Amphiphilic [5:1]- and [3:3]-hexakisadducts of C60

FULL PAPER

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

Martin Braun,^[a]Uwe Hartnagel,^[a]Elena Ravanelli,^[a]Boris Schade,^[b]Christoph Böttcher,^[b]

Otto Vostrowsky,^[a]and Andreas Hirsch*^[a]

Keywords: Amphiphiles / Fullerenes / Liposomes / Micelles / Peptides

We have synthesized and characterized a variety of new am-

which can range from zero up to sixfold positive or sixfold

phiphilic hexakisadducts of C₆₀involving mixed octahedral negative, can be built up by protonation or deprotonation.

[5:1]- and [3:3]-addition patterns. The [5:1]-adducts 3 and 13

contain five pairs of didodecyl or diethyl malonates as non-

polar addends and, as their polar part, an extended bis(ma-

lonate) involving C₁₄and ethylene glycol chains and two bi-

All the amphiphilic [3:3]-hexakisadducts are very soluble in

water in their completely charged forms. Initial investi-

gations on the aggregation properties of the amphiphilic

[3:3]-hexakisadducts, conducted using transmission electron

otin termini. For the first time, amphiphilic [3:3]-hexakisad- microscopy (TEM) and pulse-gradient spin echo (PGSE)

ducts have been prepared using the e,e,e-trisadduct 18, NMR spectroscopy, reveal the pH-dependent formation of

which contains a cyclo-[3]-octyl malonate addend, as the pre- aggregates.

cursor. As polar groups, we used malonates featuring car-

boxy, amino, or peptide termini. The charge on the termini,

( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,

Germany, 2004)

eral advantages over conventional lipid-based drug-delivery

systems.^[8]First, a higher loading capacity for lipophilic gu-

est molecules located between the bilayers can be expected

because the radially arranged alkyl chains prevent dense

packing within the unloaded vesicle. Secondly, the aggre-

gation properties of the buckysomes can be modulated re-

adily by variations in pH. Thirdly, the presence of the 18

carboxylic groups of 1 enables further functionalization,

such as targeting with labels or antibodies, without losing

the aggregation properties.

The biofunctional amphifullerene 2 can intercalate into a

dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) bi-

layer and serve as a transmembrane anchor for proteins lo-

cated outside the membrane.^[3Ϫ5]The biotin anchor in 2 is

able to bind proteins such as avidin and streptavidin. As a

consequence, the possibility of biocompatibilization of lipo-

somes is provided. The amphiphilic behavior of 2 was dem-

onstrated by LangmuirϪBlodgett (LB) investigations.^[5]

Since the investigation of the supramolecular properties

of these first examples of amphiphilic hexakisadducts of

Introduction

Recently, we introduced two examples, 1^[1,2]and 2,^[3Ϫ5]

of amphiphilic [5:1]-hexakisadducts of C₆₀that involve an

octahedral addition pattern.^[6]The remarkably facile access

to these stereochemically defined multiple adducts required

control over the regioselectivity of the subsequent additions

to the [6,6]-bonds in equatorial sites. This control was

achieved using the template mediation strategy that we in-

troduced previously^[7]in which 9,10-dimethylanthracene

(DMA) units act as reversible-binding precursor addends.

The globular amphiphile 1 readily dissolves in water at

physiological pH, forming unilamellar vesicles (bucky-

somes) having diameters typically between 100 and 400 nm,

and has

a very small critical micelle concentration

(CMC).^[1]Stable monolayers of 1 at the air/water interface

were prepared by the Langmuir technique.^[2]Because of the

presence of 18 carboxylic groups, which can be depro-

tonated successively, electrostatic interactions between the

globular amphiphiles can be modified systematically, mak-

ing them interesting vehicles for the delivery of nonpolar

drug molecules. Amphifullerene 1 is expected to offer sev-

C

₆₀was very encouraging, we decided to synthesize a whole

range of amphifullerenes^[9]by systematically changing the

nature of the hydrophilic and lipophilic addends and the

nature of the hexaaddition pattern itself. In this contri-

bution, we introduce the syntheses of three new types of

amphifullerenes involving [5:1]- and [3:3]-addition patterns

that feature neutral as well as cationic and anionic polar

groups. These new amphifullerenes are now available for the

systematic investigation of their aggregation and encapsul-

ation properties.

[a]

Institut für Organische Chemie der Universität Erlangen-

Nürnberg,

Henkestr. 42, 91054 Erlangen, Germany

Fax: (internat.) ϩ 49-(0)9131-8526864

E-mail: andreas.hirsch@organik.uni-erlangen.de

[b]

Forschungszentrum für Elektronenmikroskopie, Institut für

Chemie, Freie Universität Berlin,

14195 Berlin, Germany

Eur. J. Org. Chem. 2004, 1983Ϫ2001

DOI: 10.1002/ejoc.200300663

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1983

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FULL PAPER

Results and Discussion

malonate (11) was achieved by coupling of the correspond-

ing alcohol 10 with malonyl chloride.^[13]The mixed [5:1]-

hexakisadduct 12 having a C_2v-symmetrical octahedral ad-

dition pattern^[6]was obtained by exhaustive DMA-me-

diated cyclopropanation^[6,7,14]of 9 with malonate 11. Sub-

sequently, the two Boc protecting groups were removed

using TFA/CH₂Cl₂. The final coupling with CDI-activated

-(ϩ)-biotin resulted in the isolation of target molecule 3.

All reaction intermediates and products were fully

Biotinylated [5:1]-Amphifullerenes

We intended to synthesize a second-generation biotinyl-

ated [5:1]-amphiphile having the following structural

properties: (i) One of the malonate addends should carry

two biotin groups instead of one attached to spacer units

that are long enough to protrude through a lecithin layer.

We expected that, compared to 2, the amphiphilic character

is more pronounced and that the ability to form micelles or

vesicles is increased. (ii) Nonpolar building blocks, C₁₈-

alkyl chains containing butadiyne units instead of saturated

C₁₂chains, should be used to allow subsequent 1,4-ad-

dition-type polymerization to occur in the same manner as

that which we reported for comparable lipofullerenes.^[10]In

contrast to the polymerization of these lipofullerenes, where

we observed the formation of perfectly spherical polymer

beads and destroyed lipid vesicles,^[10]now it is conceivable

for polymerization to occur inside the intact bilayer mem-

brane.

All these structural features are represented in the target

molecule 3. The synthesis of 3 is shown in Scheme 1. The

new biotin linker 7, which involves an extended polar part

when compared with 2, was obtained by carbonyldiimida-

zole (CDI) activated coupling^[11]of 15-hydroxypentade-

canoic acid (5), which was derived from commercially avail-

able pentadecanolide (4), with the N-Boc-protected glycol

6. Subsequently, the corresponding malonate 8 was synthe-

sized. Cyclopropanation^[12]of 8 with C₆₀led to the methan-

ofullerene 9. The synthesis of bis(10,12-octadecadiynyl)

1

characterized by means of H and ¹³C NMR spectroscopy,

IR or UV/Vis spectroscopy, mass spectrometry, and elemen-

tal analysis. The ¹³C NMR spectrum of 3 perfectly displays

the expected signals for the terminal biotin groups and the

two resonances of the C₆₀unit’s sp²-hybridized carbon

atoms, clearly demonstrating local T_hsymmetry around the

fullerene nucleus (Figure 1).

The interactions of the bifunctional amphifullerene 3

with lipid membranes, as well as polymerization reactions

within the corresponding composites, are currently under

investigation. Because of the ‘‘trans’’ orientation of the two

biotinylated transmembrane side chains of amphifullerene

3, bolaamphiphilic character can be expected. Two charac-

teristic low-energy orientations (a and b in Figure 2) of the

amphiphilic side chains were obtained according to semi-

empirical calculations. The possible intercalation into a

DPPC lipid membrane segment is shown in Figure 2. After

intercalation of 3 into the membrane, the biotin units may

act as transmembrane anchors and molecular recognition

signals and the ten polymerizable malonate chains may al-

low photopolymerization to occur.^[15]

1984

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Eur. J. Org. Chem. 2004, 1983Ϫ2001

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

Scheme 1. Synthesis of the biotinylated amphiphilic mixed [5:1]-hexakisadduct 3 having a C_2v-symmetrical addition pattern around the

C₆₀core (i: NaOH; ii: CDI; iii: malonic acid, CDI; iv: C₆₀, CBr₄, DBU, toluene, room temp.; v: malonyl dichloride, pyridine; vi: DMA,

CBr₄, DBU, toluene, room temp.; vii: TFA, CH₂Cl₂; viii: CDI, biotin)

Hexakisadduct 3 did not meet our expectations regarding increase the polar character and to improve the water solu-

its solubility and aggregation properties in water. Accept- bility of such a bis(biotinylated) derivative, we synthesized

able solubility was found only in organic solvents such as the [5:1]-hexakisadduct 13 having five ethyl malonate ad-

CHCl₃, CH₂Cl₂, and DMF. In water, 3 is soluble only in dends rather than five octadecadiynyl malonate units

the presence of a co-solvent, such as methanol. Thus, we (Scheme 2). In this case, to overcome the general problem

have not investigated the self-aggregation behavior of 3. To of separating the desired hexakisadducts from other ad-

Eur. J. Org. Chem. 2004, 1983Ϫ2001

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FULL PAPER

Figure 1. ¹³C NMR spectrum (100.5 MHz, room temp., CDCl₃) of hexakisadduct 3; the resonances at δ ϭ 37 and 70 ppm belong to the

carbon atoms of the diethyl ether moiety of the spacer; B ϭ biotin

trometry. Again, we found that appreciable solubility of the

short-chain bis(amino)amphifullerene 16 and its biotinyl-

ated derivative 13 exists only in organic solvents, e.g.,

CHCl₃and CH₂Cl₂; relative to their corresponding octade-

cadiynyl analogues, 12 and 3, they display enhanced solu-

bility in methanol.

Water-Soluble [3:3]-Amphifullerenes

The water-insoluble amphifullerenes 3 and 13 exhibit de-

mixing properties and do not self-assemble in water, prob-

ably because they possess insufficiently low numbers of po-

lar moieties. To improve their amphiphilic character, either

larger polar addends are necessary, as exemplified by the

dendrofullerene 1, or a more balanced ratio of polar and

nonpolar addends should be considered. For this purpose,

we chose [3:3]-hexakisadducts containing three pairs of

non-dendritic polar chains as target systems. To guarantee

easy access to amphiphilic [3:3]-hexakisadducts in satisfac-

tory yields, we used macrocyclic cyclo-[3]-octyl malonate

(17)^[16]for the initial addition to C₆₀(Scheme 3). Recently,

Figure 2. CPK model of a DPPC lipid bilayer with amphifullerene

3 in ‘‘trans’’ (left) and ‘‘cis’’ (right) orientations of its biotinylated

transmembrane side chains, obtained by optimization from semi-

empirical PM3 geometries (HyperChem 6.01)

ducts formed simultaneously during the exhaustive cyclo- we reported that multiple adducts of C₆₀having specific

propanation step, we reversed the sequence of addition addition patterns are accessible in good yields with remark-

steps. For this purpose, we prepared the cherry-red, C_2v- able, and, in many cases, complete regioselectivity in one

symmetrical [5:0]-pentakisadduct 14^[14]and used it as our synthetic step when flexible cyclo-[n] malonates are used as

starting material. The subsequent cyclopropanation reac- addends.^[16]The high regioselectivities are a result of the

tion with the Boc-protected spacer malonate 8, to complete nearly balanced distribution of strain energy within the flex-

the C_2v-symmetrical octahedral addition pattern, afforded ible alkyl chains of the cyclo-[n] malonates. For example, the

the bright-yellow N-Boc-protected [5:1]-hexakisadduct 15 e,e,e-trisadduct 18 (Scheme 3), in which the cyclic malonate

in 63% yield after purification by flash chromatography is attached to three adjacent octahedral [6,6]-binding sites,

(FC) and high-performance liquid chromatography can be obtained with very pronounced regioselectivity and

(HPLC). After cleavage of the Boc protecting groups using an isolated (HPLC) 64% yield upon reaction of C₆₀with 17.

TFA/CH₂Cl₂, the bis(amino)amphifullerene 16 was ob- In the context of amphiphilic fullerenes, the tris(malonate)

tained in quantitative yield. The final coupling of two (ϩ)- addend in 18, which comprises three C₁₂chains, serves as

biotin moieties, by CDI activation, to the amino termini the non-polar unit of the amphiphile. The remaining octa-

resulted in the formation of target molecule 13.

hedral binding sites within 18 are free for the addition of

All reaction intermediates and products were fully three polar malonates. A very favorable observation that

1

characterized by means of H and ¹³C NMR, IR, and UV/ supports this purpose is the fact that completing an octa-

Vis spectroscopy, elemental analysis, and mass spec- hedral addition pattern proceeds with very good regioselec-

1986

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Eur. J. Org. Chem. 2004, 1983Ϫ2001

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

Scheme 2. Synthesis of amphiphilic bis(amino) hexakisadduct 16 and its biotinylated derivative 13 [i: malonate 8, CBr₄, DBU; ii: TFA,

CH₂Cl₂; iii: CDI, -(ϩ)-biotin]

tivity both when using or not using the template mediation in basic solutions at pH ϭ 9Ϫ10. Similar to carbon nano-

strategy.^[6]Both cationic or anionic end groups can be used tubes, the self-assemblies possess diameters of ca. 70 A and

˚

to increase the water solubility and enable pH-dependent are very long (Figure 4). The diameters are similar to those

aggregation.

of micelles formed from structurally related dendritic poly-

carboxylic fullerene derivatives.^[1]We observed no aggre-

gates by TEM at neutral or acidic values of pH, which is

due possibly to electrostatic repulsion between individual

highly charged molecules and the fact that the addends car-

rying amino termini are very long and so can wrap around

the whole molecule to shield its apolar moieties from the

aqueous phase (monomolecular micelles).

Cationic Water-Soluble [3:3]-Amphifullerenes

As a first example of a cationic [3:3]-amphifullerene, we

undertook the synthesis of compound 21 (Scheme 3). To

provide the lipophilic e,e,e-trisadduct 18 with polar moiet-

ies, the octahedral addition pattern was completed by

DMA-templated cyclopropanation^[7]using an excess of the

spacer malonate 8. The Boc-protected, C₃-symmetrical

[3:3]-hexakisadduct 19 was obtained in 55% yield after sep-

aration using HPLC. The cleavage of the Boc protection

groups was achieved using TFA. The resulting amphifuller-

ene 20 was protonated to give target molecule 21

(Scheme 3). All reaction intermediates and products were

fully characterized by ¹H and ¹³C NMR, IR or UV/Vis

spectroscopy, elemental analysis, and mass spectrometry.

