoCl2 90 90:10 88
6 ZnCl2 93 85:25 94
7 Al(OIPA)3 61 87:13 24
8 benzoic acid 75 84:16 78
9 acetic acid 59 76:24 65
10 Cu(OAc)2·H2O 81 90:10 88
11 Cu(OTf)2 (5%) 90 96:4 96
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a

Conditions: Cyclohexanone (1a) (0.5 mmol), p-nitrobenzaldehyde (2a) (0.1 mmol), catalyst 3g (20% equiv), and additive (10% equiv) are stirred in DMSO/H2O (8:2) (1 mL) at room temperature for 3 days.

b

Combined isolated yield of anti-4a and syn-4a.

c

ee and dr were determined by HPLC analysis using a Chiralpac AD-H chiral column. The absolute configuration of 4a was assigned by comparison of the retention times of known compounds.

Looking at Table 3, entry 2, it is seen that the best yield and ee were obtained by using Cu(OTf)2 as an additive. It was observed that the yield and ee values decreased when a lower equivalent amount of Cu(OTf)2 (5% equiv) was used. As a result of these trials, a new proline derivative catalyst and the Cu(OTf)2 binary catalyst system was used for the first time, and a very high yield (99%), enantiomeric excess (98%), and diastereomeric ratio (97:3) was obtained.

We made a possible prediction for the aldol reaction mechanism of cyclohexanone and aromatic aldehydes in the presence of 3g catalyst and Cu(OTf)2 (Figure 3). According to this mechanism, the oxygen side of the catalyst forms a symmetric complex with copper. The basic nitrogen in the pyrroline ring then attacks the carbonyl of cyclohexanone and an enamine structure is formed. Afterward, the aldehyde adds this enamine from only one surface.

Figure 3.

Figure 3

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Postulated mechanism of the new aldol method.

With this developed new method, a total of 14 chiral 1,3-keto alcohols were synthesized using different aldehydes and cyclohexanone. Benzaldehyde derivatives containing electron withdrawing and donating groups and hetero aromatic aldehydes were used as aldehyde derivatives. Four of them are original (4k, 4l, 4m, and 4n), and all synthesized chiral keto alcohols, their % yields, and ee values are given below (Table 4).

Table 4. Synthesized Cyclohexanone Derivative Chiral 1,3-Keto Alcohols and Their Yieldsa.

graphic file with name ao3c07948_0007.jpg

entry product Ar yield(%)b dr (anti/syn)c ee (%)c
1 4a 4-NO2C6H4 99 97:3 98
2 4b Ph 97 93:7 96
3 4c 3-CH3C6H4 93 95:5 91
4 4d 2-furyl 86 70:30 87
5 4e 2-naphthyl 94 95:5 99
6 4f 2-CH3OC6H4 90 86:14 98
7 4g 4-CH3OC6H4 92 98:2 96
8 4h 2-FC6H4 89 88:12 99
9 4i 2-BrC6H4 85 82:18 99
10 4j 2-thienyl 87 91:9 97
11 4k 2-PhOC6H4 80 96:4 99
12 4L 2-(4-FC6H4)OC6H4 84 83:17 99
13 4m 2-(4-CH3)SC6H4 56 99:1 97
14 4n 2-(4-FC6H4)SC6H4 67 83:17 99
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a

Conditions: Cyclohexanone (1a) (0.5 mmol), aldehyde (2a–2n) (0.1 mmol), catalyst 3g (20% eq), and Cu(OTf)2 (10% eq) are stirred in DMSO/H2O (8:2) (1 mL) at room temperature for 3 days.

b

Combined isolated yield of anti- and syn-isomers.

c

ee and dr were determined by HPLC analysis using a chiral column. The absolute configuration of 4a–4n was assigned by comparison of the retention times of known compounds.

As can be seen from Table 4, the anti-diastereoisomer of keto alcohols was obtained with a higher percentage in all products. The configurations of keto alcohols were determined by comparing the HPLC retention times of the enantiomers in previous studies under the same conditions.19,51,52Anti-diastereoisomer was separated from syn-diastereoisomer by column chromatography, using hexane and increasing amounts of ethyl acetate as eluents.

Then we examined the effect of different ketones in the reaction by using different ketones instead of cyclohexanone (1a). Acetone (1b), cycloheptanone (1c), benzyl methyl ketone (1d), acetophenone (1e), and 2-heptanone (1f) were used as ketones, and the reaction results are shown in Table 5.

