Regioselective di- and tetra-functionalisation of γ-cyclodextrin using capping methodology

Article abstract of DOI:10.1039/c3ob40234g

Alkylation of γ-cyclodextrin with 3 equiv. of 1,3-bis[bis(4-tert- butylphenyl)chloromethyl]benzene, followed by permethylation afforded selectively a singly capped (A,B), as well as two doubly capped (A,B:D,E and A,B:E,F) methylated γ-CDs. Deprotection with HBF₄ gave quantitatively the corresponding diols and tetrols, which constitute valuable starting compounds for further functionalisation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob40234g

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Organic & Biomolecular Chemistry
Regioselective di- and tetra- functionalisation of a γ-View Article Online
cyclodextrin using capping methodology
Matthieu Jouffroy,a Dominique Armspach,*a Dominique Matt,*a
and Loïc Toupetb
Alkylation of γ-cyclodextrin with 3 equiv. of 1,3–bis[bis(4-tert-butylphenyl)chloro-
methyl]benzene, followed by permethylation afforded selectively a singly capped (A,B), as
well as two doubly capped (A,B:D,E and A,B:E,F) methylated γ-CDs. Deprotection with
HBF4 gave quantitatively the corresponding diol and tetrols, which constitute valuable
starting compounds for further functionalisation.
a Laboratoire de Chimie Inorganique Moléculaire et Catalyse,
Institut de Chimie UMR 7177 CNRS, Université de Strasbourg,
1, rue Blaise Pascal,
67008 Strasbourg cedex (France)
Fax: (+33)3-68-851-637
E-mail: d.armspach@unistra.fr; dmatt@unistra.fr
b Institut de Physique de Rennes UMR 6251 CNRS,
Université de Rennes 1,
Campus de Beaulieu - Bâtiment 11A
35042 Rennes cedex (France)

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Introduction
The commercially available α-, β- and γ-cyclodextrins (CDs) are cyclic oligosaccharides
respectively made up of six, seven and eight α-1,4-linked glucopyranose units. They have
found numerous applications in areas ranging from drug formulation to biomimetic chemistry
and homogeneous catalysis.1–7 In order to access tailor-made CDs responding to specific
requirements, differentiating between the chemically equivalent groups that decorate both
faces of either native or persubstituted CDs is often needed.8 This can be achieved via direct
regioselective multisubstitution of native CDs using sulfonating,9–11 alkylating (trityl-
based)12–15 or silylating reagents,16–19 or indirectly by regioselective multideprotection of
persubstituted analogues, notably perbenzylated and persilylated ones.20–24 Unfortunately,
both strategies have so far only been successful with the smallest and most rigid members of
the family, namely α- and β-CD as well as some of their persubstituted derivatives. In
contrast, methods dealing with regioselective γ-CD functionalisation remain scarce and those
proposed in the literature are regarded as unsatisfactory by their own originators.23 The
synthesis of sophisticated γ-CDs remains an attractive target, all the more so because the large
γ-CD cavity is ideal for performing intra-cavity reactions,10,25 notably catalytic ones. In fact,
γ-CD is less suitable for all types of regiofunctionalisation because of its more flexible nature,
which means that whatever the functionalisation strategy employed, it always results in the
formation of mixtures of several regioisomers, the separation of which is not compatible with
standard chromatography on silica. We have previously described the use of a rigid and bulky
dialkylating reagent, namely 1,3–bis[bis(4-tert-butylphenyl)chloro-methyl]benzene (1), which
was found suitable for linking primary hydroxyl groups of neighbouring glucose units in α-
and β-CD. Hereafter, we show that this reagent is also effective in the case of the more
challenging γ-CD, for easily accessing important di- and tetrasubstituted CD intermediates (6,
7 and 8).
Results and discussion
A previous study has shown that alkylation of either α- and β-CD with one equivalent of 1
and subsequent methylation of the remaining free hydroxyl groups with NaH/MeI in N,N-
dimethylformamide (DMF) resulted in the formation of A,B-capped CDs 2 and 3 in yields up
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10
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to 55 %. By raising the ratio 1/β-CD to 2, it was also possible to obtain A,B:D,E doubly
capped β-CD 4 as a single tetrafunctionalised regioisomer in 50 % yield (Scheme 1).
OH
O
HO
tBu
OH
O
O
OH
O
tBu
O
HO
OH
OH
OH
Cl
Cl
HO
HO
O
HO
O
OH
tBu
O
OH
OH
O
tBu
1
O
HO
O
1. 1 m eq., DMAP, Pyridine
O
OH
HO
2. NaH, MeI,Imidazole, DMF
n
OH
α-CD, n = 1
β-CD, n = 2
OMe
OMe
MeO
MeO
O
OMe
O
OMe
B
O
O
O
O
OMe
OMe
O
Ar
MeO
O
O
O
Ar
MeO
Ar
OMe
Ar
O
O
OMe
OMe
OMe
OMe
A
D
O
MeO
MeO
Ar
Ar
O
O
MeO
Ar
Ar
O
O
O
O
O
MeO
O
Ar
MeO
Ar
Ar
A
OMe O
OMe
O
Ar
O
O
O
B
E
MeO
HO
O
O
O
O
OMe
OMe
MeO
MeO
n
n
OMe
OMe
2, n = 1, m = 1
3, n = 2, m = 1
4, n = 2, m = 2
Ar = p-tBu-C6H4
Scheme 1: Synthesis of A,B singly capped and A,B:D,E doubly capped, methylated CDs.
