Regiospecific 2(A),2(C)-disulfonation of β-cyclodextrin

Article abstract of DOI:10.1016/S0040-4039(00)01218-1

The regiospecific 2(A),2(C)-disulfonation of β-cyclodextrin has been achieved by the reaction of β-cyclodextrin with 1,4-dibenzoylbenzene-3',3_-disulfonyl imidazole and molecular sieves in DMF. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01218-1

Tetrahedron Letters 41 (2000) 7085±7088
Regiospeci®c 2A,2C-disulfonation of b-cyclodextrin
Katsunori Teranishi*
Faculty of Bioresources, Mie University, Kamihama 1515, Tsu, Mie 514-8507, Japan
Received 15 June 2000; revised 13 July 2000; accepted 14 July 2000
Abstract
The regiospeci®c 2A,2C-disulfonation of b-cyclodextrin has been achieved by the reaction of b-cyclodextrin
with 1,4-dibenzoylbenzene-30,300-disulfonyl imidazole and molecular sieves in DMF. # 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: b-cyclodextrin; regiospeci®city; disulfonation.
Cyclodextrins are cyclic oligosaccharides consisting of six or more a-1,4-linked d-glucopyranose
units, which possess primary hydroxyl groups at the C-6 positions and secondary hydroxyl
groups at the C-2 and C-3 positions.1 Because the cyclodextrins have a hydrophobic and optically
active interior, they have been utilized as transporters of hydrophobic molecules and as miniature
molecular mimics of enzymes. In order to enhance their ability as acceptors or arti®cial enzymes,
regiospeci®c multifunctionalization techniques on the primary and secondary hydroxyl groups
have been investigated. Several signi®cant regiospeci®c disulfonations on the two primary
hydroxyl groups have been developed to modify the primary face.2 However, the regioselective
bifunctionalization on the secondary face has proved more dicult to accomplish.3 Published
disulfonations on the two C-2 hydroxyl groups of a- and b-cyclodextrins a€orded the
regioisomeric 2A,2B-, 2A,2C-, and 2A,2D-disulfonates (the glucose units are lettered A to F or G
clockwise, viewed from the C-6 position) in extremely low yields, respectively.4
I have developed an interesting regiospeci®c monosulfonation on the C-2 hydroxyl groups of
the cyclodextrins using a combination of sulfonyl imidazole and molecular sieves.5 This sulfonyl
reaction system is very useful, since the mild non-alkaline reaction conditions do not induce
decomposition of the sulfonates, and the reaction occurs independently of the nature of the
sulfonyl groups. Furthermore, I have recently shown that 2A,2B-disulfonated a-,6 b-,6 and
g-cyclodextrins7 can be exclusively regiospeci®cally prepared using benzophenone-3,30-disulfonyl
imidazole and molecular sieves in DMF. In this preliminary letter, to provide a useful method for
the bifunctionalization on the A,C-secondary face of the cyclodextrins, I will show the highly
regiospeci®c preparation of 2A,2C-disulfonated b-cyclodextrin using 1,4-dibenzoylbenzene-30,300-
disulfonyl imidazole (1) as a sulfonyl reagent (Scheme 1).
* Corresponding author. Tel: +81-59-231-9615; fax: +81-59-231-9684; e-mail: teranisi@bio.mie-u.ac.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01218-1

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Scheme 1.
Compound 1 was easily prepared by the following procedure. A mixture of 1,4-dibenzoyl-
benzene (10 g) and chlorosulfonic acid (50 ml) was heated at 120ꢀC for 24 h, and then the cooled
reaction mixture was poured into ice (200 ml). The precipitate was ®ltered and washed with
water, followed by crystallization from ethyl acetate and recrystallization from chloroform to
give pure 1,4-dibenzoylbenzene-30,300-disulfonyl chloride (7.3 g). 1,4-Dibenzoylbenzene-30,300-di-
sulfonyl chloride (6.2 g) was treated with imidazole (2.0 g) and triethylamine (4.2 ml) in chloro-
form (240 ml) at room temperature, and the reaction mixture was washed with water. The
chloroform solution was evaporated to dryness, followed by crystallization from a mixture of
chloroform and dichloromethane to give 1 (6.4 g).8
A mixture of b-cyclodextrin (2.0 g, 1.76 mmol), which was dried under vacuum at 120ꢀC for 12
h, 1 (0.96 g, 1.76 mmol), and freshly activated powder 4 A molecular sieves (6.0 g) in N,N-
dimethylformamide (DMF; 118 ml) was stirred at 30ꢀC for 48 h. The HPLC analysis of the
reaction mixture showed that 2A,2C-disulfonated b-cyclodextrin 2 was highly regiospeci®cally
a€orded in 24% yield, and 2A,2B- and 2A,2D-disulfonated b-cyclodextrins (3 and 4) were given as
minor disulfonates in 3.1% and 1.0% yields, respectively,9 whereas 6-sulfonate(s) and 3-sulfo-
nate(s) resulting from the reaction were not observed by HPLC analysis. Then, the molecular
sieves were removed by ®ltration and the ®ltrate was concentrated under reduced pressure. DMF
(4 ml) was added to dissolve the residue and subsequently water (100 ml) was added to the
solution. The solution was subjected to a simple open reverse-phase column chromatography
(20mmÂ150mm, Fuji Silisia Chromatorex-ODS DM1020T gel). Elution with water and
subsequently water:MeOH (9:1) removed unreacted cyclodextrin (recovered in 30% yield). Next,
stepwise gradient elution with water:MeOH (65:35) could satisfactorily give the pure fractions of
2, which were then concentrated to give 2 in 18% yield. The impure fractions of 2 contaminated
with the other disulfonate isomers 3 and 4 were applied on a reverse-phase HPLC chromato-
graphy to give disulfonates 2±4 in 1.0, 1.3, and 0.2% yields, respectively.10
The structural assignments of 2±4 were performed by 1H NMR, H±H COSY, 13C NMR, H±C
COSY, and FABMS spectra, and by subsequent epoxidation.11 The 1H NMR spectra assigned by
the H±H COSY NMR experiments exhibit an appreciable down®eld shift of the H-1, H-2, and H-
3 protons of the two glucose units of 2±4 (see Fig. 1). In particular, the chemical shifts of the H-2
protons show a larger down®eld shift than do the H-3 protons. These NMR data indicate that
the disulfonation onto two C-2 hydroxyl groups was performed by a single 1,4-dibenzoylbenzene-
30,300-disulfonyl molecule, whereas the regiochemistry of 2±4 could not be determined. For the
desired compound 2,12 the 13C NMR peaks at 79.61 and 80.48 ppm for C-2 carbons of the
substituted glucose units are largely shifted down®eld from the other C-2 peaks, and the 13C

