Improved syntheses of bis(β-cyclodextrin) derivatives, new carriers for gadolinium complexes

Article abstract of DOI:10.1039/b517068k

In the last decade a number of reports have been published on the synthesis and characterization of bridged cyclodextrin dimers (bis-CDs) connected with linkers of different lengths and structures. These dimers, having two hydrophobic cavities in close proximity, display much higher binding affinities and molecular selectivities than parent CDs, forming stable supramolecular adducts. We describe new synthetic protocols for the preparation of bis(β-CDs) bearing 2-2′, 3-3′ and 6-6′ bridges. Some of the critical steps were carried out either under high-intensity ultrasound (US) or microwave (MW) irradiation. Bis(β-CDs) containing 6-6′ ureido- and thioureido-bridges were prepared in high yields by a MW-promoted aza-Wittig reaction using polymer-bound triphenylphosphine, while those containing 2,2′ and 3,3′ bridges were prepared from mono-alkenyl β-CDs by the cross-metathesis reaction (homodimerization) in the presence of 2 ^nd-generation Grubbs catalyst under sonochemical conditions. By these improved protocols CD dimers could be obtained in gram amounts to prepare stable adducts of bis-CDs with contrast agents (CAs) containing gadolinium(iii) chelates. In the case of Gd(iii) chleate "G-1" the inclusion complexes were found to be 2 to 3 orders of magnitude more stable than that formed by β-CD (K_ass = 4.3 × 10⁴ M^-1 vs 8.0 × 10² M^-1). Relaxivity increased as well by factors of 3 and 4, viz. from 9.1 mM^-1 s^-1 (β-CD) to 27.7 and 35 mM^-1 s^-1. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b517068k

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Improved syntheses of bis(b-cyclodextrin) derivatives, new carriers for
gadolinium complexes
a
a
b
c
c
c
Silvio Aime, Eliana Gianolio, Giovanni Palmisano, Bruna Robaldo, Alessandro Barge, Luisa Boffa and
a
Giancarlo Cravotto*
Received 1st December 2005, Accepted 10th January 2006
First published as an Advance Article on the web 25th January 2006
DOI: 10.1039/b517068k
In the last decade a number of reports have been published on the synthesis and characterization of
bridged cyclodextrin dimers (bis-CDs) connected with linkers of different lengths and structures. These
dimers, having two hydrophobic cavities in close proximity, display much higher binding affinities and
molecular selectivities than parent CDs, forming stable supramolecular adducts. We describe new
ꢀ
ꢀ
ꢀ
synthetic protocols for the preparation of bis(b-CDs) bearing 2–2 , 3–3 and 6–6 bridges. Some of the
critical steps were carried out either under high-intensity ultrasound (US) or microwave (MW)
ꢀ
irradiation. Bis(b-CDs) containing 6–6 ureido- and thioureido-bridges were prepared in high yields by
a MW-promoted aza-Wittig reaction using polymer-bound triphenylphosphine, while those containing
ꢀ
ꢀ
2
(
,2 and 3,3 bridges were prepared from mono-alkenyl b-CDs by the cross-metathesis reaction
nd
homodimerization) in the presence of 2 -generation Grubbs catalyst under sonochemical conditions.
By these improved protocols CD dimers could be obtained in gram amounts to prepare stable adducts
of bis-CDs with contrast agents (CAs) containing gadolinium(III) chelates. In the case of Gd(III) chleate
“
G-1” the inclusion complexes were found to be 2 to 3 orders of magnitude more stable than that
4
−1
2
−1
formed by b-CD (Kass = 4.3 × 10 M vs 8.0 × 10 M ). Relaxivity increased as well by factors of 3 and
, viz. from 9.1 mM (b-CD) to 27.7 and 35 mM s .
−
1
−1
−1 −1
4
s
Introduction
groups) that can bind firmly to a b-CD unit. If the dimers are
to display two binding sites per molecule, the two CD units
must be connected with an appropriate spacer. Cooperative
interactions between the two sites may then occur, resulting in
significantly higher binding constants compared to the monomeric
Cyclodextrins (CDs) play important roles in chemical, biological
and pharmaceutical technology; among their numerous applica-
tions they are used for analytical separations, in enzyme mimics,
as drug carriers and to deliver diagnostic agents. CDs are among
the most promising and widely employed oligosaccharide hosts
for drug complexation, as CD-encapsulated drugs usually have a
better bioavailability, a longer half-life in the body, unhindered
1
2
3
4,5
9
species.
10
11
Since the pioneer works of Tabushi and Harada much effort
has been devoted to making bis-CDs with a variety of functional
12–14
tethers.
