Hydrogen-bond-mediated aglycone delivery (HAD): A highly stereoselective synthesis of 1,2-cis α- D -glucosides from common glycosyl donors in the presence of bromine

Article abstract of DOI:10.1002/chem.201406589

Described herein is the expansion of the picoloyl protecting-group assisted H-bond mediated aglycone delivery (HAD) method recently introduced by our laboratory. At first it was noticed that high α-stereoselectivity is only obtained with S-ethyl glycosyl donors and only in the presence of dimethyl(methylthio)sulfonium trifluoromethanesulfonate (DMTST), in high dilution, and low temperature. Combining the mechanistic studies of the HAD reaction and bromine-promoted glycosylations allowed a very effective method to be devised that allows for highly stereoselective α-glycosidation of practically all common leaving groups (S-phenyl, S-tolyl, S/O-imidates) at regular concentrations and ambient temperature.

Full text of DOI:10.1002/chem.201406589

DOI: 10.1002/chem.201406589
Full Paper
&
Carbohydrates
Hydrogen-Bond-Mediated Aglycone Delivery (HAD): A Highly
Stereoselective Synthesis of 1,2-cis a-d-Glucosides from Common
Glycosyl Donors in the Presence of Bromine
Jagodige P. Yasomanee and Alexei V. Demchenko*[a]
Abstract: Described herein is the expansion of the picoloyl
protecting-group assisted H-bond mediated aglycone deliv-
ery (HAD) method recently introduced by our laboratory. At
first it was noticed that high a-stereoselectivity is only ob-
tained with S-ethyl glycosyl donors and only in the presence
of dimethyl(methylthio)sulfonium trifluoromethanesulfonate
(DMTST), in high dilution, and low temperature. Combining
the mechanistic studies of the HAD reaction and bromine-
promoted glycosylations allowed a very effective method to
be devised that allows for highly stereoselective a-glycosida-
tion of practically all common leaving groups (S-phenyl, S-
tolyl, S/O-imidates) at regular concentrations and ambient
temperature.
Introduction
O-Glycosylation reactions form a new chirality center and un-
controlled reactions commonly provide mixtures of 1,2-cis and
1,2-trans diastereomers. Obtaining an O-glycosidic linkage with
complete stereoselectivity requires special care and the last
few decades have witnessed a number of new techniques that
have been developed to address this challenge in many differ-
ent ways.[1] Among a plethora of methods available, a very suc-
cessful technique involving the participatory assistance of the
neighboring acyl substituent has been developed for the syn-
thesis of 1,2-trans glycosides.[2] On the other hand, although
a number of dedicated methodologies are available for 1,2-cis
glycosylation, obtaining complete stereoselectivity in 1,2-cis
glycoside synthesis still remains a challenge.[3]
Scheme 1. a-Glycosylation by H-bond mediated aglycone delivery (HAD) as-
sisted by picolinyl/picoloyl substituents.
challenging a-glucosides,[5] b-rhamnosides,[5] and b-manno-
sides[6] with high or even complete selectivity. The HAD ap-
proach was also successfully extended to the synthesis of fura-
nosides by Yang[7] and glycosides of deoxysugars by Mong.[8]
We also have applied this technique to the synthesis of both
linear and branched a-glucans.[9] Although the synthesis of
these oligosaccharides was successful, we also encountered
some intrinsic problems with this method related to the weak-
ening of the H bonding with bulky or sterically hindered ac-
ceptors, as well as loss of reactivity/stereoselectivity in certain
cases.[9]
Our group has been studying picolinyl and picoloyl substitu-
ents both at the neighboring (C-2)[2c,4] and remote positions
(C-3, 4, and 6). Among other interesting findings, we intro-
duced the H-bond mediated aglycone delivery (HAD) con-
cept.[5] Over the course of that study we acquired compelling
evidence that the nucleophile, the hydroxyl of the glycosyl ac-
ceptor, forms the hydrogen bond with the picolinyl (or picolo-
yl) nitrogen and it is delivered at the anomeric center in the
syn-fashion with respect to the picolinyl (or picoloyl) group to
form the new glycosidic bond (Scheme 1).
The study detailed herein is dedicated to the refinement of
the synthesis of only one 1,2-cis-glycosidic linkage, a-d-gluco-
syl. Being among the most abundant linkages in Nature, the
synthesis of a-d-glucosides remains challenging to chemists.
Our preliminary results dedicated to the HAD-assisted synthesis
of this important linkage are summarized in Table 1. In particu-
lar, 4-O-picoloylated S-ethyl glycosyl donor 1a was found to be
very beneficial in this application.[5] In most cases, high stereo-
selectivity was obtained, but the reactions had to be per-
formed under very high dilution (5 mm of glycosyl acceptor,
ten times lower concentration than a typical glycosylation),
and at low temperature. These reaction conditions became
standard for HAD-mediated glycosylations. Dimethyl(methyl-
This new mode to control stereoselectivity of glycosylation
allowed the synthesis of both 1,2-trans and 1,2-cis glycosidic
linkages. The HAD method was also applied to the synthesis of
[a] Dr. J. P. Yasomanee, Prof. A. V. Demchenko
Department of Chemistry and Biochemistry
University of Missouri–St. Louis
One University Boulevard, St. Louis, MO 63121 (USA)
E-mail: demchenkoa@umsl.edu
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406589.
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thio)sulfonium trifluoromethanesulfonate (DMTST) was found
to be the promoter of choice because it does not interfere
with the N atom of the picoloyl group, like many other electro-
philic promoters do.[5] A variety of glycosyl acceptors, both pri-
mary 2 and secondary 4, 6, and 8,[10] gave very high or com-
plete 1,2-cis selectivity with 4-O-picoloyl donor 1a. As a result,
pure a-linked disaccharides 3, 5, 7, and 9 could be isolated in
high yields of 73–91% (Table 1).[5]
thioglycoside 1c (a/b=6.7:1, 90%, entry 2). This was rather un-
expected considering the structural similarity of S-ethyl versus
S-aryl glycosides and the activation modes thereof. As a ration-
ale for lower selectivity observed with S-aryl glycosides we pro-
pose the following. In case of S-aryl glycosides, the sulfur atom
is less nucleophilic than that of their S-ethyl counterparts.
Therefore, interaction of S-aryl glycosides with DMTST is slug-
gish and as a result, excess DMTST would begin interfering
with the picoloyl nitrogen making it unavailable to
perform effective HAD. A similar reduction of selectiv-
ity was previously observed even with S-ethyl glyco-
sides if a large excess of DMTST (6 equiv) was used.[5]
Having had no success with aryl thioglycosides, we
Table 1. A survey of previous results on the 4-O-picoloyl-assisted a-glycosylation.[5]
decided to study O/S-imidates, another popular class
of glycosyl donors.[12] When the S-benzoxazolyl (SBox)
glycosyl donor 1d was first activated with AgOTf, the
best promoter for SBox imidates,[13] a reverse selectiv-
Entry
Acceptor
t
Product
Yield [%]
ity was obtained with a slight shift towards the 1,2-
trans linked disaccharide 3 (a/b=1:1.9, 79%, entry 3).
A higher, yet far from satisfactory, a-selectivity was
obtained when SBox donor 1d was activated with
DMTST. In this case, disaccharide 3 was obtained in
80% yield (a/b=6.1:1, entry 4). A similar outcome
was achieved upon AgOTf-promoted activation of S-
thiazolinyl (STaz)[14] donor 1e (a/b=6.3:1, 86%,
entry 5).
[h]
(a/b ratio)
1
4
5
73 (>25:1)
2
3
Finally, we tested O-trichloroacetimidate (TCAI)
donor 1 f. Over the course of this study, we noticed
that only moderate selectivity and modest yield of 3
were obtained in the TMSOTf-promoted activation of
TCAI donor 1 f (a/b=5.9:1, 44%, entry 6). The out-
come of the glycosidation of TCAI donor 1 f could be
significantly enhanced by performing the activation
in the presence of TfOH instead. In this case, disac-
charide 3 was isolated in 92% yield and improved a-
selectivity (a/b=9.7:1, entry 7). This was the highest
stereoselectivity observed in this series of experi-
ments, but it also indicated that the S-ethyl used in
our original study remains the best leaving group for
the purpose of the HAD.
