A new approach to A,B-difunctionalisation of cyclodextrins using bulky 1,3-bis[bis(aryl)chloromethyl]benzenes as capping reagents

Article abstract of DOI:10.1039/b504012d

1,3-Bis[bis(4-tert-butylphenyl)chloromethyl]benzene and 1,3-bis[bis(4-anisyl)chloromethyl]benzene were employed as regioselective capping reagents for the preparation of C-6^A,C-6^B-bridged, permethylated α- and β-CD derivatives; isola

Full text of DOI:10.1039/b504012d

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A R T I C L E
A new approach to A,B-difunctionalisation of cyclodextrins using
bulky 1,3-bis[bis(aryl)chloromethyl]benzenes as capping reagents
Dominique Armspach,*a Laurent Poorters,a Dominique Matt,*a Belkacem Benmerad,b
Fadila Balegrouneb and Loic Toupetc
a Laboratoire de Chimie Inorganique Mole´culaire, Universite´ Louis Pasteur, UMR 7513 CNRS,
1 rue Blaise Pascal, 67008, Strasbourg cedex, France
b Universite´ des Sciences et de la Technologie, Institut de Chimie BP 32, El Alia Bab-Ezzouar,
Alger, Algeria
c Groupe Matie`re Condense´e et Mate´riaux, UMR 6626, Universite´ de Rennes 1, Campus de
Beaulieu, Baˆt. 11A, F-35042, Rennes cedex, France
Received 21st March 2005, Accepted 23rd May 2005
First published as an Advance Article on the web 10th June 2005
1,3-Bis[bis(4-tert-butylphenyl)chloromethyl]benzene and 1,3-bis[bis(4-anisyl)chloromethyl]benzene were employed as
regioselective capping reagents for the preparation of C-6A,C-6B-bridged, permethylated a- and b-CD derivatives;
isolated yields up to 55% of proximally capped, methylated CDs were obtained, thus opening the way to the
straightforward preparation of a wide range of A,B-functionalised CDs. As revealed by a single crystal X-ray
diffraction study, the benzene-1,3-bis[bis(4-tert-butylphenyl)methyl] spacer is perfectly suited for A,B-capping of
b-cyclodextrin.
Introduction
Results and discussion
Chemical modification of natural cyclodextrins (CDs) gives ac-
cess to a wide range of cavity-shaped molecules that find applica-
tions in many areas of contemporary chemistry.1–4 Modification
of CDs is usually achieved by substituting some or all of the
hydroxyl groups present atthe surface ofthe macrocycle. It is well
known that the primary OH groups are the most nucleophilic
ones and accordingly may be selectively functionalised with
the secondary ones left unaffected.5 Partial poly-substitution
reactions at the primary face can also be achieved and efficient
methologies for producing selectively di-,6–9 tri-10,11 and tetra-
substituted12,13 regioisomers have recently become available.
However, the development of synthetic strategies leading to
A,B-difunctionalised CDs still remains a challenge14–17 and as
a result, the latter have attracted less attention than other
CD regioisomers, although recent work has underlined their
relevance in homogeneous catalysis.18 To date, direct proximal
dialkylation of CDs cannot be achieved in yields higher than
ca. 10% and does not give easy access to difunctionalised
methylated CDs,19 which are key starting materials for further
modification, in particular for the introduction of phosphorus-
based ligands. In some recent reports we have shown that
supertrityl chloride 1 (STrCl) is a valuable alkylating agent
suited for the selective formation of either A,B,D,E-tetra or
A,D-diprotected, methylated a-CDs,13,20 the selectivity of these
reactions relying on the bulkiness of the supertrityl group.
However, the efficiency of this reagent for A,B-dialkylation
remains poor. We thought that A,B-disubstitution could be
significantly improved by using synthons incorporating two
bulky alkylating units separated by a rigid spacer, the length
of which is compatible with the separation of two neighbouring
glucose units.
The “bis-trityl” dichlorides used in this study, 2–4, were conve-
niently prepared in three steps according to Scheme 1. Each syn-
thesis starts with the preparation of a Grignard reagent derived
from the appropriate aryl bromide. Reaction of the thus formed
ArMgBr complex with dimethyl isophthalate and subsequent
hydrolysis gave the expected bulky diol. Treatment of the latter
with acetyl chloride afforded quantitavely the corresponding
dichloride. All intermediates were purified by simple recrystalli-
sation, chromatographic purification being unnecessary.
Scheme 1 Synthesis of 1,3-bis[bis(aryl)chloromethyl]benzenes.
Several bases were used to carry out the alkylation (Scheme 2).
The best results for the capping reactions were obtained in DMF
2 5 8 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 8 8 – 2 5 9 2
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
©

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Scheme 2 Formation of A,B-capped, methylated CDs.
using DMAP/proton sponge (method B, see experimental sec-
tion) with a CD : dichloride ratio of 1 : 1 (Table 1). Using DMAP
in pyridine (method A) gave slightly lower yields, but yields
remained high when dichloride 2 was used. The resulting alkyla-
tion products were not isolated, but instead directly treated with
MeI/NaH in order to methylate the remaining hydroxyl groups.