Although the synthesis and properties of bis-CDs that
6
excretion and no extra toxicity. When they are used to host
are linked through their primary face (positions 6) are well doc-
contrast agents (CAs), the resulting complexes have a much
larger molecular mass; moreover the change from a quasispherical
molecular shape (such as that of the classic [GdDOTA]-complex)
to the more irregular shape of the CD:[GdDOTA]-complex,
umented, few reports have appeared to date on dimers connected
15–17
through their secondary face (positions 2 and 3).
The latter are
actually harder to prepare because selective mono-substitution is
not so easily achieved on the secondary as on the primary side
7
resulting in a slower rotation in water, will enhance contrast.
18
and, moreover, their isolation has proved more troublesome.
However, data published to date have shown but a poor binding to
CDs of lanthanide(III) chelates with polyazamacrocyclic ligands.
In fact even c-CD, the largest commercially available member of
the family, is too small to fully include these CAs; as the guest is
only partially lodged in it, a weak complex results. To overcome
the snag one might use substituted c-CDs that associate more
While selective 6-monosubstitution can usually be achieved via
monotosylation, monosubstitution on the secondary face is not
straightforward, the resulting products generally requiring time-
consuming chromatographic purifications. Recently we described
the preparation of 2,2 bis-CDs from 6-O-TBDMS-b-CD through
the monotosyl and 2-monoazido derivatives, to end with an aza-
ꢀ
8
efficiently with the CA, or resort to CD dimers in association with
CAs bearing at least two substituents (e.g. two phenyl or cyclohexyl
Wittig reaction by treatment with CS
2
and triphenylphosphine
17
(
PPh
3
). These dimers were linked by a thioureidic unit directly
connected to the secondary rims. Although this synthetic
procedure is very efficient, it suffers from the drawback of residual
a
Dipartimento di Chimica I.F.M., Universit a` di Torino, Via Giuria 7, 10125,
Torino, Italy
PPh remaining trapped in the dimer cavities as a stable inclusion
3
b
Dipartimento di Scienze Chimiche e Ambientali, Universit a` dell’Insubria,
complex. The improved procedure presented here overcomes the
Via Valleggio 11, 22100, Como, Italy
hurdle by employing polymer-bound PPh under MW irradiation,
3
c
Dipartimento di Scienza e Tecnologia del Farmaco, Universit a` di Torino,
resulting in much shorter reaction times and higher yields
(Scheme 1).
Via Giuria 9, 10125, Torino, Italy. E-mail: giancarlo.cravotto@unito.it;
Fax: +39 011 6707687
1
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ꢀ
Scheme 1 Synthesis of the 6–6 ureido- (1) and thioureido-tethered (2) bis-CDs.
ꢀ
ꢀ
The key step in our synthesis of 2,2 and 3,3 bis-CDs is the
metathesis reaction (homodimerization) with ruthenium catalysts,
which we carried out under sonochemical conditions, reducing the
reaction time (2 h vs. 8 h under conventional conditions) without
significantly improving yields (Scheme 2). Olefin metathesis is
now established as an important reaction of wide application in
Results and discussion
In the present work we improved the synthetic protocols for the
ꢀ
ꢀ
ꢀ
preparation of 2–2 , 3–3 and 6–6 bis(b-CDs), testing the critical
20
steps both under high-intensity ultrasound (US) and under
21
MW irradiation. These techniques, that often complement each
other, have emerged as effective promoters of organic reactions,
cutting down reaction times to minutes or even seconds rather
than hours or days. Against the vast literature on US- and
MW-promoted reactions, only a couple of reports have so far
concerned the modification of CDs under these non-conventional
19
synthetic organic chemistry, the most commonly used catalysts
being first- and second generation Grubbs (Ru) reagents. The
tethering of two b-CD molecules with chains of different lengths
can afford a wide range of bis-CDs differing only in the spacing.
We are investigating all these water-soluble bridged bis(b-CDs)
as host molecules for CA-adducts containing gadolinium(III)
chelates, and their fully substituted derivatives 6-O-TBDMS, 2,3-
Me-b-CD as chiral selectors for enantioselective gas chromatog-
raphy (GC).
22,23
conditions.
In a previous paper we compared several CD
functionalizations carried out both under conventional conditions
and under US, showing that the sonochemical procedures were
very advantageous in terms of yields and reaction times.
22
ꢀ
Scheme 2 Synthesis of the 2–2 bridged bis(b-CDs) 9 and 11. Reagents and conditions: a) TBDMSCl, imidazole, dry pyridine, stirring rt, 8 h;
◦
b) 5-bromopentane, LiH, dry THF–DMSO, reflux, 4 h; c) acetic anhydride, dry pyridine, MW, 50 C, 1 h; d) Grubbs catalyst, Ar, dry CH
2
Cl
2
,
◦
◦
US, 34 C, 2 h; e) KOH, 2 M, MeOH, H
2
O, US, 40 C, 30 min; f ) AcCl 2% in MeOH, CH
2
Cl
2
, MW, reflux, 15 min.
