Toward the supramolecular cyclodextrin dimers using nucleobase pairs

Article abstract of DOI:10.1055/s-0030-1258354

The synthesis of eleven new cyclodextrin derivatives having nucleobase moiety - thymin-1-yl, adenin-9-yl, and guanin-9-yl - is described. These two moieties are linked by different spacers, such as aminoethyl and 1,2,3-triazolyl group. Direct nucleophilic substitution and 1,3-dipolar cycloaddition were performed in good yields (13-73%) for some of the synthesized compounds. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258354

PAPER
235
Toward the Supramolecular Cyclodextrin Dimers Using Nucleobase Pairs
S
upramolecular Cy
a
clodextrin
n
Dimer
s
essa Legros,a Florian Hamon,a Bruno Violeau,a Frédéric Turpin,b Florence Djedaini-Pilard,c Jérôme Désiré,a
Christophe Len*d
a
Université de Poitiers, UMR 6514 CNRS, Synthèse et Réactivité des Substances Naturelles, 40 avenue du Recteur Pineau,
86022 Poitiers cedex, France
Biocydex, 40 avenue du Recteur Pineau, 86022 Poitiers cedex, France
Université de Picardie Jules Verne, UMR 6219 CNRS, Laboratoire des Glucides, 33 rue Saint Leu, 80039 Amiens, France
Université de Technologie de Compiègne, Ecole Supérieure de Chimie Organique et Minérale, EA 4297 UTC/ESCOM,
b
c
d
1 allée du Réseau Jean-Marie Buckmaster, 60200 Compiègne, France
Fax +33(3)44971591; E-mail: christophe.len@utc.fr
Received 1 September 2010; revised 20 October 2010
organization behaviors have not been extensively investi-
gated.17 The supramolecular assembly could be obtained
by association of nucleobases such as adenine and thym-
ine or guanine and cytosine. Few examples of CD deriva-
Abstract: The synthesis of eleven new cyclodextrin derivatives
having nucleobase moiety – thymin-1-yl, adenin-9-yl, and guanin-
9-yl – is described. These two moieties are linked by different spac-
ers, such as aminoethyl and 1,2,3-triazolyl group. Direct nucleo-
philic substitution and 1,3-dipolar cycloaddition were performed in tives having nucleobase were described in the literature,
but only the study of CD monomers were reported.18–23 As
good yields (13–73%) for some of the synthesized compounds.
previously reported by Len’s group,18 the apparent associ-
Key words: click chemistry, nucleobase, cyclodextrin
ation constant between two nucleobases appended per-
methylated cyclodextrin derivatives was determined by
NMR in CDCl3. The self-assembly property of CD deriv-
Cyclodextrins (CDs) are versatile macrocyclic maltooli-
atives 13b and 14b was KTT = 22 M–1 and KAA = 16 M–1
gosaccharides composed of a-(1→4)-linked D-glucopyra-
4
respectively. The association constant for heterodimeriza-
nose units in C1 chair conformation and are produced
tion of 13b and 14b in a 1:1 stoichiometry was KAT = 385
M–1 supporting the formation of supramolecular het-
erodimer of modified cyclodextrins. The presence of
bulky CDs did not perturb the interactions between nucleo-
bases. In this paper, we report our contribution regarding
the synthesis of different CD monomers having a nucleo-
base such as adenine, thymine, and guanine. Such com-
pounds are obtained by nucleophilic substitution and by
click chemistry coupling. In order to access dimers having
different physical properties, three major structural varia-
tions have been studied: (i) glycone moiety such as
monoamino-b-CD, monoazido-b-CD, monoamino per-
methylated or monoazido permethylated b-CD deriva-
tives; (ii) nature of the linker such as aminoethyl group or
1,2,3-triazol-4-yl methyl group; and (iii) modulation of
the nucleobase such as adenine, thymine, or guanine.
from starch by enzymatic conversion in nature. The most
common CDs have six, seven, and eight D-glucopyranose
units and are referred to as a-, b-, and g-CD, respectively.
In the case of b-CD, the polyhydroxylated compound has
got a primary face of 7 hydroxy groups and a secondary
face of 14 hydroxy groups. As a consequence of the struc-
ture, the molecule is hydrophilic and features a conical
cavity that is essentially hydrophobic in nature. It is well
known that CDs can form inclusion complexes with a va-
riety of guest molecules due to its unique hydrophobic
cup-like structure. Among these properties, the ability to
form drug carrier,1–3 separation reagents,4–6 enzyme mim-
ics,7,8 photochemical sensors,9,10 catalysis,11,12 host–guest
interactions,13 and molecular recognition14 are probably
the most commercially valuable. Compared to CD mono-
mers, the bridged bis(b-CD) derivatives with functional
linkers have two hydrophobic cavities in a close proximity
constituting an improved development.15 This property
may afford distinctly different association abilities and
molecular selectivities.16 Various structural architectures
of covalent CD dimers could be prepared, but one chal-
lenge will be to obtain supramolecular CD dimers with
noncovalent interactions such as H bonding, staking, elec-
trostatic, and charge-transfer interactions. The equilibri-
um between the noncovalent dimers and the
corresponding monomers could permit modulation of as-
sociation. To the best of our knowledge, these molecular
Synthesis of 2-Bromoethyl and Alkynyl Precursors for
b-CD
Alkylation of pyrimidine bases gave predominantly N1-
monosubstituted, N1,N3-bis-substituted and O4-mono-
substituted derivatives. Regioselective N1-alkylation us-
ing silylation of the nucleobase strategy was developed to
furnish the bromoethyl and propargyl derivatives. Cou-
pling of dibromoethane with silylated thymine in the pres-
ence of NaI at 105 °C without solvent furnished the
bromide 224–27 in 32% yield. Coupling of propargyl bro-
mide with silylated thymine at 80 °C in acetonitrile gave
the alkyne 328,29 in 89% yield. Alkylation of purine fur-
nished often a ratio of N7/N9 isomers. The N9-alkylated
adenine derivatives 527 and 628,29 were obtained from un-
protected adenine (4). Starting from 4, selective alkylation
SYNTHESIS 2011, No. 2, pp 0235–0242
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x
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Advanced online publication: 10.12.2010
DOI: 10.1055/s-0030-1258354; Art ID: P13610SS
© Georg Thieme Verlag Stuttgart · New York

