# Steroid-Fullerene hybrids: A review

Malika Ibrahim-Ouali, Frédéric Dumur

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Malika Ibrahim-Ouali, Frédéric Dumur. Steroid-Fullerene hybrids: A review. ARKIVOC - Online Journal of Organic Chemistry, 2022, 2022 (1), 10.24820/ark.5550190.p011.734. hal-03648063

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# Steroid-Fullerene hybrids: A review

Malika Ibrahim-Ouali,\*a and Frédéric Dumurb

Email address: malika.ibrahim@univ-amu.fr

**Received** mm-dd-yyyy

**Accepted** mm-dd-yyyy

**Published on line** mm-dd-yyyy

## Abstract

Among carbon-based materials, fullerenes have emerged as very fascinating nanocarbons on account of the interesting properties and applications of some of their derivatives in medicine or materials chemistry. The low solubility of C₆₀, the most famous family member, has limited its use in medicinal chemistry but its covalent functionalization with different moieties such as porphyrins or other bioactive molecules changes its physicochemical properties, such as its solubility and biocompatibility. New hybrid compounds, bearing fullerene and steroid units in the same molecule can be regarded as promising functional chimeras with encouraging biomedical applications and have become a topic of considerable interest in the last few years. Recent developments in the syntheses of steroid-fullerene hybrids are described herein.

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

**Keywords:** steroid; C₆₀-fullerene; hybrid molecules; linkage.

<footnote><sup>a</sup>Aix Marseille Univ, CNRS, Centrale Marseille, iSm2, F-13397 Marseille, France</footnote>

<footnote><sup>b</sup>Aix Marseille Univ, CNRS, ICR, UMR 7273, F-13397 Marseille, France</footnote>
# Table of Contents

1. Introduction

2. Synthesis of steroid- fullerene hybrids

3. Conclusions

4. Acknowledgments

5. References

## 1. Introduction

Steroids constitute an extensive and important class of biologically active polycyclic compounds that are widely used for therapeutic purposes.¹⁻³ Even after decades of research, the total synthesis of steroid nuclei by improved strategies continues to receive considerable attention. Numerous methods⁴,⁵ have been exploited for the total synthesis of steroids which are widely distributed in nature, and which possess practical medical importance. Research into steroid total synthesis continues to this day.

The C₆₀ fullerene is the most common fullerene. Since its discovery, it is at the origin of many studies in various fields.⁶ Indeed, the family of fullerenes and especially its main representative, C₆₀, has exceptional physicochemical properties at the origin of their interest. These compounds have unique optical,⁷⁻⁹ electrophysical,¹⁰⁻¹² mechanical,¹³⁻¹⁵ tribological,¹⁶⁻¹⁸ sorption¹⁹⁻²² and biological²³⁻²⁵ properties. New dyes and catalysts²⁶⁻³⁰ have even been discovered among functionalized fullerenes. The use of functionalized fullerenes in the field of medical chemistry, in particular for the treatment of significant diseases, seems interesting because of their wide range of biological activity.

In recent years, hybrid systems have grown in importance due to their many applications in medicine and drug development. Hybrid systems are formed from different molecular entities, natural or not, to obtain functional molecules in which the characteristics of various moieties are amplified or modulated or lead to completely new properties. These hybrids can be made from carefully selected components, either through direct covalent bonds or through the integration of key functional characteristics.

These promising molecules make it possible to generate new molecular entities by intelligently combining two or more different classes of compounds of synthetic or natural origin. The interest is to be able to mix the structural characteristics of two or more biologically active molecules in the same molecule or their covalent coupling can improve the characteristics of the individual components or reveal new properties. In all cases, this approach is interesting because it offers a multitude of possibilities for generating a wide range of molecules for applications in biology, medicine and in the field of materials.

This article provides an overview of the various syntheses of steroid-fullerene hybrids along with interesting biological activities. To the best of our knowledge and much to our surprise, there are no reports on this subject.

## 2. Synthesis of steroid-fullerene hybrids

One of the main drawbacks to the potential use of C₆₀ in medical applications is its lack of solubility in water and its very poor solubility in most conventional organic solvents.³¹⁻³² Covalent binding of [60]fullerene to
suitably functionalized molecules is an effective approach to overcome this problem of solubility. Thus,
steroids which are bioactive molecules have been covalently connected to C₆₀ fullerene by various authors.

Two main reactions were used to synthesize these systems: nucleophilic cyclopropanation using the Bingel
protocol and thermal addition of steroidal compounds. The Bingel reaction is a fullerene cyclopropanation
reaction to a methanofullerene, first discovered by C. Bingel³³ with the bromo derivative of diethyl malonate
in the presence of a base such as sodium hydride or DBU (Scheme 1).

