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Article

Carbohydrate-Based Chiral Ligands for the Enantioselective Addition of Diethylzinc to Aldehydes

by
F. Javier López-Delgado
,
Daniele Lo Re
,
F. Franco
* and
J. A. Tamayo
*
Department of Medicinal and Organic Chemistry, School of Pharmacy, University of Granada, Campus de Cartuja, 18071 Granada, Spain
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2025, 18(8), 1088; https://doi.org/10.3390/ph18081088
Submission received: 23 June 2025 / Revised: 14 July 2025 / Accepted: 18 July 2025 / Published: 23 July 2025
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Background: Carbohydrate-derived chiral ligands are promising tools in asymmetric catalysis due to their structural diversity, chirality, and availability. However, ligands based on galactose or sorbose have been scarcely explored in the enantioselective addition of dialkylzinc reagents to aldehydes. Methods: A series of chiral diols and β-amino alcohols was synthesized from methyl D-glucopyranoside, methyl D-galactopyranoside, and D-fructose. These ligands were tested in the titanium tetraisopropoxide-promoted enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes. Results: Several ligands, particularly those with a D-fructopyranose backbone, exhibited excellent catalytic activity, with conversion rates up to 100% and enantioselectivities up to 96% ee. Notably, this study reports for the first time the use of β-amino alcohols derived from fructose and sorbose in this transformation. Conclusions: Carbohydrate-based ligands represent effective, inexpensive, and structurally versatile scaffolds for developing highly enantioselective catalysts, expanding the utility of sugars in asymmetric organometallic reactions.

1. Introduction

The enantioselective addition of dialkylzinc compounds to molecules containing prochiral carbonyl groups is a powerful tool for obtaining enantiopure secondary or tertiary alcohols [1,2,3,4,5]. Since the early work of Oguni, Noyori, and Soai [6,7,8,9,10,11], where they reported the asymmetric addition of diethylzinc to carbonyl compounds in the presence of catalytic amounts of a β-amino alcohol, research in this field has grown exponentially [12,13,14].
It has been well established that Ti(IV) complexes efficiently catalyze the asymmetric addition of dialkylzinc reagents to aldehydes, affording high yields and excellent enantioselectivities [15,16]. A variety of chiral ligands have been successfully employed in this transformation, including chiral diols [17,18], BINOL derivatives [19,20,21], disulfonamides [22,23], and N-sulfonylated amino alcohols [23,24,25].
The growing demand for efficient and stereoselective catalysts in environmentally friendly organic synthesis highlighted the potential of carbohydrate-based organocatalysts as chiral ligands. Carbohydrates are abundant, inexpensive, chiral, and biocompatible natural products that offer a versatile platform for catalyst development. Their rigid pyranose and furanose rings provide structural stability and precise stereochemical control, while their multiple hydroxyl groups serve as functional binding sites and can be easily modified to influence catalytic behavior and selectivity. The non-racemic nature, presence of multiple stereogenic centers, and lone electron pairs on ring oxygen atoms further enhance their utility in fine-tuning catalytic performance. Given these features—particularly their low cost, built-in chiral information, and the wide variety of naturally available chiral substrates—carbohydrates are ideal candidates for the development of chiral ligands in asymmetric synthesis and chiral auxiliaries in organocatalysis [26,27,28].
Carbohydrate-based ligands have proven effective in a wide range of asymmetric transformations [26,27,28] including additions of diorganozinc reagents to aldehydes [29,30,31,32,33,34,35,36].
Interestingly, in the asymmetric addition of diethylzinc to carbonyl compounds, only a few examples involving glucose [29,30,31,32,33] have been reported, and only one example using fructose [34] is known. Moreover, no studies to date employed ligands with galactose or sorbose configuration in the enantioselective alkylation of carbonyl compounds with dialkylzinc reagents. This gap is particularly notable given the structural diversity and chiral richness of carbohydrates, which make them ideal scaffolds for designing novel ligand architectures. The present work seeks to address this underexplored area by investigating carbohydrate-based ligands in the asymmetric alkylation of carbonyl compounds, thereby expanding the scope of carbohydrate applications in asymmetric catalysis. As part of our ongoing research in carbohydrate chemistry, and building on our experience in the synthesis of carbohydrate derivatives [37,38,39], we sought to explore the potential of sugar-based scaffolds as chiral ligands in catalytic asymmetric transformations. We initially prepared diols derived from methyl D-glucopyranoside and methyl D-galactopyranoside, which were evaluated as ligands in asymmetric catalysis. Subsequently, structurally related diols based on D-fructose were synthesized and tested under similar conditions. Finally, in the search for ligands with improved catalytic performance, we turned our attention to aminohydroxyfructose derivatives. To the best of our knowledge, these ligands remain largely unexplored in the context of asymmetric catalysis, despite their promising structural features. We report the synthesis and evaluation of carbohydrate-derived chiral ligands, including diols from methyl D-glucopyranoside (Figure 1A), methyl D-galactopyranoside (Figure 1B), and D-fructose (Figure 1C,D), as well as amino alcohols from D-fructose and with L-sorbose configuration (Figure 1E,F). These ligands were tested in the enantioselective addition of diethylzinc to aromatic and aliphatic aldehydes. Their straightforward synthesis from inexpensive, readily available sugars underscores their practical value. Notably, to the best of our knowledge, this is the first report describing the use of β-amino alcohols derived from fructose and sorbose as chiral ligands in the asymmetric alkylation of carbonyl compounds with dialkylzinc reagents.

