Synthesis of rhenium chelated MAG3 functionalized rosette nanotubes

Article abstract of DOI:10.1016/j.tetlet.2012.01.090

Rosette nanotubes (RNTs) are discrete nanostructures self-assembled from a guanine-cytosine hybrid motif (G∧C) under aqueous conditions. These materials have substantial design flexibility and a range of applications, which are partly attributed to their

Full text of DOI:10.1016/j.tetlet.2012.01.090

Tetrahedron Letters 53 (2012) 1645–1651
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of rhenium chelated MAG3 functionalized rosette nanotubes
Alaaeddin Alsbaiee a,b, Mustapha St. Jules a,b, Rachel L. Beingessner a, Jae-Young Cho a,
Takeshi Yamazaki a,b, Hicham Fenniri a,b,c,
⇑
a National Institute for Nanotechnology, University of Alberta, 11421 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9
b Department of Chemistry, University of Alberta, 11421 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9
c Department of Biomedical Engineering, University of Alberta, 11421 Saskatchewan Drive, Edmonton, Alberta, Canada T6G 2M9
a r t i c l e i n f o
a b s t r a c t
Article history:
Rosette nanotubes (RNTs) are discrete nanostructures self-assembled from a guanine–cytosine hybrid
motif (G^C) under aqueous conditions. These materials have substantial design flexibility and a range
of applications, which are partly attributed to their diverse surface functionalization. Given the potential
for interesting properties resulting from a metal-RNT construct, here we describe an oxorhenium-func-
tionalized RNT. More specifically, we present the synthesis of a twin G^C motif expressing the mercapto-
acetyl triglycine (MAG3) ligand. We then examine the chelation reaction of the MAG3 with ReOCl3(PPh3)2
and self-assemble the resulting ReO-MAG3-G^C conjugate into RNTs under DMSO and aqueous
conditions.
Received 26 October 2011
Revised 18 January 2012
Accepted 20 January 2012
Available online 28 January 2012
Keywords:
Rosette nanotubes
Self-assembly
Mercaptoacetyl triglycine
Metal oxide
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
Rhenium
Introduction
Along with functionalizing the RNTs with organic groups, we
have also described the site-specific nucleation and growth of
Rosette nanotubes (RNTs) are biocompatible architectures gen-
erated under physiological conditions through the self-assembly
of a guanine–cytosine hybrid motif (G^C) via an entropically dri-
ven, hierarchical process (Fig. 1).1 As a result of their ease of outer
surface functionalization with covalently attached pendant groups
and tunable nature of their lengths2 and diameters,3 there is sub-
stantial flexibility in the RNT design to tailor their properties for
biomedical and other materials applications. RNTs functionalized
with lysine, RGDSK or a combination of both for example, have been
shown to be excellent interfacial biomaterial for osteoblast (bone
cells) adhesion to titanium (Ti), for hydrogel implant materials used
in bone repair,4 and for vascular stents.5 This may have a tremen-
dous impact for patients who often face inflammation, infection
and the need for revision surgery to replace the implant devices.
In addition to serving as interfacial materials, RNTs are also
being examined as scaffolds to deliver small drug molecules and
large bioactive peptides and nucleic acids. The therapeutic agents
can be bound to the RNTs either covalently1 on the surface or by
passive entrapment such as by electrostatic interactions6 with
charged peptides that are already expressed on the surface or by
incorporation into their inner channel.7,8
1.4 nm Au NPs on the surface of the RNTs.9 This work paved the
way to the nucleation of catalytically active metal NPs and the
exploration of their catalytic properties.