This journal is © The Royal Society of Chemistry 2006
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ꢀ
Fig. 1 1,8-Bis-(b-CD-2 -yl)oct-4-ene (9).
I–VI I–VII
I
For the sake of clarity bis-CD 9 is depicted in Fig. 1 both as
bridged cyclic heptamer consisting of six equal b-D-glucose units
and a monoalkylated one and according to the classic schematic
representation.
to acetates. The 6-O-TBDMS-2 ,3 -O-acetyl-2 -O-alkenyl-b-
CD was subjected to homodimerization in the presence of a
commercially available second-generation Grubbs catalyst. In this
manner two different bis(b-CD)s with a spacer arm of either 8
or 20 carbons were prepared in good yields. Residual ruthenium
was removed from the crude reaction mixtures by oxidation with
ꢀ
18
ꢀ13,14
The well-known procedure to prepare 2–2 and 6–6
ureido-
or thioureido-bridged bis-CDs was greatly improved by us in
terms of shorter reaction times (30–90 min vs. 10–20 h under
conventional conditions), ease of purification and, better yields by
a small amount of Pb(OAc) followed by filtration through a
silica plug. The length of the alkenyl chain strongly influenced
4
using polymer-bound PPh
this procedure is also suitable for the preparation of thiourea-
bridged CD-glycoconjugates and CD-glycodendrimers. Our
protocol also did away with the most serious drawback of the
standard procedure, the formation of stable inclusion complexes
3
under MW irradiation. Conceivably
the reaction rate; in fact the short allyl chain of 6-O-TBDMS-
I–VI I–VII
I
2
,3 -O-acetyl-2 -O-propenyl-b-CD utterly failed to react.
24
25
Successively the acetates could be rapidly hydrolyzed under US
◦
(30 min at 40 C) and silyl groups cleaved off in a few minutes
under acidic conditions and MW. Both deprotection reactions can
be successfully carried out in any US device and domestic MW
oven, respectively. Parallel syntheses following the same procedure
of the dimers with PPh
3
and PPh oxide, guests that proved difficult
3
to remove even by competition with other aromatic or cyclohexyl
compounds (under reflux or under US) or by HPLC purification
ꢀ
as depicted in Scheme 2, afforded the dimer 9 isom [i.e., a 3–3
ꢀ
(
gradient CH
3
CN–H
2
O).
bis(b-CD) linked by a C bridge] starting from 5 and 9b [i.e., a 2–2
8
Olefin metathesis has been reported by Sina y¨ et al. as a
bis(b-CD) linked by a C20 bridge] starting from 4b (Fig. 2).
We studied the interactions of our bridged bis-CDs with some
suitably functionalized CAs for diagnostic magnetic resonance
ꢀ
useful reaction to prepare bis(a- or b-CD)s linked at 6–6 by
26
one or two aliphatic bridges. We were the first to carry it out
sonochemically starting from 2- or 3-monoalkenyl b-CD. High-
intensity ultrasound strongly accelerates olefin metathesis; this
reaction of course requires suitable apparatus for work under
modified atmosphere (argon).
28
imaging (MRI), e.g. with the complex shown in Fig. 3. Ditopic
guests can be expected to bind to bis-CDs more strongly than
monotopic ones. The strength of a Gd(III) chelate as CA for MRI
is related to its relaxivity (r1p), that can be much enhanced by
attaching it to a macromolecular system such as a bis-CD. To
minimize the toxicity of the resulting adduct, this should be non-
covalent rather than covalent in nature, a condition that requires
the Gd(III) chelate to contain suitable hydrophobic groups to
behave as guests in the CD cavities.
27
6
-O-TBDMS-b-CD was reacted at room temperature in anhy-
drous THF with a stoichiometric amount of alkenyl bromide in the
presence of lithium hydride, yielding the 2-monoalkenyl derivative
as major product beside a small amount of the 3-monoalkenyl
derivative. The use of US here was not appropriate, because
it would lead to polyalkylation right away. These derivatives
could be much more easily separated after CD derivatization
Firstly, we investigated host–guest interactions of G-1 with 6–6ꢀ
ureido- (1) and thioureido- (2) bis-CDs. Its relaxivity increased,
1
126 | Org. Biomol. Chem., 2006, 4, 1124–1130
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to the residual proton and carbon resonance of the solvent:
CDCl
3
(d
H
= 7.26, d
C
= 77.0). For spectra recorded in D
2
O t-
butanol was added as external reference (d
H
= 1.29). Chemical
shifts (d) are given in ppm, and coupling constants (J) in Hz.