2
93 (>25:1)
4
6
5
7
3
4
16
24
81 (>25:1)
81 (21:1)
8
9
While the rationale of the reduced stereoselectivity
in case of S-aryl glycosides is related to the possible
interference of DMTST with the N atom of picoloyl
group, in case of O/S-imidates, the basis for the reduced selec-
tivity is arguably different. It is our assumption that the pres-
ence of the additional N-atom of the S/O-imidoyl leaving
group, and as a result additional H-bond acceptor site, might
be the reason for decreased stereoselectivity recorded with
glycosyl O/S-imidates. This effect is particularly strong in case
of the SBox leaving group, which is activated by the direct
pathway via the anomeric sulfur.[13a,15] This leaves the nitrogen
atom of the SBox leaving group available to form the undesira-
ble H bond with the glycosyl acceptor. In turn, this effect is
weakened in case of STaz and TCAI donors, which are activated
via the remote N atom.[14a,15,16] A lower selectivity in case of the
STaz donor in comparison to that of the TCAI donor could be
related to the interference of the promoter. Thus, complexa-
Results and Discussion
As an extension of this study we have decided to perform fur-
ther refinement of the synthesis of a-glucosyl linkage in appli-
cation to other classes of glycosyl donors, activators, systems,
etc. In an attempt of identifying better glycosyl donors for
HAD, we wanted to investigate the compatibility of popular
leaving groups. For instance, we attempted the coupling of 4-
O-picoloylated thiophenyl glycoside 1b with glycosyl acceptor
2[11] to obtain disaccharide 3 under the previously reported
standard glycosylation conditions.[5] To our surprise, only
a moderate a-stereoselectivity was obtained (a/b=5.3:1, 85%,
entry 1, Table 2). A very similar result in terms of the yield and
stereoselectivity was obtained in the glycosidation of p-tolyl
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glycosyl donor a-10, which,
upon reaction with bromine,
produced the b-bromide inter-
Table 2. Effect of the leaving group and promoters on the stereoselectivity.
mediate
predominantly.
As
a result, disaccharide 11 was ob-
tained in the good yield of 67%
and with the exclusive a-selec-
tivity (entry 2). The average yield,
which is due to the competing
isomerization of b- to a-bro-
mide, could be further improved
by using HgBr2 as the co-pro-
moter. In this case disaccharide
11 was isolated in an improved
yield of 86% (entry 3). However,
the stereoselectivity dropped no-
ticeably (a/b=8.0:1) because
mercury(II) salts can readily acti-
Entry
1
Donor
Conditions
Product
(yield [%], a/b ratio)
DMTST (2 equiv), 2.5 h
3 (85, 5.3:1)
3 (90, 6.7:1)
3 (79, 1:1.9)
1b
1c
2
3
DMTST (2 equiv), 3 h
AgOTf (2 equiv), 2 h
vate
a-bromides
(Helferich
conditions).[19]
1d
1d
Other, more reactive, thiogly-
cosides such as the standard
armed thioglycoside donor 12,[20]
failed to produce high levels of
stereoselectivity. This is because
per-O-benzylated a-bromide is
sufficiently reactive in the pres-
ence of bromine and able to
produce glycosides directly. This
reaction proceeds via the oxacar-
4
5
DMTST (2 equiv), 6 h
AgOTf (2 equiv), 6 h
3 (80, 6.1:1)
3 (86, 6.3:1)
1e
6
7
TMSOTf (0.5 equiv), 3 h
TfOH (0.5 equiv), 2 h
3 (44, 5.9:1)
3 (92, 9.7:1)
1 f
1 f
tion of AgI used for the activation of STaz with picoloyl nitro-
gen makes it less effective in conducting HAD. This negative
result could not be improved with DMTST because the STaz
imidate activation with this promoter is very sluggish.[14b]
Having concluded that the S-ethyl is the best leaving group
for HAD reactions, it came to our attention that another ap-
proach for a-glucosylation recently introduced by our labora-
tory was also based on the S-ethyl leaving group.[17] Over the
course of that study we demonstrated that bromine-mediated
glycosidation of S-ethyl donor equipped with the superdisarm-
ing protecting group pattern (3,4,6-tri-O-benzoyl-2-O-benzyl)[18]
proceed via the highly reactive 1,2-trans bromide intermediate
(Scheme 2). We also demonstrated that the 1,2-trans glycosyl
bromide is the only intermediate leading to products while
1,2-cis bromide remains unreactive and the oxacarbenium in-
termediate does not form. Consequently, the nucleophilic dis-
placement of b-bromide takes place in the concerted bimolec-
ular fashion leading to exclusive a-stereoselectivity.[17]
Scheme 2. Bromine-promoted synthesis of a-glycosides.[17]
benium intermediate and hence provides lower stereoselectiv-
ity. Thus, coupling of glycosyl donor 12 with acceptor 2 in the
presence of Br2 produced disaccharide 13 in 68% yield and
poor selectivity (a/b=2.4:1, entry 4). In this context, the glyco-
sidation of the 4-O-benzoylated donor 14 with acceptor 2 was
even less selective and disaccharide 15 was produced in 75%
yield and a/b=1:1.8 (entry 5).
For instance, 3,4,6-tri-O-benzoyl-2-O-benzyl thioglycoside (b-
10) was coupled with acceptor 2 in the presence of bromine
to afford disaccharide 11 with exclusive 1,2-cis selectivity
(entry 1, Table 3). The low yield of 28% was due to the fact
that b-10 predominantly forms a-bromide (~68%), which does
not react under these reaction conditions. We were able to en-
hance the utility of this reaction by synthesizing and applying
The series of results presented in Table 3 clearly demonstrate
that bromine-mediated activation of thioglycosides offers
a promising method for the synthesis of a-glucosides. Howev-
er, notable limitations including modest yields and high sub-
strate specificity (only works for superdisarmed a-thioglycoside
which is harder to synthesize than its more conventional b-
counterpart)[17,21] narrow the application of this highly stereo-
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selectivity in HAD reactions im-
plies that this additive can be
used to further enhance the
yield if so desired.
Table 3. Bromine-mediated activation of S-ethyl donors.[17]
Encouraged by these intrigu-
ing findings, we decided to rein-
vestigate other glycosyl donors
1b–f, which previously gave low
stereoselectivity in HAD reac-
tions (vide supra). To our delight,
both thioglycoside (1b and 1c)
and thioimidate (1d and 1e)
donors produced disaccharide 3
in high yields of 72–87% and
complete 1,2-cis selectivity in
each case, with or without HgBr2
(entries 4–9, Table 4). The highly
Entry
1
Donor
Conditions
Br2, 16 h
Product
Yield [%] (a/b ratio)
28 (a only)
b-10
11
11
2
3
4
Br2, 16 h
67 (a only)
86 (8.0:1)
68 (2.4:1)
reactive
trichloroacetimidate
a-10
a-10
Br2/HgBr2, 5 h
Br2, 0.25 h
11
13
15
donor 1 f also gave high a-selec-
tivity upon activation with Br2
(a/b=18:1, entry 10). The high
or even complete a-selectivity
obtained from all 4-O-picoloylat-
ed glycosyl donors 1a–f indi-
cates that, unlike previously
tested promoter systems, bro-
12
14
5
Br2, 16 h
75 (1:1.8)
mine-promoted
glycosylations
are less sensitive to the nature
of the leaving and protecting
groups. These results also indi-
Table 4. Br2-mediated activation of various glycosyl donors 1a–i leads to
good yields and complete a-selectivity.
selective method. Having also encountered some limitations of
the HAD approach, we wondered whether combining these
two promising techniques would allow us to develop a more
flexible methodology for a-glycosylation. With this general
idea in mind, a test glycosylation reaction of 4-picoloylated thi-
oglycoside donor 1a with glycosyl acceptor 2 in the presence
of Br2 was set up. To our delight, disaccharide 3 was produced
in 77% yield and complete a-selectivity (entry 1, Table 4). The
use of HgBr2 as an additive further enhanced the yield to 83%
and, remarkably, the stereoselectivity still remained complete
(entry 2).