Table 5. Synthesized Different Ketone Derivative Chiral 1,3-Keto Alcohols and Their Yieldsa.

graphic file with name ao3c07948_0008.jpg

entry product R1 yield(%)b dr (anti/syn)c ee (%)c
1 4o methyl 52   68
2 4p –(CH2)5– 83 75:15 73
3 4q benzyl 46   64
4 4r phenyl 0    
5 4s pentyl 0    
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a

Conditions: Ketone (1b–1f) (0.5 mmol), aldehyde (2a) (0.1 mmol), catalyst 3g (20% eq), and Cu(OTf)2 (10% eq) are stirred in DMSO/H2O (8:2) (1 mL) at room temperature for 3 days.

b

Combined isolated yield of anti- and syn-isomer.

c

ee and dr were determined by HPLC analysis using a chiral column. The absolute configuration of 4o–4q was assigned by comparison of the retention times of known compounds.

When studies with different ketones were examined, it was observed that while new aldol products (4o, 4p, and 4q) were formed with acetone, cycloheptanone, and benzyl methyl ketone, no aldol products (4r and 4s) were formed with the other two ketones.

Finally, all the synthesized chiral keto alcohols were reduced asymmetrically with the R-CBS–oxazaborolidine complex. The chiral 1,3-diols structures were obtained as a result of asymmetric reduction, and their results are given in Table 6. When chiral keto alcohols were reduced with R-CBS, a single enantiomer of diols was obtained. The synthesized chiral diols, except for 5b and 5o, are original and have been newly introduced into the literature. The configurations of the new chiral alcohols were determined based on the HPLC retention times of 5b synthesized in a previous study.19

Table 6. Synthesized Chiral 1,3-Diols and Their Yieldsa.

graphic file with name ao3c07948_0009.jpg

graphic file with name ao3c07948_0010.jpg

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a

Conditions: To a mix of 1 M CBS catalyst [0.1 mmol (0.1 mL) solution in toluene] and 1.5 mmol 2 M BH3–SMe2 in toluene, 1 mmol of keto alcohol is added in 5 mL of dry toluene at 0 °C under a N2 atmosphere, and the mixture is stirred for 2h. Isolated yield of products. ee values were determined by HPLC analysis using chiral columns. The absolute configuration of 5a–5q was assigned by comparison of the retention times of known compounds.

Conclusions

In this study, we synthesized 17 novel chiral 1,3-diols (5a–5q) with high enantiomeric excess from chiral 1,3-keto alcohols (4a–4q) via organocatalyzed asymmetric aldol reaction and asymmetric reduction. We developed a two-step asymmetric synthesis method to obtain a single enantiomer of 1,3-diols with two stereogenic centers. First, a new organocatalyzed asymmetric aldol reaction was improved using a proline-derived catalyst and Cu(OTf)2 as an additive in DMSO–H2O. Chiral 1,3-keto alcohols are obtained as starting compounds with ee up to 99%. Then, they were reduced asymmetrically using the R-CBS–oxazaborolidine complex. Thus, a single enantiomer of the 1,3-diols was obtained in an excellent way.

These molecules are important intermediates that can be used in the synthesis of drugs and chiral ligands because of their molecular motifs. In particular, 1,3-diol compounds can form chiral ligands or organometallic complexes, as well as are found in various pharmaceuticals. It is also possible to synthesize various heterocyclic compounds that have important biological activities using 1,3-diols with two stereogenic centers.

Experimental Section

The chemicals were commercially purchased from Aldrich, Acros, or Merck and were used without any purification. All the obtained new compounds were purified by column chromatography and defined by infrared (IR), 1H nuclear magnetic resonance (NMR), and 13C NMR spectroscopic methods, elemental analysis, and gas chromatography–mass spectrometry (GC–MS). Reactions were monitored by thin-layer chromatography (TLC) using silica gel plates, and the products were purified by flash column chromatography on silica gel (230–400 mesh). NMR spectroscopy was conducted at 500 MHz for 1H and 125 MHz for 13C using Me4Si as an internal standard in CDCl3. GC–MS spectra were recorded on a Shimadzu/QP2010 Plus spectrometer. IR spectra were recorded on a Bruker Vertex 70 IR spectrometer. Melting points were determined with the Buchi Melting Point B-540 and were not corrected. To determine the values, HPLC was performed on a Shimadzu/DGU-20 A5 HPLC apparatus equipped with 25 cm Chiralcel OD, Chiralcel OD-H, Chiralcel OJ-H, and Chiralpac AD-H chiral columns. Optical rotations were measured with an Optical Activity AA-55 digital polarimeter at room temperature.

