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An efficient approach to chiral fullerene derivatives bycatalytic enantioselective 1,3-dipolar cycloadditionsSalvatore Filippone1, Enrique E. Maroto1, Angel Martın-Domenech1, Margarita Suarez1,2

and Nazario Martın1,3*

Fullerene chirality is an important but undeveloped issue of paramount interest in fields such as materials science andmedicinal chemistry. So far, enantiopure fullerene derivatives have been made from chiral starting materials or obtained byseparating racemic mixtures. Here, we report the enantioselective catalytic synthesis of chiral pyrrolidinofullerenes (themost widely studied fullerene derivatives), which proceeds in high yields under very mild conditions at low temperatures.The combination of a particular metal catalyst—Ag(I) or Cu(II)—and a chiral ligand is able to direct the cycloaddition ofbuckminsterfullerene C60, the first non-coordinating dipolarophile used in such reactions, to opposite enantiofaces ofN-metallated azomethine ylides. This methodology has proven to be quite general, affording enantiomeric excessesof greater than 90%. Furthermore, well-defined chiral carbon atoms linked to the fullerene sphere are able to perturb theinherent symmetry of the fullerene p-system as revealed by circular dichroism measurements.

Since the discovery of fullerenes, their potential for applicationsin fields such as materials science and medicinal chemistryhas boosted the interest of the scientific community in these

new molecular carbon allotropes1,2. Although much is knownabout their chemical reactivity, the refined control of some funda-mental aspects, such as the chemical control of regio- and, particu-larly, stereoselectivity, are important issues that still remain to beproperly addressed3.

Despite the fact that fullerene chirality has been recognized as animportant issue4,5, racemic organofullerenes are often used, even infields such as medicinal chemistry (for instance, in HIV protease inhi-bition) where the stereochemical configuration is a key factor6. Only afew examples of enantiomerically pure fullerene derivatives have beenreported so far, such as those used as helicity inducers in polymers7, orhomochiral prolinofullerenes used in peptide synthesis8. Indeed, thelack of a general enantioselective synthetic methodology has limitedthe use of enantiopure fullerene derivatives, which are usually obtainedafter chiral high performance liquid chromatography isolation or areprepared from chiral starting materials8–12.

In this context, recent developments in catalytic chiral cyclo-addition reactions of azomethine ylides13–15 could lead to a powerfulmethodology for the synthesis of stereoisomerically pure pyrrol-idino[3,4:1,2][60]fullerenes. These heterocyclic-fused compoundsare probably the most widely used fullerene derivatives because oftheir stability and versatility, as well as the availability of the requiredstarting materials16,17. Moreover, prolinofullerene, the biggest non-natural amino acid belonging to this class, represents a valuablebuilding block for the synthesis of fulleropeptides18.

Despite the availability of different catalytic systems19–25, thestereochemical outcome in [3þ 2] cycloaddition reactions of azo-methine ylides depends strongly on both the dipolarophile andthe 1,3-dipole used. Furthermore, the use of the curved doublebond of C60 as the 2p component in such a reaction is highly chal-lenging because of its non-ligand character. Indeed, to the best ofour knowledge, this is the first time in which a dipolarophileunable to coordinate with the metallic centre of the catalyst is

used. Furthermore, this feature, in addition to the sphericalsymmetry, could make the cycloaddition onto the fullerene spherea possible benchmark to test the efficiency of a catalytic system.It also represents a unique scenario to shed light onto mechanisticaspects. Herein, we report a switchable, highly diastereo- and enantio-selective catalytic cycloaddition of N-metallated azomethine ylidesonto C60 as the first efficient synthesis of chiral pyrrolidino-[3,4:1,2][60]fullerenes (Fig. 1).

Results and discussionThermal treatment of imine-ester 1a with C60 resulted in the for-mation of mixtures of two diastereomeric pyrrolidinofullerenes

HN AB

HN AB

HN AB

HN AB

*M

ANB– +

*

trans

Non-coordinatingdipolarophile

cis

Figure 1 | N-metallated azomethine ylide complexes, prepared from a chiral

ligand, a metal salt, an imino-ester and a base, are able to cycloadd to a

non-coordinating dipolarophile such as the all-carbon sphere C60.

Depending on the metal and ligand used in such complexes, it is possible to

control the stereochemical outcome in terms of diastereo- and

enantioselectivities. Pyrrolidinofullerenes, the most widely used fullerene

derivatives, have been easily prepared as cis or trans stereoisomers with

good enantiomeric excesses.