It should be noted that these initial experiments were per-
formed in normal concentration (50 mm of 3), with which typi-
cal HAD reactions give only average stereoselectivity. For com-
parison, DMTST-promoted activation of 1a gave disaccharide 3
with a/b=2.8:1 selectivity (entry 3).[5] The lower stereoselectiv-
ity in HAD-mediated glycosylations in regular concentration
was rationalized by a competition between the H-bonded ac-
ceptor and the free acceptor in solution.[5] This issue was previ-
ously addressed by using high dilution conditions (5 mm of ac-
ceptor), which became mandatory for most reactions using
HAD.[6,9] The result of the bromine-promoted activation indi-
cates that HAD reactions can now be successfully conducted
in normal concentrations. Furthermore, the fact that the reac-
tion in the presence of HgBr2 still maintained complete stereo-
Entry
Donor
Conditions
Product
(yield [%], a/b ratio)
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1b
1c
1c
1d
1e
1 f
1g
1h
1i
Br2, 4.5 h
3 (77, a only)
3 (83, a only)
3 (85, 2.8:1)
Br2/HgBr2, 2 h
DMTST, 4 h
Br2, 5.5 h
Br2/HgBr2, 3 h
Br2, 16 h
Br2/HgBr2, 16 h
Br2, 16 h
Br2, 16 h
Br2, 0.5 h
Br2, 6 h
Br2, 10 h
Br2, 24 h
3 (72, a only)
3 (79, a only)
3 (70, a only)
3 (86, a only)
3 (71, a only)
3 (87, a only)
3 (89, 18.0:1)
16 (79, a only)
17 (81, a only)
18 (73, a only)
9
10
11
12
13
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cate that bromine may serve as an effective and inexpensive
promoter for a variety of glycosylation reactions. It should be
noted that some of the leaving groups tested here have never
been previously activated with bromine. To make this protocol
even more appealing and versatile, we investigated a series of
partially benzoylated glycosyl donors 1g–i. Although these re-
actions were a bit slower than the glycosidation of 2,3,6-tri-O-
benzylated donor 1a (entries 11–13 vs. 1, Table 4) disaccharides
16–18 have been obtained in 73–81% yield and complete a-
selectivity.
A low temperature (À408C) NMR monitoring of the reaction
of glycosyl donor 1a with Br2 showed direct and rapid forma-
tion of the respective a-bromide. Based on our previous mech-
anistic study,[17] we believe that b-bromide will be also forming
at the beginning of the reaction. However, in the
highly benzylated system it very rapidly equilibrates
Scheme 3. Mechanistic rationale of Br2-promoted HAD reaction.
Table 5. Glycosylation of various acceptors using Br2-promoted HAD.
into the thermodynamically stable a-bromide. There-
fore, in this particular case the b-bromide intermedi-
ate is expected to be a very insignificant intermediate
en route to glycosylation products. Highly benzylated
a-bromide is expected to be reactive under these re-
action conditions, as seen from experiments with
perbenzylated and 4-benzoyl thioglycosides 12 and
14, respectively (Table 3). In case of 4-O-picoloylated
glycosyl donor, bromide leaving group departs and
the 4-O-picoloyl-mediated HAD ensures that the nu-
cleophile is delivered exclusively from the bottom
face of the resulting oxacarbenium intermediate
(Scheme 3). Minimal formation of other electrophilic
species in the bromine-promoted HAD may be the
key to the success of this method unlike other cases
with electrophilic promoters including DMTST, where-
in excess promoter may interfere with the hydrogen-
bond acceptor (picoloyl nitrogen). Glycosidation of
partially benzylated donors 1g–i is slower than that
of 1a (Table 4); nevertheless, the rates of the reaction
are still practical.
Entry
1
Donor
Acceptor
Product
(yield [%],[a] a/b ratio)
1a
19
21
20 (49, 21.0:1)
22 (51, 17.1:1)
2
1a
3
4
5
1a
1b
1b
8
8
9 (<10)
9 (60, a only)
Since all 4-O-picoloylated glycosyl donors gave ex-
ceptional 1,2-cis selectivity upon coupling with pri-
mary acceptor 2 in the presence of Br2, we attempted
to expand the approach to different acceptors rang-
ing from highly reactive aliphatic alcohols to sterically
hindered secondary sugar alcohols. Although a vast
majority of reactions proceeded with high selectivi-
ties and good yields (Table 5), we noticed some un-
usual trends, the nature of which is still hard to ra-
tionalize. For instance, glycosyl donor 1a was practi-
cally ineffective when treated with secondary glycosyl
acceptor 8 (entry 3), even in the presence of HgBr2.
Interestingly, S-phenyl donor 1b could be efficiently
coupled both with primary and secondary glycosyl
acceptors. Most glycosidations of 1b produced high
yields and very high 1,2-cis selectivity (entries 4–7).
4
21
5 (72, a only)
22 (60, 18.2:1)
6
7
1b
1b
23
19
4
4
4
24 (47, 13.0:1)
20 (68, 19.3:1)
5 (43, a only)
5 (58, a only)
5 (78, 21.0:1)
8
9
10
11[b]
1c
1d
1e
1 f
[a] Reactions were stopped at 16 h unless noted otherwise; [b] reaction was complet-
ed within 2.5 h.
Also, glycosidations of S-tolyl and S/O-imidoyl donors 1c–f pro-
vided comparable results and consistently high a-selectivities
(entries 8–11).
Conclusion
As a result of this in depth study, we have expanded the HAD
concept to different 4-O-picoloylated glycosyl donors with
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dient elution) to give the title compound as a white amorphous
widely used leaving groups including SPh, STol and S/O-imi-
dates. Having investigated a variety of promoter systems we
determined the superior properties of Br2 as promoter for
HAD. Very high selectivities and good yields have been record-
ed in most cases with all classes of glycosyl donors at room
temperature, while previously investigated reactions required
low temperature. All bromine-promoted reactions have been
performed under regular dilution (50 mm concentration of the
acceptor) unlike other promoter systems that would only work
in low concentration (5 mm).
Clearly, the bromine-promoted HAD enhances the utility of
the two previously developed techniques, HAD[5] and bromine-
assisted glycosidation of thioglycosides,[17] by complementing
each other. The bromine-mediated activation pathway is un-
common in synthesis, and many glycosyl donors investigated
herein have never been activated under these conditions. The
conversion rates remain relatively slow, which creates the basis
for further study, and the ability to enhance the yields by
using an additive such as HgBr2 has been demonstrated. Fur-
ther investigation of the HAD method in conjunction with the
bromine activation and beyond are currently underway in our
laboratory.
solid in 94% yield (0.56 g, 0.87 mmol). Analytical data for 1b: Rf =
0.44 (ethyl acetate/hexane, 1:1, v/v); ½aŠ25 =À38.7 (c=1.0, CHCl3);
D
1H NMR: d=3.62 (dd, 1H, J2,3 =8.8 Hz, H-2), 3.64–3.70 (m, 2H, H-6a,
6b), 3.89 (m, 1H, H-5), 3.94 (dd, 1H, J3,4 =8.9 Hz, H-3), 4.48 (s, 2H,
2
CH2Ph), 4.73 (dd, 2H, J=11.2 Hz, CH2Ph), 4.76 (d, 1H, J1,2 =8.5 Hz,
H-1), 4.81 (dd, 2H, 2J=10.3 Hz, CH2Ph), 5.40 (dd, 1H, J4,5 =9.8 Hz,
H-4), 7.00–8.00 (m, 23H, aromatic), 8.72 ppm (d, 1H, J=3.1 Hz, aro-
matic); 13C NMR: d=69.7, 72.3, 73.6, 75.7 (”2), 77.5, 80.8, 84.0,
87.6, 125.7, 127.2, 127.6, 127.7, 127.8 (”2), 128.1 (”3), 128.3 (”5),
128.5 (”2), 128.6 (”2), 129.1 (”2), 132.1 (”2), 133.6, 137.1, 138.0 (”
2), 138.1, 147.6, 150.0, 164.3 ppm; HR FAB MS [M+H]+ calcd for
C39H38NO6S 648.2420, found 648.2437.
