Direct experimental evidence for the high chemical reactivity of α- and β-xylopyranosides adopting a 2,5B conformation in glycosyl transfer

Article abstract of DOI:10.1002/chem.201003251

The effect of a ^2,5B boat conformation on xyloside reactivity has been investigated by studying the hydrolysis and glycosylation of a series of synthetic xyloside analogues based on a 2-oxabicyclo[2.2.2]octane framework, which forces the xylose analogue to adopt a ^2,5B conformation. The locked β-xylosides were found to hydrolyze 100-1200 times faster than methyl β-D-xylopyranoside, whereas the locked α-xylosides hydrolyzed up to 2× 10⁴ times faster than methyl α-D-xylopyranoside. A significant rate enhancement was also observed for the glycosylation reaction. The high reactivity of these conformers can be related to the imposition of a ^2,5B conformation, which approximates a transition state (TS) boat conformation. In this way, the energy penalty required to go from the chair to the TS conformation is already paid. These results parallel and support the observation that the GH-11 xylanase family force their substrate to adopt a ^2,5B conformation to achieve highly efficient enzymatic glycosidic bond hydrolysis. Copyright

Full text of DOI:10.1002/chem.201003251

FULL PAPER
DOI: 10.1002/chem.201003251
Direct Experimental Evidence for the High Chemical Reactivity of a- and
2,5
b-Xylopyranosides Adopting a B Conformation in Glycosyl Transfer
Luis Amorim,[a] Filipa Marcelo,[a, b] Cyril Rousseau,[c, g] Lidia Nieto,[d]
Jesffls JimØnez-Barbero,[d] JØrôme Marrot,[e] AmØlia P. Rauter,[b] Matthieu Sollogoub,[a]
Mikael Bols,[c] and Yves BlØriot*[a, f]
Dedicated to Professor Pierre Sinaꢀ
Abstract: The effect of a 2,5B boat con-
formation on xyloside reactivity has
been investigated by studying the hy-
drolysis and glycosylation of a series of
synthetic xyloside analogues based on
faster than methyl a-d-xylopyranoside.
A significant rate enhancement was
also observed for the glycosylation re-
action. The high reactivity of these con-
formers can be related to the imposi-
tion of a 2,5B conformation, which ap-
proximates a transition state (TS) boat
conformation. In this way, the energy
penalty required to go from the chair
to the TS conformation is already paid.
These results parallel and support the
observation that the GH-11 xylanase
family force their substrate to adopt a
2,5B conformation to achieve highly ef-
ficient enzymatic glycosidic bond hy-
drolysis.
a 2-oxabicycloACHTUNGTRENNUNG[2.2.2]octane framework,
which forces the xylose analogue to
adopt a 2,5B conformation. The locked
b-xylosides were found to hydrolyze
100–1200 times faster than methyl b-d-
xylopyranoside, whereas the locked a-
xylosides hydrolyzed up to 2ꢁ104 times
Keywords: conformation analysis ·
enzyme catalysis · glycosides · gly-
cosylation · hydrolysis · structure–
activity relationships
Introduction
2-fluorosugars[4] enabled the trapping of both covalent gly-
cosyl–enzyme intermediates and Michaelis complexes, al-
lowing dissection of the mechanism at the atomic level of an
increasing number of glycosidases. The chemical hydrolysis
of glycosides has also been much studied and is known to
proceed by a specific acid-catalyzed process in which the
rate-determining step is the formation of a cyclic oxacarbe-
nium-like ion intermediate.[5] Although an understanding of
the mechanism has reached a high level of sophistication,[6]
some of its more subtle aspects, including transition-state
Glycosyl transfer is a biologically important process.[1] An
in-depth understanding of its mechanism is of central impor-
tance for synthetic manipulations of sugars[2] and for eluci-
dating the biochemical requirements by which glycosidases
act on natureꢀs oligosaccharides.[3] Dramatic progress has
been achieved in recent years on understanding chemical
and enzymatic glycosyl transfer reactions. X-ray crystallo-
graphic analysis of glycosidases in the presence of 2-deoxy-
[a] L. Amorim, F. Marcelo, Prof. M. Sollogoub, Prof. Y. Blꢂriot
UPMC Univ Paris 06
[f] Prof. Y. Blꢂriot
Present address:
Institut Parisien de Chimie Molꢂculaire (UMR 7201)
FR 2769, C181, 4 place Jussieu
75005 Paris (France)
Universitꢂ de Poitiers, UMR 6514
Laboratoire “Synthꢅse et Rꢂactivitꢂ des Substances Naturelles”
40 avenue du Recteur Pineau, 86022 Poitiers Cedex (France)
E-mail: yves.bleriot@univ-poitiers.fr
[b] F. Marcelo, Prof. A. P. Rauter
Carbohydrate Chemistry Group, CQB-FCUL
Departamento de Quꢃmica e Bioquꢃmica
Faculdade de CiÞncias da Universidade de Lisboa
1749-016 Lisbon (Portugal)
[g] Dr. C. Rousseau
Present address:
Universitꢂ d’Artois, IUT de Bꢂthune
UCCS Artois, UMR 8181
1230 rue de l’Universitꢂ, BP 819
62408 Bꢂthune cedex (France)
[c] Dr. C. Rousseau, Prof. M. Bols
Department of Chemistry, University of Copenhagen
Universitetsparken 5, 2100 Kbh Ø (Denmark)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003251.
[d] Dr. L. Nieto, Prof. J. Jimꢂnez-Barbero
Centro de Investigaciones Biolꢄgicas
CSIC, 28040 Madrid (Spain)
[e] Dr. J. Marrot
Institut Lavoisier
Universitꢂ de Versailles-Saint-Quentin
UMR 8180, 78035 Versailles (France)
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7345

(TS) conformation, are still under investigation, because the
transient nature of the cyclic oxacarbenium ion has so far
prevented its direct observation.[7] Several techniques have
been exploited to gain further insight into this conforma-
tional aspect, including kinetic isotope effect measure-
ments[8] and computational chemistry.[9] Kinetic studies of
the hydrolysis of glycosides and analogues is also a powerful
method to probe the pseudorotational itinerary of glycosides
during glycosyl transfer.
conformation to the invoked 2,5B conformation, which may
stereoelectronically assist the formation and breakdown of
the glycosidic bond. The influence of a boat conformation
on the reactivity of simple tetrahydropyranyl acetals was
previously investigated by Kirby, Deslongchamps and co-
workers,[18] who studied acetals of type B in which the THP
ring was fixed in the symmetrical boat conformation by a
three-carbon bridge. An increase of reactivity towards spon-
taneous hydrolysis was observed for these compounds, and
some part of this higher reactivity was attributed to the
higher ground-state energy of the boat conformation. For
our purpose, we used a similar strategy to design and study
xylopyranoside analogues locked in the requisite 2,5B boat
conformation. The atomic framework mimicking xylopyra-
nose has to be sufficiently rigid to restrict conformational
preferences but not too constraining to avoid undesired al-
ternative pathways for the reaction. To retain all the hydrox-
yl groups of the parent glycoside, unlike previously reported
glucoside analogues,[19] and force the pyranose ring into a
The hydrolysis of glycosides proceeds via transition states
that display substantial oxacarbenium-ion like structures
2
ꢀ
with a double-bond character of the O5 C1 bond and an sp
hybridization of the anomeric carbon. This demands that at,
or extremely close to, this transition state, C5, O5, C1, and
C2 lie in an approximately coplanar conformation, an ar-
rangement accommodated only by 4H3, 3H4, B2,5, and 2,5B
conformations.[10] Whereas half-chair conformers have been
extensively invoked in glycosyl transfer, boat conformers
have aroused some controversy[11] despite an increasing
body of independent experimental data in glycosyl transfer.
Indeed, a 2,5B conformation has been observed by X-ray
crystallography for the xylosyl unit of a covalently linked a-
2-fluoro-xylobioside-enzyme intermediate located in the
“ꢀ1” subsite of the GH-11 b-xylanase family active site, and
has been proposed for the corresponding transition state
A.[12] This hypothesis has been further supported by MM-
boat conformation, a 2-oxabicycloACTHUNTGRNEUNG[2.2.2]octane skeleton was
selected to generate xyloside analogues of type C. Tethering
of the xylopyranose C-2 and C-5 carbon atoms with a two-
carbon bridge, starting from a 2R,5S-bis-vinyl xylopyrano-
side derivative and exploiting the powerful ring-closing
metathesis (RCM) methodology,[20] was chosen. The synthe-
sis of dixyloside mimics containing the bicyclic xyloside was
also achieved.
Results and Discussion
Glycoside synthesis: The synthesis of the methyl b-xyloside
analogue was first investigated; this required a glucopyra-
nose precursor in which hydroxyl groups at the 2- and 6-po-
sitions could be sequentially modified (Scheme 1). The or-
thogonally protected sugar 1[21] was selected as a suitable
starting material. Because installation of the “vinylic arm”
at C-2 by addition of vinyl magnesium bromide onto a
methyl b-2-uloside would predominantly give the wrong
manno-like stereoisomer,[22] sugar 1 was oxidized and olefi-
nated at the 2-position to afford the exomethylenic deriva-
tive 2[23] (65% yield over two steps). Further dihydroxyla-
tion proceeded exclusively from the a-face to quantitatively
afford diol 3. Oxidation of the neopentylic position was
found to be problematic and required preliminary protec-
tion of the tertiary alcohol as its benzyl ether through a sily-
lation/benzylation/desilylation sequence (80% yield over
three steps). The resulting alcohol 4 was oxidized and olefi-
nated to yield the unsaturated derivative 5 (72% yield). In-
stallation of the second vinylic appendage at C-5 was ach-
ieved through regioselective opening of the benzylidene
group to yield alcohol 6 (88% yield), which was transformed
into the key diene 7 (62%).[24] Bicycle ring closure was then
examined. Whereas RCM of 7 failed with first generation
Grubbsꢀ catalyst, cyclization took place smoothly with the
second-generation catalyst to give the highly strained unsa-
turated bicycle 8 in excellent 95% yield. Final hydrogena-
PBSA free energy analysis[13] of Xyl11–substrate complexes
and by recent molecular dynamic simulations using hybrid
QM/MM methodology applied to noncovalent complexes of
phenyl b-xyloside with BCX xylanase and a Tyr69Phe
mutant.[14] Such a conformation is attained more easily for
xylosides than for glucosides owing to the lack of a bulky
hydroxymethyl substituent, which is forced into a pseudo-
ACHTUNGTRENNUNGaxial orientation in the latter case. This could explain the
high specificity of the GH-11 xylanase family for xylosyl
units, in contrast to the more promiscuous behavior of the
GH-10 xylanase family, which utilizes a 4C1 conformation
for the intermediate.[15] The 2,5B conformation has also been
suggested by Hosie and Sinnott for the enzymatic hydrolysis
of glucosides.[16]
As part of an ongoing program on the implication of boat
conformations in glycosyl transfer,[17] and regarding the im-
portance of the 2,5B conformation in enzymatic xyloside hy-
drolysis, we were interested in evaluating the anomeric reac-
4
tivity of xylopyranosides when moving from the classic C1
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Chemical Reactivity of a- and b-Xylopyranosides
FULL PAPER
Scheme 1. Synthesis of locked b-xyloside 9 and diethyl b-xyloside 10.
tion quantitatively furnished the target methyl b-xyloside
analogue 9. In parallel, diene 7 was hydrogenolyzed to yield
the diethyl derivative 10, a b-xyloside analogue adopting a
and 22, respectively (Scheme 3). The synthesis of pseudodix-
ylosides incorporating the bicyclic xylopyranoside unit was
necessary for the structure to resemble the xylanase sub-
strate. Xylosyl donor 18 was therefore transformed into a
more reactive thioxylosyl donor 23 (thiophenol, BF3·OEt2),
which was obtained as mixture of anomers. Coupling of 23
with methyl b-xyloside 24[26] yielded an inseparable mixture
of disaccharides in which the isopropylidene present in 24
had been removed.[27] Peracetylation of the crude mixture
furnished the separable peracetylated a-disaccharide 25 and
b-disaccharide 26 (57% yield over two steps, unoptimized,
1:3 ratio). The crystal structure of the latter was solved.
