New large-scale preparations of versatile 6-O-monotosyl and 6-monohydroxy permethylated α-, β-, and γ-cyclodextrins

Article abstract of DOI:10.1246/cl.2002.514

New practical methods for preparation of versatile 6-O-monotosyl and 6-monohydroxy permethylated α-, β-, and γ-cyclodextrins are described.

Full text of DOI:10.1246/cl.2002.514

514
Chemistry Letters 2002
New Large-Scale Preparations of Versatile 6-O-Monotosyl and 6-Monohydroxy
Permethylated ꢀ-, ꢁ-, and ꢂ-Cyclodextrins
Takahiro Kaneda,ꢀ Tatsuhiko Fujimoto, Jun’ichiro Goto, Kaori Asano, Yoshitaka Yasufuku,
Jone Hwa Jung, Chiaki Hosono, and Yoshiteru Sakata
The Institute of Scientific and Industrial Research, Osaka University, 8-1 Mihogaoka, Ibaraki, Osaka 567-0047
(Received February 6, 2002; CL-020133)
New practical methods for preparation of versatile 6-O-
monotosyl and 6-monohydroxy permethylated ꢀ-, ꢁ-, and ꢂ-
cyclodextrins are described.
Cyclodextrins (CDs), 1,4-dehydrated cyclic hexamer (ꢀ),
heptamer (ꢁ), and octamer (ꢂ) of ꢀ-D-glucopyranose, are
commercially available, hydrophilic, chiral, and native host
molecules with a unique shape like a bottomless flowerpot. For
their predominant characteristics, the molecules have been
widely used as building blocks for assembling a variety of
artificial enzymes1 and superstructures such as molecular
machines.2
Although the extraordinary hydrophilic properties of the host
molecules are advantageous for complexation in water, they are
usually disadvantageous for chemical modifications3 because
their poor solubilities in organic solvents prevent the performance
of various types of organic reactions and of purification methods.
If a balance between the two conflicting peculiarities can be
obtained, a new trend will be added to the field of cyclodextrins.
O-Permethylation4 of CD skeletons provides a promising
approach for this idea as represented, for examples, by super-
cyclodextrins.5
Like the essential roles of tosylates 5 in the CD chemistry, the
corresponding permethylated tosylates 6 are, undoubtedly, of
great value as starting materials for making various amphiphilic
and lipophilic CD derivatives, such as amines, esters, ethers,
halides, and sulfides. Therefore, a facile preparative method for 6
or equivalents 4 is desired. To date, three methods have been
reported (Scheme 1): the experiments were carried out on less
than a 5 g-scale,6{9 and the overall yields of 4ꢀ and 6ꢀ were 438;9
and 16%,7 respectively, through 3 and 5 steps from the CDs. In
these methods, it seemed as if a ‘‘direct’’ permethylation process
of 5 to 6 was avoided because of the difficulties mentioned below.
Here, we describe the title method based on a new 20 g-scale
direct permethylation reaction.
We encountered some problems in the early stage of this
work, especially with poor reproducibility on the direct
permethylation of 5 to 6. When a reaction had been started at
ambient temperature, it was not easy to keep the reaction
temperature constant because of the spontaneously accelerated
exothermic reaction, even in a 1 g-scale experiment. The resulting
products completely lost the tosyl group. When a reaction was
carried out under milder conditions, the desired product was
seldom obtained in a good yield or was usually accompanied by
iodide 7,10 which could be produced by a side reaction of 6 with
NaI as an expected product. Once the by-product had been
formed, it was difficult to remove it from the mixture by
chromatography. Although ‘‘reproduction’’ of 6 from 7 by
Scheme 1. Synthesis of 6-monofunctionalized permethylated
ꢀ-, ꢁ-, and ꢂ-cyclodextrins 4 and 6.
treatment of the mixture with AgOTs11 was successful,10 the
expensive reagent was not suited for a large-scale experiment.
When much milder conditions had been employed, the incom-
plete permethylation produced terrible blends. After several years
of patient research, we were able to establish the following
reproducible procedure in which the reaction temperature was
precisely regulated at 3 stages.
Powdered tosylate 5ꢁ12 (19.4 g, 17.2 mmol), which had been
dried at 60 ꢁC for 2 d in vacuo, was placed in a 1-L, four-necked,
jacketed flask equipped with a mechanical stirrer and a
thermometer. During stirring at 300 rpm, dry DMF (500 ml)
was added. The resulting clear solution was cooled to 0 ꢁC by
circulating the medium from a thermostat to the jacket, and then
NaH (40 g, 1.0 mol, 60% dispersion in oil) was added. After
maintaining the temperature for 2 h, MeI (100 ml, 228 g,
1.61 mol) was added. The temperature was raised to 15 ꢁC after
Copyright Ó 2002 The Chemical Society of Japan