<figure><img src="image_4.png" /><figcaption>**Scheme 1.** The Bingel reaction.</figcaption></figure>

In 1999, Schuster and coworkers³⁴ reported the synthesis of steroid-fullerene hybrids using the Prato
reaction.³⁵ The Prato reaction is a particular example of the well-known 1,3-dipolar cycloaddition of
azomethine ylides to olefins. The amino acid *N*-methylglycine reacts with paraformaldehyde when heated at
reflux in toluene to provide an ylide which reacts with a double bond in a 6,6-ring position of the fullerene *via*
a 1,3-dipolar cycloaddition to yield a pyrrolidinofullerene (Scheme 2).

<figure><img src="image_5.png" /><figcaption>**Scheme 2.** The Prato reaction.</figcaption></figure>

Here, the Prato reaction³⁵ was used to synthesize the steroidal fulleropyrrolidine precursors **1**, **2**, and **3**
(Figure 1).
<figure><img src="image_6.png" /></figure>

1

<figure><img src="image_7.png" /></figure>

2

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

3

<figure><img src="image_9.png" /></figure>

4

**Figure 1.** Synthesis of steroidal fulleropyrrolidine precursors 1, 2, and 3 and the tetraphenylporphyrin carboxylic acid 4.

Union of these precursors with tetraphenylporphyrin carboxylic acid 4 was realized through a standard EDCI coupling to furnish the fullerene-steroid hybrids 5-7 (Figure 2).
<figure><img src="image_10.png" /></figure>

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

<figure><img src="image_12.png" /><figcaption>**Figure 2.** Synthesis of steroid-fullerene hybrids 5, 6, and 7.</figcaption></figure>

In 2001, Yang et al.³⁶ described the synthesis of two new steroid-fullerene hybrids by a Diels-Alder reaction as the key step.
The synthetic pathway is depicted in Scheme 3. Treatment of the available steroid 3'-acetoxy pregna-5,16-dien-20-one 8 with LiOH led to 9 in 90% yield. This latter was easily transformed by reaction with tert-butyldimethylsilyl triflate into the desired silyloxydiene 10 in an isolated yield of 85%. Reaction of C₆₀ with 10 in toluene at 90 °C for 2 h led to the desired molecule 12 in a yield of 30% (in two steps, 40% yield based on C₆₀ consumed) after hydrolysis of the enol silyl ether and deprotection of the hydroxy group at C-3 using classic acid conditions.

A biological study on the cytotoxic effects of hybrid **12** has been carried out at the cellular level. The authors observed its effect on the transmembrane membrane of the reconstituted sarcoplasmic reticulum Ca²⁺-ATPase (SR Ca²⁺-ATPase) in soybean phospholipid liposomes. Thus, they were able to conclude that compound **12** can inhibit the enzyme. In addition, they also observed its effect on the survival of human lung adenocarcinoma A549 cells. The authors find that the survival of A549 cells after treatment with the steroid- C₆₀ **12** is reduced. Eukaryotic cells are rich in membrane structures. Steroid-fullerene hybrids could be the cause and lead to abnormal cell functions and therefore decrease the survival of A549 cells.

<figure><img src="image_13.png" /></figure>

Reagents: a-THF/H₂O, LiOH, 90%; b- TBSOTf, NEt₃, 85%; c- C₆₀, toluene, Δ; d- pTsOH, Δ, 40% (two steps).

**Scheme 3.** Synthesis of steroid-fullerene hybrid **12**.

In 2009, Martin et al.³⁷ reported the synthesis of a new series of hybrid functionalized chimeras **17-18** (Scheme 4) and **21** (Scheme 5) by cyclopropanations between C₆₀ and readily available malonates bearing different steroid moieties **15-16**, and **20** using the Bingel–Hirsch protocol.

The synthesis of these hybrid molecules is shown in Schemes 4 and 5. The malonates **15**, **16** and **20** necessaries for the synthesis of these hybrid systems were prepared by treating three different sterols - cholesterol **13**, β-sitosterol **14**, and ergosterol **19** - with acetyl chloride (ethoxycarbonyl) commercially available. The reactions, carried out in anhydrous dichloromethane and pyridine at 0 °C, gave the desired
malonates **15**, **16** (Scheme 4), and **20** (Scheme 5) with respective yields of 85%, 74% and 70%. Cyclopropanation under Bingel-Hirsch conditions, by treatment of **15**, **16**, or **20** with C₆₀ in the presence of CBr₄ and DBU allowed the covalent binding of malonates **15-16**, and **20** previously synthesized with C₆₀ fullerene. The expected hybrid systems **17**, **18**, and **21** were obtained very quickly (2 h) with moderate yields (50 to 58%) as stable brown solids.

