# Access to Thioglycoconjugate Bioorganometallic Ferrocenes via a Copper-Catalyzed Coupling

Ahmed El Rhaz, Estelle Messé, Pascal Retailleau, William Erb, Samir Messaoudi, Franck Le Bideau

► To cite this version:

Ahmed El Rhaz, Estelle Messé, Pascal Retailleau, William Erb, Samir Messaoudi, et al., Access to Thioglycoconjugate Bioorganometallic Ferrocenes via a Copper-Catalyzed Coupling. Organic Letters, 2025, 27 (29), pp.7979-7985. 10.1021/acs.orglett.5c02292. hal-05222831

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# Access to Thioglycoconjugate Bioorganometallic Ferrocenes Via a Copper-Catalyzed Coupling

Ahmed El Rhaz,ª Estelle Messé,ª Pascal Retailleau,ᵇ William Erb,ᶜ Samir Messaoudi,ᵈ* Franck Le Bideauª*

<figure><img src="image_2.png" /></figure>

**ABSTRACT:** The synthesis of thiosugar-ferrocene conjugates through Ullmann-type coupling is reported. The method provides access to compounds showing direct attachment of the thiol to the ferrocene, a type of molecule of which only one example had ;previously been reported. This methodology, which has been extended to other thiols (alkyl, (hetero)aryl), enables products to be obtained in excellent yields under relatively mild operating conditions. Several of these compounds have been tested against HTC116 cells without yielding convincing results, the best IC₅₀ remaining at the micromolecular level.

Bioorganometallic chemistry focuses on the synthesis and study of the biological activity of organometallic complexes.¹ It involves designing molecules that combine an organometallic motif with a bioligand known for its affinity toward the biological target, such as steroids,² sugars,³ peptides,⁴ proteins,⁵ natural products,⁶ or drugs.⁷ The ferrocenyl substituent has been extensively used in this field⁸ as it can undergo reversible oxidation within cells *via* a Fen-ton-like mechanism, generating reactive oxygen species (ROS) that may play a role in eradicating tumor cells, bacteria, fungi, or para-sites⁸. The lipophilicity of this organometallic can also increase hy-drophobic interactions between the drug and its target while the various positions and ways of functionalization can be advanta-geous for developing orally administrable formulations. To date, ferrocerone (Figure 1), used in the 1970s for the treatment of ane-mia in USSR, remains the only ferrocene-derived drug approved for use.⁹ Ferroquine,¹⁰ and ferrocifen,¹¹ the respective analogues of chloroquine and tamoxifen (Figure 1), are two drug candidates ex-tensively studied for the treatment of malaria and breast cancer, but have not yet received market authorization.

One of the most promising strategies in drug development is the introduction of a carbohydrate motif into bioactive molecules, which can potentially offer several advantages, such as improved bioavailability,¹² solubility,¹³ or biological activity by selectively targeting cancerous tissue through overexpression of glucose trans-porters (GluT) on the surface of cancer cells.¹⁴ The combination of carbohydrates with organometallic complexes in the discovery of new bioactive molecules is, therefore, an interesting area of study for researchers working in the field of bioorganometallic chemistry.

Synthesis and applications of such targets were reviewed in 2004 by Metzler-Nolte et al.⁴ and since then, other significant studies in the field have been reported.¹⁵

Several studies have been published on the synthesis of ferro-cenyl-carbohydrate conjugates and their antibacterial, antiparasitic, and anticancer activities. For instance, the ferrocene glycoconju-gate **1** (Figure 1) showed good antibacterial activity against *E. coli* and *Pseudomonas aeruginosa* with minimum inhibitory concentra-tions (MIC) of 4.68 and 9.37 µg/mL, respectively.¹⁶ In addition, the ferroquine glycoside analogue **2** (Figure 1) exhibits micromolar-level activity (0.77 µM) against chloroquine-resistant (CQR) Dd2 strains of *Plasmodium falciparum*.¹⁷ In both compounds, it was demonstrated that the sugar nucleus plays an important role in the biological activity observed.