1Departamento de Quımica Organica I, Facultad de Ciencias Quımicas, Universidad Complutense de Madrid, Ciudad Universitaria s/n, 28040 Madrid,Spain, 2Laboratorio de Sıntesis Organica, Facultad de Quımica, Universidad de la Habana, 10400 La Habana, Cuba, 3IMDEA- Nanociencia, Campus de laUniversidad Autonoma de Madrid, 28049 Madrid, Spain. *e-mail: nazmar@quim.ucm.es

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cis-2a and trans-2a in a 60/40 ratio (Fig. 2, Table 1, entry 1).A preliminary screening of different metal–ligand pairs revealedthe feasibility of the metal-mediated azomethine ylide cyclo-addition onto the fullerene sphere—the reactions occur quickly(1–2 hours) at room temperature, giving rise to the pyrrolidino-fullerenes in high yield. More importantly, however, catalyticamounts (10%) of copper(II) triflate and the achiral ligand1,3-bis(diphenylphosphino)propane (dppp), in the presence of tri-ethylamine, were able to address the lack of diastereoselectivity,

resulting in the formation of cis-2a with 80% diastereomericexcess (Fig. 2; Table 1, entry 2).

The Fesulphos (3) catalytic systems reported by Carretero21 gaverise to the formation of the unique diastereomer, cis-2a; however,enantiomeric excesses observed in the reactions were well belowthose reported for other non-fullerene dipolarophiles (Table 1,entries 3,4). We have attributed this result to the non-ligand prop-erties of the [60]fullerene which, in sharp contrast to the otherdipolarophiles used so far, does not coordinate with the metal

HN Ar

R1

R2 HN Ar

R2

R1HNAr

R1

R2

Fe

Ph2P

S

P P

Ph

Ph

Ph

Ph

PPh2

PPh2

R2

R1 N Ar

(2S,5S)-cis-2a–g (2R,5R)-cis-2a–g trans-2a–g

a: Ar = pMeO-Ph; R1 = COOMe; R2 = H b: Ar = 2-Thienyl; R1 = COOMe; R2 = Hc: Ar = pF-Ph; R1 = COOMe; R2 = Hd: Ar = pCN-Ph; R1 = COOMe; R2 = He: Ar = pMeO-Ph; R1 = COOEt; R2 = Mef: Ar = Ph; R1 = P(O)(OEt)2; R2 = Hg: Ar = R1 = 2-Pyridyl; R2 = HC60, PhMe [M], base,

ligand (3, 4 or 5)

1

+ or

3

4

(±)-5

Figure 2 | Catalytic metal–ligand complexes allow the cycloaddidion of the iminoesters 1a–g to C60 under mild conditions. Using the chiral catalyst formed

by Cu(II) acetate and Fesulphos (3) results in the cis-pyrrolidinofullerenes 2a–g with a 2S,5S configuration. In contrast, the combination of Ag(I) acetate with

the BPE ligand 4 induces the formation of the opposite enantiomers (2R,5R)-2a–g. The preparation of trans-pyrrolidinofullerenes has been carried out using

Binap 5 and Cu(II)OTf2, for the imines 1a,b.

Table 1 | Asymmetric Cu(II) and Ag(I)-catalysed 1,3-dipolar cycloadditions of azomethine ylides 1a-g to C60 using differentchiral ligands.

Entry* Dipole Metal salt Ligand Time (h) T (88888C) Yield (%) Diastereomeric excess (%) Enantiomeric excess (%)

1 1a – – 16 110 30 20 –2 1a Cu(OTf)2

† dppp§ 2 r.t. 68 80 –3 1a Cu(MeCN)4ClO4

† 3 4 0 45 94 64 (2S,5S)-2a4 1a Cu(MeCN)4PF6

† 3 4 0 60 98 73 (2S,5S)-2a5 1a Cu(AcO)2 3 2 215 88 .99 90 (2S,5S)-2a6 1a Cu(MeCN)4PF6

‡ 3 2 215 60 .99 92 (2S,5S)-2a7 1b Cu(AcO)2 3 2 215 49 .99 93 (2S,5R)-2b}

8 1c Cu(AcO)2 3 4 215 40 .99 90 (2S,5S)-2c9 1d Cu(AcO)2 3 2 215 60 .99 88 (2S,5S)-2d10 1e Cu(AcO)2 3 4 215 40 95 80 (2S,5S)-2e11 1f Cu(AcO)2 3 25 r.t. 25 95 65 (2R,5S)-2f}