236
V. Legros et al.
PAPER
Cl
with dibromoethane and propargyl bromide using K2CO3
in DMF gave the derivatives 5 and 6 in 40 and 39% yield,
respectively (Scheme 1). The regioselectivity of N9 (ver-
sus N7) alkylation of guanine derivative was improved
through the use of 2-amino-6-chloropurine (7) as initial
substrate. Taddei et al. reported a simple regioselective
preparation of 9-(2-bromoethyl)purine derivative 8 (56%
yield) starting from 6-chloro derivative 7 and dibromo-
ethane using K2CO3 in DMF at room temperature for 48
hours27 (Scheme 2).
N
N
N
H
N
7
NH2
CCH2Br, K2CO3
HC
DMF, MW, 85 °C, 40 min
52%
BrC2H4Br, K2CO3
DMF, MW, 85 °C, 40 min
40%
Cl
Cl
N
N
N
N
N
N
O
N
NH2
N
NH2
Br
NH
(i) HMDS, (NH4)2SO4
reflux, 12 h
8
9
N
O
(ii) BrC2H4Br, NaI
105 °C, 25 h
32%
HBr (1 M)
69%
HCl (1 M)
50%
Br
O
2
O
N
O
NH
O
N
N
N
N
NH
NH
N
H
1
O
NH
BSA, MeCN
reflux, 12 h
NH2
N
NH2
Br
N
O
then HC CCH2Br
reflux, 16 h
89%
10
11
Scheme 2 Synthesis of alkylated guanine derivatives 10 and 11
3
NH2
BrC2H4Br, K2CO3
DMF, r.t., 24 h
N
lowed by sodium azide substitution, as described previ-
ously. Total azidolysis using Staudinger conditions
afforded the hydroxylated mono-6-amino b-CD. The per-
methylated monoazido b-CD was synthesized by the reac-
tion of the hydroxylated mono-6-azido b-CD with methyl
iodide in basic conditions. The permethylated monoamino
b-CD was obtained using a similar method as described
above.30
N
N
40%
N
Br
NH2
5
N
N
NH2
N
H
N
HC CCH2Br, K2CO3
DMF, r.t., 24 h
N
N
N
4
39%
Synthesis of Aminoethyl-b-CD Derivatives Having 1-
Pyrimidine and 9-Purine Moiety
N
6
Reaction of b-CD derivative 12a with an excess of bro-
mide 2 in anhydrous DMSO at 50 °C for 16 hours fur-
nished the desired CD derivative 13a in 14% yield
(Scheme 3).
Scheme 1 Synthesis of alkylated nucleobases 2, 3, 5, and 6
Lindsell et al. described the synthesis of (prop-2-ynyl)pu-
rine derivative 9 (69%) as a regioisomeric mixture of N9
and N7 (ratio 82:18) starting from compound 7 and prop-
argyl bromide using Na2CO3 in DMF at room temperature
for 44 hours.29 The methodology developed to obtain
adenine derivatives 5 and 6 was applied under microwave
(MW) irradiation at 85 °C for 40 minutes. In our hands,
starting from 6-chloropurine derivative 7, regioselective
alkylation furnished the N9 isomers 8 and 9 in 40% and
52% yield, respectively. The 2-bromoethyl derivative 8
was dissolved in aqueous HBr (1 N) and heated at reflux
for six hours to furnish the guanine derivative 10 in 69%
yield. The propargyl derivative 9 in aqueous HCl (1 N)
gave the guanine analogue 11 in 50% yield (Scheme 2).
Starting from b-CD derivative 12a and permethylated
analogue 12b, application of this procedure afforded the
cyclodextrin derivatives 13b, 14a,b, and 15 in 16, 38, 44,
and 20% yield, respectively (Scheme 3 and Figure 1). Us-
ing the same protocol, reaction of hydroxylated 6-amino
b-CD 12a and 9-(2-bromoethyl)guanine 10 did not gener-
ate the hydroxylated guanine analogue.