2. Results and Discussion

Since our objective was to synthesize chiral ligands derived from simple carbohydrates, we began by exploring diols obtained from D-glucose and D-galactose, which are commercially available and relatively inexpensive starting materials.
In this manner, eight carbohydrate-derived diol ligands (Figure 2. 1–8) previously described in literature were readily synthesized using previously reported procedures [40,41,42,43,44,45,46] (see supporting info) and evaluated with the enantioselective addition of diethylzinc to benzaldehyde. We investigated the influence of the trans-diol configuration at C2 and C3, in combination with various protecting groups at C4 and C6, as well as different stereochemistry at C1 and C4.

2.1. Optimization of Reactions Conditions in the Enantioselective Addition of Diethylzinc to Benzaldehyde

The reaction conditions for the addition of diethylzinc to benzaldehyde were optimized based on the conditions reported by Bauer et al. [29] for the asymmetric addition of diethylzinc to aldehydes using similar ligands derived from α-D-methylglucopyranoside.
For this reason, ligand 1 was used for the optimization, in which parameters such as solvent, temperature, ligand concentration, the amount of Et2Zn, and the amount of Ti(OiPr)4 were studied (Table 1).
Pharmaceuticals 18 01088 i001
Table 1. Optimization of diethylzinc addition to benzaldehyde catalyzed by ligand 1 a.
Table 1. Optimization of diethylzinc addition to benzaldehyde catalyzed by ligand 1 a.
EntryLigand
(%)		Ti(OiPr)4 (eq.)Et2Zn b (eq.)SolventT (°C)Conversion (%) dee
(%) e
1-1.43Hexane c01000
2101.43Hexane c09132 (S)
3201.43Hexane c08656 (S)
4301.43Hexane c05255 (S)
5401.43Hexane c02045 (S)
620-3Hexane c030
7200.83Hexane c04247 (S)
82013Hexane c08152 (S)
9201.23Hexane c07255 (S)
10201.63Hexane c08848 (S)
112023Hexane c09846 (S)
12201.43Hexane c2510038 (S)
13201.43Hexane c−286044 (S)
14201.43Hexane c−761246 (S)
15201.43Toluene c07053 (S)
16201.43DCM c07049 (S)
17201.42Hexane c06554 (S)
18201.42.5Hexane c09852 (S)
a 0.25 mmol of benzaldehyde, reaction time 3 h. b The commercial Et2Zn used is a 1M solution in hexane. c 0.25 mL. d Determined by GC using a Supelco α-DEX 325 column, helium flow: 0.8 mL/min, temperature: isothermal at 110 °C. e Absolute configuration assigned by comparing the optical rotation of the purified product with literature data.
The enantioselective addition of Et2Zn to benzaldehyde was initially investigated by varying the molar ratio of the ligand (entry 1–5). In the absence of a ligand, Ti(OiPr)4 appeared to activate Et2Zn, generating a catalytic species capable of promoting the addition reaction. However, this transformation proceeded without stereocontrol, yielding the corresponding racemic secondary alcohol (entry 1). When the ligand was introduced at loadings between 10% and 40% (entry 2–5), a degree of enantioselectivity was observed (ee 32–45%). On other hand, as the ligand concentration increased, the conversion rate progressively declined, suggesting a possible inhibitory effect at higher ligand loadings.
To further elucidate the role of Ti(OiPr)4, we examined its influence on both the yield and enantioselectivity of the reaction in the presence of ligand 1. As expected, Ti(OiPr)4 was essential, as no enantioselective addition of Et2Zn to benzaldehyde occurred in its absence (entry 6). The reaction tolerated an increase in Ti(OiPr)4 concentration of up to 1.4 equivalents, beyond which a slight decrease in enantioselectivity was observed (entry 10 and 11). Importantly, the reaction was highly sensitive to temperature variations. Attempts to modify the temperature from 0 °C were unsuccessful. Elevating the temperature to 25 °C resulted in a higher conversion rate but led to a significant erosion of enantioselectivity (entry 12). Conversely, decreasing the temperature to −28 °C or −76 °C led to a drastic reduction in conversion, while enantioselectivity remained moderate (entries 13 and 14). We also investigated the effect of solvent choice on the reaction outcome. Hexane was superior both in conversion rate and enantioselectivity compared with toluene and DCM (entries 16 and 17). On other hand, enantioselectivity remained largely unaffected by changes in Et2Zn stoichiometry, with the highest enantiomeric excess obtained at 3 equivalents of Et2Zn. The highest conversion rate was achieved with 2.5 equivalents of Et2Zn, although this condition resulted in a slightly lower enantiomeric excess than the reaction conducted with 3 equivalents. Therefore, prioritizing enantioselectivity over conversion, we selected 3 equivalents of Et2Zn as the optimal stoichiometry under the optimized reaction conditions with ligand 1.