The latter step is necessary for product purification, the
non-methylated species being too polar for chromatographic
separation and also prone to ether cleavage. The highest yields
were observed using the tert-butyl derivative 3 as capping agent,
the corresponding disubstituted CDs 6 and 7 being isolated in 55
and 35% yield respectively (Table 1). The methoxy derivative 2,
which is also electron-rich, also gave rise to significant amounts
of A,B-disubstituted species (up to 52% of 5 using method A).
Conversely, when the non-substituted dichloride 4,21 which lacks
such electron-donating groups, was employed, only traces of
alkylated products were observed. Besides the expected A,B-
capping products, the reaction mixture generally contained
small amounts of “overtritylated” products and compounds
resulting from monoalkylation (8, 9, and 10, respectively)
together with unreacted starting material. The composition of
the reaction mixture during the first alkylation step did not
change significantly after 5 h. This could arise from a competing
proton-catalysed ether cleavage. We noted that adding an excess
of the capping reagent to the reaction mixture resulted in
decreased yields of capped species 5–7, as significant amounts
of poly-substituted CDs were produced.
The assignement of all capped species produced were made
possible through derivatisation. Thus, deprotection of 5 (or 6)
and 7 with aqueous HBF4 in MeCN afforded the diols 11 and
12,19 respectively. An X-ray diffraction study carried out on 7
confirmed the A,B-substitution pattern (Fig. 1). In the solid
state the CD torus of 7 adopts a slightly elongated circular
shape, with all glucose units in the standard 4C1 conforma-
tion, those adjacent to the capped ones being slightly tilted
towards the cavity centre. The longest O-4 · · · Oꢀ-4 separation
C
ꢀ
G
˚
is between units A and E (10.21 A), while the O-4 · · · O -4
˚
separation is 8.94 A. The bulky capping unit ideally fits with
the O-6 · · · O-6 separation (5.63 A vs. 5.30 A on average) and
A
B
˚
˚
covers ca. 60% (!) of the primary face surface.
In summary, by choosing a “bis-trityl” derivative that matches
the separation between two adjacent glucose units in the rigid
CD torus and tuning its reactivity by means of electron donor
groups, we have managed for the first time to devise a reasonably
high-yielding synthesis for A,B regioisomers of both a- and b-
CD derivatives. We believe this methodology can be extended
to the larger c-CD as well as to other CD regioisomers just by
changing the nature of the spacer separating both anchor points
in the “bis-trityl” reagent. Overall, these results give easy access
to a wide variety of valuable functionalised CD cavities.
Table 1 Capping efficiency determined after methylation of the unre-
acted hydroxy groups
Entry CD
Capping reagent Methoda Products Yield (%)
5
52
4
1
2
3
4
5
a-CD
2
2
3
3
3
A
B
A
B
B
8
5
29
14
46
22
55
6
a-CD
a-CD
a-CD
b-CD
8
6
9
6
9
Experimental
7
35
5
10
All manipulations were performed in Schlenk-type flasks under
dry nitrogen. Solvents were dried by conventional methods and
distilled immediately prior to use. CDCl3 was passed down a 5 cm
a See text and Experimental section for details.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 8 8 – 2 5 9 2
2 5 8 9

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Elemental analysis found C, 73.35, H, 6.10; C36H32O4Cl2·C5H12
(599.56 + 72.15) requires C, 73.31, H, 6.6%.
1,3-Bis[bis(4-tert-butylphenyl)chloromethyl]benzene (3)
1,3-Bis[bis(4-tert-butylphenyl)chloromethyl]benzene was pre-
pared from 4-bromo-tert-butylbenzene (61.453 g, 288.350 mmol)
and dimethyl isophthalate (12.000 g, 61.795 mmol). The crude
diol was recrystallised from heptane (400 mL) before being
subjected to the above chlorination procedure to afford the pure
product as a pale yellow solid (19.902 g, 46%). Mp 206–208 ◦C.
dH (CDCl3, 300.1 MHz) 1.31 (s, 36 H, But), 7.11 (m, 8 H, AAꢀ part
of AAꢀBBꢀ system), 7.06–7.24 (3 H, H-4,5,6 of 1,3-phenylene),
7.27 (m, 8 H, AAꢀ part of AAꢀBBꢀ system), 7.44 (t, 1 H, 4J 2 Hz,
H-2 of 1,3-phenylene). dC (CDCl3, 75.5 MHz) 31.1 (CH3), 34.3
(Cquat of But), 81.0 (C–Cl), 124.3 (CH of But-phenyl), 126.4 (C-2
or C-5 of 1,3-phenylene), 128.1 (C-4,6 of 1,3-phenylene), 129.0
(CH of But-phenyl), 132.0 (C-2 or C-5 of 1,3-phenylene), 141.9
(Cquat of But-phenyl), 144.8 (C-1,3 of 1,3-phenylene), 150.3 (Cquat
of anisyl). Elemental analysis found C, 81.71, H, 8.24; C48H56Cl2
(703.89) requires C, 81.91, H, 8.02%.