Synthesis of 1,2,3-Triazol-b-CD Derivatives Having 1-
Pyrimidine and 9-Purine Moiety
The Huisgen 1,3-dipolar cycloaddition reaction of organic
azides and alkynes31 is an extremely useful method in or-
ganic chemistry due to the development of Cu(I) catalysis
in 2001,32 which offers a major improvement in both rate
and regioselectivity of the reaction. Few examples of
Huisgen 1,3-dipolar cycloaddition were described in the
area of CD chemistry using 6-azido b-CD18,33 or ana-
logues.34 To the best of our knowledge, only one paper re-
The monoamino-b-CD, monoazido-b-CD, monoamino
permethylated, or monoazido permethylated b-CD deriv-
atives were prepared as described in the literature. The hy-
droxylated mono-6-azido b-CD was prepared by using a
two-step approach with tosylation of the native b-CD fol-
Synthesis 2011, No. 2, 235–242 © Thieme Stuttgart · New York

PAPER
Supramolecular Cyclodextrin Dimers
237
O
NH
O
N
NH2
HN
O
O
RO
O
RO
O
O
O
RO
RO
OR
OR
OR
OR
O
O
OR
OR
RO
RO
RO
RO
O
O
2, Et3N, DMSO
50°C, 16 h
O
O
OR
OR
O
O
RO
RO
RO
RO
O
O
OR
OR
OR
OR
O
O
OR
OR
OR
OR
RO
OR
RO
O
O
O
O
O
OR
OR
OR
O
RO
RO
O
O
RO
RO
O
O
OR
12a R = H
12b R = Me
OR
13a R = H (14%)
13b R = Me (16%)
Scheme 3 Synthesis of CD derivatives 13 having thymine nucleobase
H
H2N
N
O
N
N
NH2
N
N
N
N
N
HN
HN
O
O
RO
O
MeO
O
O
O
RO
MeO
OMe
OR
OR
OMe
O
O
OR
OMe
RO
MeO
O
O
OR
OMe
O
O
OR
OMe
O
O
RO
MeO
RO
MeO
O
O
RO
MeO
OR
OMe
O
O
OR
OMe
OR
OMe
RO
MeO
O
O
OR
O
OMe
MeO
O
OR
O
OMe
O
O
RO
O
RO
MeO
O
O
OR
OMe
14a R = H
14b R = Me
15
Figure 1 CD derivatives 14a,b and 15 having adenine and guanine nucleobases
ported the synthesis of nucleobase and CD having a 1,2,3- azo-4-yl compound 17a in 32% yield (Scheme 4 and
triazole-4-methyl group.18 Starting from the mono-6-azi- Table 1, entry 1).
do b-CD 16a and the permethylated analogue 16b, the
Starting from mono-6-azido b-CD 16a, the use of alkynes
Cu(I)-catalyzed azide-alkyne cycloaddition reaction
6 and 11 gave the cycloadducts 18a and 19a in 57% and
(CuAAC) was investigated for the transformation of the
propargylated nucleobases 3, 6, and 11 under various con-
ditions (Scheme 4 and Table 1). Two sources of Cu(I) –
CuI and (EtO)3PCuI – were tested using the methodology
60% yield, respectively (Table 1, entries 2 and 3). In our
hands, similar methodology with conventional heating
gave after 24 hours the target compound 17a in 12% yield.
The CuAAC reaction using (EtO)3PCuI as a source of
described in the literature (Table 1, entries 1–12). First,
Cu(I) benefits from increased solubility in organic sol-
treatment of azido derivative 16a with alkyne 3 in the
vents such as DMF. The azido derivative 16a with alkyne
presence of CuI in a large excess in aqueous t-BuOH so-
3 in the presence of (EtO)3PCuI as catalyst in DMF at
lution under microwave irradiation furnished the 1,2,3-tri-
90 °C for two days afforded the 1,2,3-triazol-4-yl com-
pound 17a in 31% yield (Table 1, entry 7). From mono-6-
Synthesis 2011, No. 2, 235–242 © Thieme Stuttgart · New York

238
V. Legros et al.
PAPER
Table 1 CuAAC Reactions Starting from 6-Azido CDs 16a and 16b and Propargylated Nucleobase Derivatives
Entry
6-Azido
CD
Alkyne
1,2,3-Triazole Cu source
CD
Reducing Irradiation Solvent
agent
Temp
(°C)
Time
(h)
Yield
(%)
1
2
16a
16a
16a
16b
16b
16b
16a
16a
16a
16b
16b
16b
16a
16a
16a
16b
16b
16b
3
6
17a
18a
19a
17b
18b
19b
17a
18a
19a
17b
18b
19b
17a
18a
19a
17b
18b
19b
CuI
–
MW
MW
MW
MW
MW
MW
no
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
t-BuOH–H2O
DMF
85
85
85
85
85
85
90
90
90
90
90
90
85
85
85
85
85
85
0.6
0.6
0.6
0.6
0.6
0.6
48
32
57
60
61
73
34
31
33
13
64
51
30
50
26
15
24
14
17
CuI
–
3
11
3
CuI
–
4
CuI
–
5
6
CuI
–
6
11
3
CuI
–
7
(EtO)3PCuI
(EtO)3PCuI
(EtO)3PCuI
(EtO)3PCuI
(EtO)3PCuI
(EtO)3PCuI
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
CuSO4
–
8
6
–
no
DMF
48
9
11
3
–
no
DMF
48
10
11
12
13
14
15
16
17
18
–
no
DMF
48
6
–
no
DMF
48
11
3
–
no
DMF
48
NaAsc
NaAsc
NaAsc
NaAsc
NaAsc
NaAsc
no
DMSO
12
6
no
DMSO
12
11
3
no
DMSO
12
no
DMSO
12
6
no
DMSO
12
11
no
DMSO
12
azido b-CD 16a, application of this method using the (Table 1, entries 8 and 9). An important factor seems to be
alkynes 6 and 11 led to the 1,2,3-triazole derivatives 18a the maintenance of the Cu(I) at a high level at all time dur-
and 19a (Figure 2) in 33% and 13% yield, respectively ing the reaction. The possibility to use Cu(II) source with