MALDI-TOF MS spectra were measured on a Bruker Reflex
III spectrometer. Sonochemical apparatus with immersion horn
developed in the author’s laboratory can control all critical
parameters (power, frequency modified atmosphere and reaction
temperature). For higher volumes (up to 120 mL) and power (up to
28
5
00 W) was employed a new type of thermostatted cup-horn, a thin
cylinder machined from a titanium rod developed in collaboration
with NTS (Italy) (Fig. 4). MW-promoted reactions were carried
out in a professional oven, Microsynth-Milestone (Italy). HPLC
separations were recorded with an Amersham AKTA purifier
1
0/100 equipped with Atlantis RP18 (4.6 × 150 and 19 × 100 mm)
columns (Waters). The longitudinal water proton relaxation rates
were measured on a Stelar Spinmaster (Mede, Italy) spectrometer
operating at 20 MHz, by means of the standard inversion–recovery
ꢀ
ꢀ
Fig. 2 3–3 Bis(b-CD) with a C
8
bridge (9 isom) and 2–2 bis(b-CD) with
◦
a C20 bridge (9b).
technique (16 experiments, 2 scans). A typical 90 pulse width
was 4 ls and the reproducibility of the T
1
data was ± 0.5%. The
◦
temperature was kept at 25± 0.1 C with a Stelar VTC-91 air-
flow heater equipped with a copper–constantan thermocouple.
Commercially available reagents and solvents were used without
further purification unless otherwise noted. b-CD was kindly
provided by Wacker Chemie. Gd(III) complex G-1 (Fig. 3) was
kindly provided by Bracco Imaging Spa (Italy).
Fig. 3 Gd(III) complex G-1.
−
1
−1
respectively, by a factor of 3 and 4, viz. from 9.1 mM
s
to 27.7
−
1
−1
and 35 mM s . The inclusion complexes formed by 1 and 2 with
3
−1
3
−1
G-1 were more stable (Kass = 3.1 × 10 M and 3.9 × 10 M ,
2
−1
respectively) than that formed by b-CD (Kass = 8.0 × 10 M ).
4
−1
With dimer 9 Kass was 4.3 × 10 M , still one order of magnitude
higher, and its relaxivity was 27.3. These results show that these
systems could be promising candidates for MRI applications.
Conclusions
An easier access to bis-CDs could vastly broaden their field
of application in research and for industrial purposes. Non-
conventional techniques such as US and MW, widely used already
in other synthetic fields, can play an important role in the
synthesis of these compounds, cutting down reaction times and
increasing yields. Stability constants and relaxivity values showed
that adducts of Gd(III) chelates with our bis-CDs can be promising
candidates for MRI applications.
Fig. 4 New high-power cup-horn reactor (cavitating tube).
Synthesis
ꢀ
ꢀ
N,N -Bis[6-O-TbDMS-mono(2-deoxy)] 2–2 thioureido-b-CD
2). The reaction was carried out in a professional MW oven
Experimental
(
with magnetic stirring and Milestone fibre-optic thermometer.
In a 50 mL two-necked round-bottomed flask equipped with
General
I
Materials and methods. Reactions were monitored by TLC on
Merck 60 F254 (0.25 mm) plates, which were visualized by UV
gas inlet and condenser, 6 -O-azido-b-CD (500 mg, 0.43 mmol),
−
1
polymer-bound PPh
3
(loading: ∼3.0 mmol g , 2% cross-linked
inspection and/or by heating after a spray with 5% H
ethanol. Merck silica gel was used for column chromatography
CC). IR spectra were recorded with a Shimadzu FT-IR 8001
2
SO
4
in
with divinylbenzene, Aldrich) (1.146 g, 3.44 mmol) and dry DMF
(18 mL) were added and stirred for a few minutes. After addition of
◦
(
a cold solution (0 C) of CS
2
(150 lL, 2.15 mmol) in DMF (3 mL),
◦
spectrophotometer. Unless stated otherwise, NMR spectra were
recorded on a Bruker 300 Avance (300 MHz and 75 MHz for
the mixture was heated under MW for 30 min at 110 C (130 W).
The reacted mixture was filtered off and DMF removed by vacuum
distillation. The residue was washed with ether (40 mL × 3) and
1
13
◦
H and C, respectively) at 25 C; chemical shifts are calibrated
This journal is © The Royal Society of Chemistry 2006
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I–VI I–VII
I
dried under vacuum. 938 mg of 2 were obtained (white powder,
6-O-TBDMS-2 ,3 -O-acetyl-2 -O-pentenyl-b-CD (6). In
0
.40 mmol, yield 93%). Spectroscopic data were in accordance
a 50 mL two-necked round-bottomed flask equipped with the
Milestone fibre-optic thermometer probe, 6-O-TBDMS-2 -O-
14
I
with the literature.