Method A. To a mixed solution of a-CD (3.000 g,
3.084 mmol) and 4-dimethylaminopyridine (DMAP) (0.382 g,
3.125 mmol) in dry pyridine (70 mL) was added 2 (1.847 g,
3.081 mmol). The solution was stirred for 13 h at 70 ◦C,
then evaporated to dryness. The residue was dissolved in
DMF (100 mL) before sodium hydride (60% in oil) (4.49 g,
112.5 mmol) was added. The mixture was stirred for 1 h at
ambient temperature whereupon it was cooled to 5 ◦C and
MeI (13.680 g, ca. 6 mL, 96.380 mmol) was added carefully
so that the temperature of the mixture did not exceed 35 ◦C. The
solution was stirred for another 14 h before MeOH (50 mL),
followed by water (300 mL), was added to destroy excess
NaH. The cyclodextrin was subsequently extracted with Et2O
(3 × 200 mL). The organic extracts were washed with H2O
(200 mL), dried over MgSO4 and finally evaporated to dryness.
The brown residue was separated by column chromatography to
afford the A,B-capped product 5 (2.761 g, 52%) together with
the monosubstituted product 8 (0.218 g, 4%) and small amounts
of less polar polytritylated products and permethylated a-CD
(TM-a-CD) which were not recovered.
Fig. 1 Molecular structure of A,B-capped CD 7. For clarity the solvent
molecules are not shown.
thick alumina column and stored under nitrogen over molecular
1
1
sieves (4 A). Routine H and 13C{ H} spectra were recorded
˚
1
with Bruker FT instruments (AC-200, AC-300, ARX-500). H
and 13C NMR spectra were recorded in CDCl3 (ref. 7.26 ppm
and 77.0 ppm, respectively). Mass spectra were recorded either
on a ZAB HF VG analytical spectrometer using m-nitrobenzyl
alcohol as matrix or on a Bruker MicroTOF spectrometer (ESI)
using CH2Cl2 as solvent.
1,3-Bis[bis(4-anisyl)chloromethyl]benzene (2)
In an oven-dried 1 L three-necked flask equipped with a
condenser, dropping funnel, and nitrogen system were placed
Mg turnings (5.257 g, 216.29 mmol) and an iodine crystal with
dry THF (150 mL). A solution of 4-bromoanisole (40.454 g,
216.285 mmol) in dry THF (50 mL) was added dropwise over
1 h with gentle heating; when the reaction started the heat was
removed. The reaction mixture, which turned grey, was stirred
for 3 h without heating. A solution of dimethyl isophthalate
(10.000 g, 51.495 mmol) in THF (40 ml) was added dropwise over
1 h. The mixture was stirred overnight at reflux under nitrogen,
whereupon it was cooled to room temperature before being
poured into a mixture of conc. H2SO4 (8 mL) and ice (300 g).
The resulting suspension was extracted with Et2O (3 × 300 mL).
The combined organic extract was washed with water (300 mL),
then dried over MgSO4. Solvent removal in vacuo gave an orange
solid, which was dissolved in Et2O (250 mL). The solution was
left to stand for 5 min, whereupon the product precipitated as a
slightly orange solid. The latter was triturated in boiling Et2O for
20 min, the suspension cooled to room temperature and filtered
through a glass frit to afford the pure diol. The latter was then
treated with boiling acetyl chloride (240 mL) for 40 h under
nitrogen. Acetyl chloride was removed in vacuo and the product
thoroughly dried to afford 2 as a red amorphous solid (24.560 g,
85%). Mp 88–90 ◦C. dH (CDCl3, 300.1 MHz) 3.81 (s, 12 H, MeO),
6,76 (m, 8 H, AAꢀ part of AAꢀBBꢀ system), 6.95 (s, 1 H, H-2 of
1,3-phenylene), 7.11 (m, 8 H, BBꢀ part of AAꢀBBꢀ system), 7.29–
7.33 (H-4,6 and H-5 of 1,3-phenylene). dC (CDCl3, 75.5 MHz)
55.2 (MeO), 81.6 (C–Cl), 112.9 (CH of anisyl), 127.2 (C-2 or C-
5 of 1,3-phenylene), 129.0 (C-4,6 of 1,3-phenylene), 130.8 (CH
of anisyl), 131.2 (C-5 or C-2 of 1,3-phenylene), 137.4 (Cquat of
anisyl), 145. 1 (C-1,3 of 1,3-phenylene), 158.9 (Cquat of anisyl).
Method B. To a mixed solution of b-CD (8.000 g,
7.048 mmol), 1,8-bis(dimethylamino)naphthalene (4.521 g,
21.095 mmol) and DMAP (0.864 g, 3.11 mmol) in dry DMF
(200 mL) was added 3 (4.962 g, 7.05 mmol). The solution
was stirred for 13 h at 70 ◦C, then allowed to reach room
temperature. After stirring for another hour, dry DMF
(200 mL) was added and the mixture was cooled to 5 ◦C
before NaH (60% in oil) (12.00 g, 300.0 mmol) was added. The
mixture was stirred for 1 h at ambient temperature, then MeI
(36.48 g, ca. 16 mL, 257.010 mmol) was added, the temperature
of the mixture being kept below 35 ◦C. The solution was stirred
for another 14 h before MeOH (50 mL), followed by H2O
(300 mL), was added to destroy excess NaH. The suspension
was subsequently extracted with Et2O (3 × 200 mL). The
organic extracts were washed with water (200 mL), dried over
MgSO4 and finally evaporated to dryness. The dark yellow
residue was separated by column chromatography to afford
respectively the A,B-capped product 7 (5.072 g, 35%) together
with the monosubstituted product 10 (0.730 g, 5%) and small
amounts of less polar polytritylated compounds.