The pH-dependent solubility of 20 in water was demon-

strated by UV/Vis spectroscopic investigations. Very low

solubility of 20 occurs at neutral pH (buffered) and in

weakly acidic solution. The saturated aqueous solutions

Using the same synthetic pathway, we prepared the Boc-

protected hexakisadduct 22 and the sixfold-protonated am-

phifullerene 23 having shorter hydrophilic malonate

branches by reaction of e,e,e-trisadduct 18 with an excess

of malonate 24. The isolated yield of 22, after chromato-

graphic purification, was 55%. The cleavage of the protec-

tion groups was achieved using TFA and the protonated

amphifullerene 23 was isolated as yellow solid in quantitat-

ive yield. All reaction intermediates and products were fully

characterized by ¹H and ¹³C NMR spectroscopy, IR or UV/

Vis spectroscopy, and mass spectrometry.

In a similar manner, we synthesized a number of related

were almost colorless because of the low concentration and amphiphilic mixed [3:3]-hexakisadducts, 25Ϫ32, by cyclo-

the hexakisadduct bands in the UV/Vis spectra were very propanation of the e,e,e-trisadduct 18 with a variety of ma-

weak because of low solubility (Figure 3). Upon lowering lonate and malonamide addends, 33Ϫ36, containing either

the pH to 5, water solubility increases, which causes a slight alkyl or oligoethylene glycol chains. Relative to the previous

increase in the absorption. Finally, at pH ϭ 3, a value at example, all these chains are considerably shorter and

which all of the amino groups are completely protonated to match the size of the nonpolar cyclo-[3]-octyl malonate moi-

give the cationic amphiphile 21, all of the material dissolved ety of the resulting amphiphiles. The N-Boc-protected ma-

to form a yellow solution from which all of the absorption lonate 33 was obtained in 72% yield by condensation of

bands characteristic of a hexakisadduct with an octahedral malonic acid with an excess of commercially available N-

addition pattern exhibited high intensities.

Boc-protected 6-aminohexan-1-ol in the presence of DMAP

Preliminary TEM investigations on the aggregation and DCC. The corresponding conversion of the mono-N-

properties of 20 revealed the formation of thin aggregates protected α,ω-diamines hexamethylenediamine, 3,6-dioxa-

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Scheme 3. Synthesis of the amphiphilic [3:3]-hexakisadduct 20 having a C₃-symmetrical addition pattern (i: 1.5 equiv. C₆₀, CBr₄, DBU;

ii: DMA, malonate 8, CBr₄, DBU; iii: TFA, CH₂Cl₂; vi: H₃O^ϩ/TFA)

1,8-octanediamine, and 4,7,10-trioxa-1,13-tridecanediamine

The malonate and malonamide spacers, as well as the N-

with malonic acid, by applying the same reaction con- protected [3:3]-hexakisadducts and the corresponding hexa-

ditions, afforded the Boc-protected malonamides 34, 35 and ammonium trifluoroacetates, were fully characterized. The

36, respectively, in comparable yields.

fast-atom bombardment (FAB) mass spectra of the Boc-pro-

The subsequent cyclopropanation of 18 with an excess of tected [3:3]-hexakisadducts 25, 26, 27, and 28 revealed, in

the malonyl derivatives 33Ϫ36 in the presence of DMA, each case, signals for the molecular ion [M^ϩ] and the [M Ϫ

CBr₄, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)^[12]6 Boc]^ϩfragment. The fullerene portion of the sp²region of

yielded, after chromatographic purifications, the N-Boc- the ¹³C NMR spectra of each of the new hexakisadducts

protected, mixed [3:3]-hexakisadducts 25Ϫ28 in 50, 28, 45, 25Ϫ32 consists of 16 resonances grouped into two character-

and 49% yields, respectively. The protecting groups were re- istic sets of signals^[6]for the fullerene’s sp²-hybridized carbon

moved using TFA in CH₂Cl₂and the hexaammonium tri- atoms at δ ϭ 141 and 145 ppm. This display clearly reflects

fluoroacetates 29Ϫ32 were isolated as yellow solids, each in the expected C₃symmetry within an octahedral addition pat-

quantitative yield.

tern. The UV/Vis spectra of 25Ϫ32 show the characteristic

1988

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Eur. J. Org. Chem. 2004, 1983Ϫ2001

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

Figure 3. UV/Vis spectra of aqueous solutions of hexakisadduct 20

at different pH values (Shimadzu UV-3102 PC)

Figure 4. Transmission electron micrograph of micellar structures

formed by the self-assembly of 20 in aqueous solution at pH ϭ

˚

9Ϫ10 (diameter ഠ 70 A); sample droplets (5 µL) were applied to

hydrophilized copper grids (400 mesh); imaging performed using a

Philips CM 12 TEM at an accelerating voltage of100 kV

features of octahedral malonate adducts of C₆₀.^[6]Micro- progress. Pulse-field gradient spin echo nuclear magnetic res-

scopic studies on self-assembling properties and aggregation onance (¹H-PGSE NMR) spectroscopy provides a powerful

behavior of the synthesized compounds are currently in tool for determining diffusion constants D and hydrodynamic

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of the DMA-template mediation technique^[7]to give the

precursor hexakisadduct 39. Only very small amounts of

tetra- and pentakisadducts were formed as side products.

The separation of these lower adducts was achieved by FC,

which resulted in analytically pure 39 being isolated in

69.8% yield. The cleavage of the protecting tert-butyl ester

groups using TFA in CH₂Cl₂afforded the water-soluble

hexaacid hexakisadduct 37 in quantitative yield. Complete

structural characterization of the reaction products was car-

ried out by ¹H and ¹³C NMR, IR, and UV/Vis spec-

troscopy, elemental analysis, and mass spectrometry.

radii of particles in translational motion in solution, and as

a consequence allows molecular and particle dimensions to

be determined.^[17]From these measurements, we obtained

particles of 11.0 and 3.5 nm diameter for the hexammonium

triflates 30 and 31, respectively, in D₂O solution.

Anionic [3:3]-Mixed Hexaadduct Amphifullerene 37

Extending this concept of mixed [3:3]-hexakisadducts

containing a cyclo-[3]-octyl malonate addend as a lipophilic

moiety, we designed the amphifullerene 37 that, after depro-

tonation of its carboxylic termini, can be transferred readily

into an anionic amphiphile. The synthesis of 37 is depicted

The UV/Vis spectrum of 37 was measured in phosphate-

in Scheme 4. For the introduction of the corresponding buffered H₂O at pH ϭ 7.2 and is shown in Figure 5. The

hydrophilic addends, bis[3-(tert-butyloxycarbonyl)propyl] use of water as the solvent allows for the detection of all

malonate 38 was treated with the trisadduct 18 by means the absorption bands characteristic for the octahedral hexa-

1990

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Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

kismalonate of C₆₀,^[6]including the high-energy absorption

at 210 nm. This absorption is usually obscured when or-

ganic solvents are used.

In phosphate buffer at pH ϭ 7.2, we determined the solu-

bility of hexaacid 37 to be 2.1 mg/mL (1 m). For compari-

son, under the same conditions, the solubility of dendro-

fullerene hexakisadduct 1, which has a considerably higher

molecular weight, is 2.5 mg/mL (0.5 m).^[18]The yellow

solution of 37 at neutral pH appears opalescent, which indi-

cates the formation of aggregates. Cryo-TEM investigations

are in progress to elucidate the structure of these aggregates.

[3:3]-Amphifullerenes Having Short Peptide Sequences

The hexaacid 37 not only represents an example of a

water-soluble amphifullerene whose degree of negative

charge, and, therefore, its aggregation properties, can be

switched by changes in pH, but it is also susceptible for

further functionalization. For example, it is conceivable to

couple its carboxy termini with peptides or other biomolec-

ules. As a consequence, not only can the supramolecular

behavior of the corresponding amphifullerenes be further

influenced, but also additional molecular recognition

phenomena, as well as a bio-compatibilization of micelles

or liposomes, can be introduced. As a first example, we car-

ried out the synthesis of the hexakis(-alanine)-decorated

[3:3]-amphifullerene 40. For this purpose, hexaacid 37 was

first treated (Scheme 5) with enantiomerically pure -ala-

nine tert-butyl ester (41) in the presence of DCC and N-

hydroxysuccinimide (NHS) to afford the coupling product

42 in 62% yield after FC purification (SiO₂; CH₂Cl₂/

MeOH, 97:3). The tert-butyl protecting groups were re-

moved using TFA in CH₂Cl₂and the hexakis(-alanine)

amphifullerene 40 was obtained almost quantitatively as a

dark-yellow solid. Compound 40 and its tert-butyl-pro-

tected precursor 42 were fully characterized by IR, UV/Vis,

and ¹H and ¹³C NMR spectroscopy and by FAB mass spec-

trometry. Because of the chirality of the amino acid, as well

as the inherent chirality of mixed [3:3]-hexakisadducts of

C₆₀, the formation of mixtures of diastereoisomers is ex-

pected. As a consequence, all signals in NMR spectra

should, in principle, split into at least two sets of signals,

but we did not observe multiple signals in any case. This

finding is probably due to the fact that the chiral centers

within the polar addends are located in a fairly remote posi-

tions relative to the chiral fullerene core. In addition, it was

not possible to separate the diastereoisomers using either

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Figure 5. The UV/Vis spectrum of 34 in phosphate-buffered H₂O

at pH ϭ 7.2 (Shimadzu UV-3102 PC)

Scheme 4. Synthesis of the amphiphilic [3:3]-hexakisadduct 37 (i:

DMA, malonate 38, CBr₄, DBU; ii: TFA, CH₂Cl₂)

thin-layer chromatography (TLC) or HPLC. The depro-

tected amphifullerene 40 is very soluble in THF, DMSO,

and water at pH ϭ 7.2, but is completely insoluble in or-

ganic solvents such as CH₂Cl₂and CHCl₃.

The corresponding coupling of 37 with N-(-alanyl)--

alanine tert-butyl ester (43) and N-(-alanyl)--phenylala-

nine tert-butyl ester (44) afforded the tert-butyl-protected

hexakis-dipeptides 45 and 46, respectively, in 64 and 48%

yield, respectively. After deprotection in TFA/CH₂Cl₂at

room temp., the C₃-symmetrical amphifullerenes 47 and 48

were obtained as mixtures of diastereoisomers, each in

quantitative yield.

Scheme 5. Synthesis of the amphiphilic [3:3]-hexakisadduct 40 [i:

DCC, NHS, -alanine tert-butyl ester (41), THF, 14 h; ii: TFA,

CH₂Cl₂]; only one of the possible diastereoisomers is represented

1992

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Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

The characterization of the protected dipeptide hexakis- duct 18, which can be prepared in one step from the highly

adduct precursors 45 and 46, as well as the free dipeptide regioselective addition of cyclo-[3]-octyl malonate 17. The

hexakisadducts 47 and 48, was performed using IR, UV, remaining three octahedral sites are available for the attach-

and ¹H and ¹³C NMR spectroscopy, C,H,N-elemental ment of three ionic or neutral polar addends. For termini,

analysis, and FAB mass spectrometry. The deprotected pep- we used carboxy, amino, and peptide moieties. This design

tido-amphifullerenes 47 and 48 exhibit solubility behavior allows for the introduction of a number of tuneable positive

similar to that of 40.

or negative charges within the polar groups by variations in

In a search for self-aggregation, we examined freshly pre- pH. In some cases, we have undertaken preliminary investi-

pared buffered D₂O solutions of the alanineamphifullerene gations on the self-assembly processes using cryo-TEM and

40 and the alanylphenylalanineamphifullerene 48 at pH ϭ PGSE NMR spectroscopy. We have shown that the solu-

1

7.2 and 9.0 by H-PGSE NMR spectroscopy experiments; bility and self-assembly properties depend on the number

the parameters of the assembly particles are summarized in of ionic charges and, therefore, the value of pH. These

Table 1. The average diffusion coefficients (D) and particle structures provide very favorable opportunities for the con-

diameters (d ϭ 2R_H, the hydrodynamic radii) are based on trolled encapsulation and release of nonpolar guest mol-

the most distinct signals in the ¹H NMR spectra of the two ecules, which makes such amphiphilic fullerenes interesting

amphiphiles 40 and 48.

candidates for drug delivery systems. Extensive investi-

gations on the aggregation and inclusion properties of am-

phiphilic [3:3]-hexakisadducts of C₆₀are currently under

way.

Table 1. Molecular dimensions of self-assembled aggregates of am-

phiphiles 40 and 48 in buffered D₂O solutions as determined by

¹H-PGSE NMR spectroscopy experiments

Compound

pH

D [m²/s]

d ϭ 2 R_H[nm]

Experimental Section

40

48

40

48

7.2

9.0

1.07 ϫ 10^Ϫ10

1.09 ϫ 10^Ϫ10

9.47 ϫ 10^Ϫ11

9.36 ϫ 10^Ϫ11

5.15Ϫ5.28

4.91Ϫ5.26

5.80Ϫ5.94

5.44Ϫ6.44

General Remarks

Chemicals: C₆₀was obtained from Hoechst AG/Aventis and sepa-

rated from higher fullerenes by a plug filtration process.^[19,20]All

analytical and reagent grade solvents were purified by distillation.

Dry solvents were prepared using customary literature pro-

cedures.^[21]

Both amphiphilic molecules, 40 and 48, tend to self-ag-

gregate in neutral and basic solutions; the average diameter

of the aggregates is 5 nm, with an average volume of 65 nm³

and a surface area of 78 nm². It is interesting to note that

the self-assemblies formed at pH ϭ 9.0 were slightly larger

than those prepared in neutral solution. This feature can be

attributed to a higher degree of solvation of the multiple

negatively charged carboxylic amphiphiles by surrounding

water molecules.

Thin-Layer Chromatography (TLC): RiedelϪde Hae¨n silica gel F₂₅₄

and Merck silica gel 60 F₂₅₄. Detection: UV lamp, H₃[P(Mo₃O₁₀)₄]/

Ce(SO₄)₂/H₂SO₄/H₂O bath, KMnO₄/H₂O, and iodine chamber.

˚

Flash Chromatography (FC): ICN Silica 32Ϫ63, 60 A; typical par-

ameters for column diameter, loading, optimum eluent mixtures,

and eluent flow rate were selected from the literature.^[22]

High-Performance Liquid Chromatography (HPLC): Shimadzu

Liquid Chromatograph LC-10AT equipped with an SCL-10AVP

system controller, LC-8A preparative liquid chromatographs, a di-

ode array detector, an auto injector, a refractive index detector, a

UV/Vis detector, a selection valve, and a fraction collector. Analyti-

cal columns: Nucleosil 5 µm, 200 ϫ 4 mm, MachereyϪNagel;

Gromsil 100 Si, NP1, 5 µm, 200 ϫ 4 mm; Rexchrom Buckyclutcher

10 ϫ 250 mm, Regis; and Nucleogel GFC 500-5, MachereyϪNagel.