The same procedure was used for the preparation of 1, CS
2
being
pentenyl-b-CD (1.540 g, 0.77 mmol), acetic anhydride (4 mL,
replaced with a stream of CO
for 90 min at 110 C (yield 84%).
2
. The mixture was heated under MW
42 mmol) and cat. DMAP (1 mmol) were dissolved in anhydrous
pyridine (20 mL). The mixture was heated under MW at 50 C
◦
◦
for 1 h in a professional oven. The mixture was diluted with
CH
2
Cl
SO
: 3, 3 : 7), yielded 1.773 g of 6 (0.69 mmol, yield 89%). 6 is a white
(hexane–EtOAc 1 : 1) = 0.25. IR (KBr): m = 1755, 1473,
373, 1250, 1044, 835 cm . H NMR (CDCl
2
, washed with 1 M H
2
SO
4
(×3) and brine, and finally dried
I
6
-O-TBDMS-2 -O-pentenyl-b-CD (4). In a 50 mL flame-dried
(
Na
2
4
). The crude product, purified by CC (hexane–EtOAc 1 : 1,
round-bottomed flask, 6-O-TBDMS-b-CD (5 g, 2.6 mmol) and
LiH (123 mg, 15.5 mmol) were dissolved in anhydrous THF
2
powder. R
f
(
20 mL). The magnetically stirred mixture was left 2 h under
reflux. After cooling to room temperature, a solution of 5-bromo-
-pentene (920 lL, 7.8 mmol) in THF (3 mL) was added dropwise.
The reaction was stirred 4 h under reflux and monitored by TLC,
eluent CHCl –CH OH 4 : 1. The reacted mixture was diluted
with EtOAc, washed with 1 M H SO and brine, and finally dried
Na SO ). The crude residue, purified by CC (CHCl –CH OH 19 :
, 9 : 1, 4 : 1) yielded 2.61 g of monoalkylated product 4 (1.31 mmol,
yield 51.1%), 0.87 g of monoalkylated product 5 (0.43 mmol, yield
7%), 0.97 g of dialkylated derivative (0.47 mmol, yield 18%) and
−
1
1
1
4
1
3
): d = 5.78 (m, 1H,
ꢀ
-H), 5.42–5.33 (m, 6 H, 3-H), 5.20–5.19 (m, 7 H, 1-H, overlapped
H, 3-H), 4.98 (m, 2 H, 5 -H), 4.79–4.67 (m, 6 H, 2-H), 4.12–3.71
1
ꢀ
ꢀ
(
2
0
m, 28 H, overlapped 2 H, 1 -H), 3.08 (d, J = 9.4 Hz, 1 H, 2-H),
3
3
ꢀ
ꢀ
.07 (m, 39 H, Ac, overlapped 2 H, 3 -H), 1.72–1.70 (m, 2 H, 2 -H),
.88 (s, 63 H, t-Bu), 0.05 (s, 42 H, Si-CH ) ppm. MALDI-TOF
2
4
3
(
1
2
4
3
3
+
MS: m/z calcd. for [M + Na] 2570.2; found 2570.0.
The same procedure was employed for the following acetyla-
tions.
1
I
Acetylation of 6-O-TBDMS-3 -O-pentenyl-b-CD (yield 90%).
traces of starting material.
NB. If carried out at this point, the separation of 4 and 5 would
be quite laborious; it became much easier after acetylation.
I–VII I–VI
I
6
-O-TBDMS-2 ,3 -O-acetyl-3 -O-pentenyl-b-CD (6 isom) is a
white powder. R
(hexane–EtOAc 1 : 1) 0.51. IR (KBr): m = 1755,
473, 1373, 1250, 1044, 835 cm . H NMR (CDCl
f
−
1
1
1
1
7
2
2
3
): d = 5.8 (m,
Compound 4 is a white powder. R
f
= 0.52 (CHCl
3
–CH OH
3
1
ꢀ
ꢀ
H, H-4 ), 5.5–5.1 (m, 13 H), 4.98 (m, 2 H, 5 -H), 4.70–4.67 (m,
H, 2-H, overlapped 1 H, 3-H), 4.12–3.69 (m, 28 H, overlapped
H, 1 -H), 2.07 (m, 39 H, Ac, overlapped 2 H, 3 -H), 1.72–1.70 (m,
−
1
4
: 1). IR (KBr): m = 3420, 1471, 1254, 1040, 1086, 835 cm . H
ꢀ
NMR (CDCl
3
): d = 5.8 (m, 1 H, 4 -H), 5.04–4.90 (m, 7 H, 1-H,
ꢀ
ꢀ
ꢀ
overlapped 2 H, 5 -H), 4.14–3.89 (m, 13 H), 3.73–3.49 (m, 28 H,
ꢀ
H, 2 -H), 0.88 (s, 63 H, t-Bu), 0.05 (s, 42 H, Si-CH
3
). MALDI-
ꢀ
overlapped 2 H, 3 -H), 3.18 (d, J = 9.4 Hz, 1 H, 2-H), 2.11–2.09
+
TOF MS: m/z calcd. for [M + Na] 2570.2; found 2570.1.
