Role of the 4,6-O-acetal in the regio-and stereoselective conversion of 2,3-di-O-sulfonyl-b-D-galactopyranosides to D-idopyranosides

Article abstract of DOI:10.1016/j.carres.2013.05.001

The recently reported conversion of 2,3-di-O-sulfonyl-D-galactopyranosides to D-idopyranosides has provided an efficient route to obtaining orthogonally-protected idopyranoside building blocks with a b-1,2-cis glycosidic linkage. In an effort to expand th

Full text of DOI:10.1016/j.carres.2013.05.001

Carbohydrate Research 376 (2013) 37–48
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Carbohydrate Research
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Role of the 4,6-O-acetal in the regio- and stereoselective conversion
of 2,3-di-O-sulfonyl-b-D-galactopyranosides to D-idopyranosides
⇑
Rachel Hevey, Xining Chen, Chang-Chun Ling
Alberta Glycomics Centre, Department of Chemistry, University of Calgary, 2500 University Drive NW, Calgary, Alberta T2N 1N4, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 April 2013
Received in revised form 29 April 2013
Accepted 1 May 2013
Available online 13 May 2013
The recently reported conversion of 2,3-di-O-sulfonyl-D-galactopyranosides to D-idopyranosides has pro-
vided an efficient route to obtaining orthogonally-protected idopyranoside building blocks with a b-1,2-
cis glycosidic linkage. In an effort to expand the scope of this process and better understand the regio- and
stereoselectivity observed in the key di-inversion step of the method, a small library of 4,6-O-acetal pro-
tected galactopyranosides has been synthesized and used as substrates in the process, together with a
number of substrates that lack the acetal functionality. The results suggest that although the substituent
at the acetal center does not contribute to the observed selectivity of the process, the acetal group is
indeed required for efficient conversion by reducing the conformational flexibility of the substrate,
resulting in enhanced reaction rates at both the O-transsulfonylation and epoxide ring-opening steps.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
4,6-O-Acetal
Conformational flexibility
2,3-Di-O-sulfonyl-galactopyranosides
Idopyranosides
O-Transsulfonylation
1. Introduction
potentially re-direct the immune response away from lipopolysac-
charides, we have become interested in chemically synthesizing a
D
- and
anosides abundant in nature. For example, they present as
heptopyranosides in the capsular polysaccharide (CPS) structure
of Campylobacter jejuni,1 or as the oxidized
-iduronic acids found
L
-idopyranosides are conformationally unique hexopyr-
carbohydrate-based conjugate vaccine against the unique 6-
D
-ido-
deoxy-b-D-ido-heptopyranoside present in the CPS of C. jejuni sero-
type HS:4 (Fig. 1).1 Previously, it was shown that subcutaneous inoc-
ulation with conjugates containing the CPS extracted from natural
sources elicited promising immunological results.5
L
in glycosaminoglycans (GAGs) such as heparin, heparan, and der-
matan sulfates. Idopyranosides can display significant conforma-
tional flexibility due to the relative high energy of their 4C1 and
1C4 chair conformations, which results in a lower energy barrier
between the chair and twist boat conformations.2 Since the idopyr-
anosides found in nature are often functionalized with O-substitu-
tions such as partial sulfation in the GAGs (various patterns at all
The synthesis of the b-linked ido-heptopyranoside present in
the C. jejuni CPS presents a significant challenge due to the unusual
configuration and the b-1,2-cis-glycosidic linkage. Recently, our
group has published a short, scalable method from
which could be used to obtain orthogonally protected
side (Scheme 1). The method relies on a di-inversion at C-2 and C-3
of 4,6-O-benzylidene-2,3-di-O-sulfonyl-b- -galactopyranosides
D-galactose
D-idopyrano-
positions) and 7-O-phosphoramidation in the C. jejuni
D
-ido-hepto-
D
pyranoside-antigen,1 accessing orthogonally-protected idopyrano-
side building blocks are key to streamlining their syntheses in
sufficient quantities for biological and pharmacological testing.
Recently, the development of efficient syntheses to obtain anti-
genic oligosaccharides related to C. jejuni CPS has drawn our interest,
as this gastrointestinal pathogen also expresses lipopolysaccharides
which have structural elements resembling human gangliosides.3
Upon recovering from C. jejuni bacterial infection, some patients de-
velop carbohydrate-specific antibodies against these lipopolysac-
charides, leading to the development of Guillain–Barré Syndrome,
an acute and severe autoimmune neurological disease resulting
from the aforementioned molecular mimicry.3,4 In an effort to
(1–2); the conversion proceeds with high regio- and stereoselectiv-
ity to give only the desired product (4), as detected in the crude 1H
NMR.6 The method was compatible with a series of nucleophiles
(MeOꢀ, AllOꢀ, BnOꢀ); more importantly, this methodology was
also found to be applicable to the synthesis of b-linked idopyrano-
side-containing oligosaccharides. We also observed that in using
the corresponding
ceeds with reduced regio- and stereoselectivity.6,7 A similar two-
step approach using methyl 4,6-O-benzylidene-3-O-tosyl-b-
a-D-galactopyranosides, the conversion pro-
D-
galactopyranoside has also been reported, which upon treatment
with base affords the intermediate 2,3-anhydro-gulopyranoside,
and subsequent attack with a nucleophile in the presence of micro-
wave irradiation provides the 2-O-substituted idopyranoside.8
The acetal protecting group is useful in orthogonal protection
strategies, as it can be either fully hydrolyzed, or regioselectively
⇑
Corresponding author. Tel.: +1 403 220 2768; fax: +1 403 289 9488.
E-mail address: ccling@ucalgary.ca (C.-C. Ling).
0008-6215/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2013.05.001

38
R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
OH
HO
2. Results and discussion
HO
HO
HO
OH
O
Conformational flexibility of the substrates greatly affects the
conversion of 4,6-O-acetal protected galactopyranosides to the cor-
responding idopyranosides. As discussed above, it is beneficial to
have a more flexible substrate so that the ring-flip can occur to
facilitate epoxide formation; however, for steps involving the O-
desulfonylation and epoxide opening, a less conformationally flex-
ible substrate should be favored, as this facilitates the intermolec-
ular nucleophilic attacks. In 4,6-O-benzylidene protected b-
galactopyranosides the 4C1 chair is most stable, as in the 4S2 or
1C4 conformers more substituents will be forced to occupy an axial
or pseudo-axial position, resulting in higher energy conformations.
Through examination of a molecular model, we also observed that
the phenyl group of the acetal may play a significant role in con-
trolling the conformational flexibility; for example, if the pyrano-
side adopts a 4C1 chair, the most stable conformation of the
molecule should occur when the six-membered acetal ring also
adopts a chair conformation placing the phenyl group in an equa-
torial position. However, when a ring-flip of the pyranoside to the
1C4 chair occurs, if the six-membered acetal ring also flips to the
opposite chair, this would place the phenyl ring in close proximity
to the C-3 substituent, thus increasing unfavorable steric interac-
tions; the introduction of additional substituents on the phenyl
ring, especially at the m- and o-positions, would increase the steric
hindrance further, thus decreasing the conformational flexibility.
Thus, the o-, m-, and p-methoxybenzylidene protected galactopyr-
anosides (5–7) and a p-nitrobenzylidene protected analog (8) were
synthesized and compared to the less sterically hindered ethyli-
dene analog (9), as well as the highly flexible methylidene analog
(10) (Fig. 2). The placement of the electron-withdrawing nitro
group on the phenyl ring could also affect the electron density of
the acetal O-4 and O-6 centers compared to the other electron-
donating methoxybenzylidene analogs; this could influence the al-
kali-coordination, thus affecting the reaction rate of the O-trans-
sulfonylation step.
NHAc
OH
O
HO
O
O
β
O
O
NHAc
O
β
OH
O
O
OH
β-D-ido-heptopyranoside
Figure 1. The b-
Campylobacter jejuni.
D-ido-heptopyranoside present in capsular polysaccharide of
opened under reductive conditions by using a combination of hy-
dride agent (such as LiAlH4, NaBH3CN, DIBAL-H, silane, and borane)
and Lewis acid (TMSOTf, AlCl3, BF3ꢁEt2O, metal triflate, etc.).9–11
Applying the Hanessian–Hullar reaction conditions12 or using
substituted benzylidenes and other related acetals could offer fur-
ther flexibility in orthogonal deprotections for our total synthesis
of C. jejuni ido-heptopyranoside analogs.
We also probed the mechanism of the regio- and stereoselective
di-inversion step of the 2,3-di-O-sulfonates and found that alkali
cations play an important role in preferentially activating sulfo-
nates that have a cis-oriented neighboring oxygen, leading to an
O-transsulfonylation as a result of S–O bond scission. The alkali
cation could coordinate with either the more electron rich oxygen
of the S@O or the slightly less electron rich oxygen of the S–O.13
After the 3-O-transsulfonylation step, a negatively charged 3-oxide
is generated, which nucleophilically substitutes the C-2 sulfonate
by attacking the backside of the stereocenter, resulting in an inver-
sion of C-2 configuration. However, this step is not straightforward,
as the molecule adopts predominantly the 4C1 chair conformation,
causing both C-2 and C-3 substituents to occupy a trans-diequato-
rial orientation; the formation of the 2,3-epoxide is not possible
from such conformation. In order for the intramolecular SN2 nucle-
ophilic substitution to occur, the molecule needs to switch to an-
other conformation so that the two substituents at C-2 and C-3
can achieve a trans-diaxial or pseudo-trans-diaxial orientation. This
can be realized through conversion to the 4S2 or 1C4 conformation.
In this work, we set out to probe the influence of conformational
flexibility on the conversion of 4,6-O-benzylidene protected galac-
topyranoside systems to idopyranosides.
In order to synthesize the desired acetal derivatives 5–8, the
respective dimethyl acetal reagents 12–15 were synthesized from
their corresponding aldehyde in near quantitative yields using
the method described by Johnsson et al.14 Camphorsulfonic acid
(CSA)-catalyzed transacetalations of compounds 12–15 with
methyl b-
D
-galactopyranoside (11) afforded the corresponding
Ph
Ph
Ph
O
O
O
O
O
+M
O
O
O
Ph
O
-
-
O
O
O
O
O
O
S
KOR'
-
O
O
O
O
O
O
H
O
H
4S2
O
O
S
O
O
S
O
4C1
R
1C4
O
O
O
S
O
R
O
S
R
R
O
O
R
1
2
R=CH3
R=PhCH3
Ph
Ph
O
O
O
O
OH
O
KOR'
O
O
O
O
oH5
OR'
3
4
(R' = Me,All,Bn)
(64-79%)
Scheme 1. Key step involving the di-inversion of C-2 and C-3 in the regio- and stereoselective conversion of D-galactopyranosides to D-idopyranosides.

R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
39
OMe
NO2
MeO
MeO
O
O
O
O
O
O
O
O
O
O
O
O
OMe
OMe
OMe
OMe
TsO
TsO
O
TsO
TsO
OTs
OTs
OTs
8
OTs
5
6
7
O
O
O
O
O
OTs
OMe
OMe
TsO
TsO
OTs
9
10
Figure 2. Different methyl 4,6-O-acetal-2,3-di-O-tosyl-b-
D-galactopyranosides to probe the influence of conformational flexibility on the conversion of galactopyranosides to
idopyranosides.
R
R
O
O
O
O
HO
HO
OH
O
R
O
O
c
a or b
OMe
OMe
OMe
+
TsO
HO
MeO
OMe
OTs
OH
OH
5
R = o-MeOPh, 92%
11
12 R = o-MeOPh
13 R = m-MeOPh
14 R = p-MeOPh
16 R = o-MeOPh, 79%
17 R = m-MeOPh, 89%
6 R = m-MeOPh, 81%
7 R = p-MeOPh, 90%
8 R = p-NO2Ph, 90%
18
19
R = p-MeOPh, 73%
R = p-NO2Ph, 84%
15
R = p-NO2Ph
9
20 R = Me, 76%
R = Me, 96%
6 9
(a) - , camphorsulfonic acid (CSA), DMF;
(b) acetaldehyde,TsOH, DMF; (c) TsCl, Py
Scheme 2. Synthesis of a series of 2,3-di-O-toluenesulfonyl-b-D-galactopyranosides (5–9) from compound 11.
4,6-O-acetal protected derivatives 16–19 in 73–89% yields
(Scheme 2).15 For compound 20, the synthesis was carried out
using acetaldehyde/p-toluenesulfonic acid as a reagent (76%). The
subsequent 2,3-di-O-sulfonylations. with p-toluenesulfonyl chlo-
ride (TsCl) in pyridine afforded the target substrates 5–9 in 81–
96% yields.