Final deprotection afforded the a-linked disaccharide 27
and the methyl b-xylobioside analogue 28, respectively. In
parallel, the bicyclic thioxyloside 23 was deacetylated to
yield the unprotected xylosyl donor 29 as a mixture of
anomers (Scheme 3).
conformation
close
to
a
4C1
chair
(J(3,4)=J(4,5a)=8.3 Hz), which was subsequently used as a
A
ACHTUNGTRENNUNG
control compound in the hydrolysis experiments
(Scheme 1).
For the locked methyl a-xyloside, the available methyl a-
glucoside 11[25] was oxidized to the 2-uloside and alkylated
with vinyl magnesium bromide to generate the expected
gluco-like branched derivative 12 (52% yield) along with its
manno-like C-2 epimer (18% yield). An identical sequence
to the one used for xyloside 9 was then applied to yield the
locked methyl a-xyloside 16. To expand the number of
locked xylosides displaying various aglycons, the synthesis of
a conformationally locked xylosyl donor was required. a-
Xyloside 16 was peracetylated to yield triacetate 17, which
furnished the locked xylosyl donor 18 in 67% yield upon
acetolysis at low temperature (Scheme 2). Glycosylation of
isopropanol with 18 in the presence of trimethylsilyl tri-
Conformational analysis: The conformation of the xyloside
analogues was first examined in the solid state. X-ray struc-
tures of compounds 9, 16, and 22 were solved and are shown
in Figure 1.
ACHTUNGTRENNUNG
a
As expected, the locked methyl a-xyloside 16 adopts a
(Scheme 3). The partial anomeric b-selectivity observed
might account for a perturbed anchimeric assistance of the
acetate group at the 2-position due to the unique conforma-
tion of xylosyl donor 18. Deacetylation under Zemplen con-
ditions furnished the locked a- and b-isopropyl xylosides 21
2,5B conformation whereas the b-isopropyl xyloside 22
2
adopts a S0 conformation close to that of the 2,5B boat. In-
terestingly, two independent molecules were observed in the
crystal lattice for the locked methyl b-xyloside 9, which can
2
adopt either a 2,5B or a S0 conformation, indicating some
Scheme 2. Synthesis of locked a-xyloside 16 and xyloside donor 18.
Chem. Eur. J. 2011, 17, 7345 – 7356
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7347

Y. Blꢂriot et al.
Scheme 3. Synthesis of xyloside analogues 21, 22, 27, and 28.
Table 1. X-ray structural data for xylosides 9, 16, and 22.
flexibility is allowed by the 2-oxabicycloACTHNUTRGNEUGN[2.2.2]octane skele-
ton. The ring conformation for each xyloside in the solid
state was also determined by calculations[28] and proved to
match or resemble a 2,5B conformation (Table 1).
Structural features including bond lengths and F torsion
angles around the anomeric center were obtained from the
X-ray structures. The methyl a-derivative 16 displays a
9
2,5B
2,5B
9
2S0
2S0
16
2,5B
2,5B
22
2S0
2S0
conformation: observed
conformation: calculated
bond lengths [ꢇ]
ꢀ
O5 C1
1.418
1.408
1.426
1.405
1.435
1.390
1.424
1.412
ꢀ
C1 O1
torsion angle F [8]
(O5-C1-O1-Csubs)
ꢀ81.1
ꢀ66.8
+72.7
ꢀ59.2
[29]
ꢀ
longer C1 O5 distance (1.435 ꢇ) than methyl a-xyloside
ꢀ
(1.413 ꢇ) and a shortening of the C1 O1 distance (1.390 vs.
1.400 ꢇ). The methyl and isopropyl b-glycosides 9 and 22,
ꢀ
respectively, show a lengthening of the C1 O1 bond (1.408
and 1.412 ꢇ) compared with the unlocked methyl b-xylo-
side[30] (1.381 ꢇ) and a similar C1 O5 distance (ca. 1.42 ꢇ).
ꢀ
The F torsion angle of the locked xylosides were measured
and found to be close to the values observed for a normal
exoanomeric orientation (ꢀ698 for methyl b-xyloside and
+708 for methyl a-xyloside). The conformation of xylosides
9, 16, 21, and 22 in solution was also investigated by NMR
spectroscopy and molecular modeling. The spatial arrange-
ment of the pyranose ring in the four xyloside analogues
after energy minimization are fairly similar, even starting
from different geometries, and indeed adopt a boat-like con-
formation (see the Supporting Information for details).
Good agreement between the experimental and computed
data was observed and additional experimental couplings
were detected that confirmed the existence of boat-like 2,5B
conformers.[31]
Hydrolysis of xylosides: The hydrolysis of methyl xylopyra-
nosides has been studied by Indurugalla and Bennet and is
believed to proceed through an exocyclic bond cleavage
Figure 1. Crystal structures of xyloside analogues 9, 16, and 22.
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Chemical Reactivity of a- and b-Xylopyranosides
FULL PAPER
pathway.[32] Acid-catalyzed hydrolysis of the synthetic
locked xylosides was investigated and monitored either by
polarimetry or by NMR analysis (depending on the amount
of glycoside available) and was shown to follow pseudo-
first-order kinetics.
Table 3, entry 2). For the locked b-xylosides, a significant in-
crease in the rate of hydrolysis was again observed. The bi-
cyclic methyl b-xyloside 9 hydrolyzed 88 times faster (k=
310ꢁ10ꢀ6 sꢀ1 at 358C; Table 3, entry 3), the isopropyl deriva-
tive 22 hydrolyzed 1210 times faster (k=4212ꢁ10ꢀ6 sꢀ1
;
Table 3, entry 4), and the pseudo disaccharide 28 approxi-
mately 800 times (k=2700ꢁ10ꢀ6 sꢀ1; Table 3, entry 5). By
comparison, locked xyloside 9 proved to hydrolyze 165
times faster at 508C (k=3330ꢁ10ꢀ6 sꢀ1) than diethyl xylo-
side 10. The higher reactivity of compound 10 compared
with methyl b-xylopyranoside is undoubtedly due to a minor
extent to the electron donation from the two extra ethyl
groups, which stabilize the oxacarbenium ion intermediate
and thus increase the glycosyl transfer rate. However, the
main contribution probably comes from the fact that the 2-
C-ethyl substituent is sterically crowdedin the axial position,
and stabilizes the 1C4 conformation. The 1C4 conformer is
about 100-fold more reactive, and an increase of just 10%
in the presence of this conformer will be enough to cause
the observed rate increase.[34]
Hydrolysis of a-xylosides: The results of kinetics studies on
the hydrolysis of a-xylosides in 2m HCl at 358C is reported
in Table 2. As a reference, the rate of hydrolysis of methyl
a-xylopyranoside was first determined (k=0.43ꢁ10ꢀ6 sꢀ1).
The hydrolysis of locked a-xylosides was then examined.
For methyl a-xyloside 16, a rate constant of 3100ꢁ10ꢀ6 sꢀ1
was obtained. Similarly, hydrolysis of locked isopropyl a-xy-
loside 21 was measured, giving a rate constant of 10100ꢁ
10ꢀ6 sꢀ1 (Table 2, entry 3). The hydrolysis rate of a-xylobio-
side 27 could not be measured precisely, because the lack of
material only allowed a single experiment. However, it was
possible to ascertain that the hydrolysis rate was much
faster than 3000ꢁ10ꢀ6 sꢀ1 (Table 2, entry 4). Overall, all the
locked a-xylosides are extremely reactive toward aqueous
acid, reacting much faster than methyl a-xylopyranoside,
being hydrolyzed at least 5000 times faster.
Glycosylation: The other main glycosyl transfer reaction,
glycosylation, was also examined using the locked and un-
locked thioxylosides 29 and 30 as glycosyl donors, N-iodo-
succinimide/trifluoromethanesulfonic acid as the promotor
system, and methanol as the acceptor (Scheme 4).
Hydrolysis of b-xylosides: Acid hydrolysis of the locked b-
xyloside analogues was also investigated at 358C in 2m HCl
(Table 3). The rate of hydrolysis for methyl b-xylopyrano-
side was measured by polarimetry, giving a rate constant of
3.49ꢁ10ꢀ6 sꢀ1 at 358C and 20.1ꢁ10ꢀ6 sꢀ1 at 508C (Table 3,
entry 1), which is close to the value reported in the litera-
ture (12.6ꢁ10ꢀ6 sꢀ1).[33] It can be argued that the pyranosidic
ring substitution pattern of the bicyclic xylosides can be
solely responsible for the high hydrolysis rate observed. To
this end, hydrolysis of the diethyl methyl b-xylopyranoside
10 was measured and this compound, which displays two
extra axial and equatorial ethyl groups at C-2 and C-5 re-
spectively, was found to hydrolyze ten times faster at 508C
Scheme 4. Glycosylation with glycosyl donors 29 and 30.
than methyl b-xylopyranoside (200ꢁ10ꢀ6 vs. 20.1ꢁ10ꢀ6 sꢀ1
;
Assuming that the rate-deter-
mining step is the formation of
the cyclic oxacarbenium ion,
formation of iodine was moni-
Table 2. Hydrolysis of methyl a-xylosides and locked xylosides.
Compound
Anomeric
substituent
k [sꢀ1
(358C)
]
Relative hydrolysis
rate (2m HCl, 358C)
G
1
2
3
4
methyl a-xylopyranoside
Me
Me
iPr
0.43ꢁ10ꢀ6
3100ꢁ10ꢀ6
1
7209
23413
@6976
tored by changes in UV absorp-
tion as an expression of the rel-
ative reaction rate.[35] The two
glycosylation reactions were
carried out at room tempera-
ture under pseudo-first-order
conditions, using an excess of
both the acceptor and promo-
tor. Since it was noticed that,
under the reaction conditions,
16
21
27
10100ꢁ10ꢀ6
@3000ꢁ10ꢀ6
methyl b-xylopyranoside
Table 3. Hydrolysis of methyl b-xylosides and locked xylosides.
Compound
Anomeric
substituent
k [sꢀ1] (358C)
Relative hydrolysis
rate (2m HCl, 358C)
1
methyl b- xylopyranoside
Me
3.49ꢁ10ꢀ6
20.1ꢁ10ꢀ6[a]
200ꢁ10ꢀ6[a]
310ꢁ10ꢀ6
1
2
3
10
9
Me
Me
10[a]
88
NIS itself releases iodine,
a
3330ꢁ10ꢀ6[a]
4212ꢁ10ꢀ6
2700ꢁ10ꢀ6
165[a]
1210
770
minor background rate was sub-
tracted for each donor concen-
tration. The results demonstrat-
ed a significant enhancement in
4
5
22
28
iPr
methyl b-xylopyranoside
[a] Measured at 508C.
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7349

Y. Blꢂriot et al.
reactivity of the locked thioxyloside 29 (k=1900ꢁ10ꢀ4 sꢀ1)
that was 226-fold faster than the conformationally flexible
thioxyloside 30[36] (k=8.4ꢁ10ꢀ4 sꢀ1) at performing glycosyla-
tion. In this case, release of steric strain can be excluded as
an explanation for the observed effect. This result can, in
part, be explained by the armed–disarmed–superarmed[37] or
conformational arming[38] principle because the ring hydrox-
yl groups at C-3 and C-4 become pseudoaxial in the bicyclic
xyloside 29. Nevertheless, it has been shown that moving
from a fully equatorial to a fully axial glycosyl donor bear-
ing benzyl and TIPS protecting groups, respectively, which
display similar electronic effects, causes a 20-fold glycosyla-
tion rate enhancement.[35]
lyzed cleavage. Additionally, the unusual structure of the xy-
loside analogues can generate specific steric effects that can
also ease the glycosidic bond hydrolysis to a lesser extent.