Conclusion and Outlook

We present here the synthesis of a series of mixed amphi-

philic hexakisadducts of C₆₀that have an octahedral ad-

dition pattern. The new [5:1]-hexakisadduct 3, which fea-

tures five nonpolar long-chain malonate addends and one

polar addend having two biotin termini, is insoluble in

water. As a consequence, it cannot be used to investigate its

superstructures that form in aqueous solution, but it rep-

resents an attractive building block for a potential co-sur-

factant-aided assembly to mixed micelles or liposomes. The

spacer carrying the biotin termini was designed in a way

that it can protrude through a layer of assembled lipid mol-

ecules, such as DPPC. This feature, in principle, makes it

available for targeting of micelles and liposomes by avidin-

mediated binding of label molecules. Progress in this direc-

tion will be reported in due course. For the first time, we

report the synthesis of amphiphilic [3:3]-hexakisadducts of

C₆₀. The key for the very facile access to these aesthetically

Preparative columns: Nucleosil 5 µm, 250

ϫ

21 mm,

MachereyϪNagel; Grom-Sil 100 Si, NP1, 5 µm, 250 ϫ 20 mm; Nu-

cleogel GFC 500-10, MachereyϪNagel; Buckyclutcher 250 ϫ

21 mm. The purity of the synthesis products was determined by

analytical HPLC (peak integration).

NMR Spectra: JEOL JNM EX 400 and JEOL JNM GX 400 (¹H:

400 MHz; ¹³C: 100.5 MHz), Bruker  300 (¹H: 300 MHz;

¹³C: 75.4 MHz), Bruker  400 (¹H: 400 MHz; ¹³C:

100.5 MHz). The chemical shifts are given in ppm relative to SiMe₄

(TMS). The resonance multiplicities are indicated as s (singlet), d

(doublet), t (triplet), q (quadruplet), and m (multiplet); broad res-

onances as br. Pulsed-field gradient measurements (¹H-PGSE

NMR) were carried out at 303 K, with an actively shielded gradient

probehead (g_max.ϭ 1.8 T/m) and a BPP-LED pulse sequence with

pleasing molecules is the simple synthesis of the e,e,e-trisad- δ ϭ 1 ms and ∆ ϭ 100 ms at pH ϭ 7.2 and ∆ ϭ 150 ms at pH ϭ 9.0.

Eur. J. Org. Chem. 2004, 1983Ϫ2001

www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1993

A Hirsch et al.

FULL PAPER

UV/Vis Spectra: Shimadzu UV-3102 PC, UV/Vis/NIR scanning

spectrophotometer; absorption maxima λ_max.are given in nm.

69.93, 69.90, 69.15 (6 C), 39.31 (1 C), 38.14 (1 C), 33.05 (1 C),

29.36 (1 C), 28.17 (3 C) ppm. IR (film/KBr): ν˜ ϭ 3362, 2930, 2868,

1708, 1524, 1456, 1391, 1365, 1252, 1173, 1113, 1043, 944, 865

cm^Ϫ1. MS (EI, 40 °C): m/z ϭ 320 [M]^ϩ, 247, 177, 164, 146, 102,

89, 74, 57, 44. C₁₅H₃₂N₂O₅(320.43): calcd. C 56.23 H 10.07 N

8.74; found C 55.81 H 10.00 N 8.53.

IR Spectra: Bruker FT-IR Vector 22, KBr pellets or thin film (NaCl

plates), ν˜ values in cm^Ϫ1

.

Mass Spectra: Micromass Zabspec, FAB (liquid secondary ion

mass spectroscopy LSIMS) mode (3-nitrobenzyl alcohol) and ESI

mode; Varian MAT 311A EI mode.

N-[13-(Boc-amino)-4,7,10-trioxatridecyl]-15-hydroxypenta-

decanoylamide (7): The hydroxy acid 5 (440 mg, 1.70 mmol) was

dissolved in dry DMF (25 mL) and then CDI (290 mg, 1.79 mmol)

was added under N₂at room temp. The imidazolide formation was

complete after several minutes. A solution of the amine 6 (545 mg,

1.70 mmol) in dry CH₂Cl₂(5 mL) was prepared, and the imidazol-

ide solution was added through a dry syringe/septum under nitro-

gen. The combined solutions were stirred for 2 h, washed with satu-

rated aqueous NaCl solution (3 ϫ 5 mL), and dried (MgSO₄). Puri-

fication by FC (SiO₂; CH₂Cl₂/EtOH, 95:5) gave 7 as a white solid

(675 mg, 70%). ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ

6.25, 4.98 (2 br., 2 H), 3.66Ϫ3.48 (m, 14 H), 3.34 (dt, 2 H), 3.20

Elemental Analyses: C, H, and N we measured by combustion and

gas chromatographical analysis using an EA 1110 CHNS analyzer

(CE Instruments).

Transmission Electron Microscopy: Sample preparation: Droplets

of the samples (5 µL) were applied to hydrophilized (glow-dis-

charged in a BALTEC MED 020, BAL-TEC AG, Liechtenstein,

for 60 s at 8 W) carbon-covered microscopical copper grids (400

mesh). The supernatant fluid was removed using a filter paper until

an ultrathin layer of the sample was obtained. A droplet of con-

trasting material (1% uranyl acetate) was added, blotted again, and

air-dried. Imaging was performed using a Philips CM 12 TEM

(FEI Company, Oregon) at a 100-kV accelerating voltage under

low-dose conditions at a primary magnification of 58300ϫ. The

defocus value was chosen to correspond to a first zero of the CTF

3

(dt, 2 H), 2.12 (t, J ϭ 7.7 Hz, 2 H), 1.98 (br., 1 H), 1.74 (m, 4 H)

1.64Ϫ1.49 (m, 4 H), 1.41 (s, 9 H), 1.36Ϫ1.18 (m, 20 H) ppm. ¹³C

NMR (100.5 MHz, room temp., CDCl₃): δ ϭ 173.1 (1 C), 156.0 (1

C), 78.9 (1 C), 70.5, 70.1, 70.1, 69.5 (6 C), 62.9 (1 C), 38.4, 37.8 (2

C), 36.8 (1 C), 32.7 (1 C), 29.6, 29.5, 29.5, 29.4, 29.3, 29.3, 28.9 (9

C), 28.4 (3 C), 25.7, 25.7 (2 C) ppm. IR (film/KBr): ν˜ ϭ 3321,

3064, 2921, 2850, 1686, 1636, 1535, 1471, 1421, 1366, 1277, 1250,

1179, 1139, 1061, 997, 867, 783, 721, 632, 578 cm^Ϫ1. MS (FAB):

m/z ϭ 693 [M ϩ Cs]^ϩ, 583 [M ϩ Na]^ϩ, 561 [M]^ϩ, 461 [M Ϫ Boc]^ϩ,

298. C₃₀H₆₀N₂O₇(560.81): calcd. C 64.25 H 10.78 N 5.00; found

C 63.92 H 10.66 N 5.12.

˚

at ca. 15 A.

15-Hydroxypentadecanoic Acid (5): Pentadecanolide (4; 2.56 g,

10.7 mmol) was dissolved in ethanol (25 mL) at 50 °C. An aqueous

1  NaOH solution (11.75 mL, 11.80 mmol) was added and stirred

at 50 °C, until TLC control [SiO₂; CH₂Cl₂/EtOAc, 95:5; R_f(5) ϭ

0.28] showed the complete hydrolysis of the lactone. The ethanol

was evaporated and the remaining alkaline solution was washed

with CH₂Cl₂. After neutralization with 1  HCl, the product was

dissolved in CH₂Cl₂, the aqueous layer was removed, and the sol-

vent CH₂Cl₂was evaporated. Drying in vacuo gave a white powder

Bis[29-(Boc-amino)-15-oxo-20,23,26-trioxa-16-azanonacosyl] Ma-

lonate (8): Malonic acid (104 mg, 1 mmol) and alcohol 7 (1.23 g,

2.2 mmol) were dissolved in dry CH₂Cl₂under N₂and the solution

was cooled in an ice bath. DMAP (41.0 mg, 0.20 mmol, 10 mol%)

and DCC (454 mg, 2.20 mmol) were then added. After stirring un-

der N₂at 0 °C for 15 min and then at room temp. for 2 h, TLC

indicated complete conversion of the starting material. Dicyclohex-

ylurea precipitated during the reaction and was filtered off. Traces

of urea were subsequently removed by repeated precipitation from

EtOAc. After evaporation of the solvent and purification by FC

(SiO₂; CH₂Cl₂/EtOH, 94:6), a white solid was obtained (714 mg,

60%). ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.22, 4.97

1

(2.64 g, 96%). H NMR (400 MHz, room temp., CDCl₃): δ ϭ 5.99

(br., 2 H; in [D₆]DMSO at δ ϭ 4.34 and 11.97 ppm, respectively),

3

3.64 (t, J ϭ 6.6 Hz, 2 H), 2.33 (t, J ϭ 7.40 Hz, 2 H), 1.53Ϫ1.67

(m, 4 H), 1.22Ϫ1.40 (m, 20 H) ppm. ¹³C NMR (100.5 MHz, room

temp., CDCl₃): δ ϭ 178.89 (1 C), 63.12 (1 C), 34.04 (1 C), 32.82 (1

C), 29.54, 29.49, 29.43, 29.34, 29.12, 29.01 (9 C), 25.70 (1 C), 24.72

(1 C) ppm. IR (KBr): ν˜ ϭ 3455, 3305, 2918, 2850, 2616, 1712, 1472,

1406, 1294, 1269, 1248, 1226, 1204, 1186, 1059, 1021, 926, 719,

596, 494 cm^Ϫ1

.

3

(2br., 4 H), 4.11 (t, J ϭ 6.8 Hz, 4 H), 3.66Ϫ3.48 (m, 12 H), 3.34

3

(s, 2 H), 3.33 (dt, 4 H), 3.20 (dt, 4 H), 2.11 (t, J ϭ 7.6 Hz, 4 H),

Monoprotected 1-N-Boc-1,13-diamino-4,7,10-trioxatridecane (6):

Bis(3-aminopropyl)diethylene glycol (26.85 g, 26.7 mL, 122 mmol)

was dissolved in 1,4-dioxane (50 mL) and a solution of Boc-anhy-

dride (4.37 g, 23.5 mmol) in dioxane (30 mL) was added dropwise

at room temperature within 5 h.^[23]The mixture was stirred for ad-

ditional 5 h and then the solvent was evaporated. The resulting

yellowish oil was dissolved in water (50 mL) and extracted with

CH₂Cl₂(4 ϫ 50 mL). The organic phases were pooled and washed

with saturated aqueous NaCl (4 ϫ 30 mL). The extraction pro-

cedure and the subsequent washing were repeated. The resulting

organic solution was dried (MgSO₄), which subsequently was fil-

tered off to give an almost colorless oil after evaporation and dry-

1.74 (m, 4 H), 1.60 (m, 4 H), 1.41 (s, 18 H), 1.35Ϫ1.19 (m, 40 H)

ppm. ¹³C NMR (100.5 MHz, room temp., CDCl₃): δ ϭ 172.9 (2

C), 166.4 (2 C), 155.8 (2 C), 78.9 (2 C), 70.5, 70.5, 70.2, 70.1, 70.1,

69.5 (12 C), 65.6 (2 C), 41.7 (1 C), 38.6, 37.9 (4 C), 36.9 (2 C),

29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.1 (20 C), 28.5 (6 C), 25.9,

25.8 (4 C) ppm. IR (film/KBr): ν˜ ϭ 3312, 3082, 2919, 2851, 1747,

1719, 1685, 1640, 1543, 1468, 1390, 1366, 1347, 1251, 1182, 1127,

1021, 997, 867, 720, 694, 603 cm^Ϫ1. MS (FAB): m/z ϭ 1322 [M ϩ

Cs]^ϩ, 1212 [M ϩ Na]^ϩ, 1190 [M]^ϩ, 1190, 990, 443. C₆₃H₁₂₀N₄O₁₆

(1189.64): calcd. C 63.61 H 10.17 N 4.71; found C 63.64 H 10.09

N 4.91.

ing in vacuo (6.70 g, 89% rel. to BocO₂). TLC control (SiO₂; 1,2-[Bis(14-{[3-(2-{2-[3-(Boc-amino)propoxy]ethoxy}ethoxy)propyl]-

CH₂Cl₂/EtOH, 9:1) indicated only traces of doubly protected diam-

carbamoyl}tetradecyloxycarbonyl)methano]-1,2-dihydro[60]fullerene

ine (R_fϭ 0.95) and no starting material. ¹H NMR (400 MHz, room (9): C₆₀(255 mg, 0.35 mmol) was dissolved in dry toluene (150 mL)

temp., CDCl₃): δ ϭ 5.12 (br., 1 H), 3.64Ϫ3.60 (m, 4 H), 3.60Ϫ3.55 under vigorous stirring and then CBr₄(64.0 mg, 0.193 mmol) and

3

(m, 4 H), 3.55Ϫ3.49 (m, 4 H), 3.20 (dt, J₁ϭ J₂ϭ 6.1 Hz, 2 H),

malonate 8 (208 mg, 0.175 mmol) were added. DBU (29.3 mg,

0.193 mmol), dissolved in toluene (20 mL), was added dropwise at

2.81 (app. dt, ³J₁ϭ 6.7, ³J₂ϭ 1.7 Hz, 2 H), 2.06 (br., 2 H),

1.78Ϫ1.69 (m, 4 H), 1.41 (s, 9 H) ppm. ¹³C NMR (100.5 MHz, room temp. over a period of 1 h. After 2 h of additional stirring

room temp., CDCl₃): δ ϭ 155.80 (1 C), 78.40 (1 C), 70.32, 70.28,

and monitoring by TLC, the reaction mixture was separated by FC

1994

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1983Ϫ2001

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

(SiO₂; toluene). The unchanged C₆₀eluted first [toluene/EtOH, 9:1; stirred at room temp. for 2 h and subsequently washed with satu-

R_f(9) ϭ 0.25]; 9 (137 mg, 41%) was obtained as a brown solid after rated aqueous NaCl (3 ϫ 5 mL). Purification by FC (SiO₂; CH₂Cl₂/

drying under high vacuum [purity (HPLC) ϭ 99%]. ¹H NMR

EtOH, 9:1) and HPLC gave 3 as a yellow wax-like solid (27.0 mg,

(400 MHz, room temp., CDCl₃): δ ϭ 6.38, 4.94 (2 br., 2 H), 4.48 82%) [purity (HPLC) ϭ 99%]. ¹H NMR (400 MHz, room temp.,

(t, ³J ϭ 6.6 Hz, 4 H), 3.66Ϫ3.49 (m, 24 H), 3.35 (dt, 4 H), 3.21 (dt, CDCl₃): δ ϭ 6.68, 6.61, 5.45, 5.30 (4 br., 8 H), 4.52 (m, 2 H), 4.32

3

4 H), 2.15 (t, J ϭ 7.7 Hz, 4 H), 1.88Ϫ1.70 (2m, 12 H), 1.65Ϫ1.55

(m, 2 H), 4.23 (t, J ϭ 6.6 Hz, 24 H), 3.66Ϫ3.50 (m, 24 H), 3.32

(m, 4 H), 1.43 (s, 18 H), 1.38Ϫ1.16 (m, 20 H) ppm. ¹³C NMR (m, 4 H), 3.15 (m, 4 H), 2.91 (dd, J₁ϭ 4.8, J₂ϭ 12.8 Hz, exo-

