An efficient strategy for the modification of α-cyclodextrin: Direct conversion of one or two adjacent 6-OHs to phthalimides

Article abstract of DOI:10.1016/S0040-4039(02)02503-0

α-Cyclodextrin was reacted with phthalimide under modified Mitsunobu conditions to give the 6^A-deoxy-6^A-phthalimido-α-cyclodextrin in 41% yield. This reaction also worked well in the modification of two methylene carbons, giving the 6^A,6^B-, 6^A,6^C- and 6^A,6^D-diphthalimido-α-cyclodextrins in 22, 9.5 and 4.6% isolated yields, respectively. All the phthalimido species can be quantitatively converted to the corresponding amino cyclodextrins by hydrazinolysis.

Full text of DOI:10.1016/S0040-4039(02)02503-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 565–568
An efficient strategy for the modification of a-cyclodextrin:
direct conversion of one or two adjacent 6-OHs to phthalimides
De-Qi Yuan,* Cheng Yang, Tarou Fukuda and Kahee Fujita*
Department of Molecular Medicinal Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521,
Japan
Received 16 October 2002; revised 6 November 2002; accepted 8 November 2002
Abstract—a-Cyclodextrin was reacted with phthalimide under modified Mitsunobu conditions to give the 6A-deoxy-6A-phthal-
imido-a-cyclodextrin in 41% yield. This reaction also worked well in the modification of two methylene carbons, giving the 6A,6B-,
6A,6C- and 6A,6D-diphthalimido-a-cyclodextrins in 22, 9.5 and 4.6% isolated yields, respectively. All the phthalimido species can
be quantitatively converted to the corresponding amino cyclodextrins by hydrazinolysis. © 2002 Elsevier Science Ltd. All rights
reserved.
Cyclodextrins (CDs) are widely employed as scaffolds
in composing host molecules because of their ability to
bind a wide range of guest molecules in aqueous solu-
tions and to modify the physical and chemical proper-
ties of bound guest molecules. Their modifications are
of particular importance for the investigation at the
frontier of various research fields ranging from
supramolecular chemistry to analytical techniques. The
modification of particular positions represents a great
challenge for chemists since the most frequently used
CDs consist of 6ꢀ8 folds of three types of hydroxyl
groups, namely the primary face 6-OH groups, the
secondary face 3-OH and 2-OH groups, and their com-
petition makes the selective modification of CDs
extremely difficult. During the past decades, methods
for selective modification of one or two hydroxyl
groups on either face have been extensively investi-
gated.1 However, chemists interested in modified CDs
still have to contend with the problems associated with
their synthesis: the multistep procedures with poor
selectivity, tedious separation and low overall yields.
The conventional method for the modification of the
primary face follows the selective 6-OH activation–dis-
placement protocol. Another strategy has been estab-
lished for the introduction of functionalities through a
nitrogen atom, in which one 6-OH is displaced by an
azide group under Vilsmeier–Haack reaction conditions
followed by reduction and subsequent alkylation or
Scheme 1. Reaction of a-CD with phthalimide under modified Mitsunobu condition. (a) Phthalimide/diethyl azodicarboxylate
(DEAD)/Ph3P/a-CD in a molar ratio of 3.3/1.8/2.4/1 in DMF, rt, 5 h; (b) 100 equiv. of hydrazine hydrate in water, 60°C,
overnight; (c) phthalimide/DEAD/Ph3P/a-CD in a molar ratio of 7/4.6/4/1 in DMF, rt, 4 h.
* Corresponding authors. Tel.: +81-95-846-5736; fax: +81-95-846-5736; e-mail: deqiyuan@net.nagasaki-u.ac.jp; fujita@net.nagasaki-u.ac.jp
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02503-0

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D.-Q. Yuan et al. / Tetrahedron Letters 44 (2003) 565–568
The structure of 1 was characterized with FAB-MS and
NMR spectroscopy. FAB-MS spectrum demonstrated
pseudo molecular ion at m/z=1124 (M+Na+). In the
1H NMR spectrum (Fig. 1, top), two multiplets around
l 7.8 ppm were observed for the phthalimide residue
and their integration area was two third that of the
anomeric protons of the CD moiety, confirming the 1:1
conjugation of a-CD and phthalimide. The substitution
position was assigned to C-6A with the aid of 2D NMR
techniques. One carbon resonates at a very high field (l
40.0 ppm) in the 13C NMR (Fig. 1, bottom) and it was
proved to be a CH2 carbon by DEPT measurements. In
the HMBC spectra, long-range couplings were observed
between the protons of this CH2 group and the car-
bonyl carbons of phthalimide. Therefore this methylene
carbon should be the phthalimide-attached position. In
consistent with this assignment, the aromatic ring
excises a very strong shielding effect on one of the
unmodified sugar residue, especially on its protons
located on the primary face (H-6% at l 2.6 and H-5% at
l 3.05). Similar strong shielding effect was reported in
the literatures.3
acylation and so forth. Elimination of reaction steps is
of general research interest in improving synthetic
efficiency and also from the viewpoint of green chem-
istry principles. In this paper, we describe a new strat-
egy to directly incorporate phthalimide functionalities
onto the primary face of a-CD under modified Mit-
sunobu conditions (Scheme 1).2 Reaction of phthal-
imide with a-CD allowed the isolation of
6A-deoxy-6A-phthalimido-a-CD 1 in a high 41% yield.