To obtain a substrate containing the 4,6-O-methylidene acetal
of galactopyranoside (10), the method described in Scheme 2
was attempted (not shown) using dimethoxymethane as a reagent
with compound 11; however, the desired compound 4,6-O-meth-
Ph
O
O
HO
TsO
OAc
O
HO
TsO
OH
O
O
a
OMe
OMe
+
OMe
TsO
OTs
OTs
OTs
22
O
21
2
b
OMOM
O
RO
TsO
O
c
O
ylidene-b-D-galactopyranoside (not shown) was found to form in
OMe
OMe
TsO
poor yield likely due to the formation of a mixture of non-cyclized
mixed acetals (MOM) and cyclized acetals (both the 1,3-dioxolane
and 1,3-dioxane forms).16 An alternative route was pursued using
OTs
OTs
10
23 R=H
24
R=MOM
the previously synthesized 4,6-O-benzylidene-2,3-di-O-tosyl-b-D-
galactopyranoside 2 as a starting material (Scheme 3). Initial at-
tempts at hydrolysis using aqueous acetic acid were sluggish,
and resulted in concomitant acetylation of O-6 to afford 22 in sub-
stantial amounts (ꢂ40% as estimated by TLC); the latter was not
desirable as subsequent conversion to 21 was considered to be dif-
ficult due to the sensitivity of the tosylate function to alkaline con-
ditions. Alternatively, hydrolysis of 2 with 50% trifluoroacetic acid–
water at room temperature proceeded smoothly to afford the 4,6-
diol 21 in 94% yield. The subsequent treatment of 21 with neat
dimethoxymethane under the catalysis of CSA was quite slow,
and in an effort to drive the reaction to completion a Soxhlet appa-
ratus containing molecular sieves (4 Å) was used to remove meth-
anol from the reaction mixture, as the methanol could be
(a) 50% TFA-H2O, 94% or 80%AcOH-H2O; (b) CSA, CH2(OMe)2 (neat);
(c) CSA, DCM, reflux, 83%
Scheme 3. The synthesis of methyl 4,6-O-methylidene-2,3-di-O-tosyl-b-
pyranoside 10.
D-galacto-
azeotropically distilled with dimethoxymethane and then removed
by passing over the bed of molecular sieves.16 The reaction affor-
ded primarily a mixture of the 6-O-MOM (23) and 4,6-di-O-MOM
(24) protected compounds, and produced only trace amounts of
the desired 4,6-O-methylidene acetal protected 10; in order to
drive the reaction to completion, dimethoxymethane was
evaporated to dry, and then the reaction mixture redissolved into

40
R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
R
R
R
O
O
O
O
O
O
OR'
O
a
O
O
OMe
O
OMe
OMe
TsO
OTs
OMe
2
5
R = Ph
25 R = Ph, R'=H
R = o-MeOPh
26
27
R = o-MeOPh, R'=H, 75%
R = m-MeOPh, R'=H, 78%
6 R = m-MeOPh
7 R = p-MeOPh
8 R = p-NO2Ph
9 R = Me
28 R = p-MeOPh, R'=H, 79%
29 R = p-NO2Ph, R'=H, 73%
30
31
32
R = Me, R'=H, 79%
10
R=H
R = H, R'=H, 30%
b
R = H, R'=Ac, 84% (2 steps)
(a) KOMe, 1,4-dioxane; (b) Ac2O, Py
Scheme 4. Conversion of 4,6-O-acetal-2,3-di-O-sulfonyl-b-
D-galactopyranosides to 4,6-O-acetal-3-O-methyl-b-D-idopyranosides.
dichloromethane and further refluxed with CSA for several days,
which upon column chromatography afforded the product 10 in
83% yield.
Table 1
1H NMR monitoring of the reaction progression of di-sulfonates 2, 7, and 8a
Time (h)
Ph
p-MeOPh
p-NO2Ph
All synthesized 4,6-O-acetal-2,3-di-O-tosyl-b-D-galactopyrano-
2
Intb
25
7
Intb
28
8
Intb
29
sides 5–10 were then reacted with potassium methoxide at room
temperature (Scheme 4). It was found that in all cases, the reac-
tions resulted in clean conversion to the 4,6-O-acetal-3-O-
0
2
4
6
8
100
60
49
30
23
16
0
33
35
51
56
59
0
8
16
19
22
25
100
69
45
41
33
31
0
23
44
38
42
43
0
8
12
21
25
26
100
82
71
60
56
43
0
14
21
28
28
39
0
4
8
12
16
18
methyl-b-D
-idopyranosides as detected by 1H NMR; for substituted
acetal derivatives 5–9, the desired idopyranosides 26–30 were iso-
lated in yields of 73–79%. This yield is comparable to the previ-
10
ously reported conversion of compound
2 to 25 (66%, not
a
Relative amounts of the starting material, intermediate epoxide, and ido-con-
optimized).6 For the unsubstituted methylidene acetal 10, the de-
sired idopyranoside 31 was isolated albeit in low yields (ꢂ30%),
presumably due to a loss of product during work-up because of
an increased water-solubility of the product. In order to increase
the isolated yield, the crude reaction mixture was acetylated, and
the 2-O-acetylated idopyranoside 32 was isolated in a much im-
proved yield (84%).
figured product were determined by periodically analyzing aliquots from the
reaction mixtures; the relative amounts of each were determined by integration of
the benzylic protons in the 1H NMR.
b
Refers to the 2,3-anhydro-talopyranoside intermediate.
BnO
TsO
OTs
O
BnO
AcO
BnO
HO
OH
O
OH
O
The consistent high regio- and stereoselective conversion of all
a
b
acetal-protected 2,3-di-O-sulfonyl
D-galactopyranosides (2, 5–10)
OMe
OMe
OMe
OMe
to -idopyranosides (25–30, 32) indicated that although there are
D
OTs
35
OAc
OH
34
some degrees of difference in ring flexibility introduced by substit-
uents attached to the acetal carbon center, this did not contribute
to significant differences in the observed reactivity and regio/stere-
oselectivity. The 4S2 conformer may be the main mediator of the
intramolecular cyclization, and in this conformation the substitu-
ent placed at the acetal carbon center does not appear to interact
significantly with the substituent at C-3, which could explain
why all synthesized 4,6-O-acetal protected substrates gave similar
33
b
TsO
BnO
OMe
OH
O
O
O
BnO
OR
R = Ts or H
OTs
37
yields of the corresponding D-idopyranoside.
36
(a) NaOMe, MeOH, quant.; (b) TsCl, Py, 82%
The reaction progression of 2, 7, and 8 with potassium methox-
ide was monitored by 1H NMR; the results indicated that indeed
the p-nitrobenzylidene acetal-containing substrate 8 reacted slow-
est (Table 1), likely due to weaker cation coordination at O-4 be-
cause of the aryl nitro-substituent. Contrary to expectations
based on electron-donating ability, substrates 2 and 7 were ob-
served to react at a similar rate, although both with the expected
regioselectivity; this may be explained by the aryl methoxy substi-
tuent competing for cation coordination making it less available to
activate the reaction.
We thus turned our attention to substrates lacking the 4,6-O-
acetal functionality, as these compounds should be even more
flexible than any of the 4,6-O-acetal-protected galactopyrano-
sides. Compound 35 was chosen as a possible substrate, as it
was thought to be readily obtained from triol 34. Compound 34
was obtained via a Zemplén transesterification of methyl 2,3-di-
Scheme 5. Initial attempts at obtaining
which lacked the 4,6-O-acetal functionality were unsuccessful, and instead resulted
in an intramolecular ring closure.
a 2,3-di-O-tosyl-b-D-galactopyranoside
topyranoside according to literature procedure (Scheme 5).11,17
Unfortunately, attempts at tri-tosylation of the triol (34) using
TsCl in anhydrous pyridine did not yield the desired 2,3,6-tri-O-
tosylate (35); instead, 3,6-anhydro product 37 was isolated. Com-
pound 37 was possibly formed via first a selective 6-O-tosylation
(?36) followed by an intramolecular SN2 nucleophilic attack from
the 3-hydroxyl group to form the 3,6-anhydro functionality. The
pyranoside may ring-flip from the 4C1 to 1C4 chair during the pro-
cess, which affords a favorable anomeric effect for b-glycosides
that helps to counterbalance the unfavorable axial orientations,
O-acetyl-4-O-benzyl-b-
pared from methyl 2,3-di-O-acetyl-4,6-O-benzylidene-b-
D
-galactopyranoside 33, which was pre-
-galac-
D

R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
41
OR
O
RO
OMe
O
OMe
O
OMe
MOMO
AcO
MOMO
OH
b
O
+
OMe
O
OMe
TsO
O
OMe
OMe
OTs
39 R=Ac, 41%
OMe
38 R=H
45 R=MOM
46, 59%
a
40
R=Me, 38%
47
, 29%
+
(a) CH2(OMe)2 (neat), CSA, 36%; (b) KOMe, 1,4-dioxane
AcO
TsO
41
OR
O
HO
TsO
OR
O
Scheme 7. 4,6-O-Protected-2,3-di-O-tosyl-b- -galactopyranoside 45 was reacted
D
b-c
with methoxide solution to probe the regio- and stereoselectivity of the resultant
reaction.
OMe
OMe
OTs
OTs
R=Ac, 38%
21
R=H
a
42 R=Me, 41%
38 R=Me
+
of all prepared 2,3-di-O-sulfonates of galactopyranosides (2, 5–10),
as all these compounds were smoothly converted to the corre-
sponding idopyranosides. However, the observation of intermedi-
ate epoxides as well as poor yields for the desired idopyranosides
in all non-acetal-protected cases confirmed the beneficial effect
of using less flexible substrates in the nucleophilic opening of
2,3-epoxides. Furthermore, the observation of unreacted disulfo-
nates in the cases of 21 and 38 also confirmed the putative reduced
reactivity of the 3-O-sulfonate in the O-desulfonylation step for the
non-acetal protected substrates; this is most likely due to the in-
creased conformational flexibility which affects the cation-medi-
ated polarization of the 3-O-sulfonate as well as the success rate
of nucleophilic attack by the incoming nucleophile on the S-
center.13
OR
AcO
OAc
O
OMe
(a) MeOTf, (tBu)2Py, DCM, 96%;
(b) KOMe, 1,4-dioxane;
(c) Ac2O, Py
OMe
43 R=Ac, 6%
44
R=Me, 12%
Scheme 6. 2,3-Di-O-tosyl-b-D-galactopyranosides 21 and 38 lacking the 4,6-O-
acetal were subjected to a methoxide solution in order to probe the regio- and
stereoselectivity of the resultant reaction.
which enables the attack of O-3 at C-6; this is similar to the pro-
cess observed by Crich et al. while studying the Hanessian–Hullar
reaction in b-galactosides.12
3. Conclusions
Since compound 21 had already two tosylates at the C-2 and C-
3 positions, another effort to obtain galactopyranosides that lack a
4,6-O-acetal functionality was carried out using the 4,6-diol 21 as a
starting material. A 4,6-di-O-methylation was attempted on diol
21 using methyl triflate as a reagent in the presence of 2,6-di-
tert-butylpyridine.18 However, only trace amounts of 4,6-di-O-
methylated compound were obtained (<1% isolated yield); instead,
the 6-O-monomethylated compound (38) was obtained in near
quantitative yield (96%) (Scheme 6). The axial OH-4 is seemingly
too unreactive to be methylated under the methylating conditions
that were used; more forceful attempts with stronger base or heat-
ing resulted in unidentified decomposition. Nevertheless, both
substrates 21 and 38 were treated with a methoxide solution as
before. However, both reactions were found to be sluggish, afford-
ing several compounds even after several days. To facilitate the
purification, both crude reaction mixtures were acetylated, and
subsequently purified by column chromatography on silica gel to
afford the 2,3-anhydro-talopyranoside intermediate which was
isolated in each case (39, 42%; 40, 38%), along with an acetylated
derivative resulting from the unreacted 2,3-di-O-tosylate (41,
38%, 42, 41%); interestingly, the expected idopyranoside was only
isolated in low yield (43, 6%; 44, 12%). Attempts to improve the
yield of idopyranoside by carrying out the reaction at higher tem-
peratures (50–80 °C) were unsuccessful, as although more idopyr-
anoside was observed to form, new by-products with elimination
were also formed as evidenced by the crude 1H NMR.
In order to confirm that the retardation of reaction rate was not
due to the unprotected OH-4 position, compound 38 was protected
with a methoxymethyl (MOM) ether (?45, 36% yield), and then
exposed to methoxide solution. Similar to the observations made
for the other substrates lacking a 4,6-O-acetal, the reaction rate
was significantly slowed resulting in isolation of both the 2,3-
anhydro-b-D-talopyranoside 46 and 3-O-methyl-idopyranoside 47
after 4 days (Scheme 7).