Given our interest in hybrid metal-RNT constructs for novel
properties, here we explore the synthesis of an oxorhenium-func-
tionalized RNT. Rhenium complexes are interesting because of
their known catalytic properties, particularly in hydrogenation
reactions.10 Moreover, radioactive 186/188Re (or its substitute tech-
netium-99 m, 99mTc)11 has been extensively used as a radiolabel
for bioimaging studies12 and has also been investigated as a possi-
ble method for the in situ treatment of cancerous tissue based on
high-energy b-emission.13
The mercaptoacetyl triglycine (MAG3) ligand is a well-estab-
lished tubular renal imaging ligand which forms a stable metal com-
plex with Re or Tc. Many different bioactive molecules such as
sugars,14 immune globulins,15 and siRNA,16 to only name a few, have
been functionalized with MAG3. From a structural standpoint, this
ligand contains a sulfhydryl atom typically protected with a benzoyl
group that requires deprotection prior to the chelation with the Re. It
also features a free carboxyl group that is not involved in chelation
and can be used as a handle to link other groups via an amide bond.
In this Letter, we describe a synthetic approach in which to con-
struct a twin-G^C motif conjugated with MAG3 (Fig. 1). We then
examine the chelation reaction of twin-G^C-MAG3 motif with Re
and investigate the self-assembly properties of the resulting ad-
duct into RNTs under aqueous and DMSO conditions.
⇑
Corresponding author. Tel.: +1 780 641 1750; fax: +1 780 641 1601.
E-mail address: hicham.fenniri@ualberta.ca (H. Fenniri).
0040-4039/$ - see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.090

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A. Alsbaiee et al. / Tetrahedron Letters 53 (2012) 1645–1651
aldehyde 11c and 0.5 M NH3 in dioxane via a double reductive ami-
nation reaction. We then envisioned the coupling of compound 2
with readily prepared MAG3 317 to generate 5 or 6, by implement-
ing standard peptide coupling conditions (HATU, DIPEA) or via the
acid chloride, anhydride or activated carbamoylimidazolium salt 4
intermediates. As shown in Figure 2 however, all of these strategies
were unproductive and only starting material was recovered. It is
speculated that the limited solubility of MAG3 3 even in the polar
solvent DMSO, along with steric interactions with the twin base 2
or 4, were the main factors that prevented the coupling from taking
place.
As a means of promoting the reaction by removing or at least
limiting this steric impediment, the protected G^C motifs 7 and
8 were prepared (Fig. 2). These molecules have a linker R of two
or four carbon atoms respectively, along with a terminal primary
amine that can be used to form an amide bond to MAG3–COOR.
Surprisingly however, neither the Fmoc deprotected 7 or 8 could
be coupled to MAG3 3 using the conditions described previously
(HATU, CDI or via the acid chloride derivative, MAG3–Cl).
The order of the coupling reaction was next modified in order to
take advantage of the higher reactivity of the aldehyde moiety on
the G^C protected base 1. As illustrated in Figure 3, N-Boc ethy-
lenediamine was first coupled to MAG3 3 in the presence of HBTU
and Et3N in DMSO to generate amine 9 in a 77% yield. Following
the removal of the Boc group on 9 under acidic conditions, a double
reductive amination reaction in the presence of 2 equiv of G^C pro-
tected base 1 and NaBH(OAc)3 provided the desired coupled prod-
uct 10 in a 51% yield. Global deprotection of the Boc and Bn groups
using a 95% TFA in thioanisole (v:v) successfully generated the tar-
get G^C base product 11.
Chelation of the MAG3 functionalized twin-G^C motif with
Rhenium
With compound 11 in-hand, several typical conditions de-
scribed in the literature for the Re complexation of the MAG3 li-
gand were examined. These involved either
a one-step Bz
deprotection-chelation protocol or an in situ Bz deprotection under
basic conditions, followed by the addition of Re in the form of Re-
OCl3(PPh3)2. While various bases (NaOH18, pyridine19 or Et3N), sol-
vents (MeOH, DMF), temperatures (rt to 80 °C), and reaction times
were examined to promote the chelation, only starting material
was isolated under these conditions. Despite this unfavorable out-
come, we had learned that the solubility of 11 and the Bz deprotec-
ted 11 in particular, was very limited in MeOH, which is a common
solvent used for this reaction. In our case, a mixture of DMF and
MeOH was a better solvent choice. As well, careful examination
of the LCMS traces revealed that ReOCl3(PPh3)2 had been oxidized
to the very stable perrhenate (ReOꢀ4 )20 anion. It was therefore evi-
dent that a normal atmosphere was also detrimental to this
reaction.