General Procedure for the Synthesis of the Racemic 1,3-Keto Alcohols (Procedure I)49

The synthesis of racemic 1,3-keto alcohols was carried out by applying the new modified method previously developed by us, by aldol condensation in the presence of a suitable ketone and aldehyde.49 10 mmol ketone, 7.5 mmol aromatic aldehyde, 10% eq of K2CO3 (0.1 g), and 15 mL of DMSO/H2O (8:2) were placed in a reaction vessel. It was stirred at room temperature for 1 day. The completion of the reaction was checked by TLC. The reaction was taken into a separatory funnel and extracted by DCM. Then the combined extracts were washed with saturated brine and dried over anhydrous Na2SO4, and the solvents were removed under reduced pressure. For purification, flash chromatography was performed on silica gel (Merck; 230–400 mesh) with hexane–ethyl acetate (v/v 9:1) as the mobile phase.

General Procedure for the Synthesis of the Chiral 1,3-Keto Alcohols (Procedure II)

5 mmol ketone, 1 mmol aromatic aldehyde, 20% equiv of 3g, 10% equiv of Cu(OTf)2, and 3 mL of DMSO/H2O (8:2) were placed in a reaction tube. It was stirred at room temperature for 1–3 days. The completion of the reaction was checked by TLC. The reaction was taken into a separatory funnel and extracted by DCM. Then the combined extracts were washed with saturated brine and dried over anhydrous Na2SO4, and the solvents were removed under reduced pressure. For the purification, flash chromatography was performed on silica gel (Merck; 230–400 mesh) with n-hexane–ethyl acetate (v/v 3:2) as the mobile phase.

General Procedure for the Synthesis of the Racemic 1,3-Diols (Procedure III)

Racemic diols were synthesized by racemic reduction of all synthesized racemic keto alcohols. Keto alcohol (1 mmol) was dissolved in methanol and cooled to 0 °C under a nitrogen atmosphere. NaBH4 (1.5 mmol) was added to the solution in portions. The reaction was stirred until complete, controlled by TLC. Then it was extracted with DCM and dried with Na2SO4 and the solvent was evaporated.

General Procedure for the Synthesis of Chiral 1,3-Diols (Procedure IV)14,53

To a solution (R)-Me-CBS (0.1 mmol, 0.1 mL of 1 M solution in toluene) was added BH3·Me2S (2 M in toluene, 1.5 mmol, 0.75 mL) and the mixture were stirred under a nitrogen atmosphere and then cooled to −10 °C. After 10 min of stirring, the solution of keto alcohol (1 mmol) in 5 mL of toluene was simultaneously added within 40 min at −10 °C until the keto alcohol disappeared based on TLC (0.5–2 h). The reaction mixture was quenched with cold (0 °C) MeOH (1 mL) carefully and the cooling bath was removed and stirring continued for 1 h. Then it was extracted with DCM, dried with Na2SO4 and the solvent was evaporated. Removal of solvents in vacuo and purification of the residue by column chromatography (n-hexane–EtOAc 7:3) yielded the diol product.14

Acknowledgments

This study has been funded by Istanbul University-Cerrahpaşa, Scientific Research Projects (project no. 35780).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.3c07948.

  • Experimental details, general procedures, experimental characterization data (IR, NMR, MS, HPLC, and elemental analysis), and 1H and 13C NMR spectra of all products (PDF)

The authors declare no competing financial interest.