Increasing the charged amount of phthalimide ensures
the synthesis of 6A,6X-dideoxy-6A,6X-diphthalimido-a-
CDs. This direct phthalimidation reaction not only
gave a good total yield but also performed unprece-
dented interesting regioselectivity. The AB (2), AC (3)
and AD (4) isomeric diphthalimido-a-CDs were iso-
lated in 22, 9.5 and 4.6% yields, respectively. This
represents hitherto the most efficient method to selec-
tively modify two adjacent methylene groups of a-CD.
These a-phthalimido-a-CDs can be transformed quanti-
tatively to the corresponding CD amines by
hydrazinolysis.
The reactions of a-CD and phthalimide were carried
Hydrazinolysis of 1 was carried out by heating 1 and
hydrazine hydrate in water at 60°C overnight. The
crude product was collected by precipitation with ace-
tone and purified via cation-exchange chromatography
to give the 6A-amino-6A-deoxy-a-CD in 88% yield (36%
based on a-CD).4 It’s NMR spectra are superimposible
upon those of the same compound prepared by using
the literature method which afforded this amino CD in
16% yield.5
out in DMF at rt in the presence of Ph3P, diethyl
,
azodicarboxylate (DEAD) and 4 A molecular sieves. In
a typical run for the preparation of monophthalimide 1,
a-CD (5 g, 5.1 mmol), Ph3P (3.2 g, 12.1 mmol) and
phthalimide (2.5 g, 17 mmol) were dissolved in DMF
(150 mL) and the solution was stirred at rt for 1 h.
DEAD solution (40% in toluene, 4 mL, 9.2 mmol) was
then added dropwise and the resultant solution was
stirred at ambient temperature for another 5 h. After
evaporation of the solvent, acetone (200 mL) was added
to the residue and the precipitates were collected by
filtration and applied to reversed-phase chromatogra-
phy (Merck pre-packed RP-18 column, size C). Gradi-
ent elution from water to 27% aqueous ethanol
afforded the pure product 1 (2.3 g, 41%).
Since we still lack an efficient method to selectively
modify two positions on the primary face of a-CD
except for the transannular 6A,6C-disulfonylation6
reported recently, we are interested in expanding this
direct phthalimidation method to the bifunctionaliza-
tion of a-CD. In general, the substitution levels of CDs
Figure 1. 1H (top, 500 MHz) and 13C (bottom, 125 MHz) NMR spectra of 1 in a mixed solvent of 40% D2O–60% DMSO-d6
(CH3CN as internal standard). The numbers with a superscript ‘A’ indicate the protons or carbons of the substituted glucoside
unit, while the primed numbers denote the protons or carbons of one of the unsubstituted units adjacent to the substituted one.

D.-Q. Yuan et al. / Tetrahedron Letters 44 (2003) 565–568
567
Figure 2. 1H NMR spectra (300 MHz) of the diphthalimido-a-CDs 2 (top), 3 (middle) and 4 (bottom) in DMSO-d6 (TMS as
internal standard). The C2 symmetrical feature of compound 4 is evident in the aromatic region as well as in the anomeric region
from l 4.7ꢀ5.2 ppm.
can be increased by using more reacting reagents. The
suitable conditions for the preparation of diphathal-
imido-a-CDs turn out to be quite similar to that used
for the preparation of mono-phthalimido-a-CD 1 but
with the amounts of phthalimide, DEAD and Ph3P
nearly doubled. The preparative reaction was carried
out by charging phthalimide, DEAD, Ph3P and a-CD
in a molar ratio of 7/4.6/4/1 and by the same proce-
dures described above for the synthesis of 1. Chro-
modify the 6A,6B-positions of a-CD. One is the consec-
utive disulfonylation with messitylenesulfonyl chlo-
ride,10 which afforded the AB, AC and AD disulfonates
in 7.3, 9.1 and 13.6%, respectively. Another one used
4,6-dimethoxy-1,3-benzenedisulfonyl chloride as cap-
ping reagent,8 by taking the advantage of the ‘looper’s
walk’ strategy, to afford the 6A,6B-disulfonate in 2.3%
yield. Obviously the present method is more efficient in
modifying the two adjacent methylene carbons of a-
CD.
matography of the reaction mixture on
a
reversed-phase Lobar column (RP-18, gradient elution
from 10 to 40% aqueous ethanol) gave 22% 2, 9.5% 3
and 4.6% 4 in addition to 13% 1. FAB-MAS and NMR
spectroscopic analysis7 indicated that 2ꢀ4 are all the
adducts of one CD and two phthalimide moieties.