Thus, taking these observations into consideration, 11 was
deprotected using NaOMe in degassed MeOH21 and then treated
with a solution of ReOCl3(PPh3)2 in DMF that was also degassed
(Fig. 3). After stirring for 2 h at room temperature, diethyl ether
was then added to precipitate the brown solid, which was purified
by simply washing with various organic solvents. We were pleased
to observe that with these measures, adduct 12 could be obtained,
but unfortunately as a mixture with many other unidentified prod-
ucts. After extensive optimization efforts, we found that quite sim-
ply, a one-step protocol worked very well in which 11 was treated
with ReOCl3(PPh3)2 and NaOMe concurrently, in a 1:1 mixture of
degassed DMF:MeOH for 30 min. The brown solid was then precip-
itated and washed with multiple organic solvents to provide 12 in
a 94% yield. Analysis of the product by IR, 1H NMR, LRMS, HRMS
Figure 1. (a) Re-complexed MAG3 functionalized twin G^C motif (upper) and
corresponding hexameric rosette maintained through 36 H-bonds (middle) and
pꢀp stacking of the rosettes into RNTs (lower).
Results and discussion
Synthesis of the MAG3 functionalized twin-G^C motif
The initial strategies that we explored to synthesize the MAG3-
functionalized G^C motif are presented in Fig. 2 and commenced
with the preparation of the twin-base 2 in excellent yields from

A. Alsbaiee et al. / Tetrahedron Letters 53 (2012) 1645–1651
1647
Figure 2. Synthetic strategies for the MAG3 functionalized twin G^C motif.
Figure 3. Synthesis of ReO-MAG3 functionalized twin G^C motif 12.

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A. Alsbaiee et al. / Tetrahedron Letters 53 (2012) 1645–1651
Figure 4. Top row–compound 11 (a) UV–Vis spectra (4.010-5 M) monitored over time at room temperature (b) SEM (TE mode) image (1 mg/mL, water, 2 d aging) (c) SEM (SE
mode) image (0.05 mg/mL, DMSO, 1 week aging). Bottom row–compound 12 (d) UV–Vis (4.8 ꢁ 10ꢀ5 M) monitored over time at room temperature (e) SEM (SE mode) image
(0.05 mg/mL, water, 1 month aging) (f) AFM image (0.05 mg/mL, DMSO, 1 week aging).
and elemental analysis established that the reaction was clean and
that 12 did not require further purification.
images of the RNTs obtained are very similar to each other. It
was also noted that for 11 and 12, the RNTs have a tendency
to associate into larger bundles. Therefore, in order to improve
the dispersion of the tubes for characterization purposes, the
self-assembly of the G^C motifs were also performed in DMSO.
From the corresponding TEM images of 11 (Fig. S4b) and 12
(Fig. S5b), the average RNT diameters were measured to be
4.5 0.5 nm and 4.7 0.4 nm respectively. Molecular modeling
of RNTs 12 (Fig. S6), which were approximated by replacing
the Re atom with carbon to simplify the calculations, resulted
in an RNT diameter of 4.7 nm. Even though this value is only
an approximation due to the replacement of the Re atom with
carbon, it bodes well with our experimental values. Overall, it
is evident from these studies that there is no barrier to the
self-assembly process by the presence of the Re-chelated MAG3
ligand in 12.
Self-assembly of the RNTs
The self-assembly of both the MAG3-functionalized motif 11
and Re chelate 12 into RNTs was investigated, in order to deter-
mine if there was any effect of the charged metal complex on the
self-organization process.
UV–Vis spectroscopy first established the absorbance profiles
pertaining to the growth of the RNTs over time. As shown in Fig-
ure 4a (and Fig. S1), compound 11 (4.0 ꢁ 10ꢀ5 M) presents two
kmax at 235 and 288 nm, which corresponds to the absorption
of the
pꢀp
stacked twin G^C bases.1 A third, less intense band
at kmax of 315 nm is also observed from the benzene ring of the
Bz protected MAG3 ligand. During the course of one week, a
hypochromic effect in the absorbance occurs, along with a small
blue shift of 2 nm at the kmax 288 and 315 nm. When compared
to the Re complex 12, a similar growth absorption profile in
water (Fig. 4d and Fig. S2) is found, with a hypochromic effect
occurring over time at the two kmax values that range between
287–288 nm and 234–236 nm. The absence of a kmax peak at
315 nm for 12 also confirms the deprotection of the Bz group.