O
NH
N
O
N
N
N3
N
O
O
RO
O
RO
O
O
O
RO
RO
OR
OR
OR
OR
O
O
OR
OR
RO
RO
RO
RO
O
O
O
O
OR
OR
O
O
RO
RO
RO
RO
O
O
OR
OR
OR
OR
O
O
OR
OR
OR
OR
RO
OR
RO
OR
O
O
O
O
OR
OR
O
O
RO
RO
O
O
RO
RO
O
O
OR
OR
17a R = H
17b R = Me
16a R = H
16b R = Me
Scheme 4 Synthesis of CD derivatives 17a,b having thymine nucleobase
Synthesis 2011, No. 2, 235–242 © Thieme Stuttgart · New York

PAPER
Supramolecular Cyclodextrin Dimers
239
NH2
O
N
N
N
N
NH
N
N
N
NH2
N
N
N
N
N
N
O
O
RO
O
RO
O
O
O
RO
RO
OR
OR
OR
OR
O
O
OR
OR
RO
RO
O
O
OR
OR
O
O
OR
OR
O
O
RO
RO
RO
RO
O
O
RO
RO
OR
OR
O
O
OR
OR
OR
OR
RO
RO
O
O
OR
O
OR
O
O
OR
O
OR
O
O
RO
RO
RO
RO
O
O
OR
OR
18a R = H
18b R = Me
19a R = H
19b R = Me
Figure 2 CD derivatives 18a,b and 19a,b having adenine and guanine nucleobases
as eluent. NMR experiments were recorded with a Bruker Avance
addition of a reducing agent in excess has been one of the
preferred methods. In general the presence of reducing
agents renders the reaction much less susceptible to oxy-
gen enabling the reaction to be run under open-air condi-
tions. Treatment of azido derivative 16a with alkyne 3 in
the presence of a CuSO4·5 H2O/sodium ascorbate
(NaAsc) mixture in DMSO at 85 °C for 24 hours gave the
cycloadduct 17a in 50% yield (Table 1, entry 13). Starting
from mono-6-azido b-CD 16a, treatment with the alkynes
6 and 11 led to the triazole moiety 18a and 19a in 26% and
15% yield, respectively (Table 1, entries 14 and 15). Us-
ing the three methods described above, the use of the per-
methylated mono-6-azido b-CD 16b afforded the
1
400 spectrometer at 400 MHz for H and at 100 MHz for 13C, or
with a Bruker Avance 500 spectrometer at 500 MHz for 1H nuclei
and at 125 MHz for 13C at 23 °C (r.t.). The chemical shifts are ex-
pressed in part per million (ppm) relative to TMS (d = 0 ppm) and
the coupling constant J in hertz (Hz). For NMR assignments of cy-
clodextrin-nucleobase conjugates, numbers 1–6¢ are referred to CD
while alphabets a–i are referred to modified nucleobases. Micro-
wave irradiations were performed with a CEM Discover apparatus.
High-resolution electrospray mass spectra (ESI-HRMS) in the pos-
itive ion mode were obtained on a Q-TOF Ultima Global hybrid
quadrupole time-of-flight instrument (Waters-Micromass),
equipped with a pneumatically assisted electrospray (Z-spray) ion-
ization source and an additional sprayer (Lock Spray) for the refer-
ence compound. The purified compounds were dissolved in
cycloadducts 17b–19b in 14–73% yields, respectively methanol (0.01 mg/mL) and the solutions were directly introduced
(5 mL/min) through an integrated syringe pump into the electrospray
source. The source and desolvation temperatures were 80 and
150 °C, respectively. N2 was used as the drying and nebulizing gas
at flow rates of 350 and 50 L/h, respectively. Typically, the capillary
voltage was 3.5 kV and the cone voltage 110 V. Lock mass correc-
tion, using appropriate cluster ions of an orthophosphoric acid solu-
tion (0.1% in H2O–MeCN, 50:50, v/v), was applied for accurate
mass measurements. The mass range was 50–2000 Da and spectra
were recorded at 2 s/scan in the profile mode at a resolution of
10,000 (FWMH). Data acquisition and processing were performed
with MassLynx 4.0 software.
(Table 1, entries 4–6, 10–12, 16–18). In accordance with
the literature, the MW-assisted protocol (Table 1, entries
1–6) offered good yields (32–73%) and shortened the re-
action time (0.6 h versus 12–48 h).
In conclusion, nucleobases such as thymine, adenine, and
guanine and cyclodextrin moieties were linked by amino-
ethyl and 1,2,3-triazole groups to provide eleven novel
potential supramolecular elements. Extension of this work
concerning the G-quartet formation with the guanine ana-
logues 15, 19a,b will be reported in due course.
9-(2-Bromoethyl)-6-chloro-9H-purin-2-amine (8)
2-Amino-6-chloropurine (0.25 g, 1.47 mmol) and K2CO3 (0.81 g,
5.87 mmol, 4 equiv) were dissolved in anhyd DMF (5 mL). Propar-
gyl bromide (0.30 mL, 3.68 mmol, 2.5 equiv.) was added and the re-
sulting solution was irradiated with MW (200 W) at 85 °C for 40
min. Then Et2O (15 mL) was added and the precipitate was collect-
ed by filtration to give 8 as a yellow solid (0.163 g, 40%). Physical
data were in accordance with the literature;27 Rf = 0.70 (7% MeOH–
CH2Cl2).
