O-xylylene protecting group in carbohydrate chemistry: Application to the regioselective protection of a single vic-diol segment in cyclodextrins

Article abstract of DOI:10.1021/jo302178f

A systematic study of the suitability of α,α′-dibromo-o- xylene as a reagent for cyclic o-xylylene protection of vic-diols in different monosaccharide substrates is reported. The installation of this protecting group, formally equivalent to a di-O-benzyla

Full text of DOI:10.1021/jo302178f

Article
pubs.acs.org/joc
o‑Xylylene Protecting Group in Carbohydrate Chemistry: Application
to the Regioselective Protection of a Single vic-Diol Segment in
Cyclodextrins
Patricia Balbuena,† Rita Goncalves-Pereira,‡ Jose L. Jimenez Blanco,*,‡ M. Isabel García-Moreno,‡
̧
́
́
David Lesur,§ Carmen Ortiz Mellet,‡ and Jose M. García Fernandez*,†
́
́
†Instituto de Investigaciones Químicas (IIQ), CSIC−Universidad de Sevilla, c/Amer
́
ico Vespucio 49, Isla de la Cartuja, E-41092
Sevilla, Spain
‡Departamento de Química Organ
Spain
́
ica, Facultad de Química, Universidad de Sevilla, c/Profesor García Gonzalez 1, E-41012 Sevilla,
́
§Laboratoire des Glucides UMR6219, Universite
́
Picardie Jules Verne, 33 rue St. Leu, 80039 Amiens, France
S
* Supporting Information
ABSTRACT: A systematic study of the suitability of α,α′-
dibromo-o-xylene as a reagent for cyclic o-xylylene protection
of vic-diols in different monosaccharide substrates is reported.
The installation of this protecting group, formally equivalent to
a di-O-benzylation reaction, proceeds with good regioselectiv-
ity toward 1,2-trans-diequatorial diol systems in pyranose and
furanose rings. Initially, the benzyl ether-type derivative of the
more acidic hydroxyl is preferentially formed. Subsequent
intramolecular etherification toward the equatorial-oriented
vicinal OH is kinetically favored. The methodology has been
implemented for the simultaneous protection of the secondary
O-2 and O-3 positions of a single D-glucopyranosyl unit in
cyclic oligosaccharides of the cyclodextrin (CD) family (cyclomaltohexa-, -hepta-, and -octaose; α, β, and γCD).
metal complex (e.g., tin, copper and silver) mediated
INTRODUCTION
■
benzylation12−16 are methods developed for selective benzyl
protection. Alternatively, regioselective debenzylation of highly
O-benzylated carbohydrates can be used for the preparation of
partially benzylated sugars in specific cases. It has been effected
with stoichiometric amounts of strong, sensitive Lewis acids
such as SnCl4 or TiCl4,17 excess alumanes (DIBAL or TRIBAL)
at high temperatures18−20 or under microwave activation,21
BCl3 or I2/Et3SiH at low temperature,22,23 and excess CrCl2
and LiI at high temperature.24 None of these methods rely on
the differential reactivity of the benzylating or debenzylating
reagent toward 1,2-diol moieties, a goal that generally requires
the formation of cyclic derivatives.1 Considering the versatility
of O-benzyl protection and the frequent need for selectively
blocking vic-diol segments in carbohydrate chemistry, the
implementation of a methodology for the installation of a cyclic
benzyl ether-type protecting group was highly desired.
Protecting group strategies are incorporated into most
approaches toward the synthesis of natural products and
other molecule targets.1,2 The choice of appropriate protecting
group strategies is especially delicate in the design and
execution of complex multifunctional molecules in order to
minimize the manipulation steps. The need for selective
protection of hydroxyl groups for the synthetic production of
carbohydrates represents a paradigmatic example in this
sense.3−5 Among the battery of hydroxyl protecting groups
currently employed in organic chemistry, benzyl ethers have
proven very useful.1 They can withstand a wide range of
reaction conditions used during manipulation of other
protecting groups such as esters, silyl ethers, carbamates, or
acetals and can be removed under mild conditions.1,6 However,
O-benzylation of polyols systems generally proceeds with low
regioselectivity, which is a quite serious drawback frequently
encountered in carbohydrate chemistry.
Full benzylation of carbohydrate hydroxyl groups is generally
trivial, although it may face some difficulties and require
optimized conditions in the case of relatively large oligosac-
charides.7 Regioselective partial benzylation is, however, much
less evident and requires ingenious strategies. For example,
regioselective reductive ring opening of the 4,6-di-O-benzyli-
dene group,8−10 transient protection with silyl ether,11 and
The use of di-O-o-xylylene structural elements for the cyclic
protection of 1,2- and 1,3-diols was first published in 1989 by
Poss and Smyth.25 This masking device can be introduced
under basic conditions by using α,α′-dibromo-o-xylene as
precursor and removed by hydrogenolysis (Scheme 1).
Received: October 8, 2012
Published: January 21, 2013
© 2013 American Chemical Society
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Such difference should result in preferred cyclic o-
xylylenation patterns, significantly broadening the utility of
the reaction in carbohydrate chemistry. To explore the
potential of the cyclic o-xylylene group for regioselective
protection, a systematic study on different monosaccharide
substrates differing in the number and orientation of hydroxyl
groups has now been undertaken. The methodology has been
further applied to the regioselective functionalization of the
secondary rim of cyclodextrins (CDs), a family of cyclic torus-
shaped oligosaccharides composed of α-(1→4)-linked gluco-
pyranosyl units that are widely used as host moieties and
Scheme 1. Protection and Deprotection of a vic-Diol by an o-
Xylylene Group
Protection of a vicinal diol segment by a cyclic xylylene group,
instead of two independent benzyl ethers, results in a
considerable efficiency improvement in terms of atom
economy.26
nanometric platforms in supramolecular chemistry.34
A
preliminary communication of this aspect was already
published35 and demonstrated application in the construction
of fluorescently active self-assembling systems.36−38 A full
account of the scope and limitations of the strategy is now
presented.
Inspired by the concept of intramolecular delivery of vicinal
functionality,27 we considered the use of the cyclic o-xylylene
group for benzyl-type protection of vic-diols in carbohydrate
chemistry. We hypothesized that differences in the acidity of
the hydroxyl groups might trigger preferential benzyl-type
protection at specific positions.28 Intramolecular etherification
should then be kinetically favored over intermolecular ether
bridging reactions. Moreover, regioselectivity might arise due to
configurational and conformational bias. In an early work, this
strategy was successfully applied to the multistep synthesis of D-
fructose derivative 3, a key intermediate in the high-yielding
synthesis of glycosidase inhibitors of the polyhydroxylated
pyrrolidine family (DMDP and DGDP), from precursor 1
(Scheme 2).29 Direct o-xylylenation of β-D-fructopyranose or
RESULTS AND DISCUSSION
■
Evaluation of the Cyclic o-Xylylene Group for
Protection of Vicinal Diols in Monosaccharides. Protec-
tion of 1,2-Diols in Pyranose Derivatives. First, we have
examined the cyclic diether protection of the trans-diequatorial
vicinal hydroxy groups 2-OH and 3-OH in methyl 4,6-O-
benzylidene-α- and β-D-glucopyranosides 4 and 539 by
treatment with 1,2-bis(bromomethyl)benzene (1.1 equiv) in
the presence of sodium hydride (5 equiv; Scheme 3). In the
Scheme 3. Xylylenation of Benzylidene Glucopyranoside
Derivatives 4 and 5
Scheme 2. Synthesis of 3 via Intramolecular Ring Closing of
Xylylenation
-fructofuranose30−32 and β-D-arabinose33 vic-diol derivatives has
further been accomplished, which found application in the
synthesis of complex oligosaccharides.
In the above commented diol examples, the regioselectivity
of the initial benzylation step and the preferred sense of the
cyclization reaction was irrelevant. Nevertheless, geometrical
considerations suggested that the o-xylylene tether would
provide the appropriate distance restriction to favor 1,2- versus
1,3-O-(o-xylylene) protection in more complex polyol systems.
Additionally, the diequatorial disposition of the oxygen atoms
at the eight-membered dioxacyclooctene-type ring must be
favored as compared to the diaxial orientation (Figure 1).
case of α-D-glucopyranoside 4, the monomeric cyclic diether
derivative 6 and the dimeric macrocyclic derivative 7 (92%
altogether) were obtained in 6:1 relative proportion, whereas
the monomeric o-xylylene derivative 8 (80% yield) was the only
1
product isolated from the β-anomer 5. MS, H and 13C NMR,
and 1D NOESY experiments supported the symmetric
structure of dimer 7, with two monosaccharide units connected
through their O-2 and O-3 positions by two o-xylylene bridges.
1D NOESY experiments confirmed that the o-xylylene
segments connected identical positions at both glucopyranoside
units.
When the xylylenation reaction was conducted on the α-D-
galacto derivative 9,39 intramolecular cyclization reaction
leading to the trans-diequatorial cyclic diether 10 (42%) was
Figure 1. trans-Diequatorial (A) and trans-diaxial (B) dispositions of
oxygens on a cyclic o-xylylene group.
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also favored over intermolecular bridging (27%). This dimer
fraction consisted of a 1:1 mixture of two bicyclic structures, 11
and 12, that could be separated and characterized in pure form.
MS and NMR data and 1D NOESY experiments confirmed
that compounds 11 and 12 corresponded to dimeric and
symmetric structures in which two o-xylylene bridges connect
identical (C-2C-2′ and C-3C-3′) or different positions (C-
2C-3′ and C-3C-2′) at both sugar rings, respectively. No
side products arising from higher cyclic or linear oligomers
were observed (Scheme 4).
between the α-D-gluco 4 and α-D-manno epimer 13 has to be
ascribed to the configurational shift at C-2 position.
In order to evaluate the potential for regioselective o-
xylylenation, triol systems were next assayed. Methyl 6-O-trityl
glycopyranosides with α-D-gluco (15),41 β-D-gluco (16),41 α-D-
manno (21),42 and α-D-galacto (22)43 configurations were used
as model pyranoid substrates for this purpose. Reactions were
carried out in DMF using 2.6 equiv of sodium hydride and 1.3
equiv of 1,2-bis(bromomethyl)benzene. The α-D-gluco deriva-
tive 15 afforded the ether-type protected adducts 17 and 18 in
5.25:1 relative proportion (50% global yield). In both
compounds the cyclic diether segment connects O-2 and O-3
positions. In the case of the β-anomer 16, the 2,3-O-(o-
xylylene) derivative (19, 39%) was also the major reaction
product, but a significant proportion of the 3,4-O-regioisomer
20 was also formed (Scheme 6).
Scheme 4. Xylylenation of the Benzylidene
Galactopyranoside Derivative 9
Scheme 6. Xylylenation of 6-O-Trityl Glucopyranoside
Derivatives 15 and 16
The above reaction conditions were next applied to methyl
4,6-O-benzylidene-α-D-mannopyranoside (13),40 having a cis-
axial/equatorial disposition of the reacting hydroxyls (Scheme
5). The corresponding 2,3-O-(o-xylylene) derivative 14 was
The regioselectivity of the cyclic protection was reversed for
the α-D-manno derivative 21. Thus, a mixture of compounds 23
and 24, both incorporating the cyclic xylylene segment at
positions O-3 and O-4, was now obtained, with no trace of 2,3-
o-xylylene protected isomers. This result confirms the
preference for trans-1,2-diol segments of cyclic o-xylylene
protection over cis-(axial/equatorial) dispositions, overcoming
even the unfavorable steric effect that may exert the trityl group
at O-6. Finally, direct o-xylylenation of the substrate with α-D-
galacto configuration 22 led preferentially to the trans-
diequatorial cyclic diether derivatives 25 and 26. A very small
proportion of the fully protected derivative 27 involving the
axial 4-OH in the cyclic groups was also isolated (Scheme 7).
It can be postulated that the observed differences in
regioselectivity depend, besides the already mentioned higher
preference for trans-diequatorial diol orientations, on the
relative acidity of the secondary hydroxyl groups and the
nucleophilicity of the resulting alkoxide. The acidity depends
on the solvent used and is modulated by intramolecular H-
bonds while steric effects control the nucleophilicity. The
involvement of OH-2 in H-bonding with O-1 in α-D-
glucopyranosides44 renders this hydroxyl group the most acidic
in compound 15, favoring initial benzylation at this position.45
The next intramolecular etherification at O-3 is then kinetically
Scheme 5. Xylylenation of the Benzylidene
Mannopyranoside Derivative 13
obtained as the only isolable product, but in a modest 26%
yield. Most probably, formation of oligomers through
intermolecular etherification competes in this case with the
intermolecular process leading to the cyclic diether, which likely
reflects a more favorable conformational arrangement of the
condensed dioxaoctene-type ring for trans-diaxial as compared
to cis-axial/equatorial relative orientations of the vicinal
oxygens. It is worth noting that in all the benzylidene
derivatives included in this study the phenyl group adopts the
equatorial disposition, so that the difference in reactivity
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(Scheme 8). No trace of 3,5- or 3,6-di-O-cyclic diethers was
Scheme 7. Xylylenation of 6-O-Trityl Manno- and Galacto-
Pyranoside Derivatives 21 and 22
observed.
Scheme 8. Xylylenation of Isopropylidene Glucofuranoside
Derivative 28
To explore the utility of the xylylenation approach for the
protection of 1,3-diol segments of carbohydrates, a stepwise
strategy was explored. Our synthetic route started from 3-O-(o-
bromomethylbenzyl)-1,2:5,6-di-O-isopropylidene-α-D-glucofur-
anose (31), prepared from commercial 1,2:5,6-di-O-isopropy-
lidene-α-D-glucofuranose (30). Selective hydrolysis of the 5,6-
O-isopropylidene group in MeCN with aqueous iodine50
provided diol 32. Formation of the nine-membered diether
ring involving OH-5 readily took place when 32 was subjected
to benzylation conditions, affording compound 33 in moderate
yield (45%, Scheme 9).
Scheme 9. Synthesis of the 1,3-Cyclic Diether 33 by Stepwise
o-Xylylenation
favored over intermolecular reactions. Differences in acidity are
less pronounced in the case of the β-gluco anomer 16, leading
to a lower selectivity, whereas it is reversed in favor of OH-3 for
the α-manno epimer. In the α-D-galactopyranoside, both OH-2-
and OH-3 hydroxyls have similar chemical reactivity as both are
involved in cis-H-bonds with vicinal oxygens.45 Although
cyclization through OH-2 must be favored after initial
alkylation at O-3, a small proportion of the O-3,O-4 cyclic
diether is also formed.
Even though the yields on the selectively o-xylylenated
derivatives 17, 19, 20, 23, and 25 are far from optimal, they are
remarkable considering that classical benzylation with benzyl
chloride under identical reaction conditions led to very complex
mixtures of no synthetic utility. Moreover, the starting
substrates are initial building blocks of low synthetic cost.
