N-Phenanthroline glycosylamines: Synthesis and copper(II) complexes

Article abstract of DOI:10.1016/j.tet.2013.12.044

A series of novel N-(1,10-phenanthrolin-5-yl)-β-glycopyranosylamines was obtained with excellent stereoselectivity and synthetically useful yields by treatment of 5-amino-1,10-phenanthroline with different unprotected monosaccharides, using (NH₄)₂SO₄ as an efficient promoter. Copper(II) complexes having a 2:1 mole ratio of the bidentate ligand phenanthroline N-glycoside and the metal were also prepared.

Full text of DOI:10.1016/j.tet.2013.12.044

Accepted Manuscript
N-phenanthroline glycosylamines: synthesis and copper(II) complexes
Katerina Duskova, Lourdes Gude, María-Selma Arias-Pérez
PII:
S0040-4020(13)01912-1
10.1016/j.tet.2013.12.044
TET 25128
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 November 2013
Revised Date: 9 December 2013
Accepted Date: 16 December 2013
Please cite this article as: Duskova K, Gude L, Arias-Pérez M-S, N-phenanthroline glycosylamines:
synthesis and copper(II) complexes, Tetrahedron (2014), doi: 10.1016/j.tet.2013.12.044.
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N-phenanthroline glycosylamines: synthesis
and copper(II) complexes
Katerina Duskova, Lourdes Gude, and María-Selma Arias-Pérez
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871 Alcalá de Henares,
Madrid, Spain
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Tetrahedron
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N-phenanthroline glycosylamines: synthesis and copper(II) complexes
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Katerina Duskova, Lourdes Gude and María-Selma Arias-Pérez 
Departamento de Química Orgánica y Química Inorgánica, Universidad de Alcalá, 28871 Alcalá de Henares, Madrid, Spain
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of novel N-(1,10-phenanthrolin-5-yl)--glycopyranosylamines was obtained with
excellent stereoselectivity and synthetically useful yields by treatment of 5-amino-1,10-
phenanthroline with different unprotected monosaccharides, using (NH4)2SO4 as an efficient
promoter. Copper(II) complexes having a 2:1 mole ratio of the bidentate ligand phenanthroline
N-glycoside and the metal were also prepared.
Available online
2013 Elsevier Ltd. All rights reserved.
Keywords:
Glycosylamines
N-glycosylation reactions
Phenanthroline derivatives
Copper(II) complexes
1. Introduction
to the prevalence of DNA G-quadruplex folding architectures in
many genomic regions of biological interest, such as gene
promoters and human telomeres.9,10
Glycosylamines are important in carbohydrate enzymology
and some of them are considered to be inhibitors of
glycosidases.1 Inhibition of glycosidase enzymes is at the heart of
the therapy of numerous diseases, since they are involved in
varied and essential biological processes. Thus, rebeccamycin
analogues are indolocarbazole N-glycosides with antitumor
activity that can inhibit topoisomerase I, kinases and/or bind to
DNA according to their chemical structure.2 Many carbohydrates,
both neutral and positively charged, are known to be generally
good binders for nucleic acids, and the interaction occurs mainly
throughout the minor groove because of their hydrogen-bonding
ability and large hydrophobic patches. On the other hand,
heterocyclic compounds such as 1,10-phenanthroline and 2,2’-
bipyridine are powerful bidentate metal chelators with
applications in diverse areas, and different metal complexes have
been extensively studied for their nuclease-like activity.3,4
We are interested in the preparation of metallo-organic
molecules that can selectively bind and stabilize the G-
quadruplex DNA structures,11 as they can act as human
telomerase inhibitors.12,13 Some common structural features of the
designed compounds have been shown to contribute to binding:
they are water-soluble metal complexes containing flat aromatic
surfaces -to favour π stacking interactions with the DNA G-
tetrads-,11 they incorporate lateral side-chains that can act as
groove binding moieties by electrostatic interactions and/or H-
bonds, and they contain positively charged metal atoms to
simulate the role of potassium or sodium ions at stabilizing the
quadruplex structure under physiological conditions.12
Phenanthroline serves as the scaffold for several potent
stabilizers of DNA G-quadruplexes,13 which can act as human
telomerase inhibitors and are currently receiving much attention
as potential targets for anticancer drug development.
The development of novel chemical compounds capable of
modulating human telomerase activity is currently a very active
and competitive area of research, mainly because of its potential
applications in the treatment of cancer and age-related diseases.5,6
The enzymatic activity of this ribonucleoprotein, encharged of
telomere length maintenance in humans, is overexpressed in 85-
90% of cancer patients,7 which has led to the recognition of
telomerase as a feasible drug target.8 Among the different
approaches for the design of telomerase inhibitors, selective G-
quadruplex ligands are currently attracting much attention,9 due
Based on the hypothesis that sugars add important features to
the shape and the stereoelectronic properties of a molecule and
often play an essential role in the biological activity, we wished
to explore the DNA-binding properties of metal complexes of N-
heteroaryl glycosylamines including two structural components:
a heteroaromatic system –DNA intercalating moiety- and a
carbohydrate unit- minor/major groove-binding moiety- (Scheme
1). Although few data have been reported about the interactions
———
 Corresponding author. Tel.: + 34 91 8854699; fax: + 34 91 8854686; e-mail: selma.arias@uah.es

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Tetrahedron
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Scheme 1
Table 1. N-Glycosylation reactions of 5-amino-1,10-phenanthroline
Temperature
(ºC)
Reaction
time (h)
Glycopyranosylamine,
yield (%)c
Entry
Monosaccharide
D-glucose
Methoda
Reaction medium
Methanol
1
2
A
B
65
40
72
5
2a, 20-26
Aqueous phosphate
bufferb
12
3
C
D
Methanol-aqueous
phosphate buffer (1:1)
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74
72
4
5
Methanol/(NH4)2SO4
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48
24
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24
88
79
6
D-galactose
D-mannose
D
D
Methanol/(NH4)2SO4
Methanol/(NH4)2SO4
2b, 68
2c, 90
80
7
8
9
L-rhamnose
L-fucose
D
D
Methanol/(NH4)2SO4
Methanol/(NH4)2SO4
2d, 90
81
10
11
2e, 67
37 a Molar ratio monosaccharide:amine 3:1 for entries 1 (yield 20%), 3-11 and 4:1 for entries 1 (yield 26%) and 2. [amine] = 0.06 M except for entry 2
0.13 M.
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b Aqueous phosphate buffer Na2HPO4/NaH2PO4, 50 mM, pH 6.5.
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c Yields of isolated products except for entries 1-3 in which cases these values correspond to the conversion of starting amine and were determined
by 1H-NMR (± 1%).