2.2. Evaluation of Chiral Diol Ligands Based on α-, β-D-Methylglucopyranoside and α-, β-D-Methylgalactopyranoside in the Enantioselective Addition of Diethylzinc to Benzaldehyde

Under the previously established conditions (ligand 20%, Ti(OiPr)4 1.4 eq, Et2Zn 3eq, 0 °C, Hexane), the ability of the synthesized D-glucose and D-galactose ligands (1–8) to induce the enantioselective addition of diethylzinc to benzaldehyde, was evaluated (Table 2).
The glucose derivatives 1–4 exhibited good conversion rates (75–90%) while maintaining moderate enantioselectivity (35–56% ee). In comparison, the galactose derivatives 5–8 also achieved high conversion (80–89%), but their enantioselectivity was noticeably lower (4–40% ee). Acetonide at C-4 and C-6 had generally a significant impact, since benzylidene derivatives led to higher enantiomeric excesses than their isopropylidene counterparts. In the glucose series (ligands 1–4), the α-methyl derivatives consistently outperformed their β-counterparts in terms of enantioselectivity. Interestingly, the opposite effect was observed in the galactose series (ligands 5–8), where the β-anomers perform slightly better than their α-counterparts, while α-methyl galactopyranoside derivatives, 5 and 6, gave the R enantiomer as the major product, setting them apart from the rest of the series.

2.3. Evaluation of Chiral Diol Ligands Based on D-Fructose in the Enantioselective Addition of Diethylzinc to Benzaldehyde

Since it was postulated that the diol motif in glucose and galactose ligands 1–8 was important for enantioselectivity, we wondered if diols derived from D-fructose would influence the enantioselectivity of the Et2Zn addition. To test this idea, we synthesized pyranose D-fructose derivatives, bearing a cis diol at C-4 and C-5 and strategically incorporating an acetonide protecting group at either C-1/C-2 or C-2/C-3. These ligands (9–14) (Figure 3), previously described in literature, were prepared following established literature procedures [47,48,49,50,51,52,53,54,55] (see Supporting Info) and tested in the enantioselective addition of Et2Zn to benzaldehyde by applying the optimized conditions used for ligands 1–8. The results are presented in Table 3.
Ligands 9 and 10, bearing an acetonide at C1 and C2 and a benzyl and benzoyl protecting group at C-3, respectively, exhibited excellent catalytic activity, achieving complete conversion with moderate to high levels of enantioselectivity. In contrast, ligand 11, which features a tosylate group at C-3, displays a high conversion rate (80%) together with a dramatic drop in terms of the enantioselectivity (6% ee), suggesting that the substituent at C-3 is crucial for the ligand’s ability to efficiently control the stereochemical outcome of the reaction.
Along the same lines, ligands 12, 13, and 14, bearing an acetonide at C-1 and C-3, displayed high conversion rates (90–99%), together with an important loss in enantioselectivity (11–15% ee), highlighting the pivotal role of C-3 in enantio-induction, reinforcing the idea that its functionalization and spatial arrangement are key to achieving effective chiral discrimination. Notably, across all tested ligands, the reaction predominantly led to the formation of the S enantiomer, indicating a consistent stereochemical preference within this system.