Alternative regioselective differentiation of the three hydroxyls
is not trivial and would require elaborated multistep syntheses,
often involving tedious purification steps that handicap the
overall yield. As an example, compound 23, with selectively
protected OH-3 and OH-4 and differentiated OH-2 and OH-6
positions, is a suitable precursor for the construction of the high
mannose oligosaccharides involved in viral and bacterial
infection, characterized by α(1−2) and α(1−6) linkages,46−49
that was obtained in just two steps from commercial methyl α-
D-mannopyranoside.
Regioselective Protection of 1,2- and 1,3-Diols in
Furanose Derivatives. Furanose substrates are very well suited
to test the relative propensity of the cyclic o-xylylenation
reaction to afford either 1,2- or 1,3-diether derivatives.
Xylylenation of commercially available 1,2-O-isopropylidene-
α-D-glucofuranose 28 under the above conditions afforded
preferentially the 5,6-di-O-cyclic diether 29 in 60% yield
Application of the o-Xylylenation Reaction to the
Regioselective Functionalization of Cyclodextrins at
Their Secondary Rim. Position-selective functionalization of
cyclodextrins is critical for the development of applications as
sensors,51,52 catalysts,53−55 artificial enzymes,56,57 or drug
delivery systems58 among others. Most reported methods are
limited to primary hydroxyls.19,59−65 Only a few examples of
the preparation of mono- and bifunctionalized CDs at the
secondary rim have recently been reported.35,66−74 In view of
the results obtained on monosaccharide substrates, and
considering that OH-2 is significantly more acidic than OH-3
and OH-6 and that the hydroxyls at the secondary CD rim are
arranged in trans-diequatorial diol segments, the possibility of
statistic o-xylylenation to access selectively O-2I,O-3I-differ-
entiated derivatives of the commercially available cyclo-
maltohexa- (αCD), -hepta- (βCD), and -octaose (γCD)
seemed very appealing.
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Protection of Secondary Hydroxyls in CD Derivatives
Selectively Protected at the Primary Rim. A concern when
considering selective cyclic protection at O-2 and O-3 within
the same glucopyranoside subunit of the CD macroring was
that it could compete with the formation of the regioisomer
involving O-2 and O-3 in two consecutive monosaccharide
subunits, since the respective interatomic distances are
practically identical (Figure 2). This question was first
Scheme 10. Synthesis of the Mono-o-xylylene βCD
Derivative 37
hydroxyls of the same glucopyranosyl unit in 35 was confirmed
by a combination of TOCSY and NOESY experiments after full
O-methylation of the remaining hydroxyls (→ 36) and removal
of the silyl ether groups (→ 37). The 1D NOESY spectrum
showed NOE contacts between the pair of signals correspond-
ing to the benzyl-type protons and the signals for H-2 and H-3
located on the carbons that support the ether functionalities.
On the other hand, the COSY spectrum confirmed that these
signals belong to the same spin system, indicating that they are
located at the same D-glucopyranose residue. This remarkable
result represents the first described procedure to distinguish
two hydroxyls at a single glucose unit in cyclodextrins.
Direct Xylylenation of Native Cyclodextrins. Taking into
account the differences in the acidity of the hydroxyl groups in
native CDs (OH-2 > OH-6 > OH-3),77 pH modulation could
favor mono-2-O-alkylation in the first step of the reaction
leading to cyclic ο-xylylenation, then allowing direct (O-2I,OI-
3)-regioselective protection with no need of prior face-selective
differentiation. (Scheme 11).
Figure 2. Interatomic distances between O-2 and O-3 in two
consecutive monosaccharide subunits in α, β, and γCDs (n = 1, 2, and
3, respectively).
addressed using per-6-O-(tert-butyldimethylsilyl)-
cyclomaltoheptaose 3475 as a model compound in order to
limit the possibilities for positional isomerism. In principle, the
formation of the first ether connection on one of the secondary
hydroxyls (OH-2 or OH-3)76 should kinetically favor
subsequent intramolecular etherification. The intermolecular
reaction must be much more strongly disfavored now as
compared with monosaccharide substrates due to steric
reasons.
Several reaction conditions for o-xylylenation of 34 with 1,2-
dibromomethylbenzene, including the use of N,N-dimethylfor-
mamide (DMF) or dichloromethane as solvents and sodium
hydride (NaH), NaH/15-crown-5-ether, or a mixture of BaO/
Ba(OH)2 as bases, were assayed (Table 1).
It was concluded that reaction with 1,2-dibromomethylben-
zene (3 equiv) and NaH (6 equiv) in DMF for 15 min were the
optimal conditions, leading to compound 35 in 33% yield
(Scheme 10), with 55% of the starting material 34 being
recovered (73% yield referred to the converted product). The
location of the xylylene protecting group at the secondary
Scheme 11. General Strategy To Obtain 2,3-O-(o-Xylylene)
Derivatives on Cyclodextrins
a
Table 1. Xylylenation Assays of the βCD Derivative 34
treaction
yield of 35
base/CD (molar ratio)
NaH (2.5/1)
solvent
(h)
(%)
DMF
DMF
DMF
DMF
DMF
DMF
6
3
b
NaH (16/1)
NaH (3.6/1)
NaH (1.4/1)
NaH (6/1)
1.5
1.5
5
<3
7
b
<3
0.25
24
30
b
NaH + 1:4 BaO-Ba(OH)2·8H2O
(2.7/1)
<3
b
NaH + 4:1 BaO-Ba(OH)2·8H2O
(2.7/1)
DMF
24
<3
It is worth pointing out that differences in OH acidities are
very sensitive to the solvent and need to be carefully adjusted
for a given reaction. In our case, the use of equimolecular LDA
in DMSO was found to provide the optimal conditions for the
target transformation.35 α, β, and γCDs were thus transformed
into the corresponding 2I,3I-O-(o-xylylene) derivatives 38, 44,
NaH + 15-crown-5 (2.5/1)
NaH + 15-crown-5 (1.9/1)
DCM
DCM
24
24
7
b
<3
a
b
All assays were carried out at room temperature. Detected by ESMS
but not isolated.
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and 49 in 24−30% yields. The use of DMF instead of DMSO,
different proportions of LDA (from 0.5 to 2.0 equiv), or other
bases (NaOEt, NaH) was found detrimental for the yield of
monoxylylenated product. The utility of this strategy for
transient protection was confirmed after methylation (→ 41,
46, and 51), a transformation that is known to preserve the
water solubility and inclusion capabilities of the CDs. The o-
xylylene cyclic ether could then be removed by hydrogenolysis
in the presence of formic acid to give the corresponding diols
42, 47, and 52 in good yields (60−94%). The availablility of the
diol system for further chemical manipulation was confirmed by
respectively, only the 2I,3I-cyclic ether regioisomer (38, 44,
and 49) was obtained in the three cases using the above
protocol, and no dimerization product was detected. However,
mass spectrometry analysis of the reaction mixture unraveled
the presence of small proportions of monoalkylated derivatives
(39, 40, 45, and 50) that were isolated by semipreparative
HPLC using a C-18 column as stationary phase and MeCN/
H2O mixtures as mobile phase. The 13C NMR spectra of
derivatives 39, 45, and 50 showed a significant shield of the C-
3I signal (72.1−72.5 ppm) in comparison with the correspond-
ing diprotected derivatives 38, 44, and 49 (78.4−81.7).
However, the C-2I signals of derivatives 39, 45, and 50 did
not display remarkable changes. This fact is in agreement with
the absence of the ether connection at O-3I and its presence at
O-2I. In the case of compound 40, both O-3I and O-2I signals
were shielded, in agreement with the presence of the ether
substituent at the primary O-6I position.
1
acetylation (→ 43, 48, and 53; Scheme 12). Their H NMR
Scheme 12. Direct Xylylenation Reactions of Cyclodextrins
and Synthesis the of Di-2I,3I-O-acetylated Derivatives 43, 48,
and 53
CONCLUSIONS
■
In summary, a systematic study of the suitability of the cyclic o-
xylylene group for protection of diols in different mono-
saccharide substrates has been conducted. It is particularly
noteworthy that the new methodology provides alternative
opportunities for selective 1,2- or 1,3-diol protection in
pyranose and furanose derivatives. o-Xylylenation of 1,2-diols
is kinetically favored, allowing regioselective protection in
polyol systems. Moreover, 1,2-trans-diequetorial diols react
preferentially over 1,2-cis-(axial/equatorial) diols. Further
selectivity can be achieved by taking into consideration the
difference in the acidity of the available OH groups. Application
of these conclusions to the selective protection of a single vic-
diol system at the secondary rim of native cyclodextrins
illustrates the potential of this approach. Given the general
character of the strategies here reported, further applications in
oligosaccharide synthetic schemes, leading to an improved
atom economy, are expected. Work in that direction is currently
sought in our laboratories.
EXPERIMENTAL SECTION
■
General Chemical Reagents and Methods. Reagents and
solvents were purchased from commercial sources and used without
further purification. Methyl 4,6-O-benzylidene-D-gluco- and -galacto-
pyranosides 4, 5, and 9 were prepared by treatment of the
corresponding methyl glycoside precursors with benzaldehyde in
presence of ZnCl2 using the reported route method.39 The
corresponding α-D-manno derivative 13 was prepared from methyl
α-D-mannopyranoside by reaction with benzaldehyde dimethyl acetal
under catalysis with camphorsulfonic acid.40 Methyl 6-O-triphenyl-
methyl-D-glycopyranosides with α-D-gluco 15,41 β-D-gluco16,41 α-D-
manno 21,42 and α-D-galacto 2243 configurations and per-6-O-(tert-
butyldimethylsilyl)cyclomaltoheptaose 3474 were obtained according
to literature procedures. 1,2-O-Isopropylidene-α-D-glucofuranose 28
and 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 30 were commer-
cially available compounds. Optical rotations were measured with a
polarimeter, using a sodium lamp (λ = 589 nm) at 22 °C in 1 cm or 1
dm tubes. IR spectra were recorded on a FTIR instrument. NMR
experiments were performed at 300 (75.5), 400 (100.6), and 500
(125.7) MHz. 1D TOCSY as well as 2D COSY and HMQC
experiments were carried out to assist in signal assignment. In the
FABMS spectra, the primary beam consisted of Xe atoms with
maximun energy of 8 keV. The samples were dissolved in m-
nitrobenzyl alcohol or thioglycerol as the matrices, and the positive
ions were separated and accelerated over a potencial of 7 keV. NaI was
added as cationizing agent. In the CIMS spectra, isobutane was used as
the reactive gas (500 mA, 8 kV). MALDI-TOF mass spectra were
spectra showed the expected chemical shifts of the H-2I (4.76−
4.72 ppm) and H-3I (5.61−5.51 ppm). The results
demonstrated the versatility of the monoxylylenation protec-
tion to obtain CD derivatives with facial differentiation at the
secondary rim of one glucose unit.
Although the number of regioisomers for di-O-protection of
α, β, and γCDs, including di-O-benzylation, in the absence of
intramolecularly favored processes are 27, 33, and 36,
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acquired on a spectrometer operating in the positive-ion mode with an
accelerating voltage of 28 keV. Samples were dissolved in MeCN at
mM concentration and mixed with a standard solution of α-cyano-4-
hydroxycinnamic acid (α-cyano; 20 mg mL−1 in 25:25:1 MeOH/
H2O/AcOH, 2 μL); 1 μL of the mixture was loaded onto the target
plate and then allowed to air-dry at room temperature. For ESI mass
spectra, 0.1 pM sample concentrations were used, the mobile phase
consisting of 50% aq MeCN at 0.1 mL min−1. HRMS spectra were
recorded in a QTRAP mass spectrometer (hybrid triple quadrupole/
linear ion trap mass spectrometer). Thin-layer chromatography was
performed on precoated TLC plates, silica gel 30F-245, with
visualization by UV light and by carrying with 10% H2SO4 or 0.2%
w/v cerium(IV) suphate-5% ammonium molybdate in 2 M H2SO4.
Column chromatography was performed on chromagel (silice 60
AC.C 70−200 μm). An analytical HPLC system equipped with a
pump and an ELSD detector was used. The separation was performed
at room temperature on an analytical column of ES 5μ (5 μm particle
size, 250 mm × 4.6 mm). The mobile phase consisted of water
(solvent A) and MeCN (solvent B). The composition of the mobile
phase varied during the run according to a linear gradient as follows:
A−B: 0 min (0:100, v/v), 0−50 min (50:50, v/v) at a flow rate of 1.0
mL/min. Data acquisition and processing were performed with the
instrument software. A preparative HPLC system equipped with a
LC4000 pump and an ELSD detector was used. The separation was
performed at room temperature on a column of ES 5μ (5 μm particle
size, 250 mm × 10 mm). The mobile phase consisted of water (solvent
A) and MeCN (solvent B). The composition of the mobile phase
varied during the run according to a linear gradient as follows: A−B, 0
min (0:100, v/v), 0−50 min (50:50, v/v) at a flow rate of 4.7 mL/min.
Data acquisition and processing were performed with the instrument
software. Elemental analyses were performed with a microanalysis
measuring apparatus.
General Procedure for o-Xylylene Protection of Methyl 4,6-
O-Benzylidene-D-Glycopyranosides (6−8, 10−12, and 14). To a
solution of the corresponding methyl 4,6-O-benzylidene-D-glycopyr-
anoside 4, 5, 9, and 13 (0.1 g, 0.35 mmol) in dry DMF (6 mL) was
added NaH (60% in mineral oil, 70 mg, 1.75 mmol), and the
suspension was stirred at room temperature for 15 min. 1,2-
Dibromomethylbenzene (102 mg, 0.385 mmol) was then added, and
the reaction mixture was further stirred for 30 min at room
temperature. After quenching with MeOH (5 mL), the solvent was
removed under reduced pressure. H2O (10 mL) and 1:1 toluene/Et2O
(15 mL) were added, and the organic layer was separated, washed with
brine (2 × 10 mL), dried (MgSO4), filtered, and concentrated. The
resulting residue was purified by column chromatography using 1:2
EtOAc/petroleum ether as eluent.
