Synthesis of mono and bis[60]fullerene-based dicationic peptoids

Article abstract of DOI:10.1002/ejoc.201403046

Increasing numbers of biological applications of fullerenyl amino acids and their derivatives encouraged us to synthesise [60]fullerenyldihydropyrrole peptides, prepared from the coupling of mono- and bis[60]fullerenyldihydropyrrolecarboxylic acids 4, 5 a

Full text of DOI:10.1002/ejoc.201403046

FULL PAPER
DOI: 10.1002/ejoc.201403046
Synthesis of Mono and Bis[60]fullerene-Based Dicationic Peptoids
Sreenu Jennepalli,[a] Katherine A. Hammer,[b] Thomas V. Riley,[b] Stephen G. Pyne,*[a] and
Paul A. Keller*[a]
Keywords: Medicinal chemistry / Antibiotics / Amino acids / Peptides / Fullerenes / Template synthesis
Increasing numbers of biological applications of fullerenyl
amino acids and their derivatives encouraged us to syn-
thesise [60]fullerenyldihydropyrrole peptides, prepared from
16, 24, 28, 29 and 46. The resulting hydrophobic scaffolded
di- and tetra-cationic derivatives were tested against Staphy-
lococcus aureus NCTC 6571 and Escherichia coli NCTC
the coupling of mono- and bis[60]fullerenyldihydropyrrole- 10418. The synthesis, characterisation and biological results
carboxylic acids 4, 5 and 41 with presynthesised peptides 13,
are discussed in this paper.
investigated approaches reduce the size of the hydrophobic
anchoring unit, we thought that alternative hydrophobic
units could match the space occupied by the binaphthyl
unit. We have had considerable experience in the synthesis
and use of amino acid substituted [60]fullerenes[17] and
given that the diameter of [60]fullerenes is 6.8 Å and the
distance from distal points of the binaphthyl moiety is
8.3 Å, we considered the possibility of replacing the bi-
naphthyl unit with a [60]fullerene. The synthesis of these
molecules and their antibacterial activities are reported
here.
Introduction
There are significant healthcare issues posed by multi-
drug-resistant human pathogenic bacteria.[1,2] Of particular
concern is the emergence of Gram-positive bacteria, for ex-
ample, Staphylococcus aureus and Enterococcus faecium,
that are resistant to the glycopeptide antibiotic, vancomy-
cin.[3–5] Recently, a new variation to the peptide class of
antibiotics has emerged, exemplified by 1 (Figure 1).[6]
These dicationic binaphthyl-templated linear peptides pos-
sess some similarity to structural aspects of vancomycin
and could potentially act in a similar way but have added
flexibility for interacting strongly with the changed peptido-
glycan cell wall moiety[7] in vancomycin-resistant bacteria.[8]
Furthermore, there is significant antimicrobial activity in
some biaryl-based cyclic β-hairpin cationic peptidomimet-
ics.[9] Whereas medicinal chemistry investigations of 1 as
antibacterial agents made significant progress with the evol-
ution of the amino acids required[10] and the better ter-
mini,[6] early investigations into alternatives to the bi-
naphthyl unit were restricted to macrocycles anchored by
hydrophobic scaffolds based on 3,3Ј-amino acid linked 1,1Ј-
binaphthyls,[11] carbazoles,[12,13] indoles,[14] benzenes[15] and
benzo[b]thiophene.[16] The outcomes of these studies indi-
cated that changing from the binaphthyl hydrophobic scaf-
fold to smaller units severely decreased activity to the point
of complete inactivity. Therefore, the hydrophobic bulk of
the scaffold is critical in the structure–activity relationships
of this class of compounds. Considering that all of these
Figure 1. Binaphthyl-anchored peptide antibiotic agents.
[a] School of Chemistry, University of Wollongong,
Wollongong, NSW 2522, Australia
The fullerene moiety is becoming increasingly prominent
in biological applications,[18] as a “substituent” but also as
templates for the construction of macromolecules. Exam-
ples of mixed fullerenyl macrocycles include glycoconju-
gates[19] and fullerenyl amino acids,[20] with the later being
of significance to this project. To date, such systems have
been the focus of a variety of materials and medicinal chem-
E-mail: keller@uow.edu.au
spyne@uow.edu.au
http://smah.uow.edu.au/chem/contacts/UOW008575.html
[b] School of Pathology and Laboratory Medicine, The University
of Western Australia,
Crawley, WA 6009, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403046.