Reaction of γ-CD with one equivalent of 1 in pyridine in the presence of 4-N,N-
dimethylaminopyridine (DMAP) at 50 °C for 18 h gave mostly mono-alkylated CD together
with traces of a singly capped CD and unreacted starting material. The resulting mixture was
then submitted to a second alkylation with NaH/MeI in DMF. Purification by standard
column chromatography gave CD 5 as well as small amounts of the desired A,B-capped CD 6
(Scheme 2 and Table 1, entry 1). It is noteworthy that the temperature of the first alkylation
step had little influence on the reaction yield (Table 1, entry 2). The formation of a capped
CD was inferred from the ESI-MS spectrum of 6, which showed intense peaks at m/z 2258.18
and 1140.58 corresponding to the [M + Na]+ and [M + 2Na]2+ ions, respectively.
1
Complete H NMR assignment of 6 relying on 2D COSY, TOCSY, ROESY and
edited HSQC experiments (see ESI) were undertaken to determine which glucose units the
cap is connected to. Connectivity between each individual glucose units was established by
ROESY thanks to through-space correlations between H-4N and H-1N+1 protons (N and N+1
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standing for neighbouring glucose moieties labelled in the alphabetical order). Moreover, the
same ROESY spectrum comprises cross-peaks that can be assigned to through-space
correlations between H-6 protons of the A and B glucose units and the aromatic Ha atom,
proof that A,B capping has indeed taken place (See ESI).
γ-CD
a) 1, DMAP, pyridine
b) NaH, MeI, Imidazole, DMF
OMe MeO
O
OMe MeO
O
MeO
O
MeO
O
O
O
OMe
OMe
O
O
OMe
OMe
MeO
OMe
OMe
OMe
O
O
O
O
OMe
OMe
B
MeO
MeO
MeO
OMe
Ar
Ar
OMe
OMe
O
O
O
Ar
Ar
O
O
O
O
O
O
H
MeO
MeO
a
O
OMe
OMe
OMe
OMe
O
Ar
OMe
Ar
O
OMe
O
Ar
Ar
MeO
MeO
MeO
MeO
O
O
O
O
A
MeO
MeO
O
OMe
OMe
O
O
MeO
MeO
O
O
O
OMe
OMe
OMe
OMe
MeO
MeO
5
6
D
OMe MeO
O
MeO
O
OMe MeO
O
MeO
O
O
O
OMe
OMe
O
O
OMe
OMe
Ar
Ar
OMe
OMe
E
OMe
O
O
E
O
O
O
H
OMe
a
MeO
OMe
MeO
Ar
Ar
O
Ar
B
Ar
Ar
B
O
Ar
O
O
O
O
O
O
O
O
O
Ar
O
Ar
H
MeO
a
H
MeO
a
OMe
OMe
H
OMe
OMe
a
O
O
Ar
MeO
O
O
Ar
MeO
O
OMe
Ar
O
Ar
O
F
Ar
Ar
MeO
MeO
O
MeO
O
O
A
O
A
OMe
O
OMe
O
MeO
O
O
MeO
MeO
OMe
OMe
OMe
MeO
OMe
MeO
7
8
Scheme 2 Alkylation of γ-CD with "bis-trityl" dichloride (1) and subsequent permethylation.
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Table 1 Experimental conditions for the capping of γ-CD.
T
(°C)
Yield (%)b Cumulated
6 : 7 : 8
Entry Equiva
One pot reaction
no
yield (%)c
1
1
1
50
1 : 0 : 0
2
3
4
1
2
2
70
70
70
no
no
3 : 0 : 0
9 : 5 : 7
3
21
32
yes
13 : 9 : 10
5
3
70
yes
3 : 14 : 14
31
6
4
70
yes
0 : 3 : 4
7
b
c
a number of equivalents of capping agent, isolated yield, % of capped species ( 6+7+8).
Alkylated species in which the "bis-trityl" group does not act as a capping unit were not
isolated.
Raising the ratio of "bis-trityl" capping reagent 1 to γ-CD from 1 to 2 afforded after
chromatographic separation the two doubly capped regioisomeric CDs 7 and 8, the mono-
capped CD 6 (Table 1, entry 3), and a complex mixture of compounds having bridged and
non-bridged glucose units. The marked "proximal regioselectivity" of this reaction originates
from the capacity of the "bis-trityl" reagent to strap only adjacent glucose units while
preventing “tritylation” of three successive monosaccharides because of steric hindrance. As a
result, only A,B:D,E and A,B:E,F regioisomers 7 and 8 were formed at the expense of the
A,B:C,D onelc
Again, the formation of a doubly capped CD was inferred from the ESI-MS spectrum of
both 7 and 8, which showed an intense peak at m/z 1441.78 for the [M + 2Na]2+ ion and a
weaker one at 2861.63 for the [M + Na]+ ion. The exclusive presence of A,B:D,E regioisomer
1
7 and of C2-symmetrical 8 were also confirmed by full H NMR assignement (see ESI).
Ultimate proof for A,B,E,F-tetrasubstitution in 8 came from an X-ray diffraction study
conducted on the fully deprotected derivative 9 (Figure 1) obtained after cleavage of the “bis-
trityl” caps with aqueous HBF4 in CH3CN (Scheme 3).
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HO
E
D
OH
HO
F
C
C
G
HO
HO
A
G
OH
B
H
A
OH
Figure 1 X-Ray structure of the tetrol derivative 9 (left, side-view showing the "bent" CD
structure; right, bottom view). For clarity, the water molecules have been omitted. The views
show a cavity-included molecule of pentane.