(Ph), 101.3 (CHPh), 99.2 (C-1), 82.0 (C-4), 79.5 (C-2), 79.3 (C-3),
72.9, 71.2 (CH2Ph), 69.3 (C-6), 62.4 (C-5), 55.4 (OMe); FABMS m/
z 791 (10%, [M + Na]+). Anal. Calcd for C44H48O12: C, 68.74; H,
6.29. Found: C, 68.63; H, 6.06.
Methyl 4,6-O-Benzylidene-2,3-O-(o-xylylene)-β-D-glucopyrano-
side (8). Amorphous solid. Yield: 109 mg (80%); Rf 0.82 (1:2
EtOAc/cyclohexane); [α]D −10.5 (c 1.0, DCM); UV (DCM) 248 nm
1
(εmM 10.3); IR (ATR) 3053, 2923, 1453, 1363, 1085, 750 cm−1; H
NMR (300 MHz, CDCl3) δ 7.51−7.17 (m, 9 H, Ph), 5.52 (s, 1 H,
CHPh), 5.15, 5.13 (2 d, 2 H, 2JH,H = 13.8 Hz, CHPh), 5.03, 4.95 (2 d,
2 H, CH2Ph), 4.37 (d, 1 H, J1,2 = 7.5 Hz, H-1), 4.33 (dd, 1 H, J6a,6b
=
10.5 Hz, J5,6a = 5.1 Hz, H-6a), 3.78 (t, 1 H, J5,6b = 9.3 Hz, H-6b), 4.02
(t, 1 H, J2,3 = J3,4 = 9.3 Hz, H-3), 3.55 (t, 1 H, J4,5 = 9.3 Hz, H-4), 3.45
(dd, 1 H, H-2), 3.39 (td, 1 H, H-5), 3.44 (s, 3 H, OMe); 13C NMR
(75.5 MHz, CDCl3) δ 137.2−126.3 (Ph), 103.9 (CHPh), 101.7 (C-1),
80.9 (C-4), 79.8.3 (C-2,3), 72.8, 72.6 (CH2Ph), 68.7 (C-6), 66.0 (C-
5), 57.5 (OMe); ESIMS m/z 407 [M + Na]+. Anal. Calcd for
C22H24O6: C, 68.74; H, 6.29. Found: C, 68.70; H, 6.35.
Methyl 4,6-O-Benzylidene-2,3-O-(o-xylylene)-α-D-galactopyrano-
side (10). Amorphous solid. Yield: 58 mg (42%); Rf 0.31 (1:1 EtOAc/
1
petroleum ether); [α]D +193.5 (c 1.0, DCM); H NMR (500 MHz,
CDCl3) δ 7.46−7.09 (m, 9 H, Ph), 5.57 (s, 1 H, CHPh), 5.14, 5.11 (2
d, 2 H, 2JH,H = 8.0 Hz, CHPh), 5.05 (s, 2 H, CH2Ph), 5.02 (d, 1 H, J1,2
= 2.5 Hz, H-1), 4.39 (d, 1 H, J3,4 = 3.5 Hz, H-4), 4.26 (dd, 1 H, J6a,6b
=
12.5 Hz, J5,6a = 1.5 Hz, H-6a), 4.14 (dd, 1 H, J2,3 = 10.5 Hz, H-2), 4.09
(t, 1 H, J5,6b = 1.5 Hz, H-6b), 4.04 (dd, 1 H, H-3), 3.87 (bs, 1 H, H-5),
3.45 (s, 3 H, OMe); 13C NMR (125.7 MHz, CDCl3) δ 138.0−126.4
(Ph), 101.0 (CHPh), 99.7 (C-1), 77.3 (C-2), 77.0 (C-3), 76.1 (C-4),
74.6, 73.8 (CH2Ph), 69.3 (C-6), 62.8 (C-5), 55.5 (OMe); CIMS m/z
385 (5%, [M + H]+), 384 (15%, [M]+), 353 (30%, [M − OMe]+).
Anal. Calcd for C22H24O6: C, 68.74; H, 6.29. Found: C, 68.47; H, 6.23.
Cyclobis[methyl 4,6-O-benzylidene-α-D-galactopyranoside]-
2I,2II:3I,3II-di-O-(o-xylylene) (11). Amorphous solid. Yield: 38 mg
(14%); Rf 0.51 (2:1 EtOAc/petroleum ether); [α]D +117.4 (c 1.2,
1
DCM); H NMR (500 MHz, CDCl3) δ 7.36−7.17 (m, 18 H, Ph),
5.52 (s, 2 H, CHPh), 4.99 (d, 2 H, J1,2 = 3.0 Hz, H-1), 4.98, 4.94 (2 d,
2
2
4 H, JH,H = 11.5 Hz, CHPh), 4.60, 4.58 (2 d, 4 H, JH,H = 7.0 Hz,
CHPh), 4.28 (d, 2 H, J3,4 = 3.5 Hz, H-4), 4.24 (bd, 2 H, J6a,6b = 11.5
Hz, H-6a), 4.09 (dd, 2 H, J2,3 = 10.0 Hz, H-2), 4.04 (bd, 2 H, H-6b),
3.98 (t, 2 H, H-3), 3.53 (bs, 2 H, H-5), 3.41 (s, 6 H, OMe); 13C NMR
(125.7 MHz, CDCl3) δ 138.1−126.3 (Ph), 100.9 (CHPh), 99.3 (C-1),
75.8 (C-2,3), 74.2 (C-4), 71.2 (CH2Ph), 69.5 (C-6), 69.3 (CH2Ph),
62.4 (C-5), 55.5 (OMe); FABMS m/z 791 (100%, [M + Na]+). Anal.
Calcd for C44H48O12: C, 68.74; H, 6.29. Found: C, 68.49; H, 6.18.
Cyclobis[methyl 4,6-O-benzylidene-α-D-galactopyranoside]-
2I,3II:3I,2II-di-O-(o-xylylene) (12). Amorphous solid. Yield: 35 mg
(13%); Rf 0.30 (2:1 EtOAc/petroleum ether); [α]D +64.9 (c 1.0,
Methyl 4,6-O-Benzylidene-2,3-O-(o-xylylene)-α-D-glucopyrano-
side (6). Amorphous solid. Yield: 108 mg (79%); Rf 0.46 (1:2
1
DCM); H NMR (500 MHz, CDCl3) δ 7.49−7.15 (m, 18 H, Ph),
1
EtOAc/petroleum ether); [α]D +109.5 (c 1.0, DCM); H NMR (500
2
5.50 (s, 2 H, CHPh), 5.03, 4.52 (2 d, 4 H, JH,H = 11.6 Hz, CHPh),
MHz, CDCl3) δ 7.53−7.14 (m, 9 H, Ph), 5.53 (s, 1 H, CHPh), 5.15,
5.00 (2 d, 2 H, 2JH,H = 14.0 Hz, CHPh), 5.08 (s, 2 H, CH2Ph), 4.87 (d,
1 H, J1,2 = 4.0 Hz, H-1), 4.28 (dd, 1 H, J6a,6b = 10.5 Hz, J5,6a = 5.0 Hz,
2
4.93, 4.62 (2 d, 4 H, JH,H = 11.9 Hz, CHPh), 4.90 (d, 2 H, J1,2 = 3.3
Hz, H-1), 4.35 (d, 2 H, J3,4 = 2.8 Hz, H-4), 4.27 (d, 2 H, J6a,6b = 12.3
Hz, H-6a), 4.07 (m, 4 H, H-2, H-6b), 3.98 (dd, 2 H, J2,3 = 10.0 Hz, H-
3), 3.64 (bs, 2 H, H-5), 3.38 (s, 6 H, OMe); 13C NMR (125.7 MHz,
CDCl3) δ 137.9−126.3 (Ph), 101.1 (CHPh), 99.2 (C-1), 75.9 (C-2),
75.6 (C-3), 74.5 (C-4), 71.1, 69.6 (CH2Ph), 69.5 (C-6), 62.5 (C-5),
55.5 (OMe); FABMS m/z 791 (5%, [M + Na]+). Anal. Calcd for
C44H48O12: C, 68.74; H, 6.29. Found: C, 68.79; H, 6.01.
H-6a), 4.02 (t, 1 H, J2,3 = J3,4 = 9.0 Hz, H-3), 3.84 (ddd, 1 H, J5,6b
=
10.5 Hz, J4,5 = 9.0 Hz, H-5), 3.71 (t, 1 H, H-6b), 3.63 (dd, 1 H, H-2),
3.53 (t, 1 H, H-4), 3.44 (s, 3 H, OMe); 13C NMR (125.7 MHz,
CDCl3) δ 137.3−126.4 (Ph), 101.9 (CHPh), 99.1 (C-1), 80.5 (C-4),
80.3 (C-2), 78.1 (C-3), 73.6, 73.1 (CH2Ph), 69.0 (C-6), 62.1 (C-5),
55.2 (OMe); CIMS m/z 385 (30%, [M + H]+), 384 (55%, [M]+), 353
(20%, [M − OMe]+). Anal. Calcd for C22H24O6: C, 68.74; H, 6.29.
Found: C, 68.72; H, 6.56.
Methyl 4,6-O-Benzylidene-2,3-O-(o-xylylene)-α-D-mannopyrano-
side (14). Amorphous solid. Yield: 35 mg (26%); Rf 0.58 (1:2 EtOAc/
cyclohexane); [α]D +50.6.5 (c 1.0, DCM); UV (DCM) 228 nm (εmM
Cyclobis[methyl 4,6-O-benzylidene-α-D-glucopyranoside]-
2I,2II:3I,3II-di-O-(o-xylylene) (7). Amorphous solid. Yield: 35 mg
(13%); Rf 0.32 (1:2 EtOAc/petroleum ether); [α]D +53.8 (c 0.8,
1
3.2); IR (ATR) 2914, 1459, 1376, 1089, 740 cm−1; H NMR (300
MHz, CDCl3) δ 7.57−7.11 (m, 9 H, Ph), 5.90 (2 d, 2 H, 2JH,H = 11.5
Hz, CHPh), 5.68 (s, 1 H, CHPh), 5.43, 4.72 (2 d, 2 H, 2JH,H = 15.9 Hz,
CHPh), 4.66 (s, 1 H, H-1), 4.32−4.24 (m, 2 H, H-6a, H-4), 4.08 (dd,
1 H, J2,3 =3.0 Hz, J3,4 = 9.9 Hz, H-3), 3.94 (t, 1 H, J6a,6b = J5,6b = 10.5
Hz, H-6b), 3.91−3.85 (m, 2 H, H-2, H-5), 3.25 (s, 3 H, OMe); 13C
NMR (75.5 MHz, CDCl3) δ 140.3−126.2 (Ph), 102.4 (CHPh), 101.4
(C-1), 78.8 (C-3), 77.3 (C-4), 71.7 (CH2Ph), 71.6 (C-2), 70.9
(CH2Ph), 68.9 (C-6), 63.7 (C-5), 54.9 (OMe); ESIMS m/z 407 [M +
1
DCM); H NMR (500 MHz, CDCl3) δ 7.34−7.12 (m, 18 H, Ph),
2
5.56 (s, 2 H, CHPh), 5.02, 4.78 (2 d, 4 H, JH,H = 11.5 Hz, CHPh),
2
4.95, 4.67 (2 d, 4 H, JH,H = 12.0 Hz, CHPh), 4.86 (d, 2 H, J1,2 = 3.5
Hz, H-1), 4.31 (dd, 2 H, J6a,6b = 10.0 Hz, J5,6a = 5.0 Hz, H-6a), 4.07 (t,
2 H, J2,3 = J3,4 = 9.0 Hz, H-3), 3.86 (ddd, 2 H, J5,6b = 10.0 Hz, J4,5 = 9.0
Hz, H-5), 3.74 (t, 2 H, H-6b), 3.64 (t, 2 H, H-4), 3.62 (dd, 2 H, H-2),
3.45 (s, 6 H, OMe); 13C NMR (125.7 MHz, CDCl3) δ 137.4−126.1
1396
dx.doi.org/10.1021/jo302178f | J. Org. Chem. 2013, 78, 1390−1403

The Journal of Organic Chemistry
Article
Na]+. HREIMS calcd for C22H24O6 385.1651, found 385.1641. Anal.
Calcd for C22H24O6: C, 68.74; H, 6.29. Found: C, 68.91; H, 6.40.
General Procedure for o-Xylylene Protection of Methyl 6-O-
Triphenylmethyl-D-glycopyranosides (17−20 and 23−27). To a
solution of methyl 6-O-triphenylmethyl-D-glycopyranoside 15, 16, 21,
and 22 (50 mg, 0.115 mmol) in dry DMF (2.3 mL) at 0 °C under Ar
atmosphere was added NaH (60% in mineral oil, 12 mg, 0.3 mmol),
and the suspension was stirred at room temperature for 15 min. Then,
a solution of 1,2-dibromomethylbenzene (39.5 mg, 0.15 mmol) in dry
DMF (1 mL) was added dropwise, and the mixture was stirred for 1 h
at room temperature. Further treatment as described for 6−8 and
column chromatography using 1:4 → 1:2 EtOAc/petroleum ether
containing 0.5% of Et3N as eluent gave 17−20 and 23−27.
Methyl 6-O-Triphenylmethyl-3,4-O-(o-xylylene)-α-D-mannopyra-
noside (23). Amorphous solid. Yield: 13 mg (21%); Rf 0.71 (1:4
1
EtOAc/petroleum ether); [α]D +23.9 (c 1.0, CHCl3); H NMR (500
MHz, CDCl3) δ 7.50−7.11 (m, 19 H, Ph), 5.74, 4.57 (2 d, 2 H, 2JH,H
=
2
12.1 Hz, CHPh), 5.42, 4.68 (2 d, 2 H, JH,H = 15.4 Hz, CHPh), 4.63
(d, 1 H, J1,2 = 1.5 Hz, H-1), 4.02 (t, 1 H, J3,4 = J4,5 =9.4 Hz, H-4), 3.79
(m, 3 H, H-2, H-3, H-5), 3.48 (d, 2 H, J5,6 = 5.2 Hz, H-6), 3.35 (s, 3 H,
OMe), 2.96 (s, 1 H, OH); 13C NMR (75.5 MHz, CDCl3) δ 143.6−
126.5 (Ph), 100.3 (C-1), 87.1 (CPh3), 81.3 (C-2), 71.4 (CH2Ph), 70.8
(C-5), 70.4 (CH2Ph), 70.3 (C-3), 68.2 (C-4), 65.2 (C-6), 54.6
(OMe); FABMS m/z 561 (20%, [M + Na]+). Anal. Calcd for
C34H34O6: C, 75.82; H, 6.36. Found: C, 75.79; H, 6.20.
