Synthesis of two mono-deoxy β-cyclodextrin derivatives as useful tools for confirming DIBAL-H promoted bis-de-O-methylation mechanism

Article abstract of DOI:10.1016/j.cclet.2012.10.023

Diisobutylaluminium hydride (DIBAL-H) promotes secondary rim regioselective bis-de-O-methylation of permethylated β-cyclodextrin (β-CD) to give diol 2. To gain an insight into the mechanism of this remarkable regioselective behavior, two corresponding per

Full text of DOI:10.1016/j.cclet.2012.10.023

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 1315–1318
www.elsevier.com/locate/cclet
Synthesis of two mono-deoxy b-cyclodextrin derivatives as useful
tools for confirming DIBAL-H promoted bis-de-O-methylation
mechanism
a,b
a
a
a
a
b
Su Long Xiao , De Min Zhou , Ming Yang , Fei Yu , Li He Zhang , Pierre Sinay ,
¨
Yong Min Zhang b,c,
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
b
´
´
Institut Parisien de Chimie Moleculaire, UMR CNRS 7201, Universite Pierre et Marie Curie-Paris 6, 4 Place Jussieu, 75005 Paris, France
c Institute for Interdisciplinary Research, Jianghan University, Wuhan Economic and Technological Development Zone, Wuhan 430056, China
Received 21 September 2012
Available online 17 November 2012
Abstract
Diisobutylaluminium hydride (DIBAL-H) promotes secondary rim regioselective bis-de-O-methylation of permethylated b-
cyclodextrin (b-CD) to give diol 2. To gain an insight into the mechanism of this remarkable regioselective behavior, two
corresponding permethylated b-CDs with an alcohol function at either 2- or 3-position were synthesized in our previous study. As a
step further to this work, the two compounds were subjected to deoxygenation reaction with tributyltin hydride in the present of 2,20-
azobisisobutyronitrile affording the corresponding 2- and 3-deoxy permethylated b-CD derivatives (19 and 16). The structures of
these two compounds were characterized by 1D and 2D NMR and HRMS. Compounds 16 and 19 were unable to react with DIBAL-
H which suggests that O-2A and O-3B are necessary for DIBAL-H promoted bis-de-O-methylation reaction of permethylated b-CD.
# 2012 Yong Min Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Cyclodextrin (CD); DIBAL-H; Deoxy; Synthesis; Mechanism
Cyclodextrins (CDs) have gained popularity among scientists due to their widespread use in many areas of science
and technology and a variety of CD derivatives aimed at a specific purpose were synthesized [1]. Per-O-methylated
CDs have attracted considerable attention due to their solubility both in water and in organic solvents [2]. On the other
hand, inclusion complexes of methylated CDs are usually more stable than the corresponding complexes of
unmodified CDs. For these reasons, the controlled chemical synthesis of modified methylated CDs having a few
specifically located hydroxyl groups available for the preparation of more elaborate molecular systems represents a
true challenge for synthetic chemists [1,3]. The traditional methods [3] for selectively modified per-O-methylated CD
were usually performed by a temporary regioselective protection of peculiar hydroxyl groups of the native CD,
followed by O-methylation and final removal of the protective groups to unmask the required hydroxyl functions. This
´ ´
* Corresponding author at: Institut Parisien de Chimie Moleculaire, UMR CNRS 7201, Universite Pierre et Marie Curie-Paris 6, 4 Place Jussieu,
75005 Paris, France.
E-mail address: yongmin.zhang@upmc.fr (Y.M. Zhang).
1001-8417/$ – see front matter # 2012 Yong Min Zhang. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.10.023