2.4. Synthesis and Evaluation of β-Amino Alcohol Ligands Based on D-Fructose in the Enantioselective Addition of Diethylzinc to Benzaldehyde

Based on these results, we proceeded to prepare fructose-derived ligands bearing both cis- and trans-β-amino alcohol moieties, which represent one of the most extensively studied classes of chiral ligands and auxiliaries [14].
Novel ligands 22–27 were synthesized from key intermediate 20 and novel ligands 28–33 from key intermediate 21 [56] (Scheme 1). Both intermediates 20 and 21 were obtained from a common precursor, the well-known 4-O-benzoyl-3-O-benzyl-1,2-O-isopropylidene-β-D-fructopyranose 15 [37] synthesized in four steps from D-fructose [48]. Key intermediated β-amino alcohol 20 was achieved from azide 16 [48,57,58]. Catalytic hydrogenation of 16 with Pd/C yielded 20 in high yield. On the other hand, key intermediate β-amino alcohol 21 was synthesized from alcohol 15 in four steps. First, sugar 15 was transformed into 5-O-methanesulfonyl derivative 17, followed by treatment with sodium azide to give compound 18 presenting a β-L-sorbopyranose configuration. Subsequent debenzoylation of 18 yielded azido alcohol 19, which was finally subjected to hydrogenation with Pd/C to obtain amino alcohol ligand 21 (Scheme 1).
In order to synthesize the β-amino alcohol ligands with q D-fructopyranose structure (22–27), compound 20 was used as the starting material. β-hydroxysulfonamide ligands were first obtained through reaction of 20 with TsCl, MsCl, and TfO2, respectively, affording ligands 22, 23, and 24 in good yields. The dialkylated ligands (25–27) were obtained through a reaction of 20 with ethyl iodide, 1,4-diiodobutane, and 1,5-diiodopentane, respectively, to yield ligands 25, 26, and 27, respectively (Scheme 2).
Ligands with L-sorbopyranose structure (28–33) were synthesized from compound 21 using the same procedure described above for ligands with D-fructopyranose structure (22–27) (Scheme 3).
Ligands 20 and 22–33 were then screened under the optimized conditions and their results are shown in Table 4. Conversion rates obtained with all ligands were good to excellent (78–100%). However, different levels of enantioselectivity were observed depending on the compound used. A dramatic loss of enantioselectivity was observed in trans β-aminoalcohols (21 and 28–33, entry 8–14). On the other hand, cis β-aminoalcohols (20 and 22–27, Table 4, entry 1–7) displayed higher enantioselectivity when compared with their trans counterparts. Importantly, all cis β-aminoalcohols (20 and 22–27, Table 4, entry 1–7) were able to catalyze the synthesis of the S enantiomer, while most of the trans β-aminoalcohols (21, 28, 30, and 32, Table 4, entry 8, 9, 11, and 13) mainly deliver the R enantiomer.
Ligand 22 was the best compound evaluated (100% conversion and 92% ee) and was selected to explore the scope of substrates for this catalytic system. The enantioselective addition of Et2Zn in the presence of 20 mol % of ligand 22 (entry 2, Table 4) to a variety of aldehydes, such as aromatic, α,β-unsaturated, and aliphatic, both cyclic and linear were therefore studied (Table 5).
Ligand 22 proved to be catalytically active for all aldehydes tested, inducing high levels of conversion (70–100%). Moderate to good yields were also achieved for all aldehydes, the aliphatic substrates being the least reactive. In terms of stereoinduction, o- and m-methylbenzaldehydes showed excellent enantioselectivity (entries 2 and 3, 92% and 96% ee, respectively). These substrates slightly outperformed the enantioselectivity achieved for benzaldehyde (entry 1). As for the p-methylbenzaldehyde, the enantioselectivity decreased slightly (entry 4, 83% ee), indicating that the rate is influenced by the position of the methyl substituents on benzaldehyde. Good to excellent degrees of enantioselectivity were maintained in p-substituted benzaldehydes presenting both electron-donating and electron-withdrawing groups (entries 5, 6, and 7). With bulky aromatic aldehyde, 2-naphthaldehyde, the corresponding secondary alcohol was achieved with excellent enantioselectivity (entry 8, 92% ee). However, a lower level of enantioselectivity and moderate yield was achieved with the electron-rich heteroaromatic aldehyde, furfural (entry 9, 13% ee). Interestingly, in this substrate the secondary alcohol obtained was the R-enantiomer. A similar pattern of asymmetric induction was observed with cinnamaldehyde. This compound reacted with good yield and a moderate level of enantioselectivity (entry 9, 72% ee), giving the R-enantiomer of the corresponding secondary alcohol. Regarding the aliphatic aldehydes, Et2Zn addition generated the corresponding secondary alcohols with low enantioselectivity in the case of cyclic aliphatic, cyclohexanecarbaldehyde (entry 11, 35% ee), and moderate enantioselectivity for linear aliphatic hexanaldehyde (entry 12, 62% ee). It is worth mentioning the sense of enantioselectivity generated by ligand 22. While most aldehydes tested underwent the ethyl group transfer to the Si face of the carbonyl group yielding the S-enantiomer, cinnamaldehyde and furfural (entries 8 and 9) showed the formation of the R-enantiomer. Such results could be attributed to the characteristic presence of the α,β-unsaturation in cinnamaldehyde and furfural causing a decrease in the energy difference between the two possible planar conformations in the active catalytic complex in both substrates, leading to a lower enantiomeric ratio [59].