12 1g Cu(AcO)2 3 3 r.t. 68 .99 –13 1a AgAcO 4 2 215 60 .99 90 (2R,5R)-2a14 1b AgAcO 4 1 215 45 .99 81 (2R,5S)-2b}

15 1c AgAcO 4 4 215 35 .99 85 (2R,5R)-2c16 1d AgAcO 4 2 215 60 .99 86 (2R,5R)-2d17 1e AgAcO 4 5 215 33 80 70 (2R,5R)-2e

The use of copper salts leads to 2S,5S enantiomers, whereas silver salts afford 2R,5R enantiomers. In both cases the acetate anion plays a leading role yielding excellent diasteromeric and enantiomeric excessvalues.*Reaction conditions: Ligand: 10% (entry 11: 100%).†Et3N (20%).‡BuN4AcO (20%).§1,3-Bis(diphenylphosphino)propane.}The different priority of the substituents connected to the stereogenic centre is responsible for the change of configuration in the series.

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cation. For this reason, we moved from non-coordinating anionssuch as PF6

2 or ClO42, to acetate, which also acts as a base. We

speculated that such an anion occupying the vacant site in themetal coordination sphere—which is normally filled by a liganddipolarophile—could allow for better stereodifferentation of thetwo faces of azomethine ylides. Indeed, even when copper(I)acetate was shown to be ineffective, copper(II) acetate along withFesulphos 3 was able to catalyse the cycloaddition of imine 1a at215 8C without the use of any base, giving rise to (2S-5S)-cis-2ain 90% of enantiomeric excess (Table 1, entry 5). Moreover, thefact that similar results were obtained using Cu(MeCN)4PF6 andtetrabutylammonium acetate confirms the important role ofthe coordinating acetate anion in the catalytic system (Table 1,entry 6). Copper(II) acetate together with (R)-Fesulphos 3 demon-strated excellent catalytic activity in the cycloaddition of differentiminecarboxylate esters (1b–e) to C60 (Table 1, entries 7–10).The pyrrolidine formation occurs in 2 hours at 215 8C with aremarkable yield improvement, up to 60%, compared with theclassical thermal process. This catalytic complex leads to the exclu-sive formation of the cis adducts, with a diastereoselectivity of.99%. Excellent asymmetric induction results were also obtained,with (2S,5S)-cis-2b–d enantiomers formed with enantiomericexcess values ranging from 88% to 93%. Cycloaddition of iminoester1e derived from alanine occurs with a slightly lower asymmetricinduction, similar to previously reported studies (Table 1, entry 10).

The scope of this methodology has also been tested with otherimines bearing different chemical functionalities. The hardly reac-tive dipole 1f, endowed with a phosphonate group, cycloadds tothe C60 at room temperature, giving rise to the cis adduct in a mod-erate enantiomeric excess (65%; Table 1, entry 11). In contrast,2-pyridyl picolylimine 1g easily produced the meso compoundcis-2g in 68% yield at room temperature (Table 1, entry 12).

Good control of the stereochemical outcome in the synthesis ofchiral fulleropyrrolidines requires the efficient formation of theopposite enantiomers. In order to face this synthetic challenge welooked for a different metal catalyst. In particular, we turned ourattention to the Ag(I)-4 pair as preliminary tests showed the prefer-ential formation of the (2R,5R)-2a enantiomer. The replacement ofthe non-ligand anion by acetate proved essential to obtain higherenantiomeric excesses. Thus, 10% of the chiral silver acetate-4complex promoted the cycloaddition of imines 1a–e again with out-standing cis diasteroselectivities but with reverse stereodifferentation.The favoured approach of C60 to the si face of the dipole gave rise tothe cycloadducts (2R,5R)-2a–e with slightly lower enantioselectiv-ities, but still achieving very good enantiomeric excess, up to 90%(Table 1, entries 13–17).

This switchable synthetic methodology has allowed us to isolateboth enantiomers of the 2,5-disubstituted fulleropyrrolidines (2a–e)with good optical purity, without using time-consuming andextremely expensive chiral chromatography. Similarly to otherderivatives12,26,27, the chiral centres linked to the fullerene sphereperturb the intrinsic symmetry of the fullerene chromophore.Furthermore, the stereocontrolled generation of new chiral carbonatoms could be used as a strategy to finely modify the inherentsymmetry of the fullerene p system. The presence of pairs ofchiral fullerene systems is clearly evident in the circular dichroism(CD) spectra that appear with exact mirror symmetries (Fig. 3).