Tolyl 2,3,6-tri-O-benzyl-4-O-picoloyl-1-thio-b-d-glucopyranoside
(1c): The title compound was obtained as a white amorphous
solid from tolyl 2,3,6-tri-O-benzyl-1-thio-b-d-glucopyranoside[23]
(0.50 g, 0.90 mmol) as described for the synthesis of 1b in 96%
yield (0.57 g, 0.86 mmol). Analytical data for 1c: Rf =0.44 (ethyl
acetate/hexane, 1:1, v/v); ½aŠ25 =À38.7 (c=1.0, CHCl3); H NMR: d=
1
D
2.30 (s, 3H, CH3), 3.59 (dd, 1H, J2,3 =8.9 Hz, H-2), 3.85 (m, 1H, H- 5),
3.93 (dd, 1H, J3,4 =9.0 Hz, H-3), 4.47 (s, 2H, CH2Ph), 4.69 (d, 1H,
J
1,2 =9.8 Hz, H-1), 4.71 (dd, 2H, 2J=11.1 Hz, CH2Ph), 4.81 (dd, 2H,
2J=10.4 Hz, CH2Ph), 5.38 (dd, 1H, J4,5 =9.7 Hz, H-4), 6.90–8.15 (m,
22H, aromatic), 8.12 ppm (d, 1H, J=3.9 Hz, aromatic); 13C NMR:
d=21.2, 69.6, 72.2, 73.5, 75.6 (”2), 77.4, 80.7, 83.9, 87.7, 125.6,
127.1, 127.4, 127.6, 127.7 (”2), 127.9 (”2), 128.2 (”5), 128.5 (”2),
128.7 (”2), 129.4, 129.8 (”2), 132.8 (”2), 137.0, 137.9 (”2), 138.0,
138.1, 147.5, 149.9, 164.2 ppm; HR FAB MS [M+H]+ calcd for
C40H40NO6S 662.2576, found 662.2539.
Experimental Section
General
Benzoxazolyl 2,3,6-tri-O-benzyl-4-O-picoloyl-1-thio-b-d-glucopyr-
anoside (1d): A mixture of 1a (0.50 g, 0.83 mmol) and activated
molecular sieves 3 Š (0.42 g) in CH2Cl2 (12.6 mL) was stirred under
argon for 1 h at RT. Freshly prepared solution of Br2 in CH2Cl2
(8.0 mL, 1:165, v/v) was then added and the resulting mixture was
stirred for 10 min at RT. After that, the volatiles were removed
under the reduced pressure at RT and the residue was dried in
vacuo for 3 h. The crude residue was dissolved in dry acetone
(10.0 mL), KSBox[13a] (0.47 g, 2.5 mmol) and 18-crown-6 (44 mg,
0.17 mmol) were added, and the resulting mixture was stirred
under argon for 2 h at RT. The solid was filtered off and washed
successively with toluene. The combined filtrate (~90 mL) was
washed with 1% aq. NaOH (15 mL) and water (3”10 mL). The or-
ganic phase was separated, dried with MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (ethyl acetate/hexane gradient elution) to give the title
compound as a pale-yellow syrup in 82% yield (0.47 g, 0.68 mmol).
Column chromatography was performed on silica gel 60 (70–
230 mesh); reactions were monitored by TLC on Kieselgel 60 F254.
The compounds were detected by examination under UV light and
by charring with 10% sulfuric acid in methanol. Solvents were re-
moved under reduced pressure at <408C. CH2Cl2 and ClCH2CH2Cl
(1,2-DCE) were distilled from CaH2 directly prior to application. Pyri-
dine was dried by refluxing with CaH2 and then distilled and
stored over molecular sieves (3 Š). Anhydrous DMF and THF were
used as received. Molecular sieves (3 or 4 Š) used for reactions
were crushed and activated in vacuo at 3908C during 8 h in the
first instance and then for 2–3 h at 3908C directly prior to applica-
tion. AgOTf was co-evaporated with toluene (3”10 mL) and dried
in vacuo for 2–3 h directly prior to application. Optical rotations
were measured with a Jasco P-1020 polarimeter. Unless noted oth-
1
erwise, H NMR spectra were recorded in CDCl3 at 300 or 600 MHz,
13C NMR spectra were recorded in CDCl3 at 75 or 150 MHz.
Analytical data for 1d: Rf =0.42 (ethyl acetate/hexane, 3:2, v/v);
Synthesis of glycosyl donors
1
½aŠ23 = +42.3 (c=1.0, CHCl3); H NMR: d=3.75–3.87 (m, 2H, H-6a,
D
6b), 4.02 (dd, 1H, J2,3 =9.8 Hz, H-2), 4.12–4.23 (m, 2H, H-3, 5), 4.55
Ethyl 2,3,6-tri-O-benzyl-4-O-picoloyl-1-thio-b-d-glucopyranoside
(1a): The title compound was synthesized according to the report-
ed procedure and the analytical data for 1a was essentially the
same as reported previously.[5]
2
2
(dd, 2H, J=11.9 Hz, CH2Ph), 4.90 (dd, 2H, J=11.2 Hz, CH2Ph), 4.98
(dd, 2H, 2J=10.6 Hz, CH2Ph), 5.65 (dd, 1H, J4,5 =9.7 Hz, H-4), 5.68
(dd, 1H, J1,2 =9.9 Hz, H-1), 7.15–7.98 (m, 21H, aromatic), 8.12 (d,
1H, J=7.8 Hz, aromatic), 8.87 ppm (d, 1H, J=4.6 Hz, aromatic);
13C NMR: d=69.1, 71.9, 75.6, 75.7, 75.9, 78.3, 80.6, 84.0, 84.9, 110.3,
119.2, 124.5, 124.6, 125.7, 127.2, 127.5, 127.8, 127.9 (”2), 128.2 (”
3), 128.3 (”2), 128.4 (”2), 128.5 (”2), 128.6 (”2), 137.1, 137.5, 137.9
(”2), 142.0, 147.6, 150.1, 152.0, 161.5, 164.2 ppm; HR FAB MS
[M+Na]+ calcd for C40H36O7N2SNa 711.2141, found 711.2164.
Phenyl
2,3,6-tri-O-benzyl-4-O-picoloyl-1-thio-b-d-glucopyrano-
side (1b): Picolinic acid (0.23 g, 1.84 mmol), N,N’-dicyclohexylcarbo-
diimide (0.38 g, 1.84 mmol), and 4-dimethylaminopyridine (23 mg,
0.19 mmol) were added to a solution of phenyl 2,3,6-tri-O-benzyl-
1-thio-b-d-glucopyranoside[22] (0.50 g, 0.92 mmol) in CH2Cl2 (10 mL)
and the resulting mixture was stirred under argon for 30 min at RT.