To the best of our knowledge, this study constitutes the first X-ray structural characterisation
of a chemically-modified γ-CD that is not persubstituted. The molecule crystallises with a
molecule of pentane included in the cavity and two independent water molecules located
outside the CD, both hydrogen bonded to neighbouring CDs. The pentane molecule is
orientated perpendicularly to the CD axis and literally shapes the large and flexible
4
methylated γ-CD. While all glucose units adopt the standard C1 conformation, 9 has a
slightly elongated shape, the separations between opposite O-4 atoms ranging between 10.16
Å (O-4A ••• O’-4E) and 12.26 Å (O-4C ••• O’-4G). Interestingly, in this methylated CD no
reduction of cavity volume is observed, contrary to TM-γ-CD dihydrate which possesses an
empty but heavily distorted hollow.26 All hydroxyl groups are pointing towards the CD polar
exterior whilst their primary hydrophobic methoxy counterparts are folded towards the
included pentane molecule. Looking at the molecule from the side, the molecule looks like a
bent torus, one pair of opposite glucose units (C and G) being well above and another (A and
E) lying under the mean plane defined by the O(4) atoms (Figure 1). Note that there is no
indication for a significant torus distortion in solution, as all anomeric protons of 9 resonate
within a narrow range (Δδ = 0.3 ppm).
Diol 10 and tetrol 11 were obtained quantitatively, respectively from 6 and 7, using the
same reaction conditions as those reported above for the preparation of 9.
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8
6
7
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i
i
i
D
OMe
O
MeO
OMe
OMe MeO
O
OMe MeO
O
MeO
O
MeO
O
MeO
O
O
O
O
OMe
OMe
OMe
O
O
O
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OH
E
E
O
O
O
O
O
O
OMe
OMe
OMe
MeO
MeO
MeO
HO
HO
HO
B
B
B
OMe
OH
OH
O
O
O
O
O
O
O
O
O
O
O
O
MeO
MeO
MeO
OMe
OMe
OMe
OMe
OMe
OMe
HO
HO
HO
OMe
OH
F
OMe
O
MeO
MeO
MeO
MeO
MeO
O
O
O
O
O
O
A
A
A
MeO
O
MeO
O
MeO
OMe
O
OMe
OMe
O
MeO
O
O
O
O
O
MeO
MeO
MeO
O
O
OMe
OMe
OMe
OMe
OMe
OMe
MeO
MeO
10
MeO
11
9
Scheme 3 Formation of polyols 9, 10, and 11 by hydrolysis of capped CDs 6, 7, and 8.
Reagents and conditions : (i) HBF4, CH3CN
The cumulated yield of singly and doubly capped species was increased by 11% by carrying
out the regioselective alkylation and subsequent methylation in an one-pot reaction sequence
(Table 1, entry 4).
Increasing the ratio of “bis-trityl” reagent 1 to γ-CD from 2 to 3 did not change the
yield of capped species, but the formation of doubly capped CDs was clearly favoured in this
case (Table 1, entry 5). Finally, the use of an even larger excess of capping reagent 1 (4
equiv.) resulted in lower amounts of capped species 6, 7, and 8 to the benefit of compounds
bearing at least one non-bridging "bis-trityl" group (Table 1, entry 6).27
In conclusion, we have managed, for the first time, to prepare significant amounts of
valuable di- and tetrafunctionalised γ-CD derivatives in a pure form. In spite of the challenge
represented by γ-CD regiofunctionalisation, we were able to obtain up to 32% yield of capped
species when using the versatile “bis-trityl” capping reagent 1. We anticipate that the use of a
larger analogue of 1 should keep the formation of “overtritylated” products to a minimum and
favour at the same time the less sterically crowded C2-symmetric A,B:E,F double-capped
species at the expense of its C1-symmetric A,B:D,E regioisomer.
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Experimental section
General: All commercial reagents were used as supplied. Solvents were dried by
conventional methods and distilled immediately prior to use. Column chromatography was
performed on silica gel 60 (particle size 40-63 µm, 230-240 mesh). CDCl3 was passed down a
5-cm-thick alumina column and stored under N2 over molecular sieves (3 Å). Routine 1H and
13C{1H} NMR spectra were recorded with Bruker FT instruments (AVANCE 400, 500
spectrometers). 1H NMR spectral data were referenced to residual protiated solvents (δ = 7.26
ppm for CDCl3) and 13C chemical shifts are reported relative to deuterated solvents (δ = 77.00
ppm for CDCl3). Mass spectra were recorded with a Bruker MicroTOF spectrometer (ESI)
using CH2Cl2, MeCN or MeOH as solvent. Elemental analyses were performed by the Service
de Microanalyse, Institut de Chimie UMR 7177, Strasbourg. Melting points were determined
with
a
Büchi 535 capillary melting point apparatus. 1,3-Bis[bis(4-tert-
butylphenyl)chloromethyl]benzene (1)5 was synthesized according to a literature procedure.
In this publication, the cyclodextrins are depicted as seen from the secondary face, the glucose
units being ranged counter-clockwise in the following order: A, B, C, D, E, F, G, H. The
numbering of the atoms within a glucose unit is as follows:
Y
H
6
H
4
5
O
O
O
1
H
2
3
Me
O
H
H
Me
O
Labelling of aromatic protons in the A,B cap are as follows (marked with a prime in the
corresponding D,E or E,F caps of respectively 7 and 8):
Hc
tBu
Hf
tBu
Hl
Hd
Hb
He
Hk
a OB
Hi
OA
Hg
H
tBu
tBu
Hj
Hh
Capping procedure: Compound 1 (2.71 g, 3.85 mmol) was added to a solution of γ-CD
(2.27 g, 1.75 mmol) and DMAP (0.26 g, 2.10 mmol) in pyridine (50 mL). The reaction
mixture was stirred at 70°C for 12 h before being cooled to room temperature. Pyridine was
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then removed under vacuum to afford a green solid, which was thoroughly dried overnight at
50 °C in vacuo. The residue was dissolved in DMF (100 mL) and NaH (60% in oil) (3.10 g,
77.5 mmol) was added carefully, followed by the addition of a catalytic amount of imidazole
(0.005 g, 0.08 mmol). The reaction mixture was stirred at room temperature for 1 h before
being cooled to 0°C. MeI (9.49 g, 4.16 mL, 66.9 mmol) was then added dropwise at 0°C and
the resulting yellow suspension was stirred at room temperature for 12 h. MeOH (20 mL) was
added slowly to quench excess NaH before pouring the reaction mixture into water (150 mL)
under stirring. The suspension was extracted with Et2O (3 × 100mL) and the resulting organic
extract dried (MgSO4) and evaporated to dryness to afford a brown residue. The crude
product was purified by column chromatography (SiO2; petroleum ether/AcOEt, 60:40 to
0:100, v/v) to afford three capped compounds in the following order of elution.
