An approach to nanobioparticles - Synthesis and characterization of fulleropeptides

Article abstract of DOI:10.1002/ejoc.201200274

Two sets of new peptides incorporating fulleropyrrolidine units - Fp-GABA_n-Gly_m-OtBu - have been designed, synthesized and completely characterized. In the first series the chain contained only GABA (γ-aminobutyric) residues, whereas in the second one glycine moieties were also inserted as well as GABA. Most of the target compounds were prepared by DCC/DMAP-assisted coupling of previously synthesized GABA-containing fulleropyrrolidinic acid and corresponding C-protected small peptides, although for two fulleropeptides [3+2] cycloadditions of azomethine ylides to C ₆₀ were employed. All new compounds were characterized by standard spectroscopic methods. Complete assignments of peptide spin systems were achieved by extensive NMR analysis (¹H, ¹³C, H,H-COSY, HSQC, HMBC and TOCSY). Copyright

Full text of DOI:10.1002/ejoc.201200274

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DOI: 10.1002/ejoc.201200274
An Approach to Nanobioparticles – Synthesis and Characterization of
Fulleropeptides
Mira Bjelakovic´,[a] Nina Todorovic´,[a] and Dragana Milic´*[b]
Keywords: Synthetic methods / Peptidomimetics / Fullerenes / Fulleropeptides / Nanoparticles
Two sets of new peptides incorporating fulleropyrrolidine
units – Fp-GABAn-Glym-OtBu – have been designed, synthe-
sized and completely characterized. In the first series the
chain contained only GABA (γ-aminobutyric) residues,
whereas in the second one glycine moieties were also in-
serted as well as GABA. Most of the target compounds were
prepared by DCC/DMAP-assisted coupling of previously
synthesized GABA-containing fulleropyrrolidinic acid and
corresponding C-protected small peptides, although for two
fulleropeptides [3+2] cycloadditions of azomethine ylides to
C60 were employed. All new compounds were characterized
by standard spectroscopic methods. Complete assignments
of peptide spin systems were achieved by extensive NMR
analysis (1H, 13C, H,H-COSY, HSQC, HMBC and TOCSY).
derivatives, the interactions of which with each other, with
other molecules or with living organisms are governed by
the properties of the introduced subunits. Such pro-
grammed functionalization can also make the fullerene core
much more soluble, thus overcoming the main limitation to
its application.
Introduction
Because of its interesting physical and chemical proper-
ties C60 represents an attractive research target, but its wide-
spread application is still limited by its quite low solubility
in water and almost all organic solvents.[1] In order to in-
crease fullerene solubility and to expand the scope of its
applications, two methodologically different efforts have
been developed. The first involves noncovalent encapsul-
ation of C60 into cyclodextrins, calixarenes,[2] phospholip-
ids,[3] micelles[4] or liposomes,[4] affording soluble complexes
with no changes in the physical properties of the carbon
core. The second approach, functionalization of C60, re-
mains the more commonly used way to improve solubility.
Because of the unique properties of C60, many research
domains – such as molecular machines,[9] new materials,
bio-jymimics and medicinal chemistry – include a focus on
fullero derivatives. Liquid crystal self-organization has been
observed in some bis-dendritic fulleropyrrolidines,[10]
whereas photoinduced electron transfer occurred in mono-
fulleropyrolidines bearing dendritic and ferrocene[11] or
porphyrin[12] subunits. Organofullerenes also showed prom-
ise in in vitro photodynamic treatment of human carcinoma
cells[13] and DNA photocleavage,[14] and cell membrane
protection might be expected due to the antioxidant proper-
ties.[15] The versatility of fullero derivatives is also illustrated
by their ability to act as phospholipid mimetics[16] and drug
carriers.[17] It is important to note that the fullerene deriva-
tives usually exhibit lower toxicities than typical drugs.[18]
Amino acids and peptides are crucial building blocks of
all living organisms and their conjugation with fullerene at-
tracts a lot of scientific interest.[19–22] Syntheses of C60-con-
taining amino acids are mainly based on different addition
reaction of suitable substrates to the fullerene (cyclopropan-
ation,[23–25] [3+2][26–28] and [4+2] cycloadditions[29–31]). The
biggest unnatural amino acid so far reported, fulleroproline,
was obtained by 1,3-dipolar cycloaddition of an azometh-
ine ylide to C60,[32] whereas a methanofullerene-substituted
amino acid prepared by cyclopropanation of C60 was the
starting material for the first fulleropeptide.[33]
[5]
Direct attachment of polar substituents to C60 leads
mainly to complex mixtures containing numerous isomers
and compounds possessing different numbers of hetero-
atomic addends. In contrast, however, carbon-carbon bond-
forming modifications of fullerenes, particularly cycload-
ditions,[6] take place much more selectively, affording well-
defined products. The reactions mostly used for this pur-
pose are SNi cyclopropanation (Bingel’s reaction)[7] and
[4+2][5] and [3+2] cycloadditions.[8] Functionalization also
offers the potential for significant change in the physico-
chemical properties of derivatives, also widening the scope
of their potential applications. In addition, the nanometer
size of C60 is large enough to allow the synthesis of “smart”
[a] ICTM – Center for Chemistry, University of Belgrade,
Studentski trg 12–16, 11158 Belgrade, Serbia
[b] Faculty of Chemistry University of Belgrade,
Studentski trg 12–16, 11158 Belgrade, Serbia
Fax: +381-112636061
E-mail: dmilic@chem.bg.ac.rs
Homepage: www.chem.bg.ac.rs/osoblje/30-en.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200274.
The synthesis of fulleropeptides is mainly based on the
coupling of various fullerene-containing amino acids with
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M. Bjelakovic´, N. Todorovic´, D. Milic´
FULL PAPER
corresponding peptides under solution[33–37] or solid-
phase[20,28,38] conditions. In previous research we showed
that fulleropyrrolidinic acid 1 (Figure 1), incorporating γ-
aminobutyric acid (GABA), could be easily and efficiently
synthesized and also further transformed into steroidal es-
ters.[15] Having a good precursor to hand, we anticipated
that its coupling with amino acids and peptides could con-
tribute to studies of fullerene-biomolecule nanoparticles.
Designed compounds with improved solubility, even in the
form of esters, represent good candidates for further investi-
gation of fullerene-based bioactive compounds. Moreover,
suitably positioned amide bonds containing both 1,4- and
1,6-carbonyl functions allow the possibility for additional
examination of potential hydrogen-bond-induced host–
guest interactions, as well as supramolecular and/or hierar-
chical self-organization. Thanks to the presence of the ter-
minal bulky fullerene subunit, incorporation of designed
compounds into more complex systems, such as mechani-
cally interlocked structures, might also be expected. For
that purpose, the assignment of all spin-active nuclei of the
peptide backbone is considered a helpful tool able to facili-
tate further studies.
Results and Discussion
Chemistry
Most of the target compounds (nine out of 11) were suc-
cessfully obtained from the previously prepared GABA-
containing fulleropyrrolidinic acid (Fp-GABA-OH, 1) and
corresponding amines by a standard DCC/DMAP amid-
ation procedure[39] (Scheme 1). Unexpectedly though,
attempts to synthesize fulleropeptides 4 and 7 by this ap-
proach (with H-Gly-OtBu and H-GABA-Gly-OtBu) failed.
No improvement was observed on prolonging the reaction
time to 36 h, on increasing the reaction temperature from
ambient to reflux, or with use of an excess of the appropri-
ate peptidic amine. At the same time, these amino com-
pounds easily underwent coupling with DCC-activated
non-fullerenic acids (see Scheme 1, the preparation of the
peptides 14, 30 and 32). As a consequence, an additional
approach involving the generation of peptidic azomethine
ylides and subsequent [3+2] cycloaddition to C60 was de-
signed (Scheme 1).
Peptide Coupling with Fp-GABA-OH
Generally, step-by-step peptide elongation was achieved
in good yields (59–77%) by treatment of the amino acid
tert-butyl ester with the corresponding Z-protected amino
acid with activation with DCC and DMAP. The obtained
fully and orthogonally protected dipeptide was selectively
and quantitatively deprotected by catalytic hydrogenation,
to afford the C-protected compound as a building block
for the next elongation step. Finally, peptides containing a
GABAx-Glyy (x = 0–2, y = 0–3) moiety underwent DCC/
DMAP-mediated coupling with Fp-GABA-OH (1) to pro-
vide C-protected fulleropeptides in satisfactory yields (57–
66%).