1H NMR (400 MHz, DMSO-d6): d = 3.90 (t, J = 6.0 Hz, 2 H,
CH2Br), 4.46 (t, J = 6.0 Hz, 2 H, NCH2), 6.97 (s, 2 H, NH2), 8.16 (s,
1 H, 8-H).
All reagents were used as purchased from commercial suppliers
without further purification. Solvents (DMF, THF) were distilled
under anhyd conditions. Petroleum ether (PE) refers to the fraction
boiling in the range 45–65 °C. TLC plates (Macherey-Nagel,
ALUGRAM® SIL G/UV254, 0.2 mm silica gel 60 Å) were visualized
under 254 nm UV light and/or by dipping the TLC plate into a so-
lution of phosphomolibdic acid (3 g) in EtOH (100 mL) followed by
heating with a heat gun. Flash column chromatography was per-
formed using Macherey-Nagel silica gel 60 (15–40 mm). Semi-pre-
parative HPLC purifications were performed using a C18 reversed
phase column and a H2O–MeCN system (98.2 to 70:30 for 20 min)
Synthesis 2011, No. 2, 235–242 © Thieme Stuttgart · New York

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V. Legros et al.
PAPER
13C NMR (100 MHz, DMSO-d6): d = 31.5 (CH2Br), 45.2 (NCH2),
123.8 (C-5), 143.7 (C-8), 150.1 (C-4), 154.7 (C-6), 160.4 (C-2).
HRMS (ESI): m/z calcd for C49H79N3O36 [M + H]+: 1286.4522;
found: 1286.4581.
6-Chloro-9-(prop-2-ynyl)-9H-purin-2-amine (9)
N-[6A-Deoxy-2A, 3A-di-O-methylhexakis(2B–G, 3B–G, 6B–G-tri-O-
methyl)-b-cyclodextrin]-N1-aminoethylthymine (13b)
Yield: 16%; mp 200 °C (dec.).
1H NMR (500 MHz, D2O): d = 7.56 (s, 1 H), 5.36–5.24 (m, 5 H),
4.00 (s, 2 H), 3.89–3.54 (m, 33 H), 3.64–3.62 (m, 21 H), 3.55–3.52
(m, 21 H), 3.43–3.37 (m, 7 H), 3.41–3.40 (m, 21 H), 3.23 (br s, 2
H), 3.18 (br s, 2 H), 1.94 (s, 3 H).
13C NMR (125 MHz, D2O): d = 166.8, 152.4, 143.1, 110.6, 97.6–
96.6, 81.4–75.9, 71.2–69.6, 59.9–58.1, 48.5, 47.4, 47.0, 11.4.
HRMS (ESI): m/z calcd for C69H119N3O36 [M + H]+: 1566.7532;
found: 1565.7573.
To a solution of 2-amino-6-chloropurine (0.25 g, 1.47 mmol, 1.04
equiv) in anhyd DMF (5 mL) were added successively K2CO3 (0.20
g, 1.44 mmol, 1.02 equiv) and propargyl bromide (0.12 mL, 1.41
mmol). The resulting solution was irradiated with MW (200 W) at
85 °C for 40 min, then CH2Cl2 (15 mL) was added, and the precip-
itate formed was collected by filtration. The desired product 9 was
obtained as a yellow solid (0.152 g, 52%), which was directly used
without further purification. Physical data were in accordance with
the literature;29 Rf = 0.60 (7% MeOH–CH2Cl2).
1H NMR (400 MHz, DMSO-d6): d = 3.50 (s, 1 H, C≡CH), 4.93 (s,
2 H, CH2), 7.05 (s, 2 H, NH2), 8.18 (s, 1 H, 8-H).
13C NMR (100 MHz, DMSO-d6): d = 32.4 (CH2), 76.1 (C≡CH),
77.8 (C≡CH), 123.0 (C5), 142.3 (C-8), 149.5 (C-4), 153.5 (C-6),
159.9 (C-2).
N-[6A-Deoxy-b-cyclodextrin]-N9-aminoethyladenine (14a)
Yield: 38%; mp 200 °C (dec.).
1H NMR (500 MHz, D2O): d = 8.52 (s, 1 H), 8.40 (s, 1 H), 5.17–
5.10 (m, 7 H), 4.38 (s, 2 H), 4.00–3.50 (m, 39 H), 3.31 (t, J = 9.0
Hz, 1 H), 3.11 (m, 2 H), 2.95 (d, J = 13.0 Hz, 1 H), 2.77 (m, 1 H).
13C NMR (125 MHz, D2O): d = 155.4, 152.2, 149.5, 142.5, 118.5,
102.0–101.7, 101.0, 83.5, 81.2–80.1, 73.1–70.2, 60.3–59.9, 48.2,
47.0, 43.2.
2-Amino-9-(2-bromoethyl)-1H-purin-6(9H)-one (10)
The bromoethyl derivative 8 (0.17 g, 0.62 mmol) was dissolved in
aq 1 M HBr (5 mL). The solution was heated at reflux for 7 h. After
cooling, the solution was neutralized with 10% aq NaOH. The pre-
cipitate was collected and washed with H2O (20 mL) to give the de-
sired product (0.11 g, 69%); Rf = 0.30 (10% MeOH–CH2Cl2).
1H NMR (400 MHz, DMSO-d6): d = 3.84 (t, J = 6.3 Hz, 2 H,
CH2Br), 4.34 (t, J = 6.3 Hz, 2 H, NCH2), 6.48 (s, 2 H, NH2), 7.72 (s,
1 H, 8-H), 10.57 (s, 1 H, NH).
HRMS (ESI): m/z calcd for C49H78N6O34 [M + H]+: 1295.4637;
found: 1295.4574.