Supplementary Material

ao3c07948_si_001.pdf (1.8MB, pdf)

References

  1. Pharmaceutical Substances: Syntheses, Patents Applications, 4th ed.; Kleeman A.; Engels J.; Kutscher B.; Reichert D., Eds.; Georg Thieme Verlag: Stuttgart, 2001; Vol. 2. p 2521, 599 Euros. ISBN: 3-13-558404-6. Org. Process Res. Dev. 2002, 6(5), 739–740. [Google Scholar]
  2. Wu X.; Liu N.; He Y.; Chen Y. Cloning, Expression, and Characterization of a Novel Diketoreductase from Acinetobacter Baylyi. Acta Biochim. Biophys. Sin. 2009, 41 (2), 163–170. 10.1093/abbs/gmn019. [DOI] [PubMed] [Google Scholar]
  3. Sit S. Y.; Parker R. A.; Motoc I.; Han W.; Balasubramanian N.; Catt J. D.; Brown P. J.; Harte W. E.; Thompson M. D.; Wright J. J. Synthesis, Biological Profile, and Quantitative Structure-Activity Relationship of a Series of Novel 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors. J. Med. Chem. 1990, 33 (11), 2982–2999. 10.1021/jm00173a013. [DOI] [PubMed] [Google Scholar]
  4. Superchi S.; Contursi M.; Rosini C. Monobenzylether of (R,R)-1,2-Diphenylethane-1,2-Diol as Chiral Auxiliary in the Diastereoselective Reduction of α-Ketoesters. Tetrahedron 1998, 54 (37), 11247–11254. 10.1016/S0040-4020(98)00657-7. [DOI] [Google Scholar]
  5. Konopelski J. P.; Boehler M. A. Enantiomerically Pure Vinylketene Acetals as Dienes in the Diels-Alder Reaction. J. Am. Chem. Soc. 1989, 111 (12), 4515–4517. 10.1021/ja00194a066. [DOI] [Google Scholar]
  6. Prasad K. R. K.; Joshi N. N. C2-Symmetric Chiral Zinc Alkoxides as Catalysts for the Enantioselective Addition of Diethylzinc to Aryl Aldehydes. Tetrahedron: Asymmetry 1996, 7 (7), 1957–1960. 10.1016/0957-4166(96)00235-2. [DOI] [Google Scholar]
  7. Başpınar Küçük H.; Yaşa H.; Yıldız T.; Yusufoğlu A. S. Detailed Studies on the Reduction of Aliphatic 3-4-6-and 13-Oximino Esters: Synthesis of Novel Isomeric Amino Esters, Oximino Alcohols, and Amino Alcohols. Synth. Commun. 2017, 47 (22), 2070–2077. 10.1080/00397911.2017.1364768. [DOI] [Google Scholar]
  8. Bode S. E.; Wolberg M.; Müller M. Stereoselective Synthesis of 1,3-Diols. Synthesis 2006, 2006, 557–588. 10.1055/s-2006-926315. [DOI] [Google Scholar]
  9. Nagoya R. Asymmetric Catalysis In Organic Synthesis. Molecules 2001, 6 (12), 1012. 10.3390/61201012. [DOI] [Google Scholar]
  10. Ojima I.Catalytic Asymmetric Synthesis: Third Edition; John Wiley & Sons, Inc., 2010. 10.1002/9780470584248. [DOI] [Google Scholar]
  11. Hayashi Y.; Aratake S.; Okano T.; Takahashi J.; Sumiya T.; Shoji M. Combined Proline-Surfactant Organocatalyst for the Highly Diastereo- and Enantioselective Aqueous Direct Cross-Aldol Reaction of Aldehydes. Angew. Chem., Int. Ed. 2006, 45 (33), 5527–5529. 10.1002/anie.200601156. [DOI] [PubMed] [Google Scholar]
  12. Davis T. A.; Chopade P. R.; Hilmersson G.; Flowers R. A. Reduction of β-Hydroxyketones by SmI2/H2O/Et3N. Org. Lett. 2005, 7 (1), 119–122. 10.1021/ol047835p. [DOI] [PubMed] [Google Scholar]
  13. Evans D. A.; Chapman K. T.; Carreira E. M. Directed reduction of .beta.-hydroxy ketones employing tetramethylammonium triacetoxyborohydride. J. Am. Chem. Soc. 1988, 110 (11), 3560–3578. 10.1021/ja00219a035. [DOI] [Google Scholar]