The target fulleropeptides 2, 3, 5, 6 and 8–12 were ob-
tained by the pathway shown in Scheme 1. The C-protected
homo-peptides H-(Gly)2-OtBu (15) and H-(Gly)3-OtBu
(17) were prepared from glycine (13) and subsequently cou-
pled with fulleropyrrolidinic acid 1 to afford fulleropeptides
Fp-GABA-Gly2-OtBu (5) and Fp-GABA-Gly3-OtBu (6),
respectively. Dipeptide 15 was transformed into hetero-tri-
peptide H-GABA-(Gly)2-OtBu (19) by use of Z-GABA (26)
in a further chain elongation process and then into tetra-
peptide H-(GABA)2-(Gly)2-OtBu (21, via fully protected
compounds 18 and 20, respectively). In the final steps, the
obtained peptides were coupled with GABA-containing
fulleropyrolidinic acid 1 (Fp-GABA-OH) by a standard
DCC/DMAP procedure to give the two remaining Gly2-
Figure 1. Target fulleropeptides 2–12 derived from fulleropyrrolid-
inic acid 1.
Here we present the synthesis and complete characteriza- containing fulleropeptides 8 and 11 (19 Ǟ 8 and 21Ǟ 11).
tion of two sets of new fulleropeptides: in the first series Analogously, the first coupling cycle of homo-tripeptide
the side chains consist of repeating GABA units (2 and 3, H-(Gly)3-OtBu (17) and Z-GABA (26) gave fully protected
Figure 1) and in the second, in addition to GABA, the sim- tetrapeptide 22, which after benzyl group removal afforded
plest natural amino acid – glycine – was also incorporated, hetero-tetrapetide 23. The second coupling cycle led to the
affording nine new fulleropyrrolidinic peptides Fp-GABAn- formation of hetero-pentapeptide 25 (via fully protected
Glym-OtBu (n = 1–3, m = 0–2; 4–12, Figure 1).
compound 24). After coupling with Fp-GABA-OH (1), the
2
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Synthesis and Characterization of Fulleropeptides
Scheme 1. Synthesis of fulleropeptides 2–12.
two remaining Gly3-containing fulleropeptides 9 and 12 H-GABA-OtBu (27), followed by catalytic hydrogenolysis
were obtained (23 Ǟ 9 and 25 Ǟ 12). and coupling with Fp-GABA-OH (1), gave fulleropeptide
For the preparation of the all-GABA-containing fullero- Fp-GABA3-OtBu (3).
peptides, Z-GABA (26) was transformed into tert-butyl 4-
The simplest fully protected hetero-dipeptide was pre-
aminobutanoate (27),[15] which was subsequently coupled pared by employing Z-GABA (26) and H-Gly-OtBu as
with fulleroacid 1 to give fulleropeptide Fp-GABA2-OtBu starting materials and subsequently transformed into H-
(2). DCC/DMAP-assisted coupling of Z-GABA (26) and GABA-Gly-OtBu (31). A second DCC/DMAP-mediated
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M. Bjelakovic´, N. Todorovic´, D. Milic´
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cycle with Z-GABA (26), followed by catalytic hydro- vided independent verification of 1H and 13C NMR assign-
genolysis, led to tripeptide H-(GABA)2-Gly-OtBu (33), ments made with the other methods.
which after coupling with fulleroacid 1 afforded fullero-
peptide Fp-GABA3-Gly-OtBu (10).
NMR Spectroscopy
All fullero compounds gave the expected 1H NMR spec-
tra, with mainly broad triplets in the downfield region (δ =
6.15–7.99 ppm) attributable to amide protons, a pyrrolid-
inic strong singlet at δ = 4.4 ppm and doublets or triplets
[3+2] Cycloadditions of Azomethine Ylides to C60
Although the GABA-containing fulleropyrrolidinic acid
Fp-GABA-OH (1) was successfully incorporated into nine
new fulleropyrrolidinic peptides (and previously also into
fullerosteroidal esters[15]), attempted amidation either with
H-Gly-OtBu or with H-GABA-Gly-OtBu by the standard
DCC/DMAP procedure failed. On the other hand, both
amino compounds had successfully been employed as
building blocks elsewhere in the peptide elongation process.
To overcome the problem and to complete the set of target
compounds, another synthetic approach based on [3+2] cy-
cloadditions of azomethine ylides to C60 was attempted
(Scheme 1). Intermediates 31 and 33, previously prepared
during the synthesis of the fulleropeptide 10, were used for
the formation of peptidic azomethine ylides. Mono-N-alkyl-
ation of the simplest hetero-dipeptide H-GABA-Gly-OtBu
(31) with benzyl bromoacetate and subsequent carboxylic
group deprotection afforded the glycino derivative 35. Fur-
ther condensation with formaldehyde and in situ thermal
decarboxylation provided the corresponding peptidic azo-
methine ylide, which smoothly underwent [3+2] cycload-
dition to C60 to give fulleropeptide 4 (Fp-GABA-Gly-
OtBu). The previously prepared tripeptide H-(GABA)2-
Gly-OtBu (33) was analogously transformed into the amino
acid 37 and subsequently into target fulleropeptide 7 (Fp-
GABA2-Gly-OtBu, Scheme 1).
in a very narrow range of δ = 3.91–4.04 ppm (ΔδH
=
0.13 ppm) belonging to glycyl CH2 groups. The three re-
maining GABA methylene groups gave the corresponding
multiplets at ca. 3.2, 2.5 and 2 ppm (N-adjacent, internal,
and CH2 groups next to carbonyl, respectively), whereas the
tert-butyl signal appeared as strong singlet at δ = 1.44–
1.48 ppm.
In the 13C NMR spectra, all peaks, both those belonging
to fulleropyrrolidinic carbons and those belonging to the
peptide chains, were observed. The C2ν-symmetric fuller-
opeptides each exhibited 16 well-resolved lines for 58 sp2
fullerene C atoms in the aromatic region (δ = 136–
155 ppm), which is in accordance with previously obtained
results for GABA-containing fulleropyrrolidinic esters.[15]
The two remaining fullerene C atoms (sp3 Cf-1 and Cf-9;
see Figure 2, e) each resonate in the aliphatic region (δ =
70.44–70.83 ppm), together with the pyrrolidinic CH2 car-
bons (δ = 67.55–67.95 ppm). The most strongly downfield-
shifted aromatic signal (δ = 154.73–155.14 ppm) was as-
signed to fullerene carbons adjacent to the functionalized
6,6-bond (Cf-2, Cf-5, Cf-8 and Cf-10; see Figure 2, e), be-
3
cause its JC,H correlation with the pyrrolidinic signal at
4.4 ppm was observed in the HMBC spectra of all com-
pounds studied (Figure 2, a, d, e). The 13C NMR chemical
shifts of the remaining 54 fullerene carbons were consistent
with fulleropyrrolidine model compound data.[41]
Structure Elucidation
All target compounds gave correct ESI MS spectra with
Assignments of individual resonances belonging to
regard to their chemical structures. Their IR spectra each amino acid spin systems were carried out by comparative
showed strong absorptions at 3228–3311, 1720–1742 and analysis of COSY and TOCSY spectra. Starting from the
1641–1653 cm–1 attributable to the amide NH, the ester CO NH peaks in the downfield region of 6.15–7.99 ppm, corre-
and the amide CO stretching bands, respectively. All com- lations with signals at δ = 3.91–4.04 ppm (doublets or trip-
pounds displayed almost identical absorption behaviour in lets, ΔδH = 0.13) were observed, thus establishing their glyc-
the UV/Vis range: characteristic absorption bands attribut- yl CH2 origins. The GABA protons were established from
able to the fullerene moiety were observed in the 254– TOCSY cross-peaks between amide NH at 6.15–7.33 ppm
260 nm range, whereas peaks belonging to the amide region and triplets at δ = 2.25–2.62 [H-C(2), ΔδH = 0.37], quints
appeared in the 303–306 and 319–325 nm ranges. In ad- at δ = 1.81–2.29 [H-C(3), ΔδH = 0.48] and triplets or quints
dition, a weak sharp peak at 430 nm, typical of fulleropyr- at δ 3.13–3.42 ppm [H-C(4), ΔδH = 0.29]. The 13C NMR
rolidines,[40] was observed in each spectrum. Because of the chemical shifts of the peptidic moieties in all synthesized
potential for incorporation of the synthesized fullero- compounds also appeared in a very narrow range, thus indi-
peptides into more complex structures, such as self-as- cating that the obtained fulleropeptides could be useful as
sembled supramolecular aggregates or nanomolecular ma- a good model system for further structure determination of
chines, complete and unambiguous assignments of all spin- more complex systems. A comparative analysis of spectro-
active nuclei were made. This was achieved by extensive scopic data obtained from different NMR experiments af-
1
NMR analysis, involving H NMR assignments with the forded the following assignments: glycyl methylene signals
aid of COSY and TOCSY spectra, correlation through appeared in the 41.70–43.22 region (Δδc = 1.52), and those
1JC,H values to provide the 13C NMR assignments for pro- belonging to GABA–C(2) and C(3) at 33.15–34.65 (Δδc =
2
3
tonated carbons and correlation through JC,H and JC,H 1.50) and 24.13–26.15 ppm (Δδc = 2.02), respectively. The
values to assign quaternary carbons. This process also pro- appearance of GABA–C(4) peaks in a significantly wider
4
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Synthesis and Characterization of Fulleropeptides
3
Figure 2. Expanded parts of HMBC spectra of compound 12 showing 2J and J connectivities in a) the aliphatic H/C, b) the amide NH/
aliphatic C, c) the amide NH/CO, and d) the aliphatic H/CO regions. e) H,H-COSY and heteronuclear multiple bond correlations in 12.