N-[6A-Deoxy-2A, 3A-di-O-methylhexakis(2B–G, 3B–G, 6B–G-tri-O-
methyl)-b-cyclodextrin]-N9-aminoethyladenine (14b)
Yield: 44%; mp 200 °C (dec.).
13C NMR (100 MHz, DMSO-d6): d = 31.5 (CH2Br), 45.2 (NCH2),
123.8 (C-5), 143.7 (C-8), 150.1 (C-4), 154.7 (C-6), 160.4 (C-2).
1H NMR (500 MHz, D2O): d = 8.31 (s, 1 H), 8.23 (s, 1 H), 5.29–
5.24 (m, 5 H), 5.17 (s, 1 H), 4.98 (s, 1 H), 4.44 (br s, 2 H), 3.88–3.51
(m, 26 H), 3.64–3.62 (m, 21 H), 3.55–3.52 (m, 21 H), 3.41–3.32 (m,
14 H) 3.41–3.40 (m, 21 H), 3.24 (br s, 2 H), 3.05 (br s, 2 H).
13C NMR (125 MHz, D2O): d = 155.5, 152.4, 149.3, 142.6, 118.5,
97.7–96.5, 80.9–76.5, 71.1–70.7, 60.0–58.0, 48.1, 47.5, 43.2.
HRMS (ESI): m/z calcd for C7H8BrN5O + Na [M + Na]+: 279.9810;
found: 279.9816.
2-Amino-9-(prop-2-ynyl)-1H-purin-6(9H)-one (11)
Compound 9 (0.13 g, 0.63 mmol) was dissolved in aq 1 M HCl (5
mL). The solution was heated at reflux for 6 h. After cooling, the so-
lution was neutralized with 10% aq NaOH. The precipitate formed
was collected and washed with H2O (20 mL) to give the desired
product (0.066 g, 50%) as a white solid. Physical data were in ac-
cordance with the literature;35 Rf = 0.30 (10% MeOH–CH2Cl2).
HRMS (ESI): m/z calcd for C69H118N6O34 [M + H]+: 1575.7673;
found: 1575.7654.
N-[6A-Deoxy-2A, 3A-di-O-methylhexakis(2B–G, 3B–G, 6B–G-tri-O-
methyl)-b-cyclodextrin]-N9-aminoethylguanine (15)
Yield: 20%; Rf = 0.50 (10% MeOH–CH2Cl2).
1H NMR (400 MHz, DMSO-d6): d = 3.40 (s, 1 H, C≡CH), 4.80 (s,
2 H, CH2), 6.56 (s, 2 H, NH2), 7.77 (s, 1 H, 8-H), 10.69 (s, 1 H, 1-H).
13C NMR (100 MHz, DMSO-d6): d = 32.0 (CH2), 75.7(C≡CH),
78.5 (C≡CH), 116.3 (C-5), 136.7 (C-8), 150.8 (C-4), 153.8 (C-2),
156.7 (C-6).
1H NMR (400 MHz, DMSO-d6): d = 10.51 (s, 1 H, NH), 7.57 (s, 1
H, He), 6.53 (s, 2 H, NH2), 5.01(m, 6 H, 1-HCD), 4.73 (m, 1 H, 1-
HCDA), 3.95 (m, 2 H, Hg), 3.71–3.57 (m, 14 H, HCD), 3.46–3.16 (m,
79 H, HCD, OCH3), 3.05–2.87 (m, 11 H, 2-HCD, Hh, 6-HCDA).
Nucleophilic Substitution Reactions between Mono-6-amino-b-
CD 12a,b and Nucleobases 2, 5, and 10; General Procedure
Mono-6-amino-b-CD (0.14 mmol) and the respective nucleobase
derivative (0.15 mmol, 1.1 equiv) were dissolved in anhyd DMSO
(5 mL). Et3N (0.05 mL) was added and the mixture was stirred at
50 °C for 16 h. The crude was then purified, either by column chro-
matography on silica gel with PE–CH2Cl2 then CH2Cl2–MeOH as
eluents for the permethylated CD derivatives, or by semi-prepara-
tive HPLC for the hydroxy-CD derivatives.
13C NMR (100 MHz, DMSO-d6): d = 156.8 (Cc), 153.4 (Ca), 151.2
(Cf), 137.9 (Ce), 116.6 (Cd), 97.7 (1-CCD, 7 C), 81.7–79.1 (2-CCD
,
C
CD), 71.4–70.9 (6-CCDB–G, CCD), 70.4–60.6 (CCD, OCH3), 58.2–
57.5 (CCD, OCH3), 48.7–48.4 (6-CCDA, Ch), 43.1 (Cg).
HRMS (ESI): m/z calcd for C69H118N6O35 [M + H]+: 1591.7716;
found: 1591.7714.
CuAAC Reactions between Mono-6-azido-b-CDs 16a,b and
Nucleobases 3, 6, and 11; General Procedures
N-[6A-Deoxy-b-cyclodextrin]-N1-aminoethylthymine (13a)
Yield: 14%; mp 200 °C (dec.).
1H NMR (500 MHz, D2O): d = 7.48 (s, 1 H), 5.14–5.08 (m, 7 H),
4.30–4.10 (m, 3 H), 4.03–3.81 (m, 25 H), 3.72–3.50 (m, 15 H), 3.47
(m, 2 H), 3.39 (m, 1 H), 1.91 (s, 3 H).