Methyl 2-O-(o-Bromomethylbenzyl)-6-O-triphenylmethyl-3,4-O-
(o-xylylene)-α-D-mannopyranoside (24). Amorphous solid. Yield:
14 mg (17%); Rf 0.46 (1:4 EtOAc/petroleum ether); [α]D +60.9 (c
Methyl 6-O-Triphenylmethyl-2,3-O-(o-xylylene)-α-D-glucopyra-
noside (17). Amorphous solid. Yield: 26 mg (42%); Rf 0.41 (1:2
1
1
1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.36−7.13 (m, 23 H,
EtOAc/petroleum ether); [α]D +37.2 (c 1.0, CHCl3); H NMR (500
Ph), 5.83, 4.63 (2 d, 2 H, 2JH,H = 12.0 Hz, CHPh), 5.47, 4.70 (2 d, 2 H,
2JH,H = 15.2 Hz, CHPh), 4.94, 4.39 (2 d, 2 H, 2JH,H = 10.4 Hz, CHPh),
MHz, CDCl3) δ 7.43−7.07 (m, 19 H, Ph), 5.21, 4.88 (2 d, 2 H, 2JH,H
=
2
13.5 Hz, CHPh), 5.14, 4.96 (2 d, 2 H, JH,H = 15.0 Hz, CHPh), 4.83
(d, 1 H, J1,2 = 3.5 Hz, H-1), 3.78 (t, 1 H, J2,3 = J3,4 = 9.1 Hz, H-3), 3.70
(m, 1 H, H-5), 3.51 (t, 1 H, J4,5 = 9.1 Hz, H-4), 3.50 (dd, 1 H, H-2),
3.42 (s, 3 H, OMe), 3.35 (dd, 1 H, J6a,6b = 9.9 Hz, J5,6a = 4.1 Hz, H-6a),
3.33 (dd, 1 H, J5,6b = 5.1 Hz, H-6b); 13C NMR (125.7 MHz, CDCl3) δ
143.8−126.9 (Ph), 98.4 (C-1), 87.0 (CPh3), 81.1 (C-3), 80.0 (C-2),
73.8, 73.1 (CH2Ph), 71.3 (C-4), 69.4 (C-5), 64.1 (C-6), 55.1 (OMe);
FABMS m/z 538 (10%, [M]+). Anal. Calcd for C34H34O6: C, 75.82; H,
6.36. Found: C, 75.73; H, 6.15.
4.75, 4.36 (2 d, 21 H, 2JH,H = 10.1 Hz, CHBr), 4.69 (d, 1 H, J1,2 = 1.2
Hz, H-1), 3.95 (dd, 1 H, J3,4 = 9.1 Hz, J2,3 = 2.8 Hz, H-3), 3.90 (t, 1 H,
J3,4 = 9.4 Hz, H-4), 3.83 (m, 2 H, H-2, H-5), 3.44 (dd, 1 H, J6a,6b = 9.7
Hz, J5,6a = 1.2 Hz, H-6a), 3.38 (s, 3 H, OMe), 3.28 (dd, 1 H, J5,6b = 6.1
Hz, H-6b); 13C NMR (75.5 MHz, CDCl3) δ 144.1−126.8 (Ph), 100.1
(C-1), 86.4 (CPh3), 82.1 (C-3), 73.8 (C-4), 72.0, 71.7, 70.5 (CH2Ph),
71.8 (C-2), 71.3 (C-5), 63.5 (C-6), 54.5 (OMe), 31.0 (CH2Br);
FABMS m/z 745, 743 (40%, 30%, [M + Na]+). Anal. Calcd for C42H41
BrO6: C, 69.90; H, 5.73. Found: C, 70.04; H, 5.87.
Methyl 6-O-Triphenylmethyl-4-O-(o-bromomethylbenzyl)-2,3-O-
(o-xylylene)-α-D-glucopyranoside (18). Amorphous solid. Yield: 7 mg
(8%); Rf 1 0.61 (1:2 EtOAc/petroleum ether); [α]D +53.7 (c 1.0,
CHCl3); H NMR (500 MHz, CDCl3) δ 7.45−6.79 (m, 23 H, Ph),
Methyl 6-O-Triphenylmethyl-2,3-O-(o-xylylene)-α-D-galactopyra-
noside (25). Amorphous solid. Yield: 11 mg (18%); Rf 0.45 (1:2
1
EtOAc/petroleum ether); [α]D +102.9 (c 0.91, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.30−7.05 (m, 19 H, Ph), 5.26, 4.77 (2 d, 2 H,
2JH,H = 13.2 Hz, CHPh), 5.14, 4.91 (2 d, 2 H, 2JH,H = 14.8 Hz, CHPh),
4.86 (d, 1 H, J1,2 = 3.1 Hz, H-1), 4.04 (bs, 1 H, H-4), 3.84 (m, 3 H, H-
2
5.21, 4.94 (2 d, 2 H, JH,H = 13.2 Hz, CHPh), 5.19, 5.02 (2 d, 2 H,
2JH,H = 14.8 Hz, CHPh), 4.98, 4.31 (2 d, 2 H, 2JH,H = 10.7 Hz, CHPh),
4.94 (d, 1 H, J1,2 = 3.6 Hz, H-1), 4.73, 4.37 (2 d, 2 H, 2JH,H = 10.1 Hz,
CHBr), 3.95 (t, 1 H, J2,3 = J3,4 = 9.1 Hz, H-3), 3.77 (ddd, 1 H, J4,5 = 9.1
Hz, J5,6b = 3.3 Hz, J5,6a = 1.6 Hz, H-5), 3.62 (dd, 1 H, H-2), 3.56 (t, 1
H, H-4), 3.44 (s, 3 H, OMe), 3.42 (dd, 1 H, J6a,6b = 10.2 Hz, H-6a),
3.16 (dd, 1 H, H-6b); 13C NMR (125.7 MHz, CDCl3) δ 143.9−126.9
(Ph), 98.3 (C-1), 86.4 (CPh3), 82.3 (C-3), 81.2 (C-2), 77.1 (C-4),
74.2, 73.3, 71.9 (CH2Ph), 69.9 (C-5), 62.8 (C-6), 54.9 (OMe), 30.8
(CH2Br); FABMS m/z 745, 743 (90%, 75%, [M + Na]+). Anal. Calcd
for C42H41BrO6: C, 69.90; H, 5.73. Found: C, 69.69; H, 5.64.
2, H-3, H-5), 3.44 (s, 3 H, OMe), 3.39 (dd, 1 H, J6a,6b = 9.7 Hz, J5,6a
=
6.6 Hz, H-6a), 3.30 (dd, 1 H, J5,6b = 5.5 Hz, H-6b), 2.30 (s, 1 H, OH);
13C NMR (125.7 MHz, CDCl3) δ 143.9−127.0 (Ph), 98.5 (C-1), 86.7
(CPh3), 76.7 (C-2), 76.4 (C-3), 73.6, 72.0 (CH2Ph), 69.1 (C-4), 68.9
(C-5), 66.0 (C-6), 55.2 (OMe); FABMS m/z 561 (10%, [M + Na]+).
Anal. Calcd for C34H34O6: C, 75.82; H, 6.36. Found: C, 75.72; H, 6.13.
Methyl 4-O-(o-Bromomethylbenzyl)-6-O-triphenylmethyl-2,3-O-
(o-xylylene)-α-D-galactopyranoside (26). Yield: 7 mg (6%); Rf 0.59
(1:2 EtOAc/petroleum ether); [α]D +28.5 (c 0.50, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.26−6.71 (m, 23 H, Ph), 5.28, 4.82 (2 d, 2 H,
2JH,H = 13.0 Hz, CHPh), 5.15, 4.83 (2 d, 2 H, 2JH,H = 15.2 Hz, CHPh),
Methyl 6-O-Triphenylmethyl-2,3-O-(o-xylylene)-β-D-glucopyra-
noside (19). Amorphous solid. Yield: 24 mg (39%); Rf 0.58 (1:2
EtOAc/cyclohexane); [α]D +37.2 (c 1.0, CHCl3); UV (DCM) 248 nm
2
4.86, 4.36 (2 d, 2 H, JH,H = 10.3 Hz, CHPh), 4.77 (d, 1 H, J1,2 = 3.8
1
(εmM 10.3); IR (ATR) 2924, 1488, 1447, 1068, 753 cm−1; H NMR
Hz, H-1), 4.45, 3.93 (2 d, 2 H, 2JH,H = 10.0 Hz, CHBr), 4.02 (bd, 1 H,
J3,4 = 2.7 Hz, H-4), 3.96 (dd, 1 H, J2,3 = 9.6 Hz, H-3), 3.85 (dd, 1 H,
(400 MHz, CDCl3) δ 7.47−7.12 (m, 19 H, Ph), 5.22, 4.90 (2 d, 2 H,
2JH,H = 13.2 Hz, CHPh), 5.10, 5.05 (2 d, 2 H, 2JH,H = 14.8 Hz, CHPh),
4.27 (d, 1 H, J1,2 = 7.6 Hz, H-1), 3.58 (m, 1 H, H-4), 3.57 (s, 3 H,
OMe), 3.51 (t, 1 H, J2,3 = J3,4 = 8.8 Hz, H-3), 3.42−3.35 (m, 3 H, H-5,
H-2), 3.80 (bt, 1 H, J5,6a = J5,6b = 6.5 Hz, H-5), 3.42 (dd, 1 H, J6a,6b
=
9.5 Hz, H-6a), 3.36 (s, 3 H, OMe), 3.24 (dd, 1 H, H-6b); 13C NMR
(125.7 MHz, CDCl3) δ 143.9−127.1 (Ph), 98.7 (C-1), 87.1 (CPh3),
78.1 (C-2), 77.6 (C-3), 76.2 (C-4), 74.0, 72.6, 72.2 (CH2Ph), 69.3 (C-
5), 62.5 (C-6), 55.2 (OMe), 31.5 (CH2Br); FABMS m/z 745, 743
(20%, 15%, [M + Na]+). Anal. Calcd for C42H41 BrO6: C, 69.90; H,
5.73. Found: C, 69.98; H, 5.68.
H-6ab), 3.34 (dd, 1 H, H-2), 2.86 (d, 1 H, J4,OH = 2.0 Hz, OH-4); 13
C
NMR (100.6 MHz, CDCl3) δ 143.5−127.1 (Ph), 103.2 (C-1), 87.1
(CPh3), 83.2 (C-3), 80.3 (C-2), 73.4 (C-5), 72.9, 72.7 (CH2Ph), 71.6
(C-4), 64.3 (C-6), 56.9 (OMe); ESIMS m/z 561 [M + Na]+. Anal.
Calcd for C34H34O6: C, 75.82; H, 6.36. Found: C, 75.67; H, 6.29.
Methyl 6-O-Triphenylmethyl-3,4-O-(o-xylylene)-β-D-glucopyra-
noside (20). Amorphous solid. Yield: (0.25 g of starting material)
14 mg (23%); Rf 0.23 (1:2 EtOAc/cyclohexane); [α]D +37.2 (c 1.0,
CHCl3); UV (DCM) 248 nm (εmM 10.3); IR (ATR) 3430, 2969,
Methyl 2-O-(o-Bromomethylbenzyl)-6-O-triphenylmethyl-3,4-O-
(o-xylylene)-α-D-galactopyranoside (27). Yield: 3 mg (4%); Rf 0.63
(1:2 EtOAc/petroleum ether); [α]D +16.4 (c 0.50, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.32−7.02 (m, 23 H, Ph), 5.46, 4.54 (2 d, 2 H,
2JH,H = 12.8 Hz, CHPh), 5.40, 4.56 (2 d, 2 H, 2JH,H = 14.5 Hz, CHPh),
1
2925, 1456, 1375, 1084, 754 cm−1; H NMR (300 MHz, CDCl3) δ
2
4.91, 4.81 (2 d, 2 H, JH,H = 11.7 Hz, CHPh), 4.81, 4.73 (2 d, 2 H,
2
2JH,H = 10.2 Hz, CHBr), 4.77 (d, 1 H, J1,2 = 3.2 Hz, H-1), 4.10 (bs, 1
7.47−7.12 (m, 19 H, Ph), 5.23, 4.82 (2 d, 2 H, JH,H = 12.8 Hz,
CHPh), 4.79, 4.65 (2 d, 2 H, 2JH,H = 14.8 Hz, CHPh), 4.25 (d, 1 H, J1,2
= 7.6 Hz, H-1), 3.58 (t, 1 H, J3,4 = J4,5 = 9.6 Hz, H-4), 3.59 (s, 3 H,
OMe), 3.57−3.50 (m, 2 H, H-3, H-6a), 3.46 (dd, 1 H, J2,3 = 9.6 Hz, H-
2), 3.38 (bd, 1 H, H-5), 3.21 (dd, 1 H, J6a,6b = 9.6 Hz, J5,6b = 3.2 Hz, H-
6b), 2.53 (bs, 1 H, OH-2); 13C NMR (75.5 MHz, CDCl3) δ 143.8−
127.0 (Ph), 103.3 (C-1), 86.3 (CPh3), 82.8 (C-3), 76.4 (C-4), 74.6 (C-
5), 73.1 (C-2), 72.5, 72.2 (CH2Ph), 62.1 (C-6), 56.5 (OMe); ESIMS
m/z 561 [M + Na]+. HREIMS calcd for C34H34O6 538.2355, found
538.2357.
H, H-4), 4.03 (dd, 1 H, J2,3 = 10.2 Hz, J3,4 = 3.3 Hz, H-3), 4.00 (dd, 1
H, H-2), 3.70 (bt, 1 H, J5,6a = J5,6b = 7.2 Hz, H-5), 3.26 (s, 3 H, OMe),
3.25 (m, 2 H, H-6a, H-6b); 13C NMR (125.7 MHz, CDCl3) δ 143.9−
127.1 (Ph), 98.5 (C-1), 86.8 (CPh3), 78.1 (C-2), 74.0 (C-3), 71.8 (C-
4), 72.1, 71.1, 69.1 (CH2Ph), 68.5 (C-5), 61.2 (C-6), 55.3 (OMe),
33.7 (CH2Br); FABMS m/z 745, 743 (20%, 15%, [M + Na]+). Anal.
Calcd for C42H41BrO6: C, 69.90; H, 5.73. Found: C, 69.93; H, 5.72.
Preparation of 1,2-O-Isopropylidene-5,6-O-(o-xylylene)-α-D-
glucofuranose (29). Compound 29 was prepared from the
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commercial 1,2-O-isopropylidene-α-D-glucofuranose 28 (100 mg,
0.454 mmol) following the procedure above-described for derivatives
6−8. Column chromatography, eluent 2:3 EtOAc/petroleum ether.
Amorphous solid. Yield: 88 mg (60%); Rf 0.50 (1:1 EtOAc/petroleum
ether); [α]D −50.5 (c 1.0, DCM); IR (ATR) νmax 3297, 2918, 1456,
1067, 1015 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.35−7.23 (m, 4 H,
Ph), 5.94 (d, 1 H, J1,2 = 4.0 Hz, H-1), 5.08, 4.70 (2 d, 2 H, 2JH,H = 13.0
chromatography using 1:1 EtOAc/petroleum ether as eluent.