7087
Figure 1. Partial 1H NMR spectra of 2±4 (500 MHz, DMSO-d6 containing 5% D2O, ref. DMSO: ꢀ 2.49). The assigned
signals are numbered according to the usual convention shown in Scheme 1, and the symbols * and ** refer to the
sulfonated glucose units. [a] Compound 2 (at 80ꢀC). [b] Compound 3 (at 80ꢀC). [c] Compound 4 (at 40ꢀC)
NMR peaks for C-1 and C-3 carbons of the substituted glucose units are shifted up®eld in a small
way from the other C-1 and C-3 peaks, supporting the notion that the sulfonation was at the two
C-2 hydroxyl groups. Then, the treatment of 2±4 with NaOH (5 equiv.) in water or a mixture of
water and MeOH at 20ꢀC for 3 h followed by open column chromatography on silica gel eluting
with CH3CN and then CH3CN:water (6:1), and ®nally CH3CN:water (6:2), a€orded the corre-
1
sponding pure di-2,3-manno-epoxides in 90, 71, and 76% yields, respectively. Their H NMR
spectra were seen to be identical with authentic published A,C-, A,B-, and A,D-di-2,3-manno-
epoxides' spectra.4b Hence, these disulfonates 2±4 were assigned to 2A,2C-, 2A,2B-, and 2A,2D-
isomers, respectively.
In summary, this study described a preparatively useful method for the regiospeci®c 2A,2C-
disulfonation and A,C-epoxidation of b-cyclodextrin using the combination of 1,4-dibenzoyl-
benzene-30,300-disulfonyl imidazole and molecular sieves.

7088
Acknowledgements
I am grateful for Grants-in-Aid for Scienti®c Research (Nos. 12045237 and 11660106) from the
Japanese Ministry of Education, Science, and Culture. The NMR instrument used in this
research was installed at the Cooperative Research Center of Mie University.
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8. Analytical data for 1: colorless needles, mp 175±177ꢀC. 1H NMR ꢀ (CDCl3, 20ꢀC): 7.14 (2H, s), 7.35 (2H, s), 7.78
(2H, t, J=7.9 Hz), 7.86 (4H, s), 8.05 (2H, s), 8.13 (2H, d, J=7.9 Hz), 8.20 (2H, d, J=7.9 Hz), and 8.40 (2H, s).
UV lmax (CH3CN) 267 nm, " 30,900. FABMS m/z: 547 (M+1).
9. A gradient elution with water to water:CH3CN (80:20) in 10 min, to water:CH3CN (70:30) in 20 min, and to
water:CH3CN (45:55) in 10 min was applied using a COSMOSIL packed column 5C18-MS (4.6 mmÂ150 mm,
Nacalai Tesque).
10. A gradient elution with water:CH3CN (80:20) to water:CH3CN (75:25) in 30 min, to water:CH3CN (70:30) in 45
min was applied using a COSMOSIL packed column 5C18-MS (20mmÂ250mm, Nacalai Tesque).
11. One of the NMR techniques, a 2D ROESY technique, could not be applied for compounds 2±4, because H-4
protons of the sulfonated glucose units and those of adjoining glucose units could not be assigned unequivocally.
12. Data for 2. 13C NMR ꢀ (80ꢀC, DMSO-d6 containing 5% D2O, ref. DMSO: ꢀ 39.50, the symbols * and ** refer to
the sulfonated glucose units): 58.85 (C-6), 59.29 (C-6), 59.77 (C-6), 59.97 (C-6), 60.05 (C-6), 60.11 (C-6), 60.46 (C-
6), 68.50, (C-3*) 69.31 (C-3**), 71.80-73.47 (C-2, 3, 5), 78.57 (C-4), 79.61 (C-2**), 79.90 (C-4), 80.48 (C-2*), 80.60
(C-4), 81.11 (C-4), 81.65 (C-4), 81.75 (C-4), 81.81 (C-4), 97.87 (C-1**), 99.10 (C-1*), 100.32 (C-1), 101.26 (C-1),
101.55 (C-1), 101.60 (C-1), 101.78 (C-1), 128.16 (ArC), 128.58 (ArC), 128.99 (ArC), 129.52 (ArC), 129.67 (ArC),
130.05 (ArC), 130.79 (ArC), 131.03 (ArC), 133.45 (ArC), 133.54 (ArC), 135.72 (ArC), 137.40 (ArC), 137.80 (ArC),
139.34 (ArC), 139.72 (ArC), 140.44 (ArC), 194.82 (CˆO), 195.42 (CˆO). UV lmax (water) 269 nm, " 24,400.
FABMS m/z: 1545 (M+1).