Benzene-1,3-bis[bis(4-anisyl)methyl]-6A,6B-capped
permethylated a-CD (5)
Rf (EtOAc) = 0.21. Mp 180–182 ◦C. ES-TOF, m/z: 1724.8 (M +
3
H+). dH (300.1 MHz, CDCl3) 2.75 (dd, 1 H, JH-2,H-1 3.6 Hz,
3JH-2,H-3 9.9 Hz, H-2), 3.12–4.14 (35 H, H-2, H-3, H-4, H-5, H-6),
3.35 (s, 9 H, MeO), 3.44 (s, 3 H, MeO), 3.45 (s, 3 H, MeO), 3.46
2 5 9 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 8 8 – 2 5 9 2

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(s, 3 H, MeO), 3.47 (s, 3 H, MeO), 3.48 (s, 3 H, MeO), 3.54 (s, 3 H,
MeO), 3.56 (s, 3 H, MeO), 3.59 (s, 3 H, MeO), 3.61 (s, 3 H, MeO),
3.62 (s, 9 H, MeO), 3.63 (s, 3 H, MeO), 3.75 (s, 3 H, MeOAr),
3.76 (s, 3 H, MeOAr), 3.76 (s, 6 H, MeOAr), 4.21 (d, 1 H, 3JH-1,H-2
124.4 [×2], 124.5, 126.4, 126.6, 126.7, 127.5, 128.3, 130.6, 131.9,
134.1 (aromatic CH), 140.1, 140.3, 142.0, 142.1, 143.1, 144.9,
148.6, 148.7, 148.7, 148.8 (aromatic Cquat). Elemental analysis
found C, 64.27, H, 8.12; C109H162O35 (2032.46) requires C, 64.41,
H, 8.03%. Crystals suitable for X-ray diffraction were grown by
diffusion of heptane into a butanone solution of 7.
3
3.7 Hz, H-1), 5.01 (d, 1 H, JH-1,H-2 3.2 Hz, H-1), 5.04 (d, 1 H,
3JH-1,H-2 3.3 Hz, H-1), 5.07 (d, 1 H, 3JH-1,H-2 3.2 Hz, H-1), 5.15 (d, 1
H, 3JH-1,H-2 3.0 Hz, H-1), 5.29 (d, 1 H, 3JH-1,H-2 3.2 Hz, H-1), 6.73–
7.77 (20 H, aromatic H). dC (75.5 MHz, CDCl3) 55.0 [×3], 55.1
(MeO on trityl), 57.5, 57.6, 57.7 [×2], 57.8, 57.9, 58.9, 59.0 [×2],
59.2, 61.6, 61.7 [×3], 61.7, 61.8 (MeO of CD), 61.5 [×2] (C-6A,B),
70.1, 71.2, 71.2 [×3], 72.0 (C-5), 70.6, 71.1, 71.3 [×2] (C-6C,D,E,F),
81.0 [×4], 81.3, 81.6, 81.7, 81.9 [×2], 82.0, 82.1 [×2], 82.1, 82.2,
82.3, 82.4, 82.5, 82.9 (C-2, C-3, C-4), 85.5, 87.3 (OC(Ar)3), 99.5,
100.0, 100.2, 100.4 [×2], 100.7 (C-1), 112.8, 112.9, 113.1, 113.3,
127.2, 127.7 [×2], 129.4, 129.8, 130.6, 132.0, 133.9 (aromatic
CH), 135.6, 136.2, 140.2, 140.3, 140.4, 141.8, 157.6, 157.7, 158.0,
158.1 (aromatic Cquat). Elemental analysis found C, 60.95, H,
7.26; C88H122O34 (1723.93) requires C 61.31, H, 7.13%.
6-O-{3-[Bis(4-anisyl)methoxymethyl]phenyl-bis(4-
anisyl)methyl}-subtituted permethylated a-CD (8)
Rf (EtOAc) = 0.17. Mp 166–168 ◦C. ES-TOF, m/z: 1738 (M −
OMe)+. dH (CDCl3, 300.1 MHz) 2.94 (s, 3 H, MeO on trityl),
2.99–4.11 (36 H, H-2, H-3, H-4, H-5, H-6), 3.13 (s, 3 H, MeO),
3.26 (s, 3 H, MeO), 3.36 (s, 3 H, MeO), 3.38 (s, 3 H, MeO),
3.39 (s, 3 H, MeO), 3.45 (s, 3 H, MeO), 3.48 (s, 3 H, MeO), 3.48
(s, 3 H, MeO), 3.49 (s, 3 H, MeO), 3.50 (s, 3 H, MeO), 3.58 (s,
3 H, MeO), 3.59 (s, 3 H, MeO), 3.64 (s, 6 H, MeO), 3.65 (s, 3
H, MeO), 3.67 (s, 3 H, MeO), 3.70 (s, 3 H, MeO), 3.78 (s, 9 H,
3
MeOAr), 3.79 (s, 3 H, MeOAr), 4.88 (d, 1 H, JH-1,H-2 2.9 Hz,
H-1), 5.05 (4 H, H-1), 5.10 (d, 1 H, 3JH-1,H-2 3.3 Hz, H-1), 6.75–
7.63 (20 H, aromatic H). dC (CDCl3, 75.5 MHz) 55.0 [×3], 55.1
(MeOAr), 57.5, 57.6, 57.7, 57.8, 58.0, 58.1, 58.2, 58.9 [×4], 61.5,
61.6, 61.7 [×2], 61.8, 61.9 (MeO of CD), 62.7 (C-6A), 66.9 (C-6),
70.8, 71.0 [×2], 71.2 [×2], 71.8 (C-5), 70.9, 71.3, 71.4, 71.5 (C-
6), 81.1, 81.1 [×2], 81.2, 81.3, 81.3, 81.4, 81.8, 81.9, 82.0, 82.1,
82.1 [×2], 82.3 [×2], 82.4 [×2], 82.5 (C-2, C-3, C-4), 85.7, 86.4
(OC(Ar)3), 98.3, 99.8 [×2], 100.0, 100.1, 100.4 (C-1), 112.8 [×4],
125.0, 125.8, 127.4, 129.3, 129.8, 130.0, 130.3, 130.6 (aromatic
CH), 135.6, 136.3, 136.7, 136.8, 143.4, 145.5, 158.1, 158.2, 158.3
[×2] (aromatic Cquat). Elemental analysis found C, 61.25, H, 7.36;
C90H128O35 (1770.00) requires C, 61.07, H, 7.29%.