<figure><img src="image_14.png" /></figure>

Reagents : a- CH₂Cl₂, pyridine, 0°C, 24 h; b- C₆₀, DBU/CBr₄, toluene, r.t.

**Scheme 4.** Synthesis of steroid-fullerene hybrids **17** and **18**.

The authors were able to observe the formation of product **21** containing two additional oxygen atoms resulting from the Bingel-Hirsch reaction between compound **20** and C₆₀ (see scheme 5). Another Diels-Alder cycloaddition reaction with **1**O₂, like that observed for ergosterol itself,³⁸ takes place at the 5,6-diene moiety of ring B. It is interesting to note that this cycloaddition is observed only when the diene system is in an environment containing oxygen and an effective triplet sensitizer, such as C₆₀. Thus, molecular oxygen, generally in a triplet ground state, is excited in a singlet state and reacts as a dienophile with the diene unit of the steroid leading to an endoperoxide following a Diels-Alder cycloaddition reaction.

The proposed structures are confirmed by their electronic spectra as well as by cyclic voltammetry, which allows concluding to the formation only of mono adducts, without observation of any formation of bis-
cycloadducts which would come from the intramolecular Diels-Alder cycloaddition of the steroid diene part of ergosterol at C-7 to the fullerene double bond.

These new hybrid derivatives **17**, **18**, and **21**, consisting of both fullerene and steroid units, can be considered as promising functional systems. The potential biomedical applications of these hybrid molecules have not been reported to date.

<figure><img src="image_15.png" /></figure>

Reagents : a- CH₂Cl₂, pyridine, 0°C, 24 h; b- C₆₀ / O₂, DBU/CBr₄, toluene, r.t.

**Scheme 5.** Synthesis of steroid-fullerene hybrid 21.

In 2013, the same authors³⁹ used epiandrosterone which is an important steroid to synthesize steroid-fullerene hybrids. Indeed, this hormone is the natural metabolite of dehydroepiandrosterone *via* the enzyme 5α-reductase and is known for its low androgenic activity. In addition, it is present in most mammals, including pigs.⁴⁰

Prato's method was here used to synthesize potentially biologically active fullerene-steroid hybrids from formyl-substituted steroid derivatives. The fullerene-steroid conjugates **27-30** were prepared in a multistep synthetic procedure in which the C₆₀ unit has been connected to the steroid unit by Prato reaction from pristine [60]fullerene and the respective formyl-containing steroids. Thus, the first step required the preparation of formyl derivatives **25** and **26** as depicted in Scheme 6. The convenient transformation of the hydroxyl group at C-3 of the epiandrosterone **22** by oxidation gave the corresponding 5α-androstan-3,17-dione **23**, whereas acetylation of **22** afforded 3β-acetoxy-5α-androstan-17-one **24**, both in yields like those previously reported. The corresponding formyl derivatives, 3-chloro-2-formyl-17-oxo-5α-androstan-2-ene **25** and 3β-acetoxy-17-chloro-16-formyl-5'-androstan-16-ene **26**, were obtained respectively by a Vilsmeier-
Haack reaction of **23** and **24** with phosphorus oxychloride and dimethylformamide in dichloromethane. The yields obtained are good (78% and 50%, respectively) and the products crystallize after basic hydrolysis with aqueous sodium acetate.

Finally, 1,3-dipolar cycloaddition reactions of azomethine ylides generated *in situ* with C₆₀ according to the Prato protocol leads to the production of *N*-methyl-2-substituted pyrrolidino [3,4: 1,2] [60] fullerenes. Thus, the reaction is carried out by mixing the chloroformyl derivative (**25** or **26**), C₆₀ and sarcosine (*N*-methylglycine), the whole brought to reflux in toluene under an argon atmosphere for 6 h (see Scheme 6). The formation of the products is confirmed by the color change of the solution from purple to brown.

Flash chromatography makes it possible to easily separate the diastereoisomers and to obtain compounds **27**, **28**, **29** and **30**, in the form of stable brown solids, with respective yields of 42%, 31%, 28% and 47%. The stereoselectivity, which provides diastereomers **27** and **30** as main products, is relatively modest. This result agrees with the fact that the electrophile, the C₆₀ attacks preferentially on the *Re* face of the 1,3-dipole.

The absolute configuration of fulleropyrrolidines was easily determined using chiroptic properties with Cotton-typical effects in CD spectra of chiral adducts. Thus, the absolute C2 configuration for compounds **27-30** was determined to be: (2*R*) for **27**, (2*S*) for **28**, (2*S*) for **29** and (2*R*) for **30**.