3

(100.5 MHz, room temp., CDCl₃): δ ϭ 173.3 (2 C), 163.6 (2 C), H), 2.75 (d, J ϭ 12.9 Hz, endo-H), 2.32 (t, J ϭ 7.4 Hz), 2.24 (t,

156.0 (2 C), 145.3, 145.2, 145.1, 144.8, 144.6, 144.6, 144.5, 143.8,

143.0, 142.9, 142.2, 141.9, 140.9, 138.9 (58 C, C₆₀sp²), 79.0 (2 C),

71.6 (2 C), 70.5, 70.5, 70.2, 70.1, 70.0, 69.5 (12 C), 67.5 (2 C), 52.4

³J ϭ 7.0 Hz), 2.16 (m), 1.81Ϫ1.56 (m), 1.56Ϫ1.43 (m), 1.41Ϫ1.20

(m), 0.89 (t, ³J ϭ 7.1 Hz) ppm. ¹³C NMR (100.5 MHz, room temp.,

CDCl₃): δ ϭ 173.6 (4 C), 163.8 (12 C), 163.5 (2 C), 145.7, 141.1

(1 C), 38.6, 37.9 (4 C), 36.7 (2 C), 29.6, 29.6, 29.6, 29.4, 29.4, 29.2, (48 C, C₆₀sp²), 77.5, 77.4 (20 C), 70.3, 69.9, 69.7, 69.6, 69.0 (24

28.9, 28.6 (14 C), 28.4 (6 C), 26.0, 25.8 (4 C) ppm. IR (KBr): ν˜ ϭ C), 66.9 (12 C), 65.2 (20 C), 62.0 (2 C), 60.4 (2 C), 55.3 (2 C), 45.3

3319, 2921, 2851, 1747, 1714, 1686, 1637, 1540, 1471, 1383, 1366,

(6 C), 40.5 (2 C), 37.4, 36.8 (4 C), 36.1 (2 C), 33.8, 31.0 (14 C),

29.7, 29.4, 29.2, 29.0, 28.8, 28.4, 28.4, 28.3, 28.0 (98 C), 25.8, 24.7

1254, 1175, 1118, 798, 526 cm^Ϫ1. UVϪVis (CH₂Cl₂): λ_max.ϭ 256,

320, 425 nm. MS (FAB): m/z ϭ 1907 [M]^ϩ, 1807, 1709, 1652, 720. (14 C), 22.1 (10 C), 19.2, 19.1 (20 C), 13.9 (10 C) ppm. IR (film/

C

₁₂₃H₁₁₈N₄O₁₆(1908.27): calcd. C 77.42, H 6.23, N 2.96; found C

KBr): ν˜ ϭ 3272, 3153, 3086, 2927, 2855, 2258, 2156, 1743, 1695,

1652, 1558, 1464, 1378, 1262, 1214, 1080, 1037, 801, 761, 715, 634

cm^Ϫ1. UV/Vis (CH₂Cl₂): λ_max.ϭ 270, 281, 317 (sh), 333 (sh) nm.

76.97, H 6.21, N 2.66.

1,2-[Bis(14-{[3-(2-{2-[3-(Boc-amino)propoxy]ethoxy}ethoxy)propyl]-

carbamoyl}tetradecyloxycarbonyl)methano]-18,36:22,23:27,45:31,

32:55,60-pentakis[bis(10,12-octadecadiynyloxycarbonyl)methano]-

1,2:18,36:22,23:27,45:31,32:55,60-dihydro[60]fullerene (12): Similar

to the procedure for the preparation of C₆₀hexakisadducts,^[6,7,14]

monoadduct 9 (53.0 mg, 34 µmol, 1 equiv.) was dissolved in dry,

degassed toluene (50 mL) under N₂. An excess of DMA (70.0 mg,

10 equiv.) was added to the solution, which was then stirred at

ambient temperature for 2 h. The diyne malonate 11^[13](65.0 mg,

10 equiv.) and CBr₄(113 mg, 10 equiv.) were subsequently added.

After a few minutes of stirring to allow complete dissolution to

occur, DBU (102 µL, 20 equiv.), diluted in dry toluene (10 mL),

was added dropwise over a period of 1 h. The reaction mixture was

stirred under N₂until TLC indicated that the reaction remained

unchanged (1Ϫ3 d). The separation from DMA and side products

was accomplished by FC (SiO₂; CH₂Cl₂/EtOH, 95:5). A sub-

sequent purification by HPLC (nucleosil; CH₂Cl₂/EtOH, 96:4) gave

C

₃₂₈H₄₂₀N₈O₃₆S₂(5115.01): calcd. C 77.02, H 8.28, N 2.19; found

C 76.41, H 8.02, N 2.01.

N-Boc-Protected [5:1]-Hexakisadduct 15 and Diaminoamphifuller-

ene [5:1]-Hexakisadduct 16: The synthesis of the [5:0]-pentakisad-

duct 14 was performed according to a literature protocol.^[12]14

(32.6 mg, 21.6 µmol, 1.0 equiv.) was dissolved in dry toluene

(15 mL). CBr₄(16.0 mg, 48.2 µmol, 2.2 equiv.) and malonate 8

(56.4 mg, 48.2 µmol, 2.2 equiv.), each dissolved in toluene (50 mL),

were added. DBU (10 µL, 3.1 equiv.) in toluene (1 mL) was added

dropwise over a period of 1 h to the stirred solution at room temp.

After additional stirring for 2 h and monitoring by TLC, the [5:1]-

hexakisadduct 15 was obtained as a bright-yellow solid (36.7 mg,

63%) after purification by HPLC (nucleosil; toluene/EtOH, 92:8)

[purity (HPLC) ϭ 98%]. The cleavage of the Boc protecting groups

of 15 (32.0 mg, 11.9 µmol) was achieved in TFA/CH₂Cl₂(5 mL/

5 mL) during a reaction time of 30 min. Subsequently, the solvents

were evaporated and the deprotected hexakisadduct 16 was dis-

solved in CH₂Cl₂and washed with saturated NaHCO₃. The sepa-

rated organic phase was dried (MgSO₄) and the solvent evaporated

to give diaminoamphiphile 16 [30.3 mg, 89%; purity (HPLC) ϭ

99%].

1

12 as a yellow solid (34.0 mg, 21%) [purity (HPLC) ϭ 100%]. H

NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.62, 4.96 (2br., 4 H),

3

4.23 (t, J ϭ 6.7 Hz, 24 H), 3.68Ϫ3.50 (m, 24 H), 3.37 (m, 4 H),

3

3.21 (m, 4 H), 2.23 (t, J ϭ 6.9 Hz, 44 H), 1.84Ϫ1.58 (m, 36 H),

1.56Ϫ1.46 (tt, 40 H), 1.43 (s, 18 H), 1.41Ϫ1.20 (m, 180 H), 0.89 (t,

³J ϭ 6.7 Hz, 30 H) ppm. ¹³C NMR (100.5 MHz, room temp.,

CDCl₃): δ ϭ 173.7 (2 C), 163.8 (12 C), 156.1 (2 C), 145.7, 141.1

(48 C, C₆₀sp²), 79.0 (2 C), 77.5, 77.4 (20 C), 70.5, 70.2, 70.1, 70.0,

69.5, 69.0 (24 C), 66.9 (12 C), 65.3, 65.2 (20 C), 45.3 (6 C), 38.9,

38.1 (4 C), 36.6 (2 C), 31.0, 29.7, 29.6, 29.5, 29.4, 29.4, 29.2, 29.0,

28.8, 28.4, 28.4, 28.0 (108 C), 25.8 (12 C), 22.1 (10 C), 19.2, 19.1

(20 C), 13.9 (10 C) ppm. IR (film/KBr): ν˜ ϭ 3416, 2929, 2856,

2258, 2153, 1746, 1652, 1520, 1466, 1365, 1264, 1218, 1123, 1082,

716, 530 cm^Ϫ1. UVϪVis (CH₂Cl₂): λ_max.ϭ 271, 280, 316 (sh), 333

15: ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.24, 4.97 (2

br., 4 H), 4.32 (q, J ϭ 7.1 Hz, 20 H), 4.23 (t, J ϭ 6.8 Hz, 4 H),

3.66Ϫ3.50 (m, 24 H), 3.34 (dt, 4 H), 3.21 (dt, 4 H), 2.13 (t, J ϭ

3

7.6 Hz, 4 H), 1.80Ϫ1.54 (m, 16 H) 1.42 (s, 18 H), 1.32 (t, ³J ϭ

7.1 Hz, 30 H) 1.28Ϫ1.21 (m, 40 H) ppm. ¹³C NMR (100.5 MHz,

room temp., CDCl₃): δ ϭ 173.1 (2 C), 163.9, 163.8 (12 C), 156.0

(2 C), 145.7, 141.1 (48 C, C₆₀sp²), 78.9 (2 C), 70.5, 70.2, 70.1, 70.0,

69.5, 69.1, 69.0 (24 C), 67.0 (2 C), 62.8 (10 C), 45.3 (6 C), 38.5,

37.8 (4 C), 36.8 (2 C), 29.7, 29.7, 29.6, 29.6, 29.5, 29.4, 29.4, 29.2,

29.0 (24 C), 28.4 (6 C), 25.8 (4 C), 14.0 (10 C). UVϪVis (CH₂Cl₂):

λ_max.ϭ 244, 272, 281, 316, 334 nm. MS (FAB): m/z ϭ 2698 [M]^ϩ,

2599 [M Ϫ Boc]^ϩ, 2498 [M Ϫ 2 Boc]^ϩ, 1510, 1352, 1194, 1036, 720

[C₆₀]^ϩ. C₁₅₈H₁₆₈N₄O₃₆(2699.03): calcd. C 70.31, H 6.27, N 2.08;

found C 69.62, H 6.22, N 2.01.

(sh) nm. MS (FAB): m/z

ϭ

4862 [M]^ϩ, 4761, 4659, 720.

C₃₁₈H₄₀₈N₄O₃₆(4862.65): calcd. C 78.55, H 8.46, N 1.15; found C

77.82, H 8.03, N 1.11.

1,2-[Bis(14-{[3-[2-(2-[3-(Biotinylamino)propoxy]ethoxy}ethoxy)-

propyl]carbamoyl}tetradecyloxycarbonyl)methano]-18,36:22,23:27,

45:31,32:55,60-pentakis[bis(10,12-octadecadiynyloxycarbonyl)-

methano]-1,2:18,36:22,23:27,45:31,32:55,60-dihydro[60]fullerene (3):

-(ϩ)-Biotin (15.6 mg, 65 µmol) was dissolved in dry DMF (2 mL)

16: ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.54 (br., 2 H),

4.33 (q, J ϭ 7.1 Hz, 20 H), 4.24 (t, J ϭ 6.7 Hz, 4 H), 3.67Ϫ3.51

3

and then DCI (6.20 mg, 38.5 µmol, 6 equiv.) was added under N₂(m, 24 H), 3.33 (dt, 4 H), 2.85 (t, J ϭ 6.6 Hz, 4 H), 2.14 (t, 4 H),

3

at room temp. After several minutes, a solution of the hexakisad-

duct 12 (31.0 mg, 6.4 µmol, 1 equiv.) in dry DMF (40 mL) was

prepared and the biotin/imidazolide reaction mixture was added

under N₂through a syringe/septum. The reaction mixture was

1.98 (br., 4 H), 1.82Ϫ1.52 (m, 16 H), 1.32 (t, J ϭ 7.1 Hz, 30 H)

1.28Ϫ1.20 (m, 40 H) ppm. ¹³C NMR (100.5 MHz, room temp.,

CDCl₃): δ ϭ 173.7 (2 C), 164.3, 164.2 (12 C), 146.2, 141.5 (48 C,

C₆₀sp²), 70.9, 70.8, 70.5, 70.3, 70.1, 69.5, 69.4 (24 C), 67.4 (2 C),

Eur. J. Org. Chem. 2004, 1983Ϫ2001

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1995

A Hirsch et al.

63.2 (10 C), 45.7 (6 C), 40.1, 38.0 (4 C), 37.2 (2 C), 30.1, 30.0, 29.9, Bis[24-(Boc-amino)-15-oxo-19,22-dioxa-16-azatetracosyl] Malonate

FULL PAPER

29.8, 29.7, 29.4 (24 C), 28.8 (6 C), 26.3 (4 C), 14.4 (10 C) ppm.

(24): According to the procedure for the synthesis of 6, an excess

of bis(2-aminoethyl)ethylene glycol (18.0 g, 122 mmol) was mono-

Boc-protected with Boc-anhydride (4.37 g) in dioxane. In a manner

analogous to that for the preparation of 7, the resulting Boc deriva-

tive was condensed with an equimolar amount of hydroxy acid 5

in the presence of CDI in DMF/CH₂Cl₂. The thus prepared amido

alcohol (2.00 g, 4.09 mmol) and malonic acid (192.2 mg,

1.85 mmol) were allowed to react in the presence of DMAP (70 mg,

0.537 mmol) and DCC (0.84 g, 4.09 mmol) as described for the syn-

thesis of 8. After FC chromatographic purification (SiO₂; EtOAc/

Biotinylated [5:1]-Hexakisadduct 13: An excess of -(ϩ)-biotin

(58.0 mg, 0.24 mmol) was activated with CDI (38.5 mg, 0.24 mmol)

in dry DMF (2 mL). After stirring for 30 min, the coupling was

performed in dry CH₂Cl₂by adding the activated biotin to the

solution of 16. FC (SiO₂; CH₂Cl₂/EtOH, 85:15) and HPLC

(CH₂Cl₂/EtOH, 92:8) gave 13 as a yellow solid [20.3 mg, 60%; pu-

rity (HPLC) ϭ 99%]. ¹H NMR (400 MHz, room temp., CDCl₃):

δ ϭ 6.41, 5.12, 4.87 (3 br., 8 H), 4.51 (m, 2 H), 4.32 (q, ³J ϭ 7.1 Hz,

3

22 H), 4.23 (t, J ϭ 6.8 Hz), 3.70Ϫ3.42 (m, 24 H), 3.30 (m, 4 H),

1

EtOH, 95:5) the malonate 24 was isolated in 48% yield. H NMR

3.17 (m, 4 H), 2.92 (dd, ³J₁ϭ 4.9, ³J₂ϭ 12.9 Hz, exo), 2.73 (d,

(400 MHz, room temp., CDCl₃): δ ϭ 6.00 (br., 2 H), 4.99 (br., 2

³J ϭ 12.6 Hz, endo), 2.32 (t, 4 H), 2.14 (t, ³J ϭ 7.6 Hz, 4 H),

3

H), 4.09 (t, J ϭ 6.7 Hz, 4 H), 3.55 (m, 8 H), 3.51 (m, 8 H), 3.42

3

1.90Ϫ1.53 (m, 24 H), 1.45 (m, 4 H), 1.32 (t, J ϭ 7.1 Hz, 30 H),

3

(dt, 4 H), 3.33 (s, 2 H), 3.29 (dt, 4 H), 2.14 (t, J ϭ 7.4 Hz, 4 H),

1.29Ϫ1.21 (m, 40 H) ppm. ¹³C NMR (100.5 MHz, room temp.,

CDCl₃): δ ϭ 173.5, 173.4, 163.9, 163.8, 162.8, 145.7, 141.1, 70.6,

70.3, 70.3, 70.1, 70.1, 69.8, 69.5, 69.1, 69.0, 67.0, 62.8, 61.8, 60.3,

60.0, 55.2, 45.3, 40.5, 40.1, 37.4, 36.8, 33.8, 29.7, 29.6, 29.4, 29.4,

29.2, 29.1, 28.4, 28.4, 28.2, 28.2, 25.8, 24.7, 14.0 (168 C) ppm. UV/

Vis (CH₂Cl₂): λ_max.ϭ 244, 270, 281, 316, 334 nm. C₁₆₈H₁₈₀N₈O₃₈S₂

(2983.39): calcd. C 67.63, H 6.08, N 3.76; found C 66.94, H 6.00,

N 3.55.