Benzene-1,3-bis[bis(4-tert-butylphenyl)methyl]-6A,6B-capped
permethylated a-CD (6)
Rf (EtOAc–cyclohexane, 80 : 20, v/v) = 0.30. Mp 212–
214 ◦C. ES-TOF, m/z: 1829.1 (M + H+). dH (CDCl3, 300.1 MHz)
1.27 (s, 9 H, But), 1.29 (s, 18 H, But), 1.29 (s, 9 H, But), 2.66 (dd,
1 H, 3JH-2,H-1 3.6 Hz, 3JH-2,H-3 9.7 Hz, H-2), 3.13–4.17 (35 H, H-2,
H-3, H-4, H-5, H-6), 3.32 (s, 3 H, MeO), 3.35 (s, 3 H, MeO),
3.36 (s, 3 H, MeO), 3.47 (s, 3 H, MeO), 3.49 (s, 3 H, MeO),
3.49 (s, 3 H, MeO), 3.52 (s, 3 H, MeO), 3.53 (s, 3 H, MeO),
3.57 (s, 6 H, MeO), 3.59 (s, 3 H, MeO), 3.59 (s, 3 H, MeO),
3
3.63 (s, 9 H, MeO), 3.64 (s, 3 H, MeO), 3.99 (d, 1 H, JH-1,H-2
3
3.5 Hz, H-1), 5.02 (d, 1 H, JH-1,H-2 3.3 Hz, H-1), 5.06 (d, 1 H,
3
3JH-1,H-2 3.1 Hz, H-1), 5.09 (d, 1 H, JH-1,H-2 3.1 Hz, H-1), 5.16
6-O-{3-[Bis(4-tert-butylphenyl)methoxymethyl]phenyl-bis(4-
tert-butylphenyl)methyl}-substituted permethylated a-CD (9)
3
3
(d, 1 H, JH-1,H-2 2.8 Hz, H-1), 5.37 (d, 1 H, JH-1,H-2 3.2 Hz, H-
1), 6.89–7.77 (20 H, aromatic H). dC (CDCl3, 75.5 MHz) 31.4
[×2], 31.4 (C(CH3)3), 34.2, 34.2 [×2], 34.3 (C(CH3)3), 57.5, 57.6,
57.7 [×4], 58.9, 59.0, 59.1, 59.3, 61.7 [×2], 61.8 [×2], 61.8, 61.9
(MeO), 60.3 [×2] (C-6A,B), 69.8, 71.2, 71.3, 71.3, 71.4, 72.1 (C-
5), 70.8, 71.0, 71.5 [×2] (C-6C,D,E,F), 81.0 [×4], 81.1 [×2], 81.3,
81.7 [×2], 82.0, 82.1 [×3], 82.2, 82.3, 82.5 [×2], 83.2 (C-2, C-3,
C-4), 85.6, 87.7 (OC(Ar)3), 99.5, 100.1, 100.2, 100.4 [×2], 100.7
(C-1), 124.3, 124.4, 124.6, 124.8, 126.3, 127.7, 128.2, 128.4 [×2],
131.1, 132.7, 133.0 (aromatic CH), 139.7, 139.9, 140.8, 141.5,
144.7, 144.9, 148.6 [×2], 148.8, 149.0 (aromatic Cquat). Elemental
analysis found C, 66.14, H, 8.27; C100H146O30 (1828.26) requires
C, 65.70, H, 8.05%.
