Conformational effects on glycoside reactivity: Study of the high reactive conformer of glucose

Article abstract of DOI:10.1021/ja047476t

The effect of conformation on glycoside reactivity was investigated by studying the hydrolysis of a selection of 3,6-anhydroglucosides as models for glucose in the highly reactive ¹C₄ conformation. Methyl 3,6-anhydro-β-D-glucopyranoside was found to hydrolyze 200-400 times faster than methyl glucosides in the ⁴C₁ conformation, while methyl 3,6-anhydro-β-D-galactopyranoside, which is in the B_1,4 conformation, was less reactive than methyl β-D-galactopyranoside. Methyl (3,6-anhydro-β-D-glucopyranosyl)-(1 → 6)-α-D-glucopyranoside, methyl (3,6-anhydro-α-D-glucopyranosyl)-(1 → 6)-α-D- glucopyranosyl-(1 → 6)-α-D-glucopyranoside, and methyl (3,6-anhydro-β-D-glucopyranosyl)-(1 → 6)-α-D-glucopyranosyl-(1 → 6)-α-D-glucopyranoside were prepared and found to react selectively at the anhydro residue. The finding that ¹C₄ conformers of glucosides are highly reactive species is in accordance with and supports previous results showing that axial OH groups are less electron withdrawing than equatorial OH groups.

Full text of DOI:10.1021/ja047476t

Published on Web 09/09/2004
Conformational Effects on Glycoside Reactivity: Study of the
High Reactive Conformer of Glucose
Ciaran McDonnell,† Oscar Lo´pez,‡ Paul Murphy,† Jose´ G. Ferna´ndez Bolan˜os,‡
Rita Hazell,§ and Mikael Bols*,§
Contribution from the Department of Chemistry, UniVersity College Dublin, Ireland;
Department of Chemistry, UniVersity of SeVilla, Spain; and Department of Chemistry,
Aarhus UniVersity, 8000 Aarhus C, Denmark
Received April 30, 2004; E-mail: mb@chem.au.dk
Abstract: The effect of conformation on glycoside reactivity was investigated by studying the hydrolysis of
a selection of 3,6-anhydroglucosides as models for glucose in the highly reactive 1C4 conformation. Methyl
3,6-anhydro-â-D-glucopyranoside was found to hydrolyze 200-400 times faster than methyl glucosides in
4
the C1 conformation, while methyl 3,6-anhydro-â-D-galactopyranoside, which is in the B1,4 conformation,
was less reactive than methyl â-D-galactopyranoside. Methyl (3,6-anhydro-â-D-glucopyranosyl)-(1 f 6)-
R-D-glucopyranoside, methyl (3,6-anhydro-R-D-glucopyranosyl)-(1 f 6)-R-D-glucopyranosyl-(1 f 6)-R-D-
glucopyranoside, and methyl (3,6-anhydro-â-D-glucopyranosyl)-(1 f 6)-R-D-glucopyranosyl-(1 f 6)-R-D-
glucopyranoside were prepared and found to react selectively at the anhydro residue. The finding that 1C4
conformers of glucosides are highly reactive species is in accordance with and supports previous results
showing that axial OH groups are less electron withdrawing than equatorial OH groups.
Introduction
A more recent development is a line of investigations dealing
with the influence of stereochemistry on the reactivity of
glycosides. It has long been known that the rate of acidic
hydrolysis of glycosides increase with the amount of axial OH
groups in the saccharide ring. This was for many years explained
by the theory of Edward, which proposed that the rate increase
was caused with relief in the transition state of the sterical strain
caused by 1,3 diaxial interactions between the OH and H in
the ground state.5 However recently Bowen et al. suggested,
based on molecular mechanics calculations in the gas phase,
that the rate increase associated with an axial 4-OH was caused
by electrostatic stabilization in the transition state.6 Miljkovic
and co-workers have addressed the reactivity difference of
galactosides and glucosides in acetolysis and reached a similar
result based on ab initio calculations and experiments.7 Withers’
group has found that the rate of hydrolysis of dinitrophenyl
glycosides is caused by inductive effects and shown by using
Kirkwood-Westheimer analysis that the rate differences be-
tween stereoisomers could be explained by these effects as well.8
Thus with these three papers a challenge of the Edward
hypothesis had begun.
Carbohydrates are among the most common organic mol-
ecules on earth, and their chemistry and synthesis of fundamental
interest. More than 50% of carbohydrate chemistry deals with
the chemistry of the glycosidic bond, and the study of glycosyl
transfer reactions is a field of long standing that continues to
progress vigorously. The common understanding of glycoside
synthesis reactions was much advanced by the demonstrations
by the group of Fraser-Reid of the importance of electronic
effects in the so-called “armed-disarmed” effects.1 This
understanding was further advanced most notably in the work
of Ley2 and Wong3 so that today the different reactivities of
glycosyl donors effectively can be employed in glycoside
synthesis, and much is known about the torsional and electronic
effects induced on the saccharide from various protection
groups.4
† University College Dublin.
‡ University of Sevilla.
§ Aarhus University.
(1) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am. Chem.
Soc. 1988, 110, 5583-5584.
Our group has reached similar results working from a different
angle. In the study of hydroxylated piperidines and pyridazines
(glycosidase inhibitors), we found that the base strength
depended on a predictable manner of the stereochemistry of
(2) Ley, S. V.; Baeschlin, D. K.; Dixon, D. J.; Foster, A. C.; Ince, S. J.; Priepke,
H. W. M.; Reynolds, D. J. Chem. ReV. 2001, 53-80.
(3) Zhang, Z.; Ollmann, I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong,
C.-H. J. Am. Chem. Soc. 1999, 121, 734-753.
(4) For some other important contributions to this field, see: (a) Friesen R.
W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111, 6656-6660. (b)
Veeneman, G. H.; Boom, J. H. v. Tetrahedron Lett. 1990, 31, 275-278.
(c) Roy, R.; Andersson, F.; Letellier, M. Tetrahedron Lett 1992, 33, 6053-
6056. (d) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269-3276. (e)
Raghavan, S. Kahne, D. J. Am. Chem. Soc. 1993, 115, 1580-1581. (f)
Geurtsen, R.; Holmes, D. S.; Boons, G. J. J. Org. Chem. 1997, 62, 8145-
8154. (g) Hashimoto, S.; Sakamoto, H.; Honda, T.; Abe, H.; Nakamura,
S.; Ikegami, S. Tetrahedron Lett. 1997, 38, 8969-8972. (h) Lahmann, M.;
Oscarson, S. Can. J. Chem. 2002, 80, 889-893.
(5) Edward, J. T. Chem. Ind. (London) 1955, 1102-1104.
(6) Woods, R. J.; Andrews, C. W.; Bowen, J. P. J. Am. Chem. Soc. 1992, 114,
859-864.
(7) Miljkovic, M.; Yeagly, D.; Deslongchamps, P.; Dory, Y. L. J. Org. Chem.
1997, 62, 7597-7604.
(8) Namchuk, M. N.; McCarter, J. D.; Becalski, A.; Andrews, T.; Withers, S.
G. J. Am Chem. Soc. 2000, 122, 1270-1277.
9
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J. AM. CHEM. SOC. 2004, 126, 12374-12385
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Conformational Effects on Glycoside Reactivity
A R T I C L E S
Figure 1. Base strength of isomeric piperidines increase with number of axial OH groups (left). Similarly the reactivity of isomeric glycosyl derivatives
increases with axial OH or OR groups (right). An explanation based on hyperconjugation for the different substituent effects of axial and equatorial OH
(center, from ref 5, note 14).
Figure 2. Different chair conformations have different base strengths in the case of piperidines (left) and reactivities in the case of glycosides (right).
the OH substituent.9 We found that axial hydroxyl groups â
and γ to the basic center were considerably less electron
withdrawing than the corresponding equatorial hydroxyl groups
(Figure 1). Large differences in electron withdrawing power
were also seen for other polar substituents.9,10 Importantly it
was shown that these stereochemical substituent contributions
also influence glycoside hydrolysis, since good linear free energy
relationships were found between stereochemical substituent
constants obtained from amines and the hydrolysis rates of
stereoisomeric glycosides.10,11 Finally the Edward hypothesis
was laid to rest by the demonstration that a change of
stereochemistry of a methyl group substituent in no way had
the same influence on glycoside hydrolysis as an OH group.12
This is supported by the work of Kirby that also shows that the
influence of torsion is much smaller than electronic effects.13
It should also be noted that although transition state structure
and solvation is very different in glycoside synthesis reactions
these effects are also observed qualitatively there.3,14
should be termed conformational substituent effects. Thus, the
base strength of a hydroxylated piperidine may be markedly
different in the two chair forms (Figure 2) and may change
conformation as a result of a change of pH.9 This is also seen
in the work of Lankin et al. on fluorinated piperidines, which
shows that fluorine prefers the axial position in the protonated
piperidine.15,16 One can calculate the base strength of various
piperidine conformers, and for the trans,trans-3,4,5-piperidine-
triol, a ∆pKa of 2.0 pH units is calculated between all-equatorial
and -axial conformers (Figure 2). Using the parallel already
found between glycoside hydrolysis and piperidine base strength,
one should accordingly anticipate that glycoside hydrolysis rates
should depend on the conformation of the glycoside, and the
conformer having more axial hydroxyl groups should be more
reactive. On extrapolation of the free energy relationships, the
methyl R-xylopyranoside would be anticipated to hydrolyze up
to 102 times faster in the 1C4 conformation. If this is correct, it
poses many interesting questions such as to which extent certain
saccharides hydrolyze from conformers with axial OH groups
and whether polysaccharide chains can be selectively cleaved
by conformationally flipping a single residue.
An interesting implication of these effects is that they are
conformationally dependent and perhaps more appropriately
(9) Jensen, H. H.; Lyngbye, L.; Jensen, A.; Bols, M. Chem.sEur. J. 2002, 8,
1218-1226.
(10) Bols, M.; Liang, X.; Jensen, H. H. J. Org. Chem. 2002, 67, 8970-8974.
(11) Jensen, H. H.; Lyngbye, L.; Bols, M. Angew. Chem., Int. Ed. 2001, 40,
3447-3449.
(14) Bu¨low, A.; Meyer, T.; Olszewski, T. K.; Bols, M. Eur. J. Org. Chem. 2004,
323-329.
(15) Lankin, D. C.; Chandrakumar, N. S.; Rao, S. N.; Spangler, D. P.; Snyder,
J. P. J. Am. Chem. Soc. 1993, 115, 3356-3357.
(12) Jensen, H. H.; Bols, M. Org. Lett. 2003, 5, 3419-3421.
(13) Dean, K. E. S.; Kirby, A. J.; Komarov, I. V. J. Chem. Soc., Perkin Trans.
2 2002, 337-341.
(16) Lankin, D. C.; Grunewald, G. L.; Romero, F. A.; Oren, I. Y.; Snyder, J. P.
Org. Lett. 2002, 4, 3557-3560.
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A R T I C L E S
McDonnell et al.