Finally, the authors observed that the conjugation of epiandrosterone derivatives with C₆₀ increases the solubility of these new hybrid systems (**27-30**) in organic solvents such as chloroform, dichloromethane and dimethylformamide, among others. It is therefore undeniable that the presence of the steroid unit in the new hybrid compounds (**27**, **28**, **29** and **30**) improves their solubility. This result allowed the authors to consider other investigations on these structures, especially biological ones.
<figure><img src="image_16.png" /></figure>

23

22

24

<figure><img src="image_17.png" /></figure>

25

26

<figure><img src="image_18.png" /></figure>

27 (42%)

28 (31%)

29 (28%)

30 (47%)

Reagents : a- acetone, Jones' reagent, r.t.; b- acetic anhydride, pyridine, r.t.;
c- POCl3, DMF, reflux; d- C60, N-methylglycine, toluene, reflux.

**Scheme 6.** Synthesis of steroid-fullerene hybrids **27-30**.

In 2014, the same authors⁴¹ described the multistep synthesis of a fullerene hybrid dumbbell having two fullerene units connected through an epiandrosterone molecule.

Thanks to the presence of a formyl group at the C-16 position of ring D of the starting product **26**, the first C₆₀ unit was introduced by a 1,3-dipolar cycloaddition reaction. And after the transformation of the acetate group
attached to position C-3 in ring A into the corresponding malonate, a cyclopropanation reaction made it
possible to introduce the second unit of C₆₀ (see Scheme 7).

After hydrolysis with potassium carbonate in methanol of the acetate group in C-3 position of the 3β-acetoxy-17-chloro-16-formyl-5α-androstan-16-ene 26, the 17-chloro-16-formyl-3β-hydroxy-5α-androstan-16-ene 31 was isolated in good yield (92%) and allowed the incorporation of the malonate moiety by reaction of 31 with (ethoxycarbonyl)acetyl chloride in anhydrous dichloromethane and pyridine at 0 °C. This latter bearing a formyl group was obtained as a pale-yellow solid in 82% yield. The 1,3-dipolar cycloaddition of 32 was done by reaction with [60]fullerene and *N*-methylglycine in refluxing toluene leading to *N*-methyl-2-(*3'*-ethylmalonate-17'-chloro-5'-α-androstan-16'-ene)pyrrolidine-[3,4:1,2][60]fullerenes 33 and 34. These molecules present a new stereocenter at C-2 in the pyrrolidine ring, and therefore, two diastereomers are formed. These stereoisomers 33 and 34 were easily separated by flash chromatography leading to stable amorphous brown solids 33 and 34 with moderate yields (34, 34%; 35, 27%).

The fullerene dumbbell derivative **35** was obtained by reaction of diastereomer **34** bearing a malonate moiety to [60]fullerene under Bingel–Hirsch conditions. Treatment of **34** with $C_{60}$ in the presence of $CBr_{4}$ and DBU led after 4 h, to the formation of the dumbbell derivative **35**. The pure fullerene dimer **35** was isolated after purification by flash chromatography as a stable brown solid in 55% yield (see Scheme 7).

The new compounds **33-35** have been characterized by spectroscopy and their redox potentials,
determined by cyclic voltammetry, reveal three reversible reduction waves for hybrids **33** and **34**, whereas
these signals are split in dumbbell **35**. The most stable conformations for the hybrid compounds (**33–35**) were
determined by theoretical calculations at semiempirical (AM1) and single point B3LYP/6-31G(d) levels, and
show the importance of the chlorine atom on the D ring of the steroid. Indeed, it seems to be clear that the
existence of a hydrogen bond C–H···Cl contributes to the stabilization of the hybrid systems.
<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /></figure>

Reagents : a- K₂CO₃ (5%), MeOH, r.t.; b- (ethoxycarbonyl)acetyl chloride, DCM, pyridine,0 °C;

c- C₆₀, N-methylglycine, toluene, reflux; d- C₆₀, CBr₄, DBU, toluene, r.t.

**Scheme 7.** Synthesis of steroid-fullerene hybrids 33-35.

The same year, Bjelakovic et al.⁴² reported the synthesis, morphological study, and preliminary *in vitro* antioxidant capacity of new fullerene-steroid hybrids.

The synthetic strategy to obtain the fullerene-peptide-steroid hybrids **40** and **42** are depicted in Schemes **8** and **9** and show firstly the synthesis of a steroid peptide dyad and then its conjugation with the fullerene subunit based on esterification and amidation reactions with protection-deprotection steps required. Two
different activating systems, DCC/DMAP and EDC/HOBt in dichloromethane were used to optimize these
reactions. The DCC/DMAP-assisted esterification of *N*-protected GABA **36** with sterol **37** led smoothly to the
ester **38** in very good yield (80%), while in the presence of EDC/HOBt no product was isolated.