range (38.24–53.93 ppm, Δδc = 15.69) than GABA–C(2) 172.60–174.29 ppm. The remaining ester carbons (tBu
and C(3) was the consequence of the pyrrolidine ring prox- group) gave the anticipated response at δ = 27.76–28.31 and
imity in compounds 4–6. Detailed regio-comparison of δ = 80.57–82.48 ppm (CH3 and C, respectively). The attri-
chemical shifts showed that GABA–C(4) also resonated in bution of the GABA residue next to the pyrrolidine ring in
1
a quite restricted field range: carbons adjacent to the pyr- each fulleropeptide was made on the basis of the H peak
rolidine ring at 53.24–53.89 ppm (Δδc = 0.65), those form- multiplicity of the γ methylene protons (triplet) and its
ing amide moieties at 38.24–39.46 ppm (Δδc = 1.22). Their HMBC connectivity with the pyrrolidine methylene carbon
different chemical shifts indicate that the influence of the and provided a starting point for simultaneous assignment
fulleropyrrolidine fragment on the magnetic environment of of the remaining 1H and 13C NMR resonances in a stepwise
the adjacent GABA CH2 groups is significant. All carbonyl manner. Sequential assignment required correlation across
carbons resonated in the expected downfield domain: glycyl the amide bonds separating two proton spin systems of ad-
at 168.71–170.35, GABA at 172.60–174.36 and ester at jacent amino acids. Differentiation of Gly and GABA
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FULL PAPER
amide carbonyl carbons was based on their HMBC corre- complex systems. In addition, the highly uniform chemical
lations. As shown for the example of Fp-hexapeptide tBu shifts also represent a powerful tool for an accurate moni-
ester 12 (Figure 2), each carbonyl group is coupled to three toring of their supramolecular organization. Finally, the
(Gly) or four (GABA) kinds of protons. In the former case solubilities of the synthesized compounds are significantly
these are: 1) the α- and β-protons of its own residue [CO- improved relative to C60.
(Gly)/CH2(Gly); CO(1)/CH2 (2,3), Figure 2, d], 2) the
neighbouring residue CH2 protons [CO(Gly2)/CH2(Gly1),
CO(Gly3)/CH2(Gly2); CO(1)/CH2(Gly3); CO(1Ј)/CH2(4);
Experimental Section
CO(1ЈЈ)/CH2(4Ј) Figure 2, d], and 3) the amide NH protons
through two bonds [CO(Gly2)/NH(Gly1); CO(Gly3)/
Abbreviations: DCC = dicyclohexylcarbodiimide, DMAP = 4-(di-
NH(Gly2); CO(1)/NH(Gly3); CO(1Ј)/NH(GABA), CO(1ЈЈ)/
methylamino)pyridine, TEA = triethylamine, DCM = dichloro-
methane.
NH(GABAЈ); Figure 2, c]. Also, the HMBC correlations of
the amide NH protons via 2JC,H with the methylene protons General: Flash column chromatography (FCC) and TLC were car-
are characteristic for all residues [NH(Gly2)/CH2(Gly2);
ried out with Merck silica gel (0.04–0.063 mm) and precoated silica
gel 60 F254 plates, respectively. Melting points were determined with
a Boetius PMHK apparatus and were uncorrected. IR spectra
NH(Gly3) /CH2(Gly3); NH(Gly1)/CH2(Gly1); NH(GABA)/
CH2(4); NH(GABAЈ)/CH2(4Ј); Figure 2, b]. Together, the
observed cross-correlated peaks allowed the attribution of
(ATR) were recorded with a Perkin–Elmer-FT-IR 1725X spectro-
photometer; ν values are given in cm–1. H and 13C NMR spectra
1
˜
the carbonyl groups (Figure 2, e) and unequivocally vali-
dated the assigned structure. The 1H and 13C NMR chemi-
cal shift assignments for peptide moieties of fulleropeptides
2–12 are given in the Experimental Section. For a table con-
taining these data and additional spectra see the Supporting
Information.
were recorded with Varian Gemini 200 and Bruker Avance spec-
trometers (at 200/500 and 50/125 MHz, respectively). Chemical
shifts (δ) are expressed in ppm and coupling constants (J) in Hz.
The homonuclear 2D spectra (DQF-COSY, TOCSY) and the het-
eronuclear 2D 1H-13C spectra (HSQC, HMBC) were recorded with
the usual settings. Samples were dissolved in the indicated solvent
systems, and TMS was used as internal reference. UV spectra were
recorded with a GBC-Cintra 40 UV/Vis spectrophotometer. The
high-resolution MS spectra were taken with an Agilent 6210 LC
ESI-MS TOF spectrometer. Fulleropyrrolidinic acid 1 (Fp-GABA-
OH), N-benzyloxycarbonyl-γ-aminobutyric acid (Z-GABA-OH,
Solubility
All of the obtained fulleropeptides are quite soluble in
moderately polar media (15 mgmL–1 in DCM/MeOH/CS2 26) and tert-butyl 4-aminobutanoate (H-GABA-OtBu, 27) were
synthesized by the published procedures.[15] Yields of the azome-
thine ylide cycloaddition reactions are reported as absolute values
without recovery of the starting fullerene (30–40%) taken into ac-
1:1:1, PhMe/DCM/MeOH 1:1:1 and toluene/MeOH 5:1).
Compounds 2 and 3, containing only GABA side chains,
and those incorporating GABAn-Gly moieties (n = 1–3; 4,
7 and 10, respectively) also reached the same level of solu-
bility in the chlorinated hydrocarbons, whereas the other
synthesized fulleropeptides are moderately soluble even in
a more polar medium (5 mgmL–1 in DCM/MeOH 1:1).
count. Fullerenic carbons, presented as Cf, were numbered in a
simplified way, as described in the literature.[25] The amino acids
incorporated into peptidic backbones, presented as G, GЈ and GЈЈ
(GABA) and Gly1, Gly2 and Gly3, were labelled and numbered in
the order of priority (starting from C terminus). For clarity, formu-
las with individually presented components of peptides are also
given in parentheses.