Amorphous solid. Yield: 95 mg (45%); Rf 0.30 (1:1 EtOAc/petroleum
ether); [α]D −298.5 (c 1.0, DCM); IR (ATR) νmax 3290, 2917, 1456,
1067, 1015 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.27−7.13 (m, 4 H,
Ph), 5.86 (d, 1 H, J1,2 = 3.6 Hz, H-1), 5.00, 4.61 (2 d, 2 H, 2JH,H = 12.9
2
Hz, CHPh), 4.91, 4.80 (2 d, 2 H, JH,H = 12.0 Hz, CHPh), 4.52 (d, 1
H, H-2), 4.09 (dd, 1 H, J3,4 = 3.6 Hz, J4,5 = 9.0 Hz, H-4), 3.94 (d, 1 H,
H-3), 3.83 (dd, 1 H, J6a,6b = 11.4 Hz, J5,6a = 3.0 Hz, H-6a), 3.67 (ddd, 1
H, J5,6b = 6.0 Hz, H-5), 3.57 (dd, 1 H, H-6b), 1.92 (bs, 1 H, OH), 1.36,
1.23 (2 s, 6 H, CMe2); 13C NMR (75.5 MHz, CDCl3) δ 136.4−128.7
(Ph), 111.8 (CMe2), 105.9 (C-1), 83.5 (C-2), 81.8 (C-3), 80.4 (C-4),
79.1 (C-5), 74.3, 72.8 (CH2Ph), 63.4 (C-6), 26.8, 26.3 (CMe2);
ESIMS m/z 345 [M + Na]+. Anal. Calcd for C17H22O6: C, 63.34; H,
6.88. Found: C, 63.40; H, 7.12.
2
Hz, CHPh), 5.00, 4.89 (2 d, 2 H, JH,H = 12.5 Hz, CHPh), 4.60 (d, 1
H, H-2), 4.19 (dd, 1 H, J3,4 = 3.0 Hz, J4,5 = 9.5 Hz, H-4), 4.03 (d, 1 H,
H-3), 3.91 (dd, 1 H, J5,6a = 3.5 Hz, J6a,6b = 12.0 Hz, H-6a), 3.74 (ddd, 1
H, J5,6b = 5.5 Hz, H-5), 3.66 (dd, 1 H, H-6b), 2.60 (bs, 1 H, OH), 1.45,
1.32 (2 s, 6 H, 2 CMe2); 13C NMR (125.7 MHz, CDCl3) δ 136.4−
128.7 (Ph), 111.8 (CMe2), 105.9 (C-1), 83.5 (C-2), 81.8 (C-3), 80.3
(C-4), 79.0 (C-5), 74.2, 72.8 (CH2Ph), 63.3 (C-6), 26.8, 26.3 (CMe2);
ESIMS m/z 345 [M + Na]+. Anal. Calcd for C17H22O6: C, 63.34; H,
6.88. Found: C, 63.41; H, 6.95.
Preparation of 2I,3I-O-(o-Xylylene)cyclomaltoheptaose De-
rivatives (35−37). Heptakis(6-O-tert-butyldimethylsilyl)-2I,3I-O-(o-
xylylene)cyclomaltoheptaose (35). To a solution of 34 (894 mg, 0.46
mmol) in dry DMF (90 mL) at 0 °C under Ar was added NaH (60%
in mineral oil, 111 mg, 2.77 mmol). The reaction mixture was stirred
for 15 min, and then a solution of 1,2-dibromomethylbenzene (366
mg, 1.39 mmol) in dry DMF (10 mL) was dropwise added. The
reaction mixture was stirred at 0 °C under Ar atmosphere for 30 min
and then was left to reach room temperature for 24 h. Further
treatment as described for 6−8 and column chromatography using
60:1 → 6:1 DCM/MeOH containing 0.5% of Et3N as eluent gave 35.
Amorphous solid. Yield: 309 mg (33%); Rf = 0.34 (9:1 DCM/
MeOH); [α]D = +133.8 (c 0.73, CHCl3); 1H NMR (500 MHz,
CD3OD) δ 7.29−7.156 (m, 4 H, Ph), 5.28, 4.99 (2 d, 2 H, 2JH,H = 14.1
Preparation of 1,2-O-Isopropylidene-3,5-O-(o-xylylene)-α-D-
glucofuranose (33). 3-O-(2-Bromomethyl)benzyl-1,2:5,6-di-O-iso-
propylidene-α-D-glucofuranose (31). To a solution of commercial
1,2:5,6-di-O-isopropylidene-α-D-glucofuranose 30 (0.5 g, 1.92 mmol)
in dry DMF (20 mL) at 0 °C under Ar atmosphere was added NaH
(60% in mineral oil, 192 mg, 4.80 mmol), and the suspension was
stirred at room temperature for 15 min. Then, a solution of 1,2-
dibromomethylbenzene (1.26 g, 4.80 mmol) in dry DMF (15 mL) was
added dropwise, and the mixture was stirred for 1 h at room
temperature. Further treatment as described for 6−8 and column
chromatography using 1:6 EtOAc/petroleum ether as eluent gave 31.
Amorphous solid. Yield: 0.51 g (60%); Rf 0.44 (1:4 EtOAc/petroleum
ether); [α]D1−129.5 (c 1.1, DCM); IR (ATR) νmax 2985, 1456, 1071,
1020 cm−1; H NMR (300 MHz, CDCl3) δ 7.34−7.18 (m, 4 H, Ph),
5.83 (d, 1 H, J1,2 = 6.0 Hz, H-1), 4.75, 4.68 (2 d, 2 H, 2JH,H = 12.0 Hz,
CHPh), 4.61, 4.52 (2 d, 2 H, 2JH,H = 9.0 Hz, CH2Br), 4.57 (d, 1 H, H-
2), 4.25 (dt, 1 H, J4,5 = 9.0 Hz, J5,6a = J5,6b = 6.0 Hz, H-5), 4.03 (dd, 1
H, J3,4 = 3.0 Hz, H-4), 4.01 (dd, 1 H, J6a,6b = 9.0 Hz, H-6a), 3.98 (d, 1
H, H-3), 3.91 (dd, 1 H, H-6b), 1.42, 1.34, 1.29, 1.25 (4 s, 12 H,
CMe2); 13C NMR (75.5 MHz, CDCl3) δ 136.4−128.7 (Ph), 111.8,
109.1 (CMe2), 105.3 (C-1), 82.5 (C-2), 81.8 (C-3), 81.4 (C-4), 72.3
(C-5), 69.7 (CH2Ph), 67.6 (C-6), 39.9 (CH2Br), 26.8, 26.7, 26.2, 25.3
(CMe2); ESIMS m/z 465, 467 [M + Na]+. Anal. Calcd for
C20H27O6Br: C, 54.18; H, 6.14. Found: C, 54.30; H, 6.18.
3-O-(o-Bromomethylbenzyl)-1,2-O-isopropylidene-α-D-glucofur-
anose (32). To a solution of 31 (0.45 g, 1.01 mmol) in MeCN (20
mL) were added iodine (50 mg, 0.196 mmol) and H2O (21 μL, 1.16
mmol). The mixture was stirred for 4 h at room temperature. The
reaction was neutralized by addition of saturated aqueous NaHCO3,
and then EtOAc (10 mL) was added. The excess of iodine was
removed by addition of 10% Na2S2O3 solution until decoloration of
the organic layer. The organic layer was separated, washed with H2O
(3 × 5 mL), dried (MgSO4), filtered, and concentrated. The resulting
residue was purified by column chromatography using 1:1 EtOAc/
petroleum ether as eluent. Amorphous solid. Yield: 0.27 g (66%); Rf
0.20 (1:1 EtOAc/petroleum ether); [α]D −311.9 (c 1.0, DCM); IR
(ATR) νmax 3413, 2933, 1454, 1072, 1016 cm−1; 1H NMR (300 MHz,
CDCl3) δ 7.32−7.19 (m, 4 H, Ph), 5.86 (d, 1 H, J1,2 = 3.6 Hz, H-1),
4.81, 4.64 (2 d, 2 H, 2JH,H = 12.0 Hz, CHPh), 4.61 (d, 1 H, H-2), 4.53
(s, 2 H, CH2Br), 4.08 (m, 2 H, H-3, H-4), 3.93 (m, 1 H, H-5), 3.76
2
Hz, CHPh), 5.12, 5.07 (2 d, 2 H, JH,H = 14.7 Hz, CHPh), 5.12 (d, 1
H, J1,2 = 3.7 Hz, H-1I), 5.01−4.94 (m, 6 H, H-1II−VII), 4.11−3.91 (m, 8
H, H-6aI−VII, H-3I), 3.90−3.82 (m, 6 H, H-3II−VII), 3.79−3.73 (m, 7 H,
H-6bI−VII), 3.69−3.64 (m, 8 H, H-5I−VII, H-4I), 3.59−3.52 (m, 7 H, H-
4
II−VII, H-2I), 3.44−3.36 (m, 6 H, H-2II−VII), 0.89 (s, 63 H, Me3C),
0.02 (s, 42 H, Me2Si); 1D TOCSY (H-1I irradiation) δ 4.11 (bd, 1 H,
J6a,6b = 11.5 Hz, H-6aI), 3.97 (m, 1 H, H-3I), 3.76 (m, 1 H, H-6bI),
3.69 (m, 2 H, H-4I, H-5I), 3.54 (dd, 1 H, J2,3 = 8.8 Hz, H-2I); 13C
NMR (125.7 MHz, CD3OD) δ 136.3−127.8 (Ph), 102.4, 102.3, 102.2,
101.9, 101.6 (C-1II−VII), 100.7 (C-1I), 81.7, 81.0, 80.9, 80.8, 80.7 (C-
4
II−VII), 80.8 (C-2I), 80.4 (C-3I), 78.4 (C-4I), 73.7, 73.6, 73.4, 73.3,
73.2 (C-3II−VII), 73.2 (CH2Ph), 73.1, 73.0, 72.9 (C-2II−VII), 72.9
(CH2Ph), 72.7, 72.5, 72.4 (C-5II−VII), 72.1 (C-5I), 62.2, 62.1, 61.9
(C6II−VII), 61.8 (C-6I), 25.2 (Me3C), 17.9 (Me3C); FABMS m/z 2059
[M + Na]+. Anal. Calcd for C92H174O35Si7: C, 54.25; H, 8.61. Found:
C, 53.98; H, 8.36.
Heptakis(6-O-tert-butyldimethylsilyl)-2II−VII,3II−VII-dodeca-O-meth-
yl-2I,3I-O-(o-xylylene)cyclomaltoheptaose (36). To a solution of 35
(114 mg, 0.06 mmol) in dry DMF (4.5 mL) at 0 °C under Ar
atmosphere were added NaH (60% in mineral oil, 134 mg, 3.36
mmol) and MeI (209 mL, 3.36 mmol), and the reaction mixture was
stirred at room temperature for 2 h. Further treatment as described for
6−8 and column chromatography using 1:4 → 1:3 EtOAc/petroleum
ether as eluent gave 36. Amorphous solid. Yield: 69 mg (56%); Rf =
1
0.34 (1:3 EtOAc/petroleum ether); [α]D = +96.9 (c 1.0, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.22−7.05 (m, 4 H, Ph), 5.26, 4.73 (2 d, 2
2
2
H, JH,H = 12.7 Hz, CHPh), 5.18, 5.12 (2 d, 2 H, JH,H = 11.6 Hz,
CHPh), 5.19−5.12 (m, 7 H, H-1I−VII), 4.10−4.01 (m, 7 H, H-6aI−VII),
3.79 (m, 1 H, H-3I), 3.79−3.61 (m, 6 H, H-4II−VII), 3.61−3.47 (m, 8
H, H-6bI−VII, H-4I), 3.59−3.35 (m, 14 H, H-5I−VII, H-3II−VII, H-2I),
3.11−3.00 (m, 6 H, H-2II−VII), 3.75, 3.70, 3.64, 3.62, 3.57, 3.56, 3.52,
3.50, 3.49, 3.47, 3.43, 3.25 (12 s, 36 H, Me), 0.85 (s, 63 H, Me3C),
0.01 (s, 42 H, Me2Si); 1D TOCSY (H-3I irradiation) δ 5.15 (d, 1 H,
J1,2 = 3.5 Hz, H-1I), 4.10 (d, 1 H, J6a,6b = 12.2 Hz, H-6aI), 3.61 (d, 1 H,
H-6bI), 3.56 (t, 1 H, J3,4 = J4,5 = 9.5 Hz, H-4I), 3.53 (m, 1 H, H-5I),
3.41 (dd, 1 H, J2,3 = 9.0 Hz, H-2I); 13C NMR (125.7 MHz, CDCl3) δ
138.4−126.8 (Ph), 99.8 (C-1I), 98.6, 98.2, 98.1, 98.0, 97.9 (C-1II−VII),
82.3, 82.2, 82.0, 81.8 (C-2II−VII, C-3II−VII), 82.0 (C-2I), 80.2, 79.2, 78.8,
78.7, 78.6, 78.5, 78.2 (C-4I−VII), 79.0 (C-3I), 74.8 (CH2Ph), 72.4
(CH2Ph), 72.3 (C-5I), 72.3, 72.2, 72.0, 71.9 (C-5II−VII), 62.6, 62.3,
62.2, 61.7, 61.5, 61.4, 61.3, 58.8, 58.7, 58.6, 58.5 (C-6I−VII, Me), 26.0
(dd, 1 H, J6a,6b = 11.4 Hz, J5,6a = 3.0 Hz, H-6a), 3.64 (dd, 1 H, J5,6b
=
8.5.0 Hz, H-6b), 1.42, 1.26 (2 s, 6 H, CMe2); 13C NMR (75.5 MHz,
CDCl3) δ 136.0−128.7 (Ph), 111.8 (CMe2), 105.1 (C-1), 82.3 (C-3),
81.9 (C-2), 79.9 (C-4), 69.4 (CH2Ph), 68.9 (C-5), 64.3 (C-6), 30.8
(CH2Br), 26.7, 26.1 (CMe2); ESIMS m/z 425, 427 [M + Na]+. Anal.
Calcd for C17H23O6Br: C, 50.63; H, 5.75. Found: C, 50.27; H, 5.32.
1,2-O-Isopropylidene-3,5-O-(o-xylylene)-α-D-glucofuranose (33).
To a solution of 32 (264 mg, 0.654 mmol) in dry DMF (25 mL) at
room temperature under Ar atmosphere was added NaH (60% in
mineral oil, 47 mg, 1.18 mmol), and the suspension was stirred at
room temperature for 4 h. The reaction was quenched by addition of
Et2O (30 mL) and H2O (15 mL), and the organic layer was separated,
washed with H2O (5 × 10 mL), dried (MgSO4), filtered, and
concentrated. The resulting residue was purified by column
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(Me3C), 18.5 (Me3C); MALDI-TOFMS m/z 2226.2 [M + Na]+. Anal.
82.0, 81.9 (C-4I−VII), 79.8 (C-2I), 73.5, 73.4, 73.3, 73.1, 72.9, 72.5,
72.3, 72.2 (C-3I−VII, C-2II−VII, C-5I−VII), 73.8, 72.8, 72.7, 72.5 (C-
Calcd for C104H198O35Si7: C, 56.62; H, 8.78. Found: C, 56.64; H, 9.05.