The solid was then filtered off and washed successively with
CH2Cl2. The combined filtrate (~100 mL) was washed with brine
(2”10 mL). The organic phase was separated, dried with magnesi-
um sulfate, and concentrated, in vacuo. The residue was purified
by column chromatography on silica gel (ethyl acetate/hexane gra-
2-Thiazolinyl 2,3,6-tri-O-benzyl-4-O-picoloyl-1-thio-b-d-glucopyr-
anoside (1e): A mixture of 1a (0.50 g, 0.83 mmol) and activated
molecular sieves 3 Š (0.42 g) in CH2Cl2 (12.6 mL) was stirred under
argon for 1 h at RT. Freshly prepared solution of Br2 in CH2Cl2
(8.0 mL, 1:165, v/v) was added and the resulting mixture was
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Full Paper
stirred for 5 min at RT. After that, the volatiles were removed under
the reduced pressure at RT and the residue was dried in vacuo for
3 h. The crude residue was in dissolved in dry acetonitrile
(10.0 mL), NaSTaz[14b] (0.35 g, 2.5 mmol) and 15-crown-5 (37 mg,
0.17 mmol) were added and the resulting mixture was stirred
under argon for 3.5 h at RT. The solid was filtered off and washed
successively with CH2Cl2. The combined filtrate (~90 mL) was
washed with 1% aq. NaOH (15 mL) and water (3”10 mL). The or-
ganic phase was separated, dried with MgSO4, and concentrated in
vacuo. The residue was purified by column chromatography on
silica gel (ethyl acetate/hexane gradient elution) to give the title
147.5, 149.9, 161.3, 164.1 ppm; HR FAB MS [M+Na]+ calcd for
C35H33O7N2Cl3Na 721.1251, found 721.1289.
Ethyl 6-O-benzoyl-2,3-di-O-benzyl-4-O-picoloyl-1-thio-b-d-gluco-
pyranoside (1g): The title compound was obtained as a white
amorphous solid from ethyl 6-O-benzoyl-2,3-di-O-benzyl-1-thio-b-
d-glucopyranoside[24] (0.36 g, 0.71 mmol) as described for the syn-
thesis of 1b in 89% yield (0.54 g, 0.90 mmol). Analytical data for
1g: Rf =0.36 (ethyl acetate/hexane, 3:2, v/v); ½aŠ28 =À1.9 (c=1.0,
D
1
CHCl3); H NMR: d=1.29 (t, 3H, J=7.4 Hz, SCH2CH3), 2.75 (m, 2H,
SCH2CH3), 3.60 (dd, 1H, J2,3 =9.2 Hz, H-2), 3.96 (dd, 1H, J3,4 =9.2 Hz,
H-3), 3.96–4.05 (m, 1H, H-5), 4.40 (dd, 1H, J5,6a =5.4 Hz, J6a,6b
12.1 Hz, H-6a), 4.54 (dd, 1H, J5,6b =2.9 Hz, H-6b), 4.59 (d, 1H, J1,2
=
=
compound as a colorless syrup in 84% yield (0.46 g, 0.70 mmol).
23
D
Analytical data for 1e: Rf =0.45 (acetone/toluene, 1:4, v/v); ½aŠ
=
9.8 Hz, H-1), 4.75 (dd, 2H, 2J=11.2 Hz, CH2Ph), 4.84 (dd, 2H, 2J=
10.2 Hz, CH2Ph), 5.52 (dd, 1H, J4,5 =9.8 Hz, H-4), 6.95–8.10 (m, 18H,
aromatic), 8.70 ppm (d, 1H, J=4.6 Hz, aromatic); 13C NMR: d=15.2,
25.1, 63.6, 75.7 (”2), 75.8, 81.7, 83.6, 85.3, 125.8, 127.2, 127.7, 128.1
(”3), 128.3 (”2), 128.4 (”2), 128.5 (”4), 129.8 (”3), 133.1, 137.1,
137.8, 137.9, 147.4, 149.9, 164.2, 166.2 ppm; HR FAB MS [M+H]+
calcd for C35H36NO7S 614.2212, found 614.2213.
+42.3 (c=1.0, CHCl3); 1H NMR: d=3.32 (t, 2H, J=8.1 Hz, SCH2),
3.58–3.68 (m, 2H, H-6a, 6b), 3.71 (dd, 1H, J2,3 =9.3 Hz, H-2), 3.94
(dd, 1H, J3,4 =9.1 Hz, H-3), 3.95 (m, 1H, H-5), 4.03–4.28 (m, 2H,
2
NCH2), 4.46 (s, 2H, CH2Ph), 4.71 (dd, 2H, J=11.3 Hz, CH2Ph), 4.78
(dd, 2H, 2J=10.2 Hz, CH2Ph), 5.34 (d, 1H, J1,2 =10.0 Hz, H-1), 5.43
(dd, 1H, J4,5 =9.7 Hz, H-4), 6.95–8.00 (m, 18H, aromatic), 8.70 ppm
(d, 1H, J=4.7 Hz, aromatic); 13C NMR: d=35.2, 64.3, 69.2, 72.0,
73.5, 75.6, 75.8, 77.8, 80.7, 83.9, 84.8, 125.7, 127.2, 127.5, 127.7,
127.9 (”2), 128.1 (”2), 128.2 (”2), 128.3 (”4), 128.6 (”2), 129.2,
129.9, 137.1, 137.6, 137.9, 138.0, 147.6, 150.0, 164.1 ppm; HR FAB
MS [M+Na]+ calcd for C36H36O6N2S2Na 679.1912, found 679.1943.
Ethyl 3-O-benzoyl-2,6-di-O-benzyl-4-O-picoloyl-1-thio-b-d-gluco-
pyranoside (1h): Benzoyl chloride (0.32 mL, 3.0 mmol) and 4-dime-
thylaminopyridine (37 mg, 0.30 mmol) were added to a solution of
ethyl 2-O-benzyl-4,6-O-benzylidene-1-thio-b-d-glucopyranoside[21]
(0.60 g, 1.50 mmol) in pyridine (10 mL) and the resulting mixture
was stirred under argon for 3 h at RT. After that, the reaction was
quenched with methanol (~3 mL) and the volatiles were removed
in vacuo. The residue was diluted with CH2Cl2 (~150 mL) and
washed with 1N HCl (15 mL), sat. aq. NaHCO3 (15 mL), and water
(2”15 mL). The organic phase was separated, dried with magnesi-
um sulfate, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane gradi-
ent elution) to give ethyl 3-O-benzoyl-2-O-benzyl-4,6-O-benzyli-
dene-1-thio-b-d-glucopyranoside (26) as a white amorphous solid
in 91% yield (0.69 g, 1.4 mmol). Analytical data for 26: Rf =0.56
2,3,6-Tri-O-benzyl-4-O-picoloyl-b-d-glucopyranosyl trichloroaceti-
midate (1 f): Hg(CF3CO2)2 (0.7 g, 1.67 mmol) was added to a mixture
of 1a (0.5 g, 0.84 mmol) in CH2Cl2 (10 mL) containing water
(0.5 mL) and the resulting mixture was stirred for 1 h at 08C. The
reaction mixture was then allowed to warm to RT and stirred for
additional 16 h. After that, the reaction mixture was diluted with
CH2Cl2 (~100 mL) and washed with sat. aq. NaHCO3 (10 mL) and
water (10 mL). The organic phase was separated, dried with mag-
nesium sulfate, and concentrated in vacuo. The residue was puri-
fied by column chromatography on silica gel (ethyl acetate/hexane
gradient elution) to afford 2,3,6-tri-O-benzyl-4-O-picoloyl-d-gluco-
pyranose (25) as a colorless syrup in 87% yield (0.41 g, 0.74 mmol).