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S.L. Xiao et al. / Chinese Chemical Letters 23 (2012) 1315–1318
Scheme 1. De-O-methylation (left) and de-O-benzylation (right) reactions of per-O-alkylated b-CD by DIBAL-H.
process was considered as the ‘‘long’’ method [1c], where a series of lengthy protection and deprotection steps have
taken place in order to selectively reach the positions which would otherwise not be selectively accessible.
In our ongoing program for selective bis-de-O-alkylation reactions of a- and b-per-O-alkylated CD mediated by
DIBAL-H [4], we have developed a simple and efficient method to get directly 2A,3B-dihydroxyl-per-O-methylated b-
CD 2 from per-O-methylated b-CD 1 by DIBAL-H promoted regioselective removal of two methyl groups [5], which
is well suited for further transformations [6]. This process was considered as the ‘‘clever’’ method, where the
chemistry of cyclodextrin is exploited to get the desired product by the shortest route [1c]. Extension of this method led
to a practical and unprecedented regioselective tetra-O-demethylation [7] and hexa-O-demethylation [8] of per-O-
methylated b-CD, using an excess of commercially available DIBAL-H as a chemical ‘‘scalpel’’ (Scheme 1).
However, the mechanism of the regioselective bis-de-O-methylation processes of 1 has been unknown. As a
characteristic, the DIBAL-H promoted regioselective bis-de-O-methylation of 1 occurs selectively on two closely
located methoxyl groups at C-2 and C-3 of two contiguous sugar residues, we proposed that one of the methoxy group
may affect the other one in DIBAL-H promoted bis-de-O-methylation [9]. In order to further confirm this proposition,
we hereby report the synthesis of the two deoxy b-CD derivatives and their behavior in the de-O-methylation reactions
promoted by DIBAL-H.
1. Results and discussion
We submitted per-O-methylated b-CD 1 to the action of DIBAL-H and observed demethylation reactions leading to
a mixture of compounds and we have been able to delineate three sets of conditions to access three different CDs, 2, 3
and 4, as major products (Scheme 1) [5,7,8].
These remarkable results appear to be in sharp contrast to the case of benzylated CDs in which debenzylation
occurs on the primary rim of the CD (Scheme 1) and such a bis-debenzylation reaction was a stepwise process [4b]. In
the case of permethylated CDs, and in spite of our efforts, we were unable to isolate a mono-alcohol on the secondary
rim, which suggests a subtly different mechanism. Therefore compounds 7 and 8 were logically designed and
Scheme 2. Proposed mechanism for the formation of 2A,3B-diol 2.