3. Materials and Methods

Solutions were dried with MgSO4 before concentration under reduced pressure. The 1H and 13C NMR spectra were recorded with Variant INOVA UNITY 300 MHz, Variant DIRECT DRIVE 400 MHz, and 500 MHz spectrometers. Chemical shifts are quoted in ppm and are referenced to as residual H in the deuterated solvent as the internal standard. Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; quint, quintet; m, multiplet, and br, broad. IR spectra were recorded with a Perkin–Elmer FT-IR Spectrum One instrument and mass spectra were recorded with Hewlett–Packard HP-5988-A and Fisons mod. Platform II and VG Autospec-Q mass spectrometers. Optical rotations were measured, unless otherwise stated, for solutions in CHCl3 (1 dm tube) with a Jasco DIP-370 polarimeter. TLC was performed on precoated silica gel (60 F254) aluminum sheets and compounds were detected with a mixture of H2SO4 in ethanol (5% in vol.), vanillin, KMnO4, and ammonium molybdate (10% w/v) in aqueous sulfuric acid (10%) containing cerium sulfate (0.8% w/v), and heating. Rf values refer to these TLC plates developed in the solvents indicated. Column chromatography was performed on silica gel silica gel 60 (230–400 mesh). The low-resolution mass spectra were recorded using an Agilent Technologies 1200 HPLC-MS system (6110 Quadrupole LC/MS) equipped with Zorbax Eclipse XDB-C18 columns (4.6 × 150 mm) and electrospray ionization (ESI). The high-resolution mass spectra were obtained using a High-Resolution Mass Spectrometer LCT-TOF Premier XE from Micromass Technology.
Enantiomeric excesses were determined by gas chromatography (GC) using a Hewlett-Packard 6890 chromatograph equipped with a flame ionization detector and chiral-fused silica capillary columns (30 m × 0.25 mm × 0.25 μm) from SUPELCO: Alpha-DEX™ 325, Beta-DEX™ 325, and Gamma-DEX™ 325, with helium as the carrier gas. The injector and detector temperatures were maintained at 270 °C.
Additionally, enantiomeric excesses were measured by high-performance liquid chromatography (HPLC) using an Agilent 1200 Series system coupled to a UV detector, with a CHIRALPAK IA chiral column from Daicel. General procedure for enantioselective addition of diethylzinc aldehydes.
In a Schlenk flask equipped with a magnetic stirrer (dried and under argon atmosphere) was added the ligand (20 mol%) which was then dissolved in hexane (0.25 mL), and Ti(OiPr)4 (104 µL, 0.35 mmol, 1.4 eq) was added and was kept under stirring at room temperature for 30 min. After this time, the reaction mixture was cooled to 0 °C, and 1 M solution of Et2Zn solution in hexane (0.75 mL, 0.75 mmol, 3 eq) was injected; the reaction mixture rapidly turned to a yellow color and was stirred for another 30 min at 0 °C. The reaction mixture acquired a dark green color, and we proceeded to the addition of the aldehyde (26.5 mg, 0.25 mmol) while stirring at a temperature of 0 °C for 3 h. After completion of the reaction, HCl 1N (3 mL) is added and then extracted with ether (3 × 5 mL). The organic phase was washed with water (3 × 5 mL) and dried with MgSO4. After filtration and concentration, the residue was purified by column chromatography (1:9/1:4, ether:hexane).