1)
6A,6B :6E,6F-Tetra-O-bis{benzene-1,3-bis[bis(4-tert-butylphenyl)methyl]}-2A,2B,
2C,2D,2E,2F,2G,2H,3A,3B,3C,3D,3E,3F,3G,3H,6C,6D,6G,6H-icosa-O-methyl-γ-cyclodextrin (8):
(420 mg, 9%). Rf (SiO2; petroleum ether/AcOEt, 30:70, v/v) =0.75; m.p. dec.; 1H NMR (500.1
MHz, CDCl3, 25ºC): δ (assignment by COSY, TOCSY and ROESY) = 1.21 (s, 18 H, tBu),
3
1.22 (s, 18 H, tBu), 1.27 (s, 18 H, tBu), 1.29 (s, 18 H, tBu), 2.76 (dd, 2 H, JH2-H1 = 3.3 Hz,
3JH2-H3 = 9.5 Hz, H-2B,F), 3.03 (s, 6 H, OMe-6D,H), 3.14 (s, 6 H, OMe-6C,G), 3.36 (s, 6 H,
OMe-2), 3.51 (s, 6 H, OMe-2), 3.54 (s, 6 H, OMe-2), 3.58 (s, 6 H, OMe-2), 3.62 (s, 6 H,
OMe-3), 3.64 (s, 6 H, OMe-3), 3.65 (s, 6 H, OMe-3), 3.71 (s, 6 H, OMe-3), 3.03–3.77 (42 H,
3
3
H-2A,C,D,E,G,H, H-3, H-4A,B,C,E,F,G, H-5, H-6A,C,D,E,G,H, H-6aB,F), 3.89 (t, 2 H, JH4-H3 = JH4-H5
=
9.3 Hz, H-4D,H), 4.16 (d, 2 H, 2JH6b-H6a = 11.4 Hz, H-6bB,F), 4.70 (br. d, 2 H, H-1B,F), 5.33 (br.
d, 2 H, H-1D,H), 5.40 (br. d, 2 H, H-1C,G), 5.57 (br. d, 2 H, H-1A,E), 6.81 (t, 2 H, 3JHc-Hb = 3JHc-
Hd = 7.6 Hz, Hc, Hc’), 7.01 (d, 2 H, 3JHb-Hc = 7.6 Hz, Hb, Hb’), 7.03 (d, 2 H, 3JHd-Hc = 7.6 Hz, Hd,
Hd’), 7.12 (d, 4 H, 3JHl-Hl = 8.4 Hz, Hl, Hl’), 7.17 (d, 4 H, 3JHf-He = 8.4 Hz, Hf, Hf’), 7.20 (d, 4 H,
3JHj-Hi = 8.4 Hz, Hj, Hj’), 7.27 (d, 8 H, 3JHe-Hf = 3JHh-Hg = 8.4 Hz, He, He’, Hh, Hh’), 7.37 (d, 4 H,
3JHi-Hj = 8.4 Hz, Hi, Hi’), 7.39 (d, 4 H, 3JHk-Hl = 8.4 Hz, Hk, Hk’), 7.52 (d, 4 H, 3JHg-Hh = 8.4 Hz,
Hg, Hg’), 7.62 (br s, 2 H, Ha, Ha’) ppm; 13C{1H} NMR (100.6 MHz, CDCl3, 25ºC): δ
(assignment by HMQC) = 31.24, 31.33, 31.37 [×2] (Me of tBu), 34.13, 34.15, 34.21 [×2]
(quat-C of tBu), 57.82, 57.96, 58.61, 58.73, 58.81, 59,57, 60.26, 60.90 (OMe), 61.45 (C-6B,F),
61.79, 62.29 (OMe), 64.16 (C-6A,E), 70.33, 70.72, 70.81 (C-5), 71.27 (C-6C,G), 71.36 (C-5),
71.93 (C-6D,H), 74.70, 80.83, 81.34 [×3], 81.67, 82.12 [×3], 82.44 [×3] (C-2, C-3, C-4), 85.98,
87.63 (OC(Ar)3), 96.24, 97.74, 97.88, 98.51 (C-1), 124.07, 124.12, 124.34, 124.42, 125.39,
126.29, 126.62, 126.81, 128.08, 130.70, 131.06, 135.68 (aromatic-CH), 140.20, 140.34,
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141.66, 142.65, 143.12, 145.43, 148.46, 148.52 [×2], 148.66 (quat-C) ppm; elemental
analysis (%) calcd for C164H228O40·CH2Cl2 (2839.54 + 84.93): C, 67.76; H, 7.93, found: C
68.08, H 7.82; MS (ESI-TOF): m/z (%): 1441.79 (95) [M + 2Na]2+ (calcd 1441.78), 2861.59
(5) [M + Na]+ (calcd 2861.57).