To date, in all reported examples of ferrocene glycoconjugates, the carbohydrate moiety is connected to the ferrocene core via var-ious spacer groups. Surprisingly, a thorough literature survey re-vealed only a few studies focusing on the direct attachment of a sugar unit to ferrocene. These ferrocene C-glycosides have been synthesized through: (i) electrophilic aromatic substitution of fer-rocene using benzylated glucose **3a**, albeit in low yield (Figure 1B);¹⁸ (ii) glycosylation of the ferrocene moiety using activated sugars in the presence of TMSOTf;¹⁹ (iii) transmetalation from lithiated glycosyl cyclopentadienides to FeCl₂,²⁰ and (iv) double C–H activation of sugar chlorides **3b** directed by a coordinating group on the ferrocene scaffold (Figure 1B).²¹
<figure><img src="image_3.png" /></figure>

(B): previous works:

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

(C): this study:

<figure><img src="image_5.png" /><figcaption>**Figure 1.** (A) Examples of bioorganometallic complexes incorporating a ferrocenyl group. (B) The only reported examples of compounds with a direct bond between the sugar and the ferrocene (C) This study leading to the direct association of thiosugars with ferrocenes.</figcaption></figure>

Building on our medicinal chemistry program with thiogalactosides,²² and the biological importance of ferrocenes, we were motivated by the scarcity of these methods to develop a straightforward and efficient approach to produce a variety of thioglyconjugated ferrocenes. Herein, we report an efficient Cu-catalyzed cross-coupling between iodoferrocenes and various sugars (Figure 1-C). This approach offers a number of advantages over the method described to date: (i) the use of an abundant and inexpensive copper catalyst, (ii) mild reaction conditions, (iii) tolerance towards various mono- and polysaccharides and (iv) access to a reactive ferrocene-thioglycoside platform that could be engaged in numerous post-functionalization. We also report the biological activity of these new glyconjugates against human colorectal carcinoma cell lines HTC-116.

To initiate this study, acetylated β-thiogalactose **5a** and iodoferrocene **6a** were selected as model substrates (Table 1). We initially attempted the coupling between both partners under our previously reported Pd-catalysis conditions for the coupling of thiosugars with aryl iodides²³ (see SI). Indeed, the oxidative addition of palladium(0) into the C–I bond of and iodoferrocene is feasible, as Sonoogashira carbonylation,²⁴ Stille²⁵ and Suzuki-Miyaura²⁶ reactions have been already reported. Surprisingly, under our PdG3-XantPhos reported conditions, the desired coupling product has never been observed. We then attempted a nickel-catalyzed reaction, which had previously shown efficiency for coupling iodinated aryls with unprotected glycosyl thiols, however the coupling also failed in the case of iodoferrocene (see SI).²⁷ Finally, we turned out our attention to copper catalysis as it was used successfully for the coupling of ferrocenyl iodides with various nucleophiles.²⁸ Thus, reaction of **5a** (1 equiv) and **6a** (1 equiv) in the presence of CuI as

a catalyst, K₃PO₄, as a base, N,N-dimethylethanolamine (DMEA) as a ligand in dioxane at 90 °C, only leads to trace amounts of coupling product **7a** detected by LCMS analysis. However, the reaction under Xue conditions²⁹ (CuCl, Cs₂CO₃, 1,10-phenanthroline (L1), MeCN, 80 °C) reported initially for the coupling of 2'-cyanoethyl thiosugars, resulted in the formation of the desired product **7a** in 50% yield (Table 1, Entry 1). Starting from this encouraging preliminary result, we screened different reaction parameters aiming to increase the yield of the desired product **7a** (Table 1).

As thiols are generally prone to oxidation, carrying out the reaction with 1.5 equiv. of the thiogalactose **5a** instead of 1 equiv. leads to increasing the yield up to 63% yield (Table S1, entry 2). The use of CuI as a catalyst, proved to be more efficient than CuCl as **7a** was obtained in 78% yield (Table 1, entry 3 vs 2).