The steroid peptide dyad **39** was coupled with Boc-Gly-OH<sup>43</sup> after a quantitative Boc-deprotection with TFA. This latter was isolated with an excellent yield (93%) and used for two different syntheses of steroidal hybrids. The reaction of **40** with Fp-GABA-OH led to fullerene-peptide-steroid hybrid **40** in a 63% yield and reaction with GABA afforded a steroid dipeptide dyad **41** presenting an elongation of the peptide chain (Scheme 9). Finally, triad **42** was isolated in a poor yield of 19% after Boc-removal and a subsequent coupling with a fullerene unit. The yield is lower than this obtained using a shorter peptide. The DCC/DMAP activating system seems to be somewhat more efficient for amidations including both Boc-Gly-OH and Fp-GABA-OH (reactions 3/4 and 4/5, respectively) than for esterification of Boc-GABA **36**.

This synthetic approach can be used to generate different steroid-fullerene derivatives with potential
biological activity. High antioxidant activity of these new hybrids, twice and 13-fold better than fullerene C60
and standard antioxidant agent vitamin C, respectively, was observed after an *in vitro* study using the Ferrous
ion Oxidation-Xylenol orange (FOX) method.
<figure><img src="image_22.png" /></figure>

37

<figure><img src="image_23.png" /></figure>

36

a →

<figure><img src="image_24.png" /></figure>

38 80%

<figure><img src="image_25.png" /></figure>

39 93%

<figure><img src="image_26.png" /></figure>

40 63%

<figure><img src="image_27.png" /></figure>

Reagents : a- DCC/DMAP, CH₂Cl₂, 0°C to r.t., 24 h; b- TFA, CH₂Cl₂, r.t., 2 h;
c- Boc-Gly-OH, TEA, DCC/DMAP, CH₂Cl₂, 0°C to r.t., 24 h;
d- Fp-GABA-OH, TEA, DCC/DMAP, CH₂Cl₂, 0°C to r.t., 24 h.

<caption>**Scheme 8.** Synthesis of steroid-fullerene hybrid 40.</caption>
<figure><img src="image_28.png" /></figure>

<figure><img src="image_29.png" /></figure>

Reagents : b- TFA, CH₂Cl₂, r.t., 2 h; c- Boc-Gly-OH, TEA, DCC/DMAP, CH₂Cl₂, 0°C to r.t., 24 h;
d- Fp-GABA-OH, TEA, DCC/DMAP, CH₂Cl₂, 0°C to r.t., 24 h.

**Scheme 9.** Synthesis of steroid-fullerene hybrid **42**.

In 2017, Martin and coworkers⁴⁴ reported for the first time a controlled diastereoselective synthesis of *cis* and *trans* steroid-fulleropyrrolidines hybrids by reaction of *N*-metallated azomethine ylides [Cu(II) or Ag(I)] with the appropriate chiral ligand and C₆₀.

To obtain the target steroid-fullerene hybrids, the authors first synthesized the imine **43** by reaction of the previously reported³⁹ 3-chloro-2-formyl-17-oxo-5α-androstan-2-ene **26** and the glycine methyl ester hydrochloride using triethylamine as a base and dichloromethane as solvent at room temperature (see Scheme 10). This imine was isolated in a good yield (77%) as a yellow oil. The coupling of this latter with C₆₀ using anhydrous silver acetate along with the achiral ligand [dppe, 1,2-bis(diphenylphosphino)ethane] in toluene at room temperature led to a mixture of the two *cis*-diastereomers **44** and **45**. It is worth pointing out that the stabilization of the *N*-metallated azomethine ylide is provided by the allylic moiety of the steroid unit. The two products were separated by flash chromatography to give **44** in a yield of 32% and **45** in a yield of 25% (see Scheme 10). We can see that the stereoselectivity is modest due to poor chiral induction of the steroid moiety on the attack to one of the faces of the dipole in the fullerene derivative.
<figure><img src="image_30.png" /></figure>

<figure><img src="image_31.png" /></figure>

<figure><img src="image_32.png" /></figure>

Reagents : a- Cl⁻, <sup>+</sup>H<sub>3</sub>N-CH<sub>2</sub>COOCH<sub>3</sub>, NEt<sub>3</sub>, DCM, r.t.; b- C<sub>60</sub>, AgOAc, dppe, toluene, r.t.