1.60 (m, 8 H), 1.41 (s, 18 H), 1.22 (m, 40 H) ppm. ¹³C NMR

(100.5 MHz, room temp., CDCl₃): δ ϭ 173.26 (2 C), 166.68 (2 C),

155.95 (2 C), 79.34 (2 C), 70.17, 69.99 (8 C), 65.65 (2 C), 41.66 (1

C), 40.29, 39.09 (4 C), 36.72 (2 C), 29.60, 29.54, 29.48, 29.37, 29.30,

29.18, 29.05, 28.43 (20 C), 28.37 (6 C), 25.75 (4 C) ppm. MS (FAB):

m/z ϭ 1069 [M ϩ Na]^ϩ, 1046 [M]^ϩ, 945 [M Ϫ Boc]^ϩ, 845 [M Ϫ 2

Boc]^ϩ. C₅₅H₁₀₄N₄O₁₄(1045.43): calcd. C 63.19 H 10.03 N 5.36;

found C 62.92, H 9.94, N 5.27.

N-Boc-Protected [3:3]-Hexakisadduct 19 and Hexaaminoamphiphile

20: e,e,e-Trisadduct 18 (59.0 mg, 43.5 µmol)^[16,19]was dissolved in

dry toluene (50 mL) and treated with an excess of DMA (54.0 mg,

260 µmol). After stirring at room temp. for 2 h, malonate 8

(310 mg, 260 µmol) and CBr₄(87.0 mg, 260 µmol) were added sub-

sequently and the reaction mixture was stirred for some minutes to

allow complete dissolution. DBU (79.0 mg, 520 µmol, 78 µL) in

dry toluene (5 mL) was added dropwise over 1 h and the solution

was stirred at room temp. and under N₂for one more day. Purifi-

cation by FC [SiO₂; CH₂Cl₂/EtOH, 95:5 to 9:1; R_f(19) ϭ 0.2 at

95:5] gave 19 as a yellow solid [118 mg, 55% yield; purity (HPLC) ϭ

99%]. The cleavage of the Boc protection groups was performed in

CH₂Cl₂(5 mL) using TFA (3 mL); after washing, the clear, yellow

solid 20 was obtained in almost quantitative yield.

N-Boc-Protected [3:3]-Hexakisadduct 22 and Sixfold-Protonated

Hexaaminoamphifullerene 23: e,e,e-Trisadduct 18 (75.0 mg, 55.2

µmol) was dissolved in dry CH₂Cl₂(25 mL) and treated with an

excess of DMA (68.35 mg, 0.331 mmol). After stirring at room

temp. for 2 h, the malonate 24 (346.7 mg, 0.331 mmol) and CBr₄

(111.25 mg, 0.331 mmol) were added and the reaction mixture was

stirred for some minutes to allow complete dissolution. DBU

(100.5 mg, 0.663 mmol, 99 µL) in dry CH₂Cl₂(15 mL) was added

dropwise over 1 h. The solution was stirred at room temp. under

N₂for one more day. Purification by FC [SiO₂; CH₂Cl₂/EtOH, 95:5

to 9:1; R_f(22) ϭ 0.2 at 95:5] gave 22 as a yellow solid [95.0 mg, 55%

yield; purity (HPLC) ϭ 97.5%]. Cleavage of the Boc protection

groups was performed in CH₂Cl₂(5 mL) and TFA (3 mL) to yield

a clear, yellow solid 23 almost quantitatively.

19: ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.27, 4.99 (2br.,

12 H), 4.67 (m, 6 H), 4.30Ϫ4.10 (m, 15 H), 4.00 (m, 3 H),

3.67Ϫ3.50 (m, 72 H), 3.35 (dt, 12 H), 3.22 (dt, 12 H), 2.14 (t, ³J ϭ

7.7 Hz, 12 H), 1.84Ϫ1.43 (m, 63 H), 1.43 (s, 54 H), 1.39Ϫ1.21 (m,

120 H), 1.17 (m, 18 H), 0.82 (m, 3 H) ppm. ¹³C NMR (100.5 MHz,

room temp., CDCl₃): δ ϭ 173.1 (6 C), 163.8, 163.7, 163.6, 163.1

(12 C), 156.0 (6 C), 146.4, 145.9, 145.6, 145.6, 145.3, 144.9, 144.8,

142.0, 141.8, 141.8, 140.9, 140.8, 140.7, 140.6 (48 C, C₆₀sp²), 78.9

(6 C), 70.5, 70.2, 70.1, 70.0, 69.5, 69.2., 69.1 (48 C), 67.0, 66.9 (12

C), 46.7, 45.6 (6 C), 38.5, 37.7 (12 C), 36.8 (6 C), 29.7, 29.7, 29.7,

29.6, 29.5, 29.4, 29.3, 29.0, 29.0 (90 C), 28.4 (18 C), 25.8 (12 C)

ppm. UV/Vis (CH₂Cl₂): λ_max.ϭ 244, 271, 282, 315, 334 nm. MS

(FAB): m/z ϭ 4943 [M ϩ Na]^ϩ, 4920 [M]^ϩ, 4820, 4621, 4316, 4096,

720. C₂₈₂H₄₀₂N₁₂O₆₀(4920.25): calcd. C 68.84, H 8.24, N 3.42;

found C 68.34, H 8.07, N 3.23.

22: ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.98 (br., 6 H),

5.00 (br., 6 H), 4.65 (m, 6 H), 4.22 (m, 12 H), 4.14 (m, 3 H), 3.98

(m, 3 H), 3.63Ϫ3.50 (m, 48 H), 3.43 (dt, 12 H), 3.29 (m, 12 H),

3

2.15 (t, J ϭ 7.6 Hz, 12 H), 2.00Ϫ1.51 (m, 39 H), 1.41 (s, 54 H),

1.35Ϫ1.21 (m, 120 H), 1.14 (m, 18 H), 0.82 (m, 3 H) ppm. ¹³C

NMR (100.5 MHz, room temp., CDCl₃): δ ϭ 173.27 (6 C), 163.83,

163.69, 163.64, 163.15 (12 C), 155.96 (6 C), 146.39, 145.89, 145.66,

145.60, 145.31, 144.89, 144.84, 141.97, 141.85, 141.78. 140.96,

140.81, 140.69, 140.65, (48 C, C₆₀sp²), 79.32 (6 C), 70.22, 70.00,

69.25, 69.21, 69.11 (28 C, C₆₀sp³), 67.03, 66.92, 66.23 (12 C), 46.66,

45.63 (6 C), 40.30, 39.10 (12 C), 36.70 (6 C), 29.96, 29.70, 29.66,

29.57, 29.50, 29.42, 29.36, 29.26, 29.17, 28.77 (78 C), 28.38 (18 C),

26.33, 25.81, 25.75, 25.60 (12 C) ppm. IR (KBr): ν˜ ϭ 3423, 2926,

2854, 1747, 1716, 1652, 1541, 1457, 1385, 1366, 1263, 1218, 1171,

1101, 804, 757, 715, 540, 528, 457 cm^Ϫ1. UV/Vis (CH₂Cl₂): λ_max.ϭ

243, 271, 281, 316, 334 nm. MS (FAB): m/z ϭ 4510 [M ϩ Na]^ϩ,

4487 [M]^ϩ, 4388 [M Ϫ Boc]^ϩ, 3885 [M Ϫ 6 Boc]^ϩ. C₂₅₈H₃₅₄N₁₂O₅₄

(4487.62): calcd. C 69.05, H 7.95, N 3.75; found C 68.33, H 7.79,

N 3.64.

1

20: H NMR (400 MHz, room temp., CDCl₃): δ ϭ 4.64 (m, 6 H),

4.32Ϫ4.07 (2m, 15 H), 4.01 (m, 3 H), 3.73Ϫ3.47 (m, 72 H), 3.31

(dt, 12 H), 3.17 (dt, 12 H), 2.55 (very br., 18 H), 2.21 (m, 12 H),

2.02 (m, 2 H), 1.84Ϫ1.44 (m, 61 H), 1.41Ϫ1.21 (m, 120 H), 1.18

1

(m, 18 H), 0.87 (m, 3 H) ppm. IR (KBr): ν˜ ϭ 3417, 3302, 3084, 23: H NMR (400 MHz, room temp., CDCl₃): δ ϭ 8.00 (m, 6 H),

2926, 2855, 1747, 1682, 1645, 1551, 1465, 1434, 1384, 1354, 1264,

1204, 1131, 1084, 874, 833, 800, 759, 721, 670, 528 cm^Ϫ1. UV/Vis 3.72Ϫ3.51 (m, 48 H), 3.30 (dt, 12 H), 3.11 (m, 12 H), 2.18 (t, J ϭ

(H₂O/pH ϭ 7.2): λ_max.ϭ 214, 244, 271, 280, 316, 334 nm. MS 7.5 Hz), 1.88Ϫ1.45 (m, 39 H), 1.40Ϫ1.23 (m, 120 H), 1.20 (m, 18

(FAB): m/z ϭ 4320 [M]^ϩ, 3332 [M Ϫ diaminomalonate]^ϩ, 2349 [M H), 0.89 (m, 3 H) ppm. ¹³C NMR (100.5 MHz, room temp.,

Ϫ 2 diaminomalonates]^ϩ, 720 [C₆₀]^ϩ.

CDCl₃): δ ϭ 176.51, 176.41 (6 C), 164.84, 164.82, 164.52, 163.95

4.64 (m, 6 H), 4.28 (m, 12 H), 4.10 (m, 3 H), 4.03 (m, 3 H),

3

1996

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1983Ϫ2001

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

(12 C), 147.17, 147.09, 146.76, 146.59, 146.30, 145.80, 143.51,

143.40, 143.06, 142.98, 142.56, 142.46, 142.19 (48 C, C₆₀sp²),

ditions outlined for the preparation of hexakisadduct 19, by treat-

ing e,e,e-trisadduct 18 (100 mg, 73.6 µmol, 1.0 equiv.) with an ex-

71.32, 71.25, 70.84, 70.78, 70.65, 69.54 (28 C, C₆₀sp³), 68.28, 67.87, cess of DMA (91.1 mg, 0.442 mmol, 6.0 equiv.) and N-protected

67.33, 66.44 (12 C), 47.71 (6 C), 40.62, 40.24, 40.12 (12 C), 37.12,

aminohexyl malonate 33 (221.8 mg, 0.442 mmol, 6.0 equiv.) in the

37.07 (6 C), 30.89, 30.84, 30.76, 30.71, 30.67, 30.58, 30.56, 30.41, presence of CBr₄(146.6 mg, 0.442 mmol, 6.0 equiv.), dissolved in

30.26, 30.10, 30.03, 29.71, 29.65, 29.54, 29.15 (78 C), 27.14, 27.04,

CH₂Cl₂(40 mL), and DBU (134.6 mg, 132.2 µL, 0.884 mmol, 12.0

26.99, 26.91 (12 C) ppm. IR (KBr): ν˜ ϭ 3423, 2925, 2854, 1747,

equiv.) in CH₂Cl₂(15 mL) under stirring for 2 d. After liquid chro-

1682, 1648, 1543, 1465, 1431, 1384, 1354, 1264, 1206, 1133, 836, matographic purification (CH₂Cl₂/EtOAc, 93:7), 25 was isolated

801, 722, 528 cm^Ϫ1. UV/Vis (H₂O, pH ϭ 7.2): λ_max.ϭ 246.5, 272, [106 mg, 50%; purity (HPLC) ϭ 98%]. H NMR (400 MHz, room

1

284, 321, 339.5 nm. MS (FAB): m/z ϭ 1944 [M]^2ϩ, 3887 [M]^ϩ, 3910 temp., CDCl₃): δ ϭ 4.74 (br., 6 H), 4.63 (m, 6 H), 4.25 (m, 12 H),

[M ϩ Na]^ϩ.

4.12 (m, 3 H), 3.98 (m, 3 H), 3.05 (m, 12 H), 1.69Ϫ1.40 (m, 39 H),

1.40 (s, 54 H), 1.31 (m, 24 H), 1.16 (m, 18 H), 0.85 (m, 3 H) ppm.

¹³C NMR (100.5 MHz, room temp., CDCl₃): δ ϭ 163.81, 163.73,

163.55, 163.13 (12 C), 155.98 (6 C), 146.23, 145.74, 145.68, 145.21,

144.89, 144.85, 142.03, 141.82, 141.75, 141.64, 140.85, 140.72 (48

C, C₆₀sp²), 78.87 (6 C), 69.22, 69.18, 69.11 (12 C), 67.00, 66.86,

66.79, 66.27 (12 C), 46.66, 45.66 (6 C), 40.46 (6 C), 29.89, 29.17,

28.78, 28.73, 28.30, 26.40, 26.34, 25.59, 25.54 (42 C), 28.40 (6 C)

ppm. IR (KBr): ν˜ ϭ 3422, 2930, 2857, 1746, 1716, 1634, 1517,

1458, 1385, 1366, 1385, 1366, 1263, 1218, 1170, 1080, 759, 714,

540, 528 cm^Ϫ1. UV/Vis (H₂O, pH ϭ 7.2): λ_max.ϭ 245, 273 (sh),

282 (sh), 320, 336 nm. MS (FAB): m/z ϭ 2859 [M]^ϩ, 2802 [M Ϫ

tBu]^ϩ, 2759 [M Ϫ Boc]^ϩ, 2704 [M Ϫ Boc Ϫ tBu]^ϩ, 2560, [M Ϫ 3

Boc]^ϩ, 2459 [M Ϫ 4 Boc]^ϩ, 2359 [M Ϫ 5 Boc]^ϩ, 2259 [M Ϫ 6

Boc]^ϩ. C₁₆₈H₁₈₀N₆O₃₄(2859.25): calcd. C 70.57, H 6.35, N 2.94;

found C 69.98, H 6.33, N 2.84.