Rf (EtOAc–cyclohexane, 80 : 20, v/v) = 0.24. FAB, m/z:
1872.9 (70%, M+), 1841.9 (100%, (M − OCH3)+). dH (CDCl3,
300.1 MHz) 1.28 (s, 36 H, But), 2.90 (s, 3 H, MeO on trityl),
2.93–4.14 (36 H, H-2, H-3, H-4, H-5, H-6), 3.11 (s, 3 H, MeO),
3.18 (s, 3 H, MeO), 3.31 (s, 3 H, MeO), 3.33 (s, 3 H, MeO), 3.37
(s, 3 H, MeO), 3.40 (s, 3 H, MeO), 3.46 (s, 9 H, MeO), 3.48 (s, 3 H,
MeO), 3.56 (s, 6 H, MeO), 3.62 (s, 6 H, MeO), 3.64 (s, 3 H, MeO),
3
3.65 (s, 3 H, MeO), 3.69 (s, 3 H, MeO), 4.77 (d, 1 H, JH-1,H-2
3
3.2 Hz, H-1), 5.01 (m, 4 H, H-1), 5.07 (d, 1 H, JH-1,H-2 3.1 Hz,
H-1), 7.14–7.61 (20 H, aromatic H). dC (CDCl3, 75.5 MHz) 31.3
[×2] (C(CH3)3), 31.4 [×2] (C(CH3)3), 34.3 [×4] (C(CH3)3), 51.9
(MeO on trityl), 57.5, 57.6, 57.7, 57.8, 58.2, 58.2, 58.3, 58.8 [×3],
58.9, 61.4, 61.6, 61.7 [2], 61.8, 61.8 (MeO of CD), 62.4 (C-6A),
70.6, 70.9, 71.0, 71.1 [×2], 71.9 (C-5), 71.1, 71.2, 71.3, 71.4,
71.6 (C-6B,C,D,E,F), 81.0, 81.1 [×3], 81.2, 81.5, 81.8, 81.9, 82.0,
82.1 [×3], 82.2 [×3], 82.3, 82.4 [×2] (C-2, C-3, C-4), 85.9, 86.7
(OC(Ar)3), 97.6, 99.7, 99.8, 100.0 [×2], 100.4 (C-1), 124.1, 124.2
[×2], 124.3, 125.3, 126.0, 127.2, 128.3, 128.5, 128.7, 129.0, 129.7
(aromatic C), 140.4, 140.9, 141.1, 141.4, 143.1, 144.8, 149.2 [×2],
149.3 [×2] (aromatic Cquat). Elemental analysis found C, 65.09,
H, 8.28; C102H152O31 (1874.33) requires C, 65.36; H, 8.17.
Benzene-1,3-bis[bis(4-tert-butylphenyl)methyl]-6A,6B-capped
permethylated b-CD (7)
Rf (EtOAc–cyclohexane, 80 : 20, v/v) = 0.27. Mp 199–
201 ◦C. ES-TOF, m/z: 2033.1 (M + H+). dH (CDCl3, 300.1 MHz)
1.25 (s, 18 H, But), 1.26 (s, 9 H, But), 1.28 (s, 9 H, But), 2.72 (dd,
1 H, 3JH-2,H-1 3.6 Hz, 3JH-2,H-3 9.6 Hz, H-2), 3.15–4.22 (41 H, H-2,
H-3, H-4, H-5, H-6), 3.97 (s, 3 H, MeO), 3.17 (s, 3 H, MeO),
3.30 (s, 3 H, MeO), 3.31 (s, 3 H, MeO), 3.33 (s, 3 H, MeO),
3.38 (s, 3 H, MeO), 3.46 (s, 3 H, MeO), 3.48 (s, 3 H, MeO), 3.50
(s, 3 H, MeO), 3.52 (s, 3 H, MeO), 3.57 (s, 3 H, MeO), 3.58 (s,
3 H, MeO), 3.59 (s, 3 H, MeO), 3.60 (s, 3 H, MeO), 3.63 (s, 6 H,
MeO), 3.64 (s, 3 H, MeO), 3.65 (s, 6 H, MeO), 4.23 (d, 1 H,
3JH-1,H-2 3.4 Hz, H-1), 5.04 (d, 1 H, 3JH-1,H-2 3.2 Hz, H-1), 5.09 (d,
1 H, 3JH-1,H-2 3.2 Hz, H-1), 5.12 (d, 1 H, 3JH-1,H-2 3.6 Hz, H-1), 5.30
(d, 1 H, 3JH-1,H-2 3.6 Hz, H-1), 5.31 (d, 1 H, 3JH-1,H-2 3.6 Hz, H-1),
5.47 (d, 1 H, 3JH-1,H-2 3.5 Hz, H-1), 6.95–7.66 (20 H, aromatic H).