2
I I − V I I ,3I I − V I I -Dodeca-O-methyl-2I ,3I -O-(o-xylylene)-
5
II−VI), 70.9 (CH2Ph), 60.7 (CH2Ph), 60.4 (C-6I−VII); ESIMS m/z
1277.2 [M + Na]+, 1293.2 [M + K]+. Anal. Calcd for C50H78O36: C,
47.85; H, 6.26. Found: C, 47.49; H, 6.02.
cyclomaltoheptaose (37). A solution of 36 (170 mg, 0.08 mmol) in
TFA/H2O (1:1, 10 mL) was stirred at 45 °C for 2 h. The solution was
concentrated and co-evaporated several times with water to eliminate
traces of the acid. The resulting residue was dissolved in water and
freeze-dried to give 37 as an amorphous solid. Yield: 108 mg (96%); Rf
= 0.47 (10:1:1 MeCN/H2O/NH4OH); [α]D = +108.7 (c 1.0, H2O);
UV (MeOH) 220 nm (εmM 10.7); IR (ATR) νmax 3391, 2926, 1675,
1454, 1132, 1084, 1017 cm−1; 1H NMR (500 MHz, D2O) δ 7.35−7.14
6I-O-(2-Hydroxymethylbenzyl)cyclomaltoheptaose (40). Com-
pound 40 was purified by semipreparative HPLC (tR 41.7 min).
Amorphous solid. Yield: 33 mg (3%); Rf = 0.40 (6:3:1 MeCN/H2O/
NH4OH); [α]D = +81.3 (c 1.0, DMSO); UV (MeOH) 212 nm (εmM
1
7.7); IR (ATR) νmax 3305, 2927, 1653, 1540, 1152, 1020 cm−1; H
NMR (500 MHz, DMSO-d6) δ 7.43−7.21 (m, 4 H, Ph), 4.88−4.80
(m, 4 H, Ph), 5.25 (d, 1 H, J1,2 = 3.4 Hz, H-1I), 5.35−5.19 (m, 6 H, H-
(m, 7 H, H-1I−VII), 4.57, 4.51 (2 d, 2 H, 2JH,H = 12.1 Hz, CHPh), 4.55
2
II−VII), 5.09, 4.98 (2 d, 2 H, JH,H = 14.7 Hz, CHPh), 4.85 (bs, 2 H,
(bs, 2 H, CH2Ph), 3.84−3.44 (m, 28 H, H-6aI−VII, H-6bI−VII, H-3I−VII
,
1
CH2Ph), 3.92−3.76 (m, 7 H, H-6aI−VII), 3.79−3.68 (m, 7 H, H-
6bI−VII), 3.79−3.62 (m, 7 H, H-5I−VII), 3.78−3.38 (m, 7 H, H-3I−VII),
3.67−3.52 (m, 7 H, H-4I−VII), 3.39−3.21 (m, 7 H, H-2I−VII), 3.60 ( ×
2), 3.55, 3.52, 3.50, 3.49, 3.42, 3.41, 3.27 ( × 4) (7 s, 36 H, 12 Me); 1D
TOCSY (H-1I irradiation) δ 3.90 (m, 1 H, H-6aI), 3.78 (m, 2 H, H-3I,
H-5I), 3.74 (m, 1 H, H-6bI), 3.62 (m, 1 H, H-4I), 3.39 (dd, 1 H, H-2I);
13C NMR (125.7 MHz, D2O) δ 136.8−128.0 (Ph), 98.1, 97.9, 97.6,
96.7, 96.0 (C-1II−VII), 97.8 (C-1I), 81.9, 81.8, 81.4, 81.2, 80.9 (C-
H-5I−VII), 3.45−3.27 (m, 14 H, H-4I−VII, H-2I−VII); 13C NMR (125.7
MHz, DMSO-d6) δ 140.6−127.0 (Ph), 102.5 (C-1II−VII), 100.4 (C-1I),
82.7, 82.1, 82.0, 81.9 (C-4I−VII), 73.7, 73.5, 72.9, 72.8, 72.6, 72.5 (C-
3
I−VII, C-2I−VII, C-5I−VII), 70.3 (CH2Ph), 60.7 (CH2Ph), 60.4 (C-
I−VII); ESIMS m/z 1277.2 [M + Na]+, 1293.2 [M + K]+. Anal. Calcd
6
for C50H78O36: C, 47.85; H, 6.26. Found: C, 47.61; H, 6.10.
2I,3I-O-(o-Xylylene)cyclomaltohexaose (44). 2I,3I-O-Xylylenation
of α-cyclodextrin following the general procedure above-described
yielded 44 as an amorphous solid after precipitation from water as
major compound and minor amounts of 45. Yield: 230 mg (24%); Rf
3
II−VII), 80.8, 80.5, 80.4, 80.3, 80.2 (C-2II−VII), 80.2 (C-2I), 79.9 (C-3I),
78.6, 78.3, 76.8, 75.4, 75.0 (C-4I−VII), 73.3, 73.0 (CH2Ph), 70.2, 71.9,
71.8, 71.6, 70.5 (C-5I−VII), 60.7, 60.6, 60.5, 60.4, 60.3, 60.2, 59.6, 58.4,
58.1 (C-6I−VII, Me); FABMS m/z 1428 (100%, [M + Na]+). Anal.
Calcd for C62H100O35: C, 52.98; H, 7.17. Found: C, 52.77; H, 7.15.
General Procedure for Synthesis of 2I,3I-Di-O-xylylenated
Cyclodextrin Derivatives 38, 44, and 49. To a solution of dry
cyclodextrin (α, β or γ) (0.88 mmol) in dry DMSO (40 mL) at 0 °C
under Ar atmosphere was added LDA (2 M in THF/n-heptane, 441
μL, 0.88 mmol). The reaction mixture was stirred for 16 h, and then a
solution of 1,2-dibromomethylbenzene (232 mg, 0.88 mmol) in dry
DMSO (5 mL) was dropwise added. The reaction mixture was stirred
at room temperature for 7 h and concentrated. The resulting residue
was purified by column chromatography using 10:1:1 → 6:3:1 MeCN/
H2O/NH4OH as eluent to yield the corresponding 2I,3I-O-xylylenated
derivative as major compound (38, 44, and 49) and minor amounts of
monosubstituted derivatives (39, 40, 45, and 50).
= 0.54 (6:3:1 MeCN/H2O/NH4OH); HPLC (tR 35.4 min); [α]D
=
+152.2 (c 1.0, DMSO); UV (MeOH) 214 nm (εmM 7.3); IR (ATR)
νmax 3334, 2927, 1645, 1409, 1151, 1078, 1027 cm−1H NMR (500
MHz, D2O, 333 K) δ 7.70−7.63 (m, 4 H, Ph), 5.48 (d, 1 H, J1,2 = 3.7
Hz, H-1I), 5.46, 5.40 (2 d, 2 H, 2JH,H = 14.6 Hz, CHPh), 5.43, 5.30 (2
d, 2 H, 2JH,H = 13.7 Hz, CHPh), 5.37−5.28 (m, 5 H, H-1II−VI), 4.41−
3.98 (m, 26 H, H-3I−VI, H-6aI−VI, H-6bI−VI, H-5I−VI, H-2I, H-4I), 3.98−
3.88 (m, 5 H, H-2II−VI), 3.91−3.78 (m, 5 H, H-4II−VI); 1D TOCSY
(H-1I irradiation) δ 4.29 (d, 1 H, J6a,6b = 12.5 Hz, H-6aI), 4.25 (dd, 1
H, J5,6b = 3.0 Hz, H-6bI), 4.21 (t, 1 H, J2,3 = J3,4 = 9.0 Hz, H-3I), 4.14
(m, 1 H, H-5I), 4.05 (dd, 1 H, H-2I), 4.03 (t, 1 H, J4,5 = 9.5 Hz, H-4I);
13C NMR (125.7 MHz, D2O, 333 K) δ 136.9−128.6 (Ph), 102.0,
101.9, 101.8, 101.7, 101.6 (C-1II−VI), 100.9 (C-1I), 82.5, 82.0, 81.9,
81.8 (C-4II−VI), 80.8 (C-3I), 80.4 (C-4I), 79.5 (C-2I), 74.2, 74.0, 73.8,
73.6 (C-3II−VI), 73.8 (CH2Ph), 72.8, 72.7, 72.5 (C-5II−VI), 72.7
(CH2Ph), 72.3, 72.2, 72.1, 71.9 (C-2II−VI), 61.0 (C-6I−VI); ESIMS m/z
1113.2 [M + K]+. Anal. Calcd for C44H66O30: C, 49.16; H, 6.19.
Found: C, 48.99; H, 5.95
2I,3I-O-(o-Xylylene)cyclomaltoheptaose (38). 2I,3I-O-Xylylenation
of β-cyclodextrin yielded 38 as an amorphous solid. Yield: 326 mg
(30%); Rf = 0.42 (6:3:1 MeCN/H2O/NH4OH); HPLC (tR 36.9 min);
[α]D = +124.2 (c 1.0, DMSO); 1H NMR (500 MHz, DMSO) δ 7.26−
7.12 (m, 4 H, Ph), 5.73−5.61 (m, 7 H, OH-6), 5.14, 4.88 (2 d, 2 H,
2JH,H = 14.3 Hz, CHPh), 5.06 (d, 1 H, J1,2 = 3.7 Hz, H-1I), 5.05, 4.94
2I-O-(2-Hydroxymethylbenzyl)cyclomaltohexaose (45). Com-
pound 45 was purified by semipreparative HPLC (tR 37.4 min).
Amorphous solid. Yield: 29 mg (3%); Rf = 0.54 (6:3:1 MeCN/H2O/
NH4OH); [α]D = +65.6 (c 1.0, DMSO); 1H NMR (500 MHz, D2O) δ
7.46−7.36 (m, 4 H, Ph), 5.16 (d, 1 H, J1,2 = 3.5 Hz, H-1I), 5.00−4.95
(m, 5 H, H-1II−VI), 4.84, 4.82 (2 d, 2 H, 2JH,H = 11.4 Hz, CHPh), 4.74,
(2 d, 2 H, JH,H = 14.3 Hz, CHPh), 4.83−4.78 (m, 6 H, H-1II−VII),
2
4.57−4.32 (m, 14 H, OH-2, OH-3), 3.80 (t, 1 H, J2,3 = J3,4 = 8.9 Hz,
H-3I), 3.68 (m, 1 H, H-6aI), 3.64−3.48 (m, 23 H, H-6bI, H-5I,H-4I, H-
2I, H-3 II−VII, H-5II−VII, H-6aI−VII), 3.35−3.21 (m, 18 H, H-4II−VII, H-
6bII−VII, H-2II−VII); 1D TOCSY (H-3I irradiation) δ 5.06 (d, 1 H, H-
1I), 4.50 (m, 2 H, OH-2, OH-3), 3.68 (m, 1 H, H-6aI), 3.58 (m, 1 H,
H-6bI), 3.54 (m, 1 H, H-5I), 3.52 (t, 1 H, J4,5 = 9.5 Hz, H-4I), 3.49 (dd,
1 H, J2,3 = 8.9 Hz, H-2I); 13C NMR (125.7 MHz, DMSO) δ = 137.1−
128.3 (Ph), 102.4, 102.3, 102.1 (C-1II−VII), 100.6 (C-1I), 82.5, 82.1,
81.8, 81.7 (C-4II−VII), 81.7 (C-3I), 81.0 (C-2I), 79.1 (C-4I), 73.8, 73.7,
73.6, 73.4 (C-3II−VII), 73.7 (CH2Ph), 73.2 (C-5I), 73.1 (CH2Ph), 73.0,
72.9, 72.8, 72.7, (C-2II−VII), 72.6, 72.5, 72.1 (C-5II−VII), 60.6, 60.5, 60.3
(C-6II−VII), 60.1 (C-6I). FABMS m/z 1259 (100%, [M + Na]+). Anal.
Calcd for C50H76O35: C, 48.54; H, 6.19. Found: C, 48.38; H, 5.96.
2I-O-(2-Hydroxymethylbenzyl)cyclomaltoheptaose (39). Com-
pound 39 was purifed by semipreparative HPLC (tR 40.0 min).
Amorphous solid. Yield: 55 mg (5%); Rf = 0.43 (6:3:1 MeCN/H2O/
NH4OH); [α]D = +94.4 (c 1.0, DMSO); 1H NMR (500 MHz,
DMSO-d6) δ 7.45−7.24 (m, 4 H, Ph), 5.01 (d, 1 H, J1,2 = 3.5 Hz, H-
2
4.71 (2 d, 2 H, JH,H = 13.3 Hz, CHPh), 4.04 (t, 1 H, J2,3 = J3,4 = 9.3
Hz, H-3I), 3.93−3.73 (m, 23 H, H-3II−VI, H-5I−VI, H-6aI−VI, H-6bI−VI),
3.59−3.47 (m, 12 H, H-4I−VI, H-2I−VI); 1D TOCSY (H-3I irradiation)
δ 5.16 (d, 1 H, H-1I), 3.82 (d, 1 H, J6a,6b = 12.0 Hz, H-6aI), 3.77 (m, 2
H, H-5I, H-6bI), 3.55 (m, 2 H, H-2I, H-4I); 13C NMR (125.7 MHz,
D2O) δ 139.0−128.2 (Ph), 101.6, 101.4, 101.3 (C-1II−VI), 99.2 (C-1I),
81.6, 81.5, 81.3, 81.2, 81.1 (C-4I−VI), 79.0 (C-2I), 73.3 (C-3II−VI), 72.5
(C-3I), 72.0 (C-5I−VI), 71.6, 71.4 (C-2I−VI), 70.8 (CH2Ph), 61.2
(CH2Ph), 60.4 (C-6I−VI); ESIMS m/z 1115.3 [M + Na]+. Anal. Calcd
for C44H68O31: C, 48.35; H, 6.27. Found: C, 48.07; H, 6.12.
2I,3I-O-(o-Xylylene)cyclomaltooctaose (49). Amorphous solid.
