Efficient monomodification of the secondary hydroxy groups of β- cyclodextrin

Full text of DOI:10.1021/jo981866e

3
32
J . Org. Chem. 1999, 64, 332-333
Efficien t Mon om od ifica tion of th e Secon d a r y
Sch em e 1
Hyd r oxy Gr ou p s of â-Cyclod extr in
Sheng-Hsien Chiu and David C. Myles*
Department of Chemistry and Biochemistry, University of
California, Los Angeles, California 90095-1569
Received September 15, 1998
In conjunction with our research on functionalized mono-
1
layer surfaces, we required access to a range of selectively
modified cyclodextrin derivatives. The internal hydrophobic
space and external hydrophilic hydroxy groups make cyclo-
2
pyridine gave, after 24 h, monotosylate â-cyclodextrin 4 as
the major product in 26% yield.
Compounds 2-4 are easily handled and purified by
column chromatography. As with the silylation, sulfonation
occurred at C-2 (vide infra). Acetylation (Ac2O, pyridine)
gave little or no selectivity.
dextrins ideal tools for investigating enzyme mimics, drug
3
4
delivery systems, catalytic reactions, host-guest interac-
tions,5 and self-assembled monolayers.6 The use of cyclo-
dextrins for these applications has been hampered by poor
solubility in many common solvents and the notoriously low
selectivity and low efficiency of monomodification reactions.
To expand the range of applications of cyclodextrin, the
development of efficient and selective synthetic modifications
of cyclodextrin is essential. Of particular interest are selec-
To capitalize upon the selective silylation and to prove
the regiochemistry of silylation, we investigated the methy-
lation of the remaining C-2 and C-3 hydroxyl groups.
Migration of the tert-butyldimethylsilyl group is known in
cyclodextrin chemistry and has been examined systemati-
cally.12 Under strongly basic conditions (MeI, NaH, THF),
the 2-O-silyl group of polysilylated cyclodextrin will migrate
to the 3-O position. The migration can be suppressed under
nonpolar and weakly basic conditions (MeSO2CF3, 2,6-di-
tert-butyl-pyridine, CH2Cl2).13 Thus, if the initial silylation
had occurred at the 2-hydroxy position, these two different
reaction conditions would generate two different products.
However, if selective silylation had occurred at C-3, these
different reaction conditions would afford the same product.
When we applied these two different methylation conditions
tive monomodifications of the secondary 2- and 3-hydroxy
groups that form the rim of the larger face of cyclodextrin.7
The readily available heptakis-6-O-(tert-butyldimethyl-
8
silyl)-â-cyclodextrin 1 shows unusual and interesting reac-
tivity when treated with excess TBSCl in pyridine for 48 h,
resulting in the conversion of 1 into a single octasilyl
derivative 2 (39%) (Scheme 1).9 We have shown that the
silylation occurred at the more acidic C-2 position of the
sugar (vide infra). To test the generality of this selective
1
0
modification, we also studied the acylation and sulfona-
tion11 of 1. We have found that 1 reacts with 2,2,2-
trimethylacetyl chloride (Piv-C1) to afford 3 in 36% yield.
Similarly, treatment of 1 with 10 equiv of tosyl chloride in
to 2, two different compounds, 5 and 6, were generated
+
(
2
Scheme 2). They have the same mass (FAB[M + Na ] )
254) but different 1H and C NMR spectra. Compound 5
13
†
To whom correspondence should be addressed at Chiron Corp., 5300
was not observed during the nonpolar methylation process.
Thus, we conclude that the structure of 2 is correctly
assigned as being the result of highly selective silylation at
one of the seven possible C-2 hydroxy groups. The structure
of compound 5 was further confirmed by its conversion to
Chiron Way, Emeryville, CA 94608. E-mail: david_myles@cc.chiron.com.
(
1) (a) Motesharei, K.; Myles, D. C. J . Am. Chem. Soc. 1994, 116, 7413.
b) Motesharei, K.; Myles, D. C. J . Am. Chem. Soc. 1997, 119, 6674. (c)
Horton, R. C.; Myles, D. C. J . Am. Chem. Soc. 1997, 119, 12980.
2) (a) Bender, M. L.; Komiyama, M. Cyclodextrin Chemistry; Springer.
(
(
Berlin. 1978. (b) Breslow, R. Pure Appl. Chem. 1994, 66, 1573. (c) D’Souza,
V. T.; Bender, M. L. Acc. Chem. Res. 1987, 20, 146.
+
14
compound 7 (FAB(M + Na ) ) 1700). Compounds 5 and 6
can be readily formed from 2, providing a synthetic pathway
for selectively generating a â-cyclodextrin with only one free
secondary hydroxyl group, in either the 2- or 3-position.
Treatment of compounds 5 and 6 with tetrabutylammonium
fluoride gave the versatile monofunctionalized â-cyclodex-
(3) (a)Szejtli, J . Cyclodextrin Technology. In Topics in Inclusion Science;
Davies, J . E. D., Ed.; Kluwer: Dordrecht, 1988. (b) Pfannemuller, B.;
Burchard, W. Makromol. Chem. 1969, 121, 1.
(
(
4) Ye, H.; Tong, W.; D’Souza, V. T. J . Am. Chem. Soc. 1992, 114, 5470.
5) (a) Ohvo, H.; Slotte, J . P. Biochemistry 1996, 35, 8108. (b) Anderson,
T.; Sundahl, M.; Westman, G.; Wennerstorm, O. Tetrahedron Lett. 1994,
5, 7103.
6) (a) Rojas, M. T.; Koniger, R.; Stoddart, J . F.; Kaifer, A. E. J . Am.
3
(
trins 8 and 9 in high yields.
Chem. Soc. 1995, 117, 336. (b) Lahav, M.; Ranjit, K. T.; Katz, E.; Willner,
I. Chem. Commun. 1997, 259. (c) Odashima, K.; Kotato, M.; Sugawara, M.;
Umezawa, Y. Anal. Chem. 1993, 65, 927.
While it is known that the 13C resonance of the 2-OMe
and 3-OMe group is around 58-61 ppm, the exact assign-
ment of the methyl groups can be ambiguous. We are able
to assign conclusively the two different types of OMe groups
(7) (a) Ueno, A.; Breslow, R. Tetrahedron Lett. 1982, 23, 3451. (b) Tian,
S.; Forgo, P.; D’Souza, V. T. Tetrahedron Lett. 1996, 37, 8309. (c) Rong, D.;
D’Souza, V. T. Tetrahedron Lett. 1990, 30, 4275. (d) Martin, K. A.;
Mortellaro, M. A.; Sweger, R. W.; Fikers, L. E.; Winn, D. T.; Clary, S.;
J ohnson, M. P.; Czarnik, A. W. J . Am. Chem. Soc. 1995, 117, 10443. (e)
Khan, A. R.; Forgo, P.; Stine, K. J .; D’souza, V. T. Chem. Rev. 1998, 98,
1
3
in the C NMR of compounds 5 and 6. In Figure 1,
compound 6 shows six carbon peaks around 58 ppm and
seven carbon peaks around 61 ppm, whereas compound 5
shows the reverse seven signals at ca. 58 ppm and six ca.
1
977.
(8) Fugedi, P. Carbohydr. Res. 1995, 192, 366.
9) Compound 2 can be directly generated by treating â-cyclodextrin itself
(
6
1 ppm.
with 15 equiv of TBSCl in pyridine for 48 h. If â-cyclodextrin is treated
with only 7.7 equiv of TBSCl for 24 h, only compound 1 is formed. In contrast
to many â-cyclodextrin derivatives, compound 1 is easily handled and
purified with normal-phase chromatography.
(12) Icheln, D.; Gehrcke, B.; Piprek, Y.; Mischnick, P.; Konig, W. A.;
Dessoy, M. A.; Morel, A. F. Carbohydr. Res. 1996, 280, 237.
(13) Mischnick, P.; Lange, M.; Gohdes, M.; Stein, A.; Petzold, K. Carbo-
hydr. Res. 1995, 277, 179.
(14) (a) Fugita, K.; Yamamura, H.; Imoto, T.; Tabushi, I.; Sanzo, H.;
Maidashi, H. Chem. Lett. 1988, 543. (b) Gadelle, A.; Defaye, J . Angew.
Chem., Int. Ed. Engl. 1991, 30, 78. (c) Alker, D.; Aston, P. R.; Harding, V.
D.; Koniger, R.; Stoddart, J . F.; White, A. J . P.; Williams, D. J . Tetrahedron
Lett. 1994, 35, 9091.
(10) (a) Czarniecki, M. F.; Breslow, R. J . Am. Chem. Soc. 1978, 7771. (b)
Vanetten, R. L.; Clowes, G. A.; Sebastian, J . F.; Bender, M. L. J . Am. Chem.
Soc. 1967, 7771. (c) Kurono, Y.; Stamoudis, V.; Bender, M. L. Bioorg. Chem.
1
976, 5, 393.
11) (a) Khan, A. R.; Barton, L.; D’Souza, V. T.J . Org. Chem. 1996, 61,
301. (b) Fugita, K.; Nagamura, S.; Tahara, T.; Kogas, T. J . Am. Chem.
(
8
Soc. 1985, 107, 3233.
1
0.1021/jo981866e CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/05/1999