Scheme 1. Hydrolysis of Various 3,6-Anhydrosugars (Top, from Ref 17): Endocyclic Protonation and Cleavage (Bottom)
We therefore in the present work investigate whether it is
true that glucose derivatives forced into a C4 conformer are
many glycosides.19 Under these conditions, 4 is converted into
7 and 12 is converted into 3,6-anhydrogalactose. An interesting
difference between these two compounds are that while both
are strained bicyclic structures, 4 is in chair and 12 is in boat
conformation (as determined by NMR).18 The first-order rate
constants were determined at 21, 31, and 41 °C for 4 and at 60,
70, and 79 °C for 12, and the Arrhenius equation was used to
calculate the rate constants at 60 °C. These values are shown
in Table 1 in comparison with known rate constants of
glycosides 9-11.19
As it is seen, the rate of hydrolysis of 4 is tremendously high,
251 times greater than the rate of hydrolysis of its 4C1 equivalent
10 and 446 times greater than the hydrolysis rate of 9 which is
the equivalent with an anomerically stabilized methoxy group.
Such a high hydrolysis rate is not entirely anticipated from
electronic effects and could also be an effect of the anhydride
being semideoxygenated as alluded to above. Second there could
be a relief of strain in going from ground state to transition
state in this reaction if the compound undergoes endocyclic
cleavage (Scheme 1), which is supported by the observations
by Haworth of furanosides being formed.17 Equally remarkable
is the contrasting slow hydrolysis rate of anhydrogalactoside
12. This compound hydrolyzes with only half the rate of methyl
â-galactoside 11. Nevertheless, given the boat conformation of
12 and the fact that the compound thereby gets two electron
withdrawing equatorial hydroxyl groups, the low reactivity is
reasonable. The striking contrast between 4 and 12 shows how
important conformation is to glycoside hydrolysis and how much
more reactive an all-axially substituted monosacharide becomes.
It also shows that release of strain does not itself provide a fast
reaction, as the release of 12 from the forced boat conformer is
a relatively slow process.
1
much more reactive glycosides. To do that, we have turned our
attention to the 3,6-anhydrides. The 3,6-anhydrides are strained
1
molecules but are still good models for glucosides in the C4
conformation as the strain is caused by the unfavorable steric
interaction between 1,3-diaxial groups, associated with this
conformation. There are cases however where the anhydrides
are in nonchair conformation, and the anhydrides have one
oxygen atom less, possibly making them a semi-deoxygenated
species. Indeed, in a classical work, Haworth described 3,6-
anhydrides as uniquely reactive compounds,17 which bode well
for the above hypothesis.
One of the interesting observations of Haworth was that the
methyl 3,6-anhydro-2,4-di-O-methyl-R-D-glucopyranoside (1)
rapidly changed anomeric configuration to â-glucoside 2 on
treatment with HCl gas (Scheme 1).17 He also found that methyl
3,6-anhydro-R-D-glucopyranoside (3) and its â-isomer 4 under
similar nonaqueous conditions were rearranged to the less
strained furanosides 5 and 6 with retention of configuration.
Even in aqueous acid, 3 converted to 5, while 6 hydrolyzed to
7. In aqueous acid, the methylated compounds 1 and 2, which
cannot form furanosides, interestingly formed the open chain
aldehyde 8 to relieve strain, and Haworth reported that 1 reacted
faster than 2.17 So while these derivatives appeared reactive,
no quantitative data existed that allowed us to compare them
with other glycosides such as glucosides in the 4C1 conformation.
In this paper we have synthesized several different 3,6-
anhydrooligosaccharides and investigated their acid-catalyzed
hydrolysis. We find that, generally, these compounds are many
orders of magnitude more reactive than the relaxed conformers
and that they hydrolyze selectively at the anhydro residue.
Anhydrocyclodextrins. Cyclodextrins with 3,6-anhydro resi-
dues are well-known, and from the above it was anticipated
that these derivatives would be highly labile toward hydrolysis
at the anhydro residues. To investigate that, we synthesized 3,6-
anhydro-â-cyclodextrin (13)20 and its permethylated analogue
(14) by treatment of 13 with MeI/NaH in DMSO. Hydrolysis
of these two compounds where studied in comparison with
Results and Discussion
Kinetic Study of Anhydromonosaccharides. Since no
previous kinetic studies had been done on the hydrolysis of 3,6-
anhydroglucosides, we started measuring the hydrolysis rate of
anhydroglucoside 417 and anhydrogalactoside 1218 in 2 M HCl
under which conditions rate constants at 60 °C are known for
(19) Overend, W. G.; Rees, C. W.; Sequeira, J. S. J. Chem. Soc. 1962, 3429-
(17) Haworth, W. N.; Owen, L. N.; Smith, F. J. Chem. Soc. 1941, 88-102.
(18) France, C. J.; McFarlane, I. M.; Newton, C. G.; Pitchen, P.; Barton, D. H.
R. Tetrahedron 1991, 47, 6381-6388.
3440.
(20) Fujita, K.; Yamamura, H.; Imoto, T.; Tabushi, I. Chem. Lett. 1988, 543-
546.
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Conformational Effects on Glycoside Reactivity
A R T I C L E S
Table 1. First-Order Rate Constants for Acidic Hydrolysis of Glycosides (Data for 9, 10, and 12 from Ref 19)
Scheme 2. Hydrolysis of Cyclodextrin Derivatives
â-cyclodextrin and permethyl â-cyclodextrin (15) (Scheme 2).21
Surprisingly, hydrolysis of 13 in 2 M HCl was not found to be
faster than that of â-cyclodextrin itself.22 At 30 °C little reaction
happened, while at 40 °C the reaction progressed very slowly
to a mixture of starting material and a hydrolyzed product.
Analogously 14 did not hydrolyze at room temperature in 2 M
HCl, but treatment for 22 h at 35 °C gave 83% conversion (17%
14 recovered by chromatography) to, according to MALDITOF
MS (Figure S4), a mixture of hydrolysis products that consisted
of oligosaccharides with 3-7 residues with and without the
anhydrosugar (Scheme 2). This hydrolysis mixture is consistent
with hydrolysis having occurred to a major extent at two
glycosidic linkages. Identical treatment of 15 gave 75% conver-
sion (as based on 25% recovery of 15) and thus appeared to
proceed with an essentially identical rate. However, MS on this
hydrolysis product revealed it to consist mainly of the hepta-
maltoside (Figure S5). As a control experiment, hydrolysis of
methyl 3,6-anhydro-2,4-di-O-methyl-R-D-glucopyranoside 117
was repeated under comparable conditions, and 1 was found to
hydrolyze completely in 1 h in 1 M HCl at 23 °C into aldehyde
8 and is thus clearly much more reactive than 14.
(22) Hirayama, F.; Kurihara, M.; Utsuki, T.; Uekama, K. Chem. Commun. 1993,
1578-1580.
(21) Freudenberg, K.; Meyer-Delius, M. Chem. Ber. 1938, 71, 1B, 1596-1600.
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A R T I C L E S
McDonnell et al.
Scheme 3. Synthesis of Glycosyl Donors 22 and 23
Scheme 4. Synthesis of Disaccharide 16
It is clear from these experiments that the anhydro residue
does not hydrolyze rapidly in 13 and 14. It appears that in the
hydrolysis of 14 the compound initially hydrolyzes at a random
residue. As soon as the cyclodextrin ring is broken, a fast second
hydrolysis step occurs at the anhydro residue to give fragments
consistent with the masses found. It is not clear why the anhydro
glucoside is unreactive in 13 and 14. A reasonable explanation
In the synthesis of 16 we used a pentenyl glycoside as leaving
group. Glucoside 1924 (R: â mixture) was semiselectively
tosylated to give 6-O-tosyl derivative 20 in 41% yield (Scheme
3). Treatment with NaH in DMF gave a high yield of anhydride
21, which was benzylated to give the two anomers 22 and 23
that were isolated in 74% and 14% yield after chromatographic
separation.
1
would be that this residue has been forced away from the C4
Coupling of 22 or 23 to methyl 2,3,4-tri-O-benzyl-R-D-
glucopyranoside (24) using TESOTf/NIS25 gave the â-linked
disaccharide 25 in 66% and 44% yield, respectively (Scheme
4). No R-isomer was isolated or observed. The â-selectivity in
this reaction is intriguing, and the yield is quite high when taking
into account that the substituent enters from the crowded endo
face. Nevertheless selectivity favors formation of the axial
product, which is similar to many glucosidations using donors
in 4C1 conformation favoring the R-anomer. Compound 25 was
uneventfully hydrogenolysed using Pd/C in EtOH and 1 atm of
H2 to give 16 in 78% yield (Scheme 4). X-ray structures were
obtained of 23 and 25 as well as of the known25 1-OMe analogue
of 23, 23a and are shown in Figure 3. The structure of 25 is of
particular interest because it is the first X-ray structure of 3,6-
anhydride â-glycoside to be reported. It is seen that 23 and 23a
are in perfect 1C4 conformations, but in 25 the anhydroglucose
is twisted into a half-chair conformation presumably because
of sterical conflict between the 1-substituent and the anhydride
conformation. However the fact that the anhydrosugar in 1320
and other anhydrocyclodextrins23 have similar 1H chemical shifts
and couplings as 3 does not support this hypothesis.
Synthesis of Anhydrooligosaccharides. As the cyclodextrin
experiments cast doubt on whether the extreme reactivity of
1
the C4 conformer is found beyond the monosaccharide level,
it was desirable to study hydrolysis of an acyclic oligosaccharide
containing a 3,6-anhydride. Such compounds have not been
made previously, and it was quickly realized that to prepare
such compounds in a practical manner required glycoside
synthesis. We synthesized a di- and two trisaccharides containing
the 3,6-anhydroglucoside moiety at the terminal end and used
two different approaches for this purpose. The disaccharide 16
was synthesized as outlined in Schemes 3 and 4 by glycoside
coupling with a 3,6-anhydroglucosyl donor. However, as this
turned out only to give the â-stereochemistry, the trisaccharides
17 and 18 were synthesized by formation of the 3,6-anhydride
at the end of the synthesis (Schemes 5 and 6).
(24) Wilson, B. G.; Fraser-Reid, B. J. Org. Chem. 1995, 60, 317-320.
(25) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.; Ottosson, H. J. Org. Chem. 1990,
55, 6068-6070.
(23) Gadelle, A.; Defaye, J. Angew. Chem., Int. Ed. Engl. 1991, 30, 78-80.
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Conformational Effects on Glycoside Reactivity
A R T I C L E S
Scheme 5. Synthesis of Trisaccharides 30 and 31
Scheme 6. Synthesis of Trisaccharides 17 and 18
bridge. This observation makes it even more surprising that the
glycosidation with 22 and 23 only gives the â-anomer 25. The
fact that 25, and hence presumably 16 as well, is not in a perfect
1C4 conformation raised some concerns as to the usefulness of
the â-isomers as models for 13 or 14. The direct glycosidation
method was therefore abandoned in the trisaccharide synthesis
because it could not provide the more desirable R-glycosides.