2)
6A,6B :6D,6E-Tetra-O-bis{benzene-1,3-bis[bis(4-tert-butylphenyl)methyl]}-2A,2B,
2C,2D,2E,2F,2G,2H,3A,3B,3C,3D,3E,3F,3G,3H,6C,6F,6G,6H-icosa-O-methyl-γ-cyclodextrin (7):
1
(460 mg, 10%). Rf (SiO2; petroleum ether/AcOEt, 30:70, v/v) = 0.70; m.p. dec.; H NMR
(500.1 MHz, CDCl3, 25ºC): δ (assignment by COSY, TOCSY and ROESY) = 1.15 (s, 9 H,
tBu), 1.20 (s, 9 H, tBu), 1.24 (s, 9 H, tBu), 1.26 (s, 18 H, tBu), 1.28 (s, 9 H, tBu), 1.29 (s, 9 H,
tBu), 1.30 (s, 9 H, tBu), 2.71 (dd, 1 H, 3JH2-H1 = 3.5 Hz, 3JH2-H3 = 9.9 Hz, H-2B), 2.78 (dd, 1 H,
3
3JH2-H1 = 4.0 Hz, JH2-H3 = 10.3 Hz, H-2E), 2.80 (s, 3 H, OMe-6F), 2.98 (s, 3 H, OMe-6G),
3.13–3.18 (3 H, H-2A,G, H-6aE), 3.26 (s, 3 H, OMe-6C), 3.31 (s, 3 H, OMe-6H), 3.43 (s, 3 H,
OMe-2), 3.44 (s, 3 H, OMe-2), 3.45 (s, 3 H, OMe-2), 3.52 (s, 3 H, OMe-2), 3.53 (s, 3 H,
OMe-2), 3.56 (s, 3 H, OMe-2), 3.57 (s, 3 H, OMe-2), 3.58 (s, 9 H, OMe-2, OMe-3), 3.62 (s, 3
H, OMe-3), 3.63 (s, 3 H, OMe-3), 3.66 (s, 3 H, OMe-3), 3.68 (s, 3 H, OMe-3), 3.71 (s, 3 H,
OMe-3), 3.73 (s, 3 H, OMe-3), 3.20–3.85 (37 H, H-2C,D,F,H, H-3, H-4A,B,E,F,G,H, H-5A,B,D,E,F,G,H
,
H-6A,C,D,G,H, H-6aB,F), 3.89 (m, 1 H, H-4D), 3.94 (m, 1 H, H-5C), 4.02 (t, 1 H, 3JH4-H3 = 3JH4-H5
3
= 9.7 Hz, H-4C), 4.18–4.26 (3 H, H-6bB,E,F), 4.28 (d, 1 H, JH1-H2 = 3.5 Hz, H-1B), 5.02 (d, 1
H, 3JH1-H2 = 3.1 Hz, H-1G), 5.08 (d, 1 H, 3JH1-H2 = 4.0 Hz, H-1E), 5.26 (br. d, 1 H, H-1A), 5.27
(br. d, 1 H, H-1H), 5.48 (d, 1 H, 3JH1-H2 = 2.9 Hz, H-1C), 5.67 (d, 1 H, 3JH1-H2 = 4.2 Hz, H-1F),
3
5.87 (d, 1 H, JH1-H2 = 2.1 Hz, H-1D), 6.94–6.99 (2 H, Hc, Hc’), 7.01–7.55 (36 H, Hb, Hb’, Hd,
Hd’, He, He’, Hf, Hf’,Hg, Hg’, Hh, Hh’,Hi, Hi’,Hj, Hj’,Hk, Hk’,Hl, Hl’), 7.60 (br s, 1 H, Ha), 7.83 (br
13
s, 1 H, Ha’) ppm; C{1H} NMR (100.6 MHz, CDCl3, 25ºC): δ (assignment by HMQC and
HSQC edit) = 31.35 [×8] (Me of tBu), 34.24 [×4] (quat-C of tBu), 57.63, 57.74 [×2], 57.88,
58.24, 58.35, 58.82 [×2], 58.89, 58.97, 59.05, 59.71, 59.99, 60.07, 61.47 (OMe), 61.59 (C-
6B), 61.69 (C-6E), 61.87, 62.00, 62.14, 62.20, 62.32 (OMe), 63.88 (C-6A), 65.07 (C-6D), 69.13
(C-4), 69.66, 70.12, 70.24 (C-5), 70.65 (C-6F), 70.69, 70.97, 71.09 (C-5), 71.28 (C-6H), 71.40
(C-6C), 71.50 (C-5), 71.97 (C-6G), 72.11 (C-5), 72.74, 79.24, 80.81, 81.03, 81.07, 81.26 [×3],
81.40, 81.47 [×3], 81.67, 81.79, 81.94, 82.22, 82.33 [×3], 82.50 [×2], 82.81, 83.06 [×2] (C-2,
C-3, C-4), 86.06, 86.36, 87.61, 87.84 (OC(Ar)3), 95.94, 96.60, 97.42, 97.97 [×2], 98.22,
98.37, 99.06 (C-1), 123.84, 124.10, 124.16, 124.37 [×2], 124.39, 124.46, 124.60 [×2], 125.39,
126.22, 126.55, 126.59, 126.88 [×2], 127.01, 128.04, 128.29, 130.48, 130.77, 131.29, 132.00,
134.47, 136.20 (aromatic-CH), 140.10, 140.22, 140.43, 140.92, 141.56, 141.74, 142.00,
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Organic & Biomolecular Chemistry
11
142.23 143.08, 144.88, 145.04, 145.64, 148.53, 148.60, 148.64 [×2], 148.66 [×3], 1V4ie8w.9Ar6ticle Online
(quat-C) ppm; elemental analysis (%) calcd for C164H228O40·2CH2Cl2 (2839.54 + 169.86): C
66.25, H 7.77, found: C 66.36, H 7.66; MS (ESI-TOF): m/z (%): 1439.31 (61) [M + K + H]2+
(calcd 1439.28), 1441.80 (34) [M + 2Na]2+ (calcd 1441.78), 2861.59 (5) [M + Na]+ (calcd
2861.57).