The alternative hyperchromic effect noted during the variable-
temperature UV–Vis experiments of 12 (Fig. S3), highlights the
reversible nature of this self-assembly process as the system is
heated.
Conclusions
In conclusion, we have described a synthetic strategy to con-
struct oxorhenium-functionalized RNTs using the MAG3 ligand.
This strategy involves a one-step deprotection-chelation protocol
of 11 using NaOMe and ReOCl3(PPh3)2 in a mixture of degassed
DMF and MeOH. This provides expedient access to 12 in excellent
yield and without the need for extensive purification. We have also
investigated the self-assembly of 11 and 12 in DMSO and water
solvents and have confirmed the formation of RNTs using UV–Vis
spectroscopy, SEM, TEM, and AFM imaging. With this synthetic ap-
proach in-hand, one aspect of our future work will involve the
Scanning electron microscopy (SEM, Fig. 4b, c, e, S4a, S5a),
transmission electron microscopy (TEM, Figs. S4b, S5b), and
atomic force microscopy (AFM, Fig. 4f, Figs. S4c, S5c) were used
to further characterize the RNT assemblies. Figure 4b and e show
representative SEM images of 11 (1 mg/mL) and 12 (0.05 mg/mL)
in water, respectively. Although the charged metal complex leads
to better solubility of 12 in water compared to 11, the SEM
186/
preparation of the radiolabeled version of G^C motif 12 using
188Re (or technetium-99 m, 99mTc). This will provide a strategy in
which to track the cellular uptake and pharmacokinetics of RNTs
in vivo.

A. Alsbaiee et al. / Tetrahedron Letters 53 (2012) 1645–1651
1649
taken up in Et2O (20 mL), washed with brine (10 mL) and dried
over anhydrous Na2SO4. Filtration, followed by silica gel flash chro-
matography (10% MeOH/CH2Cl2) yielded 7 (C79H98N14O18, 109 mg,
91%) as a pale yellow foam. Rf = 0.79 (SiO2, 10% MeOH/CH2Cl2). 1H
NMR (400 MHz, CDCl3) d (ppm) 7.74–7.28 (19H, m), 5.57 (4H, s),
4.39 (4H, t, J = 7.2 Hz), 4.33 (2H, d, J = 7.3 Hz), 4.23 (1H, t,
J = 7.3 Hz), 3.47 (6H, s), 3.38–3.26 (2H, m), 2.96 (4H, t, J = 7.2 Hz),
2.88 (2H, t, J = 5.6 Hz), 1.54 (18H, s), 1.32 (36H, s).13C NMR
(150 MHz, CDCl3) d (ppm) 165.6, 161.2, 161.0, 160.3, 156.5,
155.6, 152.5, 149.3, 144.1, 141.2, 134.9, 128.5, 127.5, 127.0,
125.2, 119.8, 92.8, 83.7, 82.9, 70.1, 66.5, 53.8, 50.8, 47.3, 41.2,
34.9, 28.1, 27.8. HRMS (ESI): calcd for (M+H)+/z, 1531.7256. Found
1531.7253.
Experimental
General
All reagent grade solvents were purified using an MBraun sol-
vent purification system. Reactions were performed under N2 or
Argon unless otherwise stated. Silica coated TLC plates were used
to monitor reaction progress and visualization was made under
UV light or by chemical staining (KMnO4/ddH2O or Ninhydrin/n-
BuOH/AcOH). All NMR characterizations were performed on a
600, 500 or 400 MHz NMR with the solvents indicated used as
internal references. The NMR data are presented as follows: chem-
ical shift, integration, multiplicity, and coupling constant.
