Chemical Synthesis of Cyclodextrins
CDs are cyclic oligosaccharides consisting of D-glucopy-
ranosyl units connected by R(1f4) glycosidic linkages.
The natural CDs which consist of 6, 7, or 8 glucose units
are well-known as R-, â-, and γ-CD, respectively.5 CDs
have a hydrophobic cavity that can include a variety of
chemical substances. CDs have been widely used in foods
and cosmetics, as well as pharmaceutical, environmental,
and industrial chemistry.6,7 Chemical modifications of
CDs have been reported not only for the biomimetic
studies but also for the improvement of the physicochem-
ical properties of their complexes such as solubility and
bioavailability.8 Many studies of de novo synthesis of CDs
and their analogues have also been reported.9,10 Structur-
ally diverse CD analogues can be readily obtained by de
novo synthesis, though substantial time and efforts are
required for the synthesis. As a pioneering work, the
chemical syntheses of R-CD and γ-CD were reported by
Ogawa and Takahashi in 1985.9b,c By employing a similar
synthetic strategy, a new member of the CD family,
namely, cyclo(1f4)-R-D-glucopentaoside, was synthesized
by Nakagawa et al.9d Kuzuhara et al. succeeded in the
synthesis of “chimera cyclodextrin”, which has the D-
glucosamine residue in place of a glucose residue in the
CD skeleton.9e-g The function of CDs having larger ring
system is also of interest. CDs having more than 9
glucose units are obtained by enzymatic digestion of
(5) Villiers, A. Compt. Rend. 1891, 112, 536.
(6) (a) Fromming, K.-H.; Szejtli, J . Cyclodextrins in Pharmacy;
Kluwer Academic: Dordercht, The Netherlands, 1994. (b) Szejtli, J .
Med. Res. Rev. 1994, 14, 353. (c) Albers, E.; Muller, B. W. CRC Crit.
Rev. Ther. Drug Carrier Syst. 1995, 12, 311. (d) Thompson, D. O. CRC
Crit. Rev. Ther. Drug Carrier Syst. 1997, 14, 1. (e) Saenger, W. Angew.
Chem., Int. Ed. Engl. 1980, 19, 344.
F IGURE 2. Structures of R-CD 1 and δ-CD 2.
(7) (a) Breslow R.; Camobell, P. J . Am. Chem. Soc. 1969, 91, 3085.
(b) Hirai, H.; Mihori, H.; Terakado, R. Makromol. Chem. Rapid
Commun. 1993, 14, 39. (c) Schneider, H.-J .; Sangwan, N. K. Angew.
Chem., Int. Ed. Engl. 1987, 26, 896. (d) Komiyama, M.; Hirai, H. J .
Am. Chem. Soc. 1983, 105, 2018. (e) Veglia, A. V.; de Rossi, R. H. J .
Org. Chem. 1988, 53, 5281. (f) Schmidt, G. M. J . J . Chem. Soc. 1964,
2014. (g) Penzien, K.; Schmidt, G. M. J . Angew. Chem., Int. Ed. Engl.
1969, 8, 608. (h) Tanaka, Y.; Sakuraba, H.; Nakanishi, H. J . Org. Chem.
1990, 55, 564. (i) Czarnik, A. W. J . Org. Chem. 1984, 49, 924. (j)
Kawajiri, Y.; Motohashi, N. J . Chem. Soc., Chem. Commun. 1989, 1336.
(k) Sakuraba, H.; Inomata, N.; Tanaka, Y. J . Org. Chem. 1989, 54, 3482.
(8) (a) Melton, L. D.; Slessor, K. N. Carbohydr. Res. 1971, 18, 29.
(b) Tahiti, Y. Bull Chem. Soc. J pn. 1993, 66, 550. (c) Hanada, F.; Kondo,
Y.; Ito, R.; Suzuki, I.; Osa, T.; Ueno, A. J . Inclusion Penom. 1993, 15,
273. (d) Wang, Y.; Ueno, A.; Toda, F.; Osa, S.; Toda, F. Chem. Lett.
1994, 167. (e) Hamasaki, K.; Ueno, A.; Toda, F.; Suzuki, I.; Osa, T.
Bull. Chem. Soc. J pn. 1994, 67, 516. (f) Bender, M. L.; Komiyama, M.
Cyclodextrin Chemistry; Spring-Verlarg: New York, 1978.
(9) (a) Ogawa, T.; Takahashi, Y. Carbohydr. Res. 1985, 138, C5. (b)
Ogawa, T.; Takahashi, Y. Carbohydr. Res. 1987, 164, 277. (c) Taka-
hashi, Y.; Ogawa, T. Carbohydr. Res. 1987, 169, 127. (d) Nakagawa,
T.; Ueno, K.; Kashiwa, M.; Watanabe, J . Tetrahedron Lett. 1994, 35,
1992. (e) Sakairi, N.; Wang, L.-X.; Kuzuhara, H. J . Chem. Soc., Chem.
Commun. 1991, 289. (f) Sakairi, N.; Kuzuhara, H. J . Chem. Soc., Chem.
Commun. 1992, 510. (g) Sakairi, N.; Wang, L.-X.; Kuzuhara, H. J .
Chem. Soc., Perkin Trans. 1 1995, 437.
F IGURE 3. Synthetic strategy for CDs.
(10) Example of the synthesis of cyclic oligosaccharides: (a) Mori,
M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1989, 192, 131. (b) Mori, M.;
Ito, Y.; Izawa, J .; Ogawa, T. Tetrahedron Lett. 1990, 31, 3191. (c)
Kuyama, H.; Nukada, T.; Nakahara, Y.; Ogawa, T. Tetrahedron Lett.
1993, 34, 2171. (d) Kuyama, H.; Nukada, T.; Nakahara, Y.; Ogawa, T.
Carbohydr. Res. 1995, 268, C1. (e) Nishizawa, M.; Imagawa, H.; Kan,
Y.; Yamada, H. Tetrahedron Lett. 1991, 32, 5551. (f) Niahizawa, M.;
Imagawa, H.; Kubo, K.; Kan, Y.; Yamada, H. Synlett 1992, 447. (g)
Collins, P. M.; Ali, M. H. Tetrahedron Lett. 1990, 31, 4517. (h) Gagnair,
D.; Vignon, M. R. Carbohydr. Res. 1976, 51, 140. (i) Bonas, G.;
Excoffier, G.; Paillet, M.; Vignon, M. Recl. Trav. Chim. Pays-Bas 1989,
108, 259. (j) Houdier, S.; Votte´ro, P. J . A. Carbohydr. Res. 1993, 248,
377. (k) Houdier, S.; Votte´ro, P. J . A. Angew. Chem., Int. Ed. Engl.
1994, 33, 354. (l) Houdier, S.; Votte´ro, P. J . A. Carbohydr. Lett. 1994,
1, 13. (m) Ashton, P. R.; Brown, C. L.; Menzer, S.; Nepogodiev, S. A.;
Stoddart, J . F.; Williams, D. J . Chem. Eur. J . 1996, 2, 580.
starch by using cyclodextrin glucanotransferase (CGTase)
only in tiny amounts.11
In the present study, the molecular clamp method
using the phthaloyl bridge was applied to the synthesis
of R-CD (1) and δ-CD (2) (Figure 2). This was the first
success in the chemical synthesis of CDs having more
than 9 glucose units.
Resu lt a n d Discu ssion
The synthetic strategy for CDs is shown in Figure 3.
CDs have a highly symmetric structure composed of only
J . Org. Chem, Vol. 67, No. 23, 2002 8183