4. Conclusions

We successfully demonstrate the application of carbohydrate-derived chiral diol ligands based on D-glucose, D-galactose, and D-fructose, as well as the synthesis of novel amino alcohol ligands with D-fructose and L-sorbose structure, in the titanium-catalyzed enantioselective addition of diethylzinc to aldehydes. The glucose- and galactose-based diol ligands (1–8) exhibited promising catalytic activity, with several ligands achieving high conversions and moderate to high enantioselectivity. Among the fructose-derived ligands, those featuring a 1,2-cis-diol motif showed particularly strong performance, with ligand 9 reaching enantiomeric excesses of up to 72%.
Among the amino alcohol ligands, the one derived from D-fructose outperformed those based on L-sorbose. Most notably, ligand 22 exhibited the highest catalytic activity, affording high conversion rates and enantioselectivities of up to 98% ee across a broad range of aromatic and aliphatic aldehydes. The results obtained with ligand 22 are comparable to, and in some cases surpass, those achieved with state-of-the-art systems. Ligand 22 is synthesized from an inexpensive, renewable monosaccharide (e.g., D-fructose) via a short, high-yielding synthetic sequence that avoids resolution steps and derivatization from non-renewable sources. Moreover, ligand 22 is air-stable, non-toxic, and structurally versatile due to its polyhydroxylated scaffold, offering a practical and sustainable approach for asymmetric catalysis.
This study reports, for the first time, the use of 5-amino-4-hydroxy pyranose monosaccharides as chiral ligands in catalytic asymmetric organometallic reactions. Furthermore, it highlights the utility of β-D-fructopyranose-configured monosaccharides as inexpensive, readily accessible, and tunable scaffolds for the development of highly enantioselective catalysts. Ongoing investigations aim to expand the substrate scope and evaluate the limitations of these ligand systems.

Author Contributions

Conceptualization, J.A.T. and F.F.; methodology, J.A.T. and F.F.; validation, J.A.T., D.L.R. and F.F.; formal analysis, J.A.T., D.L.R., F.J.L.-D. and F.F.; investigation, J.A.T., F.J.L.-D. and F.F.; resources, J.A.T.; data curation, J.A.T., D.L.R. and F.F.; writing—original draft preparation, D.L.R. and J.A.T.; writing—review and editing, D.L.R. and J.A.T.; visualization, D.L.R. and J.A.T.; supervision, J.A.T. and F.F.; project administration, J.A.T. and F.F.; funding acquisition, J.A.T. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Junta de Andalucía, grant number P09-FQM-4498.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

Acknowledgments

The authors are deeply grateful to Regional Government of Andalusia (Junta de Andalucía, Spain) for financial support (Project P09-FQM-4498) and for a fellowship (F.J.L.D).

Conflicts of Interest

The authors declare no conflict of interest.