Bis[(6-(Boc-amino)hexyl] Malonate (33): Malonic acid (104 mg,

1.00 mmol) was treated with N-Boc-protected 6-aminohexan-1-ol

(477.5 mg, 2.20 mmol, 1.1 equiv.) in the presence of DMAP and

DCC according to the procedure for preparing malonate 8. 33 was

isolated (167 mg, 72%) as a colorless oil. ¹H NMR (400 MHz,

room temp., CDCl₃): δ ϭ 4.59 (br., 2 H), 4.09 (t, ³J ϭ 6.8 Hz, 4

3

H), 3.32 (s, 2 H), 3.06 (m, 4 H), 1.59 (q, J ϭ 7.0 Hz), 1.50Ϫ1.39

(m, 4 H), 1.39 (s, 18 H), 1.25Ϫ1.34 (m, 8 H) ppm. ¹³C

NMR(100.5 MHz, room temp., CDCl₃): δ ϭ 166.62 (2 C), 155.95

(2 C), 78.98 (2 C), 65.40 (2 C), 41.56 (1 C), 40.38 (2 C), 33.81 (2

C), 29.89 (2 C), 28.36 (6 C), 26.30, 25.43 (4 C) ppm. MS (FAB):

m/z ϭ 503 [M^ϩ], 403 [M^ϩϪ Boc], 347 [M^ϩϪ Boc Ϫ tBu], 303

[M^ϩϪ 2 Boc]. C₂₅H₄₆N₂O₈(502.64): calcd. C 59.74, H 9.22, N

5.57; found C 59.71, H 8.98, N 5.54.

Bis[6-(Boc-amino)hexyl] Malonamide (34), Bis[8-(Boc-amino)-3,6-

dioxaoctyl] Malonamide (35) and Bis[13-(Boc-amino)-4,7,10-triox-

atridecyl] Malonamide (36): By procedures similar to that for the

synthesis of 8, condensation of malonic acid (104 mg, 1 mmol, 1.0

equiv.) with N-Boc-hexamethylenediamine, N-Boc-8-amino-3,6-di-

oxaoctylamine, and N-Boc-13-amino-4,7,10-trioxatridecylamine

(each 2.20 mmol, 2.2 equiv.), respectively, in the presence of DMAP

and DCC gave 34 (61%), 35 (67%), and 36 (58%).

Hexaammonium Trifluoroacetate Amphifullerene 29: The cleavage

of the Boc protection groups of 25 (100 mg) in CH₂Cl₂(5 mL) and

TFA (3 mL) resulted in the formation of the hexaammonium tri-

fluoroacetate salt 29 as a clear, yellow solid in quantitative yield

[purity (HPLC) ϭ 99%]. ¹H NMR (300 MHz, room temp.,

CD₃OH): δ ϭ 7.85 (br., 18 H), 4.69 (m, 6 H), 4.35 (m, 12 H), 4.14

(m, 3 H), 4.02 (m, 3 H), 2.92 (t, ³J ϭ 6.7 Hz, 12 H), 1.95Ϫ1.51 (m,

39 H), 1.35 (m, 24 H), 1.34Ϫ1.11 (m, 18 H), 0.83 (m, 3 H) ppm.

¹³C NMR (75 MHz, room temp., CD₃OH): δ ϭ 165.29, 165.23,

164.69, 164.47 (12 C), 147.71, 147.50, 147.25, 146.82, 146.76,

146.50, 146.29, 144.09, 143.91, 143.33, 143.22, 142.99, 142.84,

142.66 (48 C, C₆₀sp²), 71.29, 71.26, 71.21, 70.99 (12 C, C₆₀sp³),

68.87, 68.61, 67.81 (12 C), 48.25 (6 C), 41.05 (6 C), 31.20, 30.85,

30.57, 30.41, 29.85, 29.82, 28.90, 28.87, 28.01, 27.43, 27.38, 27.34,

27.00, 26.95 (42 C) ppm. IR (KBr): ν˜ ϭ 3443, 30.95, 2935, 2859,

1745, 1681, 1539, 1463, 1433, 1385, 1355, 1264, 1206, 1136, 1082,

993, 838, 801, 759, 723, 669, 540, 527 cm^Ϫ1. UV/Vis (H₂O, pH ϭ

7.2): λ_max.ϭ 214.5, 245.5, 271, 282.5, 319, 337 nm. MS (FAB): m/

z ϭ 720 [C₆₀]^ϩ,1131 [M]^2ϩ, 2259 [M]^ϩ, 2281 [M ϩ Na]^ϩ.

34: ¹H NMR (300 MHz, room temp., CDCl₃): δ ϭ 6.97 (br., 2 H),

3

4.54 (br., 2 H), 3.22 (q, J ϭ 6.9 Hz, 4 H), 3.13 (s, 2 H), 3.01 (q,

³J ϭ 6.8 Hz, 4 H), 1.54Ϫ1.42 (m, 8 H), 1.42 (s, 18 H), 1.36Ϫ1.27

(m, 8 H) ppm. ¹³C NMR (75 MHz, room temp., CDCl₃): δ ϭ

169.34 (2 C), 158.12 (2 C), 81.15 (2 C), 45.07, 42.26 (4 C), 41.36 (1

C), 32.01, 31.21 (4 C), 30.48 (6 C), 28.30, 28.16 (4 C) ppm. MS

(FAB): m/z ϭ 501 [M^ϩ], 401 [M^ϩϪ Boc], 345 [M^ϩϪ Boc Ϫ tBu],

301 [M^ϩϪ 2 Boc]. C₂₅H₄₈N₄O₆(500.67): calcd. C 59.97, H 9.66,

N 11.19; found C 59.81, H 9.53, N 10.96.

35: ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 7.34 (br., 2 H),

3

5.26 (br., 2 H), 3.57 (m, 8 H), 3.52 (t, J ϭ 5.1 Hz, 8 H), 3.43 (m,

4 H), 3.27 (m, 4 H), 1.40 (s, 18 H) ppm. ¹³C NMR (100.5 MHz,

room temp., CDCl₃): δ ϭ 167.19 (2 C), 155.93 (2 C), 79.24 (2 C),

70.29, 70.18 (8 C), 42.76 (1 C), 40.49 (2 C), 39.41 (2 C), 28.48 (6

C) ppm. MS (FAB): m/z ϭ 565 [M^ϩ], 465 [M^ϩϪ Boc], 365 [M^ϩ

Ϫ 2 Boc]. C₂₅H₄₈N₄O₁₀(564.67): calcd. C 53.18, H 8.57, N 9.92;

found C 53.06, H 8.52, N 9.94.

N-Boc-Protected Bis(6-aminohexyl) Malonamide [3:3]-Hexakisad-

duct 26: By the same procedure as described for 25, the title com-

pound was prepared from the reaction of e,e,e-trisadduct 18

(100 mg, 73.6 µmol, 1.0 equiv.), DMA (91.1 mg, 0.442 mmol, 6.0

equiv.), bis[6-(Boc-amino)hexyl] malonamide (34; 221.3 mg,

0.442 mmol, 6 equiv.), CBr₄(146.6 mg, 0.442 mmol, 6.0 equiv.) and

DBU (134.6 mg, 132.2 µL, 0.884 mmol, 12 equiv.) in CH₂Cl₂. After

chromatographic purification (toluene/EtOAc, 70:30), 26 was ob-

36: ¹H NMR (300 MHz, room temp., CDCl₃): δ ϭ 7.39 (br., 2 H),

3

5.02 (br., 2 H), 3.65Ϫ3.47 (m, 12 H), 3.33 (q, J ϭ 6.1 Hz, 4 H),

3

3.18 (q, J ϭ 6.1 Hz, 4 H), 3.09 (s, 2 H), 1.82Ϫ1.66 (m, 8 H), 1.40

tained [135 mg, 28%; purity (HPLC)

ϭ

98.5%]. ¹H NMR

(s, 18 H) ppm. ¹³C NMR (75 MHz, room temp., CDCl₃): δ ϭ

167.73 (2 C), 156.47 (2 C), 79.27 (2 C), 70.94, 70.91, 70.58, 70.11,

69.91 (12 C), 43.17 (1 C), 38.87 (2 C), 38.13 (2 C), 30.02 (2 C),

29.22 (2 C), 28.85 (6 C) ppm. MS (FAB): m/z ϭ 709 [M^ϩ], 610

[M^ϩϪ Boc], 510 [M^ϩϪ 2 Boc]. C₃₃H₆₄N₄O₁₂(708.88): calcd. C

55.91, H 9.10, N 7.90; found C 55.75, H 8.98, N 7.78.

(400 MHz, room temp., CDCl₃): δ ϭ 6.92 (br., 3 H), 6.60 (br., 3

H), 4.92 (br., 3 H), 4.75 (br., 3 H), 4.61 (m, 6 H), 4.13 (m, 3 H),

3.99 (m, 3 H), 3.45Ϫ3.10 (m, 12 H), 3.05Ϫ3.20 (m, 12 H), 3.01 (m,

12 H), 1.70Ϫ1.40 (m, 39 H), 1.39 (s, 54 H), 1.26 (m, 24 H), 1.15

(m, 18 H), 0.84 (m, 3 H) ppm. ¹³C NMR (100.5 MHz, room temp.,

CDCl₃): δ ϭ 163.54, 163.07 (12 C), 156.08, 155.99 (6 C), 145.51,

145.17, 144.70, 144.48, 144.14, 142.27, 142.06, 141.76, 140.96,

140.82, (48 C, C₆₀sp²), 78.84 (6 C), 71.14, 70.97, 69.48 (12 C),

N-Boc-Protected Bis(6-aminohexyl) Malonate [3:3]-Hexakisadduct

25: The title compound was prepared under the same reaction con-

Eur. J. Org. Chem. 2004, 1983Ϫ2001

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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1997

A Hirsch et al.

FULL PAPER

66.99, 66.38 (6 C), 52.25 (3 C), 46.86 (3 C), 40.49, 40.28 (12 C), 145.78, 145.61, 145.55, 145.02, 144.17, 143.97, 143.85, 143.61,

29.86, 29.63, 29.31, 29.18, 28.81, 26.57, 26.44, 26.35, 25.58 (42 C),

28.44, 28.42 (6 C) ppm. IR (KBr): ν˜ ϭ 3418, 2931, 2857, 1747,

143.49, 143.28, 142.09, 142.02 (48 C, C₆₀sp²), 73.15, 72.69 (6 C),

71.50, 71.45, 71.37, 71.00, 70.66, 70.31 (30 C), 68.25, 67.90 (6 C),

1632, 1523, 1548, 1392, 1366, 1261, 1223, 1172, 1138, 1106, 1075, 54.37 (3 C), 44.58 (3 C), 41.18, 40.65 (12C), 30.65, 30.54, 30.24,

865, 802, 752, 710, 539, 524. UV/Vis (CH₂Cl₂): λ_max.ϭ 244, 273.5 29.81, 27.67, 26.93 (12 C) ppm. IR (KBr): ν˜ ϭ 3442, 2927, 2857,

(sh), 282.5 (sh), 320, 337 nm. MS (FAB): m/z ϭ 2852 [M]^ϩ, 2753

[M Ϫ Boc]^ϩ, 2697 [M Ϫ Boc Ϫ tBu]^ϩ, 2653 [M Ϫ 2 Boc]^ϩ, 2553

1742, 1682, 1541, 1458, 1432, 1385, 1275, 1206, 1180, 1132, 837,

802, 723, 539, 522 cm^Ϫ1. UV/Vis (H₂O, pH ϭ 7.2): λ_max.ϭ 214,

[M Ϫ 3 Boc]^ϩ, 2453 [M Ϫ 4 Boc]^ϩ, 2353 [M Ϫ 5 Boc]^ϩ, 2252 [M 244 (sh), 272 (sh), 283 (sh), 319, 335.5 nm. MS (FAB): m/z ϭ 2467

Ϫ 6 Boc]^ϩ, 720 [C₆₀]^ϩ. C₁₆₈H₁₈₆N₁₂O₂₈(2853.34): calcd. C 70.72, [M ϩ Na]^ϩ, 2445 [M]^ϩ, 1440, 720 [C₆₀]^ϩ.

H 6.57, N 5.89; found C 70.09, H 6.34, N 5.86.

N-Boc-Protected Bis[13-(Boc-amino)-4,7,10-trioxatridecyl] Malona-

Hexaammonium Trifluoroacetate Amphiphile 30: The stable hexa-

mide [3:3]-Hexakisadduct 28: A mixture of e,e,e-trisadduct 18

ammonium triflate 30 (75.1 mg, 95%) was obtained from the depro-

(100 mg, 73.6 µmol, 1.0 equiv.), DMA (91.1 mg, 0.442 mmol, 6.0

tection of 26 (100 mg) using an excess of TFA in CH₂Cl₂. ¹H NMR

(400 MHz, room temp., CD₃OD): δ ϭ 8.83 (m, 3 H),8.72 (m, 3 H),

7.82 (br., 18 H), 4.80 (m, 3 H), 4.64 (m, 3 H), 4.15 (m, 3 H), 4.01

equiv.), bis[13-(Boc-amino)-4,7,10-trioxatridecyl] malonamide (36;

313.4 mg, 0.442 mmol, 6 equiv.), CBr₄(146.6 mg, 0.442 mmol, 6.0

equiv.), and DBU (134.6 mg, 132.2 µL, 0.884 mmol, 12 equiv.) was

stirred for 3 d; after chromatographic purification (LC: EtOAc/

(m, 3 H), 3.38Ϫ3.20 (m, 12 H), 2.89 (m, 12 H), 1.83Ϫ1.45 (m, 39

H) 1.36 (m, 24 H), 1.20 (m, 18 H), 0.89 (m, 3 H) ppm. ¹³C NMR

EtOH, 92:8; HPLC: toluene/MeOH, 91:9), 28 was obtained

(100.5 MHz, room temp., CD₃OD): δ ϭ 165.06, 164.83, 164.60,

[121.9 mg, 49%; purity (HPLC) ϭ 98.5%]. ¹H NMR (400 MHz,

164.21 (12 C), 146.84, 146.75, 146.25, 145.97, 145.85, 145.50,

room temp., CDCl₃): δ ϭ 7.50Ϫ6.90 (br., 6 H), 5.00 (m, 6 H), 4.59

(m, 6 H), 4.10 (m, 3 H), 3.97 (m, 3 H), 3.70Ϫ3.35 (m, 84 H), 3.17

(m, 12 H), 1.80Ϫ1.40 (m, 39 H), 1.40 (s, 54 H), 1.17 (m, 18 H),

144.70, 144.51, 144.25, 143.94, 143.71, 143.58, 143.28, 142, 13,

142.05 (48 C, C₆₀sp²), 73.52, 72.88, 71.12, 71.10 (12 C), 68.35,

67.44 (6 C), 54.87 (3 C), 48.65 (3 C), 41.00, 40.94, 40.75, 40.70 (12

0.85 (m, 3 H) ppm. ¹³C NMR (100.5 MHz, room temp., CDCl₃):

C), 30.66, 30.56, 30.33, 30.30, 29.87, 28.63, 28.53, 27.67, 27.57,

δ ϭ 164.45, 163.66, 163.03, 162.92 (12 C), 156.02 (6 C), 145.49,

145.31, 145.07, 144.80, 144.66, 144.58, 144.38, 144.14, 142.26,

27.37, 27.02, 26.95 (42 C) ppm. IR (KBr): ν˜ ϭ 3424, 2935, 2859,

1744, 1678, 1541, 1460, 1385, 1275, 1204, 1179, 1135, 836, 800,

141.73, 141.00, 140.81 (48 C, C₆₀sp²), 78.81 (12 C), 71.37, 71.15

722, 539, 522 cm^Ϫ1. UV/Vis (H₂O, pH ϭ 7.2): λ_max.ϭ 215, 242.5

(6 C), 70.86, 70.47, 70.35, 70.25, 70.17, 69.76, 69.49, 69.01, 68.75

(42 C), 66.81, 66.27 (6 C), 52.33 (3 C), 46.78 (3 C), 39.21, 38.49,

38.23, 38.02 (12 C), 29.61, 29.21, 20.00, 28.79, 28.73, 26.42, 25.54

(sh), 272 (sh), 281 (sh), 317.5, 336 nm. MS (FAB): m/z ϭ 2253

[M]^ϩ, 1440 [C₆₀dimer]^ϩ, 720 [C₆₀]^ϩ.