13C NMR (125 MHz, D2O): d = 166.8, 153.0, 142.2, 111.5, 102.0–
101.0, 83.3–80.8, 71.5–70.5, 67.5, 60.5–59.5, 48.8, 47.6, 45.0, 11.3.
General Procedure A: Mono-6-azido-b-CD (1.10 mmol, 1 equiv),
the alkyne derivative (1.1 equiv), and CuI (9 equiv) were suspended
in a mixture of t-BuOH–H2O (1:1, 10 mL). The mixture was irradi-
ated with MW (200 W) at 85 °C for 40 min. Acetone (15 mL) was
then added and the precipitate was collected by filtration. The crude
was then purified by semi-preparative HPLC for the hydroxy cyclo-
dextrins or by silica gel column chromatography for the permeth-
ylated cyclodextrins (CH2Cl2–MeOH, 100:0 to 30:70).
Synthesis 2011, No. 2, 235–242 © Thieme Stuttgart · New York

PAPER
Supramolecular Cyclodextrin Dimers
241
General Procedure B: Mono-6-azido-b-CD (1.55 mmol, 1 equiv),
the alkyne derivative (1 equiv), and CuSO4·5H2O (0.5 equiv) were
dissolved in DMSO (3 mL). To the solution was added sodium
ascorbate (1 equiv), then the mixture was stirred at r.t. overnight.
Acetone (10 mL) was added and the precipitate was collected by fil-
tration. The crude was then purified by semi-preparative HPLC for
the hydroxy cyclodextrins or by silica gel column chromatography
for the permethylated cyclodextrins (PE–CH2Cl2, 50:50, then
CH2Cl2–MeOH, 30:70).
1H NMR (400 MHz, D2O): d = 8.20 (s, 1 H, He), 8.10 (s, 2 H, Ha,
Hi), 5.45 (s, 2 H, Hg), 5.21–4.97 (m, 7 H, 1-HCD, 6-HCDA), 4.46 (m,
1 H, 6¢-HCDA), 4.03 (t, J = 9.0 Hz, 1 H, 5-HCDA), 3.90 (m, 1 H, HCD),
3.72–3.38 (m, 75 H, HCD, OCH3), 3.26–3.16 (m, 21 H, HCD, OCH3),
2.55–2.53 (d, J = 10.3 Hz, 1 H, 6¢-HCDB), 2.23 (m, 1 H, 6-HCDB).
13C NMR (100 MHz, D2O): d = 155.4 (Cb), 152.5 (Ca), 148.4 (Cf),
141.8 (Ce, Ch), 126.4 (Ci), 118.2 (Cd), 97.5–97.0 (1-CCD, 7 C),
81.1–76.5 (CCD), 70.7–70.1 (5-CCDA, 6-CCDB–G, CCD), 59.9–57.8
(OCH3, CCD), 51.5 (6-CCDA), 38.2 (Cg).
General Procedure C: Mono-6-azido-b-CD (4.30 mmol, 1 equiv),
the alkyne derivative (1.5 equiv), and (EtO)3PCuI (0.5 equiv) were
dissolved in DMF (3 mL). The mixture was stirred at 90 °C for 48
h. Acetone (15 mL) was then added and the precipitate was collect-
ed by filtration. The crude was then purified by semi-preparative
HPLC for the hydroxy cyclodextrins or by silica gel column chro-
matography for the permethylated cyclodextrins (CH2Cl2–MeOH,
100:0 to 30:70).
HRMS (ESI): m/z calcd for C70H116N8O34 + Na [M + Na]+:
1635.7492; found: 1635.7488.
N9-[1-(6A-Deoxy-b-cyclodextrin)-1,2,3-triazol-4-ylmethyl]gua-
nine (19a)
1H NMR (400 MHz, DMSO-d6): d = 10.58 (s, 1 H, NH), 7.94 (s, 1
H, He), 7.64 (s, 1 H, Hi), 6.42 (s, 2 H, NH2), 5.84–5.61 (m, 14 H),
B–G
5.15 (s, 2 H, Hg), 4.97 (s, 1 H, 1-HCDA), 4.82–4.72 (m, 7 H, 1-HCD
,
6-HCDA), 4.53–4.46 (m, 6 H), 4.31 (t, J = 5.7 Hz, 1 H, 6-OHCDB),
N1-[1-(6A-Deoxy-b-cyclodextrin)-1,2,3-triazol-4-ylmeth-
yl]thymine (17a)
Mp 200 °C (dec.).
1H NMR (500 MHz, D2O): d = 8.10 (s, 1 H), 7.66 (s, 1 H), 5.20 (s,
1 H), 5.10–5.03 (m, 9 H), 4.63 (s, 1 H), 4.30 (s, 1 H), 4.08–3.50 (m,
37 H), 3.01 (s, 1 H), 2.70 (s, 1 H), 1.92 (s, 3 H).
3.91 (m, 1 H, 5-HCDA), 3.59–3.26 (m, 37 H, 2-HCD, 3-HCD, 4-HCD
,
5-HCDB–G, 6-HCDC–G), 3.04 (d, J = 6.8 Hz, 1 H, 6-HCDB), 2.83 (m, 1
H, 6¢-HCDB).
13C NMR (100 MHz, DMSO-d6): d = 156.9 (Cb), 153.6 (Ca), 151.1
(Cf), 142.4 (Ch), 137.3 (Ci), 124.5 (Ce), 116.3 (Cd), 102.2–101.4
(1-CCD, 7 C), 83.4–81.2 (4-CCD, 7 C), 73.2–71.8 (2-CCD, 3-CCD, 5-
CCDB–G, 20 C), 70.0 (5-CCDA), 60.1–59.9 (6-CCDC–G), 59.1 (6-CCDB),
50.4 (6-CCDA), 37.8 (Cg).