2. Results and discussion
43 between carbohydrates and G-quadruplexes, recent studies on
sugar-DNA conjugates have shown that favourable interactions
occur between the carbohydrate and the DNA G-tetrad through
stacking interactions as well as hydrogen bonding or hydrophobic
contacts, when they are available.14 Moreover, it has been shown
that carbohydrates can give rise to significant differences in the
affinity for a quadruplex target and they are promising motifs for
selective G-quadruplex recognition and the design of new G-
quadruplexes ligands.14,15
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Few synthetic methods have been reported for the direct N-
glycosylation of aromatic compounds and carbohydrates without
hydroxyl protection or activation.16-23 Usually, the reaction can be
accomplished by heating at reflux in protic solvents and, in some
cases, better results can be achieved under mildly acidic
conditions.16-23 It is known that the reaction is strongly influenced
by the reactivity of the starting amine and the best preparative
yields were obtained for aromatic amines of moderate basicity.18-
20
An increase of the amine basicity seems to be related with
In this paper we describe the synthesis and characterization of
a series of N-(1,10-phenanthrolin-5-yl)--glycopyranosylamines
2a-e and their copper(II) complexes (Scheme 1). N-glycosylation
reactions were accomplished by treatment of 5-amino-1,10-
phenanthroline with different unprotected monosaccharides using
(NH4)2SO4 as a convenient promoter. To the best of our
knowledge, these phenanthroline N-glycosides and their
lesser stability of the N-glycoside, which undergoes side
reactions more easily.18 Hydrolysis, Amadori rearrangement or
melanoidine formation were described mainly in water, at high
temperature and in acid media.18,21,22 Moreover, the steric features
of the amine and the sugar as well as the reaction conditions exert
a strong influence on the stereoselectivity of the N-glycosylation.
Frequently, mixtures of the  and  anomers are obtained.19,23
59 complexes have been not reported previously.
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3
As a first step toward the synthesis of the N-phenanthroline
Table 2. Selected NMR parameters of the N--glycopyrano-
sylamines 2a-e
ACCEPTED MANUSCRIPT
glycosylamines, we decided to study the N-glycosylation of 5-
amino-1,10-phenanthroline and D-glucose in order to optimize
the reaction conditions in terms of yield, reaction time and
stereoselectivity of the N-glycosidic linkage. According to a
coupling strategy developed for the glycosylation of indolines
and applied for the synthesis of some indolo[2,3-a]carbazol
glycosides,20 the N-glycosylation reactions were performed using
a large excess of sugar (3-4 equiv.). Heating in methanol resulted
in low conversion even after 72 h (20-26%, Table 1, entry 1). In
aqueous phosphate buffer at pH 6.522 during 5 h at 40 ºC lesser
conversion was observed (12% Table 1, entry 2). Using a 1:1
mixture of methanol and aqueous phosphate buffer to work in
homogeneous medium at 65 ºC for 74 h the yield could be
increased to 72%. (Table 1, entry 3). With 3 equiv. of
monosaccharide and a catalytic amount of (NH4)2SO4 as
activator20 in methanol at 65 ºC for 24 h the starting 5-amino-
1,10-phenanthroline was exhausted and the N-glycosylation
occurred stereoselectively leading to the N--glycoside.
1
2a
2b
2c
2d
2e
1
2
3
4
5
6
7
8
9
(ppm)
H-1
-
4.64
6.89
7.00
8.12
8.84
84.7
4.62
6.90
7.01
8.11
8.87
85.2
5.01
6.27
7.07
8.13
8.60
81.4
5.02
6.24
7.03
8.20
8.59
81.0
4.62
6.86
6.97
8.17
8.86
84.8
NH
H-6’
6.14
6.84
8.03
8.66
-
H-7’
H-4’
C-1
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11
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J (Hz)
3JH1-H2
3JH1-NH
1JC1-H1
-
-
-
8.4
7.7
8.5
7.6
-
-
8.5
7.9
9.0
158
9.0
157
151
151
151
ppm and the introduction of carbohydrate moieties only slightly
affected their chemical shifts. From COSY and TOCSY correla
tions two groups of aromatic signals could be differentiated. The
assignment of these sets of signals to the two pyridine rings of
the phenanthroline system was based on the NOE correlations
found in the 2D ROESY spectra (Scheme 2). Thus, in the case of
2a the correlation between the singlet due to H-6’ at 7.00 ppm
and the doublet of doublets centred at 8.12 ppm allowed the
assignment of this signal to H-7’ while H-4’ resonates at 8.84
By using this procedure 5-amino-1,10-phenanthroline could
be glycosylated stereoselectively and the conversion was nearly
quantitative for all monosaccharides tested: D-glucose, D-galacto
se, D-mannose, L-rhamnose and L-fucose. The N--
glycopyranosylamines 2a-e (Scheme 1) could be obtained in
synthetically useful yields. - Anomers and/or other by-products
were not detectable in yields higher than 2%. The products were
isolated in yields ranging from 67% to 90% (Table 1, entries 4, 6,
7, 9 and 11); the lower yields being due to the fact that
1
ppm. The analysis of the direct and long-range H-13C correlated
26 derivatives 2b and 2e were more difficult to purify. Longer
spectra (gC2HSQCSE and gCH2MBC) allowed the assignment
of carbon resonances, once the signals of the respective protons
were established. Data are given in Table 2 and in the
experimental section.
reaction times led to lower yields (Table 1, entries 5, 8 and 10)
probably because the resulting N-glycosides underwent slow
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transformations
(decomposition,
hydrolysis,
Amadori
rearrangement, etc.) in the reaction conditions. This trend
suggests that the yield is ultimately limited by the stability of the
N--glycopyranosylamine.
The -anomeric configuration was assigned on the basis of
NOE experiments (2D ROESY spectra). The NOE cross-peaks
observed between H-1 and H-3/H-5 protons in all cases and
between H-1 and H-2 protons in 2c,d (Scheme 2) indicate an
axial disposition of the anomeric proton. In 2a,b,e the large
vicinal coupling constant of 7.6-7.9 Hz between anomeric H-1
and H-2 shows their trans-diaxial orientation and corroborates -
configuration.17,19,23,24 Moreover, anomeric proton and carbon
chemical shifts17,19,23,24 as well as the value of the 13C-1H direct
coupling constant for the C-1 carbon (1JCH = 151-158 Hz, Table
2)25 also support this statement. The experimental values of the
vicinal coupling constants for the protons of the pyranoside ring
The copper(II) complexes 3a-e were prepared by adding an
ethanolic solution of Cu(NO3)2∙3H2O to the corresponding N-
phenanthroline
glycosylamine
2a-e
(Phe-NH-Gly)
in
dimethylsulfoxide and heating the mixture at 65 ºC for 6 h. A 2:1
molar ratio ligand:copper salt was employed and the complexes
were isolated in good yields (ranging from 64 to 80%).