ꢀ
ꢀ
(
(
(
(
m, 2 H, 3 -H), 1.72–1.70 (m, 2 H, 2 -H), 0.88 (s, 63 H, t-Bu), 0.05
I
Acetylation of 6-O-TBDMS-2 -O-undec-10-enyl-b-CD (yield
1
3
ꢀ
s, 42 H, Si-CH
3
) ppm. C NMR (CDCl
C5 ), 101.9 (C1), 81.6 (C4), 73.4 (C2), 73.2 (C3), 72.2 (C5), 61.5
3
): d = 137.8 (C4 ), 114.7
I–VI I–VII
I
7
2%). 6-O-TBDMS-2 ,3 -O-acetyl-2 -O-undec-10-enyl-b-CD
ꢀ
(
6b) is a white powder. R (hexane–EtOAc 3 : 7) 0.61. IR (KBr):
f
ꢀ
ꢀ
C6), 29.6 (C2 ), 28.2 (C3 ), 25.8 (C-Me
5.2 (Si-Me
3
), 18.2 (C-Me
3
), −5.0,
−
1
1
m = 1755, 1475, 1373, 1250, 1040, 838 cm . H NMR (CDCl
3
):
+
−
2
) ppm. MALDI-TOF MS: m/z calcd. for [M + Na]
ꢀ
d = 5.78 (m, 1 H, 10 -H), 5.39–5.33 (m, 6 H, 3-H), 5.18–5.10 (m,
2
024.0; found 2025.1.
ꢀ
7
H, 1-H, overlapped 1 H, 3-H), 4.98 (m, 2 H, 11 -H), 4.75–4.68
Compound 5 is a white powder. R
f
= 0.62 (CHCl
3
–CH OH 4 :
3
ꢀ
(m, 6 H, 2-H), 4.12–3.71 (m, 28 H, overlapped 2 H, 1 -H), 3.08 (d,
−
1 1
1
(
2
2
(
). IR (KBr): m = 3420, 1471, 1254, 1040, 1086, 835 cm . H NMR
ꢀ
J = 9.4 Hz, 1 H, 2-H), 2.07 (m, 39 H, Ac, overlapped 2 H, 9 -H),
ꢀ
CDCl
3
): d = 5.8 (m, 1 H, 4 -H), 5.16–4.93 (m, 7 H, 1-H, overlapped
ꢀ
ꢀ
1
.59 (m, 2 H, 2 -H), 1.37 (m, 2 H, 8 -H), 1.27 (s, 10 H, aliphatic
chain), 0.88 (s, 63 H, t-Bu), 0.05 (s, 42 H, Si-CH ). MALDI-TOF
MS: m/z calcd. for [M + Na] 2654.2; found 2650.9.
ꢀ
H, 5 -H), 3.94–3.90 (m, 14 H), 3.73–3.51 (m, 28 H, overlapped
ꢀ
ꢀ
ꢀ
3
H, 3 -H), 2.20–2.10 (m, 2 H, 3 -H), 1.86–1.88 (m, 2 H, 2 -H), 0.88
) ppm. MALDI-TOF MS:
+
s, 63 H, t-but), 0.05 (s, 42 H, Si-CH
3
+
m/z calcd. for [M + Na] 2024.0; found 2026.2.
The same procedure was followed to synthesize other
monoalkenyl analogues.
ꢀ
ꢀI–VI ꢀI–VII
ꢀ
1
,8-Bis-(6 -O-TBDMS-2 ,3
-O-acetyl-b-CD-2 -yl)oct-4-
ene (7). US-promoted metathesis reactions were performed
under argon atmosphere in a 1 mm thick Teflon tube inserted
in a Delrin reactor thermostatted by two Peltier modules.