(30 C), 28.44 (6 C) ppm. UV/Vis (CH₂Cl₂): λ_max.ϭ 244, 270.5, 281,

N-Boc-Protected Bis[8-(Boc-amino)-3,6-dioxaoctyl] Malonamide

318, 336 nm. MS (FAB): m/z ϭ 3381 [M]^ϩ, 3323 [M Ϫ tBu]^ϩ, 3277

[3:3]-Hexakisadduct 27: The title compound was obtained from the

[M Ϫ Boc]^ϩ, 3177 [M Ϫ 2 Boc]^ϩ, 3077 [M Ϫ 3 Boc]^ϩ, 2977 [M Ϫ

reaction of the e,e,e-trisadduct 18 (100 mg, 73.6 µmol, 1.0 equiv.),

DMA (91.1 mg, 0.442 mmol, 6.0 equiv.), bis[8-(Boc-amino)-3,6-di-

oxaoctyl) malonamide (35; 249.5 mg, 0.442 mmol, 6 equiv.), CBr₄

4 Boc]^ϩ, 2877 [M Ϫ 5 Boc]^ϩ. C₁₉₂H₂₃₄N₁₂O₄₈(3477.96): calcd. C

66.30, H 6.78, N 4.83; found C 65.67, H 6.64, N 4.85.

(146.6 mg, 0.442 mmol, 6.0 equiv.), and DBU (134.6 mg, 132.2 µL,

0.884 mmol, 12 equiv.) in CH₂Cl₂(25 mL). After chromatographic

Hexaammonium Trifluroacetate Amphiphile 32: The trifluoroacet-

ate 32 was obtained (85.0 mg, 94% yield) by deprotection of 28

purification [LC: CH₂Cl₂/EtOH, 95:5; HPLC: toluene/MeOH,

1

(100 mg) using an excess of TFA in CH₂Cl₂. H NMR (400 MHz,

1

93:7), 27 was obtained [100 mg, 45%; purity (HPLC) ϭ 98%]. H

room temp., CDCl₃): δ ϭ 9.18 (m, 3 H), 9.07 (m, 3 H), 7.79 (m,

NMR (400 MHz, room temp., CDCl₃): δ ϭ 7.40 (br., 6 H), 5.29

18 H), 4.55 (m, 6 H), 4.15 (m, 3 H), 3.97 (m, 3 H), 3.70Ϫ3.25 (m,

(br., 3 H), 5.17 (br., 3 H), 4.59 (m, 6 H), 4.13 (m, 3 H), 3.98 (m, 3

82 H), 3.03 (m, 12 H), 1.97Ϫ1.47 (m, 39 H), 1.20 (m, 18 H), 0.88

H), 3.51 (m, 60 H), 3.27 (m, 12 H), 1.75Ϫ1.45 (m, 15 H), 1.40 (s,

(m, 3 H) ppm. ¹³C NMR (100.5 MHz, room temp., CDCl₃): δ ϭ

54 H), 1.20 (m, 18 H), 0.90 (m, 3 H) ppm. ¹³C NMR (100.5 MHz,

163.96, 163.90, 163.84, 163.06 (12 C), 145.47, 145.28, 144.91,

room temp., CDCl₃): δ ϭ 163.74, 163.13, 163.03, 162.97 (12 C),

144.69, 144.47, 144.26, 144.03, 143.41, 142.90, 142.60, 142.50,

156.07, 156.03 (6 C), 145.50, 145.34, 145.11, 144.83, 144.56, 144.35,

142.43, 142.16, 141.64, 140.94, 140.88 (48 C, C₆₀sp²), 71.69, 71.55

144.21, 141.88, 141.76, 141.00, 140.88 (48 C, C₆₀sp²), 79.08 (6 C),

(6 C), 70.31, 70.24, 70.02, 69.90, 69.80, 69.66, 69.55, 69.46, 69.41,

71.16, 70.72 (6 C), 70.33, 70.16, 70.13, 69.47, 69.44, (30 C), 66.96,

68.35, 68.13, 67.96 (42 C), 67.00, 66.56 (8 C), 53.21 (3 C), 46.92 (3

C), 39.90, 39.74 (6 C), 37.21, 37.15 (6 C), 29.67, 29.28, 29.24, 28.91,

28.79, 28.43, 26.31, 26.10, 25.69 (30 C) ppm. IR (KBr): ν˜ ϭ 3442,

2926, 1741, 1682, 1558, 1541, 1523, 1458, 1434, 1385, 1275, 1206,

66.48 (6 C), 51.89 (3 C), 46.79 (3 C), 40.29 (12 C), 29.27, 29.06,

28.80, 28.59, 26.44, 25.61 (12 C), 28.44 (6 C) ppm. IR (KBr): ν˜ ϭ

3420, 2926, 2857, 1746, 1694, 1521, 1456, 1385, 1367, 1258, 1172,

1105, 710, 524 cm^Ϫ1. UV/Vis (CH₂Cl₂): λ_max.ϭ 243.5, 273 (sh),

1179, 1131, 837, 802, 723, 538, 522 cm^Ϫ1. UV/Vis (H₂O, pH ϭ 7.2):

284 (sh), 320.5, 336.5 nm. MS (FAB): m/z ϭ 3068 [M^ϩϩ Na],

λ_max.ϭ 214.5, 245.5, 271, 282.5, 319, 337 nm. MS (FAB): m/z ϭ

2946 [M^ϩϪ Boc], 2889 [M Ϫ Boc Ϫ tBu]^ϩ, 2845 [M^ϩϪ 2 Boc],

2878 [M^ϩ], 2371, 1440, 720 [C₆₀^ϩ].

2745 [M^ϩϪ 3 Boc], 2645 [M^ϩϪ 4 Boc], 2545 [M^ϩϪ 5 Boc], 2445

[M^ϩϪ 6 Boc]. C₁₆₈H₁₈₆N₁₂O₄₂(3045.33): calcd. C 66.26, H 6.16,

tert-Butyl Ester [3:3]-Hexakisadduct 39 and [3:3]-Hexakisadduct

Amphiphile 37: Trisadduct 18 (49.90 mg, 0.037 mmol, 1.0 equiv.)

N 5.52; found C 65.65, H 6.02, N 5.43.

Hexaammonium Trifluoroacetate Amphiphile 31: The hexaam-

monium trifluoroacetate 31 was obtained (76.25 mg, 95% yield)

from the deprotection of 27 (100 mg) using an excess of TFA in

CH₂Cl₂. ¹H NMR (400 MHz, room temp., CD₃OD): δ ϭ 4.78 (m,

was treated in degassed dry toluene (20 mL) with DMA (45.60 mg,

6 equiv.), malonate 38 (74.70 mg, 6 equiv.), CBr₄(73.20 mg, 6

equiv.) and DBU (66 ꢀL, 12 equiv., diluted in 7 mL of toluene).

After purification by FC {SiO₂; toluene/ethyl acetate, 9:1 [R_f(39) ϭ

3 H), 4.60 (m, 3 H), 4.14 (m, 3 H), 3.99 (m, 3 H), 3.86 (m), 0.15] to 8:2 [R_f(39) ϭ 0.45]}, a bright yellow solid (39) was obtained

3.73Ϫ3.40 (m, 60 H), 3.15 (m, 12 H), 1.80Ϫ1.20 (m, 33 H),), 0.90 and dried in high vacuum (64.70 mg, 69.8%). The cleavage of the

(m, 3 H) ppm. ¹³C NMR (100.5 MHz, room temp., CD₃OD): δ ϭ

tert-butyl esters was carried out in toluene (15 mL) with TFA

165.03, 164.82, 164.56, 164.01 (12 C), 146.81, 146.40, 145.92, (3 mL) at room temp. After stirring for 6 h, the solvent was evapo-

1998

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1983Ϫ2001

Amphiphilic [5:1]- and [3:3]-Hexakisadducts of C₆₀

FULL PAPER

rated and the completeness of the deprotection confirmed by ¹H

NMR (quantitative yield of 37).

C), 67.05, 66.32 (12 C), 48.65 (6 C), 46.86, 46.81, 45.51 (6 C), 32.16

(6 C), 29.36, 29.27, 28.89 (12 C), 28.04 (18 C), 26.46, 25.68 (6 C),

24.32, 24.22, 24.15 (6 C), 18.42 (6 C) ppm. IR (KBr): ν˜ ϭ 3406,

2976, 2933, 2857, 1743, 1677, 1655, 1526, 1458, 1384, 1369, 1263,

1218, 1153, 1079, 1017, 994, 847, 759, 714, 540, 528 cm^Ϫ1. UV/Vis

(CH₂Cl₂): λ_max.ϭ 242, 271, 282, 317, 335 nm. MS (FAB): m/z ϭ

2942 [M]^ϩ, 2886 [M Ϫ tBu]^ϩ, 2607 [M Ϫ 6 tBu]^ϩ, 720 [C₆₀]^ϩ.

1

39: H NMR (400 MHz, room temp., CDCl₃): δ ϭ 4.67 (m, 6 H),

4.40Ϫ4.20 (m, 12 H), 4.15 (m, 3 H), 4.00 (m, 3 H), 2.31 (m, 12 H),

1.98 (m, 12 H), 1.78 (m, 3 H), 1.60 (m, 6 H), 1.49 (m, 6 H), 1.44

(s, 54 H), 1.16 (m, 18 H), 0.81 (m, 3 H) ppm. ¹³C NMR (100.5

MHz, room temp., CDCl₃): δ ϭ 171.70 (6 C), 163.62, 163.61,

163.43, 163.13 (12 C), 146.51, 145.93, 145.75, 145.71, 145.32,

144.94, 144.91, 142.01, 141.90, 141.64, 141.61, 141.02, 140.80,

140.60, 140.52 (48 C, C₆₀, sp²), 80.61 (6 C), 69.21, 69.12 (12 C),

C₁₆₈H₁₆₈N₆O₄₂(2943.15): calcd. C 68.56, H 5.75, N 2.86; found C

68.12, H 5.79, N 2.79.

1

40: H NMR (300 MHz, room temp., [D₈]THF): δ ϭ 8.41 (s br., 6

66.90, 66.21 (6 C), 66.03, 65.92 (6 C), 46.71, 45.33 (6 C), 31.73 (6 H), 7.53 (m, 6 H), 4.69 (m, 6 H), 4.66 (m, 6 H), 4.45 (t, ³J ϭ

C), 29.34, 29.22, 28.82, 28.20 (12 C), 28.13 (18 C), 26.33, 25.62 (6

6.05 Hz, 6 H), 4.30 (m, 12 H), 4.05 (m, 3 H), 3.93 (m, 3 H), 2.29

(t, J ϭ 6.10 Hz, 12 H), 1.99 (m, 12 H), 1.76 (m, 3 H), 1.54 (m, 6

3

C), 23.91 (6 C) ppm. UV/Vis (CH₂Cl₂): λ_max.ϭ 245, 270, 281, 316,

334 nm. MS (FAB): m/z ϭ 2516 [M]^ϩ, 2460 [M Ϫ tBu]^ϩ, 2181, H), 1.51 (m, 6 H), 1.32 (d, ²J ϭ 7.15 Hz, 18 H), 1.19 (m, 18 H),

2077, 720 [C60]^ϩ. C150H138O36 (2516.60): calcd. C 71.58 H 5.53; 0.80 (m, 3 H) ppm. ¹³C NMR (75 MHz, room temp., [D₈]THF):

found C 70.72 H 5.21.

δ ϭ 174.58 (6 C), 172.26, 171.98 (6 C), 164.08, 164.00, 163.76,

163.76, 163.31 (12 C), 147.24, 146.85, 146.71, 146.57, 146.28,

145.88, 145.80, 145.70, 145.68, 143.08, 142.99, 142.65, 142.59,

141.97, 141.86, 141.64 (48 C, C₆₀sp²), 70.36, 70.27 (12 C), 68.21,

66.36 (12 C), 48.51, 48.45 (6 C), 47.94, 46.77 (6 C), 32.41 (6 C),

30.44, 30.21, 29.75 (12 C), 27.48, 26.51 (6 C), 18.23, 18.18 (6 C)

ppm. IR (KBr): ν˜ ϭ 3382, 3074, 2934, 2857, 2556, 1745, 1635,

1541, 1458, 1384, 1354, 1263, 1217, 1167, 1079, 1042, 1020, 898,

806, 754, 713, 667, 538, 527 cm^Ϫ1. MS (FAB): m/z ϭ 2607 [M ϩ

37: ¹H NMR (400 MHz, room temp., [D₈]THF): δ ϭ 10.92 (br.,

12 H), 4.70 (m, 3 H), 4.63 (m, 3 H), 4.38Ϫ4.22 (m, 12 H), 4.07 (m,

3 H), 3.96 (m, 3 H), 2.35 (m, 12 H), 1.96 (m, 12 H), 1.78 (m, 6 H),

1.53 (m, 9 H), 1.40 (m, 3 H), 1.21 (m, 18 H), 0.85 (m, 3 H) ppm.

¹³C NMR (100.5 MHz, room temp., [D₈]THF): δ ϭ 174.01, 173.92

(6 C), 164.02, 163.91, 163.82, 163.33 (12 C), 147.31, 146.80, 146.61,

146.40, 145.94, 145.91, 145.71, 143.02, 142.73, 142.11, 141.90,

141.81, 141.64 (48 C, C₆₀, sp²), 70.44, 70.34, 70.23 (12 C), 66.81,

66.71, 66.38 (12 C), 47.89, 46.69 (6 C), 30.64, 30.55, 30.44, 30.24,

29.78, 29.73, 27.52, 26.61, 26.42, 25.79, 25.65, 25.61, 25.46, 25.41,

H]^ϩ, 2562 [M Ϫ CO₂]^ϩ, 2477, 720 [C₆₀]^ϩ. UV/Vis (H₂O): λ_max.

ϭ

212.5, 244, 271.5, 280, 316, 337 nm.