Interestingly, Cu complexation improved the solubility properties
of the N-glycopyranosylamines. This behaviour is particularly
important for the potential applications of these metallo-organic
derivatives.
4
indicate that these derivatives are almost completely in the C1
1
The N-glycopyranosylamines 2a-e were studied in depth by
1H and 13C NMR in (CD3)2SO. 2D-NMR techniques (1H-1H
gCOSY, TOCSY, ROESYAD, gC2HSQCSE, gCH2MBC) were
used for the identification and unambiguous assignment of the
conformation (2a,b,c) or C4 form (2d,e). The large values of
3
coupling constants JNH-H1 (7.6-9.0 Hz, Table 2) are consistent
with an anti relationship between NH and H-1 in (CD3)2SO
solution and may be rationalized in terms of a conformation
around C1-N bond that exhibits stabilizing exo-anomeric
interactions,25 greater for -manno and -rhamno derivatives
1
proton and carbon resonances. At 300 and 500 MHz the H NMR
spectra of 2a-e in (CD3)2SO exhibited high complexity in the
region around 3.2-5.2 ppm corresponding to the saccharide
moieties, due to the observation of the vicinal coupling constants
with OH and NH protons. Changes observed after D2O addition
facilitated the identification of acidic OH and NH proton
resonances and the analysis of the remaining signals. The
interpretation of the 1H-1H COSY and TOCSY spectra was based
on the unequivocal assignment of the signals corresponding to
the anomeric protons (H-1) and the 6-OH protons (apparent
triplet) in 2a-c or CH3-6 groups in 2d,e owing to their shape and
chemical shifts. In all cases, the NH proton appeared as a doublet
about 6.3-6.9 ppm. Aromatic protons resonate around 9.1-7.0
Scheme 2

4
Tetrahedron
ACCEPTED MANUSCRIPT
(2c,d). The comparison of the aromatic and NH proton chemical
shifts of the N-glycopyranosilamines 2a-e with those of the
parent amine 1 indicates a deshielding of NH (ca. 0.7 ppm) and
aromatic H-4’ and H-6’ protons (ca. 0.2 ppm) when 2-OH adopts
an equatorial position (2a,b,e, Table 2). The different values of
3JNH-H1 seem to be also influenced by the spatial disposition of the
2-OH. These findings might be related to a small dependence of
these parameters on the conformation around the C1-N bond
and/or the hydrogen bonding pattern, influenced by the 2-OH
spatial orientation.
All reagents were commercially available (Sigma-Aldrich) in
high purity and used as received. The N-glycosylation reactions
were monitored by thin-layer chromatography (TLC) and their
composition was determined by 1H-NMR spectroscopy. TLC was
performed on precoated Kieselgel 60 F254 aluminium sheets;
plates were eluted with methanol, dried and then eluted with
methanol-NH4OH (30%) 10:1; detection was first by UV and
then by charring with sulphuric acid in ethanol (1:4, v/v). Flash
chromatography was performed on Fluka Silica Gel 60 (230-400
mesh) enriched with approx. 0.1% Ca, using methanol as eluent.
Melting points were taken on an Electrothermal Digital IA9100
apparatus and were uncorrected. Optical rotations were measured
in HPLC grade dimethylsulfoxide on a Perkin-Elmer 341
polarimeter; []D values are given in 10-1 deg∙cm2∙g-1;
concentration is given in mg∙mL-1. FAB mass spectra were
obtained on a V. G. Autoexpec spectrometer using 3-nitrobenzyl
alcohol as the matrix. ESI mass (+ mode) spectra were performed
on a Thermo Scientific TSQ Quantum LC/MS or an Agilent 6210
LC/MS/TOF instruments. IR spectra (KBr disks) were recorded
on a FT-IR Perkin-Elmer Spectrum 2000 spectrophotometer. All
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The Cu(II) complexes 3a-e were characterized by elemental
analysis, MS spectrometry and FTIR-spectroscopy. A common
structural feature in these derivatives is the presence of a 2:1
mole ratio of the bidentate ligand and the metal. In order to avoid
interferences, ESI-MS spectra were recorded using water as
mobile phase. When the spectra were obtained in aqueous acetic
-
acid higher fragmentation and partial interchange of NO3 anion
for CH3COO- was observed leading to a superposition of sets of
peaks with m/z differences of 3 units. Thus, for 3a [Cu(Phe-NH-
Gly)2NO3]+/ [Cu(Phe-NH-Gly)2CH3COO]+ and [Cu(Phe-NH-
Gly)NO3]+/ [Cu(Phe-NH-Gly)CH3COO]+ species were found in
the spectrum. In these conditions the divalent fragment [Cu(Phe-
NH-Gly)2]2+ was also detected. In general, the complexes
exhibited very comparable IR features, suggesting that they are
of similar structure. A sharp band at ca. 1384 cm-1 appeared after
1
NMR spectra (1H, 13C, 2D H-1H gCOSY, TOCSY, ROESYAD,
gC2HSQCSE, gCH2MBC) were recorded on a Varian 300
UNITY-Plus or VNMRS-500 spectrometer in (CD3)2SO at 298 K
using standard pulse sequences. Chemical shifts are reported
relative to the residual (CHD2)2SO (H 2.50 ppm), or (CD3)2SO
(C 39.5 ppm); resonance patterns are reported with the notations
-
complex formation which was assigned to NO3 vibration. The
25 strong broad band in the region of 3300-3400 cm-1 corresponding
s (singlet), d (doublet), t (triplet), q (quartet), and m (multiplet);
in addition, the notations ap and br are used to indicate an
apparent multiplicity and a broad signal; geminal H-6 protons at
the sugar moieties resonating at low and high frequency were
assigned as H-6a and H-6b, respectively. Lorentz-Gauss
to O-H and N-H stretching vibrations showed a shift of 40 cm-1
26
towards lower frequency in 3b while it was shifted to higher
frequency in 3c (50 cm-1), 3d (72 cm-1) and 3e (20 cm-1)
compared to the ligands. These changes might be related to the
existence of different hydrogen bond networks in complexes and
in the free N-glycopyranosylamines.