Compound 8
Compound 2
A solution of N-Fmoc-butylenediamine hydrochloride (54.2 mg,
A solution of compound 1 (5.0 g, 7.8 mmol) in 1,2-dichloroeth-
ane (30 mL) was treated with 0.5 M NH3 in dioxane (62.5 mL,
31.3 mmol) and NaBH(OAc)3 (3.8 g, 18 mmol). After stirring at rt
for 24 h, the reaction was quenched with ddH2O (20 mL). The or-
ganic phase was separated, washed with brine (10 mL), dried over
anhydrous Na2SO4 and concentrated under reduced pressure (rot-
ovap). Purification by silica gel flash chromatography provided
compound 2 (C62H83N13O16, 4.20 g, 85%) as a yellow solid. Rf = 0.2
(SiO2, EtOAc). mp = 97–98 °C. 1H NMR (400 MHz, CDCl3) d (ppm)
7.45–7.25 (11H, m), 5.56 (4H, s), 4.42 (4H, t, J = 7.0 Hz), 3.47 (6H,
s), 3.09 (4H, t, J = 7.0 Hz), 1.55 (18H, s), 1.27 (36H, s). 13C NMR
(125 MHz, CDCl3) d (ppm) 165.6, 161.1, 160.2, 155.6, 152.4,
149.2, 134.9, 128.5, 127.8, 92.8, 83.6, 82.8, 69.8, 50.4, 41.0, 34.8,
28.1, 27.8. HRMS (ESI): calcd for (M+H)+/z, 1266.6153. Found
1266.6150.
0.156 mmol) and Et3N (217
lL, 1.25 mmol) in 1,2-dichloroethane
(15 mL) was stirred for ꢂ10 min after which
1
(100 mg,
0.156 mmol) and NaBH(OAc)3 (43.1 mg, 0.203 mmol) were added.
After stirring O/N, TLC and LCMS showed that the reaction was
complete. An additional equivalent of 1 (100 mg, 0.156 mmol)
and NaBH(OAc)3 (43.1 mg, 0.203 mmol) were then added to the
mixture, which was left to stir for a further 24 h at rt. The reaction
was then quenched with ddH2O (10 mL) and the solvent was re-
moved under reduced pressure. The resulting yellow residue was
taken up in Et2O (20 mL), washed with brine (10 mL), and dried
over anhydrous Na2SO4. Filtration, followed by silica gel chroma-
tography (0-10% MeOH/CH2Cl2) offered
8
(C81H102N14O18,
214 mg, 88%) as a pale yellow foam. Rf = 0.45 (SiO2, 5% MeOH/
CH2Cl2). 1H NMR (500 MHz, CDCl3) d (ppm) 7.74–7.28 (19H, m),
5.57 (4H, s), 4.41 (4H, t, J = 7.3 Hz), 4.34 (2 H, d, J = 7.2 Hz), 4.21
(1H, t, J = 7.2 Hz), 3.48 (6H, s), 3.20–3.16 (2H, m), 2.93 (4H, t,
J = 7.3 Hz), 2.78–2.62 (2H, m), 1.56 (18H, s), 1.60–1.52 (4H, m),
1.31 (36H, s).13C NMR (125 MHz, CDCl3) d (ppm) 165.6, 161.2,
161.0, 160.3, 156.5, 155.6, 152.5, 149.3, 144.1, 141.2, 134.9,
128.5, 127.5, 127.0, 125.2, 119.8, 92.8, 83.7, 82.9, 70.0, 66.5, 53.8,
50.8, 47.3, 41.2, 35.0, 28.1, 27.8, 27.5, 24.9. HRMS (ESI): calcd for
(M+H)+/z, 1559.7569. Found 1559.7576.