For the trisaccharides, the known tolylthio-2,3,4-tri-O-benzyl-
â-D-glucopyranoside (26)26 was acetylated to 6-acetate 27 and
coupled to 24 using the NIS/TfOH promotor system (Scheme
5).27 This gave the R-linked disaccharide 28 in 64% yield with
a small amount of â-isomer (3%) being separated chromato-
graphically. After deacetylation with NaOMe/MeOH, the alcohol
29 was obtained in 92% yield. Renewed reaction of 29 with 26
and NIS/TfOH gave, after deacetylation, the R- and â-tri-
saccharides 30 and 31 in 35% and 11% yields, respectively.
(26) Yamago, S.; Kokubo, K.; Hara, O.; Masuda, S.; Yoshida, J. J. Org. Chem.
2002, 67, 8584-8592.
(27) Veeneman, G. H.; van Leeuwen, S. H.; van Boom, J. H. Tetrahedron Lett.
1990, 31, 1331-1334.
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A R T I C L E S
McDonnell et al.
Figure 3. X-ray structures of methyl 3,6-anhydro-2,4-di-O-benzyl-R-D-glucopyranoside (23a), 23, and 25.
Scheme 7. Hydrolysis of 16-18
These trisaccharides were converted into anhydrides as
outlined in Scheme 6. Reaction of 30 with TsCl/pyridine gave
6”-tosylate 32 in 80% yield. Hydrogenolysis with H2/Pd
proceeded in high yield to unprotected 33 that was treated with
NaOH to give the 3,6-anhydride 17 in 61% yield. In an identical
sequence of reactions, the â-anomer 31 was converted into 18
(Scheme 6).
chemical shift as 36 most notably the triplet at 4.69 ppm (Figure
S7). However, no hydrolysis to methyl isomaltoside occurred
in this case and within a 24 h period the reaction stopped at 37.
The rate of conversion of 18 or formation of 37 was first-order
and gave the rate constant 5.9 × 10-4 s-1 (Table 2).
The rate of reaction of the trisaccharide 17 was too fast to
measure by 1H NMR spectroscopy in 1.3 M DCl, so the reaction
kinetics were done at 0.13 M DCl. Under these conditions the
17 was rapidly converted to the methyl isomaltoside without
any formation of furanoside intermediate being observed. The
reaction was first-order in substrate and product, and the rate
constant was determined (Table 2).
Hydrolysis of Anhydrooligosaccharides. With the sub-
stances 16-18 at hand, their reaction with aqueous acid was
studied (Scheme 7). This was done in DCl in D2O at room
1
temperature (26 °C), and the reactions were followed by H
NMR. The reaction of 16 was carried out in 1.3 M DCl. On
analysis, this reaction was found to be more complicated than
expected. In addition to the cleavage of the disaccharide linkage,
a parallel reaction involving the rearrangement of the disac-
charide to another species also occurred; this species underwent
subsequent hydrolytic cleavage so that after 24 h methyl R-D-
glucopyranoside was the only glycoside present. The intermedi-
ate had a singlet at 5.03 ppm and triplet at 4.69 ppm (Figure
S6), which is close to methyl 3,6-anhydro-â-D-glucofuranoside
having a similar singlet (5.01 ppm, H-1) and triplet (4.89 ppm,
H-4). The rearrangement product of the parallel reaction is most
likely the furanoside 36. No evidence was seen of cleavage of
the methyl glycoside within this time frame.
The anhydrosugars 16-18 are all extremely reactive toward
aqueous acid and thus behave similarly to 4. Indeed if, from
the Arrhenius data, the hydrolysis rate of 4 in 2 M HCl is
calculated at 26 °C, a rate constant of 7.23 × 10-5 s-1 is
obtained, and it is thus clear that the three oligosaccharide
analogues actually react even faster than 4. The reason for this
is probably that methanol is a poorer leaving group than the
more acidic sugar alcohol. The rearrangements observed for 16
and 18 are similar to those observed by Haworth for the
hydrolysis of R-anomer 3. Curiously Haworth did not observe
rearrangement in the â-anomer 4; an observation we can confirm
by NMR. Likewise it is intriguing that it is the R-anomer 17 in
which no rearrangement is observed. It therefore appears that
whether hydrolysis or rearrangement occurs largely depends on
the leaving group. One effect of the leaving group could be,
due to the difference in basicity of the exocyclic oxygen, to
influence the ratio of exo- and endocyclic protonation and, as
only endocyclic protonation can lead to rearrangement, thereby
to affect the rearrangement/hydrolysis ratio.
The rate of conversion of 16 was determined by measuring
the rate of decrease in the intensity of the singlet (H-1′, peak 1)
at 4.78 ppm in relation to the total of the doublets corresponding
to H-1 in substrate, product, and intermediate. This degradation
was shown to follow pseudo-first-order kinetics and have a rate
constant of 8.8 × 10-4 s-1 (Table 2).
A similar conversion of 18 to what is likely to be furanoside
37 was observed when this quite similar compound was treated
with 1.3 M DCl in D2O. Compound 37 had a very similar
The observation from X-ray that intermediate â-glucoside 25
is in halfchair conformation raises the possibility that â-glyco-
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A R T I C L E S
Table 2. First-Order Rate Constants for Acidic Hydrolysis of Glycosides 16-18 as Determined by NMR
(4 mL) was kept at room temperature for 17 h. Then the solution was
neutralized with saturated aqueous NaHCO3 and concentrated to
dryness. The residue was purified by column chromatography (CH2Cl2
f 10:1 CH2Cl2-MeOH) to give the title compound (67 mg, 95%) in
sides 4, 16 and 18 may be in this conformation as well. In this
conformation the molecule still has the 3 and 4 OR/OH groups
in axial position and 2-OH in an intermediate position which
should also make it much more reactive than the all equatorial
4C1 conformation. On the other hand, all published X-rays of
anhydro R-glucosides have shown them to be in 1C4 conforma-
tion making it very likely that 17 is in this conformation as
well. The reason 17 hydrolyzes faster than 4, 16, and 18
therefore may be due to its more perfect conformation.
1
1
a 1:0.9 R/â mixture, as deduced by H NMR spectroscopy. H NMR
(500 MHz, D2O) δ 5.44 (d, 1H, J1,2 3.9 Hz, H-1R), 5.40 (m, 1H, J1,2
1.0 Hz, J1,3 0.5 Hz, H-1â), 4.79 (t, 1H, J4,3 4.9 Hz, J4,5 4.9 Hz, H-4â),
4.72 (t, 1H, J3,4 5.2 Hz, J4,5 5.2 Hz, H-4R), 4.52 (dd, 1H, J2,3 2.7 Hz,
H-3R), 4.44 (m, J3,4 4.9 Hz, J2,3 1.0 Hz, J1,3 0.5 Hz, H-3â), 4.37 (ddd,
1H, J5,6a 6.5 Hz, J5,6b 7.4 Hz, H-5â), 4.28 (ddd, 1H, J5,6a 6.2 Hz, J5,6b
7.3 Hz, H-5R), 4.14 (m, 1H, H-2â), 4.13 (m, 1H, H-2R), 3.94 (dd, 1H,
J6a,6b 9.2 Hz, H-6aR), 3.91 (dd, 1H, J6a,6b 8.7 Hz, H-6aâ), 3.80 (dd,
1H, H-6bâ), 3.54 (dd, 1H, H-6bR); 13C NMR (75.5 MHz, D2O) δ 103.7
(C-1â), 98.8 (C-1R), 86.7 (C-3â), 86.4 (C-3R), 83.1 (C-4â), 79.3 (C-
2â), 79.0 (C-4R), 75.6 (C-2R), 71.1 (C-6â), 70.7 (C-5â), 70.6 (C-5R),
70.4 (C-6R).
Conclusion
1
It has been experimentally verified that the C4 conformers
of glucosides are indeed highly reactive species. Oligosaccha-
rides containing the 3,6-anhydroglucopyranoside unit in this
conformation were found to undergo selective hydrolysis or
rearrangement at that position. One exception is the slow and
unspecific hydrolysis of the anhydro-â-cyclodextrins. However
since the opening of the cyclodextrin ring is followed by
immediate specific hydrolysis at the anhydroglucoside, it is
proposed that a conformational distortion of the anhydro residue
is the cause of its low reactivity in the cyclodextrin ring. The
high reactivity of the all-axial conformers opens many interesting
questions such as do some glycosides undergo conformational
change during hydrolysis or can conformational flipping be used
to achieve selective glycoside hydrolysis or transfer? Future
research may address these questions.
Permethylated-3A,6A-anhydro-â-cyclodextrin (14): Sodium hy-
dride (0.083 g, 3.49 mmol) in dry DMSO (2 mL) under an N2
atmosphere was heated to 50 °C for 45 min. The resulting solution
was cooled to room temperature, whereupon 13 (0.065 g, 0.058 mmol)
dissolved in dry DMSO (2 mL) was added dropwise over 10 min. The
solution was stirred at room temperature for 2 h. Methyl iodide (0.22
mL, 3.49 mmol) was added dropwise over 10 min and left to stir
overnight. CH2Cl2 (15 mL) and MeOH (2 mL) were added to the
mixture which was washed with water (4 × 15 mL), dried (MgSO4),
and filtered, and solvents were removed in vacuo. Chromatography
(20:1 CH2Cl2-EtOH) gave the title compound 14 as a white solid
(0.037 g, 30%); RF 0.54 (20:1 CH2Cl2-EtOH); mp 127-130 °C; [R]D
1
+144° (c 0.5 CHCl3); H NMR (CDCl3, 200 MHz) δ 5.52 (d, 1H, J
Experimental Section
3.6 Hz), 5.24 (d, 1H, J 2.6 Hz), 5.16 (d, 1H, J 3.3 Hz), 5.03 (d, 1H, J
3.3 Hz), 5.00 (d, 1H, J 2.9 Hz), 4.96 (d, 1H, J 3.3 Hz), 4.87 (d, 1H, J
3.3 Hz), 4.55 (t, 1H, J 4.5 Hz), 4.36 (bs, 1H), 4.10 (apt t, 2H, J 10.0
Hz), 3.66-3.88 (m, 13H), 3.38-3.66 (m, 61H), 3.56 (apt t, 1H), 3.44
(dd, J 7.7, 2.9 Hz), 3.36 (bs, 3H), 3.30 (apt t, 3H, J 1.8 Hz), 3.23 (bs,
4H), 2.96-3.20 (m, 9H); 13C NMR (CDCl3, 50 MHz) δ 99.1, 98.7,
98.2, 97.9, 97.0, 96.7, 95.7 (each d, 7 × C-1), 81.9, 81.8, 81.5, 81.4,
81.2, 80.9, 80.7, 80.5, 79.3, 78.3, 77.2, 76.4, 72.3, 70.5, 70.2, 70.0,
General Procedure for Determining the Rate of Glycoside
Hydrolysis: A solution of about 5 mg/mL of glycoside in 2 M aq.
HCl was added to a cuvette preheated to the desired temperature, and
the optical rotation was measured as a function of time until a constant
value.
3,6-Anhydro-D-glucofuranose (7): A solution of methyl 3,6-
anhydro-â-D-glucopyranoside (4, 76 mg, 0.43 mmol) in 2 M aq. HCl
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12381

A R T I C L E S
McDonnell et al.