Remarkably, enantiomers obtained from the same catalyticcomplex give rise to CD spectra with the same sign and behaviourin the 430 nm region of the electronic spectra. This relevant UV–visband is considered the fingerprint for all fullerene monoadductsat 6,6 junctions (between two fused hexagons) regardless of thenature of the organic addend saturating the double bond. On thisbasis, a sector rule has been proposed26–28, which links the Cotton

CDCD

260

300

340

−4

0

4

θ (m

deg)

Abs

orba

nce

−20

0

20

300400500600700

θ (m

deg)

Compound 2a Compound 2c

Compound 2b Compound 2d

Abs

orba

nce

−20

0

20

300400500600700

400 450 500 550 600

400 450 500 550 600 400 450 500 550 600

400 450 500 550 600

200

300

−2−1012

θ (m

deg)

Abs

orba

nce

θ (m

deg)

Abs

orba

nce

Wavelength (nm) Wavelength (nm)

Wavelength (nm) Wavelength (nm)

CD CD

CD

UV UV

UVUV

Figure 3 | Circular dichroism and UV spectra of fulleropyrrolidines 2a–d (concentration, 4 3 1024 M in toluene). All products produce the typical UV–vis

profile of [60]fullerene monoadducts. The 430 nm band is considered as the fingerprint for all saturated C–C bonds between two hexagons of the C60

sphere, regardless of the nature of substituents involved. This UV–vis band corresponds to a symmetric chromophore, which is perturbed by the presence of

the two new chiral centres, giving rise to a Cotton effect as observed in the CD spectra. Therefore, all the enantiomers formed by the Ag(I)-4 catalyst (solid

line) present the same sign and the same Cotton effect at 430 nm. This effect is opposite to that shown by the enantiomers obtained from the Cu(II)-3

catalyst (dotted line).

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effect (CE) associated with this diagnostic UV–vis band and thestereochemical environment around the 6,6 junction. As we havenot been able to obtain crystals suitable for X-ray diffraction,we have used this rule to assign the absolute stereochemistry ofthe obtained compounds (see Supplementary Information). Allthe pyrrolidinofullerenes formed from the Ag(I)-4 catalyticcomplex showed in their CD spectra a positive CE, which is consist-ent with a (2R,5R) stereochemistry. Likewise, the negative CE corre-sponding to the Cu(II)-3 system is in agreement with the (2S,5S)configuration. This assignment has been confirmed by comparisonto the stereochemistry of the fullerene-free pyrrolidines obtainedfrom the Cu(MeCN)4ClO4-3 catalyst by other researchers21, andthe pyrrolidino fullerene 2a obtained using the same catalyticsystem (Table 1, entry 3). If we assume the same facial selectivityin the approach of [60]fullerene to the azomethine ylide, the(2S,5S) configuration could be easily demonstrated.

The scope of our methodology has been expanded to enable acomplete switch in the diastereoselectivity. We screened a catalyticcomplex formed from copper(II) triflate (10%) and Binap 5, with tri-ethylamine as the base, described by Komatsu as an exo-selective

catalytic system for such dipolar cycloadditions29. The Binap-Cu(II)triflate pair was able to efficiently catalyse the reaction at room temp-erature with high yields both with the p-metoxybenzylidene 1a andthiophenylmethylidene 1b glycinates. Obviously, the spherical sym-metry of [60]fullerene does not allow the formation of endo/exoisomers; however, this catalytic complex proved to be very useful ininverting the diastereochemical outcome obtained with Cu(II)-Fesulphos or Ag(I)-4, forming trans pyrrolidinofullerenes 2a,bwith 90% and 80% diastereomeric excess, respectively (Fig. 4).