Ground state energy differences between different conform-
ers are generally not directly correlated with the transition
state energies, but the conformational constraint imposed by
the [2,2,2] bicyclic system might play a role and favor some
release of ring strain during glycosyl transfer while keeping
the bicycle integrity. Other minor factors, such as solvation
effects,[41] can also play a role in explaining the important
structural discrepancies between the locked and unlocked
xylosides studied in this work.
Conclusions
Discussion
Four monosaccharides 9, 16, 21, and 22 locked in a 2,5B con-
formation have been synthesized as xyloside mimics. Incor-
poration of the locked xylosyl unit in two disaccharides 27
and 28 has been also achieved. All these sugar mimics were
found to hydrolyze very fast in acid and 102–104 times faster
than the corresponding unlocked xylosides; the a-glycosides
being much more reactive than the b-glycosides. A 200-
times rate enhancement was also observed for the glycosyla-
tion reaction using locked xylosyl donors. These data dem-
onstrate that xylosides can have their anomeric reactivity
boosted during chemical glycosyl transfer when adopting a
Reactivity of the constrained xylosides: The clear conclusion
from the results summarized in Tables 2 and 3 is that the
locked xylosides are hydrolyzed at much faster rates than
the corresponding unconstrained xylosides. High to very
high rate enhancements are observed for the hydrolysis or
glycosylation reactions with the locked xylosides. The mech-
anism by which the bicyclic xylosides are hydrolyzed may
follow a classical “exocyclic” pathway, because rate en-
hancements in the same range of magnitude are observed
for the hydrolysis and the glycosylation; the latter being
known to proceed through an exocyclic cleavage mecha-
nism. Additionally, bicyclic xylosides 22 and 26, the struc-
tures of which have been solved by X-ray crystallography,
have been obtained by glycosylation with locked xylosyl
donors 18 and 23, supporting an exocyclic pathway.
2
2,5B or close S0 conformation. This is possible because the
2,5B conformation can theoretically be adopted by the TS
during xyloside hydrolysis, because the sterically encumber-
ing C5 hydroxymethyl group (which can generate unfavor-
AHCTUNGTREGaNNNU ble C2–C5 flagpole positioning in the boat conformation)
The very high reactivity of the locked xylosides can be di-
rectly related to their unusual boat conformation. Ground
state destabilization and the imposition of conformations on
the substrate that approximate those of the oxacarbenium
ion have been investigated by other groups,[39] and it was
found that reactivity increased, because much of the energy
penalty required to go from the chair to the TS conforma-
tion had been already paid. This is also the case here and a
dramatic effect is observed. The locked xylosides are spatial-
ly maintained in a conformation domain that is either close
to or identical to the expected 2,5B conformation for the oxa-
carbenium TS, which perfectly fulfills the stereochemical re-
quirements demanded of an oxacarbenium ion. Glycosyl
transfer can therefore take place with only minimal nuclear
motion through a subtle electrophilic migration of the
anomeric carbon. It can be argued that such a pathway pres-
ents an endocyclic lone pair contribution more akin to syn
elimination geometry and, indeed, Deslongchamps and
Kirby provided solid evidence for such syn geometries.[40] If
we examine the stereoelectronic effects that can take place
in the locked a- and b-xylosides, a significant antiperiplanar
is absent. Therefore, the very high reactivity observed can
be directly related to the fact that much of the energy penal-
ty required to go from the chair to the TS conformation has
been already paid in this case. This trick is already being
used by several glycosidases that distort the pyranose ring of
their substrate towards unusual conformations to achieve a
highly efficient catalytic cycle. This work parallels and sup-
ports substrate distortion towards a 2,5B conformation ob-
served for the GH-11 xylanase family.[12] These results also
suggest that transient 2,5B conformations of xylosides can
indeed be acceptable candidates for direct acid hydrolysis,
as suggested by Berti and Tanaka on the basis of kinetic iso-
tope effect studies.[42]
Experimental Section
Kinetic studies: Rates of hydrolysis of the xylosides were determined
either by polarimetry or NMR analysis depending on the amount of gly-
coside available.
Polarimetric method: A solution of glycoside (ca. 5 mgmLꢀ1 in 2m aq.
HCl) was added to a cuvette that was pre-heated to the desired tempera-
ture. The polarimeter was reset, whereupon the cuvette was positioned in
the apparatus. The optical rotation was measured as a function of time
(sodium lamp). Measurement was continued until the rotational value
had stabilized. The rate of the reaction K was determined at each tem-
nO–s*Cꢀ
interaction can be excluded, but synperiplanar
OR
lone pairs can interact with the s*Cꢀ of both anomers and,
OR
apparently, stabilize the developing oxacarbenium ion char-
acter in the transition state very efficiently during acid-cata-
7350
www.chemeurj.org
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7345 – 7356

Chemical Reactivity of a- and b-Xylopyranosides
FULL PAPER
perature as the slope of the linear regression ln[(a(t)ꢀ-a(1))/
(a(0)ꢀa(1))] versus time (a(t) is the rotation measured at time t, a(1)
is the rotation measured at the end of reaction and a(0) is the rotation
measured at the beginning of reaction). From these temperature experi-
ments the hydrolysis rate was determined at 358C.
clohexane/EtOAc, 2:1) afforded diol 3 (2.63 g, quantitative yield) as a
colorless oil; [a]D =ꢀ140.5 (c=2.0 in CHCl3); 1H NMR (CDCl3,
400 MHz): d=7.52–7.29 (m, 10H; ArH), 5.59 (s, 1H; H-7), 4.92 (d, J=
11.6 Hz, 1H; CHPh), 4.87 (d, J=11.6 Hz, 1H; CHPh), 4.44 (s, 1H; H-1),
4.40 (dd, J=4.8, 10.4 Hz, 1H; H-6), 4.07 (dd, J=4.7, 11.8 Hz, 1H; H-8),
4.00 (dd, J=8.9, 11.8 Hz, 1H; H-8’), 3.84–3.79 (m, 2H; H-3, H-6b), 3.65
(t, J=9.8 Hz, 1H; H-4), 3.64 (app s, 1H; OH), 3.59 (s, 3H; OCH3), 3.48
(ddd, J=4.8, 9.8, 10.0 Hz, 1H; H-5), 2.70 ppm (dd, J=4.7, 8.9 Hz, 1H;
OH); 13C NMR (CDCl3, 100 MHz): d=138.6, 137.6 (ipso ArC), 129.4–
126.4 (10ꢁArC), 107.9 (C-1), 101.8 (C-7), 82.5 (C-3), 80.2 (C-4), 76.0
(CH2Ph), 75.5 (C-2), 69.1 (C-6), 67.6 (C-5), 61.1 (C-8), 58.6 ppm (OCH3);
HRMS (CIMS): m/z calcd for C22H27O7: 403.1757 [M+H]+; found:
403.1760.
NMR method: An NMR spectrum of
a solution of glycoside (ca.
2 mgmLꢀ1 in DCl (2m in D2O)) was taken every 5 min at 358C until the
signal of the starting material disappeared. DMSO was used as a stan-
dard for the shift and integration calibration. The rate of the reaction K
at 358C was determined as the slope of the linear regression ln(signal in-
tegration) versus time.
Crystallography: CCDC-679052 (9), 703314 (16), 703315 (22), and 682061
(26) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Compound 4: tert-Butyldimethylsilyl chloride (2.89 g, 19.29 mmol) and
DMAP (0.39 g, 3.21 mmol) were added to a solution of diol 3 (2.60 g,
6.43 mmol) in anhydrous pyridine (7 mL) at RT under argon. The reac-
tion mixture was stirred at RT overnight and then at 608C for 3 h to com-
plete the reaction. The reaction mixture was co-evaporated with toluene
under reduced pressure and then diluted with CH2Cl2 (100 mL) and
water (40 mL). The organic layer was separated, dried (MgSO4), and con-
centrated. The crude silylated product was directly engaged in the next
step. Sodium hydride (1.00 g, 25.72 mmol, 60% w/w) was added to a solu-
tion of the crude silylated product in anhydrous DMF (20 mL) at 08C.
After 30 min stirring, BnBr (4.60 mL, 38.57 mmol) was added at 08C and
the reaction mixture was stirred overnight at RT. Methanol (10 mL) was
added and the mixture was concentrated under reduced pressure. The
residue was then diluted with Et2O (100 mL) and water (40 mL). The
aqueous layer was extracted with Et2O (3ꢁ80 mL) and the organic layers
were combined, dried (MgSO4), filtered, and concentrated under reduced
pressure. The crude, fully protected product was engaged in the next step
without further purification. TBAF (1m in THF, 19.29 mL, 19.29 mmol)
was added to a solution of the fully protected product in THF (15 mL).
After 6 h, the reaction mixture was diluted with water (30 mL) and
CH2Cl2 (80 mL) and the aqueous layer was extracted with CH2Cl2 (3ꢁ
60 mL). The organic layers were combined, dried (MgSO4), filtered, and
concentrated. Purification by flash chromatography (cyclohexane/EtOAc,
5:1) afforded alcohol 4 (2.53 g, 80% over three steps) as a white solid;
m.p. 1128C (cyclohexane/EtOAc); [a]D =ꢀ22.8 (c=1.0 in CHCl3);
1H NMR (CDCl3, 400 MHz): d=7.58–7.34 (m, 15H; ArH), 5.68 (s, 1H;
H-7), 5.07 (d, J=11.1 Hz, 1H; CHPh), 5.00 (d, J=10.9 Hz, 1H; CHPh),
4.97 (d, J=10.9 Hz, 1H; CHPh), 4.87 (d, J=11.1 Hz, 1H; CHPh), 4.54 (s,
1H; H-1), 4.48–4.43 (m, 2H; H-6, H-8), 4.31 (dd, J=3.5, 13.1 Hz, 1H; H-
8’), 4.04–3.98 (m, 2H; H-3, H-4), 3.89 (t, J=10.2 Hz, 1H; H-6’), 3.74 (dd,
J=3.5, 8.4 Hz, 1H; CH2OH), 3.59 (s, 3H; OCH3), 3.58–3.52 ppm (m,
1H; H-5); 13C NMR (CDCl3, 100 MHz): d=139.8, 138.2, 137.7 (ipso
ArC), 129.5–126.5 (15ꢁArC), 107.5 (C-1), 101.8 (C-7), 85.2 (C-3 or C-4),
81.0 (C-4 or C-3), 80.0 (C-2), 76.5 (CH2Ph), 69.2 (C-6), 67.6 (C-5), 67.3
(CH2Ph), 59.4 (C-8), 58.1 ppm (OCH3); HRMS (CIMS): m/z calcd for
C29H36O7N: 510.2492 [M+NH4]+; found: 510.2486.
General: Optical rotations were measured at (20ꢁ2)8C with a Perkin–
Elmer Model 241 digital polarimeter, using a 10 cm, 1 mL cell. Mass
spectra (CI (ammonia)) were obtained with a JMS-700 spectrometer.
1H NMR spectra were recorded at 400 MHz with a Brꢈker DRX 400 for
solutions in CDCl3 or D2O at RT. Assignments were confirmed by COSY
experiments. 13C NMR spectra were recorded at 100.6 MHz with
a
Brꢈker DRX 400 spectrometer. Assignments were confirmed by J-mod
and HMQC techniques. Reactions were monitored by thin-layer chroma-
tography (TLC) using Silica Gel 60 F254 precoated plates (layer thickness
0.2 mm; E. Merck, Darmstadt, Germany) and detected by charring with
either a 10% ethanolic solution of H2SO4 or with a solution of 0.2% w/v
cerium sulfate and 5% ammonium molybdate in 2m H2SO4. Flash
column chromatography was performed using silica gel 60 (230–400
mesh, E. Merck).