69.4, 69.2, 68.3, 60.9, 60.8, 60.4, 60.3, 60.2, 59.0, 58.0, 57.9, 57.8,
57.6, 57.4, 24.2, 56.9, 56.8. HRMS-ES: found 1405.6450, requires
1405.6463.
â anomer), 98.6 (d, C-1, R anomer), 76.3, 73.5, 73.4, 69.8, 69.7, 69.5,
30.3 (t, OCH2CH2CH2CHdCH2, R anomer), 30.2 (t, OCH2CH2CH2-
CHdCH2, â anomer), 28.9 (t, OCH2CH2CH2CHdCH2, â anomer), 28.6
(t, OCH2CH2CH2CHdCH2, R anomer), 21.9 (q, PhCH3). LRMS-ES:
425.9 [M + Na]+.
Hydrolysis of 14: A solution of 14 (0.117 g, 0.12 mmol) dissolved
in 2 M aq. HCl (2.5 mL) was stirred at 35 °C for 22 h. The solution
was cooled to room temperature and washed with CH2Cl2 (4 × 15
mL). The combined organics were dried (MgSO4) and filtered, and
solvent was removed in vacuo. Chromatography (20:1 CH2Cl2-EtOH)
yielded 14 (0.02 g, 17%), and a mixture of hydrolysis products (0.079
g) with the same RF value were isolated; RF 0.40 (20:1 CH2Cl2-EtOH);
1H NMR (CDCl3, 200 MHz) δ 9.80, 9.79, 5.58-5.59 (m), 5.25-5.30
(m), 5.28-5.29 (m), 4.94-4.97 (m), 3.40-3.95 (m), 3.28-3.33 (m),
3.14-3.21 (m); 13C NMR (CDCl3, 50 MHz) δ 202.4, 97.8, 96.1, 95.6,
95.2, 95.2, 89.2, 85.0, 84.1, 83.4, 82.1, 81.8, 81.4, 81.2, 80.7, 79.9,
79.4, 73.0, 72.5, 71.2, 70.7, 70.3, 70.0, 69.8, 69.2, 68.2, 59.8, 59.2,
58.6, 58.2, 57.9, 57.7, 57.4, 57.3. LRMS-MALDI: 1423.6, 1405.5,
1265.3, 1220.3, 1061.2, 1015.2, 857.2, 811.1. LRMS-FAB:1423, 1265,
1219, 1061, 1015, 857, 653.
Pent-4′-enyl 3,6-anhydro-D-glucopyranoside (21): A solution of
20 (1.23 g, 3.06 mmol) in EtOH (12 mL) and NaOH (1 M, 12 mL)
was stirred at room temperature for 16 h, heated to 45 °C for 2 h, and
cooled to room temperature. The reaction was neutralized with solid
CO2, and the solvents were removed in vacuo to leave a white solid.
The crude product was extracted with boiling acetone (∼50 mL), dried
(MgSO4), and filtered, and the acetone was removed in vacuo.
Chromatography (1:1 toluene-EtOAc) gave the title compound 21 as
a clear oil (0.62 g, 89%) of inseparable anomers with a 1:5 R/â
diastereomeric ratio; RF 0.23 (1:1 toluene-EtOAc); 1H NMR (CDCl3,
200 MHz) δ 5.68-5.79 (m, 1H, OCH2CH2CH2CHdCH2, both ano-
mers), 5.09 (d, 1H, J 4.3 Hz, H-1, R anomer), 4.89-4.98 (m), 4.79
(apt t, 1H, R anomer), 4.55 (apt t, 1H, J 5.3 Hz, â anomer), 4.38 (dd,
1H, J 5.3, 2.9 Hz, â anomer), 4.30 (d, 1H, R anomer), 4.25 (d, 1H, â
anomer, 4.06-4.22 (m), 3.80 (dd, 1H, J 10.0, 3.1 Hz, â anomer), 3.68-
3.79 (m), 2.98-3.58 (m); 13C NMR (CDCl3, 50 MHz) δ 137.0 (d,
OCH2CH2CH2CHdCH2, â anomer), 136.7 (d, OCH2CH2CH2CHdCH2,
R anomer), 112.2 (t, OCH2CH2CH2CHdCH2, R anomer), 114.0 (t,
OCH2CH2CH2CHdCH2, â anomer), 102.0 (d, C-1, â anomer), 95.1
(d, C-1, R anomer), 86.8, 86.6, 82.9, 79.1, 76.7, 73.3, 73.3, 71.4, 70.3,
69.7 67.8, 67.0, 29.3 (t, OCH2CH2CH2CHdCH2, R anomer), 29.1 (t,
OCH2CH2CH2CHdCH2, â anomer), 27.5 (t, OCH2CH2CH2CHdCH2,
R anomer), 27.5 (t, OCH2CH2CH2CHdCH2, â anomer). LRMS-ES:
253.2 [M + Na]+. HRMS-ES: found 253.1049, requires 253.1052 [M
+ Na]+.
Pent-4′-enyl 3,6-Anhydro-2,4-di-O-benzyl-R-D-glucopyranoside
(22) and Pent-4′-enyl 3,6-Anhydro-2,4-di-O-benzyl-â-D-glucopyrano-
side (23): To a mixture of sodium hydride (0.65 g, 16.2 mmol, 60%
dispersed in mineral oil) in dry DMF (10 mL) under an N2 atmosphere,
21 (0.62 g, 2.70 mmol) dissolved in dry DMF (10 mL) was added
dropwise. The solution was stirred for 30 min. Benzyl bromide (1.92
mL, 16.2 mmol) was added dropwise over 20 min. The solution was
stirred at room temperature for 24 h, poured onto ice-water (50 mL),
and extracted with Et2O (2 × 50 mL), and the combined organic
portions were dried (MgSO4), filtered, and concentrated under reduced
pressure. Chromatography (4:1 pentane-Et2O) gave the title com-
pounds, 22 (0.81 g, 74%) as a white solid and 23 as a white solid. 23
was recrystallized from EtOH to give clear crystals (0.16 g, 14%).
Analytical data for 23: RF 0.68 (1:1 pentane-EtOAc); mp 81-82
°C; [R]D + 125° (c 0.5 CHCl3); 1H NMR (CDCl3, 400 MHz) δ 7.06-
7.23 (m, 10H, aromatic H’s), 5.75 (ddt, J 17.0, 10.1, 6.8 Hz, OCH2-
CH2CH2CHdCH2), 4.98 (d, 1H, J 2.9 Hz, H-1), 4.97 (dd, 1H, J 3.5,
1.6 Hz, OCH2CH2CH2CHdCH2), 4.93 (d, 1H, J 12.1 Hz, CH2Ph),
4.88-4.91 (m, 1H, OCH2CH2CH2CHdCH2), 4.72 (d, 1H, J 12.3 Hz,
CH2Ph), 4.49 (d, 1H, J 12.1 Hz, CH2Ph), 4.47 (d, 1H, J 12.3 Hz,
CH2Ph), 4.30 (t, 1H, J 2.7 Hz, H-5), 4.26 (t, 1H, J 4.7 Hz, H-4), 3.98
(m, 2H, OCH2CH2CH2CHdCH2, H-6a), 3.75 (dd, 1H, J 10.3, 2.9 Hz,
H-6b), 3.67 (dd, 1H, J 4.7, 2.5 Hz, H-3), 3.62 (t, 1H, J 3.7 Hz, H-2),
3.43 (td, 1H, J 9.6, 6.8 Hz, OCH2CH2CH2CHdCH2), 2.08 (m, 2H,
OCH2CH2CH2CHdCH2), 1.70 (m, 2H, OCH2CH2CH2CHdCH2); 13C
NMR (CDCl3, 100 MHz) δ 139.2 (d, OCH2CH2CH2CHdCH2), 138.5,
138.3 (each s, ipso C), 128.5, 128.5, 128.1, 127.9, 127.7 (each d,
aromatic C), 115.1 (t, OCH2CH2CH2CHdCH2), 98.3 (d, C-1), 76.3,
75.6, 74.8, 74.2, 72.3, 71.9, 69.9, 68.6 (C-2-C-6, OCH2CH2CH2CHd
CH2 and 2 × CH2Ph), 30.4 (t, OCH2CH2CH2CHdCH2), 29.0 (t, OCH2-
CH2CH2CHdCH2); IR (KBr) υ 2964, 2941, 1636, 1497, 1453,
1369,1026, 904 cm-1; HRMS-ES: found 433.2007, requires 433.1991
[M + Na]+. X-ray crystallography data: Appendix A2.
Hydrolysis of 15: A solution of 15 (63 mg, 0.044 mmol) dissolved
in 2 M aq. HCl (1.39 mL) was heated at 35 °C for 22 h. The solution
was then cooled to room temperature and washed with CH2Cl2 (4 ×
10 mL). The combined organics were dried (MgSO4) and filtered, and
CH2Cl2 was removed in vacuo. Chromatography (20:1 CH2Cl2-EtOH)
yielded 15 (0.016 g, 25%) and the hydrolysis product (0.041 g, 65%);
RF 0.35 (20:1 CH2Cl2-EtOH); 1H NMR (CDCl3, 200 MHz) δ 5.59 (d,
2H, J 3.3 Hz, 2 × H-1), 5.50 (d, 2H, J 3.3 Hz, 4 × H-1), 5.29 (d, 1H,
J 3.7 Hz, 1 × H-1), 4.56 (d, 1H, J 7.3 Hz), 3.59-3.99 (m, 21H), 3.44-
3.55 (m, 56H), 3.27-3.34 (m, 21H), 3.12-3.25 (m, 8H); 13C NMR
(CDCl3, 50 MHz) δ 96.1, 95.7, 95.2, 89.3, 84.9, 84.2, 82.2, 81.8, 81.2,
80.7, 72.6, 72.2, 71.3, 70.5, 70.2, 69.8, 69.3, 69.1, 68.3, 59.8, 59.2,
59.1, 58.7, 58.5, 58.2, 58.0, 57.8, 57.5. LRMS-MALDI: 1469.1 [M +
Na]+. LRMS-FAB: 1469 [M + Na]+.
Hydrolysis of 1: A solution of 1 (55 mg, 0.27 mmol) was allowed
to stir in 2 M aq. HCl (5.4 mL) at room temperature. TLC showed the
starter was completely consumed after 1 h. The product was extracted
from the acid with CH2Cl2 (4 × 15 mL). The combined organic portions
were washed with H2O (30 mL), dried (MgSO4), and filtered, and the
1
solvent was removed at reduced pressure to obtain crude 8; H NMR
(CDCl3, 200 MHz) δ (selected data) 9.74 (s), 4.39 (dd, 1H, J 7.7 Hz,
2.2), 3.51, 3.41 (each s, 6H, 2 × OCH3); 13C NMR (CDCl3, 50 MHz)
δ 201.3, 83.2, 80.1, 77.4, 73.3, 68.0, 58.3, 57.6. LRMS-ES: 245.3
[M + MeOH + Na]+.