In addition to the versatility of this methodology, we wouldlike to emphasize that this is the first case in which the catalyticcycloaddition of N-metallated azomethine ylides occurs in asupra-antara manner, giving rise efficiently to trans pyrrolidinederivatives. Indeed, all the previously reported cycloadditions ofN-metallated azomethine ylides afforded pyrrolidines bearingsubstituents at C2 and C5 with cis stereochemistry due to themore stable w-shaped geometry of the dipole, and to a concertedmechanism. Nevertheless, theoretical and experimental studieshave proposed the existence of a stepwise mechanism30 when elec-tron-poor olefins are used, even if the bond formation between

C60

N

BM

HN

HN

cis-2a–e d.e. = 95–99%(Table 1, entries 5-16)

trans-2a d.e. = 90%trans-2b d.e. = 80%

Ar ArMeO

O

MeO

O

ArMeO

OM

O

ON Ar

N ArMeO

OM

O

ON Ar

MO

ON Ar

M

P PPhPh

PhPh

CuO

ON Ar

2+

(±)-5

C60

3 or 4

Figure 4 | Proposed concerted versus stepwise mechanism for the stereochemical outcome observed from the metal–ligand–iminoester complex. When

the Fesulphos (3) or BPE (4) ligands are used, the chiral N-metallated azomethine ylide—formed after deprotonation by the acetate anion—cycloadds to the

C60 on a different enantioface, in a concerted supra–supra manner (left side). In contrast, the use of Binap (5) provokes the formation of an enolate-like

species (right side). The addition occurs stepwise, producing a zwitterionic intermediate followed by ring-closing from the opposite face in a

supra–antara manner, d.e.: diastereomeric excess.

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C2–C3 and C4–C5 in the cycloaddition process occurs through asupra–supra approach. The high (endo) stereocontrol in suchcycloaddition, despite the loss of concertedness, has been accountedfor by the interaction between the metal (lithium) and the ligandelectron-withdrawing moiety of the dipolarophile30.

The inherent electronic nature of fullerene C60 as a non-coordi-nating electron-poor olefin provides a useful contribution to theage-old debate on the concerted versus stepwise mechanism of1,3-dipolar cycloadditions31. These unexpected results constituteexperimental evidence of the intervention of a stepwise pathwayoperating with this catalytic complex (Binap-Cu(II)). Thus, a plaus-ible explanation could involve a first nucleophilic attack to the C60double bond of the metallated iminoester, acting as an enolaterather than a dipole.

The zwitterionic intermediate formed is stabilized by thebenzylic position of the cationic part and by the well known stabilityof the anionic fullerene moiety (Fig. 4). In the presence of CuOTf2-Binap, the closure of the pyrrolidine ring occurs on the oppositedipole face causing the formation of the trans adduct, althoughin a modest enantiomeric excess (20–40%). The lack of trans dia-stereoselectivity observed in imineglicinates bearing an electron-poor aromatic ring such as 1c,d is further evidence in favour ofthis mechanism as the lower stabilization of intermediate 6 facili-tates the alternative concerted mechanism (7) (see SupplementaryTable S1). However, further studies are necessary to clarify if thecis diastereoselectivity observed with catalysts 3 and 4 is due to aconcerted mechanism, even if asynchronous, or to a supra–suprastepwise addition on the C60 double bond.

ConclusionsWe have described a new and efficient synthetic methodology for acontrolled chiral functionalization of fullerene derivatives, which, incontrast to the classical thermal conditions used for the racemates, iscarried out under very mild conditions at lower temperatures andwith remarkably higher yields. The ultimate stereochemicaloutcome in the preparation of chiral pyrrolidinofullerenes isachieved by means of readily available chiral metal complexesused in catalytic amounts. Pyrrolidinofullerenes with controlledstereochemistry have thus been synthesized in very high enantio-meric excesses for the first time, paving the way to the preparationof new and versatile chiral fullerenes of paramount interest in medi-cinal chemistry as well as in materials science.

Received 7 May 2009; accepted 5 August 2009;published online 13 September 2009

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AcknowledgementsThis work was supported by the MICINN of Spain (project CT2008-00795/BQU andConsolider-Ingenio 2010C-07-25200) and the CAM (project P-PPQ-000225-0505). S.F.thanks the MICINN for a Ramon y Cajal contract, and E.E.M. thanks the MICINN fora Doctoral Fellowship.

Author contributionsN.M. and S.F. conceived and designed the experiments; E.M. and M.S. performed theexperiments; A.M. analysed the data; N.M. and S.F. co-wrote the paper. All authorsdiscussed the results and commented on the manuscript.

Additional informationSupplementary information and chemical compound information accompany this paper atwww.nature.com/naturechemistry. Reprints and permission information is available online athttp://npg.nature.com/reprintsandpermissions/. Correspondence and requests for materialsshould be addressed to N.M.

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