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Pharmaceuticals 18 01088 g001
Figure 1. General structures of the ligands described in this paper.
Figure 1. General structures of the ligands described in this paper.
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Pharmaceuticals 18 01088 g002
Figure 2. D-glucose and D-galactose-based ligands tested in this study.
Figure 2. D-glucose and D-galactose-based ligands tested in this study.
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Pharmaceuticals 18 01088 g003
Figure 3. D-fructose ligands featuring 1,2-cis-diol moieties.
Figure 3. D-fructose ligands featuring 1,2-cis-diol moieties.
Pharmaceuticals 18 01088 g003
Pharmaceuticals 18 01088 sch001
Scheme 1. Synthesis of aminoalcohol ligand intermediate 20 and 21. Reagent and conditions: (a) I2, Ph3P, imidazole, toluene. (b) NaN3, dry DMF, 110 °C. (c) MeONa 1M in MeOH. (d) ClMs, Py, 0 °C. (e) H2, Pd/C, MeOH.
Scheme 1. Synthesis of aminoalcohol ligand intermediate 20 and 21. Reagent and conditions: (a) I2, Ph3P, imidazole, toluene. (b) NaN3, dry DMF, 110 °C. (c) MeONa 1M in MeOH. (d) ClMs, Py, 0 °C. (e) H2, Pd/C, MeOH.
Pharmaceuticals 18 01088 sch001
Pharmaceuticals 18 01088 sch002
Scheme 2. Synthesis of chiral β-aminoalcohol ligands derived from D-fructose. Reagents and conditions: (a) TsCl, Na2CO3, acetone-H2O; (b) MsCl, dry Py, 0 °C; (c) TfO2, Et3N, DMAP, dry DCM; (d) EtI, K2CO3, CH3CN, 60 °C; (e) 1,4-diiodobutane, K2CO3, CH3CN, 60 °C to 78 °C; and (f) 1,5-diiodopentane, K2CO3, 60 °C to 78 °C.
Scheme 2. Synthesis of chiral β-aminoalcohol ligands derived from D-fructose. Reagents and conditions: (a) TsCl, Na2CO3, acetone-H2O; (b) MsCl, dry Py, 0 °C; (c) TfO2, Et3N, DMAP, dry DCM; (d) EtI, K2CO3, CH3CN, 60 °C; (e) 1,4-diiodobutane, K2CO3, CH3CN, 60 °C to 78 °C; and (f) 1,5-diiodopentane, K2CO3, 60 °C to 78 °C.
Pharmaceuticals 18 01088 sch002
Pharmaceuticals 18 01088 sch003
Scheme 3. Synthesis of chiral β-amino alcohol ligands with L-sorbopyranose structures. Reagents and conditions: (a) TsCl, Na2CO3, acetone/H2O; (b) MsCl, dry Py, 0 °C; (c) Tf2O, Et3N, DMAP, dry DCM; (d) EtI, K2CO3, CH3CN, 60 °C; (e) 1,4-diiodobutane, K2CO3, CH3CN, 60 °C to 78 °C; and (f) 1,5-diiodopentane, K2CO3, 60 °C to 78 °C.
Scheme 3. Synthesis of chiral β-amino alcohol ligands with L-sorbopyranose structures. Reagents and conditions: (a) TsCl, Na2CO3, acetone/H2O; (b) MsCl, dry Py, 0 °C; (c) Tf2O, Et3N, DMAP, dry DCM; (d) EtI, K2CO3, CH3CN, 60 °C; (e) 1,4-diiodobutane, K2CO3, CH3CN, 60 °C to 78 °C; and (f) 1,5-diiodopentane, K2CO3, 60 °C to 78 °C.
Pharmaceuticals 18 01088 sch003
Table 2. Evaluation of the catalytic activity of chiral diol ligands based on α-, β-D-methylglucopyranoside and α-, β-D-methylgalactopyranoside in the enantioselective addition of diethylzinc to benzaldehyde a.
Table 2. Evaluation of the catalytic activity of chiral diol ligands based on α-, β-D-methylglucopyranoside and α-, β-D-methylgalactopyranoside in the enantioselective addition of diethylzinc to benzaldehyde a.
LigandConversion (%) bee (%) bConfiguration c
18656(S)
27546(S)
37735(S)
49040(S)
58921(R)
6904(R)
78040(S)
88914(S)
a 0.25 mmol of benzaldehyde, 0.2 eq of ligand, 1.4 eq of Ti(OiPr)4 and 3 eq of Et2Zn in 0.25 mL of hexane at 0 °C, 3 h. b Determined by GC using a Supelco α-DEX 325 column, helium flow: 0.8 mL/min, temperature: isothermal at 110 °C. c Absolute configuration assigned by comparing the optical rotation of the purified product with literature data.
Table 3. Evaluation of the catalytic activity of chiral diol ligands based on β-D-fructopyranose in the enantioselective addition of diethylzinc to benzaldehyde a.
Table 3. Evaluation of the catalytic activity of chiral diol ligands based on β-D-fructopyranose in the enantioselective addition of diethylzinc to benzaldehyde a.