Pent-4′-enyl 6-O-Toluenesulfonyl-D-glucopyranoside (20): To a
solution of 19 (1.85 g, 7.45 mmol) in dry pyridine (40 mL) under an
N2 atmosphere, p-toluenesulfonyl chloride (1.56 g, 8.20 mmol) dissolved
in pyridine (20 mL) was added slowly. The resulting solution was stirred
at room temperature for 4 days. The pyridine (azeotroped with toluene)
was removed under reduced pressure at <40 °C. The resulting residue
was dissolved in CH2Cl2 (50 mL) and was washed successively with
satd. aq. NaHCO3 (2 × 50 mL) and satd. aq. KHCO3 (1 × 50 mL),
dried (MgSO4), and filtered, and the solvent was removed in vacuo.
Chromatography (CH2Cl2) gave the title compound 20 (1.23 g, 41%)
as inseparable diastereomers (R/â 1:5); RF 0.80 (20:1 CH2Cl2-EtOH);
1H NMR (CDCl3, 200 MHz) δ 7.71 (m, 2H, J 8.4 Hz, ortho-H’s), 7.23
(d, 2H, J 8.4 Hz, meta-H’s), 5.64-5.75 (m, 1H, OCH2CH2CH2CHd
CH2, both anomers), 5.22 (bs, OH), 4.90-4.94 (m), 4.88 (d, 1H, J 2.0
Hz, R anomer), 4.67 (d, 1H, J 3.7 Hz, â anomer), 4.60 (bs, OH), 4.53
(d, J 3.5 Hz, R anomer), 4.13-4.32 (m), 3.67 (apt t, 1H, J 6.7 Hz, â
anomer), 3.41-3.56 (m), 3.41-3.53 (m), 3.38 (dd, 1H J 10.0 Hz, 2.9,
â anomer), 3.25 (t, 1H, J 8.6 Hz, R anomer), 2.34 (s, OCH3), 1.93-
2.01 (m, OCH2CH2CH2CHdCH2), 1.55-1.62 (m, OCH2CH2CH2CHd
CH2); 13C NMR (CDCl3, 50 MHz) δ 145.1 (s, ipso C, both anomers),
138.3 (d, CH2CH2CHdCH2, â anomer), 138.2 (d, CH2CH2CHdCH2,
R anomer), 132.9 (s, ipso C R anomer), 132.8 (s, ipso C, â), 130.1,
128.2 (each d, aromatic C’s), 115.3 (t, OCH2CH2CH2CHdCH2, R
anomer), 115.2 (t, OCH2CH2CH2CHdCH2, â anomer), 102.6 (d, C-1,
Analytical data for 22: RF 0.72 (1:1 pentane-EtOAc); mp 46-47
1
°C; [R]D +38 (c 0.2 CHCl3); H NMR (CDCl3, 400 MHz) δ 7.17-
7.29 (m, 10H, aromatic H’s), 5.75 (ddt, J 17.0, 10.1, 6.8 Hz, OCH2-
9
12382 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Conformational Effects on Glycoside Reactivity
A R T I C L E S
CH2CH2CHdCH2), 4.94 (m, 1H, J 17.0, 3.5, 1.6 Hz, OCH2CH2CH2-
CHdCH2), 4.94 (d, 1H, J 2.2 Hz, H-1), 4.89 (m, 1H, J 10.1, 2.0, 1.2
Hz, OCH2CH2CH2CHdCH2), 4.66 (d, 1H, J 11.5 Hz, CH2Ph), 4.61
(d, 1H, J 11.8 Hz, CH2Ph), 4.52 (d, 1H, J 11.8 Hz, CH2Ph), 4.51 (d,
1H, J 11.5 Hz, CH2Ph), 4.30 (t, 1H, J3,4 3.1 Hz, H-3), 4.23 (dd, 1H, J
5.1, 2.3 Hz, H-5), 4.01 (d, 1H, J6a,6b 9.8 Hz, H-6a), 3.83 (dd, 1H, J 4.5,
J4,3 3.1 Hz, H-4), 3.76 (dd, 1H, J6b,6a 9.8 Hz, H-6b), 3.73-3.79 (m,
1H, OCH2CH2CH2CHdCH2), 3.56 (bs, 1H, H-2), 3.43 (dt, 1H, J 9.6,
6.8 Hz, OCH2CH2CH2CHdCH2), 2.08 (m, 2H, OCH2CH2CH2CHd
CH2), 1.70 (m, 2H, OCH2CH2CH2CHdCH2); 13C NMR (CDCl3, 100
MHz) δ 138.3 (d, OCH2CH2CH2CHdCH2), 138.1, 137.7 (each s, ipso
C), 128.7, 128.5, 128.1, 127.9, 127.8, 127.1 (each d, aromatic C), 114.9
(t, OCH2CH2CH2CHdCH2), 99.7 (d, C-1), 75.6, 72.8, 72.5, 72.3, 72.2,
71.6, 67.9, 30.5 (t, OCH2CH2CH2CHdCH2), 28.9 (t, OCH2CH2CH2-
(5 mL), and pyridine (5 mL) in the presence of DMAP was stirred for
2 h. Water (20 mL) was added, and the product was extracted with
CH2Cl2 (2 × 40 mL). The combined organic portions were dried
(MgSO4) and filtered, and the solvent was removed in vacuo.
Chromatography (10:1 pentane-EtOAc) gave the title compound 27
as a clear oil (1.23 g, 83%); RF 0.62 (2:1 pentane-EtOAc); [R]D -18°
1
(c 0.9, CHCl3); H NMR (400 MHz, CDCl3) δ 7.00-7.38 (m, 19H,
aromatic H’s), 4.84 (d, 1H, J 10.4 Hz, OCH2Ph), 4.83 (d, 1H, J 11.0
Hz, OCH2Ph), 4.76 (d, 1H, J 11.0 Hz, OCH2Ph), 4.75 (d, 1H, J 10.2
Hz, OCH2Ph), 4.49 (d, 1H, J1,2 9.8 Hz, H-1), 4.48 (d, 1H, J 11.0 Hz,
OCH2Ph), 4.27 (dd, 1H, J6a,6b 11.5 Hz, J 1.0 Hz, H-6), 4.12 (dd, 1H,
J6b,6a 11.5 Hz, J 5.1 Hz, H-6b), 3.61-3.65 (m, 1H, H-5), 3.41-3.49
(m, 2H, H-3, H-4), 3.39 (t, 1H, J2,1 9.8 Hz, H-2), 2.23 (s, 3H, PhCH3)
1.95 (s, 3H, C(O)CH3); 13C NMR (100 MHz, CDCl3) δ 170.7 (s,
C(O)CH3), 138.3, 138.0, 137.9, 137.7 (each s, 5 × ipso C’s), 132.8,
129.7, 129.7, 128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 128.1, 127.9,
127.8 (each d, aromatic C’s), 87.8 (d, C-1), 86.8, 80.9, 77.6, 76.9 (each
d, C-2-C-5), 75.9, 75.5, 75.1 (each t, 3 × OCH2Ph), 63.4 (t, C-6),
21.2, 20.9 (each q, C(O)CH3 and PhCH3); IR (KBr) υ 3031, 2871,
1741 (CdO), 1362, 1237, 1088 cm-1. Anal. Calcd for C36H38O6S: C,
72.21; H, 6.40; S, 5.36. Found: C, 71.86; H, 6.36; S, 5.67. LRMS-ES:
621.2 [M + Na]+.
Methyl 6-O-Acetyl-2,3,4-tri-O-benzyl-R-D-glucopyranosyl-(1f6)-
2,3,4-tri-O-benzyl-R-D-glucopyranoside (28) and Methyl 6-O-Acetyl-
2,3,4-tri-O-benzyl-â-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-R-
D-glucopyranoside (28a): To a stirred solution of 27 (1.32 g, 2.20
mmol), 24 (1.02 g, 2.20 mmol), and NIS (0.99 g, 4.40 mmol) predried
under a high vacuum for 4 h in CH2Cl2 (2 mL) and Et2O (10 mL)
under an N2 atmosphere at -40 °C, trifluoromethanesulfonic acid (100
µL) was added. The reaction was stirred for 5 min, satd. aq. NaHCO3
solution (0.1 mL) was added, and the reaction was allowed to warm to
room temperature. The reaction was diluted with CH2Cl2 (25 mL) and
washed successively with 10% aq. sodium thiosulfate (2 × 30 mL)
and satd. aq. NaHCO3 solution (30 mL). The organic portion was dried
(MgSO4) and filtered, and solvent was removed in vacuo. Chromatog-
raphy (6:1 pentane-EtOAc) gave the title compounds 28 (1.32 g, 64%)
and 28a (0.06 g, 3%) as white solids.
CHdCH2); IR (KBr) υ 2931, 2886, 1642, 1497, 1453, 1205, 694 cm-1
.
LRMS-ES: 433.2 [M + Na]+. HRMS-ES: found 433.1985, requires
433.1991 [M + Na]+.
Methyl O-[3,6-Anhydro-2,4-di-O-benzyl-â-D-glucopyranosyl]-
(1f6)-2,3,4-tri-O-benzyl-R-D-glucopyranoside (25): A mixture of 22
or 23 (0.08 g, 0.195 mmol) and 24 (0.113 g, 0.244 mmol), NIS (0.067
g, 0.30 mmol) and activated, crushed 4 Å molecular sieves were
subjected to a high vacuum for 4 h. The mixture was dissolved in dry
CH2Cl2 (1 mL) and cooled to -20 °C and treated with TESOTf (8.6
µL, 0.038 mmol). The reaction was stirred for 45 min at -20 °C, diluted
with CH2Cl2 (1.5 mL), filtered, washed successively with 10% aq.
sodium thiosulfate (1 × 2.5 mL), aq. satd. NaHCO3 (1 × 2.5 mL), and
dried (MgSO4), and filtered, and the solvent was removed in vacuo.
Chromatography (4:1 pentane-EtOAc and 1% triethylamine) gave the
title compound 25 (95 mg, 62% with â pentenyl and 68 mg, 44% with
R pentenyl) as a white solid and recovered 24 (34 mg, 30%); RF 0.64
(2:1 pentane-EtOAc); mp 78-80 °C; [R]D -4° (c 0.2 CHCl3); 1H NMR
(CDCl3, 400 MHz) δ 7.13-7.30 (m, 25H, aromatic H’s), 5.05 (d, 1H,
J 2.5 Hz, H-1′), 4.90 (d, 1H, J 10.7 Hz, OCH2Ph) 4.75 (d, 1H, J 10.7
Hz, OCH2Ph), 4.74 (d, 1H, J 10.7 Hz, OCH2Ph), 4.72 (d, 1H, J 12.1
Hz, OCH2Ph), 4.65 (d, 1H, J 11.5 Hz, OCH2Ph), 4.59 (d, 1H, J 11.9
Hz, OCH2Ph), 4.56 (d, 1H, J 11.5 Hz, OCH2Ph), 4.54 (d, 1H, J 11.5
Hz, OCH2Ph), 4.50 (d, 1H, J1,2 3.1 Hz, H-1), 4.49 (d, 3H, J 11.5 Hz,
OCH2Ph), 4.27 (t, 1H, J 2.9 Hz, H-3′), 4.22 (dd, 1H, J3,2 4.8 Hz, J 2.0
Hz, H-5′), 3.99-4.04 (m, 2H), 3.92 (apt t, 1H, J 9.2 Hz), 3.85 (dd,
1H, J2,3 4.8 Hz, J2,1 3.1, H-4′), 3.69-3.74 (m, 2H), 3.59-3.63 (m, 2H),
3.40-3.50 (m, 2H) 3.28 (s, 3H, OCH3); 13C NMR (CDCl3, 100 MHz)
δ 138.9, 138.4, 138.3, 137.9, 137.6 (each s, ipso C’s), 128.6, 128.5,
128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.8, 127.7 (each d,
aromatic C), 99.9, 98.1 (each d, C-1, C-1′), 82.2, 81.8, 80.0, 78.1, 75.9,
75.9, 75.2, 73.5, 72.6, 72.4, 71.9, 71.7, 70.0, 67.2, 55.3 (s, OCH3); IR
(KBr) υ 2897, 1454, 1262, 1163, 1026 cm-1; HRMS-ES: found
811.3452, requires 811.3458 [M + Na]+.