S.L. Xiao et al. / Chinese Chemical Letters 23 (2012) 1315–1318
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Scheme 3. Synthesis of the mono-deoxy permethylated b-CDs 16 and 19. Reagents and conditions: (a) CH3I, NaH, DMF; (b) O-phenyl
chlorothioformate, DMAP, pyridine, dichloromethane; (c) AIBN, tributylstannane, toluene; (d) (i) BnBr, NaH, DMF; (ii) CH3I, NaH, DMF; (iii) Pd/
C, H2, CH3OH.
synthesized for studying the mechanism of de-O-methylation reactions and a mechanism of DIBAL-H promoted de-
O-methylation was proposed [9] in our previously study (Scheme 2). In this mechanism, it was thought that two
oxygen atoms at O-2A and O-3B were necessary to form the chelating intermediates 9–13.
In order to further confirm this mechanism, two mono-deoxy-permethylated b-CD derivatives (16 and 19) were
logically designed and synthesized regioselectively from the major intermediate 2 (Scheme 3) [9].
When transformation of 7 into 14 was performed with O-phenyl chlorothioformate in the presence of DMAPat 80 8C,
an unexpected carbonyl compound 15 was obtained in 82% yield. This compound was characterized by 13C NMR
spectrum, which showed a signal at d 151.48 ppm (C O), instead of a signal at d 195.76 ppm for C S group. The
replacement of C S group by C O group was probably due to the presence of oxygen in the reaction medium. In order to
get the desired compound, a similar reaction was performed under an inert atmosphere condition which gave a mixture of
14 and 15 in a ratio of 71:28, according to HPLC analysis (CH3OH/H2O:60/40 by volume). Having the same Rf (0.43,
eluent:cyclohexane/acetone = 1:1) on TLC, the separation by chromatography was not feasible at this stage. This
phenomenonwasfirstreportedbyRemyetal. [10], whoobservedina similarreactiontheformationofasideproductwith
replacement of C S group by C O group in 8.3% yield. Since these two compounds could not be separated, further
deoxygenation of 14 was performed directly from the mixture of 14 and 15 according to the classical Barton–McCombie
conditions (Bu3SnH, AIBN, 100 8C) [11] to give the compound 16 in 54% yield, compound 15 being recovered in 35%
B
yield. 1H NMR spectrum of 16 showed two sets of peaks at d 1.88 and 2.32 ppm, corresponding to two protons at C3 ,
while 13C NMR spectrum displayed a signal at d 30.84 ppm, corresponding to C3 .
B
The same reaction was also carried out for compound 8. In contrast with reaction of 7, the two compounds (17 and
18) could be separated out by chromatography and thus characterized respectively by 1H, 13C, 1H–1H COSY, 1H–13C
COSY NMR and HRMS. When the reaction was carried under the air, the ratio of 17:18 = 2:1; if the reaction was
performed under nitrogen, the ratio of 17:18 = 10:1. Similarly, deoxygenation of 17 provided compound 19 in good
A
yield. 1H NMR spectrum of 19 showed two sets of peaks at d 1.73 and 2.27 ppm, corresponding to two protons at C2
,
while 13C NMR spectrum displayed a signal at d 34.65 ppm, corresponding to C2A. The detailed data for NMR and
HRMS can be found as supporting information in this journal.
With the two mono functionalized per-O-methylated b-CDs (16 and 19) in hand, we turned our attention to
investigation of their behaviors upon action of DIBAL-H. The reaction conditions were that used for preparing the
2A,3B-dihydroxy-per-O-methylated b-CD 3 [6] as well as de-O-methylation reaction of compound 7 and 8 [9]. Unlike
compound 7, no new product was formed on TLC analysis when the two deoxy-derivatives were treated for 18 h at
0 8C in toluene with a commercially available DIBAL-H (0.2 M, 9 equiv.) and the recovered product was
characterized by NMR as the starting material (Scheme 4). This result indicates that O-2A and O-3B of per-O-
methylated b-CD were necessary for DIBAL-H promoted double 2A,3B-de-O-methylation reaction, which agreed well
with our previously proposed mechanism [9].
Combined with our previous studies, the DIBAL-H promoted regioselective bis-de-O-methylation of 1 may include
two steps: the first step would consist in the formation of the complex of 1 with DIBAL-H slowly between two

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S.L. Xiao et al. / Chinese Chemical Letters 23 (2012) 1315–1318
Scheme 4. DIBAL-H promoted de-O-methylation reactions of compounds 16 and 19, as well as compounds 7 and 8 [9].
methoxy groups at C-2A and C-3B located on two adjacent sugar units, followed by de-O-methylation at C3B; the
second step would be the formation of the complex of 13 with an excess of DIBAL-H quickly between the methoxy
group at C-2A and the hydroxyl group at C-3B, followed by de-O-methylation at C2A to afford almost quantitatively the
2A,3B-diol 3. In both cases, the presence of a C-2 methoxy group and a C-3 methoxy or hydroxyl group are necessary
for complex formation. Being in absence of C-3 methoxy group, compound 16 could not form an appropriate complex,
thus failed to give rise to further de-O-methylation. The same explanation could be applied to compound 19, in which
the methoxy group at C-2 was replaced by a hydrogen atom, the complex of transition state could not be formed,
therefore no de-O-methylation occurred.
Acknowledgments
Financial support of this study from CNRS is gratefully acknowledged. The authors express their gratitude to
Cyclolab (Hungary) for a generous supply of starting material. S.L. Xiao thanks the China Scholarship Council for a
PhD fellowship.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.cclet.2012.10.023.
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