**Scheme 10.** Synthesis of steroid-fullerene hybrids **44** and **45**.

The same reaction was done with other catalytic systems to ascertain their stereocontrol in the 1,3-dipolar cycloaddition of azomethine ylides onto C₆₀ even in the presence of a chiral moiety, such as the imine **43**. Thus, the reaction of steroid iminoester **43** onto C₆₀ with the catalytic complex Cu(II)-Fesulphos at 0 °C led to cis-(2S,5R)-2-methoxycarbonyl-5-(3'-β-acetoxy-17'-chloro-5'-α-16'-androstene) pyrrolidino [3,4:1,2] [60]fullerene **44** with an excellent diastereomeric induction (see Scheme 11). Using the catalytic system AgOAc/(R,R)-BPE at the same temperature, the cis diastereoisomer (2R,5S) (cis-2-methoxycarbonyl-5-(3'-β-acetoxy-17'-chloro-5'-α-16'-androstene)pyrrolidino[3,4:1,2]-[60]-fullerene **45** showing an opposite configuration in the pyrrolidine ring is obtained, also with excellent diasteroselectivity. For both catalysts, the counterion of the metal salt which is acetate reacts like a base and is probably located in the empty metal
coordination sphere, which is the origin of this good stereodifferentiation.⁴⁵ This diastereodivergent study was completed using bulky chiral ligand DTBM-Segphos⁴⁶,⁴⁷ to obtain the *trans*-diastereomers. Thus, the use of the Cu(II)-(*R*)-DTBM-Segphos complex in the presence of triethylamine as the base at room temperature leads to the *trans*-diastereoisomer **46** with (*2R*, *5R*) configuration. And, the same reaction carried out with the Cu(II)-(*S*)-DTBM-Segphos complex under the same conditions leads to the *trans*-diastereomer **47** with a (*2S*, *5S*) configuration.

This is an efficient stereodivergent protocol to synthesize hybrid systems in a diastereoselective manner
allowing access to a variety of optically active fullerene hybrids.
<figure><img src="image_33.png" /></figure>

**46** (2R, 5R)-trans

d.e = 95%

yield 62%

<figure><img src="image_34.png" /></figure>

**44** (2S, 5R)-cis

d.e = 94%

yield 60%

<figure><img src="image_35.png" /></figure>

**47** (2S, 5S)-trans

d.e = 93%

yield 63%

<figure><img src="image_36.png" /></figure>

<figure><img src="image_37.png" /></figure>

**45** (2R, 5S)-cis

d.e = 93%

yield 57%

Reagents: a-Cu(AcO)₂, FeSulphos, 0 °C, 2 h; b-AgOAc, BPE, 0 °C, 2 h; c- Cu(OTf)₂, R-DTBM-Segphos, NEt₃, 2 h, r.t.; d- Cu(OTf)₂, S-DTBM-Segphos, NEt₃, 2 h, r.t.

<figure><img src="image_38.png" /></figure>

FeSulPhos

<figure><img src="image_39.png" /></figure>

BPE

<figure><img src="image_40.png" /></figure>

R = 2,3-tBu-3-OMe-Ph

DTBM-Segphos

<caption>**Scheme 11.** Synthesis of steroid-fullerene hybrids **44-47**.</caption>
In 2018, the same authors⁴⁸ described the synthesis of new [60]fullerene-steroid hybrids by Bingel–Hirsch protocol of the corresponding steroid containing malonates with C₆₀.

The synthesis started with the preparation of compounds **52**, **53**, and **54** from commercially available epiandrosterone **48**, in which functional groups in C3 and C17 positions were transformed. Thus, the steroid derivative **48** was treated with acetic anhydride in pyridine and led to the corresponding 3β-acetoxy-5α-androstan-17-one **49** in a good yield. As expected, the reduction of compound **49** with sodium borohydride in methanol afforded with stereoselective control the 3β-acetoxy-5α-androstan-17β-ol **50**. In the following step, 5α-androstan-3β,17β-diol **51** was isolated after basic hydrolysis of the previous compound in a similar yield as this reported.⁴⁹,⁵⁰

The steroid derivatives **48**, **50**, and **51** were transformed into the corresponding malonates **52-54** by reaction with the commercially available (ethoxycarbonyl)acetyl chloride (Scheme 12). The reaction was carried out in anhydrous dichloromethane and pyridine at 0°C and led to the derivatives **52**, **53**, and **54** in 80, 72, and 75% yields, respectively.

