Regioselective sulfonylation at O-2 of cyclomaltoheptaose with 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole

Article abstract of DOI:10.1016/S0008-6215(02)00482-2

2^I-O-p-Tolylsulfonylcyclomaltoheptaose was obtained in 42% yield by reaction of 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole on NaH-deprotonated cyclomaltoheptaose in DMF and further converted into the corresponding mono-2^I,3^I-

Full text of DOI:10.1016/S0008-6215(02)00482-2

Carbohydrate Research 338 (2003) 451–453
www.elsevier.com/locate/carres
Note
Regioselective sulfonylation at O-2 of cyclomaltoheptaose with
1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole
Ho Law,a,1 Isabelle Baussanne,a Jose´ M. Garc´ıa Ferna´ndez,b Jacques Defayea,*
aDe´partement de Pharmacochimie Mole´culaire, CNRS and Uni6ersite´ Joseph Fourier-Grenoble 1 (UMR 5063), BP 138, F-38243 Meylan, France
bInstituto de In6estigaciones Qu´ımicas, CSIC, Ame´rico Vespucio s/n, Isla de la Cartuja, E-41092 Se6illa, Spain
Received 6 August 2002; accepted 11 November 2002
Abstract
2I-O-p-Tolylsulfonylcyclomaltoheptaose was obtained in 42% yield by reaction of 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole on
NaH-deprotonated cyclomaltoheptaose in DMF and further converted into the corresponding mono-2I,3I-manno-epoxide. © 2003
Elsevier Science Ltd. All rights reserved.
Keywords: 2I-O-p-Tolylsulfonylcyclomaltoheptaose; b-Cyclodextrin; 1-(p-Tolylsulfonyl)-(1H)-1,2,4-triazole; 2I,3I-Anhydro-manno-b-cyclodextrin
NaH-deprotonated b-CD in DMF5 or reaction of 1-p-
Supramolecular interactions between cyclomal-
tooligosaccharides (cyclodextrins, CDs) and guest
molecules depend on various contributions which are
still being discussed and may include inter alia release
of cavity-bound high-energy water, CDs-ring strain re-
lease on complexation, and van der Waals and hydro-
gen-bonding interactions.1 Modifications at the
secondary hydroxyl groups rim offers an opportunity to
introduce recognition features different from the well
studied rigid cyclodextrins core. 2I-O-p-Tolylsulfonyl-
cyclomaltoheptaose (3, Scheme 1), a convenient precur-
sor of the corresponding b-CD 2I,3I-manno-epoxide,2 is
a key compound for such minimal modification of the
most commonly available CD, namely cyclomaltohep-
taose (b-cyclodextrin, b-CD, 1). Monosulfonylation at
C-2 of b-cyclodextrin has already been elegantly
achieved by Ueno and Breslow3 by reaction with 3-ni-
trophenyl p-toluenesulfonate in DMF, although in only
ꢀ10% yield. Regioselective opening of a b-CD 2,3-
stannylidene acetal is however a more convenient
approach4 in terms of yield (32%). More recent synthe-
ses include reaction of p-toluenesulfonyl chloride on
tolylsulfonylimidazole in the presence of molecular
sieves in the same solvent.6 Since 1,2,4-triazolides are
known to be more reactive towards nucleophiles as
compared to imidazolides,7 we anticipated that 1-(p-
tolylsulfonyl)-(1H)-1,2,4-triazole (2) could result in im-
proved tosyl group transfer by reaction with
deprotonated b-cyclodextrin.
1-(p-Tolylsulfonyl)-(1H)-1,2,4-triazole (2) was ob-
tained in 90% yield by a modification of the method of
Katigiri et al.8 Reaction of molar proportions of 2 and
NaH-deprotonated b-cyclodextrin in DMF at room
* Corresponding author. Tel.: +33-476041018; fax: +33-
476041013
E-mail address: j.defaye@ujf-grenoble.fr (J. Defaye).
1 Present address: Eras Labo, F-38330 Saint Nazaire Les
Eymes.
Scheme 1. (i) DMF/NaH+2/rt; (ii) aq K2CO3/rt.
0008-6215/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0008-6215(02)00482-2