3)
6A,6B-Bis-O-bis{benzene-1,3-bis[bis(4-tert-butylphenyl)methyl]}-2A,2B,2C,2D,2E,
2F,2G,2H,3A,3B,3C,3D,3E,3F,3G,3H,6C,6D,6E,6F,6G,6H-docosa-O-methyl-γ-cyclodextrin
(6):
1
(490 mg, 13%). Rf (SiO2; AcOEt) = 0.24; m.p. dec.; H NMR (500.1 MHz, CDCl3, 25ºC): δ
(assignment by COSY, TOCSY and ROESY) = 1.29 (s, 9 H, tBu), 1.30 (s, 9 H, tBu), 1.32 (s,
3
3
18 H, tBu), 2.81 (dd, 1 H, JH2-H1 = 3.8 Hz, JH2-H3 = 9.7 Hz, H-2B), 3.18 (s, 6 H, OMe-6C,E),
3.19–3.34 (9 H, H-2A,C,D,E,F,G,H, H-5B, H-6aB), 3.36 (s, 3 H, OMe-6H), 3.37 (s, 3 H, OMe-6G),
3.38 (s, 3 H, OMe-6F), 3.39 (s, 3 H, OMe-6D), 3.40 (s, 3 H, OMe-2), 3.51 (s, 3 H, OMe-2),
3.52 (s, 3 H, OMe-2), 3.55 (s, 3 H, OMe-2), 3.56 (s, 3 H, OMe-2), 3.57 (s, 3 H, OMe-2), 3.61
(s, 3 H, OMe-2), 3.65 (s, 6 H, OMe-2, OMe-3), 3.64 (s, 3 H, OMe-3), 3.66 (s, 3 H, OMe-3),
3.67 (s, 3 H, OMe-3), 3.70 (s, 3 H, OMe-3), 3.72 (s, 3 H, OMe-3), 3.73 (s, 3 H, OMe-3), 3.74
(s, 3 H, OMe-3), 3.35–3.88 (34 H, H-3, H-4, H-5A,C,D,E,F,G,H, H-6A,C,E,F, H-6aD,G,H), 3.94–4.01
2
3
(3 H, H-6bD,G,H), 4.22 (d, 1 H, JH6b-H6a = 11.8 Hz, H-6bB), 4.42 (d, 1 H, JH1-H2 =3.8 Hz, H-
3
3
1B), 5.12 (d, 1 H, JH1-H2 = 3.0 Hz, H-1F), 5.16 (d, 1 H, JH1-H2 = 3.1 Hz, H-1G), 5.40 (d, 1 H,
3JH1-H2 = 3.1 Hz, H-1H), 5.41 (d, 1 H, 3JH1-H2 = 2.7 Hz, H-1E), 5.45 (d, 1 H, 3JH1-H2 = 3.3 Hz, H-
1D), 5.51 (d, 1 H, 3JH1-H2 = 3.2 Hz, H-1A), 5.56 (d, 1 H, 3JH1-H2 = 2.9 Hz, H-1C), 7.02–7.06 (br.
t, 1 H, Hc), 7.11–7.15 (2 H, Hb, Hd), 7.21–7.56 (16 H, He, Hf, Hg, Hh, Hi, Hj, Hk, Hl), 7.70 (br
13
s, 1 H, Ha) ppm; C{1H} NMR (100.6 MHz, CDCl3, 25ºC): δ (assignment by HMQC and
HSQC edit) = 31.47 [×4] (Me of tBu), 34.34 [×2] (quat-C of tBu), 57.88, 58.26, 58.38, 58.55,
58.77, 58.85, 58.86, 59.01 [×6], 59.07, 59.51, 60.76, 61.03, 61.21, 61.58, 61.70 (OMe), 61.90
(C-6B), 62.13, 62.28 (OMe), 63.77 (C-6A), 70.45, 70.59, 70.84, 70.89 [×2], 70.93 (C-5),
71.20 [×2] (C-6), 71.24 (C-5), 71.29, 71.44, 71.54, 71.88 (C-6), 71.89 (C-5), 76.22, 76.71,
77.21, 77.25, 79.47, 79.83, 80.52, 81.48, 81.63, 81.68, 81.81, 81.84, 81.86, 81.92, 82.00,
82.08, 82.19 [×2], 82.25 [×2], 82.43, 82.56, 82.59, 83.03 (C-2, C-3, C-4), 86.31, 87.71
(OC(Ar)3), 97.49, 97.61 [×2], 97.88, 98.24, 98.37, 98.42, 98.58 (C-1), 124.33, 124.47, 124.54
[×2], 126.35, 126.56, 126.95, 127.24, 128.51, 130.82, 131.80, 134.48 (aromatic-CH), 140.25,
140.36, 142.10, 142.86, 142.91, 145.10, 148.70, 148.78 [×2], 148.95 (quat-C) ppm; elemental
analysis (%) calcd for C118H178O40·CH2Cl2 (2236.20 + 84.93): C 61.56, H 7.81, found: C
61.45, H 7.63; MS (ESI-TOF): m/z (%): 1140.58 (36) [M + 2Na]2+ (calcd 1140.58), 2258.20
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Organic & Biomolecular Chemistry
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12
(64) [M + Na]+ (calcd 2258.18).
