Practical and convenient modifications of the A,C-secondary hydroxyl face of cyclodextrins

Article abstract of DOI:10.1016/S0040-4020(03)00259-X

A practical and convenient method for the preparation of α-, β-, and γ-cyclodextrin derivatives, in which the secondary hydroxyl faces of A- and C-glucose units are regioselectively modified, has been developed. Reactions of α-, β-, and γ-cyclodextrins wi

Full text of DOI:10.1016/S0040-4020(03)00259-X

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Tetrahedron 59 (2003) 2519–2538
Practical and convenient modifications of the A,C-secondary
hydroxyl face of cyclodextrins
*
Katsunori Teranishi
Faculty of Bioresources, Mie University, Kamihama 1515, Tsu, Mie 514-8507, Japan
Received 5 December 2002; accepted 13 February 2003
Abstract—A practical and convenient method for the preparation of a-, b-, and g-cyclodextrin derivatives, in which the secondary hydroxyl
faces of A- and C-glucose units are regioselectively modified, has been developed. Reactions of a-, b-, and g-cyclodextrins with 1,4-
dibenzoylbenzene-30,300-disulfonyl imidazole in N,N-dimethylformamide in the presence of molecular sieves regioselectively afforded the
corresponding cyclic 2A,2C-(1,4-dibenzoylbenzene-30,300-disulfonyl)-cyclodextrins. Subsequent treatment of the sulfonylated cyclodextrins
with sodium hydroxide or aqueous ammonia afforded the corresponding 2A,3A:2C,3C-di-manno-epoxy-cyclodextrins or 3A,3C-diamino-
3A,3C-dideoxy-(2AS,2CS,3AS,3CS)-cyclodextrins, respectively, which can serve as important intermediates for further functionalizations of
the cyclodextrins. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
regioselective sulfonyl reagents and optimization of the
reaction conditions. The primary hydroxyl groups of
cyclodextrins are basic in nature, and are highly reactive
toward normal electrophilic reagents in the presence of a
weak base, such as pyridine. The secondary hydroxyl face,
being larger than the primary hydroxyl face, functions as the
preferential locus for the molecular inclusion of large
molecules.10 Consequently, cyclodextrin derivatives that
have their secondary hydroxyl faces modified have
significantly different properties than those that have their
primary hydroxyl faces modified.11 Thus, functionalization
of the secondary face is as important as the primary
hydroxyl groups. However, regioselective sulfonylations of
the secondary hydroxyl groups have proven to be difficult,
achievable only by using the following chemical controls,
thus limiting the potential applications of cyclodextrins.
One method for the absolute regioselective sulfonylation of
the C-2 hydroxyl groups involves the protection of the
primary hydroxyl groups;7h,j,l however this method is
troublesome due to the additional protection and deprotec-
tion steps. The relatively acidic C-2 hydroxyl groups, which
have pKa values of 12,12 can be selectively deprotonated in
the presence of a limited amount of strong base, such as
NaH, under anhydrous conditions, without the protection of
the primary hydroxyl groups. Subsequently, the resulting
alkoxides can regioselectively react with electrophilic
reagents.7f Selective activation of the C-2 hydroxyl groups
with dibutyltin oxide, followed by reaction with p-toluene-
sulfonyl chloride under anhydrous conditions,7e or for-
mation of suitable inclusion complex of sulfonyl reagents
and cyclodextrins4d,7a,i,k can also lead to C-2-mono-
sulfonylation. Of the three hydroxyl groups, the C-3
hydroxyl groups are the least reactive, and thereby generally
Cyclodextrins are cyclic oligosaccharides consisting of six
or more a-1,4-linked D-(þ)-glucopyranose units, which
possess primary hydroxyl groups at the C-6 positions and
secondary hydroxyl groups at the C-2 and C-3 positions.1
Since cyclodextrins contain cavities that are hydrophobic
and optically active, they are often utilized in the formation
of inclusion complexes with a wide range of guest
molecules, as transporters of hydrophobic molecules, or as
miniature molecular mimics of enzymes.2 In order to
modify the inclusion behavior of cyclodextrins, a wide
variety of chemically-modified cyclodextrins have been
developed.3 However, selective and efficient modification
methods are still being developed for the preparation of
modified cyclodextrins. Due to the large number of
hydroxyl groups, modifications of these groups can result
in a large number of positional isomers within the
cyclodextrin framework. Correspondingly, regioselective
modifications of cyclodextrins can be difficult, in which one
of main obstacles is the extensive purification required.
In the last few decades, regioselective mono- and multi-
functionalization techniques on the primary and/or second-
ary hydroxyl groups have been investigated. As a result,
several significant sulfonylation techniques have been
demonstrated for the mono-,4 di-,5 and multi-sulfonylations6
of the primary hydroxyl groups, and mono-,7 di-,8 and multi-
sulfonylations9 of the secondary hydroxyl groups of
cyclodextrins. These sulfonylation techniques required
Keywords: cyclodextrin; regioselectivity; sulfonylation.
*
Tel./fax: þ81-59-231-9615; e-mail: teranisi@bio.mie-u.ac.jp
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00259-X