  14. Yildiz T.; Yusufoǧlu A. Asymmetric Synthesis of New Chiral 1,2- and 1,3-Diols. Monatsh. Chem. 2013, 144 (2), 183–190. 10.1007/s00706-012-0792-7. [DOI] [Google Scholar]
  15. Gupta P.; Mahajan N.; Taneja S. C. Recent Advances in the Stereoselective Synthesis of 1,3-Diols Using Biocatalysts. Catal.: Sci. Technol. 2013, 3, 2462–2480. 10.1039/c3cy00125c. [DOI] [Google Scholar]
  16. Baer K.; Kraußer M.; Burda E.; Hummel W.; Berkessel A.; Gröger H. Sequential and Modular Synthesis of Chiral 1,3-Diols with Two Stereogenic Centers: Access to All Four Stereoisomers by Combination of Organo- and Biocatalysis. Angew. Chem., Int. Ed. 2009, 48 (49), 9355–9358. 10.1002/anie.200900582. [DOI] [PubMed] [Google Scholar]
  17. Sonoike S.; Itakura T.; Kitamura M.; Aoki S. One-Pot Chemoenzymatic Synthesis of Chiral 1,3-Diols Using an Enantioselective Aldol Reaction with Chiral Zn 2+ Complex Catalysts and Enzymatic Reduction Using Oxidoreductases with Cofactor Regeneration. Chem. - Asian J. 2012, 7 (1), 64–74. 10.1002/asia.201100584. [DOI] [PubMed] [Google Scholar]
  18. Andreu C.; Del Olmo M. Exploring the Potential of Some Yeast Strains in the Stereoselective Synthesis of Aldol Reaction Products and Its Reduced 1,3-Dialcohol Derivatives. J. Mol. Catal. B: Enzym. 2013, 92, 57–61. 10.1016/j.molcatb.2013.03.017. [DOI] [Google Scholar]
  19. Acetti D.; Brenna E.; Fuganti C.; Gatti F. G.; Serra S. Baker’s Yeast Reduction of β-Hydroxy Ketones. Eur. J. Org Chem. 2010, 2010 (1), 142–151. 10.1002/ejoc.200901006. [DOI] [Google Scholar]
  20. Ahmad K.; Koul S.; Taneja S. C.; Singh A. P.; Kapoor M.; Riyaz-ul-Hassan; Verma V.; Qazi G. N. Enzyme Directed Diastereoselectivity in Chemical Reductions: Studies towards the Preparation of All Four Isomers of 1-Phenyl-1,3-Butanediol. Tetrahedron: Asymmetry 2004, 15 (11), 1685–1692. 10.1016/j.tetasy.2004.04.022. [DOI] [Google Scholar]
  21. Berti F.; Bincoletto S.; Donati I.; Fontanive G.; Fregonese M.; Benedetti F. Albumin-directed stereoselective reduction of 1,3-diketones and β-hydroxyketones to anti diols. Org. Biomol. Chem. 2011, 9 (6), 1987–1999. 10.1039/c0ob00648c. [DOI] [PubMed] [Google Scholar]
  22. Vitale P.; Perna F. M.; Agrimi G.; Scilimati A.; Salomone A.; Cardellicchio C.; Capriati V. Asymmetric Chemoenzymatic Synthesis of 1,3-Diols and 2,4-Disubstituted Aryloxetanes by Using Whole Cell Biocatalysts. Org. Biomol. Chem. 2016, 14 (48), 11438–11445. 10.1039/C6OB02320G. [DOI] [PubMed] [Google Scholar]
  23. Levayer F.; Rabiller C.; Tellier C. Enzyme Catalysed Resolution of 1,3-Diarylpropan-1,3-Diols. Tetrahedron: Asymmetry 1995, 6 (7), 1675–1682. 10.1016/0957-4166(95)00212-8. [DOI] [Google Scholar]
  24. Ward D. E.; Liu Y.; How D. Preparation of Desymmetrized Meso Derivatives by Kinetic Resolution of Meso/Dl Stereoisomeric Mixtures. J. Am. Chem. Soc. 1996, 118 (12), 3025–3026. 10.1021/ja953576a. [DOI] [Google Scholar]
  25. Jakob F.; Schneider C. Enzyme-Catalyzed Kinetic Resolution of 1,3-Anti-Diol Monoesters - Efficient Preparation of Enantiomerically Highly Enriched and Unsymmetrically Substituted 1,3-Anti-Diols. Eur. J. Org Chem. 2007, 2007 (18), 2958–2963. 10.1002/ejoc.200700096. [DOI] [Google Scholar]