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istry projects and, thus far, take the form of fullerene pen- tivity.[6] Therefore, no ideal stereochemical combination has
dents to amino acid oligomers with linkers, fullerenyl- been identified, prompting us in this study to investigate a
capped amino acids and the most prevalent, the incorpora- range of different stereochemical possibilities. The peptide
tion of the fulleroproline moiety. In most instances, the C60 chains are then capped with a variety of small terminal
unit is an anchor, and not representative of a true α-amino hydrophobic units; here, we targeted the ester and oxazole
acid side chain, with linker units providing space between termini (R in structure 2, Figure 2).
the two moieties. The fullerenoprolines provide examples
closer to the incorporation of fullerenoamino acids in pept-
ide chains. In our proposed target molecules, the fullerene
moiety will be a true fullerenyl α-amino acid and will be
incorporated directly into the peptide chain. Additionally,
the peptide chain will be rich in arginines and lysines, which
are amino acids that are not necessarily prevalent with
known fullerenyl peptides. However, recent examples of cat-
ionic fullerenyl conjugates[21] suggest that the incorporation
of protonated “basic” side chains should pose no issues.
Therefore, the combination of the hydrophobic C60 unit and
the protonated basic side chains has the potential for inter-
esting solubility issues, which could be beneficial for the
delivery of bioactive molecules.
Chemistry
The synthesis of the target compounds began with the
generation of the [60]fullerenyl amino acid scaffold 5, which
was achieved by applying known chemistry to generate the
acid 4.[17] Thus, the reaction of commercially available tert-
butyl 2-[(diphenylmethylene)amino]acetate (3) with [60]-
fullerene under Bingel reaction conditions produced a
[60]fullerenyldihydropyrrole tert-butyl ester derivative in
60% yield, which was treated with TFA to give fullerenyl
acid 4 (90%; Scheme 1). This acid was treated with tert-
butylglycinate under EDCI/HOBt or HBTU peptide cou-
pling conditions, followed by TFA treatment to give acid 5
(48%). This second step adds the short linker to the mol-
ecule in the form of a Gly unit.
Results and Discussion
The target compounds contain [60]fullerene anchoring
cationic peptide chains and are exemplified by the general
structure 2 (Figure 2). Significant SAR studies have been
established with respect to the cationic amino acid side
chains. Therefore, this study focused on a short linker be-
tween the fullerene moiety with a peptide of variable length,
but restricted to either n = 0 or 1. The amino acid side
chains will be either Lys or Arg, or combinations thereof –
these would be tested as the dicationic salts, either chlorides
or trifluoroacetic acid (TFA) salts. We have previously re-
ported that despite the multiple stereogenic elements pres-
ent in the molecule, different diastereomers of the same
molecules had little difference in their antibacterial ac-
Scheme 1. Synthesis of the fullerenyl amino acid hydrophobic an-
chor. Reagents and conditions: (a) DBU, CBr4, toluene, 6 h, room
temp., C60, 60%; (b) TFA, CH2Cl2, room temp., 3 h, 90%; (c) tert-
butyl glycinate, CH2Cl2, EDCI/HOBt or HBTU, room temp., 5 h,
48%.
The next stage towards [60]fullerenyl-anchored peptide
molecules is the synthesis of the peptide moieties. In this
approach, we wanted to make a number of derivatives to
encompass a range of analogues without necessarily mak-
ing systematic one-step changes; instead, we wished to en-
compass a range of derivatives. Scheme 2 outlines the syn-
thesis of the tripeptide (e.g., 13 and 14) and tetrapeptide
(e.g., 16) moieties for linking to the fullerenyl hydrophobic
scaffold. Thus, free amine 6, containing an isopentyl ester,
was synthesised by reported procedures,[6] and coupled with
Fmoc-d-Arg-OH (R = Pmc or Pbf) to produce dipeptides
7 (R = Pmc) and 8 (R = Pbf) (Scheme 2). These differ only
in the protecting group, and both were made because of the
ready availability of starting materials at the time. Subse-
quent Fmoc deprotection and coupling with d- or l-(Boc)-
Lys-OH resulted in tripeptides 11 and 12, which, upon
Fmoc deprotection, gave the free amines 13 and 14, respec-
tively. The reaction of 14 with Fmoc-Gly-OH produced tet-
rapeptide 15, which was Fmoc deprotected to yield 16. This
sequence produced two tripepetides, 13 and 14, and a tetra-
peptide, 16, with a terminal isopentyl ester and a free amino
Figure 2. Structure of the target [60]fullerene-based dicationic
peptoids 2.