The above results are in sharp contrast with the use of conform-
ationally less flexible 4,6-O-acetal analogs of galactopyranoside.
The presence of the 4,6-O-acetals clearly enhanced the reactivity
In conclusion, we have synthesized a small library of methyl
4,6-O-acetal-2,3-di-O-tosyl-b-D-galactopyranoside derivatives and
then treated them with methoxide. Despite the conformational
flexibility difference between the o-, m-, and p-methoxybenzyli-
dene, p-nitrobenzylidene, ethylidene, and methylidene acetals, all
4,6-O-acetal-protected substrates resulted in a highly regio- and
stereoselective conversion to the corresponding methyl 4,6-O-ace-
tal-3-O-methyl-b-D-galactopyranoside derivatives, as was previ-
ously reported for the 4,6-O-benzylidene acetal; either the 4S2 or
1C4 conformer is likely responsible for mediating the intramolecu-
lar cyclization in the majority of cases. However, all non-4,6-O-ace-
tal-protected substrates reacted at much reduced reaction rates at
both the first O-transsulfonylation step and the subsequent trans-
diaxial epoxide opening, indicating that the torsional strain affor-
ded by the acetals assists in both mechanistic steps of the di-inver-
sion transformation probably by reducing the conformational
stability of the substrates.
4. Experimental data
4.1. General methods
All commercial reagents were used as supplied unless other-
wise stated. Thin layer chromatography was performed on Silica
Gel 60-F254 (E. Merck, Darmstadt) with detection by fluorescence,
charring with 5% aqueous sulfuric acid, or a ceric ammonium
molybdate solution. Column chromatography was performed on
Silica Gel 60 (Silicycle, Ontario) and solvent gradients given refer
to stepped gradients and concentrations are reported as % v/v. Or-
ganic solutions were concentrated and/or evaporated to dry under
vacuum in a water bath (<60 °C). Molecular sieves were stored in
an oven at 100 °C and flame-dried under vacuum before use.
Amberlite IR-120H ion exchange resin was washed multiple times
with MeOH prior to use. Optical rotations were determined in a
5 cm cell at 20 2 °C;
½
a 2D0
values are given in units of
ꢃ

42
R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
10ꢀ1 deg cm2/g. NMR spectra were recorded on Bruker spectrome-
ters at either 400 or 600 MHz (as indicated), and the first-order
proton chemical shifts dH and dC are reported in d (ppm) and refer-
enced to residual CHCl3 (dH 7.24, dC 77.23, CDCl3). 1H and 13C NMR
spectra were assigned with the assistance of 2D gCOSY and 2D
gHSQC experiments. High-resolution ESI-QTOF mass spectra were
recorded on an Agilent 6520 Accurate Mass Quadrupole Time-of-
Flight LC/MS spectrometer. All of the data were obtained with
the assistance of the analytical services of the Department of
Chemistry, University of Calgary.
4.19 (dd, 1H, J = 3.6, 1.2 Hz, H-4), 4.06 (dd, 1H, J = 12.5, 1.9 Hz,
H-6b), 3.79 (s, 3H, OMe), 3.75–3.71 (m, 1H, H-2), 3.66 (ddd,
1H, J = 9.5, 8.8, 3.6 Hz, H-3), 3.56 (s, 3H, OMe), 3.47 (m, 1H, H-
5), 2.52 (m, 2H, 2-OH and 3-OH). 13C NMR (CDCl3, 100 MHz):
dC 159.81 (Ar), 139.12 (Ar), 129.53 (Ar), 119.03 (Ar), 115.29
(Ar), 112.00 (Ar), 104.02 (C-1), 101.57 (ArCH), 75.59 (C-4),
73.02 (C-3), 72.06 (C-2), 69.40 (C-6), 66.97 (C-5), 57.35 (OMe),
55.57 (OMe). HRMS m/z calcd for C15H20O7 (M+Na)+: 335.1101;
found: 335.1090.
4.5. Methyl 4,6-O-(p-nitrobenzylidene)-b-D-galactopyranoside
4.2. General procedure for the synthesis of dimethyl acetals (12–
15)
(19)
The glycoside starting material (11, 841 mg, 4.33 mmol) and p-
nitrobenzaldehyde dimethyl acetal (15, 1.751 g, 8.88 mmol) were
dissolved into dry DMF (10 mL), CSA (to pH 3) was added, and
the reaction solution left mixing at 75 °C under argon. After 30 h
the solution was neutralized with Et3N (to pH 8), and evaporated
to dry via co-evaporation with toluene (3 ꢄ 10 mL). The crude mix-
ture was purified by column chromatography on silica gel using
2?2.5?3% MeOH–CH2Cl2 to afford the desired product 19 as a
white solid (1.197 g, 3.66 mmol, 84% yield). Rf 0.38 (acetone:hex-
A solution of the aldehyde (3.5 mmol), trimethyl orthoformate
(5.9 mmol), and acidic resin (Amberlite IR-120H, 15 mg) in dry
MeOH (4.0 mL) was heated at 110 °C in a microwave reactor for
20 min, as reported previously for the synthesis of p-anisaldehyde
dimethyl acetal.14 Upon cooling back to room temperature, the
solution was filtered and diluted with EtOAc (50 mL). The organic
phase was washed with saturated NaCl(aq) solution (2 ꢄ 50 mL),
and the combined aqueous layers further extracted with EtOAc
(70 mL). The organic phases were combined, dried with Na2SO4, fil-
tered, and evaporated to dry to afford the product (89–98% yields).
anes 7:3).
½
a 2D0
ꢃ
:
ꢀ18.0° (c 0.85, acetone). 1H NMR (CDCl3,
400 MHz): dH 8.23–8.18 (m, 2H, Ar), 7.70–7.66 (m, 2H, Ar), 5.63
(s, 1H, ArCH), 4.37 (dd, 1H, J = 12.5, 1.5 Hz, H-6a), 4.26–4.25 (m,
1H, H-4), 4.22–4.19 (m, 1H, H-1), 4.11 (dd, 1H, J = 12.5, 1.9 Hz, H-
6b), 3.76–3.68 (m, 2H, H-2 and H-3), 3.57 (s, 3H, OMe), 3.53–3.51
(m, 1H, H-5), 2.47–2.40 (m, 2H, 2-OH and 3-OH). 13C NMR (CDCl3,
150 MHz): dC 148.62 (Ar), 143.91 (Ar), 127.76 (Ar), 123.67 (Ar),
104.07 (C-1), 99.98 (ArCH), 75.66 (C-4), 72.79 (C-3), 71.91 (C-2),
69.45 (C-6), 66.78 (C-5), 57.58 (OMe). HRMS m/z calcd for
4.3. Methyl 4,6-O-(o-methoxybenzylidene)-b-D-
galactopyranoside (16)
The glycoside starting material (11, 511 mg, 2.63 mmol) and o-
anisaldehyde dimethyl acetal (12, 810 mg, 4.45 mmol) were dis-
solved into dry DMF (6.0 mL), camphorsulphonic acid (CSA; to
pH 3) was added, and the reaction solution left mixing at room
temperature under argon. After 18 h the solution was neutralized
with Et3N (to pH 8), and evaporated to dry via co-evaporation with
toluene (3 ꢄ 5 mL). The crude mixture was purified by column
chromatography on silica gel using 2?3% MeOH–CH2Cl2 to afford
the desired product 16 as a white solid (649 mg, 2.08 mmol, 79%
C
14H17NO8 (M+NH4)+: 345.1292; found: 345.1295.
4.6. Methyl 4,6-O-ethylidene-b- -galactopyranoside (20)
D
The glycoside starting material (11, 731 mg, 3.77 mmol) and
acetaldehyde (0.25 mL, 4.5 mmol) were dissolved into dry MeCN
(7.3 mL), p-toluenesulfonic acid (to pH 3) was added, and the
reaction solution left mixing at room temperature under argon.
After 21 h the solution was neutralized with Et3N (to pH 7) and
evaporated to dry. The crude mixture was purified by column
chromatography on silica gel using 2?3?4?5% MeOH–CH2Cl2
to afford the desired product 20 as a white solid (628 mg,
yield). Rf 0.46 (acetone:hexanes 7:3). ½a D20
ꢃ : ꢀ46.4° (c 1.05, CHCl3).
1H NMR (CDCl3, 400 MHz): dH 7.64 (dd, 1H, J = 7.6, 1.8 Hz, Ar),
7.30 (ddd, 1H, J = 8.3, 7.5, 1.8 Hz, Ar), 6.96 (ddd, 1H, J = 7.5, 7.5,
0.8 Hz, Ar), 6.85 (dd, 1H, J = 8.3, <1 Hz, Ar), 5.93 (s, 1H, ArCH),
4.31 (dd, 1H, J = 12.5, 1.4 Hz, H-6a), 4.19 (d, 1H, J = 7.5 Hz, H-1),
4.19 (dd, 1H, J = 3.9, 1.0 Hz, H-4), 4.09 (dd, 1H, J = 12.5, 1.9 Hz, H-
6b), 3.81 (s, 3H, OMe), 3.74 (ddd, 1H, J = 9.5, 7.6, 1.7 Hz, H-2),
3.64 (ddd, 1H, J = 9.5, 9.5, 3.8 Hz, H-3), 3.58 (s, 3H, OMe), 3.45
(m, 1H, H-5), 2.52 (d, 1H, J = 9.4 Hz, 3-OH), 2.52 (d, 1H, J = 1.8 Hz,
2-OH). 13C NMR (CDCl3, 100 MHz): dC 156.63 (Ar), 130.62 (Ar),
127.94 (Ar), 126.06 (Ar), 120.93 (Ar), 110.76 (Ar), 104.01 (C-1),
96.70 (ArCH), 75.68 (C-4), 73.07 (C-3), 72.20 (C-2), 69.54 (C-6),
67.12 (C-5), 57.36 (OMe), 55.80 (OMe). HRMS m/z calcd for
2.85 mmol, 76% yield). Rf 0.39 (MeOH:CH2Cl2 7:93). ½a D20
ꢃ : ꢀ24.7°
(c 1.03, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 4.71 (q, 1H,
J = 5.1 Hz, CH3CH), 4.13 (dd, 1H, J = 12.5, 1.5 Hz, H-6a), 4.12 (d,
1H, J = 7.6 Hz, H-1), 3.96 (dd, 1H, J = 3.8, 1.0 Hz, H-4), 3.84 (dd,
1H, J = 12.5, 1.9 Hz, H-6b), 3.67 (ddd, 1H, J = 9.7, 7.6, 2.3 Hz, H-
2), 3.58 (ddd, 1H, J = 9.6, 8.0, 3.8 Hz, H-3), 3.52 (s, 3H, OMe),
3.33 (m, 1H, H-5), 3.10 (d, 1H, J = 2.4 Hz, 2-OH), 2.94 (d, 1H,
J = 8.0 Hz, 3-OH), 1.35 (d, 3H, J = 5.1 Hz, CH3CH). 13C NMR (CDCl3,
100 MHz): dC 104.02 (C-1), 99.42 (CH3CH), 74.97 (C-4), 72.75 (C-
3), 71.70 (C-2), 68.82 (C-6), 66.80 (C-5), 57.31 (OMe), 20.96
(CH3CH). HRMS m/z calcd for C9H16O6 (M+NH4)+: 238.1285;
found: 238.1288.
C
15H20O7 (M+Na)+: 335.1101; found: 335.1100.