dC (CDCl3, 75.5 MHz) 31.3 [×4] (C(CH3)3), 34.2 [×4] (C(CH3)3),
57.6, 58.1, 58.2, 58.5, 58.6 [×3], 58.8, 58.9, 59.0 [×2], 59.1, 60.9,
61.3, 61.3, 61.3, 61.6, 61.7, 61.9 (MeO), 62.1, 62.6 (C-6A,B), 70.0,
70.8 [×4], 70.9, 71.6 (C-5), 71.1 [×2], 71.4, 71.5, 71.9 (C-6C,D,E,F,G),
79.6 [×2], 80.2, 80.7, 80.9, 81.4, 81.5, 81.5, 81.6, 81.7 [×3], 81.8,
81.9, 82.0, 82.1, 82.2, 82.2 [×2], 82.5, 82.9 (C-2, C-3, C-4), 86.0,
87.6 (OC(Ar)3), 98.0 [×2], 98.7, 98.8, 98.9 [×2], 99.2 (C-1), 124.3,
6-O-{3-[Bis(4-tert-butylphenyl)methoxymethyl]phenyl-bis(4-
tert-butylphenyl)methyl}-substituted permethylated b-CD (10)
Rf (EtOAc–cyclohexane, 80 : 20, v/v) = 0.13. ES-TOF, m/z:
2047.2 (M − CH3O)+, 2077 (M)+. dH (CDCl3, 300.1 MHz) 1.29
(s, 9 H, But), 1.29 (s, 18 H, But), 1.31 (s, 9 H, But), 2.87 (dd, 1 H,
3JH-2,H-1 3.2 Hz, 3JH-2,H-3 9.3 Hz, H-2), 2.93 (s, 3 H, MeO on trityl),
2.99–3.90 (41 H, H-2, H-3, H-4, H-5, H-6), 3.14 (s, 3 H, MeO),
3.18 (s, 3 H, MeO), 3.22 (s, 3 H, MeO), 3.32 (s, 3 H, MeO), 3.35 (s,
3 H, MeO), 3.36 (s, 3 H, MeO), 3.38 (s, 3 H, MeO), 3.48 (s, 9 H,
MeO), 3.50 (s, 3 H, MeO), 3.51 (s, 3 H, MeO), 3.55 (s, 3 H,
MeO), 3.57 (s, 3 H, MeO), 3.62 (s, 3 H, MeO), 3.63 (s, 6 H,
MeO), 3.65 (s, 3 H, MeO), 3.65 (s, 3 H, MeO), 4.74 (d, 1 H,
3
3JH-1,H-2 3.2 Hz, H-1), 5.06 (d, 1 H, JH-1,H-2 3.2 Hz, H-1), 5.07
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 8 8 – 2 5 9 2
2 5 9 1

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(d, 1 H, 3JH-1,H-2 3.3 Hz, H-1), 5.15–5.18 (m, 3 H, H-1), 5.20 (d, 1
H, 3JH-1,H-2 3.4 Hz, H-1), 6.96–7.57 (20 H, aromatic H). Elemental
analysis found C, 64.22, H, 8.17; C111H168O36 (2078.55) requires
C, 64.13, H, 8.15%.
residual carbon atoms (occupancy ca. 0.25) were found outside
the CD which could be assigned to a hexane molecule near a
special position. The whole structure was refined with SHELXL
(huge option)25 by the full-matrix least-squares technique (use
of F2 magnitude; x, y, z, bij for C and O atoms, x, y, z in riding
mode for H atoms; 1527 variables and 7957 observations with
I > 2.0 r(I); calc. w = 1/[r2(Fo2) + (0.115P)2 + 6.76 P] where
2A,2B,2C,2D,2E,2F,3A,3B,3C,3D,3E,3F,6C,6D,6E,6F-Hexadeca-O-
methyl-a-cyclodextrin 11
2
2
P = (Fo + 2 Fc )/3 with the resulting R = 0.082, Rw = 0.147
−3
˚
Aqueous HBF4 (34%, 1.15 mL) was added to a solution of
6 (1.000 g, 0.547 mmol) in MeCN (40 mL). The solution
was stirred for 20 min at room temperature, whereupon Et3N
(2.5 mL) was added. Addition of H2O (160 mL) caused the
“bis-trityl-(OH)2” to precipitate. The latter was filtered and the
filtrate extracted with CH2Cl2 (4 × 80 mL). The organic phase
was washed with saturated aqueous NaHCO3 (2 × 80 mL) before
being dried (MgSO4) and evaporated to dryness, affording 11 as
a colourless solid (0.630 g, 96%). Rf (CH2Cl2–MeOH, 85 : 15,
v/v) = 0.22. Mp 113–115 ◦C. dH (300.1 MHz, CDCl3) 2.39 (br s,
1 H, OHA or B), 2.61 (br s, 1 H, OHB or A), 3.38 (s, 3 H, MeO-6),
3.39 (s, 9 H, MeO-6), 3.47 (s, 3 H, MeO-2), 3.48 (s, 9 H, MeO-2),
3.49 (s, 3 H, MeO-2), 3.50 (s, 3 H, MeO-2), 3.63 (s, 6 H, MeO-3),
3.64 (s, 9 H, MeO-3), 3.65 (s, 3 H, MeO-3), 3.12–4.03 (36 H, H-2,
and Sw = 1.107, Dq < 0.49 e A . CCDC reference number
260388. See http://www.rsc.org/suppdata/ob/b5/b504012d/
for crystallographic data in CIF or other electronic format.
References
1 ‘Cyclodextrins’, Comprehensive Supramolecular Chemistry, vol. 3, ed.
J. L. Atwood, J. E. D. Davies, D. D. Macinol, F. Vo¨gtle and J.-
M. Lehn, Pergamon, Oxford, 1996.
2 Modified Cyclodextrins, ed. C. J. Easton and S. F. Lincoln, Imperial
College Press, London, 1999.
3 E. Engeldinger, D. Armspach and D. Matt, Chem. Rev., 2003, 103,
4147–4173.
4 E. Engeldinger, D. Armspach, D. Matt, L. Toupet and M. Wesolek,
C. R. Chim., 2002, 5, 359–372.
5 A. R. Khan, P. Forgo, K. J. Stine and V. T. D’Souza, Chem. Rev.,
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6 I. Tabushi, Y. Kuroda, K. Yokota and L. C. Yuan, J. Am. Chem. Soc.,
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8 A. J. Pearce and P. Sinay¨, Angew. Chem., Int. Ed., 2000, 39, 3610–
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9 T. Lecourt, A. Herault, A. J. Pearce, M. Sollogoub and P. Sinay¨,
Chem. Eur. J., 2004, 10, 2960–2971.