(ethyl acetate/hexane, 3:7, v/v); ½aŠ27 =À32.1 (c=1.0, CHCl3);
D
1H NMR: d=1.32 (t, 3H, J=7.4 Hz, SCH2CH3), 2.78 (m, 2H,
SCH2CH3), 3.52–3.68 (m, 2H, H-2, 5), 3.71–3.83 (m, 2H, H-4, 6a), 4.37
(dd, 1H, J5,6b =4.9 Hz, J6a,6b =10.5 Hz, H-6b), 4.69 (d, 1H, J1,2 =9.7 Hz,
1
Analytical data for 25: Rf =0.38 (acetone/toluene, 3:7, v/v); H NMR
of a-25: d=3.47–3.63 (m, 3H, H-5, 6a, 6b), 3.82–3.95 (m, 2H, H-3,
5), 4.44 (d, 1H, J1,2 =9.7 Hz, H-1), 4.55–5.03 (m, 6H, 3”CH2Ph), 5.35
(dd, 1H, J4,5 =9.5 Hz, H-4), 7.00–8.80 ppm (m, 19H, aromatic);
1H NMR of b-25: d=3.68 (dd, 1H, J1,2 =3.4 Hz, J2,3 =9.4 Hz, H-2),
4.28–4.51 (m, 4H, H-3, 5, 6a, 6b), 4.55–5.03 (m, 6H, 3”CH2Ph),
5.25–5.44 (m, 2H, H-1, 4), 7.00–8.80 ppm (m, 19H, aromatic); select-
ed 13C NMR data for 25: d=68.6, 69.1, 69.5, 72.3, 73.0, 73.3, 73.6,
73.7, 74.9, 75.4, 75.5, 79.1 (”2), 80.0, 81.7, 83.0, 91.5, 97.6 ppm; HR
FAB MS [M+H]+ calcd for C33H34NO7 556.2335, found 556.2317. Tri-
chloroacetonitrile (0.22 mL, 2.21 mmol) and K2CO3 (0.20 g,
1.48 mmol) were added to a solution of 25 (0.41 g, 0.74 mmol) in
CH2Cl2 (5.0 mL) and the resulting mixture was stirred under argon
for 16 h at RT. After that, the solid was filtered off and washed suc-
cessively with CH2Cl2. The combined filtrate (~50 mL) was concen-
trated in vacuo and the residue was purified by column chroma-
tography on silica gel (acetone/toluene gradient elution) to give
the title compound as a white amorphous solid in 64% yield
2
H-1), 4.72 (dd, 2H, J=10.6 Hz, CH2Ph), 5.47 (s, 1H, >CHPh), 5.65
(dd, 1H, J3,4 =9.4 Hz, H-3), 7.00–8.10 ppm (m, 15H, aromatic);
13C NMR: d=15.2, 25.6, 68.7, 70.5, 75.0, 75.5, 78.9, 79.9, 86.0, 101.4,
126.2 (”2), 127.9, 128.3 (”2), 128.4 (”4), 128.5 (”2), 129.1, 129.9 (”
2), 130.0, 133.2, 137.0, 137.3, 165.5 ppm; HR FAB MS [M+H]+ calcd
for C29H31O6S 507.1841, found 507.1863.
A mixture of compound 26 (0.65 g, 1.3 mmol) and freshly activated
molecular sieves (3 Š, 1.0 g) in THF (20 mL) was stirred under
argon for 1 h at RT. NaCNBH4 (1.0 g, 16.2 mmol) was added fol-
lowed by dropwise addition of a 2m solution of HCl in Et2O
(8.1 mL, 16.2 mmol) and the resulting mixture was stirred for 1 h at
RT. After that, the volatiles were removed in vacuo. The residue
was diluted with CH2Cl2 (~50 mL), the solid was filtered off and
was washed successively with CH2Cl2. The combined filtrate (~
150 mL) was washed with sat. aq. NaHCO3 (15 mL) and water (2”
15 mL). The organic phase was separated, dried with magnesium
sulfate, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane gradi-
ent elution) to give ethyl 3-O-benzoyl-2,6-di-O-benzyl-1-thio-b-d-
glucopyranoside (27) as a colorless syrup in 87% yield (0.57 g,
1.1 mmol). Analytical data for 27: Rf =0.41 (ethyl acetate/hexane,
(0.33 g, 0.47 mmol). Analytical data for 1 f: Rf =0.43 (acetone/tolu-
1
ene, 3:7, v/v); ½aŠ25 =À38.7 (c=1.0, CHCl3); H NMR: d=3.57–3.74
D
(m, 2H, H-6a, 6b), 3.85 (dd, 1H, J2,3 =8.0 Hz, H-2), 3.93–4.04 (m, 2H,
2
H-3, 5), 4.47 (s, 2H, CH2Ph), 4.71 (dd, 2H, J=11.4 Hz, CH2Ph), 4.84
(dd, 2H, 2J=10.8 Hz, CH2Ph), 5.48 (dd, 1H, J4,5 =9.6 Hz, H-4), 5.87
(d, 1H, J1,2 =7.9 Hz, H-1), 6.95–8.05 (m, 17H, aromatic), 8.74 ppm
(m, 2H, aromatic); 13C NMR: d=68.9, 71.8, 73.5, 74.4, 75.3, 79.2,
81.0, 81.7, 91.0, 98.3, 127.2, 127.6 (”2), 127.9 (”2), 128.1 (”2), 128.2
(”2), 128.3 (”4), 128.6 (”2), 128.7, 129.2, 137.2, 138.0 (”2), 138.1,
3:7, v/v); ½aŠ27 = +21.1 (c=1.0, CHCl3); H NMR: d=1.32 (t, 3H, J=
1
D
7.4 Hz, SCH2CH3), 2.77 (m, 2H, SCH2CH3), 3.53–3.62 (m, 2H, H-2, 6a),
3.72–3.86 (m, 3H, H-4, 5, 6b), 4.51–4.63 (m, 4H, H-1, 11= CH2Ph),
2
2
1
4.82 (d, 1H, J=10.7 Hz, = CH2Ph), 5.32 (dd, 1H, J3,4 =9.1 Hz, H-3),
2
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7.05–7.60 (m, 13H, aromatic), 8.01 ppm (d, 2H, J=8.4 Hz, aromat-
ic); 13C NMR: d=15.3, 25.5, 70.5, 71.3, 73.9, 75.4, 78.5, 79.1, 79.8,
85.3, 127.9 (”2), 128.0 (”2), 128.5 (”4), 128.6 (”4), 129.7, 130.1 (”
2), 133.6, 137.5, 137.9, 167.3 ppm; HR FAB MS [M+H]+ calcd for
C29H33O6S 509.1998, found 509.1207.
warm to RT over a period of 1 h and stirred at RT for the time
specified in the Tables. Upon completion, Et3N (0.3 mL) was added
and the resulting mixture was stirred for 30 min. After that, the
mixture was diluted with CH2Cl2 (10 mL), the solid was filtered off
and was washed successively with CH2Cl2. The combined filtrate (~
30 mL) was washed with 20% aq. NaHCO3 (10 mL) and water (3”
10 mL). The organic phase was separated, dried with magnesium
sulfate, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane gradi-
ent elution). Anomeric ratios (or anomeric purity) were determined
by comparison of the integral intensities of relevant signals in
1H NMR spectra.
The title compound was then obtained as a white amorphous
solid from 27 (0.52 g, 1.0 mmol) as described for the synthesis of
1b in 92% yield (0.58 g, 0.95 mmol). Analytical data for 1h: Rf =
0.36 (ethyl acetate/hexane, 3:2, v/v); ½aŠ27 =À28.8 (c=1.0, CHCl3);
D
1H NMR: d=1.35 (t, 3H, J=7.4 Hz, SCH2CH3), 2.80 (m, 2H,
SCH2CH3), 3.64–3.77 (m, 3H, H- 2, 6a, 6b), 3.94 (m, 1H, H-5), 4.49
(dd, 2H, 2J=12.0 Hz, CH2Ph), 4.69 (d, 1H, J1,2 =9.7 Hz, H-1), 4.70
(dd, 2H, 2J=10.8 Hz, CH2Ph), 5.56 (dd, 1H, J4,5 =9.8 Hz, H-4), 5.74
(dd, 1H, J3,4 =9.3 Hz, H-3), 6.85–8.05 (m, 18H, aromatic), 8.63 ppm
(d, 1H, J=4.0 Hz, aromatic); 13C NMR: d=15.1, 25.2, 69.2, 70.6,
73.5, 75.1, 75.9, 77.2, 79.1, 85.2, 125.3, 127.0, 127.5, 127.7 (”2),
127.8, 128.2 (”4), 128.3 (”2), 128.4 (”3), 129.4, 129.7, 133.1, 136.9,
137.1, 137.7, 146.9, 150.0, 163.7, 165.7 ppm; HR FAB MS [M+H]+
calcd for C35H36NO7S 614.2212, found 614.2218.