Compound 4
Compound 2 (200 mg, 0.158 mmol) and N,N’-carbonyldiimidaz-
ole (28 mg, 0.17 mmol) were dissolved in dry THF (30 mL) and re-
fluxed for 48 h. The reaction was then quenched with ddH2O,
concentrated under reduced pressure and the product was taken
up with EtOAc. The organic layer was separated, washed with a
brine solution, dried over anhydrous Na2SO4, filtered, and concen-
trated. Filtration over a pad of silica gel provided 159 mg of a yel-
low solid. (C66H85N15O17, 74%). Rf = 0.38 (SiO2, 5% MeOH/Et2O).
mp = 87 °C. HRMS (ESI): calcd for (M+H)+/z, 1360.6318. Found
1360.6321. This yellow solid (159 mg, 0.117 mmol) was then dis-
Compound 9
N-Boc ethylenediamine (44 mg, 0.27 mmol),
3
(100 mg,
L,
0.273 mmol),17 HBTU (103 mg, 0.273 mmol) and Et3N (72
l
0.52 mmol) were dissolved in DMSO (4 mL) and stirred at rt for
4 h. Et2O was then added to precipitate the product, which was col-
lected, washed with CH2Cl2, and dried to provide 9 as a white solid
(C22H31N5O7S, 107 mg, 77%). mp = 223.2 °C (decomposed). 1H NMR
(500 MHz, DMSO-d6) d (ppm) 8.47 (1H, t, J = 5.3 Hz), 8.21 (1H, t,
J = 6.6 Hz), 8.08 (1H, t, J = 5.9 Hz), 7.94–7.90 (2H, m), 7.78 (1H, t,
J = 5.7 Hz), 7.72–7.68 (1H, m), 7.58–7.56 (2H, m), 6.78 (1H, t,
J = 5.6 Hz), 3.88 (2H, s), 3.77 (2H, d, J = 5.6 Hz), 3.74 (2H, d,
J = 5.7 Hz), 3.65 (2H, d, J = 5.9 Hz), 3.10–3.05 (2H, m), 3.00–2.90
(2H, m), 1.36 (9H, s). 13C NMR (150 MHz, DMSO-d6) d (ppm)
190.8, 169.6, 169.5, 169.3, 167.7, 156.1, 136.4, 134.5, 129.6,
127.3, 78.2, 43.0, 42.6, 42.5, 39.2, 32.9, 28.6. HRMS (ESI): calcd
for (M+Na)+/z = 532.1836. Found 532.1834.
solved in MeCN (5 mL) and treated with iodomethane (36 lL,
0.585 mmol). After stirring for 24 h at rt, the reaction mixture
was concentrated under reduced pressure to afford 4 as a viscous
yellow oil. (C67H88N15O17I, 148 mg, 92%). 1H NMR (400 MHz,
DMSO-d6) d (ppm) 9.43 (1H, s), 7.85 (1H, s), 7.68 (1H, s), 7.41–
7.30 (10H, m), 5.58 (4H, s), 4.55 (2H, br s), 4.35 (2H, br s), 3.89
(5H, br s), 3.74 (2H, br s), 3.41 (6H, s), 1.51 (18H, s), 1.26 (36H,
br s). HRMS (ESI): calcd for (M+H)+/z, 1374.6475. Found 1374.6477.
Compound 7
A solution of N-Fmoc-ethylenediamine hydrochloride (25 mg,
0.078 mmol) and Et3N (22.0
(10 mL) was stirred for ca. 10 min after which
l
L, 0.156 mmol) in 1,2-dichloroethane
(50 mg,
1
Compound 10
0.078 mmol) and NaBH(OAc)3 (21.5 mg, 0.101 mmol) were added.