Conclusions
General Procedures
We have designed and synthesized two sets of new fuller-
opyrrolidines containing repeating GABA and GABAn-
Glym (n, m = 1–3) units. Most of the target compounds
A) DCC/DMAP-Assisted Amidation: DCC (0.10 mmol) was added
to a solution of fulleropyrrolidinic acid 1 (Fp-GABA-OH, 85 mg,
0.10 mmol), amine (0.10 mmol) and DMAP (0.01 mmol) in dry
(nine out of 11) were successfully prepared by DCC/ DCM (200 mL) and the reaction mixture was stirred at room tem-
perature under Ar for 24 h. Insoluble material (dicyclohexylurea,
DCU) was filtered off. In cases of fulleroamide preparations, the
solvent was removed under vacuum and the reaction mixture was
purified by FCC on SiO2 with use of the solvents listed below as
eluents. Subsequent precipitation from CH2Cl2/MeOH/CS2 solu-
tion with MeOH gave pure fulleropeptides.
DMAP-supported amidation of a previously synthesized
GABA-containing fulleropyrrolidinic acid [Fp-GABA-OH
(1)] with the appropriate C-protected small peptides.
Attempts to use H-Gly-OtBu and H-GABA-Gly-OtBu as a
building blocks in the above process did not provide the
expected fulleropeptides, so the two remaining compounds
were obtained by different synthetic approach involving
[3+2] cycloadditions of azomethine ylides to C60 as the key
steps. The presented NMR analysis shows that the assign-
ment of peptide spin system can be achieved easily and une-
quivocally by complementary use of standard 2D NMR ex-
periments (H,H-COSY, HMBC, HSQC, TOCSY). The
spin-active nuclei of all synthesized compounds resonate in
very narrow ranges, suggesting that the obtained fuller-
B) [3+2] Cycloadditions of Azomethine Ylides to C60: A suspension
of C60 (200 mg, 0.28 mmol), the corresponding amino acid
(0.28 mmol)
and
paraformaldehyde
(42 mg,
1.40 mmol,
5 mol equiv.) in PhMe (250 mL) was heated at reflux and the sol-
vent was then evaporated to dryness. The residue was purified by
FCC on SiO2 with use of the gradients of solvents listed below as
eluents. The first fraction was unconsumed C60 and the second the
monoadduct (fulleropeptide 4 or 7). Subsequent precipitation from
CH2Cl2/MeOH/CS2 solution with MeOH gave the pure fulleropep-
opeptides represent a good model system for further more tide.
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Synthesis and Characterization of Fulleropeptides
Fulleropeptide 2 (Fp-GABA2-OtBu, Fp-GЈ-G-OtBu, Procedure A):
Fp-GABA-OH (1, 100 mg, 0.12 mmol), H-GABA-OtBu (27,
20 mg, 0.12 mmol), DMAP (1.5 mg, 0.012 mmol) and DCC
(25 mg, 0.12 mmol) in dry DCM (200 mL) were used. Elution with
GABA), 169.18 (COGly), 154.90 (Cf-2, 5, 8, 10), 147.24 (Cf-52, 60),
146.19 (Cf-32, 39, 41, 48, 3, 4, 25, 26), 146.00 (Cf-51, 53, 56, 59),
145.61 (Cf-21, 30), 145.36 (Cf-14, 19, 23, 28), 145.23 (Cf-49, 50, 54,
55), 144.50 (Cf-33, 38, 42, 47), 143.03 (Cf-31, 40), 142.57 (Cf-35,
PhMe/EtOAc 1:1 gave fulleropeptide 2 (71 mg, 61%). Rf = 0.73 36, 57, 58), 142.19 (Cf-13, 20, 22, 29), 142.01 (Cf-34, 37, 43, 46),
1
(PhMe/EtOAc/MeOH 5:5:1). H NMR (500 MHz, CDCl3/CS2): δ
141.83 (Cf-16, 17, 44, 45), 140.12 (Cf-15, 18, 24, 27), 136.06 (Cf-6,
= 6.15 (br. s, 1 H, NHGABA), 4.42 (s, 4 H, CH2pyrr.), 3.37 (q, J =
7, 11, 12), 82.11 (CtBu), 70.56 (Cf-1, 9), 67.55 (CH2pyrr.), 53.24
6.5 Hz, 2 H, CH2 ), 3.15 (t, J = 7.0 Hz, 2 H, CH24Ј), 2.58 (t, J = (CH2 ), 42.07 (CH2Gly), 33.94 (CH2 ), 28.00 (CH3tBu), 24.17
4
4
2
7.0 Hz, 2 H, CH22Ј), 2.32 (t, J = 7.0 Hz, 4 H, CH2 ), 2.28 (quint, (CH ) ppm. IR: ν = 3303, 2972, 2796, 1739, 1653, 1536, 1508,
2
3
˜
2
J = 7.0 Hz, 2 H, CH23Ј), 1.85 (quint, J = 7.0 Hz, 2 H, CH2 ), 1.45
1366, 1222, 1154, 1034 cm–1. UV/Vis (CHCl3): λmax (ε) = 430
3
(s, 9 H, CH3tBu) ppm. 13C NMR (125 MHz, CDCl3/CS2): δ =
(1700), 325 (17000), 303 (17000), 256 nm (55000 mol–1 dm3 cm–1).
172.76 (COGABA), 172.65 (COGABAЈ), 154.92 (Cf-2, 5, 8, 10), 147.30 ESI-TOF-MS: m/z = calcd. for C72H23N2O3 963.17032 [M + H]+;
(Cf-52, 60), 146.24 (Cf-32, 39, 41, 48), 146.06 (Cf-3, 4, 25, 26), found 963.17012.
146.02 (Cf-51, 53, 56, 59), 145.64 (Cf-21, 30), 145.42 (Cf-14, 19, 23,
Fulleropeptide
5
(Fp-GABA-Gly2-OtBu, Fp-G-Gly2-Gly1-OtBu,
28), 145.28 (Cf-49, 50, 54, 55), 144.54 (Cf-33, 38, 42, 47), 143.09
(Cf-31, 40), 142.63 (Cf-35, 36, 57, 58), 142.21 (Cf-13, 20, 22, 29),
142.05 (Cf-34, 37, 43, 46), 141.88 (Cf-16, 17, 44, 45), 140.18 (Cf-15,
18, 24, 27), 136.10 (Cf-6, 7, 11, 12), 80.57 (CtBu), 70.60 (Cf-1, 9),
Procedure A): Fp-GABA-OH (1, 80 mg, 0.094 mmol), H-(Gly)2-
OtBu (15, 18 mg, 0.094 mmol), DMAP (1.1 mg, 0.009 mmol) and
DCC (19 mg, 0.094 mmol) in dry DCM (200 mL) were used. Elu-
4
67.69 (CH2pyrr.), 53.54 (CH24Ј), 39.24 (CH2 ), 34.32 (CH22Ј), 33.15
tion with PhMe/EtOAc/MeOH 5:5:0.5 gave fulleropeptide
5
(63 mg, 65%). Rf = 0.61 (PhMe/EtOAc/MeOH 5:5:1). 1H NMR
(500 MHz, CDCl3/CS2/CH3OH): δ = 7.08 (br. t, J = 4.5 Hz, 1 H,
NHGly2), 6.83 (br. s, 1 H, NHGly1), 4.44 (s, 4 H, CH2pyrr.), 4.04 (d,
J = 5.5 Hz, 2 H, CH2Gly2), 3.93 (d, J = 5.0 Hz, 2 H, CH2Gly1), 3.19
2
3
(CH2 ), 28.09 (CH3tBu), 24.84 (CH2 ), 24.36 (CH23Ј) ppm. IR: ν =
˜
3311, 2970, 2923, 2805, 2739, 1720, 1644, 1533, 1427, 1362, 1339,
1225, 1149 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (3900), 323
(39000), 305 (40000), 255 nm (98000 mol–1 dmcm–1). ESI-TOF-
MS: m/z = calcd. for C74H27N2O3 991.20162 [M + H]+; found
991.20145.