Yield: 408 mg (29%); Rf = 0.52 (MeCN/H2O/NH4OH 6:3:1);
HPLC (tR 37.0 min); [α]D = +154.8 (c 0.91, H2O). UV (MeOH) 212
nm (εmM 6.3); IR (ATR) νmax 3350, 2926, 1645, 1414, 1155, 1081,
1
1025 cm−1; H NMR (500 MHz, D2O) δ 7.10−6.96 (m, 4 H, Ph),
5.28 (d, 1 H, J1,2 = 3.7 Hz, H-1I), 5.20, 4.73 (2 d, 2 H, 2JH,H = 13.4 Hz,
CHPh), 5.16, 5.09 (2 d, 2 H, 2JH,H = 14.0 Hz, CHPh), 5.12−4.98 (m, 7
H, H-1II−VIII), 4.13−4.03 (m, 7 H, H-5II−VIII), 3.97−3.62 (m, 27 H, H-
1I), 4.87−4.81 (m, 8 H, H-1II−VII, CH2Ph), 4.63, 4.60 (2 d, 2 H, 2JH,H
=
14.0 Hz, CHPh), 3.87 (t, 1 H, J2,3 = J3,4 = 9.3 Hz, H-3I), 3.75−3.46 (m,
27 H, H-3II−VII, H-5I−VII, H-6aI−VII, H-6bI−VII), 3.45−3.25 (m, 14 H, H-
3
2
I−VIII, H-6aI−VIII, H-6bI−VIII, H-5I, H-4I, H-2I), 3.63−3.47 (m, 14 H, H-
4
I−VII, H-2I−VII); 1D TOCSY (H-1I irradiation) δ 3.87 (t, 1 H, H-3I),
II−VIII, H-4II−VIII); 1D TOCSY (H-1I irradiation) δ 3.93 (t, 1 H, J2,3
=
=
3.65 (m, 1 H, H-6aI), 3.57 (m, 2 H, H-5I, H-6bI), 3.41 (m, 1 H, H-4I),
3.33 (m, 1 H, H-2I); 13C NMR (125.7 MHz, DMSO-d6) δ 141.5−
127.1 (Ph), 102.5, 102.4, 102.2 (C-1II−VII), 100.4 (C-1I), 82.6, 82.3,
J3,4 = 8.3 Hz, H-3I), 3.92 (m, 2 H, H-6aI, H-5I), 3.89 (d, 1 H, J6a,6b
11.5 Hz, H-6bI), 3.79 (m, 1 H, H-2I), 3.75 (m, 1 H, H-4I); 13C NMR
(125.7 MHz, D2O) δ 136.2−128.0 (Ph), 102.3, 102.2, 102.0, 101.7,
1399
dx.doi.org/10.1021/jo302178f | J. Org. Chem. 2013, 78, 1390−1403

The Journal of Organic Chemistry
Article
101.6, 101.0 (C-1II−VIII), 100.3 (C-1I), 81.7, 81.1, 80.5, 80.0, 79.8, 79.6,
79.2, 79.1 (C-4I−VIII), 79.1 (C-2I), 78.4 (C-3I), 73.8 (CH2Ph), 73.7,
73.5, 73.2, 72.9, 72.8, 72.7, 72.6, 72.5, 72.3, 72.1, 72.0, 71.9, 71.8, 71.7
(C-2II−VIII, C-3II−VIII, C-5I−VIII), 60.5, 60.3, 60.1, 59.9 (C-6I−VIII);
ESIMS m/z 1421.3 [M + Na]+, 719.1 [M + 2K]2+. Anal. Calcd for
C56H86O40: C, 48.07; H 6.19. Found: C, 47.95; H, 6.06.
irradiation) δ 5.01 (d, 1 H, J1,2 = 4.0 Hz, H-1I), 3.80 (m, 1 H, H-5I),
3.72 (d, 1 H, J6a,6b = 12.5 Hz, H-6bI), 3.60 (t, 1 H, J2,3 = J3,4 = 9.0 Hz,
H-3I), 3.42 (m, 1 H, H-2I), 3.29 (m, 1 H, H-4I); 13C NMR (125.7
MHz, D2O) δ 137.6−126.8 (Ph), 100.7 (C-1I), 99.2, 99.0, 98.8, 98.7,
98.6 (C-1II−VI), 84.1 (C-3I), 82.2, 81.6, 81.3, 81.2, 81.1, 81.0, 80.7,
80.6, 80.1 (C-2II−VI, C-3II−VI, C-4I−VI), 78.6 (C-2I), 75.6 (CH2Ph), 73.1
(CH2Ph), 71.0, 70.9, 70.8, 70.7, 70.6 (C-5I−VI, C-6I−VI), 61.9, 61.6,
61.3, 60.4, 58.3, 57.9, 57.8, 57.6, 57.5, 57.1 (Me); ESIMS m/z 1321.4
[M + Na]+, 1337.3 [M + K]+. Anal. Calcd for C60H98O30: C, 55.46; H
7.60. Found: C, 55.37; H, 7.55.
2I-O-(2-Hydroxymethylbenzyl)cyclomaltooctaose (50). Com-
pound 50 was purified by semipreparative HPLC (tR 40.0 min).
Amorphous solid. Yield: 99 mg (7%); Rf = 0.37 (6:3:1 MeCN/H2O/
NH4OH); [α]D = +119.0 (c 0.5 in MeOH); UV (MeOH) 212 nm
(εmM 11.0); IR (ATR) νmax 3350, 2923, 1663, 1413, 1156, 1080, 1025
cm−1; 1H NMR (500 MHz, D2O) δ 7.40−7.29 (m, 4 H, Ph), 5.19 (d,
1 H, J1,2 = 3.5 Hz, H-1I), 5.02−4.98 (m, 7 H, H-1II−VIII), 4.82, 4.80 (2
d, 2 H, 2JH,H = 12.4 Hz, CHPh), 4.70, 4.66 (2 d, 2 H, 2JH,H = 12.8 Hz,
CHPh), 3.96 (t, 1 H, J2,3 = J3,4 = 9.5 Hz, H-3I), 3.82−3.72 (m, 31 H,
H-3II−VIII, H-5I−VIII, H-6aI−VIII, H-6bI−VII), 3.56−3.44 (m, 16 H, H-
2
II−VIII,3II−VIII,6I−VIII-Docosa-O-methyl-2I,3I-O-(o-xylylene)-
cyclomaltooctaose (51). Amorphous solid. Yield: 147 mg (54%); Rf =
1
0.24 (20:1 DCM/MeOH); [α]D = +177.7 (c 1.0, CHCl3); H NMR
(500 MHz, CDCl3) δ 7.24−6.98 (m, 4 H, Ph), 5.22, 4.75 (2 d, 2 H,
2JH,H = 12.7 Hz, CHPh), 5.08 (bs, 2 H, CH2Ph), 5.06 (d, 1 H, J1,2 = 3.6
Hz, H-1I), 5.30−5.08 (m, 7 H, H-1II−VIII), 4.91, 4.59 (2 d, 2 H, 2JH,H
=
12.9 Hz, CHPh), 3.87−3.70 (m, 9 H, H-6aI−VIII, H-3I), 3.70−3.62 (m,
24 H, H-3II−VIII, H-5I−VIII, H-6bI−VIII, H-2I), 3.27−3.11 (m, 7 H, H-
4
I−VIII, H-2I−VIII); 1D TOCSY (H-1I irradiation) δ 3.96 (d, 1 H, H-3I),
3.74 (m, 3 H, H-5I, H-6aI, H-6bI), 3.52 (m, 2 H, H-2I, H-4I); 13C
NMR (125.7 MHz, D2O) δ 139.1−128.3 (Ph), 101.6, 101.5, 101.3,
101.1 (C-2I, C-1II−VIII), 99.1 (C-1I), 80.4, 80.2, 80.0, 79.5, 79.4 (C-
2
II−VIII), 3.66, 3.63, 3.62, 3.58, 3.53, 3.51, 3.50, 3.49, 3.46, 3.45, 3.44,
3.43, 3.42, 3.32, 3.31 (18 s, 66 H, Me); 1D TOCSY (H-1I irradiation)
δ 3.82 (d, 1 H, J5,6a = 2.4 Hz, J6a,6b = 8.9 Hz, H-6aI), 3.79 (t, 1 H, J3,4
=
4
I−VIII), 72.9 (C-3II−VIII), 72.3 (C-2II−VIII), 72.1 (C-3I), 71.8, 71.6, 71.4
J4,5 = 9.0 Hz, H-4I), 3.71 (t, 1 H, J2,3 = 9.0 Hz, H-3I), 3.68 (m, 2 H, H-
5I, H-6bI), 3.54 (dd, 1 H, J1,2 = 3.0 Hz, H-2I); 13C NMR (125.7 MHz,
CDCl3) δ 138.0−127.0 (Ph), 99.6 (C-1I), 98.5, 98.2, 98.1, 98.0, 97.8,
97.7 (C-1II−VIII), 82.4, 82.3, 82.2, 82.1, 82.0, 81.9, 81.8, 81.7, 81.6 (C-
(C-5I−VIII), 71.6, 71.2 (CH2Ph), 61.3 (CH2Ph), 60.2 (C-6I−VIII);
ESIMS m/z 728.1 [M + K + H]2+. Anal. Calcd for C56H88O41: C,
47.46; H, 6.26. Found: C, 47.33; H, 6.46.
General Procedure for Synthesis of Permethylated Cyclo-
dextrin Derivatives 41, 46, and 51. To a solution of
monoxylylenated cyclodextrin derivatives 38, 44, or 49 (0.16 mmol)
in dry DMF (12 mL) at 0 °C under Ar atmosphere were added NaH
(60% in mineral oil, 589 mg, 14.73 mmol) and MeI (917 μL, 14.73
mmol), and the mixture was stirred at room temperature for 12 h.
Then, the reaction mixture was quenched with water (15 mL) and
extracted with Et2O (4 × 15 mL). The combined organic layer was
washed with water (3 × 10 mL), dried (Na2SO4), concentrated, and
purified by column chromatography using 20:1 DCM/MeOH as
eluent to yield the corresponding methylated compounds 41, 46, and
51.
2
I−VIII, C-3II−VIII), 81.4 (C-3I), 80.0, 79.8, 79.4, 79.2, 79.1, 77.8, 77.2,
77.0 (C-4I−VIII), 74.4 (CH2Ph), 72.6 (CH2Ph), 71.4, 71.3, 71.1, 71.0,
70.8, 70.7 (C-5I−VIII, C-6I−VIII), 61.8, 61.4, 61.3, 61.1, 61.0, 59.2, 59.1,
59.0, 58.7, 58.6, 58.4 (Me); ESIMS m/z 1729.8 [M + Na]+, 1745.8 [M
+ K]+. Anal. Calcd for C78H130O40: C, 54.85; H 7.67. Found: C, 54.85;
H, 7.70.
General Procedure for Synthesis of Cyclodextrin Derivatives
42, 47, and 52. To a solution of methylated derivatives 41, 46, or 51
(0.16 mmol) in 1:1 EtOAc/MeOH (10 mL) and aqueous HCOOH
(10%, 1.6 mL) was added 10% Pd/C (80 mg). The resulting
suspension was hydrogenated at 1 atm for 16 h, then filtered through
Celite, and concentrated. The residue was purified by column
chromatography using the eluent indicated in each case to afford the
corresponding methylated derivatives 42, 47, and 52.
2
II−VII,3II−VII,6I−VII-Nonadeca-O-methyl-2I,3I-O-(o-xylylene)-
cyclomaltoheptaose (41). Amorphous solid. Yield: 243 mg (99%); Rf
= 0.23 (20:1 DCM/MeOH); [α]D = +164.3 (c 1.0, CHCl3); UV
(MeOH) 216 nm (εmM 6.9); IR (ATR) νmax 2927, 1457, 1135, 1033
2
II−VII,3II−VII,6I−VII-Nonadeca-O-methylcyclomaltoheptaose (42).
1
cm−1; H NMR (500 MHz, D2O) δ 7.25−7.13 (m, 4 H, Ph), 5.26−
Column chromatography, eluent 10:1:0 → 10:1:0.5 MeCN/H2O/
NH4OH) gave 42 as an amorphous solid. Yield: 137 mg (60%); Rf =
0.42 (10:1:0.5 MeCN/H2O/NH4OH); [α]D = +158.7 (c 1.0, CHCl3);
5.14 (m, 7 H, H-1I−VII), 4.98, 4.91 (2 d, 2 H, 2JH,H = 14.6 Hz, CHPh),
2
4.95, 4.92 (2 d, 2 H, JH,H = 14.5 Hz, CHPh), 3.85 (m, 1 H, H-6aI),
1
IR (ATR) νmax 3443, 2929, 1454, 1143, 1034 cm−1; H NMR (500
3.79−3.67 (m, 6 H, H-6aII−VII), 3.68−3.52 (m, 7 H, H-4I−VII), 3.66−
3.43 (m, 7 H, H-6bI−VII), 3.64−3.43 (m, 8 H, H-3I−VII, H-2I), 3.58−
3.40 (m, 7 H, H-5I−VII), 3.28−3.17 (m, 6 H, H-2II−VII), 3.57, 3.53, 3.48,
3.47, 3.44, 3.43, 3.41, 3.38 ( × 2), 3.36, 3.27 ( × 3), 3.26 ( × 3), 3.25,
3.23, 3.17 (15 s, 57 H, Me); 1D TOCSY (H-6aI irradiation) δ 5.17 (d,
1 H, J1,2 = 3.7 Hz, H-1I), 3.78 (t, 1 H, J2,3 = J3,4 = 9.5 Hz, H-3I), 3.67
(dd, 1 H, J6a,6b = 11.0 Hz, J5,6b = 4.0 Hz, H-6bI), 3.60 (t, 1 H, J4,5 = 10.5
Hz, H-4I), 3.57 (m, 1 H, H-5I), 3.44 (dd, 1 H, H-2I); 13C NMR (125.7
MHz, D2O) δ 136.7−128.1 (Ph), 98.1 (C-1I), 97.7, 97.6, 97.5, 97.3,
96.7, 96.2 (C-1II−VII), 81.6, 81.5, 81.2, 81.0 (C-3II−VII), 80.5, 80.3, 80.2
(C-2II−VII), 79.9 (C-3I), 79.2 (C-2I), 77.9, 77.8, 77.7, 76.9, 76.0, 75.6
(C-4I−VII), 73.3 (CH2Ph), 72.4 (CH2Ph), 70.6, 70.5 (C-5I−VII), 70.9,
70.8, 70.6, 70.5, 70.4 (C-6II−VII), 69.5 (C-6I), 60.2, 60.6, 60.0, 59.7,
58.5, 58.4, 58.3, 58.2, 58.0 (Me); FABMS m/z 1526 (100%, [M +
Na]+). Anal. Calcd for C69H114O35: C, 55.12; H 7.64. Found: C, 54.93;
H, 7.46.