After stirring O/N, TLC and LCMS analysis revealed that the reaction
was complete. An additional equivalent of 1 (50 mg, 0.078 mmol)
and NaBH(OAc)3 (21.5 mg, 0.101 mmol) were then added to the
mixture, which was left to stir for a further 24 h at rt. The reaction
was then quenched with ddH2O (10 mL) and the solvent was re-
moved under reduced pressure. The resulting yellow residue was
TFA/thioanisole (1 mL, 95/5, v/v) was added to a solution of 9
(343 mg, 0.673 mmol) in CH2Cl2 (2 mL) at rt. After stirring for
1 h, the TFA was removed under reduced pressure. Et2O was then
added to precipitate the product, which was washed with Et2O
(3ꢁ) and CH2Cl2 (4ꢁ) to afford a pink solid (C19H24F3N5O7S,

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A. Alsbaiee et al. / Tetrahedron Letters 53 (2012) 1645–1651
213 mg, 61%). This material (163 mg 0.313 mmol) was then dis-
solved in DMF (10 mL), treated with Et3N (132 L, 0.964 mmol),
Acknowledgments
l
and sonicated until it dissolved. Aldehyde 1 (400 mg, 0.625 mmol)
was then added and the solution was stirred for ca. 10 min before
the addition of NaBH(OAc)3 (272 mg, 1.28 mmol). The mixture was
stirred at rt for 24 h before the DMF was removed under reduced
pressure. The viscous yellow residue was then dissolved in EtOAc,
washed with ddH2O, brine, and dried over anhydrous Na2SO4. Fil-
tration, followed by silica gel flash chromatography (0–5% MeOH/
DCM) offered the coupled adduct 10 as a solid (C79H103N17O21S,
269 mg, 51%). Rf = 0.42 (SiO2, 5% MeOH/CH2Cl2). mp = 88.8–
89.3 °C. 1H NMR (600 MHz, CD3OD) d (ppm) 7.88–7.31 (15H, m),
5.60 (4H, s), 4.32 (4H, t, J = 7.3 Hz), 3.92 (4H, br s), 3.88–3.84 (4H,
m), 3.44 (6H, s), 3.34–3.29 (2H, m), 2.93 (4H, t, J = 7.0 Hz), 2.86
(2H, s), 2.82 (4H, t, J = 7.3 Hz), 1.54 (18H, s), 1.28 (36H, s). 13C
NMR (150 MHz, CD3OD) d (ppm) 190.8, 170.8, 170.6, 170.1,
169.9, 165.8, 161.6, 160.9, 160.5, 156.2, 152.5, 149.3, 136.1,
135.0, 133.7, 128.7, 128.33, 128.32, 126.9, 92.9, 84.2, 83.0, 70.1,
51.3, 42.9, 42.5, 42.2, 41.5, 37.6, 35.5, 34.3, 32.1, 27.1, 26.7. HRMS
(ESI): calcd for (M+H)+/z = 1658.7308. Found 1658.7315. Elemental
analysis: Found: C 56.51; H 6.29; N 13.95; S 1.94. Calc. for
[C79H103N17O21S+CH3OH]: C, 56.83; H, 6.38; N, 14.08 S, 1.90.
We thank the National Research Council of Canada (NRC), the
University of Alberta, and the Natural Science and Engineering Re-
search Council (NSERC) for supporting this research program. A.A.
thanks Alberta Innovates for the Alberta Innovates Graduate Stu-
dent Scholarship in Nanotechnology.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.090.
References and notes
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11072; (b) Moralez, J. G.; Raez, J.; Yamazaki, T.; Motkuri, R. K.; Kovalenko, A.;
Fenniri, H. J. Am. Chem. Soc. 2005, 127, 8307–8309; (c) Fenniri, H.; Deng, B. L.;
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Compound 11
2. Beingessner, R. L.; Diaz, J. A.; Hemraz, U. D.; Fenniri, H. Tetahedron Lett. 2011,
52, 661–664.
3. (a) Borzsonyi, G.; Beingessner, R. L.; Yamazaki, T.; Cho, J.-Y.; Myles, A. J.; Malac,
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4. (a) Chun, A. L.; Moralez, J. G.; Webster, T. J.; Fenniri, H. Biomaterials 2005, 26,
7304–7309; (b) Chun, A. L.; Moralez, J. G.; Fenniri, H.; Webster, T. J.
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30, 1309–1320; (e) Zhang, L.; Ramsaywack, S.; Fenniri, H.; Webster, T. J. Tissue
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Rodriguez, J.; Fenniri, H.; Webster, T. J. Int. J. Nanomedicine 2008, 3, 323–333;
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563.