The concomitant use of CuI and ligand **L2** gave the best result

<figure><img src="image_6.png" /><figcaption>**Table 1.** Screening of the reaction conditions.</figcaption></figure>

<table><thead><tr><th>entry</th><th>catalyst</th><th>ligand</th><th>yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>CuCl</td><td><b>L1</b></td><td>50<sup>b</sup></td></tr><tr><td>2</td><td>CuCl</td><td><b>L1</b></td><td>63<sup>c</sup></td></tr><tr><td>3</td><td>CuI</td><td><b>L1</b></td><td>78<sup>c</sup></td></tr><tr><td>4</td><td>CuCl</td><td><b>L2</b></td><td>78<sup>c</sup></td></tr><tr><td>5</td><td>CuI</td><td><b>L2</b></td><td>99<sup>c,d</sup></td></tr><tr><td>6</td><td>CuI</td><td><b>L2</b></td><td>93<sup>c</sup></td></tr><tr><td>7</td><td>CuI</td><td><b>L3</b></td><td>76<sup>c</sup></td></tr></tbody></table>

Reaction conditions: **5a** (0.45 mmol, 1.5 equiv), **6a** (0.3 mmol, 1.0 equiv), Cu-catalyst (20 mol%), ligand **L** (20 mol%), Cs₂CO₃ (0.6 mmol, 2 equiv), MeCN (2 mL), 80 °C, 4 h.ª yields of isolated **7a**.ᵇ 1 equiv of thiosugar **5a**.ᶜ 1.5 equiv of **5a**.ᵈ 50 mol% of CuI and 50 mol% of **L2**

When using 20 mol% (93%, entry 6), while the **L3** ligand proved far less effective (76%, entry 7). Of note, increasing the catalyst loading to 50% led to a near-quantitative yield (entry 5 vs 6). Other reaction parameters including solvent effect, the base as well as the reaction temperature were also examined (see SI). The best reaction conditions involve the use of CuI as catalyst (20 mol%), the ligand neocuprine **L2** (20 mol%), acetonitrile as solvent and cesium carbonate as base. Regarding the almost similar results obtained with the 20 vs 50 mol% catalytic systems (93 vs 99%), we preferred the lowest one for atom economy purpose. Reactions were carried out in sealed tubes at 80 °C for 4 hours.

Product **7a** was easily characterized by 2D NMR analysis. ¹H NMR data suggested that the β-configuration of the glycoside was maintained with the characteristic coupling constant (*J*<sub>H1,H2</sub> = 9.9 Hz) between the protons in positions C1 and C2. Growing crystals of **7a** was also found possible, thus unambiguously assigning its structure by X-ray diffraction analysis (Table 1).

With the optimized conditions in hand (Table 1, entry 6), we turned our attention to examine the scope and limitations of this
reaction regarding the thiosugar nature and different substituted ferrocenes. Pleasantly, this reaction is compatible with a wide range of protected mono and poly-thiosugars (Scheme 1). Thus, β-protected thiosugars including thioglucose **5b** (β-thioGlc), thioglycosamine **5c** (β-thioGlcNAc), thiogalactose **5c** (β-thioGal), thiofucose **5d** (β-thioFuc) were successfully coupled with ferrocene **6a** in yields ranging between 40 to 95%. Moreover, the use of β-thiofuranose **5j** gave the desired ferrocene furanoside **7j** in moderate 43% yield.

<figure><img src="image_7.png" /><figcaption>**Scheme 1.** Scope of the coupling of various thiosugars **5** with substituted ferrocenes **6**.</figcaption></figure>

Substituted ferrocenes

<figure><img src="image_8.png" /></figure>

Reaction conditions: **5** (0.48 mmol, 1.5 equiv), **6** (0.32 mmol, 1 equiv), CuI (20 mol%), ligand **L2** (20 mol%), $Cs_2CO_3$ (0.64 mmol, 2 equiv), MeCN (2 mL), 80 °C, 4 h. <sup>a</sup> yields of isolated products after column purification. <sup>b</sup> yields of isolated products using 50 mol% of CuI and 50 mol% of **L2** were used.