13C NMR (125 MHz, D2O): d = 167.1, 152.2, 142.4, 126.5, 111.2,
101.9–101.4, 83.2–80.5, 73.0–70.4, 60.3, 59.1, 51.4, 42.9, 11.3.
HRMS (ESI): m/z calcd for C50H77N5O36 + Na [M + Na]+:
HRMS (ESI): m/z calcd for C50H76N8O35 + Na [M + Na]+:
1346.4246; found: 1346.4211.
1371.4311; found: 1371.4312.
N1-{[6A-Deoxy-2A, 3A-di-O-methylhexakis(2B–G, 3B–G, 6B–G-tri-
O-methyl)-b-cyclodextrin]-1,2,3-triazol-4-ylmethyl}thymine
(17b)
N9-{[6A-Deoxy-2A, 3A-di-O-methylhexakis(2B–G, 3B–G, 6B–G-tri-
O-methyl)-b-cyclodextrin]-1,2,3-triazol-4-ylmethyl}guanine
(19b)
Rf = 0.40 (7% MeOH–CH2Cl2).
Rf = 0.40 (7% MeOH–CH2Cl2).
1H NMR (400 MHz, D2O): d = 8.08 (s, 1 H, Hi), 7.61 (s, 1 H, Hf),
5.31–4.94 (m, 10 H, 1-HCD, Hg, 6-HCDA), 4.55 (m, 1 H, 6¢-HCDA),
4.17 (m, 1 H, 5-HCDA), 4.00 (m, 1 H, HCD), 3.87–3.55 (m, 53 H, 3-
1H NMR (400 MHz, D2O): d = 8.08 (s, 1 H, He), 7.82 (s, 1 H, Hi),
5.41–4.99 (m, 10 H, Hg, 1-HCD, 6-HCDA), 4.43 (m, 1 H, 6¢-HCDA),
4.03 (m, 1 H, 5-HCDA), 3.87 (m, 1 H, HCD), 3.71–3.40 (m, 72 H, HCD
,
H
CD, 4-HCD, 5-HCD, 6-HCDC–G, OCH3), 3.49–3.46 (m, 22 H, OCH3),
OCH3), 3.26–2.90 (m, 24 H, HCD, OCH3), 2.60 (m, 2 H, 6¢-HCDB, 6-
3.35–3.32 (m, 21 H, OCH3), 3.06 (s, 3 H, HCD), 2.86–2.74 (m, 2 H,
HCDB).
6-HCDB, 6¢-HCDB), 1.85 (s, 3 H, He).
13C NMR (100 MHz, D2O): d = 158.0 (Cb), 153.1 (Ca), 141.7 (Ch,
Ci), 126.0 (Ce), 106.2 (Cd), 97.3–96.9 (1-CCD, 7 C), 80.7–76.8
(CCD), 70.3–69.7 (5-CCDA, 6-CCDB, CCD), 59.7–57.3 (CCD, OCH3),
51.0 (6-CCDA), 37.6 (Cg).
HRMS (ESI): m/z calcd for C70H116N8O35 + Na [M + Na]+:
1651.7441; found: 1651.7448.
13C NMR (100 MHz, D2O): d = 166.5 (Cc), 151.7 (Ca), 142.1–
142.3 (Ch, Cf, 2 C), 126.6 (Ci), 111.1 (Cd), 97.5–96.9 (1-CCD, 7 C),
81.1–76.4 (CCD), 70.8–70.2 (CCD, 5-CCDA, 6-CCDB), 59.9–57.8
(OCH3, CCD), 58.4–57.8 (OCH3, CCD), 51.5 (6-CCDA), 42.9 (Cg),
11.5 (Ce).
HRMS (ESI): m/z calcd for C70H117N5O36 + Na [M + Na]+:
1626.7376; found 1626.7381.
Acknowledgment
N9-[1-(6A-Deoxy-b-cyclodextrin)-1,2,3-triazol-4-ylmethyl]ade-
nine (18a)
Mp 200 °C (dec.).
1H NMR (500 MHz, D2O): d = 8.29 (s, 1 H), 8.26 (s, 1 H), 7.99 (s,
1 H), 5.60 (s, 2 H), 5.15–5.00 (m, 7 H), 4.97 (d, J = 5.0 Hz, 1 H),
4.59 (dd, J = 5.0, 10.0 Hz, 1 H), 4.11 (t, J = 5.0 Hz, 1 H), 4.00–3.40
(m, 37 H), 2.78 (d, J = 10.0 Hz, 1 H), 2.60 (d, J = 9.5 Hz, 1 H).
The authors are deeply indebted to the ‘Ministère de l’Enseigne-
ment Supérieur et de la Recherche’, the ‘Centre National de la Re-
cherche Scientifique’ (CNRS), the ‘Université de Poitiers’ and
« Biocydex » for their constant support. The authors gratefully
acknowledge Dr. Serge Pilard of Université de Picardie Jules Verne
(UPJV) for the mass spectrometry measurements.
13C NMR (125 MHz, D2O): d = 155.6, 152.7, 148.9, 142.6, 142.1,
125.9, 118.6, 101.9, 81.3–80.4, 73.1–70.6, 60.0–58.8, 51.2, 38.4.
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Synthesis 2011, No. 2, 235–242 © Thieme Stuttgart · New York

242
V. Legros et al.
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