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1
transformation was used to improve the resolution of the H
NMR spectra. Errors: H,  ± 0.01 ppm, J ± 0.1 Hz; 13C,  ± 0.1
1
The same coordination environments around copper centre
can be assumed for the Cu(II) complexes 3a-e bearing in mind
the similar behaviour observed. However, detailed structure
studies by X-ray analysis were not possible because of the
difficulties in obtaining suitable crystals, and exact coordination
geometry and spatial disposition of the non-symmetrical
substituted N-phenanthroline glycosylamine ligands could not be
established. Structure studies on related Cu(II) complexes
indicate that the copper atom is usually pentacoordinate and that
geometries ranging from distorted trigonal bipyramidal to square
pyramidal are typical of them.26
ppm.
5-Amino-1,10-phenanthroline (1) was prepared from 5-nitro-
1,10-phenanthroline as previously described27 by reduction with
hydrazine hydrate using Pd/C 10% as catalyst. H (500 MHz;
(CD3)2SO) 6.14 (2H, br s, NH2), 6.84 (1H, s, H-6), 7.49 (1H, dd,
J 8.1, 4.3 Hz, H-8), 7.72 (1H, dd, J 8.4, 4.3 Hz, H-3), 8.03 (1H,
dd, J 8.1, 1.7 Hz, H-7), 8.66 (1H, dd, J 8.4, 1.7 Hz, H-4), 8.67
(1H, dd, J 4.3, 1.7 Hz, H-9), 9.04 (1H, dd, J 4.3, 1.7 Hz, H-2). C
(125 MHz; (CD3)2SO) 101.8 (C-6), 121.8 (C-4a), 122.0 (C-3),
123.2 (C-8), 130.6 (C-6a), 130.8 (C-4), 132.7 (C-7), 140.5, 142.7
(C-5, C-10a), 144.8 C-9), 146.2 (C-10b), 149.3 (C-2).
3. Conclusion
4.2. Synthesis of N-(1,10-phenanthrolin-5-yl)--glycopyranosyl
amines
Treatment of 5-amino-1,10-phenanthroline with different
unprotected monosaccharides under optimized conditions led to
N-(1,10-phenanthrolin-5-yl)--glycopyranosylamines
with
General Procedures
excellent stereoselectivity and synthetically useful yields. Cu(II)
complexes having a 2:1 mole ratio of the bidentate ligand
phenanthroline N-glycoside and the metal were also prepared
with good yields. Regarding the potential applications, the high
solubility of these metallo-organic compounds may be
particularly important for an efficient activity. In addition, the
introduction of chirality via the carbohydrate unit might confer
selectivity and good binding affinity towards the chiral DNA
Method A. 5-Amino-1,10-phenanthroline (49 mg, 0.25 mmol)
was dissolved in 4 mL of MeOH. D-glucose monohydrate (0.75
or 1.00 mmol) was then added and the mixture was stirred at 65
ºC. After 72 h, the reaction was allowed to cool to room
temperature and concentrated.
Method B. A stirred suspension of 5-amino-1,10-phenanthroline
(49 mg, 0.25 mmol) and D-glucose monohydrate (198 mg, 1.00
mmol) in 2 mL of aqueous Na2HPO4/NaH2PO4, (50 mM, pH 6.5)
was heated at 40 ºC for 5 h. The reaction mixture was worked up
as described above.
55 biomolecule. Further experiments designed to confirm these
hypotheses are currently underway.
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4. Experimental
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4.1. General methods
Method C. This procedure is analogous to method B using a 1:1
mixture of MeOH (2 mL, to dissolve the amine) and aqueous

5
phosphate buffer (2 mL) and a molar ratio monosaccharide:
amine 3:1 at 65 ºC for 74 h.
N-(1,10-phenanthrolin-5-yl)-β-D-mannopyranosylamine
ACCEPTED MANUSCRIPT
(2c). Slightly yellowish solid; yield: 336 mg (90%); Rf = 0.42;
mp 239-242 ºC (decomposition); [Found: C, 57.7; H, 5.5; N,
11.4. C18H19N3O5∙H2O requires C, 57.6; H, 5.6; N, 11.2%]; [α]D
22
Method D. stirred solution of the 5-amino-1,10-
A
1
2
3
4
phenanthroline (195 mg, 1 mmol), the monosaccharide (3 mmol)
and ca. 4 mg of (NH4)2SO4 in 16 mL of MeOH was heated at 65
ºC for 24 or 48 h. During this time a pale yellow precipitate was
accumulated. The reaction mixture was cooled and the solid
-149 (c 1.70 in DMSO); IR (KBr) νmax 3307 br (NH and OH),
1617 s (NH), 1520 s (C=C), 1086 s, 1058 s, 741 cm-1; H (500
MHz; (CD3)2SO) 3.34 (1H, ddd, J 9.4, 5.9, 2.1 Hz, H-5), 3.45
(1H, ddd, J 9.4, 9.1, 4.9 Hz, H-4), 3.47 (1H, ddd, J -11.7, 6.3,
5.9 Hz, H-6a), 3.50 (1H, ddd, J 9.1, 6.1, 3.2 Hz, H-3), 3.73 (1H,
ddd, J -11.7,5.4, 2.1 Hz, H-6b), 3.93 (1H, dd, J 4.9, 3.2 Hz, H-2),
4.40 (1H, dd, J 6.3, 5.4 Hz, 6-OH), 4.74 (1H, d, J 6.1 Hz, 3-OH),
4.80 (1H, d, J 4.9 Hz, 4-OH), 5.01 (1H, d, J 9.0 Hz, H-1), 5.20
(1H, d, J 4.9 Hz, 2-OH), 6.27 (1H, d, J 9.0 Hz, NH), 7.07 (1H, s,
H-6’), 7.58 (1H, dd, J 8.1, 4.2 Hz, H-8’), 7.78(1H, dd, J 8.6, 4.2
Hz, H-3’), 8.13 (1H, dd, J 8.1, 1.6 Hz, H-7’), 8.60 (1H, dd, J 8.8,
1.6 Hz, H-4’), 8.7 7 (1H, dd, J 4.2, 1.6 Hz, H-9’), 9.08 (1H, dd, J
4.2, 1.6 Hz, H-2’); C (125 MHz; (CD3)2SO) 60.7 (C-6), 66.7 (C-
5 obtained was separated by filtration and washed with MeOH
(2x10 mL) and H2O (2x10 mL) to eliminate excess of sugar and
possible traces of the starting amine and/or other by-products as
well to remove the (NH4)2SO4 salt, followed by Et2O. This
6
7
8
protocol
provided
pure
N-(1,10-phenanthrolin-5-yl)--
9
glycopyranosyl amines 2a, 2c and 2d. For derivatives 2b and 2e
the starting sugar could not be completely removed and a
subsequent purification was required. The product was
preadsorbed on silica gel and purified by flash chromatography.