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Mono and Bis[60]fullerene-Based Dicationic Peptoids
Scheme 2. Reagents and conditions: (a) Fmoc-d-arg-(Pmc/Pbf)-OH, Fmoc-l-arg-(Pmc)-OH or Fmoc-d-lys(Boc)-OH, EDCI, HOBt,
CH2Cl2, room temp., 4 h, 66% for 7, 75% for 8, 65% for 18 and 68% for 19; (b) piperidine, CH3CN, room temp., 4 h, 77–88%; (c)
Fmoc-d or l-Lys-(Boc)-OH, EDCI, HOBt, CH2Cl2, room temp., 4 h, 79% for 11, 80% for 12, 86% for 22 and 72% for 23; (d) Same
conditions as (b) 88% for 13, 77% for 14, 84% for 24, and 85% for 25; (e) Fmoc-Gly-OH, EDCI, HOBt, CH2Cl2, room temp., 4 h, 75%
for 15, 71% for 26 and 82% for 27; (f) Same conditions as (b) 80% for 16, 88% for 28, and 86% for 29.
substituent, ready for peptide coupling with a fullerenyl possible by coupling with the oxazole-terminated tripeptide
amino acid.
24, and the tetrapeptide version of 28, with the extra glycine
The synthesis of the peptide moieties containing an ox- amino acid in the peptide chain, was used to produce 32.
azole terminus started with the synthesis of 17 by reported Coupling the acid 4 with peptide 29, which contained two
methods[22] (Scheme 2). Oxazole 17 then underwent stan- Boc-protected lysines with an oxazole terminus, yielded 33.
dard coupling with N,NЈ-diprotected forms of either l-Arg The reaction required the use of CHCl3/CH2Cl2 (1:1) as
or d-Lys to produce 18 and 19, which were deprotected to solvent mixture because of the better solubility of the di-
the free amines 20 and 21, respectively. Reaction of these Boc protected lysine containing peptide, whereas the syn-
amines with Fmoc-d-Lys-(Boc)-OH gave 22 and 23, which thesis of compounds 31 and 32 required only CH2Cl2 as a
were Fmoc deprotected to give 24 and 25, respectively; a single solvent. Deprotection of 30–33 with TFA gave the
final coupling with Fmoc-Gly-OH gave tetrapeptides 26 corresponding dication TFA or HCl salts after anion ex-
and 27 and, after Fmoc deprotection, free amines 28 and change (Scheme 3).
1
29 were obtained for further coupling reactions to hydro-
Analysis of the H NMR spectrum of the fullerenyl di-
phobic scaffolds.
cation peptide 34 revealed a doublet of doublets centred at
The protected fullerenyl peptoids 30–33 were successfully δ = 7.36 and 7.47 ppm, assigned to the para and meta pro-
synthesised by coupling [60]fullerenyldihydropyrrole acid 4 tons, respectively, of the gem diphenyl substituents of the
with the presynthesised peptides 16, 24, 28 and 29 under proline moiety, with the corresponding ortho protons as-
EDCI/HOBt peptide coupling conditions (Scheme 3). In a signed to the doublet at δ = 8.03 ppm. The methylene moi-
typical example, the tetrapeptide 16 was added dropwise to ety of the glycine unit was assigned to the broad singlet at
a solution of acid 4 and HOBt in CH2Cl2, which was soni- δ = 3.26 ppm. Analysis of the HRMS (ESI) revealed a peak
cated for 15 min to aid solubility. EDCI was added at the at m/z 1436.3822, assigned to the monocationic species of
same temperature and the reaction mixture was stirred for 34 (C97H49N9O6).