Method C: general procedure for glycosylation in the presence
of TMSOTf or TfOH: A mixture of glycosyl donor 1 f (0.13 mmol),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
sieves (4 Š, 200 mg) in ClCH2CH2Cl (26 mL, 5 mm) was stirred under
argon for 1 h at RT. The mixture was then cooled to À308C and
TMSOTf (or TfOH, 0.07 mmol) was added. The resulting mixture
was allowed to warm to RT over a period of 1 h and stirred at RT
for the time specified in the Tables. Upon completion, Et3N
(0.3 mL) was added and the resulting mixture was stirred for
30 min. After that, the mixture was diluted with CH2Cl2 (10 mL), the
solid was filtered off and washed successively with CH2Cl2. The
combined filtrate (~30 mL) was washed with 20% aq. NaHCO3
(10 mL) and water (3”10 mL). The organic phase was separated,
dried with magnesium sulfate, and concentrated in vacuo. The resi-
due was purified by column chromatography on silica gel (ethyl
acetate/hexane gradient elution). Anomeric ratios (or anomeric
purity) were determined by comparison of the integral intensities
of relevant signals in 1H NMR spectra.
Ethyl 3,6-di-O-benzoyl-2-O-benzyl-4-O-picoloyl-1-thio-b-d-gluco-
pyranoside (1i): The title compound was obtained as a white
foam from ethyl 3,6-di-O-benzoyl-2-O-benzyl-1-thio-b-d-glucopyra-
noside[25] (0.47 g, 0.9 mmol) as described for the synthesis of 1b in
89% yield (0.50 g, 0.80 mmol). Analytical data for 1i: Rf =0.36
(ethyl acetate/hexane, 3:2, v/v); ½aŠ27 =À2.1 (c=1.0, CHCl3);
D
1H NMR: d=1.30 (t, 3H, J=7.4 Hz, SCH2CH3), 2.77 (m, 2H,
SCH2CH3), 3.72 (dd, 1H, J2,3 =9.5 Hz, H-2), 4.13 (m, 1H, H-5), 4.45
(dd, 1H, J5,6a =5.6 Hz, J6a,6b =12.2 Hz, H-6a), 4.59 (dd, 1H, J5,6b
3.1 Hz, H-6b), 4.69 (dd, 2H, J=10.8 Hz, CH2Ph), 4.72 (d, 1H, J1,2
9.7 Hz, H-1), 5.60 (dd, 1H, J4,5 =9.8 Hz, H-4), 5.77 (dd, 1H, J3,4
=
=
=
2
9.3 Hz, H-3), 6.95–8.05 (m, 18H, aromatic), 8.62 ppm (d, 1H, J=
4.0 Hz, aromatic); 13C NMR: d=15.2, 25.4, 63.5, 70.5, 75.3, 75.6,
75.8, 79.2, 85.4, 125.6, 127.3, 128.0, 128.3 (”2), 128.4 (”2), 128.5 (”
4), 129.4, 129.7, 129.8 (”4), 133.2, 133.3, 137.1 (”2), 146.8, 150.2,
163.8, 165.7, 166.2 ppm; HR FAB MS [M+H]+ calcd for C35H34NO8S
628.2005, found 628.2014.
Method D: general procedure for glycosylation in the presence
of Br2: A mixture of a glycosyl donor (0.13 mmol), glycosyl accept-
or (0.10 mmol), and freshly activated molecular sieves (3 Š,
200 mg) in ClCH2CH2Cl (26 mL, 5 mm) was stirred under argon for
1 h at RT. Br2 (0.14 mmol) was added and the resulting mixture was
stirred at RT for 2–16 h as specified in the Tables. Upon completion,
the mixture was diluted with CH2Cl2 (10 mL) and the solid was fil-
tered off and washed successively with CH2Cl2. The combined fil-
trate (~30 mL) was washed with 20% aq. NaHCO3 (10 mL) and
water (3”10 mL). The organic phase was separated, dried with
magnesium sulfate, and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (ethyl acetate/
hexane gradient elution). Anomeric ratios (or anomeric purity)
were determined by comparison of the integral intensities of rele-
Synthesis of glycosides and disaccharides
Method A: general procedure for glycosylation in the presence
of DMTST: A mixture of a glycosyl donor (0.13 mmol), glycosyl ac-
ceptor (0.10 mmol), and freshly activated molecular sieves (4 Š,
200 mg) in ClCH2CH2Cl (26 mL, 5 mm) was stirred under argon for
1 h at RT. The mixture was then cooled to À308C and DMTST[26]
(0.26 mmol) was added. The resulting mixture was allowed to
warm to RT over a period of 1 h and stirred at RT for the time
specified in the Tables. Upon completion, Et3N (0.3 mL) was added
and the resulting mixture was stirred for 30 min. After that, the
mixture was diluted with CH2Cl2 (10 mL), the solid was filtered off
and washed successively with CH2Cl2. The combined filtrate (~
30 mL) was washed with 20% aq. NaHCO3 (10 mL) and water (3”
10 mL). The organic phase was separated, dried with magnesium
sulfate, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate-hexane gradi-
ent elution). Anomeric ratios (or anomeric purity) were determined
by comparison of the integral intensities of relevant signals in
1H NMR spectra.
1
vant signals in H NMR spectra.
Method E: general procedure for glycosylation in the presence
of Br2 and HgBr2: A mixture of a glycosyl donor (0.13 mmol), gly-
cosyl acceptor (0.10 mmol), and freshly activated molecular sieves
(3 Š, 200 mg) in ClCH2CH2Cl (26 mL, 5 mm) was stirred under argon
for 1 h at RT. Br2 (0.14 mmol) was added and the resulting mixture
was stirred for 15 min at RT. Thereafter, mercury(II) bromide
(0.14 mmol) was added and the resulting mixture was stirred at RT
for the time specified in the Tables. Upon completion, the reaction
mixture was diluted with CH2Cl2 (10 mL), the solid was filtered off
and washed successively with CH2Cl2. The combined filtrate (~
30 mL) was washed with 20% aq. NaHCO3 (10 mL) and water (3”
10 mL). The organic phase was separated, dried with magnesium
sulfate, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate/hexane gradi-
ent elution). Anomeric ratios (or anomeric purity) were determined
by comparison of the integral intensities of relevant signals in
1H NMR spectra.
Method B: general procedure for glycosylation in the presence
of AgOTf: A mixture of a glycosyl donor (0.13 mmol), glycosyl ac-
ceptor (0.10 mmol), and freshly activated molecular sieves (4 Š,
200 mg) in ClCH2CH2Cl (26 mL, 5 mm) was stirred under argon for
1 h at RT. The mixture was then cooled to À308C and AgOTf
(0.26 mmol) was added. The resulting mixture was allowed to
Chem. Eur. J. 2015, 21, 6572 – 6581
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Full Paper
Methyl 2,3,4-tri-O-benzyl-6-O-(2,3,6-tri-O-benzyl-4-O-picoloyl-a-
d-glucopyranosyl)-a-d-glucopyranoside (3): The title compound
was obtained by methods A–E as a white amorphous solid from 4-
O-picoloylated glycosyl donors and acceptor 2 in yields and stereo-
selectivity listed in the Tables. Analytical data for 3 were in accord
with those reported previously.[5]
3.6 Hz, J2,3 =9.6 Hz, H-2), 3.42 (s, 3H, OCH3), 3.59 (dd, 1H, J4,5 =
9.5 Hz, H-4), 3.71 (dd, 1H, J2’,3’ =9.8 Hz, H-2’), 3.74–3.88 (m, 3H, H-5,
6a, 6b), 3.99 (dd, 1H, J3,4 =9.3 Hz, H-3), 4.33 (dd, 1H, J5’,6a’ =5.2 Hz,
J
6a’,6b’ =11.9, H-6a’), 4.43 (m, 1H, H-5’), 4.47–4.63 (m, 4H, H-1, 6b’,
2 2
CH2Ph), 4.64 (dd, 2H, J=12.0 Hz, CH2Ph), 4.81 (dd, 2H, J=11.9 Hz,
CH2Ph), 4.89 (dd, 2H, J=10.9 Hz, CH2Ph), 5.11 (d, 1H, J1’,2’ =3.5 Hz,
2
H-1’), 5.53 (dd, 1H, J4’,5’ =9.7 Hz, H-4’), 5.97 (dd, 1H, J3’,4’ =9.8 Hz, H-
3’), 7.05–8.05 (m, 33H, aromatic), 8.67 ppm (d, 1H, J=4.5 Hz, aro-
matic); 13C NMR: d=55.4, 63.1, 66.2, 67.6, 70.6, 70.7, 72.1, 72.3,
73.5, 75.3, 75.9, 77.5, 77.9, 80.0, 82.3, 96.9, 98.2, 125.6, 127.3, 127.7,
127.9 (”2), 128.0, 128.1 (”3), 128.2 (”2), 128.3, 128.4, 128.5 (”2),
128.6 (”10), 128.7 (”3), 129.8, 129.9 (”2), 130.0 (”2), 133.2, 137.2,
137.7, 138.3, 138.6, 139.0, 147.1, 150.3, 163.9, 165.0, 166.3 ppm; HR
FAB MS [M+H]+ calcd for C61H60NO14 1030.4014, found 1030.3994.