After drying in vacuum the purity of the products was checked
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1
by TLC, H-NMR and analytical data. Derivatives 2a-e were
4), 70.6 (C-2), 73.8 (C-3), 77.7 (C-5), 81.4 (C-1, JC1-H1 158 Hz),
obtained as monohydrates and exhibited poor solubility in water
and organic solvents.
102.5 (C-6’), 121.4 , 121.9(C-3’, C-4’a), 122.8 (C-8’), 129.2,
129.5 (C-4’, C-6’a), 133.4 (C-7’), 138.7, 140.7 (C-5’, C-10’a),
145.4, 145.5 (C-9’, C-10’b), 149.0 (C-2’); LRMS (ESI) m/z 358
(M + H)+.
N-(1,10-phenanthrolin-5-yl)-β-D-glucopyranosylamine (2a).
Pale yellow powder; yield: 332 mg (88%); Rf = 0.51; mp 214-216
ºC (decomposition); [Found: C, 57.2; H, 5.6; N, 11.4.
C18H19N3O5∙H2O requires C, 57.6; H, 5.6; N, 11.2%]; [α]D22 -130
(c 3.03 in DMSO); IR (KBr) νmax 3355 br (NH and OH), 1621 s
(NH), 1548 s (C=C), 1077 s, 1028 s, 737 cm-1; H (500 MHz;
(CD3)2SO) 3.21 (1H, tdap, J 9.6, 8.7, 5.1 Hz, H-4), 3.34 (1H,
tdap, J 8.7, 8.1, 4.4 Hz, H-3), 3.39 (1H, ddd, J 9.6, 5.6, 2.2 Hz,
H-5), 3.49 (2H, m, H-2, H-6a), 3.73(1H, ddd, J -11.8, 5.7, 2.2
Hz, H-6b), 4.48 (1H, tap, J 5.7 Hz, 6-OH), 4.64 (1H, tap, J 8.4,
7.7 Hz, H-1), 4.97 (1H, d, J 5.1 Hz, 4-OH), 5.05 (2H, dap, J 4.4
Hz, 2-OH, 3-OH), 6.89 (1H, d, J 7.7 Hz, NH), 7.00 (1H, s, H-6´),
7.55 (1H, dd, J 8.1, 4.3 Hz, H-8’), 7.75 (1H, dd, J 8.4, 4.3 Hz, H-
3’), 8.12 (1H, dd, J 8.1, 1.6 Hz, H-7’), 8.74 (1H, dd, J 4.3, 1.6
Hz, H-9’), 8.84 (1H, dd, J 8.4, 1.6 Hz, H-4’), 9.05 (1H, dd, J 4.3,
1.6 Hz, H-2’); C (125 MHz; (CD3)2SO) 60.4 (C-6), 69.7 (C-4),
N-(1,10-phenanthrolin-5-yl)-β-L-rhamnopyranosylamine (2d)
Slightly yellowish solid; yield: 324 mg (90%); Rf = 0.58; mp
216-218 ºC (decomposition); [Found: C, 60.5; H, 5.7; N, 11.4.
C18H19N3O4∙H2O requires C, 60.2; H, 5.9; N, 11.7%]; [α]D22 +119
(c 2.80 in DMSO); IR (KBr) νmax 3308 br (NH and OH), 1617 s
(NH), 1519 s (C=C), 1091 s, 1066 s, 739 cm-1; H (500 MHz;
(CD3)2SO) 1.19 (3H, d, J 6.2 Hz, CH3-6), 3.23 (1H, tdap, J 9.3,
5.4 Hz, H-4), 3.42 (1H, dq, J 9.3, 6.2 Hz, H-5), 3.46 (1H, ddd, J
9.3, 6.0, 3.4 Hz, H-3), 3.92 (1H, dd, J 5.0, 3.4 Hz, H-2), 4.73
(1H, d, J 6.0 Hz, 3-OH), 4.84 (1H, d, J 5.4 Hz, 4-OH), 5.02 (1H,
d, J 9.0 Hz, H-1), 5.23 (1H, d, J 5.0 Hz, 2-OH), 6.24 (1H, d, J 9.0
Hz, NH), 7.03 (1H, s, H-6’), 7.57 (1H, dd, J 8.1, 4.2 Hz, H-8’),
7.78 (1H, dd, J 8.4, 4.2 Hz, H-3’), 8.20 (1H, dd, J 8.1, 1.8 Hz, H-
7’), 8.59 (1H, dd, J 8.4, 1.6 Hz, H-4’), 8.77 (1H, dd, J 4.2, 1.8
Hz, H-9’), 9.08 (1H, dd, J 4.2, 1.6 Hz, H-2’); C (125 MHz;
(CD3)2SO) 17.6 (C-6), 70.7, 71.6 (C-2, C-4), 72.3, 73.5 (C-3, C-
5), 81.0 (C-1, 1JC1-H1 157 Hz), 102.0 (C-6’), 121.3, 121.9(C-3’, C-
4’a), 122.8 (C-8’), 129.2, 129.4 (C-4’, C-6’a), 133.4 (C-7’),
138.6, 140.7 (C-5’, C-10’a), 145.4, 145.6 (C-9’, C-10’b), 149.0
(C-2’); LRMS (ESI) m/z 342 (M + H)+.
1
72.1 (C-2), 77.1, 77.2 (C-3, C-5), 84.7 (C-1, JC1-H1=151 Hz),
101.3 (C-6’), 121.5, 121.6 (C-3’, C-4’a), 122.8 (C-8’), 129.6,
130.1 (C-4’, C-6’a), 133.3 (C-7’), 139.90, 140.5 (C-5’, C-10’a),
145.2, 145.4 (C-9’, C-10’b), 148.9 (C-2’); LRMS (ESI) m/z 358
(M + H)+.
N-(1,10-phenanthrolin-5-yl)-β-D-galactopyranosylamine (2b).
Pale yellow powder; yield: 254 mg (68%); Rf = 0.45; mp 225-
228 ºC (decomposition); [Found: C, 57.3; H, 5.3; N, 11.5.
N-(1,10-phenanthrolin-5-yl)-β-L-fucopyranosylamine
(2e).
Pale yellow powder; yield: 239 mg (67%); Rf = 0.55; mp 230-232
22
C18H19N3O5∙H2O requires C, 57.6; H, 5.6; N, 11.2%]; [α]D -95
ºC (decomposition); [Found: C, 60.4; H, 6.2; N, 12.0.