Communications
J . Org. Chem., Vol. 64, No. 2, 1999 333
F igu r e 1. 100 MHz 13C NMR spectra of 5 and 6.
Sch em e 2
Thus, by simply counting the signals in the 13C NMR, we
have been able to determine the substitution patterns on
the modified cyclodextrins. The nonpolar methylation reac-
lowing protection of the remaining secondary alcohols as
methyl ethers and subsequent desilylation. We believe that
these compounds will find widespread use as versatile
intermediates for the synthesis of novel cyclodextrin deriva-
tives. By comparing the 13C NMR spectra of compounds 5
and 6, we were also able to accurately distinguish and assign
the carbon signals of the 2-OMe and 3-OMe groups. The
method may be useful for assigning the position of any
functional group monofunctionalized on the secondary face
of â-cyclodextrin following proper derivatization of the free
alcohols.
tion was then applied to compound 3 and 4. From the 13
C
NMR signals, we concluded that the modifications occurred
on the 2-OH. This general NMR interpretation method can
be used for assigning the position of any 2- or 3-hydroxy
monofunctionalized cyclodextrin by persilylating the primary
alcohols and permethylating the remaining secondary hy-
droxy groups.
In conclusion, we have demonstrated a highly selective
and synthetically practical monomodification strategy for the
secondary face of â-cyclodextrin. Silylation, acylation, and
sulfonation of heptakis-6-O-(tert-butyldimethylsilyl)cyclo-
dextrin 1 occur efficiently and with high regioselectivity in
all cases to afford a single regioisomer. J udicious choice of
migrating silyl or nonmigrating conditions for methylation
allows us to control precisely the position of the silyl group
at the 2-O- or 3-O position. Thus, the corresponding free
monohydroxy compounds can be generated selectively fol-
Ack n ow led gm en t. Financial support for this research
was provided by the National Science Foundation (CHE-
9
501728) and the Alfred P. Sloan Foundation.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and NMR spectra for obtained compounds.
J O981866E