452
H. Law et al. / Carbohydrate Research 338 (2003) 451–453
temperature, followed by concentration, acetone precip-
itation from an aqueous solution of the residual unre-
acted b-cyclodextrin, and filtration over an RP18
Sep-Pack reverse-phase column, resulted in a pure com-
pound in 42% yield, which proved to be the b-CD
2I-p-toluenesulfonate 3 by 1H and 13C NMR spec-
troscopy, and comparison with literature data. Conver-
sion into the known2 b-CD 2I,3I-manno-epoxide 4 was a
further proof of the expected structure.
The significant increase in O-2 monotosylation yield
by use of 1-(p-tolylsulfonyl)-(1H)-1,2,4-triazole, in
comparison with previously reported methodologies,3–6
must be ascribed, essentially, to the favorable reactivity
and stability features of the reagent. The formation of a
b-CD inclusion-complex intermediate, which was pos-
tulated by Ueno and Breslow3 in the case of tosyl
transfer from 3-nitrophenyl p-toluenesulfonate to the
C-2 hydroxyl group of b-CD, was rejected on the basis
of NMR titration experiments in DMF-d6. Thus, no
change in the resonance of H-3 and H-5 of b-CD was
observed in the presence of an up to 10-fold molar
excess of 2. The other protons were as well unaffected.
was stirred at room temperature (rt) for 2 h and then
washed with water (3×20 mL) to remove triethylam-
monium chloride. The organic phase was dried over
anhyd Na2SO4, and concd to a syrup which crystallised
in cyclohexane to give 2 as a white solid (5.95 g, 90%):
1
mp 106–108 °C, lit.8 107 °C; H NMR (CDCl3): l 8.81
(d, 2 H, Ar), 8.10 (d, 2 H, Ar), 2.01 (s, 3 H, Me).
1.3. 2I-O-p-Tolylsulfonylcyclomaltoheptaose (3)
To a soln of b-CD (1, 2 g, 1.70 mmol) in DMF (50 mL)
at 0 °C was added NaH (60% in mineral oil, 70 mg,
1.76 mmol) and the soln was stirred for 2 h at this
temperature.
1-(p-Tolylsulfonyl)-(1-H)-1,2,4-triazole
(0.392 g, 1.76 mmol) in DMF (15 mL) was then added
dropwise and the mixture was further stirred for 2 h
while allowing it to reach the rt. It was then concd and
to the resulting solid in water (10 mL), acetone (70 mL)
was added in order to precipitate the residual b-CD.
The filtrate was concd and filtrated on a RP18 Sep-Pack
column (reverse phase) using 9:1 MeCN–water as elu-
ent to give the pure title compound (95 mg, 42%) as a
white solid; mp 225–228 °C, [h]D +105° (c 1, DMF),
1
no physicochemical data in lit.; NMR H (D2O): l 7.84
1. Experimental
(d, 2 H, J 8.5 Hz, Ar), 7.37 (d, 2 H, J 8.5 Hz, Ar),
4.96–4.91 (m, 6 H, H-1II–VII), 4.79 (br s, 1 H, H-1I), 4.
28 (br s, 1 H, H-2I), 4.01 (t, 1 H, J2,3=J3,4=9.0 Hz,
H-3I), 3.80–3.60 (m, 27 H, H-3II–VII, H-5I–VII, H-
6aI–VII, H-6bI–VII), 3.55–3.41 (m, 12 H, H-2II–VII, H-4I–
VI), 3.27 (t, 1 H, J3,4=J4,5=9.0 Hz, H-4VII), 2.32 (s, 3
H, Me); 13C (D2O): spectrum identical to that reported
in Refs. 3–5. Anal. Calcd for C49H76O37S·7H2O: C,
41.58; H, 6.41; S, 2.27. Found: C, 41.31; H, 6.34; S,
2.07.
1.1. General methods
b-Cyclodextrin was ‘Pharmaceutical grade’ from
Wacker Chemie, dried at 110 °C for 24 h before use.
p-Toluenesulfonyl chloride (99+%) and 1,2,4-triazole
(98%) were purchased from Aldrich and used without
further purification. DMF was freshly distilled over
calcium hydride and stored over molecular sieves. TLC
was performed on E. Merck plastic sheets coated with
Silica Gel 60 F254, using 7:7:5:4 EtOAc–2-propanol–
28% aq NH4OH–water as eluent. The spots were visu-
alized in UV light and also by dipping into 15% aq
H2SO4 containing 2% of ammonium dimolybdate and
1% cerium(IV) sulfate followed by heating at 150 °C.
Solvents were concd under diminished pressure with a
rotary evaporator. Melting points were measured in a
capillary Gallenkamp melting point apparatus. Optical
rotations were measured at 20 °C, using a Perkin–
Elmer 341 polarimeter. NMR spectra were recorded in
D2O with a Bruker 500 AMX spectrometer. Assigment
of the proton resonances was assisted by 2D COSY and
1D TOCSY experiments.
1.4. Cyclo{4)-(2,3-anhydro-a-
4)-a- -glucopyranosyl-[(1“4)-a-
(1“4)-a- -glucopyranosyl-(1“} (4)
D-mannopyranosyl)-(1“
D
D-glucopyranosyl]4-
D
A soln of 3 (0.1 g, 0.078 mmol) in aq K2CO3 (0.25%, 10
mL) was stirred for 16 h at rt, then neutralized by
addition of dilute HCl, and passed onto a Sephadex
G-15 column with elution with water to give, after
freeze-drying, pure 4 (79 mg, 91.5%) as a white solid;
mp 260–263 °C; [h]D +86.5° (c 1, DMF), no physico-
chemical data in lit. FAB+MS: m/z 1139 [M+Na]+.
1H NMR: spectrum identical to that reported in Ref. 2.
Anal. Calcd for C42H68O34·6H2O: C, 41.18; H. 6.58.
Found: C, 41.09; H, 6.32.
1.2. 1-(p-Tolylsulfonyl)-(1H)-1,2,4-triazole (2)
1.5. Titration experiment
To a soln of 1,2,4-triazole (2.07 g, 30 mmol) and Et3N
(3.03 g, 30 mmol) in dry CH2Cl2 (60 mL), p-toluenesul-
fonyl chloride (5.73 g) was added at 0 °C. The mixture
This was carried out at 303 K using a 500 MHz NMR
instrument. A 5.6 mM soln of b-CD in DMF-d6 was

H. Law et al. / Carbohydrate Research 338 (2003) 451–453
453
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