MHz, D2O) δ 5.18−5.14 (m, 6 H, H-1II−VII), 4.94 (d, 1 H, J1,2 = 3.6,
H-1I), 3.80−3.64 (m, 8 H, H-6aI−VII, H-3I), 3.66−3.63 (m, 6 H, H-
4
II−VII), 3.66−3.43 (m, 10 H, H-6bI−VII, H-4I, H-5I, H-2I), 3.62−3.53
(m, 12 H, H-3II−VII, H-5II−VII), 3.29−3.21 (m, 6 H, H-2II−VII), 3.52,
3.49, 3.43, 3.40, 3.27, 3.26 (7 s, 57 H, Me); 1D TOCSY (H-1I
irradiation) δ 3.79 (t, 1 H, J2,3 = J3,4 = 9.5 Hz, H-3I), 3.64 (dd, 1 H,
J6a,6b = 11.5 Hz, H-6aI), 3.57 (m, 1 H, H-6bI), 3.50 (m, 2 H, J4,5 = 9.5
Hz, H-4I, H-5I), 3.45 (dd, 1 H, H-2I); 13C NMR (125.7 MHz, D2O) δ
100.3 (C-1I), 98.2, 97.6, 97.4, 97.1, 96.9, 96.8 (C-1II−VII), 81.5, 81.2,
81.1, 80.9, 80.7, 80.4, 80.2, 80.0 (C-2II−VII, C-3II−VII), 77.8, 77.3, 77.0,
76.6 (C-4I−VII), 73.0 (C-3I), 71.8 (C-2I), 70.8, 70.7, 70.6, 70.5, 70.4,
70.3, 70.2 (C-5I−VII, C-6I−VII), 60.3, 59.8, 59.7, 59.5, 59.4, 58.9, 58.4,
58.2, 58.1, 58.0 (Me); ESIMS m/z 1423 [M + Na]+. Anal. Calcd for
C61H108O35: C, 52.28; H; 7.77. Found: C, 52.32; H, 7.78.
2
II−VI,3II−VI,6I−VI-Hexadeca-O-methylcyclomaltohexaose (47). Col-
II−VI,3II−VI,6I−VI-Hexadeca-O-methyl-2I,3I-O-(o-xylylene)-
umn chromatography, eluent 10:1:0 → 10:1:0.5 MeCN/H2O/
NH4OH) gave 47 as an amorphous solid. Yield: 180 mg (94%); Rf
= 0.50 (10:1:1 MeCN/H2O/NH4OH); [α]D = +166.7 (c 1.0, CHCl3);
2
cyclomaltohexaose (46). Amorphous solid. Yield: 185 mg (89%); Rf
= 0.28 (20:1 DCM/MeOH); [α]D = +162.6 (c 1.0, CHCl3); UV
(MeOH) 214 nm (εmM 7.3); IR (ATR) νmax 2931, 1457, 1365, 1139,
1
IR (ATR) νmax 3447, 2935, 1454, 1032 cm−1; H NMR (500 MHz,
1
1026 cm−1; H NMR (500 MHz, D2O) δ 7.20−7.09 (m, 4 H, Ph),
D2O) δ 5.11−5.08 (m, 5 H, H-1II−VI), 4.89 (d, 1 H, J1,2 = 3.9, H-1I),
2
5.26, 4.94 (2 d, 2 H, JH,H = 15.6 Hz, CHPh), 5.16−4.92 (m, 6 H, H-
3.83 (t, 1 H, J2,3 = J3,4 = 9.3 Hz, H-3I), 3.80−3.55 (m, 28 H, H-4II−VI
,
2
1
I−VI), 4.91, 4.59 (2 d, 2 H, JH,H = 12.9 Hz, CHPh), 3.92 (dd, 1 H,
H-3II−VI, H-5I−VI, H-6aI−VI, H-6bI−VI), 3.47 (m, 1 H, H-4I), 3.45 (m, 1
H, H-2I), 3.28−3.13 (m, 5 H, H-2II−VI), 3.52, 3.50, 3.49, 3.44, 3.38,
3.28 (7 s, 58 H, Me); 1D TOCSY (H-3I irradiation) δ 4.90 (d, 1 H, H-
1I), 3.80 (m, 1 H, H-5I), 3.62 (m, 2 H, H-6aI, H-6bI), 3.47 (t, 1 H, J3,4
= J4,5 = 10.5 Hz, H-4I), 3.45 (dd, 1 H, H-2I); 13C NMR (125.7 MHz,
J6a,6b = 10.9 Hz, J5,6a = 3.9 Hz, H-6aI), 3.80−3.60 (m, 13 H, H-6aII−VI
H-6bI−VI, H-5I, H-3I), 3.59−2.56 (m, 17 H, H-3II−VI, H-4I−VI, H-5I−VI
,
,
H-2I), 3.24−2.94 (m, 5 H, H-2II−VI), 3.77, 3.53, 3.48, 3.42, 3.40, 3.37,
3.32, 3.29, 3.28, 3.26, 3.25, 3.09 (12 s, 48 H, Me); 1D TOCSY (H-6aI
1400
dx.doi.org/10.1021/jo302178f | J. Org. Chem. 2013, 78, 1390−1403

The Journal of Organic Chemistry
Article
D2O) δ 101.1 (C-1I), 99.8, 98.5, 98.4, 98.1 (C-1II−VI), 81.8 (C-2I),
81.6, 81.4, 80.9, 80.2, 80.1, 79.7, 78.7 (C-2II−VI, C-3II−VI, C-4I−VI), 73.2
(C-3I), 71.4, 71.1, 71.0, 70.9, 70.8, 70.7, 70.4 (C-5I−VI, C-6I−VI), 60.9,
60.4, 60.2, 58.9, 58.4, 58.3, 57.7, 57.5, 57.4 (Me); ESIMS m/z 1219.4
[M + Na]+; 1235.4 [M + K]+. Anal. Calcd for C52H92O30: C, 52.17; H
7.75. Found: C, 52.01; H, 7.40.
71.5, 71.4, 71.3, 71.2, 71.1 (C-5II−VI, C-6II−VI), 71.2 (C-2I), 70.8 (C-6I),
69.3 (C-3I), 62.1 (C-5I), 61.8, 61.7, 60.3, 59.1, 59.0, 58.9, 57.9, 57.8,
57.7, 57.6 (Me), 21.1, 20.9 (MeCO); ESIMS m/z 1303.5 ([M +
Na]+); 1319.5 ([M + K]+). Anal. Calcd for C56H96O32: C, 52.49; H,
7.55. Found: C, 52.42; H, 7.68
2I,3I-Di-O-acetyl-2II−VIII,3II−VIII,6I−VIII-docosa-O-methylcyclomal-
tooctaose (53). Amorphous solid. Yield: 81 mg (80%); Rf = 0.23
2
II−VIII,3II−VIII,6I−VIII-Docosa-O-methylcyclomaltooctaose (52). Col-
1
(20:1 DCM/MeOH); [α]D = +142.7 (c 1.0, CHCl3); H NMR (500
umn chromatography, eluent 10:1:0 → 10:1:1 MeCN/H2O/NH4OH
gave 52 as an amorphous solid. Yield: 180 mg (70%); Rf = 0.44
MHz, CDCl3) δ 5.53 (dd, 1 H, J2,3 = 10.5 Hz, J3,4 = 9.0 Hz, H-3I),
5.34−4.95 (m, 7 H, H-1II−VIII), 5.24 (d, 1H, J1,2 = 3.5 Hz, H-1I), 4.72
(dd, 1 H, H-2I), 3.94 (dd, 1 H, J6a,6b = 10.8 Hz, J5,6a = 3.4 Hz, H-6aI),
3.91−3.78 (m, 9 H, H-6aII−VIII, H-5I), 3.78−3.60 (m, 8 H, H-4I−VIII),
3.60−3.45 (m, 7 H, H-3II−VIII), 3.56−3.45 (m, 15 H, H-5II−VIII, H-
6bI−VIII), 3.69, 3.68, 3.63, 3,62, 3.56, 3.52, 3.51, 3.50, 3.49, 3.47, 3.45,
3.41 (14 s, 66 H, Me), 3.21−3.08 (m, 7 H, H-2II−VIII), 2.06, 2.03 (2 s, 6
H, MeCO); 1D TOCSY (H-2I irradiation) δ 5.53 (dd, 1 H, H-3I), 5.24
(d, 1 H, H-1I), 3.95 (dd, 1 H, H-6aI), 3.81 (m, 1 H, H-5I), 3.76 (t, 1 H,
J4,5 = 9.2 Hz, H-4I), 3.49 (d, 1 H, H-6bI); 13C NMR (125.7 MHz,
CDCl3) δ 170.1, 170.0 (CO), 98.6, 98.0, 97.8, 97.7, 97.6, 97.4 (C-
1
(10:1:1 MeCN/H2O/NH4OH); [α]D = +167.5 (c 1.0, CHCl3); H
NMR (500 MHz, D2O) δ 5.32−5.25 (m, 7 H, H-1II−VIII), 5.05 (d, 1 H,
J1,2 = 3.6, H-1I), 3.93−3.74 (m, 16 H, H-6aII−VIII, H-4II−VIII, H-5I, H-
3I), 3.71−3.52 (m, 16 H, H-5II−VIII, H-6aI, H-6bI−VIII), 3.53 (m, 1 H,,
H-4I), 3.41 (dd, 1H, J2,3 = 10.1, H-2I), 3.32−3.25 (m, 7 H,, H-2I−VIII),
3.48, 3.47, 3.45, 3.44, 3.43, 3.29, 3.28 (7 s, 48 H, Me); 1D TOCSY (H-
1I irradiation) δ 3.88 (m, 1 H, H-5I), 3.82 (t, 1 H, J2,3 = J3,4 = 9.5 Hz,
H-3I), 3.62 (m, 1 H, H-6aI), 3.58 (m, 1 H, H-6bI), 3.53 (t, 1 H, J4,5
=
9.5 Hz, H-4I), 3.30 (dd, 1 H, H-2I); 13C NMR (125.7 MHz, D2O) δ
99.4 (C-1I), 96.4, 96.2, 95.8, 95.6, 95.2, 95.1 (C-1II−VIII), 81.2, 81.0,
80.9, 80.7, 80.6, 80.4, 80.3, 80.1 (C-2II−VIII, C-3II−VIII), 77.8, 75.5,
75.0,74.6, 74.5, 74.2, 73.3, 73.1 (8 C, C-4I−VIII), 72.4 (C-3I), 71.7 (C-
2I), 70.9, 70.8, 70.7, 70.6, 70.5, 60.9, 69.8, 69.7, 69.4 (C-5I−VIII, C-
1
2
4
6
II−VIII), 98.0 (C-1I), 82.6, 82.5, 82.3, 82.0, 81.9, 81.8, 81.6, 81.5 (C-
II−VIII, C-3II−VIII), 80.3, 80.2, 79.5, 78.1, 77.1, 76.8, 76.6, 76.0 (C-
I−VIII), 71.7 (C-2I), 71.4, 71.3, 71.2, 71.1, 71.0, 70.9, 70.6 (C-5I−VIII, C-
I−VIII), 69.8 (C-3I), 62.1, 62.0, 61.8, 61.5, 61.3, 61.1, 60.9, 59.2, 59.1,
6
I−VIII), 58.9, 58.8, 58.6, 58.5, 58.4, 58.3, 58.2, 58.1, 57.9, 57.6 (Me);
ESIMS m/z 1627.7 [M + Na]+; 1643.7 [M + K]+. Anal. Calcd for
C70H124O40: C, 52.36; H 7.78. Found: C, 52.31; H, 7.83.
59.0, 58.8, 58.6, 58.5, 58.1 (Me), 21.1, 20.7 (MeCO); ESIMS m/z
1711.8 [M + Na]+; 1728.7 [M + K]+. Anal. Calcd for C74H128O42: C,
52.60; H, 7.64. Found: C, 52.46; H, 7.52.
General Procedure for Synthesis of 2I,3I-Di-O-acetylated
Cyclodextrin Derivatives 43, 48, and 53. The 2I,3I-unprotected
derivative 42, 47, or 52 (0.06 mmol) was dissolved in Ac2O/pyridine
(1:1, 1 mL) and stirred at 45 °C for 4 days. Then, water (10 mL) was
added, and the mixture was extracted with DCM (4 × 5 mL). The
combined organic layer was washed with H2SO4 (2 N, 35 mL) and
saturated aqueous NaHCO3 (2 × 5 mL), dried (Na2SO4), filtered, and
concentrated. The residue was purified by column chromatography
using 20:1 DCM/MeOH as eluent to give the corresponding
diacetylated derivatives 43, 48, and 53.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of newly synthesized compounds and
HPLC chromatograms of compounds 38−40, 44, 45, 49, and
50. This material is available free of charge via the Internet at
http://pubs.acs.org.
2I,3I-Di-O-acetyl-2II−VII,3II−VII,6I−VII-nonadeca-O-methylcyclomalto-
heptaose (43). Amorphous solid. Yield: 53 mg (60%); Rf = 0.18 (20:1
AUTHOR INFORMATION
Corresponding Author
*E-mail: jljb@us.es; jogarcia@iiq.csic.es.
■
1
DCM/MeOH); [α]D = +145.2 (c 1.0, CHCl3); H NMR (500 MHz,
CDCl3) δ 5.51 (dd, 1 H, J2,3 = 10.6 Hz, J3,4 = 9.4 Hz, H-3I), 5.21 (d, 1
H, J1,2 = 3.6 Hz, H-1I), 5.15−4.93 (m, 6 H, H-1II−VII), 4.76 (dd, 1 H,
H-2I), 3.98 (dd, 1 H, J6a,6b = 10.9 Hz, J5,6a = 3.5 Hz, H-6aI), 3.87−3.71
(m, 14 H, H-4I−VII, H-6aII−VII, H-5I), 3.60−3.44 (m, 13 H, H-5II−VII, H-
6bI−VII), 3.53−3.48 (m, 6 H, H-3II−VII), 3.63, 3.62, 3.60, 3.58, 3.55,
3.53, 3.48, 3.46, 3.42, 3.37, 3.35 (12 s, 57 H, Me), 3.17−3.05 (m, 6 H,
H-2II−VII), 2.06 (s, 6 H, MeCO); 1D TOCSY (H-1I irradiation) δ 5.51
(dd, 1 H, H-3I), 4.76 (dd, 1 H, H-2I), 3.98 (dd, 1 H, H-6aI), 3.86 (m, 1
H, H-5I), 3.75 (t, 1 H, J4,5 = 9.5 Hz, H-4I), 3.55 (d, 1 H, H-6bI); 13C
NMR (125.7 MHz, CDCl3) δ 170.7, 170.2 (CO), 99.5, 99.3, 98.9 (C-
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This study was supported by the Spanish Ministerio de Ciencia
■
e Innovacio
́
n (contract numbers SAF2010-15670 and
́
CTQ2010-15848), the Junta de Andalucia (Project P08-
FQM-03711), and the European Regional Development
Funds (FEDER and FSE).
1
II−VII), 98.2 (C-1I), 82.7, 82.4, 82.1, 82.0, 81.9, 81.8 (C-2II−VII), 81.7,
81.5, 81.2 (6 C, C-3II−VII), 80.7, 80.6, 80.4, 79.6 (C-4II−VII), 78.6 (C-
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■
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