Compound 6 (520 mg, 0.20 mmol) and 2 -generation Grubbs Ru
catalyst (0.03 g, 0.04 mmol) were dissolved in dry CH Cl (35 mL)
and sonicated (19.1 kHz, 50 W cm ) for 2 h at 34 C. After
cooling down to rt, the reaction was stopped by adding Pb(OAc)
(0.05 mmol) and sonicating for additional 20 min at 25 C. The
mixture was dried under vacuum. Purification by CC, eluent
(hexane–EtOAc 1 : 1, 2 : 3, 3 : 7) afforded 338 mg of dimer
(0,07 mmol, yield 69%). 64 mg of the starting material were
ꢀ
R
ꢀ
R
29
I
nd
6
-O-TBDMS-2 -O-undecenyl-b-CD (4b). Starting from 6-O-
TBDMS-b-CD (1.5 g, 0.75 mmol), LiH (36 mg, 4.5 mmol) and
1-bromo-1-undecene (494 lL, 2.25 mmol). The following were
obtained: 2-monoalkylated product (548 mg, 0.26 mmol, yield
4%) and dialkylated derivative (87 mg, 0.04 mmol, yield 5%),
recovering 485 mg of the starting material. 4b is a white powder.
2
2
−
2
◦
1
4
◦
3
R
f
= 0.66 (CHCl
3
–CH
3
OH 4 : 1). IR (KBr): m = 3420, 1472, 1253,
−
1
1
ꢀ
1
4
3
1
2
041, 839 cm . H NMR (CDCl
.90 (m, 7 H, 1-H, overlapped 2 H, 11 -H), 4.14–3.89 (m, 13 H),
3
): d = 5.78 (m, 1 H, 10 -H), 5.04–
ꢀ
recovered. 7 is a white powder. R (hexane–EtOAc 1 : 1) 0.04. IR
f
ꢀ
−1
1
.73–3.49 (m, 28 H, overlapped 2 H, 3 -H), 3.18 (d, J = 9.4 Hz,
(KBr): m = 1754, 1470, 1244, 1035, 832 cm . H NMR (CDCl
3
):
ꢀ
ꢀ
ꢀ
H, 2-H), 2.05–2.03 (m, 2H, 9 -H), 1.59 (m, 2H, 2 -H), 1.37 (m,
d = 5.42–5.33 (m, 12 H, 3 -H, overlapped 2 H, 4,5-H), 5.17–5.11
ꢀ
ꢀ
ꢀ
ꢀ
H, 8 -H), 1.27 (s, 10 H, aliphatic chain), 0.88 (s, 63 H, t-Bu), 0.05
(m, 14 H, 1 -H, overlapped 2 H, 3 -H), 4.79–4.67 (m, 12 H, 2 -H),
(
s, 42 H, Si-CH
3
) ppm. MALDI-TOF MS: m/z calcd. for [M +
4.12–3.71 (m, 56 H, overlapped 4 H, 1,8-H), 3.08 (d, J = 9.4 Hz,
+
ꢀ
Na] 2108.12; found 2110.08.
2 H, 2 -H,), 2.07 (m, 78 H, Ac, overlapped 4 H, 3,6-H), 1.72–1.70
1
128 | Org. Biomol. Chem., 2006, 4, 1124–1130
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(
m, 4 H, 2,7-H), 0.88 (s, 126 H, t-Bu), 0.05 (s, 84 H, Si-CH
3
ꢀ
).
The same procedure was followed to obtain the following final
products.
1
3
C-NMR (CDCl
7.8 (C4 ), 72.1, 72.0, 71.8 (C2 ,3 ,5 ), 61.5 (C6 ), 29.6 (C2,7), 28.2
3
) d = 170.1 (Me
3
ꢀ
CO), 129.2 (C4,5), 97.3 (C1 ),
ꢀ
ꢀ
ꢀ
ꢀ
7
ꢀ
ꢀ
1
,8-Bis-(6 -O-TBDMS-b-CD-3 -yl)oct-4-ene (9 isom) (yield
97%). 9 isom is white powder (Found: C, 46.5; H, 6.3; Calcd
70: C, 46.4; H, 6.4%). R CN–H O 4 :
= 0.23 (CH
.6). IR (KBr): m = 3420, 1472, 1245, 1036, 835 cm . H NMR
(600 MHz, CDCl
): d = 5.5 (m, 2 H, 4,5-H), 4.97 (brs, 14 H, 1 -H),
3.78–3.49 (m, 42 H, overlapped 4 H, 1,8-H), 1.99 (m, 4 H, 3,6-H),
(
(
C3,6), 26.2 (C-Me
Si-Me
3
), 21.2 (Me
3
CO), 18.6 (C-Me
3
), −4.5, −5.0
+
2
). MALDI-TOF MS: m/z calcd. for [M + Na] 5089.3;
for C92
H
152
O
f
3
2
found 5092.1.
−
1
1
1
The same procedure was followed to synthesize 1,20-bis-
ꢀ
ꢀ
ꢀI–VI ꢀI–VII
ꢀ
3
(
6 -O-TBDMS-2 ,3
-O-acetyl-b-CD-2 -yl)eicos-10-ene (7b).