4.4. Methyl 4,6-O-(m-methoxybenzylidene)-b-D-
galactopyranoside (17)
The glycoside starting material (11, 988 mg, 5.09 mmol) and
m-anisaldehyde dimethyl acetal (13, 1.470 g, 8.07 mmol) were
dissolved into dry DMF (10 mL), and the procedure in Section 4.3
was followed to obtain the crude product, which was subse-
quently purified by column chromatography on silica gel using
1.5?2.5?3% MeOH–CH2Cl2 to afford the desired product 17 as
a white solid (1.412 g, 4.52 mmol, 89% yield). Rf 0.29 (ace-
4.7. Methyl 4,6-O-(o-methoxybenzylidene)-2,3-di-O-tosyl-b-D-
galactopyranoside (5)
The diol starting material (16, 545 mg, 1.75 mmol) and p-toluene-
sulfonyl chloride (TsCl; 1.390 g, 7.29 mmol) were dissolved into dry
pyridine (5 mL) and left mixing at 45 °C for 36 h. The reaction was
quenched with water (5 mL) and then concentrated and co-evapo-
rated with toluene (2 ꢄ 20 mL). The crude product was redissolved
into EtOAc (60 mL), washed with saturated NaCl(aq) solution
(2 ꢄ 60 mL), water (60 mL), dried with Na2SO4, filtered, and evapo-
tone:hexanes 1:1). ½a D20
ꢃ
: ꢀ39.0° (c 0.96, CHCl3). 1H NMR (CDCl3,
400 MHz): dH 7.25 (dd, 1H, J = 8.0, 7.8 Hz, Ar), 7.05 (m, 2H, Ar),
6.88 (ddd, 1H, J = 8.2, 2.6, 1.0 Hz, Ar), 5.51 (s, 1H, ArCH), 4.33
(dd, 1H, J = 12.5, 1.5 Hz, H-6a), 4.19 (d, 1H, J = 7.4 Hz, H-1),

R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
43
rated to dry. The crude mixture was purified by column chromatogra-
4.10. Methyl 4,6-O-(p-nitrobenzylidene)-2,3-di-O-tosyl-b-
D-
phy on silica gel using 25?30% EtOAc–toluene to afford the desired
product 5 as a white solid (996 mg, 1.60 mmol, 92% yield). Rf 0.64
galactopyranoside (8)
(acetone:CH2Cl2 1:19). ½a D20
ꢃ
: +0.7° (c 1.02, CHCl3). 1H NMR (CDCl3,
The diol starting material (19, 919 mg, 2.94 mmol) and TsCl
(2.019 g, 10.6 mmol) were dissolved into dry pyridine (20 mL)
and the procedure in Section 4.7 was followed to obtain the crude
product, which was subsequently purified by column chromatog-
raphy on silica gel using 25% EtOAc–toluene to afford the desired
product 8 as a white solid (1.643 g, 2.65 mmol, 90% yield). Rf 0.31
400 MHz): dH 7.79–7.74 (m, 2H, Ar), 7.73–7.69 (m, 2H, Ar), 7.59 (dd,
1H, J = 7.6, 1.7 Hz, Ar), 7.31 (ddd, 1H, J = 8.3, 7.5, 1.8 Hz, Ar), 7.28–
7.25 (m, 2H, Ar), 7.19–7.15 (m, 2H, Ar), 6.98 (ddd, 1H, J = 7.5, 7.5,
0.8 Hz, Ar), 6.86 (dd, 1H, J = 8.3, <1 Hz, Ar), 5.66 (s, 1H, ArCH), 4.88
(dd, 1H, J = 9.9, 7.7 Hz, H-2), 4.58 (dd, 1H, J = 9.9, 3.7 Hz, H-3), 4.38
(dd, 1H, J = 3.7, <1 Hz, H-4), 4.25 (d, 1H, J = 7.7 Hz, H-1), 4.22 (dd,
1H, J = 12.5, 1.6 Hz, H-6a), 3.98 (dd, 1H, J = 12.5, 1.7 Hz, H-6b), 3.83
(s, 3H, OMe), 3.38–3.37 (m, 1H, H-5), 3.21 (s, 3H, OMe), 2.40 (s, 3H,
Ts), 2.35 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC 156.73 (Ar),
145.09 (Ar), 144.56 (Ar), 134.84 (Ar), 133.56 (Ar), 130.50 (Ar),
129.77 (Ar), 129.53 (Ar), 128.45 (Ar), 128.31 (Ar), 127.87 (Ar),
125.82 (Ar), 120.97 (Ar), 110.92 (Ar), 101.66 (C-1), 96.84 (ArCH),
77.27 (C-3), 76.48 (C-2), 74.60 (C-4), 68.91 (C-6), 66.29 (C-5), 57.02
(OMe), 56.01 (OMe), 21.86 (Ts), 21.82 (Ts). HRMS m/z calcd for
(acetone:hexanes 3:2). ½a D20
ꢃ
: +14.4° (c 0.91, CHCl3). 1H NMR (CDCl3,
400 MHz): dH 8.20–8.18 (m, 2H, Ar), 7.82–7.77 (m, 2H, Ar), 7.74–
7.69 (m, 2H, Ar), 7.62–7.60 (m, 2H, Ar), 7.31–7.24 (m, 4H, Ar),
5.49 (s, 1H, ArCH), 4.78 (dd, 1H, J = 9.9, 7.7 Hz, H-2), 4.64 (dd, 1H,
J = 9.9, 3.7 Hz, H-3), 4.56 (dd, 1H, J = 3.7, <1 Hz, H-4), 4.30 (dd,
1H, J = 12.5, <1 Hz, H-6a), 4.23 (d, 1H, J = 7.7 Hz, H-1), 4.04 (dd,
1H, J = 12.5, 1.6 Hz, H-6b), 3.48 (m, 1H, H-5), 3.11 (s, 3H, OMe),
2.40 (s, 6H, Ts). 13C NMR (CDCl3, 100 MHz): dC 148.52 (Ar),
145.55 (Ar), 144.69 (Ar), 143.56 (Ar), 134.64 (Ar), 133.11 (Ar),
130.01 (Ar), 129.51 (Ar), 128.41 (Ar), 127.60 (Ar), 123.51 (Ar),
101.57 (C-1), 99.50 (ArCH), 76.94 (C-3), 76.35 (C-2), 74.73 (C-4),
68.79 (C-6), 65.97 (C-5), 57.18 (OMe), 21.91 (Ts), 21.81 (Ts). HRMS
m/z calcd for C28H29NO12S2 (M+NH4)+: 653.1469; found: 653.1449.
C
29H32O11S2 (M+NH4)+: 638.1724; found: 638.1721.
4.8. Methyl 4,6-O-(m-methoxybenzylidene)-2,3-di-O-tosyl-b-D-
galactopyranoside (6)
The diol starting material (17, 321 mg, 1.03 mmol) and TsCl
(826 mg, 4.33 mmol) were dissolved into dry pyridine (3.5 mL)
and the procedure in Section 4.7 was followed to afford the pure
product 6 as a white solid (517 mg, 0.834 mmol, 81% yield). Rf
4.11. Methyl 4,6-O-ethylidene-2,3-di-O-tosyl-b-D-
galactopyranoside (9)
The diol starting material (20, 720 mg, 3.27 mmol) and TsCl
(1.862 g, 9.77 mmol) were dissolved into dry pyridine (7.5 mL)
and the procedure from Section 4.7 was followed to obtain the
crude product, which was subsequently purified by column chro-
matography on silica gel using 30?35% EtOAc–toluene to afford
the desired product 9 as a white solid (1.651 g, 3.12 mmol, 96%
0.62 (acetone:CH2Cl2 1:19). ½a D20
ꢃ
: +17.6° (c 1.02, CHCl3). 1H NMR
(CDCl3, 400 MHz): dH 7.79–7.72 (m, 4H, Ar), 7.28–7.22 (m, 5H,
Ar), 7.01–6.99 (m, 1H, Ar), 6.98–6.95 (m, 1H, Ar), 6.88 (ddd, 1H,
J = 8.2, 2.6, 0.9 Hz, Ar), 5.30 (s, 1H, ArCH), 4.84 (dd, 1H, J = 9.9,
7.7 Hz, H-2), 4.62 (dd, 1H, J = 9.9, 3.7 Hz, H-3), 4.42 (dd, 1H,
J = 3.7, 0.6 Hz, H-4), 4.27 (dd, 1H, J = 12.3, 1.5 Hz, H-6a), 4.24 (d,
1H, J = 7.7 Hz, H-1), 3.98 (dd, 1H, J = 12.5, 1.7 Hz, H-6b), 3.81 (s,
3H, OMe), 3.41–3.40 (m, 1H, H-5), 3.19 (s, 3H, OMe), 2.40 (s, 3H,
Ts), 2.39 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC 159.69 (Ar),
145.29 (Ar), 144.57 (Ar), 138.71 (Ar), 134.79 (Ar), 133.60 (Ar),
129.93 (Ar), 129.53 (Ar), 129.39 (Ar), 128.48 (Ar), 128.30 (Ar),
118.88 (Ar), 115.16 (Ar), 111.87 (Ar), 101.67 (C-1), 101.08 (ArCH),
77.25 (C-3), 76.34 (C-2), 74.48 (C-4), 68.76 (C-6), 66.19 (C-5),
57.03 (OMe), 55.54 (OMe), 21.89 (Ts), 21.82 (Ts). HRMS m/z calcd
for C29H32O11S2 (M+NH4)+: 638.1724; found: 638.1718.
yield). Rf 0.62 (EtOAc:toluene 1:1). ½a D20
ꢃ
: +28.3° (c 1.03, CHCl3).
1H NMR (CDCl3, 400 MHz): dH 7.81–7.77 (m, 2H, Ar), 7.75–7.72
(m, 2H, Ar), 7.32–7.29 (m, 2H, Ar), 7.27–7.25 (m, 2H, Ar), 4.78
(dd, 1H, J = 10.0, 7.7 Hz, H-2), 4.52 (q, 1H, J = 5.1 Hz, CH3CH), 4.52
(dd, 1H, J = 10.0, 3.6 Hz, H-3), 4.19 (dd, 1H, J = 3.7, 0.7 Hz, H-4),
4.17 (d, 1H, J = 7.8 Hz, H-1), 4.07 (dd, 1H, J = 12.5, 1.6 Hz, H-6a),
3.75 (dd, 1H, J = 12.5, 1.7 Hz, H-6b), 3.29 (m, 1H, H-5), 3.11 (s,
3H, OMe), 2.42 (s, 3H, Ts), 2.40 (s, 3H, Ts), 1.30 (d, 3H, J = 5.1 Hz,
CH3CH). 13C NMR (CDCl3, 100 MHz): dC 145.34 (Ar), 144.57 (Ar),
134.73 (Ar), 133.40 (Ar), 129.91 (Ar), 129.49 (Ar), 128.48 (Ar),
128.44 (Ar), 101.57 (C-1), 99.45 (CH3CH), 77.23 (C-3), 76.41 (C-2),
73.97 (C-1), 68.21 (C-6), 66.01 (C-5), 57.12 (OMe), 21.91 (Ts),
21.82 (Ts), 20.87 (CH3CH). HRMS m/z calcd for C23H28O10S2
(M+NH4)+: 546.1462; found: 546.1452.
4.9. Methyl 4,6-O-(p-methoxybenzylidene)-2,3-di-O-tosyl-b-D-
galactopyranoside (7)
The diol starting material15 (18, 919 mg, 2.94 mmol) and TsCl
(2.019 g, 10.6 mmol) were dissolved into dry pyridine (20 mL)
and the procedure in Section 4.7 was followed to obtain the crude
product, which was subsequently purified by column chromatog-
raphy on silica gel using 25% EtOAc–toluene to afford the desired
product 7 as a white solid (1.643 g, 2.65 mmol, 90% yield). Rf 0.55
4.12. Methyl 2,3-di-O-tosyl-b-D-galactopyranoside (21)
The starting material (2, 838 mg, 1.42 mmol) was dissolved into
a solution of trifluoroacetic acid (5.0 mL) and water (5.0 mL), and
left mixing at room temperature. After 4 h, the reaction was di-
luted with water (50 mL), and then the product extracted with
EtOAc (2 ꢄ 50 mL). The combined organic phases were neutralized
with Et3N (to pH 8), then washed with saturated NaHCO3(aq) solu-
tion (50 mL), saturated NaCl(aq) solution (50 mL), dried with
Na2SO4, filtered, and then evaporated to dry. The crude mixture
was purified by column chromatography on silica gel using
15?20% acetone–hexanes to afford the pure product 21 as a white
solid (670 mg, 1.33 mmol, 94% yield). Rf 0.23 (EtOAc:toluene 1:1).
(EtOAc:toluene 1:1). ½a D20
ꢃ
: +26.0° (c 0.95, CHCl3). 1H NMR (CDCl3,
400 MHz): dH 7.78–7.72 (m, 4H, Ar), 7.36–7.30 (m, 2H, Ar), 7.27–
7.22 (m, 4H, Ar), 6.89–6.83 (m, 2H, Ar), 5.26 (s, 1H, ArCH), 4.84
(dd, 1H, J = 9.9, 7.8 Hz, H-2), 4.61 (dd, 1H, J = 9.9, 3.7 Hz, H-3),
4.39 (dd, 1H, J = 3.7, <1 Hz, H-4), 4.23 (d, 1H, J = 7.7 Hz, H-1),
4.25–4.21 (m, 1H, H-6a), 3.95 (dd, 1H, J = 12.5, 1.5 Hz, H-6b), 3.80
(s, 3H, OMe), 3.39 (m, 1H, H-5), 3.18 (s, 3H, OMe), 2.40 (s, 3H,
Ts), 2.39 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC 160.36 (Ar),
145.23 (Ar), 144.55 (Ar), 134.81 (Ar), 133.60 (Ar), 129.90 (Ar),
129.52 (Ar), 128.44 (Ar), 128.30 (Ar), 127.81 (Ar), 113.67 (Ar),
101.62 (C-1), 101.15 (ArCH), 77.33 (C-3), 76.43 (C-2), 74.36 (C-4),
68.67 (C-6), 66.12 (C-5), 57.02 (OMe), 55.53 (OMe), 21.88 (Ts),
21.81 (Ts). HRMS m/z calcd for C29H32O11S2 (M+NH4)+: 638.1724;
found: 638.1707.