3
H-3, H-4, H-5, H-6), 5.02 (d, JH-2,H-1 3.3 Hz, 1 H, H-1), 5.03–
3
5.06 (4 overlapping d, 4 H, H-1), 5.08 (d, JH-2,H-1 3.3 Hz, 1 H,
H-1). dC (75.5 MHz, CDCl3) 57.64, 57.69 [×3], 57.75 and 57.77
(MeO-2), 58.75, 58.76 [×2] and 58.89 (MeO-6), 61.47, 61.50,
61.52 [×2] and 61.56 [×2] (MeO-3), 61.76 and 62.19 (C-6A,B),
70.95, 70.99 [×2] and 71.07 (C-5C,D,E,F), 71.29, 71.32 and 71.37
[×2] (C-6C,D,E,F), 72.37 and 72.73 (C-5A,B), 81.08 [×3], 81.13 [×3],
81.77, 81.82 [×2], 81.92 [×4], 81.98, 82.07 [×2], 82.19 and 82.51
(C-2, C-3, C-4), 99.36, 99.51, 99.59, 99.66, 99.69, 99.73 (C-1).
Elemental analysis found C, 51.98, H, 7.53; C52H92O30 (1197.27)
requires C, 52.15, H, 7.75.
10 J. Boger, D. G. Brenner and J. R. Knowles, J. Am. Chem. Soc., 1979,
101, 7630–7631.
11 R. Heck, L. Jicsinsky and A. Marsura, Tetrahedron Lett., 2003, 44,
5411–5413.
12 C. C. Ling, A. W. Coleman and M. Miocque, Carbohydr. Res., 1992,
223, 287–291.
Collection and reduction of X-ray data
13 L. Poorters, D. Armspach and D. Matt, Eur. J. Org. Chem., 2003,
Single crystals were obtained by slow diffusion of heptane
containing a small amount of hexane into a butanone solution of
7. Due to the very high desolvatation abilities of this compound,
the sample was captured inside the crystallisation solvent with
oil, then very quickly mounted in a capillary and set in the 110 K
1377–1381.
14 I. Tabushi, T. Nabeshima, K. Fujita, A. Matsunaga and T. Imoto,
J. Org. Chem., 1985, 50, 2638–2643.
15 R. Breslow, J. W. Canary, M. Varney, S. T. Waddell and D. Yang,
J. Am. Chem. Soc., 1990, 112, 5212–5219.
16 W. Wang, A. J. Pearce, Y. Zhang and P. Sinay¨, Tetrahedron:
Asymmetry, 2001, 12, 517–523.
17 D. Q. Yuan, C. Yang, T. Fukuda and K. Fujita, Tetrahedron Lett.,
2003, 44, 565–568.
18 Y. T. Wong, C. Yang, K.-C. Ying and G. Jia, Organometallics, 2002,
21, 1782–1787.
19 Z. Chen, J. S. Bradshaw, Y.-F. Shen, Y. Habata and M. L. Lee, J. Org.
Chem., 1997, 62, 8529–8534.
20 D. Armspach and D. Matt, Carbohydr. Res., 1998, 310, 129–133.
21 E. Tresper, D. Freitag, DE 2425194, Bayer AG, 1975.
22 Z. Otwinowski and W. Minor, ‘Processing of X-ray Diffraction
Data Collected in Oscillation Mode’, in: Methods Enzymol., 1997,
276 (Macromolecular Crystallography, Part A, ed. C. W. Carter and
R. M. Sweet), 307–326.
3
1
1
4
nitrogen flow. C109H162O35· (C7H16)· (C4H8O)· (C6H14), Mr =
2
2240.28, orthorhombic, P2122121, a = 16.3780(3), b = 27.7666(4),
3
˚
˚
c = 30.3256(5) A, V = 13790.9(4) A , Z = 4, Dx = 1.085 Mg
−3
−1
˚
m , k(MoKa) = 0.71073 A, l = 0.78 cm , F(000) = 4862, T =
120 K. The sample (0.22 × 0.14 × 0.10 mm) was studied on a
NONIUS Kappa CCD with graphite monochromatised MoKa
radiation. The cell parameters were obtained with Denzo and
Scalepack22 with 10 frames (w rotation: 1◦ per frame). Data
collection23 (2hmax = 52.5◦, 472 frames via 0.6◦ x rotation and
15 s per frame, range hkl: h 0–19; k 0–33; l 0–36) gave 107 864
reflections. Data reduction with Denzo and Scalepack led to
13 094 independent reflections, from which 7957 had I > 2.0 r(I).
The structure was solved with SIR200224 which revealed the non-
hydrogen atoms of the compound and one heptane molecule
23 Nonius – KappaCCD Software, Nonius BV, Delft, The Netherlands,
1999.
24 M. C. Burla, M. Camalli, B. Carrozini, G. Cascarano, C. Giacovazzo,
G. Polidori and R. Spagna, J. Appl. Cryst., 2001, 34, 523–526.
25 G. M. Sheldrick, SHELX-97. Program for the refinement of crystal
structures, University of Go¨ttingen, Germany, 1997.
1
2
disordered over two positions. After further refinements,
1
molecule of heptane and molecule of butanone were found,
both lying outside the CD 2cavity. After structure solution, three
2 5 9 2
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 2 5 8 8 – 2 5 9 2