Compound 2: Anhydrous DMSO (3.43 mL, 48.4 mmol) was added drop-
wise to a solution of oxalyl chloride (3.17 mL, 36.3 mmol) in anhydrous
CH2Cl2 (80 mL) at ꢀ788C under argon. After 15 min, a solution of alco-
hol 1 (4.50 g, 12.1 mmol) in anhydrous CH2Cl2 (40 mL) was added drop-
wise and the solution was stirred at ꢀ788C for 1 h. Triethylamine
(10.1 mL, 72.6 mmol) was then added and the reaction mixture was al-
lowed to reach RT and stirred for 90 min. Water (60 mL) was added and
the aqueous layer was extracted with CH2Cl2 (3ꢁ80 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude ketone was coevaporated with toluene and
used directly without further purification. n-Butyl lithium (2.5m in n-hex-
anes, 19.4 mL, 48.4 mmol) was added dropwise to
a solution of
Ph3PCH2Br (17.3 g, 48.4 mmol) in anhydrous THF (80 mL) at 08C under
argon. The reaction mixture was stirred for 30 min at 08C until a bright-
orange color persisted. A solution of the crude ketone in anhydrous THF
(70 mL) was then quickly added and the reaction mixture was stirred for
2 h at RT. The reaction mixture was diluted with water (50 mL) and
CH2Cl2 (100 mL). The organic layer was dried (MgSO4), filtered, and
concentrated. Purification by flash chromatography (cyclohexane/EtOAc,
20:1 then cyclohexane/EtOAc, 4:1) afforded alkene 2 (2.90 g, 65% over
two steps) as a white solid. M.p. 183–1848C (cyclohexane/EtOAc); [a]D =
ꢀ89.4 (c=1.0 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=7.56–7.29 (m,
10H; ArH), 5.62 (s, 1H; H-7), 5.57 (app t, 2H; H-8, H-8’), 4.92 (d, J=
12.1 Hz, 1H; CHPh), 4.86 (d, J=12.1 Hz, 1H; CHPh), 4.81 (s, 1H; H-1),
4.39 (dd, J=4.9, 10.5 Hz, 1H; H-6a), 4.18 (br d, J=9.3 Hz, 1H; H-3),
3.85 (t, J=10.5 Hz, 1H; H-6’), 3.74 (t, J=9.3 Hz, 1H; H-4), 3.63 (s, 3H;
OCH3), 3.56 ppm (ddd, J=4.9, 9.3, 10.5 Hz, 1H; H-5); 13C NMR (CDCl3,
100 MHz): d=141.8 (C-2), 138.7, 137.9 (ipso ArC), 129.4–126.5 (10ꢁ
ArC), 111.4 (C-8), 101.6 (C-1, C-7), 84.0 (C-4), 78.5 (C-3), 73.8 (CH2Ph),
69.9 (C-6), 66.9 (C-5), 57.9 ppm (OCH3); HRMS (CIMS): m/z calcd for
C22H28O5N: 386.1967 [M+NH4]+; found: 386.1970.
Compound 5: Anhydrous DMSO (1.52 mL, 21.44 mmol) was added drop-
wise to a solution of oxalyl chloride (1.56 mL, 17.87 mmol) in anhydrous
CH2Cl2 (20 mL) at ꢀ788C under argon. After 15 min, a solution of alco-
hol 4 (0.88 g, 1.79 mmol) in anhydrous CH2Cl2 (10 mL) was added drop-
wise and the reaction mixture was stirred for 1 h. Triethylamine
(3.74 mL, 26.80 mmol) was then added and the reaction mixture was
stirred for 90 min and allowed to reach RT. Water was added to the reac-
tion mixture (10 mL) and the aqueous layer was extracted with CH2Cl2
(3ꢁ40 mL). The organic layers were combined, dried (MgSO4), filtered,
and concentrated under reduced pressure. The crude aldehyde was co-
evaporated with toluene and used without further purification. n-Butyl-
lithium (2.5m in n-hexanes, 2.86 mL, 7.15 mmol) was added dropwise to a
solution of Ph3PCH2Br (2.55 g, 7.15 mmol) in anhydrous THF (20 mL) at
08C under argon. The reaction mixture was stirred for 30 min at 08C
until a bright-orange color persisted, and a solution of the crude aldehyde
in anhydrous THF (10 mL) was quickly added. The reaction mixture was
stirred for 90 min at RT, quenched with water (10 mL) and diluted with
CH2Cl2 (40 mL). The organic layer was dried (MgSO4), filtered, and con-
centrated. Purification by flash column chromatography (cyclohexane/
EtOAc, 20:1) afforded vinyl derivative 5 (0.63 g, 72% over two steps) as
Compound 3: Exoalkene 2 (2.40 g, 6.51 mmol) was dissolved in a 20:1
acetone/water mixture (105 mL) and NMO (1.75 g, 13.03 mmol) followed
by OsO4 (2.5% in tBuOH, 1.60 mL, 0.13 mmol) were added. The reac-
tion mixture was stirred for 2 d at RT until TLC indicated complete con-
sumption of the starting material. The reaction was quenched by addition
of aqueous saturated solution of Na2S2O3. The reaction mixture was
stirred for 30 min, extracted with EtOAc, dried over MgSO4, filtered, and
concentrated under vacuo. Purification by column chromatography (cy-
Chem. Eur. J. 2011, 17, 7345 – 7356
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7351

Y. Blꢂriot et al.
a
colorless oil; [a]D =ꢀ86.3 (c=2.0 in CHCl3); 1H NMR (CDCl3,
81.4 (C-4), 76.7 (C-5), 76.5 (CH2Ph), 75.6 (CH2Ph), 67.4 (CH2Ph),
57.4 ppm (OCH3); HRMS (CIMS): m/z calcd for C31H38O5N: 504.2750
[M+NH4]+; found: 504.2746.
400 MHz): d=7.52–7.28 (m, 15H; ArH), 6.04 (dd, J=12.0, 11.4 Hz, 1H;
H-8), 5.79 (dd, J=2.0, 12.0 Hz, 1H; H-9), 5.67 (dd, J=2.0, 11.4 Hz, 1H;
H-9’), 5.59 (s, 1H; H-7), 4.94 (d, J=11.7 Hz, 1H; CHPh), 4.89 (d, J=
11.7 Hz, 1H; CHPh), 4.82 (d, J=12.3 Hz, 1H; CHPh), 4.73 (d, J=
12.3 Hz, 1H; CHPh), 4.53 (s, 1H; H-1), 4.41 (dd, J=4.8, 10.3 Hz, 1H; H-
6), 3.86 (d, J=9.5 Hz, 1H; H-3), 3.84 (t, J=10.3 Hz, 1H; H-6’), 3.73 (t,
J=9.5 Hz, 1H; H-4), 3.54 (s, 3H; OCH3), 3.57–3.51 ppm (m, 1H; H-5);
13C NMR (CDCl3, 100 MHz): d=140.3, 139.1, 137.8 (ipso ArC), 130.9 (C-
8), 129.3–126.5 (15ꢁArC), 122.5 (C-9), 107.6 (C-1), 101.6 (C-7), 83.6 (C-
3), 83.4 (C-2), 80.5 (C-4), 75.9 (CH2Ph), 69.2 (C-6), 68.0 (C-5), 67.4
(CH2Ph), 57.7 ppm (OCH3); HRMS (CIMS): m/z calcd for C30H33O6:
489.2277 [M+H]+; found: 489.2259.
Compound 8: Compound 7 (350 mg, 0.72 mmol) was dissolved in anhy-
drous CH2Cl2 (90 mL) and the solution was degassed three times fol-
lowed by addition of 2nd generation Grubbs catalyst (61 mg, 0.07 mmol)
under argon. The reaction mixture was heated to reflux overnight, cooled
at RT, and an excess of [PbACTHNUTRGNEUNG(OAc)4] was added. The reaction mixture was
stirred for 2 h, filtered through a Celite plug, eluted with CH2Cl2, and
concentrated under reduced pressure. Purification by flash column chro-
matography (cyclohexane/EtOAc, 4:1) afforded the bicyclic alkene 8
(315 mg, 95%) as a white solid. M.p. 938C (cyclohexane/EtOAc); [a]D =
ꢀ62.2 (c=1.0 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=7.45–7.29 (m,
15H; ArH), 6.58 (app dd, J=1.2, 8.8 Hz, 1H; H-7), 6.44 (dd, J=5.6,
8.8 Hz, 1H; H-6), 4.91 (d, J=1.2 Hz, 1H; H-1), 4.88 (s, 2H; CH2Ph), 4.73
(d, J=11.8 Hz, 1H; CHPh), 4.71 (d, J=12.0 Hz, 1H; CHPh), 4.65–4.62
(m, 2H; CHPh, H-5), 4.54 (d, J=12.0 Hz, 1H; CHPh), 3.69 (br s, 1H; H-
3), 3.51 (t, J=1.6 Hz, 1H; H-4), 3.45 ppm (s, 3H; OCH3); 13C NMR
(CDCl3, 100 MHz): d=139.6, 138.4, 138.1 (ipso ArC), 133.4 (C-7), 128.9–
128.1 (12ꢁArC), 127.95 (C-6), 127.8–127.6 (3ꢁArC), 101.3 (C-1), 84.5
(C-4), 81.5 (C-2), 79.5 (C-3), 73.1 (CH2Ph), 71.4 (CH2Ph), 68.7 (C-5), 68.0
(CH2Ph), 56.2 ppm (OCH3); HRMS (CIMS): m/z calcd for C29H34O5N:
476.2437 [M+NH4]+; found: 476.2442.
Compound 9: Palladium on carbon (10% w/w, 78 mg, 120 mgmmolꢀ1 of
starting material) was added to a solution of bicyclic alkene 8 (300 mg,
0.66 mmol) dissolved in a 2:1 EtOAc/MeOH mixture (12 mL). The solu-
tion was degassed three times, and air was replaced by H2. After stirring
for 1.5 h at RT, the reaction mixture was filtered through a Rotilabo
Nylon 0.45 mm filter and the solvent was evaporated to afford the xylo-
side analogue 9 (125 mg, quantitative yield) as a white crystalline solid.
M.p. 1318C (EtOAc); [a]D =ꢀ80.7 (c=1.0 in MeOH); 1H NMR (D2O,
400 MHz): d=4.47 (d, J=1.3 Hz, 1H; H-1), 3.75–3.72 (m, 1H; H-5), 3.66
(dd, J=2.5, 1.1 Hz, 1H; H-4), 3.47 (t, J=2.5 Hz, 1H; H-3), 3.41 (s, 3H;
OCH3), 1.95–1.87 (m, 1H; H-6), 1.77–1.69 (m, 1H; H-7), 1.66- 1.58 (m,
1H; H-6’), 1.57–1.50 ppm (m, 1H; H-7’); 13C NMR (D2O, 100 MHz): d=
103.3 (C-1), 77.9 (C-3), 77.6 (C-4), 72.9 (C-5), 71.8 (C-2), 56.7 (OCH3),
22.2 (C-6), 16.7 (C-7); HRMS (CIMS): m/z calcd for C8H18O5N: 208.1185
[M+NH4]+; found: 208.1189.