  26. Kłossowski S.; Redzej A.; Szymkuć S.; Ostaszewski R. Studies towards Enzymatic Kinetic Resolutions of 1,3-Diol Peptidomimetics Obtained via the Ugi Reaction. Arkivoc 2013, 2013 (4), 134–143. 10.3998/ark.5550190.p008.122. [DOI] [Google Scholar]
  27. Ichibakase T.; Nakajima M. Direct Enantioselective Aldol-Tishchenko Reaction Catalyzed by Chiral Lithium Diphenylbinaphtholate. Org. Lett. 2011, 13 (7), 1579–1581. 10.1021/ol103156h. [DOI] [PubMed] [Google Scholar]
  28. Ralston K. J.; Hulme A. N. The Evans-Tishchenko Reaction: Scope and Applications. Synthesis 2012, 44, 2310–2324. 10.1055/s-0032-1316544. [DOI] [Google Scholar]
  29. Mukherjee S.; Yang J. W.; Hoffmann S.; List B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471–5569. 10.1021/cr0684016. [DOI] [PubMed] [Google Scholar]
  30. Zlotin S. G.; Kucherenko A. S.; Beletskaya I. P. Organocatalysis of Asymmetric Aldol Reaction. Catalysts and Reagents. Russ. Chem. Rev. 2009, 78 (8), 737–784. 10.1070/RC2009v078n08ABEH004040. [DOI] [Google Scholar]
  31. Kucherenko A. S.; Siyutkin D. E.; Maltsev O. V.; Kochetkov S. V.; Zlotin S. G. Asymmetric Organocatalysis: From Proline to Highly Efficient Immobilized Organocatalysts. Russ. Chem. Bull. 2012, 61, 1313–1320. 10.1007/s11172-012-0177-4. [DOI] [Google Scholar]
  32. Dalko P. I.Enantioselective Organocatalysis: Reactions and Experimental Procedures; John Wiley & Sons, Inc., 2007, p 559. [Google Scholar]
  33. Kucuk H. B.; Kanturk G.; Yerlikaya S.; Yildiz T.; Senturk A. M.; Guzel M. Novel β-hydroxy ketones: Synthesis, spectroscopic characterization, molecular docking, and anticancer activity studies. J. Mol. Struct. 2022, 1250, 131772. 10.1016/j.molstruc.2021.131772. [DOI] [Google Scholar]
  34. Yadav G. D.; Deepa; Singh S. Prolinamide-Catalysed Asymmetric Organic Transformations. ChemistrySelect. 2019, 4, 5591–5618. 10.1002/slct.201900764. [DOI] [Google Scholar]
  35. Mhaldar S. N.; Tilve S. G. An Approach towards (+)-Allokainic Acid via Diphenylprolinol-Catalyzed Direct Cross-Aldol Reaction. Org. Biomol. Chem. 2023, 21, 5469–5474. 10.1039/D3OB00707C. [DOI] [PubMed] [Google Scholar]
  36. Wang W.; Qin Z.; Tan Z.; Yang W. Organocatalytic Enantioselective Cross-Aldol Reaction of Aryl Ketones with Heteroaromatic Trifluoromethyl Ketone Hydrates for the Synthesis of α-Trifluoromethyl Tertiary Alcohols. Org. Biomol. Chem. 2023, 21 (25), 5234–5239. 10.1039/D3OB00619K. [DOI] [PubMed] [Google Scholar]
  37. Yıldız T.; Yaşa H.; Hasdemir B.; Yusufoğlu A. S. Different Bio/Lewis Acid-Catalyzed Stereoselective Aldol Reactions in Various Mediums. Monatsh. Chem. 2017, 148 (8), 1445–1452. 10.1007/s00706-017-1967-z. [DOI] [Google Scholar]
  38. Can H.; Yıldız T.; Onar H. C. ¸. Synthesis of Chiral 1,3-Keto-Acetates through Enzymatic Kinetic Resolution with Amano Lipase from Pseudomonas Fluorescens. ChemistrySelect 2020, 5 (25), 7543–7547. 10.1002/slct.202001987. [DOI] [Google Scholar]
  39. Yıldız T. An Enzymatic and Environmentally Friendly Route for the Synthesis of Chiral β-Hydroxy Ketones. ChemistrySelect 2019, 4 (27), 7927–7931. 10.1002/slct.201901718. [DOI] [Google Scholar]