<figure><img src="image_41.png" /><figcaption>Reagents: a- acetic anhydride, pyridine, 5 h, r.t.; b- NaBH₄, MeOH, r.t., 25 min; c- K₂CO₃, 5%, MeOH, r.t., 24 h; d- CH₃CH₂OCOCH₂COCl, pyridine, DCM, 0 °C.</figcaption></figure>

**Scheme 12.** Synthesis of steroid derivatives **52-54**.

The steroid-fullerene hybrids **52**, **53**, or **54** were synthesized using the Bingel–Hirsch conditions by reaction of C₆₀ and the malonyl steroids **52**, **53**, or **54**, with CBr₄ and DBU at room temperature (see Scheme 13). The cyclopropanation process was confirmed by the change of the color of the solution (purple to brown) leading to the [6,6] mono-adduct. In the case of compounds **55** and **56**, the reaction was finished in 2 h and furnished after purification by flash chromatography, compounds **55** and **56** in 68 and 58% yields, respectively, as stable
brown solids. While, the reaction between C₆₀ and dimalonate **54** led to three hybrid systems **57**, **58**, and **59** in 42%, 12%, and 11% yields, respectively.

<figure><img src="image_42.png" /></figure>

Reagents : a- C₆₀, DBU/CBr₄, toluene, r.t.

<caption>**Scheme 13.** Synthesis of steroid-fullerene hybrids **55-59**.</caption>
In 2020, Martin and coworkers⁵¹ developed a synthetic strategy based on a multistep approach to synthesize novel fullerene-steroid hybrids.

The synthesis required the obtention of malonyl derivatives **61** and **62** to fix the [60]fullerene cage by a Bingel–Hirsch reaction (Scheme 14). Thus, dehydroepiandrosterone **60** (DHEA) was transformed into malonates **61** and **62** by reaction with commercially available (ethoxycarbonyl)acetyl chloride and malonyl chloride, respectively. These reactions were carried out in anhydrous dichloromethane (DCM) and pyridine at 0 °C. The purified compounds **61** and **62** were obtained with 82% and 78% yields, respectively. The Bingel–Hirsch protocol was used to synthesize the novel methano[60]fullerenes **63** and **64**, by reaction of either **61** or **62** with [60]fullerene in the presence of CBr₄ and DBU at room temperature. After 2 h and purification by flash chromatography, compounds **63** and **64** were isolated as stable brown solids in 74 and 51 % yields, respectively.

It is interesting to note that the DHEA moiety in the [60]fullerene systems **63**, and **64** increases the solubility in organic solvents, such as chloroform, dichloromethane, dimethylformamide, and dimethylsulfoxide. This fact might be useful since biological studies could be realized in some of these solvents. Indeed, in general, *in vitro* tests with the HIV-1 protease are performed in DMSO⁵² due to the poor solubility of fullerene derivatives in water.

The TEM analysis showed that steroid-fullerene hybrids in water give nano-sized spherical vesicles with highly heterogeneous size populations. Moreover, DFT theoretical calculations revealed that hydrogen bonds play a major role in the geometry of these hybrid systems. And finally, these derivatives could have an application as HIV-1 protease inhibitors as suggested by molecular docking studies. All the characteristics of C₆₀-steroid derivatives (including polarity, lipophilicity) constitute promising results to further explore the biomedical aspects of these molecular chimeras.
<figure><img src="image_43.png" /></figure>

Reagents : a- CH₃CH₂OCOCH₂COCl, pyridine, DCM,0 °C; b- ClOCOCH₂COCl, pyridine, DCM,0 °C; c- C₆₀, DBU, CBr₄, toluene, r.t.

**Scheme 14.** Synthesis of steroid-fullerene hybrids **63** and **64**.

The same year, Martin and coworkers⁵³ also reported the synthesis of two new diastereomeric steroid [60]fullerene hybrids in a single 1,3-dipolar cycloaddition reaction.

The synthetic pathway is depicted in Scheme 15. A 1,3-dipolar cycloaddition reaction of steroidal derivatives with C₆₀ *via* azomethine ylides generated *in situ* led to *N*-methyl-2-substituted pyrrolidino-[3,4:1,2][60]fullerenes possessing steroidal moieties. Thus, the reaction of the enantiopure formyl steroidal derivative (*8S*,*9S*,*10R*,*13S*,*14S*,*17R*,*20S*)-3-oxopregn-4-ene-20-carboxaldehyde, **65**, C₆₀, and sarcosine in toluene under argon atmosphere led to the corresponding fullerene cycloadducts **66** and **67** after 5 h of reflux (Scheme 15).
The formation of the five-membered ring occurred with the formation of a new stereogenic center on the C-2 of the pyrrolidine ring by a stereospecific *syn* process. Since the configuration of the stereogenic centers of the steroid always remains the same, the reaction led to a mixture of diastereoisomers of derivatives **66** and **67**, which were separated by flash chromatography. Thus, products **66** and **67** were isolated as stable brown solids with yields of 68% and 13%, respectively. The diastereoselectivity of the reaction could be explained by a preferential electrophilic attack of C₆₀ on the *Re* face of the 1,3-dipole. As a result, the steric interactions due to the presence of the methyl group at C-20 are at the origin of the attack on the *Si* face. Thus, the 5:1 ratio (*Re*: *Si*) observed is explained by an attack on the [60]fullerene on the *Re* face of the 1,3-dipole due to lower steric hindrance.