Compound 6: Lithium aluminum hydride (0.23 g, 6.15 mmol) was careful-
ly added in portions to a solution of alkene 5 (0.60 g, 1.23 mmol) dis-
solved in a 1:1 CH2Cl2/Et2O mixture (20 mL) at 08C under argon. After
10 min, the reaction mixture was warmed to 408C, and a solution of
AlCl3 (0.49 g, 3.69 mmol) in Et2O (10 mL) was added dropwise under
argon. The reaction was stirred for 90 min by which time TLC indicated
no trace of starting material remained. The reaction mixture was cooled
to 08C and quenched by slow addition of EtOAc followed by water. The
organic layer was separated, dried (MgSO4), filtered, and concentrated
under reduced pressure. Purification by flash column chromatography
(cyclohexane/EtOAc, 4:1 then cyclohexane/EtOAc, 2:1) afforded the pri-
mary alcohol 6 (0.53 g, 88%) as a white solid. M.p. 1218C (cyclohexane/
EtOAc); [a]D =ꢀ19.6 (c=1.0 in CHCl3); 1H NMR (CDCl3, 400 MHz):
d=7.55–7.44 (m, 15H; ArH), 6.21 (dd, J=11.4, 18.0 Hz, 1H; H-7), 5.96
(dd, J=2.1, 18.0 Hz, 1H; H-8), 5.82 (dd, J=2.1, 11.4 Hz, 1H; H-8’), 5.24
(d, J=11.0 Hz, 1H; CHPh), 5.05 (d, J=10.9 Hz, 1H; CHPh), 5.00 (d, J=
11.0 Hz, 1H; CHPh), 4.98 (d, J=12.3 Hz, 1H; CHPh), 4.92 (d, J=
12.3 Hz, 1H; CHPh), 4.76 (d, J=10.9 Hz, 1H; CHPh), 4.61 (s, 1H; H-1),
4.07 (dd, J=2.3, 11.9 Hz, 1H; H-6), 3.98 (d, J=9.5 Hz, 1H; H-3), 3.91
(dd, J=4.4, 11.9 Hz, 1H; H-6’), 3.74 (t, J=9.5 Hz, 1H; H-4), 3.63 (s, 3H;
OCH3), 3.62–3.59 ppm (m, 1H; H-5); 13C NMR (CDCl3, 100 MHz): d=
140.6, 139.4, 138.8 (ipso ArC), 131.1 (C-7), 129.0–127.7 (15ꢁArC), 122.3
(C-8), 107.0 (C-1), 87.7 (C-3), 83.4 (C-2), 77.0 (C-4), 76.6 (CH2Ph), 76.5
(C-5), 75.7 (CH2Ph), 67.6 (CH2Ph), 62.5 (C-6), 57.6 ppm (OCH3); HRMS
(CIMS): m/z calcd for C30H38O6N: 508.2699 [M+NH4]+; found:
508.2709.
Compound 10: Palladium on carbon (6.2 mg, 120 mgmmolꢀ1 of starting
material) was added to a solution of derivative 7 (25 mg, 50 mmol) dis-
solved in a 2:1 EtOAc/MeOH mixture (3 mL). The solution was degassed
three times, and air was replaced by H2. After stirring for 23 h at RT, the
reaction mixture was filtered through a Rotilabo Nylon 0.45 mm filter
eluted with methanol and concentrated under reduced pressure. Purifica-
tion by flash column chromatography (toluene/acetone, 1:1) afforded the
corresponding diethyl derivative 10 (10 mg, 91%) as a colorless oil;
[a]D =ꢀ20.5 (c=0.2 in MeOH); 1H NMR (D2O, 400 MHz): d=4.26 (s,
1H; H-1), 3.48 (s, 3H; OCH3), 3.40 (d, J=8.3 Hz, 1H; H-3), 3.31–3.22
(m, 2H; H-4, H-5), 1.87 (dq, J=7.4, 14.8 Hz, 1H; H-6a), 1.63 (q, J=
7.5 Hz, 2H; H-8a, H-8b), 1.44 (dq, J=7.4, 14.8 Hz, 1H; H-6b), 0.97 (t,
J=7.4 Hz, 3H, CH3), 0.95 ppm (t, J=7.5 Hz, 3H; CH3); 13C NMR (D2O,
100 MHz): d=107.0 (C-1), 79.8 (C-3), 78.3 (C-4 or C-5), 75.6 (C-2), 72.2
(C-4 or C-5), 57.9 (OCH3), 24.3 (C-6), 20.7 (C-8), 9.3, 8.3 ppm (2ꢁCH3);
HRMS (ESI): m/z calcd for C10H20O5Na: 243.1208 [M+Na]+; found:
243.1210.
Compound 7: Anhydrous DMSO (1.28 mL, 18.00 mmol) was added drop-
wise to a solution of oxalyl chloride (1.22 mL, 14.00 mmol) in anhydrous
CH2Cl2 (20 mL) at ꢀ788C under argon. After 15 min, a solution of pri-
mary alcohol 6 (0.98 g, 2.00 mmol) in anhydrous CH2Cl2 (10 mL) was
added dropwise and the reaction was stirred for 1 h. Triethylamine
(3.30 mL, 24.00 mmol) was then added and the reaction mixture was
stirred for 90 min and allowed to reach RT. Water (20 mL) was added
and the aqueous layer was extracted with CH2Cl2 (3ꢁ60 mL). The organ-
ic layers were combined, dried (MgSO4), filtered, and concentrated
under reduced pressure. The crude aldehyde was coevaporated with tolu-
ene and used without further purification. n-Butyllithium (2.5m in n-hex-
anes, 3.20 mL, 8.00 mmol) was added dropwise to
a solution of
Ph3PCH2Br (2.86 g, 8.00 mmol) in anhydrous THF (15 mL) at 08C under
argon. The reaction mixture was stirred for 30 min at 08C until a bright-
orange color persisted, and a solution of the crude aldehyde in anhydrous
THF (15 mL) was then quickly added. The reaction mixture was stirred
for 2 h at RT, quenched with water (20 mL) and diluted with CH2Cl2
(80 mL). The organic layer was separated, dried (MgSO4), filtered, and
concentrated. Purification by flash chromatography (cyclohexane/EtOAc,
30:1) afforded the bis vinyl derivative 6 (0.60 g, 62% over two steps) as a
white solid. M.p. 1138C (cyclohexane/EtOAc); [a]D =ꢀ128.1 (c=1.0 in
CHCl3); 1H NMR (CDCl3, 400 MHz): d=7.41–7.31 (m, 15H; ArH),
6.10–6.00 (m, 2H; H-6, H-8), 5.82 (dd, J=1.9, 17.9 Hz, 1H; H-9), 5.67
(dd, J=1.9, 11.4 Hz, 1H; H-9’), 5.54 (d, J=17.3 Hz, 1H; H-7), 5.35 (d,
J=10.6 Hz, 1H; H-7’), 5.07 (d, J=11.0 Hz, 1H; CHPh), 4.86–4.77 (m,
4H; 2ꢁCH2Ph), 4.59 (d, J=10.5 Hz, 1H; CHPh), 4.49 (s, 1H; H-1), 3.91
(dd, J=5.9, 9.5 Hz, 1H; H-5), 3.81 (d, J=9.5 Hz, 1H; H-3), 3.54 (s, 3H;
OCH3), 3.33 ppm (t, J=9.5 Hz, 1H; H-4); 13C NMR (CDCl3, 100 MHz):
d=140.5, 139.3, 138.7 (ipso ArC), 135.4 (C-6), 131.1 (C-8), 128.8–127.5
(15ꢁArC), 122.0 (C-9), 118.1 (C-7), 106.6 (C-1), 87.4 (C-3), 83.3 (C-2),
Compound 12: Anhydrous DMSO (4.6 mL, 64.69 mmol) was added drop-
wise to a solution of oxalyl chloride (4.2 mL, 48.20 mmol) in anhydrous
CH2Cl2 (60 mL) at ꢀ788C under argon. After 15 min, a solution of pri-
mary alcohol 6 (6.07 g, 9.76 mmol) in anhydrous CH2Cl2 (40 mL) was
added dropwise and the reaction was stirred for 1 h. Anhydrous triethyla-
mine (11.5 mL) was then added and the reaction mixture was stirred for
90 min and allowed to reach RT. Water (150 mL) was added and the
aqueous layer was extracted with CH2Cl2 (3ꢁ100 mL). The organic
layers were combined, dried (MgSO4), filtered, and concentrated under
reduced pressure. The crude aldehyde was coevaporated with toluene
and used without further purification. Vinyl magnesium bromide (1m in
THF, 10.5 mL) was added to a solution of the crude ketone in anhydrous
THF (15 mL) cooled at 08C and the reaction mixture was stirred at RT
7352
www.chemeurj.org
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7345 – 7356

Chemical Reactivity of a- and b-Xylopyranosides
FULL PAPER
for 2 h. Saturated ammonium chloride (20 mL) and water (10 mL) were
added and the aqueous layer was extracted with EtOAc (3ꢁ50 mL). The
organic layer was separated, dried (MgSO4), filtered, and concentrated.
Purification by flash chromatography (cyclohexane/EtOAc, 8:1) afforded
the vinyl derivative 12 (3.40 g, 52% over two steps) as an oil. [a]D =+38
(c=1.0 in CHCl3); 1H NMR(CDCl3, 400 MHz): d=7.52–7.30 (m, 10H;
ArH), 6.19 (dd, J=11.1, 17.5 Hz, 1H; H-7), 5.66 (dd, J=1.6, 17.5 Hz,
1H; H-8), 5.61 (s, 1H; CHPh), 5.45 (dd, J=1.6, 11.1 Hz, 1H; H-8’), 4.94
(d, J=12.1 Hz, 1H; CHPh), 4.89 (d, J=12.1 Hz, 1H; CHPh), 4.57 (s,
1H; H-1), 4.35 (dd, J=4.3, 9.8 Hz, 1H; H-6), 3.97–3.79 (m, 4H; H-3, H-
4, H-5, H-6’), 3.49 ppm (s, 3H; OMe); 13C NMR (CDCl3, 100 MHz): d=
138.7, 137.4 (ipso ArC), 135.8 (C-7), 128.9–127.4 (ArC), 117.4 (C-8),
103.5 (C-1), 101.3 (CHPh), 80.9 (C-4), 80.5 (C-3), 76.7 (C-2), 74.8
(CH2Ph), 69.0 (C-6), 63.4 (C-5), 55.4 ppm (OMe); MS (CI, NH3): m/z
(%): 416 (100) [M+NH4]+; HRMS (FAB+): m/z calcd for C23H26O6Na:
421.1627 [M+Na]+; found: 421.1629. Further elution afforded the C-2
epimer (1.14 g, 18% over two steps) as an oil. [a]D =ꢀ53 (c=1.0 in
CHCl3); 1H NMR (CDCl3, 400 MHz): d=7.57–7.32 (m, 10H: ArH), 5.79
(dd, J=10.7, 17.2 Hz, 1H; H-7), 5.66 (s, 1H; CHPh), 5.55 (dd, J=0.9,
17.2 Hz, 1H; H-8), 5.40 (dd, J=0.9, 10.7 Hz, 1H; H-8’), 4.91 (d, J=
11.4 Hz, 1H; CHPh), 4.74 (d, J=11.4 Hz, 1H; CHPh), 4.41 (dd, J=4.9,
10.4 Hz, 1H; H-6), 4.35 (s, 1H; H-1), 4.19 (t, J=9.4 Hz, 1H; H-4), 3.95
(t, J=10.4 Hz, 1H; H-6’), 3.62 (d, J=9.4 Hz, 1H; H-3), 3.55 (s, 3H;
OMe), 3.53–3.45 ppm (m, 1H; H-5); 13C NMR (CDCl3, 100 MHz): d=
138.2 (C-7), 138.3, 138.0 (ipso ArC), 129.4–126.5 (ArC), 117.5 (C-8),
104.0 (C-1), 101.8 (CHPh), 80.1 (C-4), 79.9 (C-3), 77.7 (C-2), 75.5
(CH2Ph), 69.0 (C-6), 67.0 (C-5), 58.2 ppm (OMe); MS (CI, NH3): m/z
(%): 416 (100) [M+NH4]+; HRMS (FAB+): m/z calcd for C23H26O6Na:
421.1627 [M+Na]+; found: 421.1626.
diluted with CH2Cl2 (80 mL). The organic layer was separated, dried
(MgSO4), filtered, and concentrated. Purification by flash chromatogra-
phy (cyclohexane/EtOAc, 7:1) afforded the divinyl derivative 14 (0.294 g,
79% over two steps) as an oil. [a]D =+56 (c=1.0 in CHCl3); 1H NMR
(CDCl3, 400 MHz): d=7.39–7.29 (m, 10H; ArH), 6.14 (dd, J=11.0,
17.4 Hz, 1H; H-8), 6.01 (ddd, J=6.4, 10.4, 17.1 Hz, 1H; H-6), 5.67 (dd,
J=1.7, 17.4 Hz, 1H; H-9), 5.51 (tt, J=1.1, 17.1 Hz, 1H; H-7), 5.43 (dd,
J=1.7, 11.0 Hz, 1H; H-9’), 5.34 (dt, J=1.1, 10.5 Hz, 1H; H-7’), 4.99 (d,
J=11.4 Hz, 1H; CHPh), 4.82 (d, J=11.4 Hz, 1H; CHPh), 4.80 (d, J=
10.6 Hz, 1H; CHPh), 4.60 (d, J=10.6 Hz, 1H; CHPh), 4.50 (s, 1H; H-1),
4.18 (dd, J=6.4, 9.5 Hz, 1H; H-5), 3.91 (d, J=9.5 Hz, 1H; H-3), 3.46 (s,
3H; OMe), 3.39 (t, J=9.5 Hz, 1H; H-4), 2.62 ppm (s, 1H; OH);
13C NMR (CDCl3, 100 MHz): d=138.5, 137.8 (2ꢁCipso), 135.7 (C-6), 135.1
(C-8), 128.3–127.5 (ArC), 118.1 (C-7), 117.1 (C-9), 102.7 (C-1), 84.7 (C-
3), 80.9 (C-4), 75.4 (CH2Ph), 75.1 (CH2Ph), 71.9 (C-5), 55.3 ppm (OMe);
MS (CI, NH3): m/z (%): 414 (100) [M+NH4]+; HRMS (CI, NH3): m/z
calcd for C24H32O5N: 414.2280 [M+NH4]+; found: 414.2278.