four hours at room temperature. As the reaction progressed,
An additional antibiotic target molecule to consider is
the turbid solution transformed into a clear brown solution the [60]fullerene that is doubly substituted with peptides
and, upon workup, the first-in-class [60]fullerenyl anchored chains. Thus, the previously unknown diacid 41 was synthe-
tetrapeptide 30 was isolated. Synthesis of compound 31 was sised from the reported bis-adduct 40,[17a] by using trimeth-
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Scheme 3. Synthesis of C60 fullerenyl-anchored amino acid oxazoles and isopentyl esters. Reagents and conditions: (a) EDCI, HOBt,
CH2Cl2, room temp., 4 h; (b) TFA/CH2Cl2 (1:1), room temp., 16 h; (c) 1 m HCl·Et2O, 0 °C to room temp., 0.5 h.
yltin hydroxide[23] at 80 °C or borontribromide at –10 °C to study failed because of poor solubility. No progress in the
room temperature; the former conditions resulted in a bet- coupling reaction was observed even after longer reaction
ter yield of 65% compared with the latter of 50% times and an increase in reaction temperature to 60 °C.
(Scheme 4). As expected, attempts to synthesise [60]fuller- Therefore, a change in solvent to a 1:2 ratio of pyridine/
ene bis-peptoid 42 by using diacid 41 and peptide 13 under chloroform was used, leading to a successful outcome with
the standard coupling conditions used previously in this 50% reaction yield of 42 (Scheme 4). Unfortunately, at-
Scheme 4. (a) (tert-butoxycarbonyl)glycine, THF, DMAP, CH2Cl2, room temp., 40 h, 80%. (b) TFA, CH2Cl2, room temp., 3 h, 90%.
(c) CH2Cl2, diphenylmethanimine, 24 h, room temp., 75%. (d) DBU, CBr4, room temp., toluene, C60, 6 h, 45%. (e) (CH3)3-
SnOH, DCE, 80 °C, 24 h, 65%. (f) BBr3, CH2Cl2, –10 °C to room temp., 18 h, 50%. (g) pyridine/chloroform (1:2), EDCI, HOBt, 8 h,
50%.
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Mono and Bis[60]fullerene-Based Dicationic Peptoids
tempted deprotection of 42 with TFA gave an insoluble was synthesised from intermediates 43 and 44 under stan-
product that could not be characterised. Analysis of the 1H dard coupling-deprotection conditions. The dipeptide 46
NMR spectrum of 42 showed a singlet signal (18 H) at δ = was then coupled to the fullerenyl amino acid 5, yielding 47
1.28 ppm, assigned to the two Boc groups attached to the in 67% yield. Subsequent deallylation followed by coupling
lysine side chains. The presence of a single peak for these to isopentyl-l-leucinate gave tetrapeptide-coupled [60]ful-
two groups indicates that both peptide side chains are in an lerenyl peptide 49 in 62% yield. Final side chain deprotec-
equivalent environment, which is consistent with the ex- tion under standard conditions followed by salt formation
pected Cs symmetry of the trans-4-disubstituted [60]-fuller- gave the final product 50 in 70% yield.
ene.[24] The presence of 29 sp2 resonances confirms this
To improve the solubility of the [60]fullerene-based pept-
symmetry. Analysis of the HRMS (ESI) indicated a peak at ides for antibacterial testing, it was necessary to use them
m/z 2884.1675, assigned to the sodiated species of 42 as dicationic salts, which were prepared by using TFA and/
(C174H164N16O20S2Na).
or 1 m HCl in ether. Peptides 31, 32 and 49 were made as
The synthesis of the fullerenyl peptide 50 was achieved the HCl salts 35, 36 and 50, respectively by treatment with
by using a modified route (Scheme 5). Initially, dipeptide 46 TFA/CH2Cl2 (1:1) to deprotect the Pmc/Pbf and N-Boc
Scheme 5. Reagents and conditions: (a) EDCI, HOBt, TEA, CH2Cl2, room temp., 4 h, 85%; (b) TFA/CH2Cl2 (4:6), room temp., 4 h,
90%; (c) HBTU, TEA, CH2Cl2, room temp., 4 h, 67%; (d) (CH3)3SnOH, 1,2-DCE, 80 °C, 6 h, 84%; (e) isopentyl l-leucinate hydrochlo-
ride, EDCI, HOBt, TEA, CH2Cl2, room temp., 4 h, 62%; (f) piperidine, CH3CN, room temp., 4 h, 72%; (g) 1 m HCl·Et2O, 0 °C to room
temp., 0.5 h, 70%.