Here too, it is worth noting the increase in the solubility of derivatives **66** and **67** in organic solvents. This fact is very interesting to consider possible biological studies on materials. Additionally, these hybrids can potentially be used as HIV-1 protease inhibitors. These are very encouraging results that could be the source of many applications (biology, materials, etc.).

<figure><img src="image_44.png" /></figure>

Reagents : a- C₆₀, N-methylglycine, toluene, reflux, under argon.

**Scheme 15.** Synthesis of steroid-fullerene hybrids **66** and **67**.

Recently, the same authors⁵⁴ reported the synthesis and characterization of a fullerene-steroid hybrid that contains H₂@C₆₀ and a dehydroepiandrosterone moiety synthesized by a cyclopropanation reaction.

The authors observed that the encapsulation of a hydrogen molecule does not in any way modify the reactivity or the stereoselectivity of the C₆₀ hollow fullerene.²⁴ The synthesis is depicted in Scheme 16. The new endohedral steroid-fullerene hybrid **69** was prepared by applying the Bingel-Hirsch protocol between 3β-ethyl malonate-5-androsten-17-one **52**⁵¹ and H₂@C₆₀. The H₂@[60]fullerene, compound **52**, CBr₄, and DBU mixture produced at room temperature very quickly leads to a change in the color of the solution from purple
to brown, identical to that observed when the reaction is carried out using unmodified C<sub>60</sub><sup>51</sup> and indicative of the success of the reaction. Thus, the [6,6]-closed mono-adduct **69** was isolated in a good yield (76%) as a stable brown solid. The endohedral hybrid is obtained with yields and reaction times similar to those obtained during hollow 60]fullerene reactions with steroids.<sup>51</sup>

It is therefore interesting to note that the presence of the H₂ molecule inside the cavity of the fullerene does not affect the reactivity of the hollow fullerene. Furthermore, the authors have shown that in the hybrid system **69**, the hydrogen molecule does not present a clear perpendicular disposition to one of the hexagonal rings of the fullerene cage.

<figure><img src="image_45.png" /><figcaption>**Scheme 16.** Synthesis of steroid-fullerene hybrid **69**.</figcaption></figure>

Theoretical studies were considered on the new endohedral steroid-fullerene hybrid **69** to evaluate its biological potential. It was thus observed that it would have higher antiviral properties, in particular against Covid-19, than its hollow counterparts. Of course, these preliminary and encouraging results will have to be verified by future *in vitro* and *in vivo* tests.

**3. Conclusions**

The present review offers up-to-date literature on the syntheses of steroid-fullerene hybrids reported during the last years. The coupling of two or more natural products to make hybrids makes it possible to obtain new types of compounds with various structures, at the origin of improved properties compared to the starting molecules or at the origin of new properties. The biological aspect and all the properties of these molecules are still not well-known. But it is expected that the synthesis of fullerene derivatives will continue in the years to come as well as the still current interest in the chemistry of steroids and their derivatives given the applications (biological or in the chemistry of materials) inherent to this family of compounds.

**4. Acknowledgements**

This work has been financially supported by the CNRS and the Ministère de l'Enseignement Supérieur et de la Recherche.
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## Authors' Biographies

<figure><img src="image_46.png" /></figure>

**Malika Ibrahim-Ouali** carried out her Ph.D. under the supervision of Professor Gramain in Clermont-Ferrand (France) in 1996. The work was focused on the synthesis of alkaloids. She was a postdoctoral fellow with Prof. Knochel (Humboldt fellowship) in 1996 in Germany where she got her first training in organometallic chemistry. In 1997, she joined Professor H. P Husson's group at the ICSN (Paris) as a postdoctoral researcher. Since 1998, she is currently an Associate Professor at Aix-Marseille University, and her field of interest remains the total synthesis of natural compounds.

<figure><img src="image_47.png" /></figure>

**Frédéric Dumur** received his Ph.D. in chemistry in 2002 from the University of Angers (France) under the supervision of Professor Pietrick Hudhomme. After Post-Doctoral studies at the University of Groningen (The Netherlands), Reims Champagne-Ardennes (France) and Versailles Saint-Quentin-en-Yvelines (France), he joined the Faculty of Sciences at Aix-Marseille University in 2008, where he is currently working as an Associate Professor. His research interests include the synthesis of phosphorescent dopants for OLEDs and photoinitiators of polymerization. He co-authored about 300 publications and 5 book chapters.

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