Analytical data of 28: RF 0.22 (3:1 pentane-EtOAc); mp 94-97
°C, (lit.17 mp 80-82 °C); [R]D +88° (c 0.2, CHCl3), (lit.17 [R]D +56°
1
(c 2.1, CHCl3)); H NMR (400 MHz, CDCl3) δ 7.16-7.27 (m, 30H,
aromatic H’s), 4.88 (d, 1H, J 2.5 Hz, H-1′), 4.87 (d, 1H, J 2.7 Hz,
H-1), 4.46-4.91 (m, 12H, 12 × OCH2Ph), 4.11 (d, 2H, J 2.9 Hz),
3.91 (t, 1H, J 9.3 Hz), 3.90 (t, 1H, J 9.3 Hz), 3.78 (dt, 1H, J 10.0 Hz,
3.0 Hz), 3.69-3.77 (m, 2H), 3.56 (t, 1H, J 9.3 Hz), 3.41-3.45 (m,
2H), 3.35-3.39 (m, 2H), 3.28 (s, 3H, OCH3), 1.90 (s, 3H, C(O)CH3);
13C NMR (100 MHz, CDCl3) δ 170.8 (s, C(O)CH3), 138.9, 138.7, 138.5,
138.4, 138.2 (each s, 6 × ipso C’s), 128.5, 128.5, 128.3, 128.2, 128.1,
128.1, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7 (each d, aromatic C’s),
98.1, 97.1 (each d, C-1, C-1′), 82.2, 81.7, 80.2, 80.1, 77.9, 75.9, 75.7,
75.1, 75.0, 73.5, 73.0, 72.5, 70.5, 68.8, 66.2, 63.1, 55.3 (q, OCH3),
20.9 (q, C(O)CH3); IR (KBr) υ 3029, 2928, 1740 (CdO), 1453, 1264,
1101 cm-1. Anal. Calcd for C57H62O12: C, 72.90; H, 6.65. Found: C,
72.50; H, 6.62. HRMS-ES: found 961.4147, requires 961.4139 [M +
Na]+.
Methyl 3,6-Anhydro-â-D-glucopyranoside-(1f6)-R-D-glucopyran-
oside (16): A solution of 25 (0.069 g, 0.087 mmol) in EtOH (4 mL) in
the presence of Pd/C was stirred in an H2 atmosphere at 10 bar in a
Parr reactor for 24 h. The reaction was filtered through Celite, and
EtOH was removed in vacuo. The resulting residue was dissolved in
water (2 mL) and washed with Et2O (2 × 3 mL). Water was removed
at reduced pressure to leave a clear solid (23 mg, 78%); RF 0.13 (3:1
1
CH2Cl2-EtOH); mp 46-48 °C; [R]D -8.2° (c 0.2, H2O); H NMR
Analytical data for 28a: RF 0.24 (3:1 pentane-EtOAc); mp 116-
119 °C; [R]D +5.6° (c 0.5, CHCl3), (lit.15 [R]D +29° (c 0.5, CHCl3));
1H NMR (400 MHz, CDCl3) δ 7.09-7.28 (m, 30H, aromatic H’s),
4.24-4.91 (m, 14H, H-1, H-1′, 6 × OCH2Ph), 4.26 (d, 1H, J 7.8 Hz),
4.25 (dd, 1H, J 11.9, 2.2 Hz), 4.11 (dd, 1H, J 12.1, 4.7 Hz), 4.08 (dd,
1H, J 9.3 Hz), 4.04-4.05 (m, 1H), 3.91 (t, 1H, J 9.3 Hz), 3.74 (ddd,
1H, J 10.2, 4.7, 1.9 Hz), 3.55-3.59 (m, 2H), 3.40-3.48 (m, 2H), 3.37
(ddd, 1H J 9.7, 4.5, 2.1 Hz), 3.25 (s, 3H, OCH3), 1.91 (s, 3H, C(O)CH3).
13C NMR (100 MHz, CDCl3) δ 170.8 (s, C(O)CH3), 138.9, 138.5, 138.4,
138.4, 138.2, 137.9 (each s, 6 × ipso C’s), 128.6, 128.5, 128.5, 128.5,
128.4, 128.2, 128.2, 128.1, 128.0, 128.0, 128.0, 128.0, 127.9, 127.8,
127.7, 127.7, 127.6 (each d, aromatic C’s), 103.9 (d, C-1′), 98.2 (d,
(D2O, 400 MHz) δ 4.88 (s, 1H, H-1′), 4.73 (d, 1H, J1,2 3.7 Hz, H-1),
4.30 (t, 1H, J 2.9 Hz, H-5′), 4.27 (apt t, 1H, H-4′), 4.22 (d, 1H, J6a′,6a′
10.3 Hz, H-6a′), 4.15 (apt t, 1H, H-3′), 4.06 (dd, 1H, J 11.1, 1.4 Hz,
H-6a), 3.89 (dd, 1H, J6b′,6a′ 10.3 Hz, J 2.9 Hz, H-6b′), 3.80 (d, 1H, J
3.7 Hz, H-2′), 3.73-3.75 (m, 1H, H-5), 3.58-3.71 (m, 2H, H-3, H-4),
3.51 (dd, 1H, J 9.8 Hz, J2,1 3.7 Hz, H-2), 3.39 (apt t, 1H, H-6b), 3.36
(s, 3H, OCH3); 13C NMR (D2O, 100 MHz) δ 102.6 (d, C-1′), 99.4 (d,
C-1), 74.3, 73.1, 71.6, 71.6, 71.2, 70.8, 70.6, 69.6, 69.1, 67.2, 55.2 (q,
OCH3). HRMS-ES: found 361.1123, requires 361.1111 [M + Na]+.
4′-Methylphenyl 6-O-Acetyl-2,3,4-O-tribenzyl-1-thio-â-D-gluco-
pyranoside (27): A solution of 26 (1.39 g, 2.50 mmol), acetic anhydride
9
J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12383

A R T I C L E S
McDonnell et al.
C-1), 84.8, 82.0, 79.9, 78.1, 75.8, 75.8, 75.1, 75.0, 74.9, 73.4, 73.0,
69.9, 68.8, 63.2, 55.3 (q, OCH3), 20.9 (q, C(O)CH3). HRMS-ES: found
961.4152, requires 961.4139 [M + Na]+.
H-1), 4.39 (d, 1H, J 11.5 Hz, OCH2Ph), 4.25 (d, 1H, J 7.8 Hz, H-1′′),
3.95 (d, 1H, J 10.4 Hz), 3.89 (t, 2H, J 9.2 Hz), 3.71-3.83 (m, 3H),
3.65 (dd, 1H, J 10.2, 3.4 Hz), 3.53-3.60 (m, 5H), 3.33-3.49 (m, 6H),
3.23 (s, 3H, OCH3), 1.88 (bs, 1H, OH); 13C NMR (100 MHz, CDCl3)
δ 139.0, 138.7, 138.6, 138.6, 138.5, 138.3, 138.1 (each s, 9 × ipso
C’s), 128.6, 128.5, 128.5, 128.4, 128.4, 128.1, 128.1, 128.1, 128.0,
128.0, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6 (each d, aromatic C’s),
103.9 (d, C-1′′), 98.1, 97.3 (each d, C-1, C-1′), 84.7, 82.3, 82.1, 81.6,
80.3, 80.1, 77.9, 77.7, 75.8, 75.5, 75.2, 75.2, 75.1, 74.9, 73.5, 72.4,
70.6, 70.0, 68.9, 66.1, 62.1, 55.2 (q, OCH3); IR (film) υ 3508 (O-H),
2938, 1496, 1454, 1268, 1070 cm-1. HRMS-FAB: found 1351.6042,
requires 1351.5970 [M + Na]+.
Methyl 2,3,4-Tri-O-benzyl-6-O-tosyl-R-D-glucopyranosyl-(1f6)-
2,3,4-tri-O-benzyl-R-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-R-
D-glucopyranoside (32): A solution of 30 (0.53 g, 0.40 mmol) and
p-toluenesulfonyl chloride (0.75 g, 4.0 mmol) in dry pyridine (10 mL)
was stirred for 16 h. Water (10 mL) and CH2Cl2 (10 mL) were added.
The organic portion was washed with water (2 × 10 mL), dried
(MgSO4), and filtered, and solvent was removed in vacuo. Chroma-
tography (2:1 pentane-EtOAc) yielded the title compound 32 (0.47 g,
80%) as an oil; RF 0.43 (2:1 pentane-EtOAc); [R]D +52.4° (c 0.5,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.79 (d, 2H, J 8.3, ortho H’s),
7.16-7.40 (m, 47H, aromatic and meta H’s), 4.59-5.04 (m, 20H, H-1,
H-1′, H-1′′, 17 × OCH2Ph), 4.44 (d, 1H, J 10.8, OCH2Ph), 4.14-4.17
(m, 2H), 3.94-4.06 (m, 4H), 3.64-3.88 (m, 7H), 3.45-3.53 (m, 5H),
3.38 (s, 3H, OCH3), 2.42 (s, 3H, PhCH3); 13C NMR (75 MHz, CDCl3)
δ 144.8, 138.9, 138.9, 138.7, 138.5, 138.4, 138.3, 138.1, 133.0 (each
s, ipso C’s), 129.9, 128.5, 128.5, 128.4, 128.4, 128.1, 128.1, 128.0,
127.9, 127.9, 127.8, 127.6, 127.6, 127.5, 127.4, 127.3 (each d, aromatic
C’s), 98.1, 97.1, 97.1 (each d, C-1, C-1′, C-1′′), 82.2, 81.7, 71.4, 80.3,
80.0, 77.8, 76.9 (each d), 75.8, 75.5, 75.1, 75.0, 74.9, 73.5, 72.5, 72.3
(each t), 70.7, 70.6, 68.7 (each d), 68.6, 65.9 (each t), 55.2 (q, OCH3),
21.7 (q, PhCH3); IR (film) υ 3030, 1496, 1453, 1362, 1096 cm-1; Anal.
Calcd for C34H34O5S: C, 72.04; H, 6.39; S, 2.16. Found: C, 71.68; H,
6.23; S, 2.55. HRMS-FAB: found 1505.6044, requires 1505.6059 [M
+ Na]+.