Compound 10 (200 mg, 0.121 mmol) was dissolved in 5 mL of
95% TFA/thioanisole (5 mL, v/v) and stirred at rt for 4 h. Et2O was
then added to precipitate the product which was purified by exten-
sive washing with Et2O and CH2Cl2 to afford 11 (C35H44N17O9S,
132 mg, 89%) as a white solid. mp = decomposed at 287 °C. 1H
NMR (600 MHz, DMSO-d6+1 drop of d-TFA+D2O) d (ppm): 7.89–
7.88 (2H, m), 7.68–7.66 (1H, m), 7.55–7.52 (2H, m), 4.40 (4H, br
s), 3.84 (2H, s), 3.76 (2H, s), 3.72 (2H, s), 3.65 (2H, s), 3.59–3.54
(4H, m), 3.48–3.43 (4H, m), 2.91 (6H, br s). 13C NMR (150 MHz,
DMSO-d6+one drop of d-TFA) d (ppm): 190.8, 170.3, 169.8, 167.8,
162.4, 161.7, 160.2, 156.5, 156.0, 148.7, 136.3, 134.5, 129.6,
127.3, 82.9, 52.2, 49.9, 43.0, 42.6, 42.5, 40.4, 36.8, 32.9, 28.4. HRMS
(MALDI): calcd for (M+H)+/z = 878.3223. Found 878.3224. Elemen-
tal analysis: Found: C, 39.77; H, 3.97; N, 18.88; S, 2.87. Calcd for
[C35H44N17O9S+(CF3COOH)3+H2O]: C, 39.78; H, 3.91; N, 19.23; S,
2.59.
5. Fine, E.; Zhang, L. J.; Fenniri, H.; Webster, T. J. Int. J. Nanomedicine 2009, 4, 91–
97.
6. Alshamsan, A.; El-Bakkari, M.; Fenniri, H. Mater. Res. Soc. Symp. Proc. 2010, 2011,
1316–1319.
7. Chen, Y.; Song, S.; Yan, Z.; Fenniri, H.; Webster, T. J. Int. J. Nanomedicine 2011, 6,
1035–1044.
Compound 12
8. Song, S.; Chen, Y.; Yan, Z.; Fenniri, H.; Webster, T. J. Int. J. Nanomedicine 2011, 6,
101–107.
9. Chhabra, R.; Moralez, J. G.; Raez, J.; Yamazaki, T.; Cho, J.-Y.; Myles, A. J.;
Kovalenko, A.; Fenniri, H. J. Am. Chem. Soc. 2010, 132, 32–33.
A mixture of 50:50 MeOH/DMF (2.5 mL) in a round bottom flask
was degassed by bubbling argon for 30 min and then transferred to
an argon filled round bottom flask containing a mixture of 11
(10.0 mg, 0.0082 mmol), ReOCl3(PPh3)2 (14.5 mg, 0.016 mmol,
2 equiv), and CH3ONa (9.0 mg, 0.167 mmol, 20 equiv). The suspen-
sion was stirred at room temperature under positive argon pres-
sure. After 30 min, the cloudy green solution turned into a cloudy
brown color. Diethyl ether was then added which precipitated
the brown complex immediately. The precipitate was then trans-
ferred with the solution into a centrifuge tube and centrifuged.
The isolated solid was washed with diethyl ether (3ꢁ), hexane
(3ꢁ), benzene (3ꢁ), chloroform (3ꢁ), CH2Cl2 (3ꢁ), and ddH2O
(2ꢁ). The solid was then dried under vacuum to provide 12
(C28H35N17O9SRe, 8 mg, 94%). 1H NMR (600 MHz, DMSO-d6 + 1
drop of TFA-d) d (ppm): 4.45–4.43 (4 H, m), 4.18–4.10 (2H, m),
3.81 (2H, s), 3.78–3.75 (2H, m), 3.72–3.70 (2H, m), 3.59 (4H, br
s), 3.53–3.47 (4H, m), 2.96 (6H, br s). Low Resolution LC–MS: calcd
for (M+2H)+/z = 974.2. Found 974.3. HRMS (MALDI): calcd for
(M+2H)+/z = 974.2238. Found 974.2234. IR: 1634 (C@O amide),
1531 (C@N), 973.0 (Re@O). Elemental analysis: Found: C, 35.00;
H, 4.47; N, 22.86. Calcd for [C28H35N17O9ReSꢀ + 2MeOH]: C,
34.78; H, 4.18; N, 22.98.
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