(c 2.54 in DMSO); IR (KBr) νmax 3402 br (NH and OH), 1616 s
22
C18H19N3O4∙H2O requires C, 60.2; H, 5.9; N, 11.7%]; [α]D +82
44 (NH), 1538 s (C=C), 1075 s, 1042 s, 737 cm-1; H (500 MHz;
(c 2.01 in DMSO); IR (KBr) νmax 3384 br (NH and OH), 1618 s
(NH), 1542 s (C=C), 1081 s, 1069 s, 735 cm-1; H (500 MHz;
(CD3)2SO) 1.18 (3H, d, J 6.3, CH3-6), 3.49 (1H, ddd, J 9.4, 5.4,
3.3, H-3), 3.57 (1H, tap, J 4.3, 3.3, H-4), 3.79 (1H, ddd, J 9.4,
8.5, 5.1, H-2), 3846 (1H, q, J 6.3, H-5), 3.80 (1H, dd, J 3.9, 3.3m,
H-4), 3.82 (1H, ddd, J 9.3, 8.5, 5.0, H-2), 4.46 (1H, d, J 3.9, 4-
OH), 4.50 (1H, d, J 4.3, 4-OH), 4.62 (1H, tap, J 8.5, 7.9, H-1),
4.82 (1H, d, J 5.4, 3-OH), 4.86 (1H, d, J 5.1, 2-OH), 6.86 (1H, d,
J 7.9, NH), 6.97 (1H, s, H-6’), 7.56 (1H, dd, J 8.2, 4.2, H-8’),
7.76 (1H, dd, J 8.6, 4.2 Hz, H-3’), 8.17 (1H, dd, J 8.2, 1.7, H-7’),
8.75 (1H, dd, J 4.2, 1.7, H-9’), 8.86 (1H, dd, J 8.6, 1.6, H-4’),
9.07 (1H, dd, J 4.2, 1.6, H-2’); C (125 MHz; (CD3)2SO) 16.5 (C-
6), 68.9 (C-2), 70.2 (C-5), 70.8 (C-4), 73.8 (C-3), 84.8 (C-1, 1JC1-
(CD3)2SO) 3.48 (1H, ddd, J 9.3, 5.0, 3.3 Hz, H-3), 3.52 (1H, ddd,
J -11.3, 5.5, 4.0 Hz, H-6a), 3.57 (1H, ddd, J -11.3, 6.1, 4.5 Hz, H-
6b), 3.66 (1H, tap, J 6.1, 5.5 Hz, H-5), 3.80 (1H, dd, J 3.9, 3.3
Hz, H-4), 3.82 (1H, ddd, J 9.3, 8.5, 5.0 Hz, H-2), 4.46 (1H, d, J
3.9 Hz, 4-OH), 4.61 (1H, tap, J 4.5, 4.0 Hz, 6-OH), 4.62 (1H, tap,
J 8.5, 7.6 Hz, H-1), 4.86 (1H, d, J 5.0 Hz, 3-OH), 4.92 (1H, d, J
5.0 Hz, 2-OH), 6.90 (1H, d, J 7.6 Hz, NH), 7.01 (1H, s, H-6’),
7.56 (1H, dd, J 8.1, 4.2 Hz, H-8’), 7.75(1H, dd, J 8.5, 4.2 Hz, H-
3’), 8.11 (1H, dd, J 8.1, 1.7 Hz, H-7’), 8.75 (1H, dd, J 4.2, 1.7
Hz, H-9’), 8.87 (1H, dd, J 8.5, 1.6 Hz, H-4’), 9.06 (1H, dd, J 4.2,
1.6 Hz, H-2’); C (125 MHz; (CD3)2SO) 60.1 (C-6), 67.9 (C-4),
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
1
69.2 (C-2), 73.7 (C-3), 75.4 (C-5), 85.2 (C-1, JC1-H1 151 Hz),
101.2 (C-6’), 121.5 (C-3’, C-4’a), 122.8 (C-8’), 129.6, 130.2 (C-
4’, C-6’a), 133.2 (C-7’), 139.9, 140.5 (C-5’, C-10’a), 145.2,
145.4 (C-9’, C-10’b), 148.8 (C-2’); LRMS (ESI) m/z 358 (M +
H)+.
151 Hz), 100.8 (C-6’), 121.5, 121.6 (C-3’, C-4’a), 122.8 (C-
H1
8’), 129.7, 130.3 (C-4’, C-6’a), 133.3 (C-7’), 140.1, 140.5 (C-5’,
C-10’a), 145.2, 145.4 (C-9’, C-10’b), 148.9 (C-2’); LRMS (ESI)
m/z 342 (M + H)+.

6
Tetrahedron
ACCEPTED MANUSCRIPT
the European Community’s Seventh Framework Programme
Synthesis of copper(II) complexes.
([FP7/2007-2013, under grant agreement 248638, to L.G. and
K.D.]). We thank C. García for her collaboration in the synthesis
of the Cu(II) complexes.
1
General method. A stirred suspension of the N-phenanthroline
2 glycopyranosylamine 2a-e (0.1 mmol) in DMSO (1 mL) was
heated at 65 ºC for 30 min (a clear solution was obtained for 2a,
2b and 2e) and then an ethanol solution of Cu(NO3)2∙3H2O
(0.052 M, 0.052 mmol) was added. The colour changed
immediately to dark green and after heating for 6 h at this
temperature the solution obtained was allowed to stand overnight
at room temperature. Solvents were removed and the residue
dissolved in the minimum amount of MeOH and treated with
acetonitrile. The precipitate was separated out, washed with
acetonitrile and dried in vacuum, affording the pure Cu(II)
complexes 3a-e as green powders. Single crystals suitable for X-
ray analysis could not be obtained in the different conditions
assayed. While the N-phenanthroline glycopyranosylamines 2a-e
have disappointing solubility, their Cu complexes exhibited
better solubility properties.
3
4
5
6
7
8
9
Supplementary Material
1H and 13C NMR spectra of N-(1,10-phenanthrolin-5-yl)--
glycopyranosylamines 2a-e, 2D-NMR spectra of 2a and MS
spectra of Cu(II) complex 3a. Supplementary data associated
with this article can be found at…
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References and notes
1. Norris, P. Curr. Top. Med. Chem. 2008, 8, 101-113.
2. Prudhomme, M. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4,
509-521.
3. Garbutcheon-Singh, K. B.; Grant, M. P.; Harper, B. W.; Krause-
Heuer, A. M.; Manohar, M.; Orkey, N.; Aldrich-Wright, J. R.
Curr. Top. Med. Chem. 2011, 11, 521-542.
4. (a) Wesselina, D.; Neykov, M.; Kaloyanov, N.; Toshkova, R.;
Dimitrov, G. Eur. J. Med. Chem. 2009, 44, 2720-2723; (b)
Ramakrishnan, S.; Rajendiran, V.; Palaniandavar, M.; Periasamy,
V. S.; Srinag, B. S.; Krishnamurthy, H.; Akbarsha, M. A. Inorg.
Chem. 2009, 48, 1309-1322; (c) Arias, M. S.; González-Álvarez,
M.; Fernández, M. J.; Lorente, A.; Alzuet, G.; Borrás, J. J. Inorg.