Methyl 2,3,4-Tri-O-benzyl-R-D-glucopyranosyl-(1f6)-2,3,4-tri-
O-benzyl-R-D-glucopyranoside (29): To a solution of 28 (1.26 g, 1.34
mmol) in toluene (20 mL), methanolic sodium methoxide (20 mL) was
added. The reaction was stirred for 3 h, neutralized with solid CO2,
and filtered through a pad of Celite, and the solvent was removed in
vacuo. Chromatography (3:2 pentane-EtOAc) yielded the title com-
pound 29 as a white solid (1.01 g 92%); RF 0.43 (1:1 pentane-EtOAc);
mp 97-100 °C (lit.18 mp 109-110 °C); [R]D +5.6° (c 0.5, CHCl3); 1H
NMR (400 MHz, CDCl3) δ 4.87 (d, 1H, J 3.9, H-1), 4.87 (d, 1H, J
10.5, OCH2Ph), 4.86 (d, 1H, J 3.7, H-1′), 4.84 (d, 1H, J 11.0, OCH2Ph),
4.80 (d, 1H, J 11.2, OCH2Ph), 4.74 (d, 1H, J 9.2 Hz, OCH2Ph), 4.71
(d, 1H, J 9.2 Hz, OCH2Ph), 4.64 (d, 1H, J 12.1 Hz, OCH2Ph), 4.57 (d,
1H, J 11.2 Hz, OCH2Ph), 4.55 (d, 1H, J 11.0 Hz, OCH2Ph), 4.49 (d,
1H, J 12.1 Hz, OCH2Ph), 3.90 (dt, 2H, J 9.2, 3.3 Hz), 3.73 (dd, 1H, J
11.2, 4.5 Hz), 3.68-3.74 (m, 1H), 3.53-3.65 (overlapping signals, 5H),
3.42 (t, 1H, J 3.5 Hz), 3.40 (t, 1H, J 3.7 Hz), 3.37 (dd, 1H, J 9.8, 3.5
Hz), 3.28 (s, 3H, OCH3); 13C NMR (100 MHz, CDCl3) δ 138.9, 138.8,
138.5, 138.4, 138.4, 138.2 (each s, 6 × ipso C’s), 128.4, 128.4, 128.4,
128.0, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6 (each d, aromatic C’s),
98.1, 97.2 (each d, C-1, C-1′), 81.5, 80.2, 77.8, 75.7, 75.5, 75.0, 74.9,
73.4, 72.5, 71.0, 70.5, 66.0, 61.9, 55.2 (q, OCH3); IR (KBr) υ 3462
(O-H), 2909, 1497, 1453, 1089 cm-1. Anal. Calcd for C57H62O12: C,
73.64; H, 6.74. Found: C, 73.35; H, 6.63. HRMS-ES: found 919.4036,
requires 919.4033 [M + Na]+.
Methyl 2,3,4-Tri-O-benzyl-R-D-glucopyranosyl-(1f6)-2,3,4-tri-O-
benzyl-R-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-R-D-gluco-
pyranoside (30) and Methyl (2,3,4-Tri-O-benzyl-â-D-glucopyrano-
syl)-(1f6)-2,3,4-tri-O-benzyl-R-D-glucopyranosyl-(1f6)-2,3,4-tri-O-
benzyl-R-D-glucopyranoside (31): To a stirred solution of 27 (1.13 g,
1.26 mmol), 29 (0.75 g, 1.26 mmol), and NIS (0.57 g, 2.52 mmol)
predried under a high vacuum for 4 h in CH2Cl2 (2 mL) and Et2O (10
mL) under an N2 atmosphere at -40 °C, trifluoromethanesulfonic acid
(100 µL) was added. The reaction was stirred for 5 min, satd. aq.
NaHCO3 solution (0.1 mL) was added, and the reaction was allowed
to warm to room temperature. The reaction was diluted with CH2Cl2
(30 mL) and washed successively with 10% aq. sodium thiosulfate (2
× 30 mL) and satd. aq. NaHCO3 solution (30 mL). The organic portion
was dried (MgSO4) and filtered, and solvent was removed in vacuo.
Chromatography (4:1 pentane-EtOAc) yielded the acetylated products
as a syrup of inseparable diastereomers. The products were dissolved
in toluene (10 mL), and methanolic sodium methoxide (10 mL) was
added. The reaction was stirred for 2 h, neutralized with solid CO2
and filtered through a pad of Celite, and the solvent was removed in
vacuo. Chromatography (3:1 pentane-EtOAc) yielded the title com-
pounds 30 (0.59 g 35%) and 31 (0.18 g, 11%) as clear oils.
Methyl (2,3,4-Tri-O-benzyl-6-O-tosyl-R-D-glucopyranosyl)-(1f6)-
2,3,4-tri-O-benzyl-â-D-glucopyranosyl-(1f6)-2,3,4-tri-O-benzyl-R-
D-glucopyranoside (34): A solution of 31 (0.16 g, 0.12 mmol) and
p-toluenesulfonyl chloride (0.22 g, 1.2 mmol) in dry pyridine (4 mL)
was stirred for 16 h. Water (4 mL) and CH2Cl2 (4 mL) were added.
The organic portion was washed with water (2 × 5 mL), dried (MgSO4),
and filtered, and solvent was removed in vacuo. Chromatography (2:1
pentane-EtOAc) yielded the title compound 34 (0.13 g, 77%) as clear
1
oil; RF 0.47 (2:1 pentane-EtOAc); [R]D +29.6° (c 0.5, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.78 (d, 2H, J 8.2 Hz, ortho H’s), 7.15-
7.38 (m, 47H, aromatic and meta H’s), 5.05 (d, 1H, J 3.4 Hz, H-1′),
4.69-5.02 (m, 16H, 16 × OCH2Ph), 4.64 (d, 1H, J 7.9 Hz, H-1′′),
4.58 (d, 1H, J 2.9 Hz, H-1), 4.51 (d, 1H, J 11.4 Hz, OCH2Ph), 4.49 (d,
1H, J 10.7 Hz, OCH2Ph), 3.98-4.18 (m, 5H), 3.45 (m, 13H), 3.35 (s,
3H, OCH3), 2.40 (s, 3H, PhCH3); 13C NMR (300 MHz, CDCl3) δ 144.9,
139.0, 138.7, 138.6, 138.2, 138.2, 137.7, 132.9 (each s, ipso C’s), 129.9,
128.6, 128.5, 128.5, 128.4, 128.4, 128.2, 128.1, 128.1, 128.0, 127.9,
127.8, 127.7, 127.7, 127.6, 127.5 (each d, aromatic C’s), 103.6 (d,
C-1′′), 98.1, 97.2 (each d, C-1, C-1′), 84.6, 82.2, 81.9, 81.6, 80.3, 80.1,
77.8, 76.9 (each d), 75.8, 75.5, 75.1, 75.0, 74.8, 73.5 (each t), 72.9 (d),
72.4 (t), 70.6, 69.9 (each d), 68.6, 66.0, 66.0 (each t), 55.2 (q, OCH3),
21.8 (q, PhCH3); IR (film) υ 3031, 1497, 1453, 1361, 1071 cm-1. Anal.
Calcd for C34H34O5S: C, 72.04; H, 6.39; S, 2.16. Found: C, 71.75; H,
6.35; S, 2.03. HRMS-FAB: found 1505.6076, requires 1505.6059 [M
+ Na]+.
Analytical data for 30: RF 0.17 (3:1 pentane-EtOAc); [R]D +96°
(c 0.5, CHCl3), (lit.19 [R]D +89° (c 1.0, CHCl3)); 1H NMR (400 MHz,
CDCl3) δ 7.11-7.26 (m, 45H, aromatic H’s), 4.46-4.90 (m, 21H, H-1,
H-1′, H-1′′, 18 × OCH2Ph), 3.87-3.92 (m, 3H), 3.51-3.92 (m, 11H),
3.31-3.44 (m, 4H), 3.25 (s, 3H, OCH3), 1.50 (bs, 1H, OH); 13C NMR
(100 MHz, CDCl3) δ 139.0, 138.9, 138.7, 138.6, 138.5, 138.4, 138.2
(each s, 9 × ipso C’s), 128.5, 128.5, 128.5, 128.4, 128.4, 128.2, 128.1,
128.1, 128.1, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, 127.6, 127.6
(each d, aromatic C’s), 98.1, 97.2, 97.1 (each d, C-1, C-1′, C-1′′), 82.2,
81.7, 81.6, 80.4, 80.3, 77.9, 77.7, 77.5 (each d), 75.8, 75.6, 75.6, 75.1,
75.1, 75.0, 73.5 (each t), 72.5, 72.4, 71.0 (each d), 70.8(t), 70.6(d),
66.0, 65.9, 62.0 (each t), 55.3 (q, OCH3); IR (film) υ 3505 (O-H),
2926, 1498, 1361, 1266 cm-1. LRMS-ES: 1351.1 [M + Na]+. HRMS-
FAB: found 1351.5938, requires 1351.5970 [M + Na]+.
Methyl 6-O-Tosyl-R-D-glucopyranosyl)-(1f6)-R-D-glucopyrano-
syl-(1f6)-R-D-glucopyranoside (33): A mixture of 32 (0.45 g, 0.30
mmol) in EtOAc (50 mL) and MeOH (50 mL) and diluted HCl (1
drop) was stirred in a Parr hydrogenator for 2 h under a hydrogen
atmosphere of 30 psi in the presence of Pd/C. The contents were filtered
Analytical data for 31: RF 0.20 (3:1 pentane-EtOAc); [R]D +14.2°
1
(c 0.5, CHCl3). H NMR (400 MHz, CDCl3): δ 7.02-7.25 (m, 45H,
aromatic H’s), 4.92 (d, 1H, J 3.3 Hz, H-1′), 4.53-4.89 (m, 16H, 16 ×
OCH2Ph), 4.49 (d, 1H, J 12.3 Hz, OCH2Ph), 4.46 (d, 1H, J 3.5 Hz,
9
12384 J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004

Conformational Effects on Glycoside Reactivity
A R T I C L E S
through a pad of Celite, and the solvents were removed in vacuo to
(10 mL), and the product was extracted with EtOAc (2 × 10 mL). The
combined organic portions were dried (MgSO4) and filtered, and solvent
was removed in vacuo for 8 h. The resulting material was stirred in
methanolic NH3 (2 mL) for 5 h, and the solvents were removed in
vacuo to give the title compound 18 as a yellow oil (26 mg, 70%); RF
0.13 (3:1 EtOAc-MeOH); [R]D +112.3° (c 0.5, H2O); 1H NMR (300
MHz, D2O) δ 4.83 (d, 2H, J 3.7 Hz, H-1′) 4.82 (bs, 1H, H-1′′), 4.71
(d, 1H, J 3.7 Hz, H-1), 4.26 (t, 1H, J 3.0 Hz), 4.21 (dd, 1H, J 5.3, 3.0
Hz), 4.18 (d, 1H, J 10.4 Hz), 4.10 (dd, 1H, J 5.5, 3.7 Hz), 4.00 (dd,
1H, J 11.4, 2.0 Hz), 3.87 (dd, 1H, J 11.2, 4.4 Hz), 3.83 (dd, 1H, J
10.2, 2.8 Hz), 3.74-3.78 (m, 2H), 3.71 (ddd, 1H, J 10.2, 4.4, 1.8 Hz),
3.64 (bs, 1H), 3.62, (t, 1H, J 2.6 Hz), 3.53 (d, 1H, J 9.2 Hz), 3.47 (dd,
1H, J 3.7, 2.2 Hz), 3.44-3.46 (m, 1H), 3.40 (t, 1H, J 9.0 Hz), 3.37
(dd, 1H, J 10.0, 9.0 Hz), 3.35 (dd, 1H, J 10.0, 9.2 Hz), 3.31 (s, 1H,
OCH3); 13C NMR (300 MHz, D2O) δ 103.5, 100.3, 98.8 (each d, C-1,
C-1′, C-1′′), 75.2, 74.4, 74.0, 72.6, 72.5, 72.4, 72.2, 71.8, 71.7, 71.0,
70.7, 70.5 (each d), 70.0, 68.0, 66.2 (each t, C-6, C-6′,C-6′′), 56.1 (q,
OCH3). LRMS-ES: 523.2 [M + Na]+.