One can be noted that for some substrates obtained in moderate yields (**7b** and **7h**), increasing the catalytic loading of CuI from 20 to 50 mol% leads to a significant increase of the yield (from 55% to 99% for **7b**, 68% to 99% for **7h**).

Additionally, we were pleased to see that α-glycosyl thiols including α-thioGal **5e**, α-thioGlc **5f**, α-thioGlcNAc **5g**, are also suitable coupling partners under our reaction conditions furnishing the desired ferrocenyl α-glycoconjugates in good yields. Surprisingly,

the α-thiofucose **5i** (α-thioFuc) proved to be less reactive under our optimized conditions, affording the desired product **7i** in only 13% yield.

Finally, the reaction scope was examined with more complex di- and tri-saccharides or rare sugar adduct. When the coupling of **6a** was carried out with β-thiolactose **5k** and β-thiomaltotriose **5l**, the expected glycoconjugates **7k** and **7l** were obtained in modest yields of 37% and 16%, respectively. However, by increasing the catalyst loading to 50 mol%, a significantly improved yield of 65% was obtained for compound **7l**. In all cases, proton NMR data for these coupling products showed that the absolute configuration of the anomeric positions was retained without any epimerization. Starting from an inseparable mixture (α/β = 1:2) of acetylated 2-deoxy-1-thioglucose **5m**, we generated the same proportion of **7m** anomeric isomers as verified by ¹H NMR analysis (see SI).

This Ullmann-type coupling is also compatible with the use of substituted iodoferrocenes (Scheme 1). Coupling racemic 1-iodo-2-(acetoxymethyl)ferrocene, 1-fluoro-3-iodoferrocene and 3-iodo-N,N-dimethylferrocenesulfonamide lead to the expected, and unfortunately inseparable, mixture of diastereoisomers **8a** (31%), **8b** (74%) and **8d** (81%), respectively. The derivative **8c** was isolated.

<figure><img src="image_9.png" /><figcaption>**Scheme 2.** Scope of the coupling of iodoferrocene **6a** with respect to other thiols **9**.</figcaption></figure>

Reaction conditions: **9** (0.48 mmol, 1.5 equiv), **6a** (0.32 mmol, 1 equiv), CuI (20 mol%), ligand **L2** (20 mol%), $Cs_2CO_3$ (0.64 mmol, 2 equiv), MeCN (2 mL), 80 °C, 4 h. <sup>a</sup> yields of isolated products after column purification. <sup>b</sup> yields of isolated products using 50 mol% of CuI and 50 mol% of **L2** were used.

In 30% yield and 80% diastereoisomeric excess from the enantiopure ($S_p$)-2-iodo-N,N-diisopropylferrocenecarboxamide (98% ee), probably due to that partial racemization of the organometallic core in these reaction conditions. The synthesis of compound **8e**, from thiosugar **5a** and 1'-iodo-N,N-diisopropylferrocenecarboxamide, in a better 54% yield suggested that steric hindrance as to be considered in such reactions.<sup>30</sup>

In order to evaluate the scope of this coupling reaction, the reactivity of other thiols was examined with iodoferrocene under our optimized conditions (Scheme 2). Arylthiols bearing electron-donating (9a) or attracting (9b-d) groups in *ortho* or *para* positions were coupled successfully with **6a**, furnishing the desired ferrocenes **10a-d** in excellent yields ranging from 71% to 87%. In addition, challenging heteroarylated complexes **10e** and **10f** were generated however in low yields (11-19%) whatever the proportions of CuI used. This result may be explained by the ability of the nitrogen
atoms of the pyridine and pyrimidine rings to sequestrate the Cu-catalyst, thus limiting its efficiency. In addition, this cross-coupling also tolerates alkyl thiols such as 3-mercaptopropane-1-ol (compound 10g) and 2-(diethylamino)ethane-1-thiol (compound 10h). The low yields observed (24 and 30%) could be attributed to the formation chelates through association of S, OH or S, Net₂ functions to copper, thus reducing its efficiency.