½
a 2D0
ꢃ
: ꢀ4.4° (c 0.99, MeOH). 1H NMR (CDCl3, 400 MHz): dH 7.83–
7.80 (m, 2H, Ar), 7.72–7.69 (m, 2H, Ar), 7.34–7.31 (m, 2H, Ar),
7.27–7.24 (m, 2H, Ar), 4.73 (dd, 1H, J = 9.7, 7.7 Hz, H-2), 4.52 (dd,
1H, J = 9.8, 3.1 Hz, H-3), 4.40 (dd, 1H, J = 3.1, <1 Hz, H-4), 4.18 (d,
1H, J = 7.7 Hz, H-1), 3.91 (dd, 1H, J = 11.8, 5.9 Hz, H-6a), 3.82 (dd,
1H, J = 11.8, 4.8 Hz, H-6b), 3.51 (m, 1H, H-5), 3.08 (s, 3H, OMe),

44
R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
2.43 (s, 3H, Ts), 2.40 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC
145.71 (Ar), 144.64 (Ar), 134.71 (Ar), 132.66 (Ar), 130.13 (Ar),
129.50 (Ar), 128.60 (Ar), 128.45 (Ar), 101.84 (C-1), 79.43 (C-3),
77.08 (C-2), 73.70 (C-5), 69.13 (C-4), 62.33 (C-6), 57.18 (OMe),
21.96 (Ts), 21.82 (Ts). HRMS m/z calcd for C21H26O10S2 (M+Na)+:
525.0859; found: 525.0843.
(dd, 1H, J = 10.1, 2.9 Hz, H-3), 4.30 (dd, 1H, J = 2.8, <1 Hz, H-4),
4.12 (d, 1H, J = 7.6 Hz, H-1), 3.70 (dd, 1H, J = 10.3, 6.6 Hz, H-6a),
3.66 (d, 1H, J = 10.3, 5.7 Hz, H-6b), 3.60–3.57 (m, 1H, H-5), 3.36
(s, 3H, OMe), 3.33 (s, 3H, OMe), 3.00 (s, 3H, OMe), 2.43 (s, 3H,
Ts), 2.40 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC 145.49 (Ar),
144.53 (Ar), 134.81 (Ar), 132.70 (Ar), 130.02 (Ar), 129.41 (Ar),
128.79 (Ar), 128.54 (Ar), 101.66 (C-1), 98.50 (CH3OCH2), 97.20
(CH3OCH2), 78.18 (C-3), 77.42 (C-2), 74.69 (C-4), 73.33 (C-5),
66.56 (C-6), 56.93 (OMe), 56.72 (OMe), 55.69 (OMe), 21.95 (Ts),
4.13. Methyl 6-O-acetyl-2,3-di-O-tosyl-b-D-galactopyranoside
(22)
21.80 (Ts). HRMS m/z calcd for
C
25H34O12S2 (M+NH4)+:
Attempts at acetal hydrolysis using a combination of acetic
acid/water at elevated temperatures resulted in the 6-O-acetylated
by-product 22 isolated as a white solid. Rf 0.57 (EtOAc:toluene
608.1830; found: 608.1817. Data for 10: Rf 0.46 (EtOAc:toluene
1:1). ½a 2D0
ꢃ
: +17.4° (c 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): dH
7.83–7.78 (m, 2H, Ar), 7.74–7.69 (m, 2H, Ar), 7.32–7.29 (m, 2H,
Ar), 7.27–7.24 (m, 2H, Ar), 5.08 (d, 1H, J = 6.4 Hz, CHaHb), 4.77
(dd, 1H, J = 10.0, 7.7 Hz, H-2), 4.59 (d, 1H, J = 6.5 Hz, CHaHb),
4.55 (dd, 1H, J = 10.0, 3.6 Hz, H-3), 4.23 (dd, 1H, J = 3.6, <1 Hz,
H-4), 4.20 (d, 1H, J = 7.7 Hz, H-1), 4.09 (dd, 1H, J = 12.4, <1 Hz,
H-6a), 3.74 (dd, 1H, J = 12.4, 1.6 Hz, H-6b), 3.39–3.38 (m, 1H, H-
5), 3.09 (s, 3H, OMe), 2.42 (s, 3H, Ts), 2.39 (s, 3H, Ts). 13C NMR
(CDCl3, 100 MHz): dC 145.45 (Ar), 144.57 (Ar), 134.66 (Ar),
133.09 (Ar), 129.95 (Ar), 129.45 (Ar), 128.52 (Ar), 101.44 (C-1),
93.43 (CH2), 76.90 (C-3), 76.33 (C-2), 74.15 (C-4), 68.13 (C-6),
66.80 (C-5), 56.95 (OMe), 21.91 (Ts), 21.79 (Ts). HRMS m/z calcd
for C22H26O10S2 (M+NH4)+: 532.1306; found: 532.1286.
1:1). ½a 2D0
ꢃ
: +15.8° (c 1.01, CHCl3). 1H NMR (CDCl3, 400 MHz): dH
7.85–7.81 (m, 2H, Ar), 7.72–7.67 (m, 2H, Ar), 7.35–7.32 (m, 2H,
Ar), 7.26–7.24 (m, 2H, Ar), 4.69 (dd, 1H, J = 9.8, 7.7 Hz, H-2), 4.53
(dd, 1H, J = 9.8, 3.1 Hz, H-3), 4.30 (dd, 1H, J = 3.1, 0.9 Hz, H-4),
4.27 (d, 2H, J = 6.4 Hz, H-6a and H-6b), 4.14 (d, 1H, J = 7.7 Hz, H-
1), 3.64 (td, 1H, J = 6.4, 0.9 Hz, H-5), 3.05 (s, 3H, OMe), 2.43 (s,
3H, Ts), 2.40 (s, 3H, Ts), 2.04 (s, 3H, Ac). 13C NMR (CDCl3,
100 MHz): dC 170.94 (Ac), 145.74 (Ar), 144.64 (Ar), 134.64 (Ar),
132.64 (Ar), 130.12 (Ar), 129.47 (Ar), 128.59 (Ar), 128.45 (Ar),
101.59 (C-1), 79.21 (C-3), 76.93 (C-2), 71.57 (C-5), 68.16 (C-4),
62.30 (C-6), 56.97 (OMe), 21.94 (Ts), 21.80 (Ts), 20.96 (Ac). HRMS
m/z calcd for C23H28O11S2 (M+Na)+: 567.0965; found: 567.0947.
4.15. Methyl 4,6-O-(o-methoxybenzylidene)-3-O-methyl-b-D-
4.14. Methyl 6-O-methoxymethyl-2,3-di-O-tosyl-b-
galactopyranoside (23), methyl 4,6-di-O-methoxymethyl-2,3-di-
O-tosyl-b- -galactopyranoside (24), and methyl 4,6-O-
methylidene-2,3-di-O-tosyl-b- -galactopyranoside (10)
D
-
idopyranoside (26)
D
A solution of KOBu-t in MeOH (2.27 M, 0.75 mL, 1.70 mmol)
was added to a solution of the di-tosylate starting material (5,
211 mg, 0.340 mmol) in 1,4-dioxane (3.3 mL). After 3 days the
reaction mixture was evaporated to dry, redissolved into EtOAc
(30 mL), washed with saturated NaCl(aq) solution (2 ꢄ 30 mL),
dried with Na2SO4, filtered, and evaporated to dry. The crude mix-
ture was purified by column chromatography on silica gel using
30% acetone–hexanes to afford the pure product 26 as a yellow so-
lid (83 mg, 0.25 mmol, 75% yield). Rf 0.30 (EtOAc:toluene 1:1).
D
A solution of the starting material (21, 406 mg, 0.805 mmol)
and CSA (to pH 2) were refluxed in neat dimethoxy methane
(20 mL) with a Soxhlet apparatus containing crushed molecular
sieves (4 Å), in order to azeotropically distill and remove evolved
MeOH from the reaction mixture. After 48 h, the reaction mixture
was evaporated to dry (at 30 °C) and could be purified by column
chromatography on silica gel using 15?20% EtOAc–toluene to af-
ford a 3:1 mixture of 23 and 24 as white solids. Alternatively, the
crude mixture could be redissolved into dry CH2Cl2 (20 mL), and
further refluxed for 48 h. The reaction mixture was neutralized
with Et3N (to pH 8), diluted with CH2Cl2 (50 mL), washed with
saturated NaCl(aq) solution (2 ꢄ 50 mL), dried with Na2SO4, fil-
tered, and evaporated to dry. The crude mixture was purified by
column chromatography on silica gel using 20% EtOAc–toluene
½
a 2D0
ꢃ
: ꢀ62.7° (c 1.05, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 7.48
(dd, 1H, J = 7.6, 1.7 Hz, Ar), 7.29 (ddd, 1H, J = 8.3, 7.5, 1.7 Hz, Ar),
6.92 (ddd, 1H, J = 7.5, 7.5, 0.9 Hz, Ar), 6.85 (dd, 1H, J = 8.3, <1 Hz,
Ar), 5.78 (s, 1H, ArCH), 4.59 (d, 1H, J = <1 Hz, H-1), 4.36 (dd, 1H,
J = 12.5, 1.5 Hz, H-6a), 4.05 (dd, 1H, J = 12.5, 1.8 Hz, H-6b), 3.98
(ddd, 1H, J = 2.7, 1.1, 1.1 Hz, H-4), 3.82 (s, 3H, OMe), 3.72 (dddd,
1H, J = 11.8, 3.2, 1.0, 1.0 Hz, H-2), 3.66–3.64 (m, 1H, H-5), 3.60
(dd, 1H, J = 2.9, 2.9 Hz, H-3), 3.58 (s, 3H, OMe), 3.46 (d, 1H,
J = 11.8 Hz, 2-OH), 3.43 (s, 3H, OMe). 13C NMR (CDCl3, 100 MHz):
dC 156.86 (Ar), 130.74 (Ar), 128.11 (Ar), 125.69 (Ar), 120.91 (Ar),
111.15 (Ar), 100.44 (C-1), 98.54 (ArCH), 78.93 (C-3), 73.45 (C-4),
70.06 (C-6), 66.96 (C-5), 66.91 (C-2), 58.45 (OMe), 57.19 (OMe),
55.83 (OMe). HRMS m/z calcd for C16H22O7 (M+Na)+: 349.1258;
found: 349.1255.