  40. Penhoat M.; Barbry D.; Rolando C. Direct Asymmetric Aldol Reaction Co-Catalyzed by l-Proline and Group 12 Elements Lewis Acids in the Presence of Water. Tetrahedron Lett. 2011, 52 (1), 159–162. 10.1016/j.tetlet.2010.11.014. [DOI] [Google Scholar]
  41. Karmakar A.; Maji T.; Wittmann S.; Reiser O. L-Proline/CoCl2-Catalyzed Highly Diastereo- and Enantioselective Direct Aldol Reactions. Chem. - Eur. J. 2011, 17 (39), 11024–11029. 10.1002/chem.201101299. [DOI] [PubMed] [Google Scholar]
  42. Corey E. J.; Helal C. J. Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. Angew. Chem., Int. Ed. 1998, 37, 1986–2012. . [DOI] [PubMed] [Google Scholar]
  43. Corey E. J.; Bakshi R. K.; Shibata S. Highly Enantioselective Borane Reduction of Ketones Catalyzed by Chiral Oxazaborolidines. Mechanism and Synthetic Implications. J. Am. Chem. Soc. 1987, 109 (18), 5551–5553. 10.1021/ja00252a056. [DOI] [Google Scholar]
  44. Yildiz T.; Yusufoğlu A. Asymmetric Synthesis of New Chiral Long Chain Alcohols. Tetrahedron: Asymmetry 2010, 21 (24), 2981–2987. 10.1016/j.tetasy.2010.12.010. [DOI] [Google Scholar]
  45. Hasdemir B.; Yaşa H.; Yıldız T.; Küçük H. B.; Onar H. C. ¸. Asymmetric Synthesis of Chiral γ- and δ-Amino Esters Using Trichlorosilane Activated with a Lewis Base Catalyst. ChemistrySelect 2020, 5 (20), 6035–6039. 10.1002/slct.202000790. [DOI] [Google Scholar]
  46. Edin M.; Bäckvall J. E.; Córdova A. Tandem Enantioselective Organo- and Biocatalysis: A Direct Entry for the Synthesis of Enantiomerically Pure Aldols. Tetrahedron Lett. 2004, 45 (41), 7697–7701. 10.1016/j.tetlet.2004.08.079. [DOI] [Google Scholar]
  47. Córdova A.; Zou W.; Dziedzic P.; Ibrahem I.; Reyes E.; Xu Y. Direct Asymmetric Intermolecular Aldol Reactions Catalyzed by Amino Acids and Small Peptides. Chem. - Eur. J. 2006, 12 (20), 5383–5397. 10.1002/chem.200501639. [DOI] [PubMed] [Google Scholar]
  48. Hayashi Y.; Itoh T.; Nagae N.; Ohkubo M.; Ishikawa H. The Effectiveness of Proteinogenic Amino Acids in the Asymmetric Aldol Reaction in DMSO and Aqueous DMSO. Synlett 2008, 2008 (10), 1565–1570. 10.1055/s-2008-1077789. [DOI] [Google Scholar]
  49. Yıldız T.; Can H.; Yusufoğlu A. S. An Effective and Environmentally Friendly Synthesis of 1,3-Keto-Alcohols. Org. Prep. Proced. Int. 2020, 52 (1), 9–21. 10.1080/00304948.2019.1693239. [DOI] [Google Scholar]
  50. Dimethyl Sulfoxide Producer Association US Environmental Protection Agency IUCLID Data Set; Leesburg, VA, September 8, 2003, Report Number 201-14721A.
  51. Song X.; Liu A. X.; Liu S. S.; Gao W. C.; Wang M. C.; Chang J. Enantiopure Azetidine-2-Carboxamides as Organocatalysts for Direct Asymmetric Aldol Reactions in Aqueous and Organic Media. Tetrahedron 2014, 70 (7), 1464–1470. 10.1016/j.tet.2013.12.081. [DOI] [Google Scholar]
  52. Martínez R.; Berbegal L.; Guillena G.; Ramón D. J. Bio-Renewable Enantioselective Aldol Reaction in Natural Deep Eutectic Solvents. Green Chem. 2016, 18 (6), 1724–1730. 10.1039/C5GC02526E. [DOI] [Google Scholar]
  53. Yildiz T. An Oxazaborolidine-Based Catalytic Method for the Asymmetric Synthesis of Chiral Allylic Alcohols. Tetrahedron: Asymmetry 2015, 26 (8–9), 497–504. 10.1016/j.tetasy.2015.03.008. [DOI] [Google Scholar]

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