2A,2B,2C,2D,2E,2F,2G,2H,3A,3B,3C,3D,3E,3F,3G,3H,6C,6D,6G,6H-icosa-O-methyl-γ-
View Article Online
cyclodextrin (9): HBF4 (0.62 mL, 34% wt/wt solution in water) was added dropwise to a
stirred solution of capped cyclodextrin 8 (400 mg, 0.14 mmol) in MeCN (12 mL) at room
temperature. After 30 min, NEt3 (2.16 mL) was added dropwise under stirring. Addition of
water (40 mL) to the reaction mixture caused the carbinol to precipitate. The resulting
suspension was filtrated and the filtrate extracted with CHCl3 (3 × 20 mL). The combined
organic extracts were washed with a saturated aqueous NaHCO3 solution (40 mL) before
being dried (MgSO4). Removal of the solvent in vacuo gave 9 (220 mg, 99%) as a colourless
solid. Rf (SiO2; CH2Cl2/MeOH, 90:10, v/v) = 0.33; m.p. 135°C; 1H NMR (400.1 MHz, CDCl3,
25ºC): δ (assignment by COSY) = 2.32 (br s, 2 H, OH), 2.99 (br s, 2 H, OH), 3.12–3.21 (8 H,
H-2), 3.34 (s, 6 H, OMe-6), 3.35 (s, 6 H, OMe-6), 3.46 (s, 12 H, OMe), 3.49 (s, 12 H, OMe),
3.57 (s, 6 H, OMe), 3.58 (s, 6 H, OMe), 3.59 (s, 6 H, OMe), 3.62 (s, 6 H, OMe), 3.48–3.90
(40 H, H-3, H-4, H-5, H-6), 5.06 (d, 2 H, 3JH1-H2 = 3.2 Hz, H-1), 5.13 (d, 2 H, 3JH1-H2 = 3.4 Hz,
3
3
13
H-1), 5.26 (d, 2 H, JH1-H2 = 3.3 Hz, H-1), 5.31 (d, 2 H, JH1-H2 = 3.6 Hz, H-1) ppm; C{1H}
NMR (100.6 MHz, CDCl3, 25ºC): δ (assignment by HMQC) = 58.52 [×2], 58.92, 59.03 [×2],
59.16, 60.69, 60.72 [×2], 60.98 (OMe), 61.38, 61.80 (C-6), 70.66, 71.14 (C-5), 71.46, 71.51
(C-6), 71.67, 72.03 (C-5), 76.12, 77.05, 78.12, 79.36, 80.98, 81.31, 81.53, 81.87, 82.06 [×2],
82.31 [×2] (C-2, C-3, C-4), 96.81, 97.57 [×2], 97.87 (C-1) ppm; elemental analysis (%) calcd
for C68H120O40·CH2Cl2 (1577.66 + 84.93): C 49.85, H 7.40, found: C 49.90, H 7.29; MS (ESI-
TOF): m/z (%): 1599.74 (100) [M + Na]+ (calcd 1599.72).
2A,2B,2C,2D,2E,2F,2G,2H,3A,3B,3C,3D,3E,3F,3G,3H,6C,6D,6E,6F,6G,6H- docosa-O-methyl-
γ-cyclodextrin (10): Capped cyclodextrin 6 (400 mg, 0.18 mmol) was deprotected with HBF4
(0.40 mL, 34% wt/wt solution in water) in MeCN (8 mL) according to the above procedure to
afford 10 (285 mg, 99%). Rf (SiO2; CH2Cl2/MeOH, 90:10, v/v) = 0.38; m.p. 115°C; 1H NMR
(400.1 MHz, CDCl3, 25ºC): δ (assignment by COSY) = 2.64 (br s, 1 H, OH), 2.94 (br s, 1 H,
OH), 3.08–3.17 (8 H, H-2), 3.29 (s, 6 H, OMe-6), 3.30 (s, 6 H, OMe-6), 3.43 (s, 15 H, OMe),
3.44 (s, 3 H, OMe), 3.45 (s, 3 H, OMe), 3.46 (s, 6 H, OMe), 3.55 (s, 3 H, OMe), 3.56 (s, 12 H,
OMe), 3.57 (s, 6 H, OMe), 3.59 (s, 3 H, OMe), 3.60 (s, 3 H, OMe), 3.40–3.83 (40 H, H-3, H-
3
3
4, H-5, H-6), 5.05 (d, 1 H, JH1-H2 = 3.5 Hz, H-1), 5.13 (3 H, H-1), 5.15 (d, 1 H, JH1-H2 = 3.7
Hz, H-1), 5.19 (d, 1 H, 3JH1-H2 = 3.8 Hz, H-1), 5.20 (d, 1 H, 3JH1-H2 = 3.5 Hz, H-1), 5.22 (d, 1
3
13
H, JH1-H2 = 3.4 Hz, H-1) ppm; C{1H} NMR (100.6 MHz, CDCl3, 25ºC): δ (assignment by
HMQC) = 58.42, 58.46 [×2], 58.49, 58.52, 58.73, 58.87 [×5], 59.02 [×2], 60.95 [×2], 61.00
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Page 13 of 15
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[×2], 61.02, 61.12, 61.15, 61.21 [×2] (OMe), 61.32, 61.60 (C-6), 70.59, 70.68, 70.78 [×3] (C-
5), 70.95 [×2] (C-5, C-6), 71.10 [×3], 71.17, 71.26 (C-6), 71.55, 72.01 (C-5), 77.25, 77.69,
77.86, 78.24, 78.42, 78.50, 78.56, 79.43, 81.48, 81.59, 81.67, 81.69, 81.80 [×9], 81.94, 82.00,
82.08 (C-2, C-3, C-4), 97.55, 97.70 [×2], 97.83, 97.94, 98.07, 98.15, 98.17 (C-1) ppm;
elemental analysis (%) calcd for C70H124O40 (1605.71): C 52.36, H 7.78, found: C 52.15, H
7.71; MS (ESI-TOF): m/z (%): 1627.77 (100) [M + Na]+ (calcd 1627.76).