Standard Procedure for the Determination of the Rate and
Specificity of Acid Glycoside Hydrolysis of 16, 17, and 18: To a
sample of 16, 17, or 18 (0.005 g) shaken with D2O (2 × 2 mL) and
dried each time on a high-vacuum for 6 h a standard sample of either
1.296 M (16 and 18) or 0.1296 M (17) DCl (0.60 mL) was added.
This was placed directly into the NMR (Varian 400 MHz) at 26 °C.
1H NMRs were taken every 10 min until the starter had been consumed.
Each reaction was left in the NMR for 24 h, and a final 1H NMR was
taken. After 16 had been fully consumed, a sample of methyl-R-D-
glucopyranoside was added (0.005 g in 0.2 mL of 1.296 M DCl) to
determine the specificity of cleavage. The reaction profiles were
determined by monitoring the changes in the intensities of specific peaks
of 1H NMR spectra. All plots were constructed using Psi plot 6.0, where
applicable, linear regression was used to determine rate constants.
leave the title compound 33 as a yellow oil (0.19 g, 95%); RF 0.13
1
(3:1 EtOAc-MeOH); [R]D +117.0° (c 0.5, MeOH); H NMR (300
MHz, CD3OD) δ 7.85 (d, 2H, J 8.2 Hz, ortho H’s), 7.49 (d, 2H, J 8.2
Hz, meta H’s), 4.89 (d, 1H, J 3.7 Hz, H-1′′), 4.79 (d, 1H, J 3.7 Hz,
H-1′), 4.74 (d, 1H, J 3.5 Hz, H-1), 4.31-4.35 (m, 1H), 4.24 (dd, 1H,
J 10.8, 5.2 Hz), 3.62-4.02 (m, 10H), 3.24-3.50 (m, 6H), 3.47 (s, 3H,
OCH3), 2.51 (s, 3H, PhCH3); 13C NMR (300 MHz, CD3OD) δ 145.1,
133.0 (each s, ipso C’s), 129.7, 127.8 (each d, aromatic C’s), 99.9,
99.9, 98.2 (each d, C-1, C-1′, C-1′′), 73.9, 73.6, 72.3, 72.0, 70.6, 70.5,
70.3, 69.8, 69.6 (each d), 69.5, 66.4, 66.0 (each t, C-6, C-6′, C-6′′),
54.5 (q, OCH3), 20.3 (q, C6H4CH3); IR (film) υ 3407 (O-H), 2924,
1451, 1358, 1176, 1033 cm-1. LRMS-ES: 695.1 [M + Na]+. HRMS-
ES: found 695.0837, requires 695.1833 [M + Na]+.
Methyl 6-O-Tosyl-â-D-glucopyranosyl-(1f6)-R-D-glucopyranosyl-
(1f6)-R-D-glucopyranoside (35): A mixture of 34 (0.12 g, 0.08 mmol)
in EtOAc (20 mL) and MeOH (20 mL) and diluted HCl (1 drop) was
stirred in a Parr hydrogenator for 2 h under a hydrogen atmosphere of
30 psi in the presence of Pd/C. The contents were filtered through a
pad of Celite, and the solvents were removed in vacuo to leave the
title compound 35 as a yellow oil (0.05 g, 88%); RF 0.16 (3:1 EtOAc-
MeOH); [R]D +62.0° (c 0.5, MeOH); 1H NMR (300 MHz, CD3OD) δ
7.81 (d, 2H, J 8.4 Hz, ortho H’s), 7.45 (d, 2H, J 8.4 Hz, meta H’s),
4.84 (d, 1H, J 3.4 Hz, H-1′), 4.68 (d, 1H, J 3.7 Hz, H-1), 4.33 (dd, 1H,
J 10.8, 1.8 Hz), 4.29 (d, 1H, J 7.8 Hz, H-1′′), 3.95 (dd, 1H, J 11.3, 1.8
Hz), 3.95 (dd, 1H, J 11.1, 5.4 Hz), 3.82-3.87 (m, 1H), 3.58-3.78 (m,
5H), 3.27-3.54 (m, 6H), 3.42 (s, 3H, OCH3), 3.18 (t, 1H, J 9.2 Hz),
3.14 (apt t, 1H), 2.46 (s, 3H, PhCH3); 13C NMR (75 MHz, CD3OD) δ
145.1, 132.9 (each s, ipso C’s), 129.8, 127.8 (each d, aromatic C’s),
103.2 (d, C-1′′), 99.9, 98.5 (each d, C-1, C-2), 76.3, 73.9, 73.7, 73.5,
72.2, 72.1, 71.3, 70.5, 70.4, 70.2, 69.7 (each d), 69.5, 68.5, 66.3 (each
t, C-6, C-6′, C-6′′), 20.4 (q, PhCH3); IR (film) υ 3405 (O-H), 1664,
1387, 1175 cm-1. LRMS-ES: 695.2 [M + Na]+. HRMS-ES: found
695.0841, requires 695.1833 [M + Na]+.
Methyl 3,6-Anhydro-R-D-glucopyranosyl-(1f6)-R-D-glucopyran-
osyl-(1f6)-R-D-glucopyranoside (17): A solution of 33 (0.195 g, 0.29
mmol) in 1 M NaOH solution (12 mL) was stirred at 70 °C for 8 h.
The reaction was neutralized with solid CO2, and the water was removed
by lyophylisation. The resulting crude material and a catalytic amount
of DMAP were dissolved in pyridine (5 mL) and acetic anhydride (5
mL) and stirred for 5 h. The reaction was quenched by the addition of
water (10 mL), and the product was extracted with EtOAc (2 × 10
mL). The combined organic portions were dried (MgSO4) and filtered,
and solvent was removed in vacuo for 8 h. The resulting material was
stirred in methanolic NH3 (3 mL) for 5 h, and the solvents were removed
in vacuo to give the title compound 17 as a yellow oil (91 mg, 61%);
RF 0.09 (3:1 EtOAc-MeOH); [R]D +45.3° (c 0.5, H2O); 1H NMR (300
MHz, D2O) δ 5.23 (d, 1H, J 2.8 Hz, H-1′′), 5.01 (d, 1H, J 3.8 Hz,
H-1′), 4.86 (d, 1H, J 3.8 Hz, H-1), 4.46 (bs, 1H), 4.38 (t, 1H, J 2.6
Hz), 4.15 (dd, 1H, J 12.0, 5.3 Hz), 4.05-4.10 (m, 2H), 3.99-4.02 (m,
2H), 3.95 (ddd, 1H, J 10.2, 5.1, 2.0 Hz), 3.87 (ddd, 1H, J 10.0, 4.7,
1.7 Hz), 3.76-3.80 (m, 2H), 3.72 (t, 1H, J 9.4 Hz), 3.64 (apt t, 1H, J
4.0, 3.6 Hz), 3.62 (dd, 1H, J 5.8, 3.8 Hz), 3.52-3.57 (m, 2H), 3.49 (s,
3H, OCH3); 13C NMR (75 MHz, D2O) δ 100.3, 98.7, 97.9 (each d,
C-1, C-1′, C-1′′), 98.7, 76.4, 74.4, 73.9, 72.4, 72.2, 72.0, 71.7, 71.0,
70.5, 70.4, 70.4 (each d), 69.6, 69.1, 66.6 (each t, C-6, C-6′, C-6′′),
56.1 (q, OCH3). LRMS-ES: 523.1 [M + Na]+. HRMS-ES: found
523.1635, requires 523.4382 [M + Na]+.
X-ray Work: In all cases data collection was done on a Siemens
SMART diffractometer with a CCD detector using ω rotation scans
with narrow frames. The crystals were kept at 120 K during data
collection. The structures were solved by direct methods using the
SIR97 program package. Refinement was done using a locally modified
ORFLS program. All crystals were thin needles of moderate or poor
diffracting power. 23a, C21H24O5, is monoclinic, C2, with a ) 39.105(8)
Å, b ) 5.6150(10) Å, c ) 16.609(3) Å, â ) 97.007(5)°, V ) 3619.5(13)
Å3, and Z ) 8. Final R ) 0.035, Rw ) 0.036 for 4865 significant
reflections, and 470 parameters.
23, C25H30O5, is monoclinic, P21, with a ) 13.295(2) Å, b )
5.6635(8) Å, c ) 14.117(2) Å, â ) 99.446(5)°, V ) 1048.5(3) Å3, Z
) 2. Final R ) 0.044, Rw ) 0.041 for 2961 reflections, and 271
parameters.
25, C48H52O10, is monoclinic, P21, with a ) 10.168(3) Å, b )
9.673(3) Å, c ) 23.850(7) Å, â ) 100.382°, V ) 2068.8(11) Å3, Z )
2. Final R ) 0.066, Rw ) 0.068 for 3306 reflections, and 523
parameters.
Acknowledgment. We thank Torben Ellebæk Pedersen for
the MALDITOF mass spectra and the EU Marie-Curie training
site program for financial support.
Supporting Information Available: Included as Supporting
Information is the rate constants for hydrolysis of 4 and 12 at
three temperatures (Table S1), logarithmic plots of the hydrolytic
decay of 16-18 (Figures S1-S3), mass spectra of cyclodextrin
hydrolysis products (Figures S4 and S5), and 1H NMR spectra
of the hydrolysis of 16 and 18. This material is available free
of charge via the Internet at http://pubs.acs.org.
Methyl (3,6-Anhydro-â-D-glucopyranosyl)-(1f6)-R-D-glucopyran-
osyl-(1f6)-R-D-glucopyranoside (18): A solution of 35 (50 mg, 0.074
mmol) in 1 M aq. NaOH solution (5 mL) was stirred at 70 °C for 8 h.
The reaction was neutralized with solid CO2, and the water was removed
by lyophylisation. The resulting crude material and catalytic DMAP
were dissolved in pyridine (3 mL) and acetic anhydride (3 mL) and
stirred for 5 h. The reaction was quenched by the addition of water
JA047476T
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J. AM. CHEM. SOC. VOL. 126, NO. 39, 2004 12385