Compound 15: Compound 14 (655 mg, 1.35 mmol) was dissolved in anhy-
drous CH2Cl2 (200 mL) and the solution was degassed three times fol-
lowed by addition of 2nd generation Grubbs catalyst (141 mg, 10% mol)
under argon. The reaction mixture was heated to reflux for 18 h, cooled
at RT, and an excess of [PbACTHNUTRGNEUNG(OAc)4] (110 mg, 1.5 equiv. of catalyst) was
added. The reaction mixture was stirred for 3 h, filtered through a Celite
plug eluted with CH2Cl2 and concentrated under reduced pressure. Purifi-
cation by flash column chromatography (cyclohexane/EtOAc, 4:1) afford-
ed the bicyclic alkene 15 (583 mg, 96%) as an oil. [a]D =+11 (c=1.0 in
CHCl3); 1H NMR (CDCl3, 400 MHz) d=7.41–7.30 (m, 10H; ArH), 6.34
(dd, J=5.0, 8.4 Hz, 1H; H-6), 6.31 (dt, J=1.5, 8.4 Hz, 1H; H-7), 4.72 (d,
J=12.3 Hz, 1H; CHPh), 4.68 (d, J=11.6 Hz, 1H; CHPh), 4.67–4.65 (m,
1H; H-5), 4.59 (d, J=11.6 Hz, 1H; CHPh), 4.57 (d, J=12.3 Hz, 1H;
CHPh), 4.52 (s, 1H; H-1), 3.97 (s, 1H; H-3), 3.56 (s, 3H; OMe), 3.44 (t,
J=1.5 Hz, 1H; H-4), 2.73 ppm (s, 1H; OH); 13C NMR (CDCl3,
100 MHz): d=138.0, 137.9 (2ꢁCipso), 136.7 (C-7), 128.8 (C-6), 128.4–127.7
(ArC), 102.1 (C-1), 82.3 (C-3), 77.3 (C-4), 76.2 (C-2), 72.5 (CH2Ph), 70.6
(CH2Ph), 69.7 (C-5), 56.8 ppm (OMe); MS (CI, NH3): m/z (%): 386 (100)
[M+NH4]+; HRMS (CI, NH3): m/z calcd for C22H28O5N: 386.1967 [M+
NH4]+; found: 386.1963.
Compound 13: Lithium aluminum hydride (1.09 g, 29.15 mmol) was care-
fully added in portions to a solution of alkene 12 (2.3 g, 5.78 mmol) dis-
solved in a 1:1 CH2Cl2/Et2O mixture (60 mL) at 08C under argon. After
10 min, the reaction mixture was warmed to 408C, and a solution of
AlCl3 (3.26 g, 24.55 mmol) in Et2O (30 mL) was added dropwise under
argon. The reaction was stirred for 90 min, by which time TLC revealed
no trace of starting material remained. The reaction mixture was cooled
to 08C and quenched by slow addition of EtOAc followed by water. A
solution of 1m HCl (10 mL) was added and the organic layer was washed
with NaHCO3 (100 mL) and water (100 mL), separated, dried (MgSO4),
filtered, and concentrated under reduced pressure. Purification by flash
column chromatography (cyclohexane/EtOAc, 3:1) afforded the diol 13
(1.96 g, 86%) as an oil. [a]D =+69 (c=1.0 in CHCl3); 1H NMR (CDCl3,
400 MHz): d=7.40–7.30 (m, 10H; ArH), 6.11 (dd, J=11.0, 17.2 Hz, 1H;
H-7), 5.66 (dd, J=1.9, 17.2 Hz, 1H; H-8), 5.43 (dd, J=1.9, 11.0 Hz, 1H;
H-8’), 5.02 (d, J=11.4 Hz, 1H; CHPh), 4.91 (d, J=11.0 Hz, 1H; CHPh),
4.82 (d, J=11.4 Hz, 1H; CH2Ph), 4.63 (d, J=11.0 Hz, 1H; CHPh), 4.49
(s, 1H; H-1), 3.93 (d, J=9.0 Hz, 1H; H-3), 3.89–3.65 (m, 4H; H-4, H-5,
H-6, H-6’), 3.45 ppm (s, 3H; OMe); 13C NMR (CDCl3, 100 MHz): d=
138.7, 138.1 (2ꢁCipso), 135.6 (C-7), 128.4–127.9 (ArC), 117.2 (C-8), 102.9
(C-1), 84.9 (C-3), 76.1 (C-4), 75.3 (CH2Ph), 75.1 (CH2Ph), 71.4 (C-5), 65.6
(C-2), 62.0 (C-6), 55.3 ppm (OMe); MS (CI, NH3): m/z (%): 418 (100)
[M+NH4]+; HRMS (CI, NH3): m/z calcd for C23H32O6N: 418.2230 [M+
NH4]+; found: 418.2232.
Compound 16: Palladium on carbon (10% w/w, 58 mg) was added to a
solution of bicyclic alkene 15 (582 mg, 1.28 mmol) dissolved in a 1:1
EtOAc/MeOH mixture (25 mL). The solution was degassed three times,
and air was replaced by H2. After stirring for 2 h at RT, the reaction mix-
ture was filtered through a Rotilabo Nylon 0.45 mm filter and the solvent
was evaporated. Purification by flash column chromatography (AcOEt/
MeOH, 10:1) afforded the xyloside analogue 16 (294 mg, 98%) as a
white crystalline solid; mp 113–1148C (EtOAc/MeOH); [a]D =+129 (c=
1.2 in MeOH); 1H NMR (D2O, 400 MHz): d=4.63 (s, 1H; H-1), 3.92–
3.90 (m, 1H; H-5), 3.89–3.87 (m, 1H; H-3), 3.61 (t, J=1.8 Hz, 1H; H-4),
3.42 (s, 3H; OMe), 2.04–1.90 (m, 2H; H-6, H-7), 1.66 (dddd, J=1.2, 3.7,
11.6, 14.8 Hz, 1H; H-6’), 1.36 ppm (dddd, J=1.9, 6.0, 13.1, 14.8 Hz, 1H;
H-7’); 13C NMR (D2O, 100 MHz): d=104.3 (C-1), 76.3 (C-3), 73.9 (C-4),
73.0 (C-5), 71.5 (C-2), 56.7 (OMe), 23.3 (C-6), 21.3 ppm (C-7); MS (CI,
NH3): m/z (%): 208 (70) [M+NH4]+; HRMS (CI, NH3): m/z calcd for
C8H18O5N: 208.1185 [M+NH4]+; found: 208.1187.
Compound 14: Anhydrous DMSO (0.267 mL) was added dropwise to a
solution of oxalyl chloride (0.242 mL) in anhydrous CH2Cl2 (4 mL) at
ꢀ788C under argon. After 15 min, a solution of primary alcohol 13
(415 mg, 2.00 mmol) in anhydrous CH2Cl2 (3 mL) was added dropwise
and the reaction was stirred for 1 h. Triethylamine (0.66 mL) was then
added and the reaction mixture was stirred for 90 min and allowed to
reach RT. Water (5 mL) was added and the aqueous layer was extracted
with CH2Cl2 (3ꢁ5 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated under reduced pressure. The crude
aldehyde was coevaporated with toluene and used without further purifi-
cation. n-Butyllithium (2.5m in n-hexanes, 1.5 mL) was added dropwise
to a solution of Ph3PCH2Br (1.34 g) in anhydrous THF (10 mL) at 08C
under argon. The reaction mixture was stirred for 30 min at 08C until the
bright-orange color persisted, and a solution of the crude aldehyde in an-
hydrous THF (5 mL) was then quickly added. The reaction mixture was
heated to reflux for 2 h, cooled to RT, quenched with water (20 mL), and
Compound 17: Acetic anhydride (3 mL) and
a catalytic amount of
DMAP (14 mg) were added to a solution of triol 16 (213 mg, 1.12 mmol)
in dry pyridine (5 mL) under argon. The reaction mixture was stirred for
12 h, the solvent was evaporated, and the residue was dissolved in
EtOAc (5 mL) and washed with water (4 mL), 1m HCl (4 mL), and brine
(4 mL). The organic layers were combined, dried (MgSO4), filtered, and
concentrated, and the residue was purified by flash column chromatogra-
phy (cyclohexane/AcOEt, 1:1) to afford triacetate 17 as a white solid
(349 mg, 98%). [a]D =+ 40 (c=1.0 in CHCl3); m.p. 109–1108C (cyclo-
hexane/AcOEt, 1:1); 1H NMR (CDCl3, 400 MHz): d=5.64 (s, 1H; H-1),
5.51–5.50 (m, 1H; H-5), 4.69 (t, J=1.9 Hz, 1H; H-4), 4.02–3.99 (m, 1H;
H-3), 3.44 (s, 3H; OMe), 2.51 (dddd, J=1.9, 4.5, 12.3, 13.4 Hz, 1H; H-6),
2.22–1.95 (m, 2H; H-6’, H-7’), 2.14 (s, 3H; OAc), 2.13 (s, 3H; OAc),
2.02 ppm (s, 3H; OAc); 13C NMR (CDCl3, 100 MHz): d=170.3, 169.8,
169.4 (3ꢁC=O), 98.4 (C-1), 78.7 (C-2), 76.6 (C-4), 72.0 (C-5), 68.7 (C-3),
Chem. Eur. J. 2011, 17, 7345 – 7356
ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7353

Y. Blꢂriot et al.
55.2 (OMe), 23.9 (C-7), 21.8, 20.9, 20.9 (3ꢁOAc), 18.4 ppm (C-6); MS
(CI, NH3): m/z (%): 334 (100) [M+NH4]+, 317 (20) [M+H]+; HRMS
(CI, NH3): m/z calcd for C14H24O8N: 334.1502 [M+NH4]+; found:
334.1493.