2A,2B,2C,2D,2E,2F,2G,2H,3A,3B,3C,3D,3E,3F,3G,3H,6C,6F,6G,6H-icosa-O-methyl-γ-
cyclodextrin (11): Capped cyclodextrine 7 (400 mg, 0.14 mmol) was deprotected with HBF4
(0.62 mL, 34% wt/wt solution in water) in MeCN (12 mL) according to the above procedure
1
to afford 11 (220 mg, 99%). Rf (SiO2; CH2Cl2/MeOH, 90:10, v/v) = 0.33; m.p. 135°C; H
NMR (400.1 MHz, CDCl3, 25ºC): δ (assignment by COSY) = 2.80–3.04 (4 H, OH), 3.11–
3.17 (8 H, H-2), 3.31 (s, 3 H, OMe-6), 3.32 (s, 6 H, OMe-6), 3.33 (s, 3 H, OMe-6), 3.44 (s, 3
H, OMe), 3.45 (s, 9 H, OMe), 3.46 (s, 3 H, OMe), 3.47 (s, 3 H, OMe), 3.48 (s, 3 H, OMe),
3.49 (s, 3 H, OMe), 3.55 (s, 9 H, OMe), 3.56 (s, 3 H, OMe), 3.58 (s, 9 H, OMe), 3.59 (s, 3 H,
OMe), 3.43–3.84 (40 H, H-3, H-4, H-5, H-6), 5.09 (2 H, H-1), 5.11 (d, 1 H, 3JH1-H2 = 3.0 Hz,
3
3
H-1), 5.14 (d, 1 H, JH1-H2 = 3.5 Hz, H-1), 5.16 (d, 1 H, JH1-H2 = 3.2 Hz, H-1), 5.22 (d, 1 H,
3JH1-H2 = 3.7 Hz, H-1), 5.24 (d, 1 H, 3JH1-H2 = 3.9 Hz, H-1), 5.31 (d, 1 H, 3JH1-H2 = 3.7 Hz, H-1)
ppm; 13C{1H} NMR (100.6 MHz, CDCl3, 25ºC): δ (assignment by HMQC) = 58.42 [×2],
58.55 [×2], 58.70, 58.80, 58.92 [×2], 59.04 [×2], 59.09 [×2], 60.67 [×2], 60.82 [×2], 60.87
[×2], 60.97, 61.06 (OMe), 61.19, 61.43, 61.52, 61.77 (C-6), 70.66 [×2], 70.76, 70.96 (C-5),
71.17, 71.21 (C-6), 71.38 [×2] (C-5, C-6), 71.47 (C-6), 71.62, 71.93, 72.23 (C-5), 75.94,
76.93, 77.27, 77.67, 78.36, 78.42, 78.67, 79.16, 81.21, 81.35, 81.44, 81.54, 81.59, 81.66 [×2],
81.68, 81.85, 81.89, 81.93, 82.00, 82.18 [×4] (C-2, C-3, C-4), 97.06, 97.35 [×2], 97.58, 97.61,
97.74 [×2], 98.10 (C-1) ppm; elemental analysis (%) calcd for C68H120O40·0.5CH2Cl2
(1577.66 + 42.47): C 50.78, H 7.53, found: C 50.82, H 7.44; MS (ESI-TOF): m/z (%):
1599.74 (100) [M + Na]+ (calcd 1599.72).
X-ray crystallographic data of 9: Single crystals of 9 were obtained by slow
diffusion of pentane into a dichloromethane solution of the compound. Crystal data for
C70.5H130O42 (9·2H2O·0.5C5H12), Mr = 1649.74, orthorhombic, space group P212121, a =
15.485(1), b = 23.254(1), c = 27.718(1) Å, V = 9981.2(8) Å3, Z = 4, ρcalcd = 1.098 g cm-3,
λ(Mo ) = 0.71073 Å, µ = 0.090 mm-1, F(000) = 3556, T = 100(2) K. The sample (0.32 × 0.25
α
K
× 0.07 mm) was studied with an Oxford Diffraction Xcalibur Saphir 3 CCD with graphite
monochromatised Mo radiation. The structure was solved with SIR-97,28 which revealed the
α
K
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Page 14 of 15
14
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non-hydrogen atoms of the molecule. After anisotropic refinement, many hydrogen atoms
were found with a Fourier difference analysis. The whole structure was refined with SHELX-
9729 and full-matrix least-square techniques. Use of F2 magnitude; x, y, z, βij for C, O atoms,
x, y, z, in riding mode for H atoms, 982 variables and 5983 observations with [I > 2.0σ(I)],
2
2
2
calcd w = 1/[σ2(Fo ) + (0.1186 P)2] where P = (Fo + 2 Fo )/3 with the resulting R = 0.0700,
RW = 0.2129, and Sw = 0.691, Δρ < 0.409 e Å-3. CCDC 862358 (9) contain the supplementary
crystallographic data for this report. These data can be obtained free of charge from The
Cambridge Christallographic Data Centre via www.ccdc.cam. ac.uk/data_request/cif.
Acknowledgments
The authors are grateful to the Région Alsace and the Centre International pour la
Recherche aux Frontières de la Chimie (CIRFC) for financial support (grant for M. J.).
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