I–VI I–VII
I
Starting from 6-O-TBDMS-2 ,3 -O-acetyl-2 -O-undecenyl-b-
CD (388 mg, 0.15 mmol). The reaction gave 184 mg of product
+
1
2
.64 (m, 4 H, 2,7-H). MALDI-TOF MS: m/z calcd. for [M + Na]
399.8; found 2399.0.
(
0.036 mmol, yield 48%). 7b is a white powder. R
f
= 0.49 (hexane–
−1
EtOAc 3 : 7). IR (KBr): m = 1754, 1472, 1245, 1036, 834 cm .
ꢀ
1
,20-Bis-(b-CD-2 -yl)eicos-10-ene (9b) (yield 92%). 9b is a
1
ꢀ
H NMR (CDCl
3
): d = 5.36–5.33 (m, 12 H, 3 -H, overlapped 2H,
white powder (Found: C, 49.1; H, 6.9; Calcd for C104
176
H O70: C,
ꢀ
ꢀ
1
4
3
4
0,11-H), 5.17–5.12 (m, 14 H, 1 -H, overlapped 2 H, 3 -H), 4.75–
.68 (m, 12 H, 2 -H), 4.2–3.71 (m, 56 H, overlapped 4 H, 1,20-H),
4
3
(
(
4
9.1; H, 7.0%). R
420, 1472, 1245, 1120, 1030, 834 cm . H NMR (D
m, 2 H, 10,11-H), 5.07 (s, 14 H, H-1 ), 3.86 (m, 26 H), 3.70–3.55
m, 56 H, overlapped 4 H, 1,20-H), 2.09 (m, 4 H, 9,12-H), 1.59 (m,
f
= 0.46 (CH
3
CN–H
2
1
O 4 : 1.6). IR (KBr): m =
ꢀ
−
1
2
O): d = 5.5
ꢀ
.8 (d, J = 9.4 Hz, 2 H, 2 -H,), 2.07 (m, 78 H, Ac, overlapped
ꢀ
H, 9,12-H), 1.59 (m, 4 H, H-2,19), 1.37 (m, 4 H, 8, 13-H), 1.27
(
s, 20 H, aliphatic chain), 0.88 (s, 126 H, t-Bu), 0.05 (s, 84 H, Si–
H, 2,19-H), 1.37 (m, 4 H, 8,13-H), 1.31–1.15 (m, 20 H, aliphatic
+
CH
5
3
). MALDI-TOF MS: m/z calcd. for [M + Na] 5257.5; found
+
chain). MALDI-TOF MS: m/z calcd. for [M + Na] 2568.0; found
239.0.
2
568.0.
ꢀ
ꢀ
1
,8-Bis-(6 -O-TBDMS-b-CD-2 -yl)oct-4-ene (8). In a titanium
Relaxometric measurements
ꢀ
ꢀI–VI ꢀI–VII
cup-horn reactor (Fig. 1), 1,8-bis-(6 -O-TBDMS-2 ,3
acetyl-b-CD-2 -yl)-oct-4-ene (980 mg, 0.19 mmol), H
-O-
ꢀ
2
O (10 mL)
The affinity constants Kass for the binding of Gd(III) complexes
2
M KOH (2.5 mL) and CH
3
OH (60 mL) were added. The
to CD-dimers, and the relaxivities of the resulting adducts were
◦
mixture was sonicated for 30 min at 40 C (22 kHz, 100 W).
The reaction was monitored by TLC, eluent hexane–EtOAc 1 : 1.
30
determined by the PRE method.
The reacted mixture was diluted with EtOAc, washed with H
and brine, and finally dried (Na SO ). 732 mg of product were
obtained (0.18 mmol, yield 96%). 8 is a white powder. R
= 0.61
CHCl –CH
OH 4 : 1). IR (KBr): m = 3420, 1474, 1254, 1086,
040, 835 cm . H NMR (CDCl
2
O
Acknowledgements
2
4
f
This work was supported by MIUR (COFIN 2004 and FIRB
(
1
4
3
3
2
003). We are grateful to NTS (Arcugnano, VI) and to Dr Ing.
−
1
1
3
): d = 5.5 (m, 2 H, 4,5-H),
Cesare Buffa for developing the new cup-horn reactor.
ꢀ
.90 (brs, 14 H, 1 -H), 4.19–3.81 (m, 26 H), 3.73–3.60 (m, 56 H,
ꢀ
overlapped 4 H, 1,8-H), 3.18 (m, 2 H, 2 -H), 2.11–2.09 (m, 4 H,
3
8
7
,6-H), 1.72–1.70 (m, 4 H, 2,7-H), 0.88 (s, 126 H, t-Bu), 0.05 (s,
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ꢀ
ꢀ
ꢀ
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H
152
O
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1
ꢀ
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