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K. Teranishi / Tetrahedron 59 (2003) 2519–2538
react after the C-2 and C-6 sulfonylations. An exception was
reported by Fujita et al., who described the successful C-3
mono-sulfonylation of a- and g-cyclodextrins, which
afforded the C-2, C-3, and C-6 mono-sulfonates as
regioisomeric mixtures,7b,c,g and the absolute regioselective
C-3 mono-sulfonylation of b-cyclodextrins.7d Ueno et al.
have demonstrated a synthetic method for preparing
mixtures of 2-O- and 3-O-monodansyl b- and g-cyclo-
dextrins in the construction of fluorescent sensors.7i,k
The regioselective 6A,6B-, 6A,6C-, 6A,6D-, or 6A,6E-
disulfonylation of the C-6 hydroxyl groups of cyclodextrins
(the glucose units are assigned as A through F, G, or H,
clockwise, as viewed from the C-6 position of a-, b-, or
g-cyclodextrins, respectively) were accomplished by trans-
annular disulfonylation using well-designed disulfonyl
chlorides, in which the distance between the two sulfonyl
groups corresponded to the distance between the two C-6
hydroxyl groups of the cyclodextrin molecules.5a–e,g,i–l,n,o,q–t
In the case of regioselective 2-O-disulfonylation, Fujita et al.
have obtained mixtures of regioisomeric 2A,2B-, 2A,2C-, and
2A,2D-disulfonylated a- and b-cyclodextrins, in low
yields.7c,8a,b Since the alkaline conditions that were
employed in the 2-O-sulfonylations caused the conversion
of the resulting 2-O-sulfonylated cyclodextrins to the
epoxides, efficient regioselective 2-O-di- or 2-O-multi-
sulfonylations could not be achieved. As a part of our
studies on the chemical modification of cyclodextrins, we
have developed an interesting regioselective monosulfona-
tion of the C-2 hydroxyl groups of a-, b-, g-, and
d-cyclodextrins using a combination of sulfonyl imidazole
and molecular sieves in DMF.7m,n,p This monosulfonylation
technique have proven to be exceptionally valuable for the
following reasons: (i) the mild non-alkaline reaction
conditions do not induce decomposition of the afforded
sulfonylated cyclodextrins, (ii) the reaction occurs indepen-
dently of the nature of the sulfonyl groups and cyclo-
dextrins, and (iii) the reactions do not require strict
anhydrous conditions. Furthermore, we have recently
reported that 2A,2B-disulfonylated a-, b-, and g-cyclo-
dextrins can be regioselectively prepared by transannular
disulfonylation using benzophenone-3,30-disulfonyl imida-
zole and molecular sieves in DMF.8c,d Herein, effective
modifications of the secondary hydroxyl face of the A- and
C-glucose units of a-, b-, and g-cyclodextrins through a
highly regioselective 2A,2C-disulfonylation followed by
further functionalization are described.13
Scheme 1. Synthesis of 3. Reagents and conditions: (a) HOSO2Cl, 24 h,
1208C; (b) imidazole, Et3N, CHCl3, 30 min, rt.
stirred at 308C for 48 h. The reaction was monitored using
reversed-phase HPLC. Upon completion of the disulfonyl-
ation reaction, HPLC analysis (Fig. 1-[I]) of the final
reaction mixture revealed that 2A,2C-disulfonylated
b-cyclodextrin (5b) (Scheme 2) was afforded, with a
relatively high yield of 24%, and that 2A,2B- and 2A,2D-
disulfonylated b-cyclodextrins (4b and 6b, respectively)
(Scheme 2) and cyclodextrin dimer 8 (Fig. 2) were afforded
as minor sulfonylated cyclodextrins with 3.1, 1.0, and 1.5%
yields, respectively (Table 1, entry 2). Moreover,
6-sulfonate(s) and 3-sulfonate(s) were not detected by
HPLC analysis or by 1H NMR measurements. Tabushi
et al. reported temperature dependence of the regioisomer
distribution in 6A,6C-, and 6A,6D-disulfonate capping of
b-cyclodextrin.5g In this study, although a significant
relationship between the 2A,2C-regioselectivity and reaction
temperature was not observed (Table 1, entries 1–3), the
regioselectivity was found to be dependent on the nature of
the solvent (Table 1, entries 4–6), which was limited due to
the low solubility of cyclodextrin. In a mixture of DMF and
MeCN (1:1) and in DMSO, the relative regioselectivity and
yield of 2A,2B-disulfonlylated b-cyclodextrin increased
while those for 2A,2C-disulfonlylated b-cyclodextrin
decreased. In comparison, with DMA as the solvent, the
relative 2A,2C-regioselectivity decreased while the relative
2A,2D-regioselectivity increased. These results suggested
that the reaction solvents can influence the distance between
the two sulfonyl groups of 3 and/or between the two C-2
hydroxyl groups of b-cyclodextrin. It is noteworthy that
these sulfonylations, as well as the published sulfonylations
using p-tolenesulfonyl imidazole7m,n,p or benzophenone-
3,30-disulfonyl imidazole,8c,d do not occur in the absence of
molecular sieves. Detailed reaction mechanisms of the
sulfonylations described herein, such as the roles of the
molecular sieves and the imidazole moieties of the sulfonyl
imidazoles, are currently under investigation. To summarize
the present experiments, reaction conditions employing
DMF as the solvent at 308C exhibited the highest 2A,2C-
regioselectivity and yield.
2. Results and discussion
Based on the investigations of regioselective 2A,2C-
disulfonylations of a-, b-, and g-cyclodextrins using several
sulfonyl imidazoles in DMF in the presence of molecular
sieves, it was determined that the employment of 1,4-
dibenzoylbenzene-30,300-disulfonyl imidazole (3) (Scheme
1) afforded the highest 2A,2C-regioselectivity. Compound 3
can be readily prepared by the reaction of 1,4-dibenzoyl-
benzene (1) with chlorosulfonic acid, followed by treatment
with imidazole using the procedure of Berlin et al.14
A
mixture of b-cyclodextrin (dried under vacuum at 1208C for
12 h), disulfonyl imidazole 3 (1.0 equiv.), and freshly
˚
activated powdered 4 A molecular sieves in DMF was
Although the sulfonylation in DMF at 308C afforded 5b with
high regioselectivity, the result was not satisfactory because
of the low yield, and therefore, it was necessary to find a