to afford the pure product 10 as
a white solid (344 mg,
0.669 mmol, 83% yield). Data for 23: Rf 0.52 (EtOAc:toluene
1:1). ½a 2D0
ꢃ
: +11.0° (c 1.02, CHCl3). 1H NMR (CDCl3, 400 MHz): dH
7.85–7.80 (m, 2H, Ar), 7.73–7.68 (m, 2H, Ar), 7.34–7.31 (m, 2H,
Ar), 7.26–7.23 (m, 2H, Ar), 4.72 (dd, 1H, J = 9.8, 7.7 Hz, H-2),
4.60 (s, 2H, CH3OCH2), 4.53 (dd, 1H, J = 9.8, 3.1 Hz, H-3), 4.40–
4.39 (m, 1H, H-4), 4.16 (d, 1H, J = 7.7 Hz, H-1), 3.77 (dd, 1H,
J = 10.5, 6.1 Hz, H-6a), 3.75 (dd, 1H, J = 10.5, 5.7 Hz, H-6b), 3.59
(ddd, 1H, J = 6.0, 5.7, <1 Hz, H-5), 3.33 (s, 3H, OMe), 3.06 (s, 3H,
OMe), 2.66 (d, 1H, J = 3.2 Hz, 4-OH), 2.43 (s, 3H, Ts), 2.40 (s, 3H,
Ts). 13C NMR (CDCl3, 100 MHz): dC 145.63 (Ar), 144.58 (Ar),
134.74 (Ar), 132.80 (Ar), 130.09 (Ar), 129.46 (Ar), 128.59 (Ar),
128.47 (Ar), 101.73 (C-1), 97.15 (CH3OCH2), 79.48 (C-3), 77.15
(C-2), 72.74 (C-5), 68.66 (C-4), 66.53 (C-6), 56.98 (OMe), 55.69
(OMe), 21.95 (Ts), 21.81 (Ts). HRMS m/z calcd for C23H30O11S2
(M+Na)+: 569.1122; found: 569.1097. Data for 24: Rf 0.56
4.16. Methyl 4,6-O-(m-methoxybenzylidene)-3-O-methyl-b-D-
idopyranoside (27)
A solution of KOBu-t in MeOH (2.39 M, 0.70 mL, 1.67 mmol)
was added to a solution of the di-tosylate starting material (6,
210 mg, 0.339 mmol) in 1,4-dioxane (3.3 mL), and the procedure
in Section 4.15 was followed to obtain the pure product 27 as a
white solid (86 mg, 0.26 mmol, 78% yield). Rf 0.38 (EtOAc:toluene
1:1). ½a 2D0
ꢃ
: ꢀ51.3° (c 1.00, CHCl3). 1H NMR (CDCl3, 400 MHz): dH
(EtOAc:toluene 1:1). ½a D20
ꢃ
: +0.6° (c 1.04, CHCl3). 1H NMR (CDCl3,
7.27–7.21 (m, 1H, Ar), 7.05–7.03 (m, 1H, Ar), 7.01–6.98 (m, 1H,
Ar), 6.86 (ddd, 1H, J = 8.2, 2.6, 0.8 Hz, Ar), 5.47 (s, 1H, ArCH), 4.59
(d, 1H, J = <1 Hz, H-1), 4.39 (dd, 1H, J = 12.5, 1.3 Hz, H-6a), 4.07
(dd, 1H, J = 12.5, 1.8 Hz, H-6b), 4.00 (ddd, 1H, J = 2.7, <1, <1 Hz,
H-4), 3.78 (s, 3H, OMe), 3.74 (dddd, 1H, J = 11.8, 3.1, <1, <1 Hz, H-
400 MHz): dH 7.86–7.82 (m, 2H, Ar), 7.73–7.69 (m, 2H, Ar),
7.34–7.31 (m, 2H, Ar), 7.27–7.25 (m, 2H, Ar), 4.87 (d, 1H,
J = 6.7 Hz, CH3OCHaHb), 4.71 (d, 1H, J = 6.6 Hz, CH3OCHaHb),
4.69 (dd, 1H, J = 10.1, 7.6 Hz, H-2), 4.60 (s, 2H, CH3OCH2), 4.49

R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
45
2), 3.69–3.68 (m, 1H, H-5), 3.66 (dd, 1H, J = 2.9, 2.9 Hz, H-3), 3.58 (s,
3H, OMe), 3.46 (s, 3H, OMe), 3.14 (d, 1H, J = 11.8 Hz, 2-OH). 13C
NMR (CDCl3, 100 MHz): dC 159.80 (Ar), 138.89 (Ar), 129.60 (Ar),
118.66 (Ar), 115.53 (Ar), 111.30 (Ar), 101.63 (ArCH), 100.47 (C-1),
78.83 (C-3), 73.50 (C-4), 69.91 (C-6), 66.92 (C-5), 66.84 (C-2),
58.58 (OMe), 57.28 (OMe), 55.54 (OMe). HRMS m/z calcd for
100.37 (C-1), 99.60 (CHCH3), 78.68 (C-3), 72.82 (C-4), 69.26 (C-6),
66.84 (C-2), 66.68 (C-5), 58.44 (OMe), 57.16 (OMe), 21.16 (CHCH3).
HRMS m/z calcd for
C
10H18O6 (M+NH4)+: 252.1442; found:
252.1441.
4.20. Methyl 3-O-methyl-4,6-O-methylidene-b-D-idopyranoside
(31) and methyl 2-O-acetyl-3-O-methyl-4,6-O-methylidene-b-D-
C
16H22O7 (M+NH4)+: 344.1704; found: 344.1702.
idopyranoside (32)
4.17. Methyl 4,6-O-(p-methoxybenzylidene)-3-O-methyl-b-D-
idopyranoside (28)
A solution of KOBu-t in MeOH (2.63 M, 0.70 mL, 1.8 mmol) was
added to a solution of the di-tosylate starting material (10, 185 mg,
0.360 mmol) in 1,4-dioxane (2.7 mL). After 3 days the reaction
mixture was concentrated, and then redissolved into dry pyridine
(1.50 mL) and acetic anhydride (Ac2O; 1.50 mL) and left heating
at 65 °C. After 2 h the reaction mixture was evaporated to dry via
co-evaporation with toluene (2 ꢄ 3 mL), then redissolved into
EtOAc (30 mL), washed with saturated NaCl(aq) solution
(2 ꢄ 30 mL), dried with Na2SO4, filtered, and evaporated to dry.
The crude mixture was purified by column chromatography on sil-
ica gel using 20?30% acetone–hexanes to afford the pure product
32 as a white solid (79 mg, 0.30 mmol, 84% yield). Rf 0.58 (ace-
tone:hexanes 1:1). 1H NMR (CDCl3, 400 MHz): dH 5.06 (d, 1H,
J = 6.2 Hz, CHaHb), 4.88 (ddd, 1H, J = 2.9, 1.5, <1 Hz, H-2), 4.67 (d,
1H, J = 6.2 Hz, CHaHb), 4.65 (d, 1H, J = 1.5 Hz, H-1), 4.23–4.20 (m,
1H, H-6a), 3.83 (dd, 1H, J = 12.4, 2.1 Hz, H-6b), 3.65–3.64 (m, 1H,
H-4), 3.61–3.60 (m, 1H, H-5), 3.58 (dd, 1H, J = 2.8, 2.8 Hz, H-3),
3.51 (s, 3H, OMe), 3.48 (s, 3H, OMe), 2.11 (s, 3H, Ac). 13C NMR
(CDCl3, 100 MHz): dC 171.25 (Ac), 98.68 (C-1), 93.38 (CH2), 76.95
(C-3), 71.92 (C-4), 69.03 (C-6), 67.65 (C-5), 66.73 (C-2), 58.80
(OMe), 56.94 (OMe), 21.39 (Ac). HRMS m/z calcd for C11H18O7
(M+Na)+: 285.0945; found: 285.0944. An initial attempt at isolat-
ing the ido-pyranoside product prior to acetylation afforded 31 as
a white solid but in a significantly lower yield (ꢂ30%). Rf 0.41 (ace-
A solution of KOBu-t in MeOH (2.59 M, 0.65 mL, 1.69 mmol)
was added to a solution of the di-tosylate starting material (7,
210 mg, 0.338 mmol) in 1,4-dioxane (2.3 mL), and the procedure
in Section 4.15 was followed to obtain the pure product 28 as a yel-
low syrup (88 mg, 0.27 mmol, 79% yield). Rf 0.40 (EtOAc:toluene
1:1). ½a 2D0
ꢃ
: ꢀ49.6° (c 0.98, CHCl3). 1H NMR (CDCl3, 400 MHz): dH
7.41–7.35 (m, 2H, Ar), 6.87–6.82 (m, 2H, Ar), 5.45 (s, 1H, ArCH),
4.58 (d, 1H, J = 1.0 Hz, H-1), 4.36 (dd, 1H, J = 12.5, 1.5 Hz, H-6a),
4.05 (dd, 1H, J = 12.5, 1.9 Hz, H-6b), 3.98 (ddd, 1H, J = 2.8, 1.2,
1.2 Hz, H-4), 3.78 (s, 3H, OMe), 3.73 (dddd, 1H, J = 11.7, 3.1, 1.1,
1.1 Hz, H-2), 3.67–3.66 (m, 1H, H-5), 3.64 (dd, 1H, J = 2.9, 2.9 Hz,
H-3), 3.58 (s, 3H, OMe), 3.45 (s, 3H, OMe), 3.16 (d, 1H,
J = 11.7 Hz, 2-OH). 13C NMR (CDCl3, 100 MHz): dC 160.44 (Ar),
130.05 (Ar), 127.63 (Ar), 113.85 (Ar), 101.73 (ArCH), 100.48 (C-1),
78.86 (C-3), 73.44 (C-4), 69.86 (C-6), 66.89 (C-5), 66.87 (C-2),
58.55 (OMe), 57.26 (OMe), 55.51 (OMe). HRMS m/z calcd for
C
16H22O7 (M+H)+: 327.1438; found: 327.1432.
4.18. Methyl 3-O-methyl-4,6-O-(p-nitrobenzylidene)-b-D-
idopyranoside (29)
A solution of KOBu-t in MeOH (2.02 M, 0.90 mL, 1.82 mmol) was
added to a solution of the di-tosylate starting material (8, 234 mg,
0.368 mmol) in 1,4-dioxane (3.7 mL), and the procedure in Sec-
tion 4.15 was followed to obtain the pure product 29 as a yellow
solid (92 mg, 0.27 mmol, 73% yield). Rf 0.36 (EtOAc:toluene 1:1).
tone:hexanes 1:1). ½a D20
ꢃ
: ꢀ80.8° (c 1.05, CHCl3). 1H NMR (CDCl3,
400 MHz): dH 5.08 (d, 1H, J = 6.3 Hz, CHaHb), 4.66 (d, 1H,
J = 6.3 Hz, CHaHb), 4.55 (d, 1H, J = <1 Hz, H-1), 4.21–4.17 (m, 1H,
H-6a), 3.81 (dd, 1H, J = 12.5, 1.8 Hz, H-6b), 3.73–3.69 (m, 2H, H-4
and H-2), 3.62–3.60 (m, 1H, H-5), 3.57–3.55 (m, 4H, H-3 and
OMe), 3.42 (s, 3H, OMe), 3.09 (d, 1H, J = 11.2 Hz, 2-OH). 13C NMR
(CDCl3, 100 MHz): dC 100.38 (C-1), 93.75 (CH2), 78.66 (C-3), 72.78
(C-4), 69.28 (C-6), 67.62 (C-5), 66.86 (C-2), 58.52 (OMe), 57.08
(OMe). HRMS m/z calcd for C9H16O6 (M+Na)+: 243.0839; found:
243.0836.
½
a 2D0
ꢃ
: ꢀ45.8° (c 1.03, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 8.22–
8.17 (m, 2H, Ar), 7.68–7.63 (m, 2H, Ar), 5.58 (s, 1H, ArCH), 4.60
(d, 1H, J = 1.1 Hz, H-1), 4.42 (dd, 1H, J = 12.5, 1.4 Hz, H-6a), 4.11
(dd, 1H, J = 12.5, 1.9 Hz, H-6b), 4.03 (ddd, 1H, J = 2.8, 1.2, 1.2 Hz,
H-4), 3.75 (dddd, 1H, J = 11.4, 3.1, 1.1, 1.1 Hz, H-2), 3.73–3.71 (m,
1H, H-5), 3.68 (dd, 1H, J = 2.9, 2.9 Hz, H-3), 3.58 (s, 3H, OMe),
3.48 (s, 3H, OMe), 2.90 (d, 1H, J = 11.4 Hz, 2-OH). 13C NMR (CDCl3,
100 MHz): dC 148.54 (Ar), 143.81 (Ar), 127.39 (Ar), 123.66 (Ar),
100.45 (C-1), 99.85 (ArCH), 78.76 (C-3), 73.56 (C-4), 69.92 (C-6),
66.76 (C-2 and C-5), 58.64 (OMe), 57.28 (OMe). HRMS m/z calcd
for C15H19NO8 (M+NH4)+: 359.1449; found: 359.1446.
4.21. General procedure for studying the di-inversion reaction
rate
A solution of KOBu-t in MeOH (2.3 M, 1.0 mmol) was added to a
solution of the di-tosylate starting material (2, 7, or 8, 0.20 mmol)
in 1,4-dioxane (2.0 mL). The reaction progress was monitored over
time by removing an aliquot, which was extracted with EtOAc
(1 mL) in water (1 mL), evaporated to dry, and analyzed by 1H
NMR to quantify the reaction progression.