4
2
(t, J = 7.0 Hz, 2 H, CH2 ), 2.68 (t, J = 7.5 Hz, 2 H, CH2 ), 2.30
(quint, J = 7.0 Hz, 2 H, CH2 ), 1.47 (s, 9 H, CH3tBu) ppm. 13C
3
NMR (125 MHz, CDCl3/CS2/CH3OH): δ = 173.55 (COGABA),
169.09 (COGly2), 168.71 (COGly1), 154.88 (Cf-2, 5, 8, 10), 147.26
(Cf-52, 60), 146.20 (Cf-32, 39, 41, 48), 146.02 (Cf-3, 4, 25, 26),
145.99 (Cf-51, 53, 56, 59), 145.61 (Cf-21, 30), 145.37 (Cf-14, 19, 23,
28), 145.24 (Cf-49, 50, 54, 55), 144.50 (Cf-33, 38, 42, 47), 143.04
(Cf-31, 40), 142.59 (Cf-35, 36, 57, 58), 142.18 (Cf-13, 20, 22, 29),
142.02 (Cf-34, 37, 43, 46), 141.84 (Cf-16, 17, 44, 45), 140.13 (Cf-15,
18, 24, 27), 136.06 (Cf-6, 7, 11, 12), 82.48 (CtBu), 70.57 (Cf-1, 9),
Fulleropeptide
3 (Fp-GABA3-OtBu, Fp-GЈЈ-GЈ-G-OtBu, Pro-
cedure A): Fp-GABA-OH (1, 100 mg, 0.12 mmol), H-(GABA)2-
OtBu (29, 29 mg, 0.12 mmol), DMAP (1.5 mg, 0.012 mmol) and
DCC (25 mg, 0.12 mmol) in dry DCM (200 mL) were used. Elution
with PhMe/EtOAc/MeOH 5:5:0.5 gave fulleropeptide 3 (84 mg,
66%). Rf = 0.54 (PhMe/EtOAc/MeOH 5:5:1). 1H NMR (500 MHz,
CDCl3/CS2): δ = 6.56 (br. t, J = 5.5 Hz, 1 H, NHGABAЈ), 6.38 (br. s,
1 H, NHGABA), 4.42 (s, 4 H, CH2pyrr.), 3.38 (q, J = 6.0 Hz, 2 H,
4
67.67 (CH2pyrr.), 53.63 (CH2 ), 43.00 (CH2Gly2), 41.96 (CH2Gly1),
CH24Ј), 3.29 (q, J = 7.0 Hz, 2 H, CH2 ), 3.16 (t, J = 6.5 Hz, 2 H,
4
2
3
34.03 (CH2 ), 27.95 (CH3tBu), 24.19 (CH ) ppm. IR: ν = 3294,
˜
2
CH24ЈЈ), 2.60 (t, J = 7.2 Hz, 2 H, CH22ЈЈ), 2.28 (m, 6 H, CH22,2Ј,3ЈЈ),
1.87 (quint, J = 7.0 Hz, 2 H, CH23Ј), 1.81 (quint, J = 7.0 Hz, 2 H,
2970, 2928, 2782, 1736, 1652, 1512, 1426, 1365, 1223, 1153, 1116,
1031 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (3600), 321 (36000),
305 (37000), 254 nm (100000 mol–1 dm3 cm–1). ESI-TOF-MS: m/z
= calcd. for C74H26N3O4 1020.19178 [M + H]+; found 1020.19096.
CH2 ), 1.44 (s, 9 H, CH3tBu) ppm. 13C NMR (125 MHz, CDCl3/
3
CS2): δ = 173.42 (COGABAЈЈ), 172.98 (COGABA), 172.92 (COGABAЈ),
155.14 (Cf-2, 5, 8, 10), 147.53 (Cf-52, 60), 146.47 (Cf-32, 39, 41,
48), 146.29 (Cf-3, 4, 25, 26), 146.24 (Cf-51, 53, 56, 59), 145.86 (Cf-
21, 30), 145.65 (Cf-14, 19, 23, 28), 145.51 (Cf-49, 50, 54, 55), 144.77
(Cf-33, 38, 42, 47), 143.32 (Cf-31, 40), 142.86 (Cf-35, 36, 57, 58),
142.43 (Cf-13, 20, 22, 29), 142.28 (Cf-34, 37, 43, 46), 142.11 (Cf-16,
17, 44, 45), 140.41 (Cf-15, 18, 24, 27), 136.33 (Cf-6, 7, 11, 12), 80.78
(CtBu), 70.83 (Cf-1, 9), 67.95 (CH2pyrr.), 53.89 (CH24ЈЈ), 39.46
Fulleropeptide
6
(Fp-GABA-Gly3-OtBu, Fp-G-Gly3-Gly2-Gly1-
OtBu, Procedure A): Fp-GABA-OH (1, 80 mg, 0.094 mmol), H-
(Gly)3-OtBu (17, 23 mg, 0.094 mmol), DMAP (1.1 mg,
0.009 mmol) and DCC (19 mg, 0.094 mmol) in dry DCM (200 mL)
were used. Elution with PhMe/EtOAc/MeOH 5:5:0.3 gave fuller-
opeptide 6 (65 mg, 64%). Rf = 0.51 (PhMe/EtOAc/MeOH 5:5:1).
1H NMR (500 MHz, CDCl3/CS2): δ = 7.02 (br. s, 1 H, NHGly3),
6.96 (br. s, 1 H, NHGly2), 6.64 (br. s, 1 H, NHGly1), 4.43 (s, 4 H,
CH2pyrr.), 4.03 (d, J = 5.0 Hz, 2 H, CH2Gly3), 3.99 (d, J = 5.0 Hz,
2 H, CH2Gly2), 3.92 (d, J = 5.0 Hz, 2 H, CH2Gly1), 3.18 (t, J =
4
2
(CH2 ), 39.44 (CH24Ј), 34.65 (CH22ЈЈ), 34.29 (CH22Ј), 33.34 (CH2 ),
28.31 (CH3tBu), 25.91 (CH23Ј), 24.90 (CH2 ), 24.64 (CH23ЈЈ) ppm.
3
IR: ν = 3292, 3081, 2929, 2869, 2788, 1723, 1641, 1546, 1430, 1365,
˜
1257, 1153 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (3900), 322
(37000), 304 (38000), 257 nm (114000 mol–1 dm3 cm–1). ESI-TOF-
MS: m/z = calcd. for C78H34N3O4 1076.25438 [M + H]+; found
1076.25621.
4
2
6.0 Hz, 2 H, CH2 ), 2.69 (t, J = 7.0 Hz, 2 H, CH2 ), 2.28 (quint, J
= 7.0 Hz, 2 H, CH2 ), 1.46 (s, 9 H, CH3tBu) ppm. 13C NMR
3
(125 MHz, CDCl3/CS2/CH3OH): δ = 174.36 (COGABA), 170.03
(COGly3), 169.55 (COGly1), 169.13 (COGly2), 154.73 (Cf-2, 5, 8, 10),
147.14 (Cf-52, 60), 146.08 (Cf-32, 39, 41, 48), 145.91 (Cf-3, 4, 25,
26), 145.85 (Cf-51, 53, 56, 59), 145.49 (Cf-21, 30), 145.26 (Cf-14,
19, 23, 28), 145.12 (Cf-49, 50, 54, 55), 144.38 (Cf-33, 38, 42, 47),
142.94 (Cf-31, 40), 142.48 (Cf-35, 36, 57, 58), 142.04 (Cf-13, 20, 22,
29), 141.90 (Cf-34, 37, 43, 46), 141.73 (Cf-16, 17, 44, 45), 140.02
(Cf-15, 18, 24, 27), 135.96 (Cf-6, 7, 11, 12), 82.28 (CtBu), 70.44 (Cf-1,
Fulleropeptide 4 (Fp-GABA-Gly-OtBu, Procedure B): A suspension
of C60 (200 mg, 0.28 mmol), amino acid 35 (76 mg, 0.28 mmol) and
paraformaldehyde (42 mg, 1.40 mmol, 5 mol equiv.) in toluene
(250 mL) was heated at reflux for 4 h. Elution with PhMe gave
unreacted C60 (130 mg, 65%), and elution with PhMe/EtOAc 6:4
afforded fulleropeptide 4 (69 mg, 26%). Rf = 0.83 (PhMe/EtOAc/
1
MeOH 5:5:1). H NMR (500 MHz, CDCl3/CS2): δ = 6.54 (br. s, 1
H, NHGly), 4.45 (s, 4 H, CH2pyrr.), 4.02 (d, J = 5.0 Hz, 2 H,
9), 67.61 (CH2pyrr.), 53.74 (CH2 ), 42.97 (CH2Gly3), 42.51 (CH2Gly2),
4
4
2
3
CH2Gly), 3.20 (t, J = 6.8 Hz, 2 H, CH2 ), 2.68 (t, J = 6.8 Hz, 2 H, 41.70 (CH2Gly1), 33.74 (CH2 ), 27.76 (CH3tBu), 24.13 (CH2 ) ppm.