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K. Teranishi / Tetrahedron 59 (2003) 2519–2538
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Figure 1. Reversed-phase analytical HPLC chromatogram (Comosil 5C18-MS column) of the final reaction mixture of sulfonylations of a-, b-, and
g-cyclodextrins. Detection was done at 300 nm wavelength. Gradient elution was done from 0:100 to 20:80 MeCN–H2O for 10 min, to 30:70 MeCN–H2O for
20 min, to 45:55 MeCN–H2O for 10 min, and to 100:0 MeCN–H2O for 10 min; flow rate of 0.8 mL/min. [I] sulfonylation of b-cyclodextrin under the
condition of entry 2 in Table 1; [II] sulfonylation of b-cyclodextrin under the condition of entry 9 in Table 2; [III] sulfonylation of a-cyclodextrin under the
condition of entry 1 in Table 3; [IV] sulfonylation of g-cyclodextrin under the condition of entry 5 in Table 3. Compound numbers are presented corresponding
peaks.
more efficient and practical sulfonylation condition. This
low yield was attributable to excessive sulfonylation (see
Fig. 1-[I]), which results in the squandering of 3.
Furthermore, the resulting excessively sulfonylated cyclo-
dextrins complicated the purification procedures due to their
low solubility in water or aqueous methanol, which are used
for the reversed-phase column chromatography. The
distribution of the sulfonylated cyclodextrins can be
controlled by reaction conditions, such as the concentrations
of the cyclodextrins and/or the sulfonyl reagents, and the
techniques during the addition of compounds.15 In the case
of the sulfonylation described herein, the control of the
concentrations of b-cyclodextrin and 3 was found to be
extremely effective in inhibiting excessive sulfonylation;
however, the slow addition of 3 did not show any improved
efficiency. As expected, as equivalent value of 3 used for
b-cyclodextrin was lower and the overall concentrations of
b-cyclodextrin and 3 were lower, as shown in Figure 1-[II],
the generation of excessively sulfonylated cyclodextrins
decreased, which in turn resulted in the increased yields of
5b, on the basis of 3 (Table 2, entries 1–9). Although
Tabushi et al. reported that regioselectivity was sensitive to
concentration of cyclodextrin and sulfonyl reagent in the
6A,6C-, and 6A,6D-disulfonate capping of b-cyclodextrin,5g
in this study the relative regioselectivities of the 2A,2B-,
2A,2C-, and 2A,2D-disulfonylations were similar among the

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K. Teranishi / Tetrahedron 59 (2003) 2519–2538
˚
Scheme 2. Modifications of a-, b-, and g-cyclodextrins. Reagents and conditions: (a) 3, 4 A molecular sieves, DMF, 48 h, 308C; (b) NaOH, H2O, 0–408C;
(c) 28% aqueous NH3, 7 days, 408C.
Figure 2. Structure of b-cyclodextrin dimer 8.