24.84, 24.79 (24 C), 23.60 (6 C) ppm. IR (KBr): ν˜ ϭ 3418, 2931, N-(

2857, 1743, 1629, 1572, 1459, 1405, 1355, 1260, 1219, 1178, 1117, N-(

L

-Alanyl)-

L

-alanine tert-Butyl Ester [3؉3]-Hexakisadduct 45 and

-alanine [3؉3]-Hexakisadduct 47: The coupling of

L-Alanyl)-

L

1075, 997, 955, 802, 713, 540, 525 cm^Ϫ1. UV/Vis (H₂O): λ_max.

ϭ

N-(-alanyl)--alanine tert-butyl ester (346.2 mg, 12 equiv.) with the

hexaacid 37 (273.9 mg, 1 equiv.) was carried out according to the

214, 246, 272, 281, 316, 334 nm. MS (FAB): m/z ϭ 2319 [M ϩ 6

Na]^ϩ, 2250 [M ϩ 3 Na]^ϩ, 2202 [M ϩ Na]^ϩ, 2179 [M]^ϩ, 2076, procedure for the synthesis of 42 by activation with DCC (12

720 [C₆₀]^ϩ.

equiv.) and NHS (12 equiv.). Purification by flash chromatography

(SiO₂; CH₂Cl₂/MeOH, 96:4) gave the [3ϩ3]-hexakisadduct 45 as a

dark-yellow solid [326.7 mg, 77%; purity (HPLC) ϭ 99%]. The

cleavage of the tert-butyl groups of the [3ϩ3]-hexakisadduct 45

(175.1 mg, 0.052 mmol) was achieved in CH₂Cl₂(20 mL) using

TFA (1.5 mL). The mixture was stirred overnight at room temp.

before the solvent and TFA were evaporated in vacuo; the peptido

amphifullerene hexakisadduct 47 was obtained (157.6 mg,

0.052 mmol) as a yellow solid in quantitative yield.

L-Alanine tert-Butyl Ester [3؉3]-Hexakisadduct 42 and L-Alanine

[3؉3]-Hexakisadduct 40: Hexaacid 37 (351.9 mg, 0.161 mmol, 1

equiv.), -alanine tert-butyl ester (41) hydrochloride (361.3 mg,

1.99 mmol, 12 equiv.), Et₃N (270 µL), and NHS (223.2 mg, 12

equiv.) were dissolved in a mixture of dry THF (50 mL) and dry

DMF (20 mL) and the resulting solution was cooled to 0 °C. DCC

(371.8 mg, 12 equiv.) in dry THF (15 mL) was slowly added and

the mixture was stirred at room temp. for 3 d. The dicyclohexylurea

that formed was filtered off and the filtrate was concentrated in

vacuo. The remaining residue was dissolved in EtOAc (100 mL)

1

45: H NMR (400 MHz, room temp., CDCl₃): δ ϭ 7.52 (br. d, 3

H), 7.33 (br. d, 3 H), 4.67 (m, 12 H), 4.36 (m, 12 H), 4.13 (m, 3

and washed with 10% aqueous citric acid, 0.5  aqueous KHCO₃, H), 3.98 (m, 3 H), 2.66, 2.35 (m, 12 H), 2.04 (m, 12 H), 1.77 (m, 3

2

and brine. The organic layer was dried (MgSO₄) and the EtOAc

was removed in vacuo. Flash chromatography (SiO₂; CH₂Cl₂/

H), 1.52 (m, 12 H), 1.45 (s, 54 H), 1.39 (d, J ϭ 7.15 Hz, 18 H),

2

1.36 (d, J ϭ 7.05 Hz, 18 H), 1.15 (m, 18 H), 0.81 (m, 3 H) ppm.

MeOH, 97:3) afforded 42 as a dark-yellow solid [307.5 mg, 73%; ¹³C NMR (100.5 MHz, room temp., CDCl₃): δ ϭ 172.38, 172.27

purity (HPLC) ϭ 99%]. The cleavage of the tert-butyl groups of

the [3ϩ3]-hexakisadduct 42 (100 mg, 0.034 mmol) was achieved

using TFA (1.5 mL) in CH₂Cl₂(20 mL). The mixture was stirred

at room temp. for 8 h before the solvent and TFA were removed in

vacuo; the alanino amphifullerene 40 (88.5 mg, 0.034 mmol) was

obtained as a yellow solid in quantitative yield.

(12 C), 171.95, 171.66 (6 C), 163.75, 163.51, 163.48, 163.12 (12

C), 146.32, 145.78, 145.72, 145.19, 145.10, 144.92, 142.13, 141.90,

141.58, 141.39, 140.95, 140.86, 140.74, 140.57 (48 C, C₆₀sp²), 81.73

(6 C), 69.24, 69.15 (12 C), 67.05, 66.31 (12 C), 48.80, 48.54 (12 C),

46.77, 45.31 (6 C), 31.76 (6 C), 29.18, 28.81 (12 C), 27.94 (18 C),

26.35, 25.60 (6 C), 24.13, 23.96, 23.87 (6 C), 18.29, 18.15, 18.09,

18.04 (12 C) ppm. IR (KBr): ν˜ ϭ 3388, 3315, 3071, 2977, 2934,

2858, 1744, 1655, 1527, 1456, 1383, 1369, 1263, 1218, 1157, 1079,

1017, 993, 847, 759, 714, 540, 528 cm^Ϫ1. MS (FAB): m/z ϭ 3370

[M]^ϩ, 3314 [M Ϫ tBu]^ϩ, 3113, 720 [C₆₀]^ϩ. UV/Vis (CH₂Cl₂):

λ_max.ϭ 246, 271.5, 281.5, 317.5, 336.5 nm. C₁₈₆H₁₉₈N₁₂O₄₈

(3369.61): calcd. C 66.30, H 5.92, N 5.92; found C 65.77, H 5.74,

N 5.85.

1

42: H NMR (400 MHz, room temp., CDCl₃): δ ϭ 6.68 (m, 6 H),

4.64 (m, 6 H), 4.44 (m, 6 H), 4.33 (m, 12 H), 4.10 (m, 3 H), 3.96

(m, 3 H), 2.33 (m, 12 H), 2.03 (m, 12 H), 1.73 (m, 3 H), 1.57 (m,

2

6 H), 1.50 (m, 6 H), 1.42 (s, 54 H), 1.33 (d, J ϭ 7.08 Hz, 18 H),

1.13 (m, 18 H), 0.78 (m, 3 H) ppm. ¹³C NMR (100.5 MHz, room

temp., CDCl₃): δ ϭ 172.10 (6 C), 171.05 (6 C), 163.48, 163.26,

162.86 (12 C), 146.07, 146.0, 145.74, 145.67, 145.57, 145.52, 145.47,

144.94, 144.70, 141.96, 141.75, 141.37, 141.28, 141.22, 140.82,

47: ¹H NMR (300 MHz, room temp., [D₆]DMSO): δ ϭ 8.12 (d,

140.70, 140.56, 140.51 (48 C, C₆₀sp²), 81.64 (6 C), 69.20, 69.16 (12 ²J ϭ 7.69 Hz, 6 H), 8.03 (d, ²J ϭ 7.68 Hz, 6 H), 4.75 (m, 6 H),

Eur. J. Org. Chem. 2004, 1983Ϫ2001

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

1999

A Hirsch et al.

4.64 (m, 6 H), 4.30 (m, 12 H), 4.18 (m, 6 H), 3.99 (m, 6 H), 2.19 127.32 (6 C), 70.30 (12 C), 66.40 (12 C), 49.27 (12 C), 47.94, 46.75

FULL PAPER

2

(m, 12 H), 1.82 (m, 6 H), 1.52 (m, 9 H), 1.25 (d, J ϭ 7.04 Hz, 18

(6 C), 38.23 (6 C), 32.35, 30.22, 29.75, 27.46, 26.54 (24 C), 18.58

H), 1.17 (d, ²J ϭ 7.06 Hz, 18 H), 1.06 (m, 18 H), 0.50 (m, 3 H) (6 C) ppm. IR (KBr): ν˜ ϭ 3383, 3074, 2936, 2858, 1742, 1647,

ppm. ¹³C NMR (75 MHz, room temp., [D₆]DMSO): δ ϭ 173.95 (6 1541, 1458, 1384, 1265, 1218, 1169, 1080, 1045, 1017, 992, 904,

C), 172.10 (6 C), 170.79, 170.66 (6 C), 162.63, 162.13, 161.79 (12

810, 758, 714, 668, 540, 528 cm^Ϫ1. UV/Vis (H₂O): λ_max.ϭ 212.5,

C), 145.74, 145.67, 144.88, 144.43, 144.01, 143.96, 143.80, 141.66, 244, 271.5, 282, 320, 337 nm. MS (FAB): m/z ϭ 3055 [M ϩ Na]^ϩ,

141.52, 141.46, 141.27, 140.47, 140.32, 140.13 (48 C, C₆₀sp²), 3033 [M ϩ H]^ϩ, 2854, 2833, 720 [C₆₀]^ϩ.

69.04, 68.85 (12 C), 66.72, 66.65, 65.76 (12 C), 47.64, 47.29 (12 C),

46.88, 45.57 (6 C), 30.97 (6 C), 29.23, 28.59, 28.12 (12 C), 26.08 (6

C), 24.84, 24.03 (6 C), 18.10, 16.99 (12 C) ppm. IR (KBr): ν˜ ϭ

Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft

(AH, 468/13-1), the Fond der Chemischen Industrie, and C Sixty

Inc.

3306, 3064, 3030, 2934, 2858, 2548, 1744, 1649, 1532, 1455, 1384,

1352, 1264, 1217, 1170, 1079, 1019, 992, 901, 810, 755, 738, 713,

701, 669, 539, 527 cm^Ϫ1. UV/Vis (H₂O): λ_max.ϭ 212, 243.5, 272,

281, 318, 336 nm. MS (FAB): m/z ϭ 3512 [M ϩ Na]^ϩ, 3489 [M ϩ

H]^ϩ, 3213, 720 [C₆₀]^ϩ.

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M. Brettreich, S. Burghardt, C. Böttcher, T. Bayerl, S. Bayerl,

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46 and N-(

L

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L

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L-Alanyl)-

L-phenylalanine [3؉3]-Hexakisadduct 48: The

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A. P. Maierhofer, M. Brettreich, S. Burghardt, O. Vostrowsky,

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described for the [3ϩ3]-hexakisadduct 53 by activation with DCC

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tected [3ϩ3]-hexakisadduct 46 as a dark-yellow solid [382.6 mg,

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tecting groups of 46 (172.1 mg, 0.045 mmol) were cleaved off with

THF/CH₂Cl₂as described in the cases above and the [3ϩ3]-hexaki-

sadduct peptido derivative 48 was obtained as a yellow solid in

quantitative yield (157.0 mg, 0.045 mmol).

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[9a]

philic fullerenes, see:

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46: ¹H NMR (400 MHz, room temp., CDCl₃): δ ϭ 7.21 (m, 18 H),

7.14 (m, 18 H), 7.06 (br. d, 6 H), 4.68 (m, 6 H), 4.60 (m, 12 H),

4.28 (m, 12 H), 4.12 (m, 3 H), 3.96 (m, 3 H), 3.03 (m, 12 H), 2.28

(m, 12 H), 2.00 (m, 12 H), 1.77 (m, 6 H), 1.53 (m, 9 H), 1.35 (d,

²J ϭ 7.01 Hz, 18 H), 1.15 (m, 18 H), 0.78 (m, 3 H) ppm. ¹³C NMR

(100.5 MHz, room temp., CDCl₃): δ ϭ 172.28, 172.20 (12 C),

171.75, 171.61, 171.54 (6 C), 163.68, 163.53, 163.47, 163.44, 163.08

(12 C), 146.27, 146.25, 145.81, 145.79, 145.74, 145.69, 145.16,

145.12, 144.89, 144.86, 142.12, 141.88, 141.86, 141.58, 141.52,

141.39, 141.35, 140.94, 140.92, 140.87, 140.75, 140.63, 140.61 (48

C, C₆₀sp²), 136.12 (6 C), 129.38 (12 C), 128.29 (12 C), 126.88 (6

C), 82.10 (6 C), 69.25, 69.17 (12 C), 67.05, 66.39, 66.30 (12 C),

48.59 (12 C), 46.77, 45.36 (6 C), 37.93, 37.90 (6 C), 31.79, 31.76 (6

C), 29.23, 29.16, 28.78, 27.89 (12 C), 26.33, 25.57 (6 C), 24.06,

23.95, 23.87 (6 C), 18.16, 17.96 (6 C) ppm. IR (KBr): ν˜ ϭ 3388,

3309, 3062, 3029, 2976, 2933, 2857, 1744, 1652, 1524, 1455, 1369,

1263, 1219, 1156, 1079, 1044, 1017, 992, 844, 738, 714, 702, 539,

528 cm^Ϫ1. UV/Vis (CH₂Cl₂): λ_max.ϭ 244, 270.5, 281.5, 318, 337.5

nm. MS (FAB): m/z ϭ 3826 [M ϩ H]^ϩ, 3770 [M Ϫ tBu]^ϩ, 3495 [M

Ϫ 6 tBu]^ϩ, 720 [C₆₀]^ϩ. C₂₂₂H₂₂₂N₁₂O₄₈(3826.19): calcd. C 69.69, H

5.85, N 4.39; found C 69.31, H 5.81, N 4.18.

B. Heinrich, J.-F. Nierengarten, Langmuir 2002, 18,

[9b]

2908Ϫ2913.

D. Felder, M. G. Nava, M. Del Pilar Carreon,

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2

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4.06 (m, 3 H), 3.92 (m, 3 H), 3.13 (dd, J ϭ 12.5, J ϭ 6.30 Hz, 6

2

H), 2.97 (dd, J ϭ 12.5, J ϭ 6.30 Hz, 6 H), 2.22 (m, 12 H), 1.92

(m, 12 H), 1.73 (m, 6 H), 1.51 (m, 9 H), 1.38 (m, 3 H), 1.23 (m, 36

H), 0.85 (m, 3 H) ppm. ¹³C NMR (75 MHz, room temp.,

[D₈]THF): δ ϭ 173.36, 173.24, 173.06 (6 C), 172.39, 172.36, 172.14

(12 C), 164.08, 164.00, 163.83, 163.79, 163.34, 163.31 (12 C),

147.23, 147.21, 146.92, 146.90, 146.70, 146.67, 146.59, 146.32,

146.30, 145.99, 145.92, 145.84, 145.72, 145.69, 143.11, 143.01,

142.99, 142.70, 142.62, 142.55, 142.57, 142.00, 141.91, 141.85,

141.72 (48 C, C₆₀sp²), 138.17 (6 C), 130.36 (12 C), 128.96 (12 C),

[11]

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[13]

[14]

2000

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.eurjoc.org

Eur. J. Org. Chem. 2004, 1983Ϫ2001

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Received October 16, 2003

Eur. J. Org. Chem. 2004, 1983Ϫ2001

www.eurjoc.org

 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

2001

Article Doi

Amphiphilic [5:1]- and [3:3]-hexakisadducts of C60

DOI: 10.1002/ejoc.200300663

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Article abstract of DOI:10.1002/ejoc.200300663

Full text of DOI:10.1002/ejoc.200300663

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