Biochem. 2009, 103, 1069-1073; (d) González-Álvarez, M.; Arias,
M. S.; Fernández, M. J.; Gude, L.; Lorente, A.; Alzuet, G.; Borrás,
J. Bioorg. Med. Chem. Lett. 2008, 18, 3286–3290; (e) Thomas, A.
M.; Nethaji, M.; Chakravarty, A. R. J. Inorg. Biochem. 2004, 98,
1087–1094; (f) Chikira, M.; Tomizava, Y.; Fukita, D.; Sugizaki,
T.; Sugawara, N.; Yamazaki, T.; Sasano, A.; Shindo, S.;
Palaniandavar, M.; Anthroline, W. E. J. Inorg. Biochem. 2002, 89,
163–173.
5. Mocellin, S.; Pooley, K. A.; Nitti, D. Trends Mol. Med. 2013, 19,
125-133
6. Armanios, M. J. Clin. Invest. 2013, 123, 996-1002.
7. Kim, N. W.; Piatyszek, M. A.; Prowse, K. R.; Harley, C. B.; West,
M. D.; Ho, P. L.; Coviello, G.M.; Wright, W.E.; Weinrich, S. L.;
Shay, J. W. Science, 1994, 266, 2011-2015.
8. (a) Ruden, M.; Puri, N. Cancer Treat. Rev. 2013, 39,444-456; (b)
Harley, C. B. Nat. Rev. Cancer, 2008, 8, 167-179.
9. Balasubramanian, S.; Hurley, L. H.; Neidle, S. Nat. Rev. Drug
Discov. 2011, 10, 261-275.
Cu(Phe-NH-Glucopyranosylamine)2(NO3)2∙4H2O (3a). Green
powder; yield: 41 mg (84%); [Found: C, 43.9; H, 4.6; N, 11.4.
C36H38CuN8O16∙4H2O requires C, 44.4; H, 4.8; N, 11.5%]; IR
(KBr) νmax 3355 br (NH and OH), 1625 (NH), 1600, 1542
-
(C=C), 1384 s (NO3 ), 1074, 1015, 724 cm-1; FAB-MS (m-NBA)
m/z 839 (M –NO3)+; LRMS (ESI, H2O-CH3COOH) m/z 839 (2)
(M – NO3)+ [Cu(Phe-NH-Gly)2NO3]+, 836 (10) [Cu(Phe-NH-
Gly)2CH3COO]+, 482 (35) Cu(Phe-NH-Gly)NO3]+, 479 (68)
[Cu(Phe-NH-Gly)CH3COO]+, 388.5 (47) [Cu(Phe-NH-Gly)2]+2,
358 (100%) [(Phe-NH-Gly) + H]+; HRMS (ESI-TOF, H2O): (M –
NO3)+ [Cu(Phe-NH-Gly)2NO3]+, found 839.1820 C36H38CuN7O13
requires 839.1824.
Cu(Phe-NH-Galactopyranosylamine)2(NO3)2∙4H2O (3b). Dark
green powder; yield: 39 mg (80%); [Found: C, 44.0; H, 4.7; N,
11.7. C36H38CuN8O16∙4H2O requires C, 44.4; H, 4.8; N, 11.5%];
IR (KBr) νma-x 3365 br (NH and OH), 1623 (NH), 1535 (C=C),
1384 s (NO3 ), 1082 br, 724 cm-1; LRMS (ESI, H2O) m/z 839 (M
– NO3)+ [Cu(Phe-NH-Gly)2NO3]+.
Cu(Phe-NH-Mannopyranosylamine)2(NO3)2∙4H2O (3c). Green
10. (a) Murat, P.; Singh, Y.; Defrancq E. Chem. Soc. Rev. 2011, 40,
5293-5307. (b) Yang, D.; Okamoto, K. Future Med. Chem., 2010,
2, 619-646;
11. (a) Campbell, N. H.; Abd Karim, N. H.; Parkinson, G. N.;
Gunaratnam, M.; Petrucci, V.; Todd, A. K.; Vilar, R.; Neidle, S. J.
Med. Chem, 2012, 55, 209-222; (b) Castor, K. J.; Mancini, J.;
Fakhoury, J.; Weill, N.; Kieltyka, R.; Englebienne, P.; Avakyan,
N.; Mittermaier, A.; Autexier, Ch.; Moitessier, N.; Sleiman, H.
ChemMedChem, 2012, 7, 85-94.
12. (a) Dixon, I. M.; López, F.; Tejera, A. M.; Estève, J.-P.; Blasco,
M. A.; Pratviel, G.; Meunier, B. J. Am. Chem. Soc. 2007, 129,
1502-1503; (b) Tan, J.-H.; Gu L.-Q.; Wu, J.-Y. Mini Rev. Med.
Chem. 2008, 8, 1163-1178.
13. (a) Wei, C.; Wang, Y.; Zhang, M. Org. Biomol. Chem. 2013, 11,
2355-2364; (b) Larsen, A. F.; Nielsen, M. C.; Ulven, T. Chem.
Eur. J. 2012, 18, 10892-10902; (c) Wang, L. H.; Wen,Y.; Liu, J.;
Zhou, J.; Li, C.; Wei, C. Y. Org. Biomol. Chem. 2011, 9, 2648-
2653; (d) Bianco, S.; Musetti, C.; Waldeck, A.; Sparapani, S.;
Seitz, J. D.; Krapcho, A. P.; Palumbo, M.; Sissi, C. Dalton Trans.
2010, 39, 5833–5841; (e) Reed, J. E.; White, A. J. P.; Neidle, S.;
Vilar, R. Dalton Trans. 2009, 2558-2568; Nielsen, M. C.; Borch,
J.; Ulven, T. Bioorg. Med. Chem. 2009, 17, 8241-8246; (f)
Kieltyka, R.; Fakhoury, J.; Moitessier, N.; Sleiman, H. F. Chem.
Eur. J. 2008, 14, 1145-1154; (g) De Cian, A.; DeLemos, E.;
Mergny, J.-L.; Teulade-Fichou, M.-P.; Monchaud, D. J. Am.
Chem. Soc. 2007, 129, 1856-1857.
37 powder; yield: 46 mg (86%); [Found: C, 44.1; H, 4.5; N, 11.9.
C36H38CuN8O16∙4H2O requires C, 44.4; H, 4.8; N, 11.5%];. IR
38
39 (KBr) νmax 3351 br (NH and OH), 1624 (NH), 1528 (C=C),
1384 s (NO3 ), 1104 br, 721 cm-1; LRMS (ESI, H2O) m/z 839 (M
-
40
41
– NO3)+ [Cu(Phe-NH-Gly)2NO3]+.