2
3
CH2 ), 2.30 (quint, J = 6.9 Hz, 2 H, CH2 ), 1.47 (s, 9 H,
IR: ν = 3288, 2928, 2782, 1736, 1653, 1532, 1425, 1367, 1226, 1156,
˜
CH3tBu) ppm. 13C NMR (125 MHz, CDCl3/CS2): δ = 172.60 (CO-
1024 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (3000), 321 (29000),
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20274
/KAP1
Date: 06-08-12 15:42:42
Pages: 11
M. Bjelakovic´, N. Todorovic´, D. Milic´
FULL PAPER
304 (30000), 255 nm (94000 mol–1 dm3 cm–1). ESI-TOF-MS: m/z =
0.009 mmol) and DCC (19 mg, 0.094 mmol) in dry DCM (200 mL)
were used. Elution with PhMe/EtOAc/MeOH 5:5:1.5 gave fuller-
opeptide 9 (62 mg, 57%). Rf = 0.17 (PhMe/EtOAc/MeOH 5:5:1).
1H NMR (500 MHz, CDCl3/CS2/CH3OH): δ = 7.84 (br. t, J =
5.5 Hz, 1 H, NHGly2), 7.64 (br. t, J = 5.2 Hz, 1 H, NHGly3), 7.38
(br. t, J = 5.2 Hz, 1 H, NHGly1), 7.06 (br. t, J = 5.5 Hz, 1 H,
NHGABA), 4.43 (s, 4 H, CH2pyrr.), 3.97 (d, J = 5.5 Hz, 2 H,
CH2Gly2), 3.91 (t, J = 5.8 Hz, 4 H, CH2Gly1,Gly3), 3.34 (q, J =
calcd. for C76H29N4O5 1077.21325 [M + H]+; found 1077.21443.
Fulleropeptide 7 (Fp-GABA2-Gly-OtBu, Fp-GЈ-G-Gly-OtBu, Pro-
cedure B): A suspension of C60 (200 mg, 0.28 mmol), amino acid
37 (101 mg, 0.28 mmol) and paraformaldehyde (42 mg, 1.40 mmol,
5 mol equiv.) in PhMe (250 mL) was heated at reflux for 12 h and
the solvents were evaporated to dryness. Elution with PhMe gave
unreacted C60 (87 mg, 44%) and elution with PhMe/EtOAc/MeOH
4
6.5 Hz, 2 H, CH2 ), 3.15 (t, J = 7.0 Hz, 2 H, CH24Ј), 2.58 (t, J =
5:5:0.1 provided fulleropeptide
7 (44 mg, 15%). Rf = 0.48
2
7.5 Hz, 2 H, CH22Ј), 2.34 (t, J = 7.0 Hz, 2 H, CH2 ), 2.26 (quint,
(C6H5CH3/EtOAc/MeOH 5:5:1). 1H NMR (500 MHz, CDCl3/
CS2): δ = 6.53 (br. s, 1 H, NHGly), 6.49 (br. s, 1 H, NHGABA), 4.42
(s, 4 H, CH2pyrr.), 3.94 (d, J = 5.0 Hz, 2 H, CH2Gly), 3.42 (q, J =
3
J = 7.0 Hz, 2 H, CH23Ј), 1.87 (quint, J = 6.5 Hz, 2 H, CH2 ), 1.47
(s, 9 H, CH3tBu) ppm. 13C NMR (125 MHz, CDCl3/CS2/CH3OH):
δ = 174.25 (COGABA), 173.92 (COGABAЈ), 170.16 (COGly3), 169.59
(COGly2), 169.12 (COGly1), 154.74 (Cf-2, 5, 8, 10), 147.22 (Cf-52,
60), 146.16 (Cf-32, 39, 41, 48), 145.98 (Cf-3, 4, 25, 26), 145.89 (Cf-
51, 53, 56, 59), 145.53 (Cf-21, 30), 145.34 (Cf-14, 19, 23, 28), 145.20
(Cf-49, 50, 54, 55), 144.45 (Cf-33, 38, 42, 47), 143.01 (Cf-31, 40),
142.56 (Cf-35, 36, 57, 58), 142.09 (Cf-13, 20, 22, 29), 141.97 (Cf-34,
37, 43, 46), 141.80 (Cf-16, 17, 44, 45), 140.10 (Cf-15, 18, 24, 27),
136.00 (Cf-6, 7, 11, 12), 82.29 (CtBu), 70.48 (Cf-1, 9), 67.69
(CH2pyrr.), 53.81 (CH24Ј), 43.20 (CH2Gly3), 42.66 (CH2Gly2), 41.76
4
6.0 Hz, 2 H, CH2 ), 3.15 (t, J = 7.0 Hz, 2 H, CH24Ј), 2.60 (t, J =
7.0 Hz, 2 H, CH22Ј), 2.34 (t, J = 7.0 Hz, 2 H, CH2 ), 2.28 (quint,
2
J = 7.0 Hz, 2 H, CH23Ј), 1.90 (quint, J = 6.5 Hz, 2 H, CH2 ), 1.47
3
(s, 9 H, CH3tBu) ppm. 13C NMR (125 MHz, CDCl3/CS2): δ =
173.40 (COGABAЈ), 172.91 (COGABA), 169.28 (COGly), 155.13 (Cf-
2, 5, 8, 10), 147.52 (Cf-52, 60), 146.47 (Cf-32, 39, 41, 48), 146.29
(Cf-3, 4, 25, 26), 146.24 (Cf-51, 53, 56, 59), 145.86 (Cf-21, 30),
145.64 (Cf-14, 19, 23, 28), 145.50 (Cf-49, 50, 54, 55), 144.76 (Cf-33,
38, 42, 47), 143.31 (Cf-31, 40), 142.85 (Cf-35, 36, 57, 58), 142.43
(Cf-13, 20, 22, 29), 142.27 (Cf-34, 37, 43, 46), 142.10 (Cf-16, 17, 44,
45), 140.40 (Cf-15, 18, 24, 27), 136.33 (Cf-6, 7, 11, 12), 82.43 (CtBu),
70.83 (Cf-1, 9), 67.94 (CH2pyrr.), 53.86 (CH24Ј), 42.31 (CH2Gly),
4
2
(CH2Gly1), 38.55 (CH2 ), 34.21 (CH22Ј), 32.86 (CH2 ), 27.85
(CH3tBu), 25.45 (CH2 ), 24.40 (CH23Ј) ppm. IR: ν = 3305, 3079,
3
˜
2930, 2794, 1740, 1648, 1538, 1428, 1390, 1230, 1158, 1031 cm–1.
UV/Vis (CHCl3): λmax (ε) = 430 (2800), 321 (26000), 305 (27000),
255 nm (86000 mol–1 dm3 cm–1). ESI-TOF-MS: m/z = calcd. for
C80H36N5O6 1162.26601 [M + H]+; found 1162.26911.
4
2
39.30 (CH2 ), 34.58 (CH22Ј), 33.94 (CH2 ), 28.27 (CH3tBu), 25.88
(CH2 ), 24.63 (CH23Ј) ppm. IR: ν = 3297, 3083, 2928, 2795, 1742,
3
˜
1644, 1543, 1428, 1367, 1224, 1157, 1035 cm–1. UV/Vis (CHCl3):
Fulleropeptide 10 (Fp-GABA3-Gly-OtBu, Fp-GЈЈ-GЈ-G-Gly-OtBu,
Procedure A): Fp-GABA-OH (1, 73 mg, 0.086 mmol), H-(GABA)
2-Gly-OtBu (33, 26 mg, 0.086 mmol), DMAP (1 mg, 0.0086 mmol)
and DCC (18 mg, 0.086 mmol) in dry DCM (200 mL) were used.