4.19. Methyl 4,6-O-ethylidene-3-O-methyl-b-D-idopyranoside
(30)
A solution of KOBu-t in MeOH (2.0 M, 4.5 mL, 8.9 mmol) was
added to solution of the di-tosylate starting material (9,
a
947 mg, 1.79 mmol) in 1,4-dioxane (15 mL), and the procedure in
Section 4.15 was followed to obtain the crude product, which
was subsequently purified by column chromatography on silica
gel using 20?25% acetone–hexanes to afford the pure product
30 as a white solid (331 mg, 1.41 mmol, 79% yield). Rf 0.19
4.22. Methyl 4-O-benzyl-b-D-galactopyranoside (34)
A NaOMe solution was added dropwise (1.5 M NaOMe/MeOH,
to pH 10) to a solution of the starting material (33, 246 mg,
0.668 mmol) in dry MeOH (3.0 mL) and left mixing at room tem-
perature for 2 h. The reaction was then neutralized to pH 6 using
ion exchange resin (Amberlite IR-120H), filtered, and evaporated
to dry to obtain the product 34 as a white solid (190 mg,
(EtOAc:toluene 1:1). ½a D20
ꢃ
: ꢀ104° (c 1.03, CHCl3). 1H NMR (CDCl3,
600 MHz): dH 4.66 (q, 1H, J = 5.1 Hz, CHCH3), 4.52 (d, 1H,
J = <1 Hz, H-1), 4.17 (dd, 1H, J = 12.5, 1.4 Hz, H-6a), 3.83 (dd, 1H,
J = 12.6, 1.9 Hz, H-6b), 3.75 (ddd, 1H, J = 2.8, 1.1, <1 Hz, H-4), 3.68
(dddd, 1H, J = 11.7, 3.1, 1.1, <1 Hz, H-2), 3.56–3.52 (m, 5H, H-5,
OMe, and H-3), 3.41 (s, 3H, OMe), 3.16 (d, 1H, J = 11.7 Hz, 2-OH),
1.32 (d, 3H, J = 5.1 Hz, CHCH3). 13C NMR (CDCl3, 150 MHz): dC
0.667 mmol, quantitative yield). Rf 0.54 (MeOH:CH2Cl2 1:9). ½a D20
ꢃ
:
ꢀ29.1° (c 1.03, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 7.37–7.26
(m, 5H, Ar), 4.78 (d, 1H, J = 11.7 Hz, PhCHaHb), 4.71 (d, 1H,
J = 11.7 Hz, PhCHaHb), 4.14 (d, 1H, J = 7.3 Hz, H-1), 3.83 (m, 1H,

46
R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
H-6a), 3.78 (dd, 1H, J = 3.1, 1.1 Hz, H-4), 3.71–3.57 (m, 3H, H-2, H-3,
and H-6b), 3.53 (s, 3H, OMe), 3.51 (ddd, 1H, J = 6.9, 5.4, 1.1 Hz, H-
5), 2.61 (broad, 1H, 2-OH), 2.46 (d, 1H, J = 5.7 Hz, 3-OH), 1.68
(broad, 6-OH). 13C NMR (CDCl3, 100 MHz): dC 138.14 (Ar), 128.83
(Ar), 128.60 (Ar), 128.37 (Ar), 104.26 (C-1), 75.57 (C-4), 75.38 (C-
5), 75.28 (PhCH2), 74.56 (C-3), 72.70 (C-2), 62.16 (C-6), 57.36
(OMe). HRMS m/z calcd for C14H20O6 (M+Na)+: 307.1152; found:
307.1154.
4.25. Methyl 4,6-di-O-acetyl-2,3-anhydro-b-
(39), methyl 4,6-di-O-acetyl-2,3-di-O-tosyl-b-
galactopyranoside (41), and methyl 2,4,6-tri-O-acetyl-3-O-
methyl-b- -idopyranoside (43)
D-talopyranoside
D
-
D
A solution of KOBu-t in MeOH (2.3 M, 1.00 mL, 2.3 mmol) was
added to a solution of the di-tosylate starting material (21,
225 mg, 0.447 mmol) in 1,4-dioxane (4.0 mL). After 4 days the reac-
tion mixture was diluted with Ac2O (3.0 mL) and dry pyridine
(3.0 mL) and then left heating at 65 °C. After 2 h the reaction mix-
ture was evaporated to dry via co-evaporation with toluene
(3 ꢄ 5 mL), redissolved into EtOAc (50 mL), washed with saturated
NaCl(aq) solution (2 ꢄ 50 mL), and then the combined aqueous
phases extracted with EtOAc (2 ꢄ 50 mL). The combined organic
layers were then dried with Na2SO4, filtered, and evaporated to
dry. The crude mixture was purified by column chromatography
on silica gel using 10?15?20% EtOAc–toluene to afford acetylated
starting material 41 as a white solid (101 mg, 0.171 mmol, 38%
yield), the idopyranoside product 43 as a colorless syrup (9 mg,
0.03 mmol, 6% yield), and then the acetylated talopyranoside inter-
mediate 39 as a white solid (48 mg, 0.18 mmol, 41% yield). Data for
4.23. Methyl 3,6-anhydro-4-O-benzyl-2-O-tosyl-b-D-
galactopyranoside (37)
The starting material (34, 133 mg, 0.467 mmol) and TsCl
(539 mg, 2.83 mmol) were dissolved into dry pyridine (1.50 mL)
and the procedure in Section 4.7 was followed to obtain the crude
product, which was subsequently purified by column chromatog-
raphy on silica gel using 10% acetone–hexanes to afford the desired
product 37 as a white solid (160 mg, 0.381 mmol, 82% yield). Rf
0.73 (EtOAc:toluene 1:1). ½a D20
ꢃ
: ꢀ38.7° (c 1.02, CHCl3). 1H NMR
(CDCl3, 400 MHz): dH 7.78–7.73 (m, 2H, Ar), 7.36–7.26 (m, 7H,
Ar), 4.56 (d, 1H, J = 11.8 Hz, PhCHaHb), 4.54 (dd, 1H, J = 4.9,
<1 Hz, H-2), 4.48 (d, 1H, J = 11.8 Hz, PhCHaHb), 4.42 (d, 1H,
J = <1 Hz, H-1), 4.27–4.24 (m, 1H, H-5), 4.22 (dd, 1H, J = 4.9,
<1 Hz, H-3), 4.10 (dd, 1H, J = 9.5, <1 Hz, H-6a), 4.10 (dd, 1H,
J = 1.7, <1 Hz, H-4), 3.90 (dd, 1H, J = 9.5, 3.1 Hz, H-6b), 3.26 (s, 3H,
OMe), 2.44 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC 145.73 (Ar),
137.66 (Ar), 133.09 (Ar), 130.33 (Ar), 128.76 (Ar), 128.25 (Ar),
128.23 (Ar), 128.00 (Ar), 100.49 (C-1), 79.22 (C-2), 77.77 (C-4),
76.51 (C-3), 75.99 (C-5), 71.48 (PhCH2), 71.21 (C-6), 56.24 (OMe),
21.89 (Ts). HRMS m/z calcd for C21H24O7S (M+NH4)+: 438.1581;
found: 438.1582.
41: Rf 0.65 (EtOAc:toluene 1:1). ½a D20
ꢃ
: +2.4° (c 1.00, CHCl3). 1H NMR
(CDCl3, 400 MHz): dH 7.80–7.72 (m, 4H, Ar), 7.32–7.27 (m, 4H, Ar),
5.55 (dd, 1H, J = 2.9, 0.9 Hz, H-4), 4.70–4.62 (m, 2H, H-2 and H-3),
4.21 (d, 1H, J = 7.5 Hz, H-1), 4.06 (dd, 1H, J = 11.5, 6.6 Hz, H-6a),
4.03 (dd, 1H, J = 11.5, 6.4 Hz, H-6b), 3.77 (ddd, 1H, J = 6.5, 6.5,
0.9 Hz, H-5), 3.11 (s, 3H, Me), 2.43 (s, 3H, Ts), 2.42 (s, 3H, Ts), 2.09
(s, 3H, Ac), 2.02 (s, 3H, Ac). 13C NMR (CDCl3, 100 MHz): dC 170.55
(Ac), 169.48 (Ac), 145.59 (Ar), 144.73 (Ar), 134.69 (Ar), 132.79
(Ar), 130.04 (Ar), 129.54 (Ar), 128.66 (Ar), 128.49 (Ar), 101.84 (C-
1), 76.84 (C-2), 75.85 (C-3), 71.02 (C-5), 68.37 (C-4), 61.57 (C-6),
57.33 (Me), 21.96 (Ts), 21.85 (Ts), 20.86 (Ac), 20.74 (Ac). HRMS m/
z calcd for C25H30O12S2 (M+Na)+: 609.1071; found: 609.1047. Data
for 43: Rf 0.55 (EtOAc:toluene 1:1). ½a D20
ꢃ : ꢀ48.2° (c 1.02, CHCl3).
4.24. Methyl 6-O-methyl-2,3-di-O-tosyl-b-D-galactopyranoside
(38)
1H NMR (CDCl3, 400 MHz): dH 4.94 (ddd, 1H, J = 3.3, 1.7, <1 Hz, H-
2), 4.79 (ddd, 1H, J = 3.0, 2.0, <1 Hz, H-4), 4.69 (d, 1H, J = 1.7 Hz,
H-1), 4.25 (dd, 1H, J = 11.2, 7.2 Hz, H-6a), 4.21 (dd, 1H, J = 11.2,
5.8 Hz, H-6b), 4.15 (ddd, 1H, J = 7.1, 5.9, 1.9 Hz, H-5), 3.60 (dd, 1H,
J = 3.3, 3.3 Hz, H-3), 3.52 (s, 3H, OMe), 3.49 (s, 3H, OMe), 2.09 (s,
3H, Ac), 2.06 (s, 3H, Ac), 2.04 (s, 3H, Ac). 13C NMR (CDCl3,
100 MHz): dC 170.76 (Ac), 170.38 (Ac), 170.31 (Ac), 98.92 (C-1),
75.71 (C-3), 70.89 (C-5), 67.35 (C-2), 66.52 (C-4), 62.56 (C-6),
59.06 (OMe), 57.35 (OMe), 21.17 (Ac), 21.00 (Ac), 20.94 (Ac). HRMS
m/z calcd for C14H22O9 (M+Na)+: 357.1156; found: 357.1151. Data
A solution of the starting material (21, 406 mg, 0.807 mmol)
and 2,6-di-tert-butylpyridine (0.53 mL, 2.5 mmol) in dry CH2Cl2
(5.0 mL) was cooled to 0 °C under argon, then methyl triflate
(0.24 mL, 2.2 mmol) was added dropwise and the mixture warmed
back up to room temperature. After 8 h, the flask was cooled back
to 0 °C and second aliquots of 2,6-di-tert-butylpyridine (0.53 mL,
2.5 mmol) and methyl triflate (0.24 mL, 2.2 mmol) were added
and the reaction mixture warmed back to room temperature. After
another 12 h, the reaction was quenched with water (50 mL) and
the product extracted with CH2Cl2 (3 ꢄ 50 mL). The combined or-
ganic phases were washed with saturated NaHCO3(aq) solution
(50 mL), saturated NaCl(aq) solution (50 mL), dried with Na2SO4, fil-
tered, and evaporated to dry. The crude mixture was purified by
column chromatography on silica gel using 20% acetone–hexanes
for 39: Rf 0.51 (EtOAc:toluene 1:1). ½a D20
ꢃ : ꢀ79.0° (c 0.96, CHCl3).
1H NMR (CDCl3, 400 MHz): dH 4.98 (dd, 1H, J = 4.3, 3.9 Hz, H-4),
4.77 (d, 1H, J = <1, H-1), 4.27 (dd, 1H, J = 11.6, 7.2 Hz, H-6a), 4.21
(dd, 1H, J = 11.6, 5.6 Hz, H-6b), 3.80 (ddd, 1H, J = 7.2, 5.6, 3.8 Hz,
H-5), 3.64 (dd, 1H, J = 4.3, 4.0 Hz, H-3), 3.56 (s, 3H, OMe), 3.28
(dd, 1H, J = 3.9, <1 Hz, H-2), 2.14 (s, 3H, Ac), 2.04 (s, 3H, Ac). 13C
NMR (CDCl3, 100 MHz): dC 170.83 (Ac), 170.80 (Ac), 98.72 (C-1),
72.70 (C-5), 64.62 (C-4), 62.22 (C-6), 57.01 (OMe), 51.41 (C-2),
51.24 (C-3), 20.96 (Ac), 20.87 (Ac). HRMS m/z calcd for C11H16O7
(M+Na)+: 283.0788; found: 283.0782.
to afford the pure product 38 as
a white solid (399 mg,
0.772 mmol, 96% yield). Rf 0.47 (acetone:hexanes 1:1). ½a D20
ꢃ
: +6.3°
(c 1.02, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 7.84–7.79 (m, 2H,
Ar), 7.71–7.68 (m, 2H, Ar), 7.34–7.30 (m, 2H, Ar), 7.27–7.22 (m,
2H, Ar), 4.72 (dd, 1H, J = 9.7, 7.7 Hz, H-2), 4.51 (dd, 1H, J = 9.7,
3.1 Hz, H-3), 4.38–4.36 (m, 1H, H-4), 4.15 (d, 1H, J = 7.7 Hz, H-1),
3.65 (dd, 1H, J = 10.0, 5.2 Hz, H-6a), 3.60 (dd, 1H, J = 10.0, 5.3 Hz,
H-6b), 3.56–3.53 (m, 1H, H-5), 3.35 (s, 3H, OMe), 3.06 (s, 3H,
OMe), 2.83 (d, 1H, J = 3.6 Hz, 4-OH), 2.42 (s, 3H, Ts), 2.39 (s, 3H,
Ts). 13C NMR (CDCl3, 100 MHz): dC 145.56 (Ar), 144.54 (Ar),
134.75 (Ar), 132.80 (Ar), 130.06 (Ar), 129.44 (Ar), 128.58 (Ar),
128.45 (Ar), 101.73 (C-1), 79.42 (C-3), 77.17 (C-2), 72.74 (C-5),
71.66 (C-6), 68.98 (C-4), 59.72 (OMe), 57.03 (OMe), 21.93 (Ts),
21.80 (Ts). HRMS m/z calcd for C22H28O10S2 (M+Na)+: 539.1016;
found: 539.1001.