Of note, our attempts to react unprotected thiogalactose under these conditions failed (see SI). However, deprotection of the coupling product **7a** can be achieved under Zamplén reaction conditions, enabling us to obtain compound **11** quantitatively (See SI).

Upon completion of syntheses, the *in vitro* growth-inhibitory potency of compounds **7a,h,k**, **10a,b,h** and **11** was evaluated against human colon carcinoma HCT116 cells at concentrations of 10⁻⁵ M (10 µM) (Figure 2). The quantification of cell survival in this cell line was established by using CellTiter Glo® (Promega) which allows the measurement of the number of living cells by luminescence (transformation of luciferin to oxyluciferin in the presence of ATP).

This method determines the number of viable cells in culture based on quantitation of the ATP (an indicator of metabolically active cells). The amount of ATP is directly proportional to the number of cells present in the culture. This first screening revealed that glycosylated ferrocenes are not significantly antiproliferative while thioaryl ferrocene complex **10b** reduced the cell viability in the growth of HCT-116 cells up to 64%. This result was confirmed by the measurement of the constant inhibition IC₅₀ of compound **10b** (IC₅₀ = 8.3± 0.96 µM) which is in the same range than the reference doxorubicin (IC₅₀ = 1.8 µM).³¹

<figure><img src="image_10.png" /><figcaption>**Figure 2.** *In vitro* viability of HCT116 cells towards compounds **7a,h,k**, **10a,b,h** and **11** at 10 µM. Qualification of cell survival was established after 72 h exposure. These results were expressed in percentage of viable cells compared to untreated cells 100%. Data are the mean ± SE (n = 3).</figcaption></figure>

From the mechanistic point of view, based on the literature reports,³² we may assume the proposed mechanism in Figure 3. Firstly, ligand L₂ is associated to CuI to generate species I. Then, the coordination of the thiol nucleophile to the Cu(I) center in the presence of the base leads to the Cu(I)-thiolate complex II, which undergoes and oxidative addition with the iodoferrocene resulting in the formation of a highly electrophilic Cu(III) species III. Finally, reductive elimination delivers the desired coupling product **Fc-S-sugar** regenerating the Cu(I) catalyst species ready to reenter the catalytic cycle.

<figure><img src="image_11.png" /><figcaption>**Figure 3.** A proposed mechanism</figcaption></figure>

In conclusion, we have developed an efficient Ullmann-type coupling for the synthesis of thioglycoconjugated-ferrocene complexes. This new methodology allows an easy and direct access to compounds comprising a direct link between various protected sugars and different ferrocene derivatives. All these molecules form part of the search for new bioorganometallic species and a preliminary study of their activity against the HTC116 colon cancer cell line was done. However, they showed no particular cytotoxicity, the best result being obtained for compound **10b** at the micromolar level. We will continue this study by testing other potential biological activities against other cancer cells and bacteria.

## ASSOCIATED CONTENT

### Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

### Supporting Information

The Supporting Information is available free of charge on the ACS Publications website.

Experimental procedures, product descriptions, NMR spectra and X-ray data are available in Supporting Information. (PDF)

X-ray data (cif file)

## AUTHOR INFORMATION

### Corresponding Authors

**Samir Messaoudi** - Laboratoire de Synthèse Organique, Ecole Polytechnique, CNRS, ENSTA, Institut Polytechnique de Paris, Palaiseau, France ; Email : samir.messaoudi@polytechnique.edu

**Franck Le Bideau** - Université Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France ; Email : franck.lebideau@universite-paris-saclay.fr

### Authors

**Ahmed El Rhaz** - Université Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France

**Estelle Messé** - Université Paris-Saclay, CNRS, BioCIS, 91400 Orsay, France

**Pascal Retailleau** - Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, 91198 Gif-sur-Yvette, France
## Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

## ACKNOWLEDGMENT

Authors acknowledge support of this project by CNRS, Ecole Polytechnique and University Paris-Saclay. The Ministère de l'Enseignement Supérieur et de la Recherche (MESR) is thanked for financial support for Ahmed El Rhaz. William Erb further acknowledge support by the Université de Rennes.

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