Compound 4 can be reasonably assigned to the C2
Unusual but very interesting AB selectivity was
observed in this direct diphthalimidation reaction. In
the consecutive reactions on CDs, the first introduced
substituent usually exercises more or less steric repul-
sion effect on the coming ones and thus direct them to
the distant positions. This steric effect was elegantly
utilized in the modifications of the ACE positions of
the primary face of a-CD11 and the secondary face of
b-CD.12 In the direct diphthalimidation reaction, how-
1
symmetrical AD isomer based on the H NMR spectra
(Fig. 2), while the determination of the regiochemistry
of 2 and 3 was carried by the procedures depicted in
Figure 3. Hydrazinolysis of compounds 2, 3 and 4
under the same conditions as for 1 afforded 5 (91%), 6
(84%) and 7 (81%), respectively. Treatment of these
amines with p-nitrobenzoic acid in the presence of
DCC and 1-hydroxybenzotriazole (HOBT) gave the
HPLC samples 8, 9 and 10 which demonstrated reten-
tion times different from each other on the reversed-
phase ODS column. Comparison of their HPLC
retention times with those of the authentic 6A,6B- and
6A,6C-di(p-nitrobenzamido)-a-CDs suggested that 2 is
6A,6B-diphthalimido-a-CD, while 3 is the AC isomer.
The authentic samples of 6A,6B- and 6A,6C-di(p-
nitrobenzamido)-a-CDs were obtained by the selective
transannular disulfonylation at the 6A,6B- (11)8 or
ever, the two phthalimide residues prefer to be closely
F)
located. The averaged relative reactivity of 6B(or
6
/
C(or E)/6D position of the intermediate monophthal-
imido-a-CD can be deduced to be 2.4:1:1 based on the
isolated yields of the diphthalimides. Obviously some
factor other than the steric interaction predominates in
locating the second molecule of phthalimide. Further
work aiming at the elucidation of the phenomena is in
progress.
In summary, direct substitution of the primary
hydroxyl group of a-CD by phthalimide under
modified Mitsunobu conditions has been effected, and
the 6A-phthalimido-a-CD can be isolated in a high 41%
yield. This strategy also works well in the synthesis of
disubstituted a-CDs, and demonstrated very interesting
AB regioselectivity by affording 6A,6B-diphthalimido-a-
CD in 22% yield. All the phthalimido-a-CD species can
be converted quantitatively to their corresponding
amino-CDs which are very important intermediates.
6A,6C-positions (12),9 subsequent substitution with N3 ,
−
reduction with Ph3P and final acylation of the amines
(Fig. 3).
The above results indicate that the present strategy
ensures a direct modification of the primary face of
a-CD. Two approaches have been reported hitherto to

568
D.-Q. Yuan et al. / Tetrahedron Letters 44 (2003) 565–568
Figure 3. The procedures for the determination of the regiochemistry of the diphthalimido-a-CDs 2, 3 and 4 based on HPLC
analysis. (a) NH2NH2·H2O, H2O, 60°C, overnight; (b) DMF, DCC, HOBT, p-nitrobenzoic acid, rt, 4 h; (c) pyridine,
4,6-dimethoxy-1,3-benzenedisulfonyl chloride, rt, 3 h; (d) pyridine, dibenzofuran-2,8-disulfonyl chloride, rt, 3 h; (e) (1) DMF,
NaN3, 80°C, 12 h; (2) DMF, Ph3P, rt, overnight, then at rt for 24 h in the presence of aqueous NH3; (3) DMF, DCC, HOBT,
p-nitrobenzoic acid, rt, 4 h. The HPLC analysis was performed on a reversed-phase column (YMC ODS-AQ-313, 250×6.0 mm
I.D.) eluted with a gradient from 20% aqueous CH3CN and with the CH3CN concentration being increased at a rate of 0.5%/min.
The UV absorbance of the elutes was detected at u=280 nm. (i) A mixture of 8, 9 and 10; (ii) mixture of (i) and the authentic
6A,6B-di(p-nitrobenzamido)-a-CD; (iii) mixture of (i) and the authentic 6A,6C-di(p-nitrobenzamido)-a-CD.