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the resulting residue was subjected to silica gel column chromatog-
raphy (MeOH/CH2Cl2, 1–4%) to afford the coupled product.
functional groups then, after removing the solvents under
reducing pressure, the residue was resuspended in a minimal
volume of CH2Cl2 and treated with an excess of 1 m HCl
in ether to obtain the target HCl salts. Peptides 30 and 33
were made as their TFA salts 34 and 37 by treatment with
TFA/CH2Cl2 (1:1) to deprotect the Pmc/Pbf and N-Boc
groups and at the same time forming the TFA salts. All
salts were characterised by HRMS, and 34, 35 and 36 re-
Protocol 2: N-Fmoc Deprotection: The Fmoc-protected amine was
stirred in piperidine/acetonitrile (1 equiv., 5 mL/0.10 mmol) over-
night at room temp., unless otherwise stated. The solvent was re-
moved under reduced pressure and the crude product was purified
by column chromatography(MeOH/CH2Cl2, 5%) to give the free
amine.
turned 1H NMR spectra of good quality. Unfortunately, Protocol 3: N-Boc, Pbf and Pmc Deprotection: The N-Boc-, Pbf- or
Pmc-protected amine was stirred for 1 h (for Boc) or overnight (for
Pbf and Pmc) in CH2Cl2/TFA (1:1, 6 mL/0.10 mmol) solution at
room temp. The solvent was removed under reduced pressure, then
the residue was resuspended in a minimal volume of CH2Cl2. The
solution was treated with an excess of 1 m HCl in diethyl ether
(2 mL/0.01 mmol) and the solvent was evaporated. The crude prod-
uct was purified by precipitation from CH2Cl2, with hexane and
diethyl ether.
due to limited solubility of these salts, we were unable to
obtain adequate 13C NMR spectra.
Antimicrobial Testing
As an initial screen for biological activity, the [60]fuller-
enyl peptides 30–33, 42, 47 and 49 and the dicationic salts
34–37, and 50 were subjected to antibacterial testing in
vitro. These twelve [60]fullerene derivatives were tested
using the broth microdilution method against Staphylococ-
cus aureus NCTC 6571 and Escherichia coli NCTC 10418.
Minimum inhibitory concentrations (MICs) for antibiotic
positive controls tested simultaneously were 4 μg/mL for
kanamycin and 2 μg/mL for chloramphenicol for E. coli
and for S. aureus were 4 μg/mL for kanamycin and 1 μg/
mL for vancomycin. Unfortunately all fullerenyl-based
compounds were inactive, even at higher concentrations,
with MIC greater than 100 to 340 (μg/mL).
Protocol 4: Allyl and Bis-1,3-benzyl Ester Hydrolysis: To a solution
of the ester in 1,2-dichloroethane (10 mL/0.10 mmol) at room temp.
was added Sn(CH3)3OH (4 equiv.) and the solution was heated at
80 °C for 4 h, then further Sn(CH3)3OH (4 equiv.) was added at
the same temperature and the reaction was continued for 4 h. The
reaction mixture was evaporated under reduced pressure and the
resulting residue was taken up in dichloromethane (15–20 mL). The
organic layer was washed with 5% HCl (3ϫ10–15 mL), brine (3ϫ
10 mL), dried with MgSO4, and evaporated under reduced pressure
to give the corresponding acid.
Acknowledgments
The authors thank the Australian National Health and Medical
Research Council (NHMRC) for funds (project grant number
APP1051105). S. J. thanks the ARC Centre of Excellence for Elec-
tromaterial Science for the provision of a scholarship.
Conclusions
The synthesis of peptides anchored by [60]fullerenes was
successful, and a series of mono- and bis-substituted fuller-
ene derivatives was synthesised. Although these derivatives
did not show any antibacterial activity, their synthesis has
progressed the development of this important field of fuller-
enyl amino acid and peptide derivatives, in particular, their
synthesis and isolation as peptide salts. This is highlighted
by the reasonable solubility of the deprotected compounds
in dimethyl sulfoxide/water and the relative ease of purifica-
tion of the protected fullerenyl peptides by column
chromatography. Furthermore, these fullerenyl peptides
have a more rigid, and thus more defined, tethered structure
than most other reported fullerenyl peptides, which tradi-
tionally employ a flexible fullerene-peptide linker. These
more rigid structural properties could become increasingly
important in the fields of medicinal chemistry and materials
science.
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Received: August 6, 2014
Published Online: November 21, 2014
Eur. J. Org. Chem. 2015, 195–201
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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