Elution with PhMe/EtOAc/MeOH 5:5:0.5 gave fulleropeptide 10
(73 mg, 75%). Rf = 0.46 (C6H5CH3/EtOAc/MeOH 5:5:1). 1H NMR
(500 MHz, CDCl3/CS2): δ = 6.89 (br. t, J = 5.5 Hz, 1 H, NHGABA),
6.83 (br. s, 1 H, NHGly), 6.62 (br. t, J = 5.5 Hz, 1 H, NHGABAЈ),
4.42 (s, 4 H, CH2pyrr.), 3.94 (d, J = 5.0 Hz, 2 H, CH2Gly), 3.38 (q,
λmax (ε)
(91000 mol–1 dm3 cm–1). ESI-TOF-MS: m/z
C76H30N3O4 1048.22308 [M + H]+; found 1048.22599.
=
430 (3400), 321 (32000), 305 (33000), 257 nm
=
calcd. for
Fulleropeptide 8 (Fp-GABA2-Gly2-OtBu, Fp-GЈ-G-Gly2-Gly1-OtBu,
Procedure A): Fp-GABA-OH (1, 80 mg, 0.094 mmol), H-GABA-
(Gly)2-OtBu (19, 26 mg, 0.094 mmol), DMAP (1.1 mg,
0.009 mmol) and DCC (19 mg, 0.094 mmol) in dry DCM (200 mL)
were used. Elution with PhMe/EtOAc/MeOH 5:5:1 gave fuller-
opeptide 8 (61 mg, 59%). Rf = 0.31 (PhMe/EtOAc/MeOH 5:5:1).
1H NMR (500 MHz, CDCl3/CS2/CH3OH): δ = 7.50 (br. t, J =
5.2 Hz, 1 H, NHGly2), 7.37 (br. t, J = 5.0 Hz, 1 H, NHGly1), 7.10
(br. t, J = 5.5 Hz, 1 H, NHGABA), 4.44 (s, 4 H, CH2pyrr.), 3.94 (d,
J = 5.5 Hz, 2 H, CH2Gly2), 3.92 (t, J = 5.5 Hz, 2 H, CH2Gly1), 3.34
4
J = 6.0 Hz, 2 H, CH24Ј), 3.34 (q, J = 6.0 Hz, 2 H, CH2 ), 3.16 (t,
J = 6.5 Hz, 2 H, CH24ЈЈ), 2.62 (t, J = 7.0 Hz, 2 H, CH22ЈЈ), 2.34 (t,
2
J = 6.5 Hz, 2 H, CH2 ), 2.27 (t, J = 6.5 Hz, 4 H, CH23ЈЈ,2Ј), 1.87
(m, 4 H, CH23,3Ј), 1.48 (s, 9 H, CH3tBu) ppm. 13C NMR (125 MHz,
CDCl3/CS2): δ = 173.64 (COGABAЈЈ), 173.19 (COGABAЈ), 173.12
(COGABA), 169.46 (COGly), 155.04 (Cf-2, 5, 8, 10), 147.52 (Cf-52,
60), 146.47 (Cf-32, 39, 41, 48), 146.29 (Cf-3, 4, 25, 26), 146.19 (Cf-
51, 53, 56, 59), 145.82 (Cf-21, 30), 145.65 (Cf-14, 19, 23, 28), 145.50
(Cf-49, 50, 54, 55), 144.75 (Cf-33, 38, 42, 47), 143.32 (Cf-31, 40),
142.86 (Cf-35, 36, 57, 58), 142.40 (Cf-13, 20, 22, 29), 142.26 (Cf-34,
37, 43, 46), 142.10 (Cf-16, 17, 44, 45), 140.41 (Cf-15, 18, 24, 27),
136.29 (Cf-6, 7, 11, 12), 82.32 (CtBu), 70.78 (Cf-1, 9), 67.94
(CH2pyrr.), 53.82 (CH24ЈЈ), 42.24 (CH2Gly), 39.24 (CH24Ј), 39.11
4
(q, J = 6.5 Hz, 2 H, CH2 ), 3.15 (t, J = 7.0 Hz, 2 H, CH24Ј), 2.57
(t, J = 7.5 Hz, 2 H, CH22Ј), 2.33 (t, J = 7.0 Hz, 2 H, CH2 ), 2.26
2
(quint, J = 7.0 Hz, 2 H, CH23Ј), 1.88 (quint, J = 6.7 Hz, 2 H, CH2 ),
3
1.47 (s, 9 H, CH3tBu) ppm. 13C NMR (125 MHz, CDCl3/CS2/
CH3OH): δ = 173.82 (COGABA), 173.73 (COGABAЈ), 169.62 (CO-
Gly2), 168.97 (COGly1), 154.73 (Cf-2, 5, 8, 10), 147.19 (Cf-52, 60),
146.14 (Cf-32, 39, 41, 48), 145.96 (Cf-3, 4, 25, 26), 145.88 (Cf-51,
53, 56, 59), 145.52 (Cf-21, 30), 145.32 (Cf-14, 19, 23, 28), 145.17
(Cf-49, 50, 54, 55), 144.43 (Cf-33, 38, 42, 47), 142.99 (Cf-31, 40),
142.53 (Cf-35, 36, 57, 58), 142.07 (Cf-13, 20, 22, 29), 141.95 (Cf-34,
37, 43, 46), 141.78 (Cf-16, 17, 44, 45), 140.07 (Cf-15, 18, 24, 27),
136.01 (Cf-6, 7, 11, 12), 82.29 (CtBu), 70.46 (Cf-1, 9), 67.66
(CH2pyrr.), 53.85 (CH24Ј), 42.78 (CH2Gly2), 41.80 (CH2Gly1), 38.65
4
2
(CH2 ), 34.63 (CH22ЈЈ), 34.04 (CH22Ј), 33.79 (CH2 ), 28.26
(CH3tBu), 26.15 (CH23Ј), 25.52 (CH2 ), 24.59 (CH23ЈЈ) ppm. IR: ν =
3
˜
3293, 3081, 2925, 2853, 2796, 1742, 1641, 1546, 1456, 1367, 1224,
1157, 1117 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (3600), 320
(32000), 306 (34000), 255 nm (96000 mol–1 dm3 cm–1). ESI-TOF-
MS: m/z = calcd. for C80H37N4O5 1133.27585 [M + H]+; found
1133.27533.
4
2
3
(CH2 ), 34.15 (CH22Ј), 33.08 (CH2 ), 27.84 (CH3tBu), 25.33 (CH2 ),
24.39 (CH23Ј) ppm. IR: ν = 3299, 3078, 2972, 2928, 2796, 1740,
˜
1650, 1539, 1427, 1368, 1225, 1157, 1032 cm–1. UV/Vis (CHCl3):
Fulleropeptide 11 (Fp-GABA3-Gly2-OtBu, Fp-GЈЈ-GЈ-G-Gly2-Gly1-
OtBu, Procedure A): Fp-GABA-OH (1, 80 mg, 0.094 mmol), H-
(GABA)2-(Gly)2-OtBu (21, 34 mg, 0.094 mmol), DMAP (1.1 mg,
0.009 mmol) and DCC (19 mg, 0.094 mmol) in dry DCM (200 mL)
λmax (ε)
(88000 mol–1 dm3 cm–1). ESI-TOF-MS: m/z
C78H33N4O5: 1105.24455 [M + H]+; found 1105.24602.
=
430 (3600), 321 (32000), 305 (33000), 260 nm
=
calcd. for
Fulleropeptide 9 (Fp-GABA2-Gly3-OtBu, Fp-GЈ-G-Gly3-Gly2-Gly1- were used. Elution with DCM/MeOH 95:5 gave fulleropeptide (11,
OtBu, Procedure A): Fp-GABA-OH (1, 80 mg, 0.094 mmol), H-
GABA-(Gly)3-OtBu (23, 31 mg, 0.094 mmol), DMAP (1.1 mg,
74 mg, 66%). Rf = 0.27 (PhMe/EtOAc/MeOH 5:5:1). 1H NMR
(500 MHz, CDCl3/CS2/CH3OH): δ = 7.57 (br. t, J = 5.5 Hz, 1 H,
8
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/KAP1
Date: 06-08-12 15:42:42
Pages: 11
Synthesis and Characterization of Fulleropeptides
1
NHGly2), 7.40 (br. t, J = 5.0 Hz, 1 H, NHGly1), 7.33 (br. t, J = TOCSY) and table with H and 13C NMR chemical shifts for the
5.5 Hz, 1 H, NHGABA), 7.19 (br. t, J = 5.5 Hz, 1 H, NHGABAЈ),
4.44 (s, 4 H, CH2pyrr.), 3.95 (d, J = 5.5 Hz, 2 H, CH2Gly2), 3.92 (d,
J = 6.0 Hz, 2 H, CH2Gly1), 3.32 (q, J = 6.5 Hz, 2 H, CH24Ј), 3.28
peptide moieties of fulleropeptides 2–12.