4.26. Methyl 4-O-acetyl-2,3-anhydro-6-O-methyl-b-
talopyranoside (40), methyl 4-O-acetyl-6-O-methyl-2,3-di-O-
tosyl-b- -galactopyranoside (42), and methyl 2,4-di-O-acetyl-
3,6-di-O-methyl-b- -idopyranoside (44)
D-
D
D
A solution of KOBu-t in MeOH (2.3 M, 0.60 mL, 1.4 mmol) was
added to a solution of the di-tosylate starting material (38,
143 mg, 0.277 mmol) in 1,4-dioxane (2.1 mL). After 3 days the reac-
tion mixture was quenched with Ac2O (1 mL), concentrated, and
then redissolved into dry pyridine (1.50 mL) and additional Ac2O

R. Hevey et al. / Carbohydrate Research 376 (2013) 37–48
47
(1.00 mL) and left heating at 65 °C. After 2 h the reaction mixture
was evaporated to dry via co-evaporation with toluene
(3 ꢄ 3 mL), redissolved into EtOAc (30 mL), washed with saturated
NaCl(aq) solution (2 ꢄ 30 mL), and then the combined aqueous
phases extracted with EtOAc (2 ꢄ 30 mL). The combined organic
layers were then dried with Na2SO4, filtered, and evaporated to
dry. The crude mixture was purified by column chromatography
on silica gel using 20?25?30% acetone–hexanes to afford acety-
lated starting material 42 as a white solid (64 mg, 0.11 mmol, 41%
yield), the idopyranoside product 44 as a colorless syrup (10 mg,
0.033 mmol, 12% yield), and then the acetylated talopyranoside
intermediate 40 as a white solid (25 mg, 0.11 mmol, 38% yield).
Ts), 2.40 (s, 3H, Ts). 13C NMR (CDCl3, 100 MHz): dC 145.48 (Ar),
144.53 (Ar), 134.75 (Ar), 132.63 (Ar), 130.01 (Ar), 129.40 (Ar),
128.78 (Ar), 128.52 (Ar), 101.61 (C-1), 98.42 (CH3OCH2), 78.15
(C-3), 77.43 (C-2), 74.57 (C-4), 73.18 (C-5), 70.88 (C-6), 59.40
(OMe), 56.98 (OMe), 56.70 (OMe), 21.95 (Ts), 21.80 (Ts). HRMS
m/z calcd for C24H32O11S2 (M+NH4)+: 578.1724; found: 578.1725.
4.28. Methyl 2,3-anhydro-4-O-methoxymethyl-6-O-methyl-b-
talopyranoside (46) and methyl 4-O-methoxymethyl-3,6-di-O-
methyl-b- -idopyranoside (47)
D-
D
A solution of KOBu-t in MeOH (2.3 M, 0.40 mL, 0.92 mmol) was
added to a solution of the di-tosylate starting material (45, 102 mg,
0.183 mmol) in 1,4-dioxane (2.0 mL), and the procedure from Sec-
tion 4.15 was followed to obtain the crude mixture, which was
subsequently purified by column chromatography on silica gel
using 10% acetone–hexanes to afford the talopyranoside interme-
diate 46 as a white solid (25 mg, 0.11 mmol, 59% yield) and the ido-
pyranoside product 47 as a colorless syrup (14 mg, 0.053 mmol,
Data for 42: Rf 0.46 (EtOAc:toluene 1:1). ½a D20
ꢃ
: +5.4° (c 1.00, CHCl3).
1H NMR (CDCl3, 400 MHz): dH 7.81–7.71 (m, 4H, Ar), 7.34–7.25 (m,
4H, Ar), 5.54 (dd, 1H, J = 3.3, <1 Hz, H-4), 4.68 (dd, 1H, J = 9.9, 7.5 Hz,
H-2), 4.61 (dd, 1H, J = 9.9, 3.3 Hz, H-3), 4.19 (d, 1H, J = 7.5 Hz, H-1),
3.65 (ddd, 1H, J = 6.3, 5.0, <1 Hz, H-5), 3.40 (dd, 1H, J = 10.3, 5.0 Hz,
H-6a), 3.39 (dd, 1H, J = 10.3, 6.3 Hz, H-6b), 3.28 (s, 3H, OMe), 3.11 (s,
3H, OMe), 2.43 (s, 3H, Ts), 2.41 (s, 3H, Ts), 2.09 (s, 3H, Ac). 13C NMR
(CDCl3, 100 MHz): dC 169.65 (Ac), 145.52 (Ar), 144.67 (Ar), 134.71
(Ar), 132.83 (Ar), 130.02 (Ar), 129.51 (Ar), 128.62 (Ar), 128.49
(Ar), 101.87 (C-1), 77.08 (C-2), 76.14 (C-3), 72.80 (C-5), 71.06 (C-
6), 69.15 (C-4), 59.66 (OMe), 57.41 (OMe), 21.96 (Ts), 21.85 (Ts),
20.81 (Ac). HRMS m/z calcd for C24H30O11S2 (M+Na)+: 581.1122;
29% yield). Data for 46: Rf 0.43 (acetone:hexanes 2:3). ½a D20
ꢃ
:
ꢀ27.7° (c 0.92, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 4.85 (d, 1H,
J = 6.9 Hz, CH3OCHaHb), 4.74 (d, 1H, J = <1 Hz, H-1), 4.69 (d, 1H,
J = 6.9 Hz, CH3OCHaHb), 3.89 (dd, 1H, J = 4.3, 3.2 Hz, H-4), 3.65–
3.58 (m, 3H, H-5, H-6a, and H-6b), 3.54 (s, 3H, OMe), 3.51 (dd,
1H, J = 4.2, 4.2 Hz, H-3), 3.44 (s, 3H, OMe), 3.36 (s, 3H, OMe), 3.24
(dd, 1H, J = 4.0, <1 Hz, H-2). 13C NMR (CDCl3, 100 MHz): dC 98.89
(C-1), 96.30 (CH3OCH2), 75.73 (C-5), 70.98 (C-6), 67.42 (C-4),
59.50 (OMe), 56.66 (OMe), 56.12 (OMe), 52.32 (C-3), 51.34 (C-2).
found: 581.1115. Data for 44: Rf 0.33 (EtOAc:toluene 1:1). ½a D20
ꢃ
:
ꢀ45.0° (c 1.01, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 4.93–4.92
(m, 1H, H-2), 4.81–4.80 (m, 1H, H-4), 4.67 (d, 1H, J = 1.7 Hz, H-1),
4.08 (ddd, 1H, J = 6.1, 6.1, 2.0 Hz, H-5), 3.58 (dd, 1H, J = 3.3, 3.3 Hz,
H-3), 3.57 (dd, 1H, J = 10.1, 6.3 Hz, H-6a), 3.52 (dd, 1H, J = 10.1,
6.0 Hz, H-6b), 3.52 (s, 3H, Me), 3.48 (s, 3H, Me), 3.34 (s, 3H, Me),
2.09 (s, 3H, Ac), 2.05 (s, 3H, Ac). 13C NMR (CDCl3, 100 MHz): dC
170.40 (Ac), 170.34 (Ac), 98.89 (C-1), 75.79 (C-3), 72.18 (C-5),
71.32 (C-6), 67.51 (C-2), 66.78 (C-4), 59.51 (Me), 58.91 (Me),
57.33 (Me), 21.20 (Ac), 21.00 (Ac). HRMS m/z calcd for C13H22O8
(M+Na)+: 329.1207; found: 329.1198. Data for 40: Rf 0.24
HRMS m/z calcd for
252.1435. Data for 47: Rf 0.38 (acetone:hexanes 2:3).
C
10H18O6 (M+NH4)+: 252.1442; found:
½
a 2D0
:
ꢃ
ꢀ13.5° (c 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): dH 4.73 (d, 1H,
J = 6.8 Hz, CH3OCHaHb), 4.63 (d, 1H, J = 6.8 Hz, CH3OCHaHb), 4.56
(d, 1H, J = 1.3 Hz, H-1), 4.00 (ddd, 1H, J = 6.5, 6.5, 1.7 Hz, H-5),
3.73 (dddd, 1H, J = 10.5, 3.3, 1.3, 1.3 Hz, H-2), 3.69 (ddd, 1H,
J = 3.3, 1.5, 1.5 Hz, H-4), 3.65 (dd, 1H, J = 3.3, 3.3 Hz, H-3), 3.62
(dd, 1H, J = 9.8, 6.5 Hz, H-6a), 3.58 (dd, 1H, J = 9.8, 6.6 Hz, H-6b),
3.55 (s, 3H, OMe), 3.42 (s, 3H, OMe), 3.42 (s, 3H, OMe), 3.38 (s,
3H, OMe), 3.06 (d, 1H, J = 10.5 Hz, 2-OH). 13C NMR (CDCl3,
100 MHz): dC 100.64 (C-1), 96.96 (CH3OCH2), 77.81 (C-3), 73.07
(C-5), 71.82 (C-4), 71.31 (C-6), 68.25 (C-2), 59.39 (OMe), 58.49
(OMe), 57.11 (OMe), 56.53 (OMe). HRMS m/z calcd for C11H22O7
(M+Na)+: 289.1258; found: 289.1249.
(EtOAc:toluene 1:1). ½a D20
ꢃ
: ꢀ119.9° (c 1.03, CHCl3). 1H NMR (CDCl3,
400 MHz): dH 4.93 (dd, 1H, J = 4.7, 3.5 Hz, H-4), 4.75 (d, 1H,
J = <1 Hz, H-1), 3.69 (ddd, 1H, J = 6.3, 5.9, 3.5 Hz, H-5), 3.64 (dd,
1H, J = 4.7, 3.9 Hz, H-3), 3.56 (s, 3H, OMe), 3.55 (dd, 1H, J = 10.2,
6.4 Hz, H-6a), 3.51 (dd, 1H, J = 10.2, 5.8 Hz, H-6b), 3.33 (s, 3H,
OMe), 3.24 (dd, 1H, J = 3.9, <1 Hz, H-2), 2.13 (s, 3H, Ac). 13C NMR
(CDCl3, 100 MHz): dC 170.86 (Ac), 98.99 (C-1), 74.38 (C-5), 70.57
(C-6), 64.84 (C-4), 59.62 (OMe), 57.09 (OMe), 51.41 and 51.35 (C-
2 and C-3), 20.85 (Ac). HRMS m/z calcd for C10H16O6 (M+Na)+:
255.0839; found: 255.0841.
Acknowledgments
We thank the Natural Sciences and Engineering Research Coun-
cil of Canada, the Canadian Foundation for Innovation, and the
Government of Alberta for support of the current project.
4.27. Methyl 4-O-methoxymethyl-6-O-methyl-2,3-di-O-tosyl-b-
D
-galactopyranoside (45)
A solution of the starting material (38, 309 mg, 0.598 mmol)
Supplementary data
and CSA (to pH 3) in neat dimethoxymethane (10 mL) was left mix-
ing at reflux with a Soxhlet apparatus containing crushed molecu-
lar sieves (4 Å). After 7 days, the reaction mixture was neutralized
with Et3N (to pH 8), evaporated to dry, and then purified by col-
umn chromatography on silica gel using 15?20% acetone–hexanes
to afford both the desired product 45 as a white solid (121 mg,
0.216 mmol, 36% yield) and unreacted starting material (161 mg,
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.carres.2013.05.
001.
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ꢃ
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