MeOH); 1H NMR (D2O, 400 MHz): d=4.90 (s, 1H; H-1), 4.00–3.89 (m,
3H; CH isopropyl, H-4, H-5), 3.62 (t, J=1.8 Hz, 1H; H-3), 2.02–1.86 (m,
2H; H-6, H-7), 1.68 (dddd, J=1.6, 3.5, 11.1, 17.2 Hz, 1H; H-7’), 1.53–1.33
(m, 1H; H-7’), 1.20 (d, J=6.1 Hz; CH3 isopropyl), 1.16 ppm (d, J=
6.1 Hz; CH3 isopropyl); 13C NMR (D2O, 100 MHz): d=100.9 (C-1), 76.5
(C-3), 73.9 (C-4), 73.0 (C-5), 72.3 (C-8), 71.4 (C-2), 23.3 (C-6), 22.7 (C-9),
21.5 (C-7), 21.1 ppm (C-9’); MS (CI, NH3): m/z (%): 236 (100) [M+
NH4]+; HRMS (CI, NH3): m/z calcd for C10H22O5N: 236.1498 [M+
NH4]+; found: 236.1499.
Compound 22: [a]D =ꢀ88 (c=1.0 in MeOH); 1H NMR (D2O, 400 MHz)
d=4.72 (d, J=1.2 Hz, 1H; H-1), 3.95 (hept, J=6.3 Hz, 1H; CH isopro-
pyl), 3.77 (m, 1H; H-5), 3.71 (dd, J=1.2, 2.8 Hz, 1H; H-4), 3.53 (t, J=
2.8 Hz, 1H; H-3), 2.05–1.96 (m, 1H; H-6), 1.76 (ddd, J=1.3, 6.4, 7.8 Hz,
1H; H-7), 1.70–1.62 (m, 2H; H-6’, H-7’), 1.22 (d, J=6.3 Hz, 3H; CH3 iso-
propyl), 1.16 ppm (d, J=6.3 Hz, 3H; CH3 isopropyl); 13C NMR (D2O,
100 MHz): d=100.2 (C-1), 78.0 (C-3), 77.6 (C-4), 72.6 (C-8), 72.6 (C-5),
71.6 (C-2), 22.7 (C-9’), 22.1 (C-6), 21.4 (C-9), 16.5 ppm (C-7); MS (CI,
NH3): m/z (%): 236 (100) [M+NH4]+, 219 (20) [M+H]+; HRMS (CI,
NH3): m/z calcd for C10H19O5: 219.1232 [M+H]+; found: 219.1230.
Compound 18: Acetic anhydride (1.3 mL) was added to a solution of tri-
acetate 17 (348 mg, 1.10 mmol) in anhydrous CH2Cl2 (7 mL) at ꢀ308C.
Sulfuric acid (43 mL, 0.78 mmol) was then added dropwise and the reac-
tion mixture was allowed to reach 08C over a period of 90 min. The reac-
tion mixture was neutralized by slow addition of saturated aqueous
NaHCO3. The organic layer was separated, and the aqueous layer was
extracted with CH2Cl2 (20 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated. Purification by flash column chro-
matography (cyclohexane/EtOAc, 4:1) afforded tetracetate 18 (253 mg,
67%) as a white solid and as a 2:5 a/b anomeric mixture. Spectroscopic
data for a anomer: 1H NMR (CDCl3, 400 MHz): d=6.81 (s, 1H; H-1a),
5.54 (s, 1H; H-3a), 4.74 (t, J=1.8 Hz, 1H; H-4a), 4.12–4.11 (m, 1H; H-
5a), 2.61–2.59 (m, 1H; H-7a), 2.39–2.09 (m, 2H; H-6a, H-7’a), 2.17, 2.16,
2.15, 2.00 (4ꢁs, 12H; 4ꢁOAc a), 1.91–1.77 ppm (m, 1H; H-6’a);
13C NMR (CDCl3, 100 MHz): d=170.0, 169.7, 169.4, 169.4 (4ꢁCO a),
91.3 (C-1a), 76.0 (C-4a), 71.9 (C-5a), 69.6 (C-3a), 23.3 (C-6a), 21.7, 21.1,
Compound 23: Thiophenol (24 mL, 0.227 mmol) and BF3·OEt2 (58 mL,
21.1, 20.9 (4ꢁOAc a), 18.2 ppm (C-7a). Spectroscopic data for
b
0.453 mmol) were added to
a solution of tetracetate 18 (52 mg,
anomer: 1H NMR (CDCl3, 400 MHz): d=6.83 (d, J=1.3 Hz, 1H; H-1b),
5.88 (t, J=2.5 Hz, 1H; H-3b), 4.86 (dd, J=1.1, 2.5 Hz, 1H; H-4b), 4.01–
4.00 (m, 1H; H-5b), 2.39–2.09 (m, 2H; H-6b, H-7b), 2.05–2.03 (m, 1H;
H-7’b), 2.14, 2.12, 1.98 (3ꢁs, 12H; 4ꢁOAc b, 1.91–1.77 ppm (m, 1H; H-
6’b); 13C NMR (CDCl3, 100 MHz): d=170.4, 169.6, 169.3, 169.2 (4ꢁCO
b), 90.8 (C-1b), 77.2 (C-4b), 72.8 (C-5b), 70.1 (C-3b), 22.2 (C-6b), 21.5,
21.1, 20.9, 20.7 (4ꢁOAc b), 17.6 ppm (C-7b); HRMS (CIMS): m/z: calcd
for C15H24O9N: 362.1446 [M+NH4]+; found: 362.1451.
0.151 mmol) in anhydrous CH2Cl2 (1 mL) at 08C under argon. After stir-
ring for 20 min at 08C, the reaction mixture was diluted with CH2Cl2
(2 mL) and neutralized with sat. NaHCO3 (2 mL). The organic layer was
separated, dried (MgSO4), filtered, and concentrated under reduced pres-
sure. Purification by flash column chromatography (cyclohexane/EtOAc,
2:1) afforded the thiophenyl derivative 23 (41 mg, 68%) as a colorless oil
and as a 1:5 a/b anomeric mixture. Spectroscopic data for a anomer:
1H NMR (CDCl3, 400 MHz): d=7.56–7.30 (m, 5H; ArH), 6.36 (s, 1H; H-
1), 5.58 (t, J=2.2 Hz, 1H; H-3), 4.83 (t, J=2.2 Hz, 1H; H-4), 4.05–4.04
(m, 1H; H-5), 2.75–2.68 (m, 1H; H-6), 2.30–2.27 (m, 1H; H-7), 2.24–2.13
(m, 1H; H-7’), 2.21, 2.19, 2.08 (3ꢁs, 9H; OAc), 2.21–1.97 ppm (m, 1H;
H-6’); 13C NMR (CDCl3, 100 MHz): d=170.5, 169.0, 166.9 (3ꢁC=O),
133.2 (ipso ArC), 132.6–127.6 (ArC), 87.7 (C-1), 77.3 (C-2), 77.1 (C-4),
73.0 (C-3), 69.7 (C-5), 23.6 (C-6), 21.8, 21.1, 20.9 (3ꢁOAc), 20.1 ppm (C-
7). Spectroscopic data for b anomer: 1H NMR (CDCl3, 400 MHz): d=
7.56–7.30 (m, 5H; ArH), 6.51 (d, J=2.2 Hz, 1H; H-1), 5.90 (t, J=2.0 Hz,
1H; H-3), 4.86 (t, J=2.0 Hz, 1H; H-4), 4.03–4.01 (m, 1H; H-5), 2.48–
2.39 (m, 1H; H-6), 2.24–2.13 (m, 1H; H-7), 2.15, 2.14, 2.00 (3ꢁs, 9H;
OAc), 2.10–2.06 (m, 1H; H-7’), 1.89 ppm (ddt, J=1.8, 3.9, 12.0 Hz, 1H;
H-6’); 13C NMR (CDCl3, 100 MHz): d=170.3, 169.5, 169.3 (3ꢁC=O),
133.2 (ipso ArC), 132.5–127.6 (ArC), 87.1 (C-1), 77.6 (C-2), 77.5 (C-4),
77.7 (C-3), 69.5 (C-5), 22.7 (C-6), 21.6, 21.0, 20.8 (3ꢁOAc), 19.8 ppm (C-
7); HRMS (CIMS): m/z calcd for C19H26O7SN: 412.1424 [M+NH4]+;
found: 412.1419.
Compound 19: A suspension of compound 18 (253 mg, 0.73 mmol), 4 ꢇ
molecular sieves (550 mg) and dry isopropanol (82 mL) in dry CH2Cl2
(4 mL) was stirred under argon at RT for 2 h. The reaction mixture was
cooled to ꢀ788C, TMSOTf (200 mL) was added dropwise and the solu-
tion was allowed to reach 08C. After 2.5 h (TLC showed some decompo-
sition) the reaction was quenched by addition of triethylamine. The sus-
pension was filtered through a Celite plug eluted with CH2Cl2. The fil-
trate was washed with sat. NaHCO3 (5 mL) and water (5 mL), dried
(MgSO4), filtered, and concentrated. Purification by flash column chro-
matography (toluene/AcOEt, 10:1) afforded a mixture of compounds 19
and 20 (148 mg, 58%) in a 1:5 ratio as an oil. Spectroscopic data for a-
anomer 19: 1H NMR (CDCl3, 400 MHz): d=5.85 (s, 1H; H-1), 5.54–5.52
(m, 1H; H-3), 4.69 (t, J=1.8 Hz, 1H; H-4), 4.02–3.94 (m, 2H; H-5, H-8),
2.56–2.55 (m, 1H; H-7), 2.32–1.97 (m, 2H; H-6, H-6’), 2.16, 2.15, 2.13,
2.02, 2.01 (6ꢁs, 18H; 6ꢁOAc), 1.84–1.74 (m, 1H; H-7’), 1.27 (d, J=
6.3 Hz, 3H; CH3 isopropyl), 1.12 ppm (d, J=6.3 Hz, 3H; CH3 isopropyl);
13C NMR (CDCl3, 100 MHz): d=170.5, 169.6, 169.6 (3ꢁCO), 95.5 (C-1),
78.0 (C-4), 72.4 (C-3), 69.9 (C-8), 68.4 (C-5), 24.0 (C-6), 23.5 (CH3 isopro-
pyl), 21.8 (CH3 isopropyl), 21.6, 21.6, 21.1, 21.0, 21.0, 20.8 (6ꢁOAc),
18.5 ppm (C-7); MS (CI, NH3): m/z (%): 362 (100) [M+NH4]+, 345 (70)
[M+H]+; HRMS (CI, NH3): m/z calcd for C16H28O8N: 362.1815 [M+
NH4]+; found: 362.1819.
Spectroscopic data for b-anomer 20: 1H NMR (CDCl3, 400 MHz): d=
5.83 (d, J=1.2 Hz, 1H; H-1), 5.82 (d, J=2.7 Hz, 1H; H-3), 2.45 (dd, J=
1.4, 2.7 Hz, 1H; H-4), 4.02–3.94 (m, 1H; H-8), 3.93–3.90 (m, 1H; H-5),
2.32–1.97 (m, 3H; H-6, H-7, H-7’), 2.16, 2.15, 2.13, 2.02, 2.01 (5ꢁs, 18H;
6ꢁOAc), 1.84–1.74 (m, 1H; H-6’), 1.26 (d, J=6.3 Hz, 3H; CH3 isopro-
pyl), 1.13 ppm (d, J=6.3 Hz, 3H; CH3 isopropyl); 13C NMR (CDCl3,
100 MHz): d=170.5, 169.6, 169.6 (3ꢁCO), 95.0 (C-1), 78.0 (C-4), 73.3 (C-
3), 70.4 (C-8), 69.1 (C-5), 23.6 (CH3 isopropyl), 22.5 (C-6), 21.9 (CH3 iso-
propyl), 21.6, 21.6, 21.1, 21.0, 21.0, 20.8 (6ꢁOAc), 17.5 ppm (C-7).
Compounds 25 and 26: A solution of thioglycosyl donor 23 (25 mg, 63.4
mmol) and xylosyl acceptor 24 (40 mg, 196 mmol) in anhydrous CH2Cl2
(1.5 mL) was cooled to - 508C under argon and activated 4 ꢇ molecular
sieves (60 mg) and NIS (45 mg, 126.8 mmol) were added to the solution.