LigandConversion (%) bee (%) bConfiguration c
910072(S)
1010053(S)
11806(S)
129915(S)
139811(S)
149612(S)
a 0.25 mmol of benzaldehyde, 20 mol % of ligand, 1.4 eq of Ti(OiPr)4, and 3 eq of Et2Zn in 0.25 mL of hexane at 0 °C, 3 h. b Determined by GC using a Supelco α-DEX 325 column, helium flow: 0.8 mL/min, temperature: isothermal at 110 °C. c Absolute configuration assigned by comparing the optical rotation of the purified product with literature data.
Table 4. Ligand screening in enantioselective addition of Et2Zn to benzaldehyde [a].
Table 4. Ligand screening in enantioselective addition of Et2Zn to benzaldehyde [a].
Pharmaceuticals 18 01088 i002
EntryLigandRβ-Amino
Alcohol		Conversion [b]ee (%) [b]Configuration [c]
120Pharmaceuticals 18 01088 i003E9149S
222Pharmaceuticals 18 01088 i004E10092S
3 23Pharmaceuticals 18 01088 i005E9840S
4 24Pharmaceuticals 18 01088 i006E10052S
5 25Pharmaceuticals 18 01088 i007E10050S
6 26Pharmaceuticals 18 01088 i008E10049S
7 27Pharmaceuticals 18 01088 i009E10055S
8 21Pharmaceuticals 18 01088 i010Z782R
9 28Pharmaceuticals 18 01088 i011Z9130R
10 29Pharmaceuticals 18 01088 i012Z981S
11 30Pharmaceuticals 18 01088 i013Z1004R
12 31Pharmaceuticals 18 01088 i014Z1003S
13 32Pharmaceuticals 18 01088 i015  [c]Z1001R
14 33Pharmaceuticals 18 01088 i016  [c]Z10019S
a Reaction conditions: 0.25 mmol of benzaldehyde, 20 mol % of ligand, 1.4 eq of Ti(OiPr)4, and 3 eq of Et2Zn in 0.25 mL of hexane at 0 °C. b Determined by GC using a chiral column Supelco α-DEXTM 325, helium flow: 0.8 mL/min, and temperature: 110 °C. c Absolute configuration assigned by comparison with GC spectrum and the data described in the literature.
Table 5. Scope in enantioselective addition of Et2Zn to aldehydes [a].
Table 5. Scope in enantioselective addition of Et2Zn to aldehydes [a].
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EntryRConversion
(%) [b]		Yield
(%)		ee
(%) [b]		Configuration [c]
1Pharmaceuticals 18 01088 i0181008092S
2Pharmaceuticals 18 01088 i019988192S
3Pharmaceuticals 18 01088 i0201009096S
4Pharmaceuticals 18 01088 i021956483S
5Pharmaceuticals 18 01088 i022957892S
6Pharmaceuticals 18 01088 i0231008985S
7Pharmaceuticals 18 01088 i024906898S
8Pharmaceuticals 18 01088 i02599 [e]8492 [e]S
9Pharmaceuticals 18 01088 i0261006213R
10Pharmaceuticals 18 01088 i027958572R
11Pharmaceuticals 18 01088 i028705935S
12Pharmaceuticals 18 01088 i029815762S
a Reaction conditions: 0.25 mmol of aldehyde, 20 mol % of 3, 1.4 eq of Ti(OiPr)4, and 3 eq of Et2Zn in 0.25 mL of hexane at 0 °C. b Determined by GC. c Absolute configuration assigned by comparison with GC spectrum and data described in the literature. e Determined by HPLC.
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López-Delgado, F.J.; Lo Re, D.; Franco, F.; Tamayo, J.A. Carbohydrate-Based Chiral Ligands for the Enantioselective Addition of Diethylzinc to Aldehydes. Pharmaceuticals 2025, 18, 1088. https://doi.org/10.3390/ph18081088

AMA Style

López-Delgado FJ, Lo Re D, Franco F, Tamayo JA. Carbohydrate-Based Chiral Ligands for the Enantioselective Addition of Diethylzinc to Aldehydes. Pharmaceuticals. 2025; 18(8):1088. https://doi.org/10.3390/ph18081088

Chicago/Turabian Style

López-Delgado, F. Javier, Daniele Lo Re, F. Franco, and J. A. Tamayo. 2025. "Carbohydrate-Based Chiral Ligands for the Enantioselective Addition of Diethylzinc to Aldehydes" Pharmaceuticals 18, no. 8: 1088. https://doi.org/10.3390/ph18081088

APA Style

López-Delgado, F. J., Lo Re, D., Franco, F., & Tamayo, J. A. (2025). Carbohydrate-Based Chiral Ligands for the Enantioselective Addition of Diethylzinc to Aldehydes. Pharmaceuticals, 18(8), 1088. https://doi.org/10.3390/ph18081088

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