Acknowledgements
60, 4786–4797.
6. Atsumi, M.; Izumida, M.; Yuan, D.-Q.; Fujita, K. Tetra-
We thank Japan Maize Products Co. Ltd for a gener-
ous gift of CDs.
hedron Lett. 2000, 41, 8117–8120.
7. Compound 2, 3 and 4 all showed the pseudomolecular ion
peak at m/z 1253(M+Na+) in the FAB-MS spectra. Their
1H (Fig. 2) and 13C NMR spectra are consistent with their
structures. The 13C NMR data (75 MHz, DMSO-d6,
References
CH3CN int., lCH CN=1.70) are as follows. Compound 2:
3
l 167.8, 167.3, 134.8, 134.7, 134.0, 130.7, 130.6, 130.4, 123.1,
122.5, 102.0, 101.2, 100.4, 100.3, 84.6, 84.0, 81.7, 81.6, 80.6,
80.0, 73.1, 72.8, 72.4, 72.1, 72.0, 71.8, 71.5, 71.4, 71.3, 71.2,
71.0, 70.7, 66.3, 59.8, 59.4, 58.1, 56.4, 39.3, 39.0. Compound
3: l 167.0, 134.0, 133.3, 130.1, 128.0, 127.3, 122.4, 121.7,
101.0, 100.9, 100.5, 99.7, 98.2, 83.2, 83.0, 80.3, 80.2, 79.5,
72.1, 72.0, 71.7, 71.4, 71.1, 70.9, 70.8, 70.6, 70.3, 68.8, 66.9,
58.6, 58.3, 57.3, 38.3, 38.0. Compound 4: l 168.2, 134.6,
131.4, 123.1, 102.1, 101.9, 101.2, 84.0, 81.4, 80.7, 73.1, 72.9,
72.4, 72.1, 71.9, 71.4, 68.8, 59.1, 57.9, 39.3.
1. Kahn, A. R.; Forgo, P.; Stine, K. J.; D’Souza, V. T. Chem.
Rev. 1998, 98, 1977–1996.
2. (a) Aronov, A. M.; Gelb, M. H. Tetrahedron 1998, 39,
4947–4950; (b) Hughes, D. L. Org. Prep. Proc. Int. 1996,
28, 127–164; (c) Mitsunobu, O. Synthesis 1981, 1–28.
3. (a) Yuan, D.-Q.; Koga, K.; Fujita, K.; Yamaguchi, M.
Tetrahedron Lett. 1997, 38, 7593–7596; (b) Yuan, D.-Q.;
Koga, K.; Yamaguchi, M.; Fujita, K. J. Chem. Soc., Chem.
Commun. 1996, 1943–1944; (c) Cucinotta, V.; D’Alessan-
dro, F.; Impellizzeri, G.; Vecchio, G. J. Chem. Soc., Chem.
Commun. 1992, 1743–1745; (d) Ikeda, H.; Du, Y.; Naka-
mura, A.; Toda, F. Chem. Lett. 1991, 1495–1498.
4. A mixture of 1 (0.1 mmol) and hydrazine hydrate (0.01 mol)
in H2O (2 mL) was stirred at 60°C overnight. After being
cooled down to rt, the reaction mixture was added dropwise
to acetone (50 mL). The resultant precipitates were collected
by filtration and applied to ion exchange chromatography
(Bio-Rad AG 50W-X2, 100–200 mesh, f-SO3H type,
washed with a gradient of 0ꢀ1.5% aq. ammonia solution)
to give the 6A-amino-6A-deoxy-a-CD (88%).
8. Breslow, R.; Schmuck, C. J. Am. Chem. Soc. 1996, 118,
6601–6605.
9. Koga, K.; Yuan, D.-Q.; Fujita, K. Tetrahedron Lett. 2000,
41, 6855–6857.
10. Fujita, K.; Matsunaga, A.; Imoto, T. J. Am. Chem. Soc.
1984, 106, 5740–5741.
11. (a) Coleman, A. W.; Ling, C.; Miocque, M. Angew. Chem.,
Int. Ed. Engl. 1992, 31, 1381; (b) Boger, J.; Brenner, D. G.;
Knowles, J. R. J. Am. Chem. Soc. 1979, 101, 7630.
12. Fujita, K.; Tahara, T.; Yamamura, H.; Imoto, T.; Koga,
T.; Fujioka, T.; Mihashi, K. J. Org. Chem. 1990, 55, 877.
5. Hanessian, S.;Benalil, A.;Laferriere, C. J. Org. Chem. 1995,