42
Cu(Phe-NH-Rhamnopyranosylamine)2NO3)2∙4H2O
(3d).
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
Green powder; yield: 30 mg (64%); [Found: C, 45.5; H, 4.5; N,
12.3. C36H38CuN8O14∙4H2O requires C, 45.9; H, 4.9; N, 11.9%];
IR (KBr) νma-x 3380 br (NH and OH), 1623 (NH), 1528 (C=C),
1384 s (NO3 ), 1107 br, 1056 br, 721 cm-1; LRMS (ESI, H2O) m/z
807 (M – NO3)+ [Cu(Phe-NH-Gly)2NO3]+.
Cu(Phe-NH-Fucopyranosylamine)2(NO3)2∙4H2O (3e). Green
powder; yield: 33 mg (70%); [Found: C, 45.4; H, 4.6; N, 11.6.
C36H38CuN8O14∙4H2O requires C, 45.9; H, 4.9; N, 11.9%]; IR
(KBr) νmax 3406 br (NH and OH), 1623 (NH), 1536 (C=C),
-
1383 s (NO3 ), 1085 br, 726 cm-1; LRMS (ESI, H2O) m/z 807 (M
– NO3)+ [Cu(Phe-NH-Gly)2NO3]+.
Acknowledgments
14. Gómez-Pinto, I.; Vengut-Climent, E.; Lucas, R.; Aviñó, A.;
Reitja, R.; González, C.; Morales. J. C. Chem. Eur. J. 2013, 19,
1920-1927 and references cited herein.
This research has received funding from the MICINN (project
CTQ2011-26822), the MINECO (project CTQ2012-32711) and

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15. Bugaut, A.; Jantos, K.; Wietor, J.-L.; Rodriguez, R.; Sanders, J. K.
ACCEPTED MANUSCRIPT
M.; Balasubramanian, S. Angew. Chem. Int. Ed., 2008, 47, 2677-
2680.
16. (a) Fusaro, M. B.; Chagnault, V.; Postel, D. Tetrahedron, 2013,
69, 542-550; (b) Dhinakaran M. K.; Das, T. M. Org. Biomol.
Chem. 2012, 10, 2077-2083; (c) Rajasekar, M.; Khan, S. M.;
Devaraj, S. N.; Das, T. M. Carbohydr. Res. 2011, 346, 1776-1785;
(d) Genady, A. R.; El-Zaria, M. E. Appl. Organometal. Chem.
2008, 227-232.
1
2
3
4
5
6
7
8
17. (a) Rajsekhar, G.; Rao, C. P.; Saarenketo, P.; Kolehmainen, E.;
Rissanen, K. Carbohydr. Res. 2002, 337, 187-194; (b) Qian, X.;
Li, Z.; Song, G. Carbohydr. Res. 2001, 336, 79-82
18. (a) Gokhale, M. Y.; Kirsch, L. E. J. Pharm. Sci. 2009, 98, 4639-
4649; (b) Kublashvili, R. I.; Labartkava, M. O.; Giorgadze, K. P.;
Ugrekhelidze, D. Sh. Chem. Nat. Compd. 2008, 44 , 413-415.
19. Du, W.; Hu, Y. Synth. Commun. 2004, 34, 2987-2992
20. Chisholm, J. D.; van Vranken, D. L. J. Org. Chem. 2000, 65,
7541-7553.
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16
17
18
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53
54
55
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57
58
59
60
61
62
63
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21. Bridiau, N.; Cabane, S.; Maugard, T. Tetrahedron, 2009, 65, 531-
535.
22. Bridiau, N.; Benmansour, M.; Legoy, M. D.; Maugard. T.
Tetrahedron, 2007, 63, 4178-4183.
23. Das, T. M.; Rao, C. P.; Kolehmainen, E. Carbohydr. Res. 2001,
334, 261-269.
24. Duus, J. O.; Gotfredsen, C. H.; Bock, K. Chem. Rev. 2000, 100,
4589–4614.
25. Batchelor, R. J.; Green, D. F.; Johnston, B. D.; Patrick, B. O.;
Pinto, B. M. Carbohydr. Res. 2001, 330, 421-426.
26. (a) Zhong K.-L.; Cao, G.-Q. Acta Cryst. 2013, E69, m40–m41; (b)
Catalan, K. J.; Jackson, S.; Zubkowski, J. D.; Perry, D. L.;
Valente, E. J.; Feliu L. A.; Polanco, A. Polyhedron, 1995, 14,
2165-2171; (c) Murphy, G.; Murphy, C.; Murphy, B.; Brian, H. J.
Chem. Soc., Dalton Trans. 1997, 2653-2660.
27. Lecomte, J. P.; Mesmaeker, A. K. D.; Demeunynck, M.; Lhomme,
J. J. Chem. Soc. Faraday Trans. 1993, 89, 3261-3269.

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Tetrahedron
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Figure Captions
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Scheme 1. Synthesis of N-(1,10-phenanthrolin-5-yl) -
glycopyranosylamines 2a-e and their copper(II)
complexes
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Scheme 2. Glycopyranosylamine 2c showing the atomic
numbering and NOE contacts.
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Table(s)
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Table 1. N-Glycosylation reactions of 5-amino-1,10-phenanthroline
Temperature
Reaction
time (h)
Glycopyranosylamine,
yield (%)c
Entry
Monosaccharide
D-glucose
Methoda
Reaction medium
Methanol
(ºC)
1
2
A
B
65
40
72
5
2a, 20-26
Aqueous phosphate
bufferb
12
3
C
D
Methanol-aqueous
phosphate buffer (1:1)
65
74
72
4
5
Methanol/(NH4)2SO4
65
65
65
65
65
65
65
65
24
48
24
24
48
24
48
24
88
79
6
D-galactose
D-mannose
D
D
Methanol/(NH4)2SO4
Methanol/(NH4)2SO4
2b, 68
2c, 90
80
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8
9
L-rhamnose
L-fucose
D
D
Methanol/(NH4)2SO4
Methanol/(NH4)2SO4
2d, 90
81
10
11
2e, 67
a Molar ratio monosaccharide:amine 3:1 for entries 1 (yield 20%), 3-11 and 4:1 for entries 1 (yield 26%) and 2. [amine] = 0.06 M except for entry 2
0.13 M.
b Aqueous phosphate buffer Na2HPO4/NaH2PO4, 50 mM, pH 6.5.
c Yields of isolated products except for entries 1-3 in which cases these values correspond to the conversion of starting amine and were determined
by 1H-NMR (± 1%).