4
(q, J = 6.0 Hz, 2 H, CH2 ), 3.16 (t, J = 7.0 Hz, 2 H, CH24ЈЈ), 2.59
Acknowledgments
2
(t, J = 7.5 Hz, 2 H, CH22ЈЈ), 2.32 (t, J = 6.5 Hz, 2 H, CH2 ), 2.27
(part of quint, J = 6.5 Hz, 2 H, CH23ЈЈ), 2.25 (t, J = 7.0 Hz, 2 H,
CH22Ј), 1.85 (m, 4 H, CH23,3Ј), 1.47 (s, 9 H, CH3tBu) ppm. 13C
NMR (125 MHz, CDCl3/CS2/CH3OH): δ = 173.95 (COGABAЈЈ),
173.91 (COGABA), 173.78 (COGABAЈ), 169.77 (COGly2), 169.00 (CO-
Gly1), 154.79 (Cf-2, 5, 8, 10), 147.22 (Cf-52, 60), 146.16 (Cf-32, 39,
41, 48), 145.98 (Cf-3, 4, 25, 26), 145.91 (Cf-51, 53, 56, 59), 145.55
(Cf-21, 30), 145.34 (Cf-14, 19, 23, 28), 145.20 (Cf-49, 50, 54, 55),
144.46 (Cf-33, 38, 42, 47), 143.01 (Cf-31, 40), 142.55 (Cf-35, 36, 57,
58), 142.09 (Cf-13, 20, 22, 29), 141.97 (Cf-34, 37, 43, 46), 141.80
(Cf-16, 17, 44, 45), 140.09 (Cf-15, 18, 24, 27), 136.02 (Cf-6, 7, 11,
12), 82.34 (CtBu), 70.50 (Cf-1, 9), 67.69 (CH2pyrr.), 53.87 (CH24ЈЈ),
This work was supported by the Serbian Ministry of Education
and Science (grant number 172002).
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42.81 (CH2Gly2), 41.84 (CH2Gly1), 38.87 (CH24Ј), 38.53 (CH2 ),
2
34.25 (CH22ЈЈ), 33.51 (CH22Ј), 32.96 (CH2 ), 27.86 (CH3tBu), 25.52
3
(CH23Ј), 25.01 (CH2 ), 24.45 (CH23ЈЈ) ppm. IR: ν = 3296, 3082,
˜
2932, 2795, 1741, 1647, 1544, 1427, 1368, 1225, 1157, 1117, 1031,
846, 772, 527 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (2800), 319
(27000), 305 (28000), 255 nm (88000 mol–1 dm3 cm–1). ESI-TOF-
MS: m/z = calcd. for C82H40N5O6 1190.29731 [M + H]+; found
1190.29755.
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(200 mL) were used. Elution with DCM/MeOH 85:15 gave fuller-
opeptide 12 (78 mg, 66%). Rf = 0.12 (PhMe/EtOAc/MeOH 5:5:1).
1H NMR (500 MHz, CDCl3/CS2/CH3OH): δ = 7.99 (br. t, J =
5.5 Hz, 1 H, NHGly2), 7.77 (br. t, J = 5.5 Hz, 1 H, NHGly3), 7.49
(br. t, J = 5.5 Hz, 1 H, NHGly1), 7.27 (br. t, J = 6.0 Hz, 1 H,
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CH2pyrr.), 3.97 (d, J = 6.0 Hz, 2 H, CH2Gly2), 3.91 (d, J = 6.0 Hz,
2 H, CH2Gly3), 3.90 (d, J = 5.5 Hz, 2 H, CH2Gly1), 3.31 (overlapped
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4
CH2 ), 3.15 (t, J = 7.0 Hz, 2 H, CH24ЈЈ), 2.58 (t, J = 6.0 Hz 2 H,
2
CH22ЈЈ), 2.31 (t, J = 6.5 Hz, 2 H, CH2 ), 2.25 (m, 4 H, CH22Ј,3ЈЈ),
1.84 (m, 4 H, CH23,3Ј), 1.46 (s, 9 H, CH3tBu) ppm. 13C NMR
(125 MHz, CDCl3/CS2/CH3OH): δ = 174.29 (COGABA), 173.92
(COGABAЈЈ), 173.79 (COGABAЈ), 170.35 (COGly3), 169.82 (COGly2),
169.02 (COGly1), 154.74 (Cf-2, 5, 8, 10), 147.20 (Cf-52, 60), 146.15
(Cf-32, 39, 41, 48), 145.98 (Cf-3, 4, 25, 26), 145.88 (Cf-51, 53, 56,
59), 145.52 (Cf-21, 30), 145.33 (Cf-14, 19, 23, 28), 145.19 (Cf-49,
50, 54, 55), 144.44 (Cf-33, 38, 42, 47), 143.01 (Cf-31, 40), 142.55
(Cf-35, 36, 57, 58), 142.08 (Cf-13, 20, 22, 29), 141.95 (Cf-34, 37, 43,
46), 141.79 (Cf-16, 17, 44, 45), 140.09 (Cf-15, 18, 24, 27), 136.00
(Cf-6, 7, 11, 12), 82.18 (CtBu), 70.47 (Cf-1, 9), 67.69 (CH2pyrr.), 53.86
(CH24ЈЈ), 43.22 (CH2Gly3), 42.69 (CH2Gly2), 41.74 (CH2Gly1), 38.80
4
2
(CH24Ј), 38.24 (CH2 ), 34.23 (CH22ЈЈ), 33.37 (CH22Ј), 32.53 (CH2 ),
27.83 (CH3tBu), 25.57 (CH23Ј), 25.02 (CH2 ), 24.47 (CH23ЈЈ) ppm. [23] K. Bingel, Chem. Ber. 1993, 126, 1957–1959.
3
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˜
1157, 1117, 1028 cm–1. UV/Vis (CHCl3): λmax (ε) = 430 (3500), 322
(32000), 306 (34000), 255 nm (103000 mol–1 dm3 cm–1). ESI-TOF-
MS: m/z = calcd. for C84H43N6O7 1247.31877 [M + H]+; found
1247.31922.
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13C NMR spectra of 2–12, 19, 21, 23, 25, 29, 31, 33, 35 and 37, 2D
NMR spectra of fulleropeptide 12 (H,H-COSY, HMBC, HSQC,
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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/KAP1
Date: 06-08-12 15:42:42
Pages: 11
M. Bjelakovic´, N. Todorovic´, D. Milic´
FULL PAPER
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Received: March 6, 2012
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20274
/KAP1
Date: 06-08-12 15:42:42
Pages: 11
Synthesis and Characterization of Fulleropeptides
Peptides Containing Fullerenes
The synthesis of 11 new fulleropeptides Fp-
GABAn-Glym-OtBu (n = 1–3, m = 0–2)
containing 4-aminobutyric acid (GABA)
and glycyl residues was achieved either by
DCC/DMAP-assisted amidation or by
[3+2] cycloaddition. In addition, the com-
plete assignment of the peptides’ spin sys-
tems was accomplished by extensive NMR
analysis.
M. Bjelakovic´, N. Todorovic´,
D. Milic´* ......................................... 1–11
An Approach to Nanobioparticles – Syn-
thesis and Characterization of Fulleropept-
ides
Keywords: Synthetic methods / Peptidomi-
metics
/
Fullerenes
/
Fulleropeptides
/
Nanoparticles
Eur. J. Org. Chem. 0000, 0–0
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11