The reaction mixture was degassed three times, and air was replaced with
argon followed by addition of TfOH (1 mL, 6.34 mmol). The reaction mix-
ture was stirred at RT for 5 min when TLC indicated complete consump-
tion of the thioglycosyl donor 23. The reaction mixture was filtered
through Celite, and eluted with CH2Cl2. The filtrate was washed with sat.
NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL). The organic layer was separat-
ed, dried (MgSO4), and the solvent was removed under reduced pressure.
NMR analysis of the crude mixture indicated the absence of isopropyli-
dene group on the synthesized disaccharides. Unfortunately, the crude
mixture of a and b anomers (1:4) proved to be inseparable by flash chro-
matography. The resulting disaccharides were then peracetylated. The
crude mixture of disaccharides (19 mg) was dissolved in anhydrous pyri-
dine (1 mL), and acetic anhydride (0.5 mL) was added. The reaction mix-
ture was stirred overnight at RT, then the reaction mixture was coevapo-
rated with toluene and concentrated under reduced pressure. Purification
by flash column chromatography (cyclohexane/acetone, 4:1) afforded the
b-disaccharide 26 (15 mg, 45%) as a white crystalline solid. M.p. 1428C
Compound 21: A mixture of compounds 19 and 20 (85 mg, 0.25 mmol)
was dissolved in MeOH (5 mL), the solution was cooled to 08C, and a
catalytic amount of NaOMe was added. The reaction mixture was stirred
at RT for 1 h then neutralized by addition of Amberlite IR-120 H+ resin.
The solution was filtered, concentrated, and purified by flash column
chromatography (AcOEt) to afford compound 21 (11 mg, 0.05 mmol)
quantitatively as an oil. Further elution afforded compound 22 (44 mg,
0.2 mmol) as a solid. Spectroscopic data for triol 21: [a]D =ꢀ21 (c=0.4 in
1
(EtOAc); [a]D =ꢀ80 (c=1.0 in CHCl3); H NMR (CDCl3, 400 MHz): d=
5.87 (s, 1H; H-1’), 5.71 (d, J=2.1 Hz, 1H; H-3’), 5.18 (t, J=9.2 Hz; H-3),
7354
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Chem. Eur. J. 2011, 17, 7345 – 7356

Chemical Reactivity of a- and b-Xylopyranosides
FULL PAPER
4.90 (dd, J=7.7, 9.2 Hz, 1H; H-2), 4.81 (dd, J=1.5, 2.1 Hz, 1H, H-4’),
4.35 (d, J=7.7 Hz, 1H; H-1), 3.99 (dd, J=5.5, 11.6 Hz, 1H; H-5a), 3.93–
3.86 (m, 2H; H-4, H-5’), 3.50 (s, 3H; OMe), 3.27 (dd, J=9.9, 11.6 Hz,
1H; H-5b), 2.15 (s, 3H; OAc), 2.13 (s, 3H; OAc), 2.09 (s, 3H; OAc),
2.06–2.03 (m, 1H; H-6’a), 1.99 (s, 3H; OAc), 2.00–1.95 (m, 2H; H-7’a, H-
7’b), 1.79–1.72 ppm (m, 1H; H-6’b); 13C NMR (CDCl3, 100 MHz): d=
170.3, 170.2, 169.7, 169.6, 169.5 (5ꢁC=O), 102.1 (C-1), 96.5 (C-1’), 78.1
(C-2’), 77.7 (C-4’), 74.5 (C-4), 73.0 (C-3), 72.8 (C-3’), 71.2 (C-2), 69.1 (C-
5’), 63.3 (C-5), 56.8 (OMe), 22.2 (C-6’), 21.5, 21.0, 20.9, 20.8, 20.7 (5ꢁ
OAc), 17.0 (C-7’); HRMS (CIMS): m/z calcd for C23H36O14N: 550.2136
[M+NH4]+; found: 550.2133.
1H; H-6’), 1.51–1.44 ppm (m, 1H; H-7’); 13C NMR (D2O, 100 MHz): d=
133.4 (ipso ArC), 131.9, 129.4, 127.9 (ArC), 93.2 (C-1), 76.7 (C-4), 75.1
(C-3), 73.3 (C-5), 71.2 (C-2), 23.3 (C-6), 22.9 ppm (C-7). Spectroscopic
data for the b anomer: 1H NMR (D2O, 400 MHz): d=7.54–7.34 (m, 5H;
ArC), 5.25 (br s, 1H; H-1), 3.83 (br s, 1H; H-5), 3.75 (s, 1H; H-4), 3.60
(s, 1H; H-3), 2.22–1.91 (m, 2H; H-6, H-7), 1.81–1.71 ppm (m, 2H; H-6’,
H-7’); 13C NMR (D2O, 100 MHz): d=133.3 (ipso ArC), 131.6, 129.4,
127.8 (ArC), 92.0 (C-1), 79.1 (C-3), 77.2 (C-4), 73.3 (C-5), 71.2 (C-2), 22.1
(C-6), 18.4 ppm (C-7); HRMS (ESI): m/z calcd for C13H16O4SNa:
291.06670 [M+Na]+; found: 291.06663.
Further elution afforded a disaccharide 25 (4mg, 12%) as a colorless oil:
[a]D =ꢀ56 (c=0.3 in CHCl3); 1H NMR (CDCl3, 400 MHz): d=5.87 (s,
1H; H-1’), 5.83 (dd, J=2.0, 2.7 Hz, 1H; H-3’), 5.21 (t, J=9.0 Hz, 1H; H-
3), 4.89–4.83 (m, 2H; H-4’, H-4), 4.38 (d, J=6.9 Hz, 1H; H-1), 4.08 (dd,
J=5.3, 11.7 Hz, 1H; H-5a), 3.95–3.94 (m, 1H; H-5’), 3.80 (dd, J=6.9,
9.0 Hz, 1H; H-2), 3.52 (s, 3H; OMe), 3.34 (dd, J=9.1, 11.7 Hz, 1H; H-
5b), 2.34–2.33 (m, 2H; H-6’a, H-7’b), 2.13 (s, 3H; OAc), 2.10 (s, 6H; 2ꢁ
OAc), 2.04 (s, 3H; OAc), 2.10–1.95 (m, 1H; H-7’b), 1.99 (s, 3H; OAc),
1.78–1.74 ppm (m, 1H; H-6’b); 13C NMR (CDCl3, 100 MHz): d=171.0,
170.9, 170.5, 170.2, 169.9 (5ꢁCO), 103.5 (C-1), 96.5 (C-1’), 78.6 (C-2’),
78.4 (C-4’), 74.3 (C-2), 73.9 (C-3), 73.2 (C-3’), 70.2 (C-5’), 70.1 (C-4), 62.7
(C-5), 56.9 (OMe), 22.3 (C-6’), 21.9, 21.5, 21.4, 21.2, 21.2 (5ꢁOAc),
17.9 ppm (C-7’); HRMS (CIMS): m/z calcd for C23H36O14N: 550.2136
[M+NH4]+; found: 550.2131.
Acknowledgements
F. Marcelo, L. Amorim, and L. Nieto thank respectively YFundażo para
CiÞncia e Tecnologia (FCT, Portugal), the European Community
(HPRN-CT-2002-00173), and the Ministry of Education and Science of
Spain (CTQ-2009-08576) for financial support.
a
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Compound 27: A few drops of 0.1m NaOMe were added dropwise to a
solution of disaccharide 25 (4 mg, 7.5 mmol) in MeOH (1 mL) until
pH 9–10 and the mixture was stirred for 3 h at RT. The reaction mixture
was neutralized with Amberlite IR 120 (H+) resin for 30 min, filtered,
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(2.4 mg, quantitative yield) as
a
colorless oil. [a]D =ꢀ68 (c=0.1 in
MeOH); 1H NMR (D2O, 400 MHz): d=4.87 (s, 1H; H-1’), 4.42 (d, J=
7.4 Hz, 1H; H-1), 3.93 (dd, J=3.6, 10.8 Hz, 1H; H-5a), 3.79 (m, 1H; H-
5’), 3.70 (d, J=2.4 Hz, 1H; H-4’), 3.64–3.57 (m, 2H; H-3, H-4), 3.54–3.51
(m, 4H; H-3’, OCH3), 3.42 (t, J=7.4 Hz, 1H; H-2), 3.30 (dd, J=6.0,
10.8 Hz, 1H; H-5b), 2.09–1.91 (m, 1H; H-6’a), 1.79–1.63 ppm (m, 3H; H-
6’b, H-7’a, H-7’b); 13C NMR (D2O, 100 MHz): d=103.0 (C-1), 102.6 (C-
1’), 78.8 (C-2), 77.3 (C-3’), 77.2 (C-4’), 75.2 (C-3 or C-4), 72.7 (C-5’), 72.2
(C-2’), 69.1 (C-3 or C-4), 64.6 (C-5), 57.0 (OMe), 21.6 (C-6’), 16.4 ppm
(C-7’); HRMS (ESI): m/z calcd for C13H26O9N: 340.1608 [M+NH4]+;
found: 340.1604.
Compound 28: A few drops of 0.1m NaOMe were added dropwise to a
solution of disaccharide 26 (13 mg, 24.4 mmol) in MeOH (3 mL) until
pH 9–10 and the mixture was stirred for 40 min at RT. The reaction mix-
ture was neutralized with Amberlite IR 120 (H+) resin for 30 min, fil-
tered, and concentrated under reduced pressure. Purification by flash
column chromatography (CH2Cl2/MeOH, 9:2) afforded the b-disacchar-
ide 28 (7.8 mg, quantitative yield) as a colorless oil. [a]D =ꢀ87 (c=0.5 in
MeOH); 1H NMR (D2O, 400 MHz): d=4.75 (s, 1H; H-1’), 4.35 (d, J=
7.8 Hz, 1H; H-1), 4.11 (dd, J=5.3, 11.8 Hz, 1H; H-5a), 3.87–3.86 (m,
1H; H-5), 3.76 (dd, J=0.8, 2.1 Hz, 1H; H-4), 3.75 (ddd, J=5.3, 9.1,
10.3 Hz, 1H; H-4), 3.59 (t, J=9.1 Hz, 1H; H-3), 3.56 (d, J=2.1 Hz, 1H;
H-3’), 3.55 (s, 3H; OMe), 3.37 (dd, J=10.3, 11.8 Hz, 1H; H-5b), 3.31 (dd,
J=7.8, 9.1 Hz, 1H; H-2), 2.14–2.05 (m, 1H; H-6’a), 1.83–1.76 (m, 1H; H-
7’a), 1.75–1.67 ppm (m, 2H; H-6’b, H-7’b); 13C NMR (D2O, 100 MHz):
d=104.2 (C-1), 100.8 (C-1’), 77.8 (C-3’), 77.6 (C-4’), 75.5 (C-4), 74.4 (C-
3), 73.2 (C-2), 73.2 (C-5’), 71.9 (C-2’), 63.3 (C-5), 57.5 (OMe), 22.2 (C-6’),
16.6 ppm (C-7’); HRMS (CIMS): m/z calcd for C13H26O9N: 340.1608
[M+NH4]+; found: 340.1600.
Compound 29: A few drops of 0.1m NaOMe were added to a solution of
thioglycoside 23 (9 mg, 22.8 mmol) in MeOH until pH 9–10 and the mix-
ture was stirred for 90 min at RT. The reaction mixture was neutralized
with Amberlite IR 120 (H+) resin for 30 min, filtered, and concentrated
under reduced pressure to afford the thioxyloside analogue 29 (6 mg,
90% yield) as a colorless oil and as a 1:5 mixture of a/b anomers. Spec-
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(m, 5H; ArH), 5.38 (s, 1H; H-1), 3.91 (s, 1H; H-3), 3.87 (d, J=2.3 Hz,
1H; H-5), 3.73 (s, 1H; H-4), 2.22–1.91 (m, 2H; H-6, H-7), 1.81–1.71 (m,
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4
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A
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Received: November 11, 2010
Published online: May 12, 2011
7356
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ꢆ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 7345 – 7356