Chemistry Letters 2002
515
3 h and then to 20 ꢁC after 2 h, and the stirring was continued for
24 h. After the addition of EtOH (50 ml) and sat. aq NaCl solution
(1.2 L) containing Na2S2O3, the mixture was extracted with
toluene (3 ꢂ 800 ml). The organic layer was dried over Na2SO4
and concentrated to about 100 ml under reduced pressure. The
residue was subjected to flash column chromatography on silica
gel (230 g) using EtOAc–toluene and EtOH–EtOAc as eluents.
The desired product 6ꢁ was obtained as white foam (18.6 g, 79%)
from 5% (v/v) EtOH–EtOAc eluates.
Compared with the tosylate, alcohol 4ꢁ may be a less
versatile intermediate but has an advantage in the SN2 reaction
site; that is, the alkoxyl oxygen atom of 4ꢁ locates at an outer or
less-hindered site from the CD framework than the carbon atom
bearing the tosyl group of 6ꢁ. The tosylate was converted to 4ꢁ
according to reductive detosylation with sodium naphthalenide13
as follows.
To a solution of naphthalene (7.32 g, 57.1 mmol) in dry THF
(100 ml), sodium (1.22 g, 53.0 mmol) was added and the mixture
was stirred at rt for 3 h. The resulting deep blue solution of sodium
naphthalenide was cooled in a dry ice-acetone bath, and a solution
of 6ꢁ (12.2 g, 8.94 mmol) in dry THF (73 ml) was then added at
such a rate that the temperature was maintained below ꢃ65 ꢁC.
After the addition, the reaction mixture was allowed to stir for
80 min, neutralized with 3N HCl in the bath, and concentrated to
dryness under reduced pressure. The residue was subjected to
flash column chromatography on silica gel (120 g) using EtOAc–
toluene and EtOH–EtOAc as eluents. The desired product 4ꢁ was
obtained as white powder (9.10 g, 84.0%) from 10% (v/v) EtOH–
EtOAc eluates.
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4
5
6
7
8
9
10 J. H. Jung, K. Asano, T. Sugimoto, C. Hosono, Y. Sakata, and
T. Kaneda, unpublished work.
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Similarly, 4ꢀ (4.28 g, 76.0%), 4ꢂ14 (4.45 g, 89.5%), 6ꢀ
(15.2 g, 79.6%), and 6ꢂ14 (6.79 g, 69.6%) were obtained from 6ꢀ
(5.00 g), 6ꢂ (5.44 g), 5ꢀ15 (16.7 g), and 5ꢂ16 (8.00 g), respec-
tively.
In conclusion, we have demonstrated new practical prepara-
tions of versatile starting materials 4 and 6 for non-hydrophilic
CD derivatives. The present permethylation technique with a
NaH-MeI combination is applicable to other polyhydroxy
compounds with NaI-susceptible substituents.
14 4ꢂ: white foam, mp 114–117 ꢁC. Anal. Found: C, 51.84; H,
7.94%. Calcd for C71H126O40ꢄH2O: C, 52.07; H, 7.88%.
TOFMS (m=z) 1641 [MþNa]þ. 1H NMR(270 MHz, CDCl 3):
ꢃ 5.32 (t, J ¼ 3:4 Hz, 2H, H1), 5.25 (d, J ¼ 3:2 Hz, 1H, H1),
5.22–5.18 (m, 4H, H1), 5.12 (d, J ¼ 3:2 Hz, 1H, H1), 4.0–3.2
(m, 117H), 2.80 (bt, J ¼ 6:1 Hz, 1H, OH). 6ꢂ: white foam, mp
102–105 ꢁC. Anal. Found: C, 52.55; H, 7.49; S, 1.79%. Calcd
for C78H132O42SꢄH2O: C, 52.28; H, 7.54; S, 1.79%. TOFMS
(m=z) 1795 [MþNa]þ. 1H NMR(270 MHz, CDCl ): ꢃ 7.77
3
We are indebted to Nihon Shokuhin Kako Co. Ltd., Mercian
Corporation, and Wacker Chemicals East Asia Ltd. for generous
gifts of ꢀ-, ꢁ-, and ꢂ-CDs, respectively. T.K. also thanks the
Ministry of Education, Science, Sports, and Culture of Japan for
its Grant-in-Aid for Scientific Research (C) (No. 11640582)
which provided financial support of this work.
(d, J ¼ 8:2 Hz, 2H, OTs), 7.34 (d, J ¼ 8:2 Hz, 2H, OTs), 5.3–
5.2 (m, 6H, CD-H1), 5.10 (d, J ¼ 3:5 Hz, 1H, H1), 5.07 (d,
J ¼ 3:2 Hz, 1H, H1), 4.52 (d, J ¼ 9:5 Hz, 1H, CH2OTs), 4.16
(dd, J ¼ 9:5, 6.5 Hz, 1H, CH2OTs), 3.9–3.1 (m, 114H), 3.04
(dd, J ¼ 9:6, 3.1 Hz, 1H), 2.45 (s, 3H, OTs).
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References and Notes
1
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3
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