Methyl 3,4,6-tri-O-benzyl-2-O-(2,3,6-tri-O-benzyl-4-O-picoloyl-a-
d-glucopyranosyl)-a-d-glucopyranoside (5): The title compound
was obtained by method D as a white amorphous solid from 4-O-
picoloylated glycosyl donors and acceptor 4 in yields and stereose-
lectivity listed in the Tables. Analytical data for 5 were in accord
with those reported previously.[5]
Methyl 2,3,6-tri-O-benzyl-4-O-(2,3,6-tri-O-benzyl-4-O-picoloyl-a-
d-glucopyranosyl)-a-d-glucopyranoside (9): The title compound
was obtained by method D as a white amorphous solid from 4-O-
picoloylated glycosyl donors and acceptor 8 in yields and stereose-
lectivity listed in the Tables. Analytical data for 9 were in accord
with those reported previously.[5]
Cyclohexyl
2,3,6-tri-O-benzyl-4-O-picoloyl-d-glucopyranoside
(20): The title compound was obtained by method D as a colorless
syrup from 4-O-picoloylated glycosyl donors and cyclohexanol (19,
50 mm), in yields and stereoselectivity listed in Table 5. Analytical
data for a-20: Rf =0.58 (acetone/toluene, 1:4, v/v); 1H NMR: d=
1.05–2.10 (m, 10H, 5”CH2 of cyclohexyl), 3.50–3.62 (m, 3H, H-6a,
6b, OCH of cyclohexyl), 3.65 (dd, 1H, J2,3 =9.6 Hz, H-2), 4.19 (dd,
Methyl 2,3,4-tri-O-benzyl-6-O-(6-O-benzoyl-2,3-di-O-benzyl-4-O-
picoloyl-a-d-glucopyranosyl)-a-d-glucopyranoside (16): The title
compound was obtained by method D as a white amorphous solid
from donor 1g and acceptor 2 in 79% yield and complete stereo-
selectivity. Analytical data for 16: Rf =0.52 (acetone/toluene, 1:4, v/
2
1H, J3,4 =9.5 Hz, H-3), 4.23 (m, 1H, H-5), 4.46 (dd, 2H, J=12.0 Hz,
v); ½aŠ27 = +62.2 (c=1.0, CHCl3); 1H NMR: d=3.37 (s, 3H, OCH3),
2
2
CH2Ph), 4.72 (dd, 2H, J=12.0 Hz, CH2Ph), 4.84 (dd, 2H, J=11.3 Hz,
CH2Ph), 4.96 (d, 1H, J1,2 =3.7 Hz, H-1), 5.42 (dd, 1H, J4,5 =9.8 Hz, H-
4), 6.95–8.15 (m, 18H, aromatic), 8.74 ppm (m, 1H, J=3.9 Hz, aro-
matic); 13C NMR: d=24.4, 24.7, 25.8, 31.7, 33.7, 68.7, 69.1, 72.4,
73.4, 73.7, 75.5, 76.2, 79.5, 80.0, 95.3, 125.9, 127.2, 127.4, 127.5,
127.9 (”2), 128.0 (”2), 128.1, 128.3 (”6), 128.6 (”2), 137.3, 138.1,
138.4, 138.8, 147.8, 149.9, 164.2 ppm; HR FAB MS [M+H]+ calcd for
C39H44O7N 638.3118, found 638.3097.
D
3.39 (dd, 1H, J1,2 =3.6 Hz, J2,3 =9.7 Hz, H-2), 3.61 (dd, 1H, J4,5
=
9.6 Hz, H-4), 3.66 (dd, 1H, J2’,3’ =9.5 Hz, H-2’), 3.72–3.85 (m, 3H, H-5,
6a, 6b), 3.99 (dd, 1H, J3,4 =9.2 Hz, H-3), 4.18 (dd, 1H, J3’,4’ =9.4 Hz,
H-3’), 4.23–4.34 (m, 2H, H-5’, 6a’), 4.47–4.74 (m, 8H, H-1, 6b’, 3”
CH2Ph), 4.77–4.85 (m, 2H, CH2Ph), 4.92 (d, 1H, 2J=11.1 Hz,
1
1= CH2Ph), 4.98 (d, 1H, 2J=10.9 Hz, = CH2Ph), 5.05 (d, 1H, J1’,2’
=
2
2
3.5 Hz, H-1’), 5.46 (dd, 1H, J4’,5’ =9.7 Hz, H-4’), 6.90–8.10 (m, 33H, ar-
omatic), 8.74 ppm (d, 1H, J=4.5 Hz, aromatic); 13C NMR: d=55.4,
63.3, 66.1, 67.8, 70.8, 71.8, 72.9, 73.6, 75.3, 75.5, 76.0, 78.0, 78.5,
80.1, 80.3, 82.3, 97.3, 98.1, 125.7, 127.2, 127.6, 127.8, 127.9 (”3),
128.0, 128.1 (”3), 128.2 (”4), 128.3 (”4), 128.5 (”2), 128.6 (”2),
128.7 (”6), 129.9 (”3), 130.1, 133.2, 137.1, 138.3, 138.4, 138.6,
139.0, 147.8, 150.1, 164.2, 166.4 ppm; HR FAB MS [M+H]+ calcd for
C61H62NO13 1016.4221, found 1016.4208.
Benzyl 2,3,6-tri-O-benzyl-4-O-picoloyl-d-glucopyranoside (22):
The title compound was obtained by method D as a colorless
syrup from 4-O-picoloylated glycosyl donors and benzyl alcohol
(21, 50 mm) in yields and stereoselectivity listed in Table 5. Analyti-
1
cal data for a-22: Rf =0.55 (acetone/toluene, 1:4, v/v); H NMR: d=
3.48–3.55 (m, 2H, H-6a, 6b), 3.64 (dd, 1H, J2,3 =9.5 Hz, H-2), 3.14
(m, 1H, H-5), 4.21(dd, 1H, J3,4 =9.5 Hz, H-3), 4.45 (dd, 2H, 2J=
Methyl 2,3,4-tri-O-benzyl-6-O-(3-O-benzoyl-2,6-di-O-benzyl-4-O-
picoloyl-a-d-glucopyranosyl)-a-d-glucopyranoside (17): The title
compound was obtained by method D as a white amorphous solid
from donor 1h and acceptor 2 in 81% yield and complete stereo-
selectivity. Analytical data for 17: Rf =0.53 (acetone/toluene, 1:4, v/
11.9 Hz, CH2Ph), 4.50–4.77 (m, 5H, 21= CH2Ph), 4.80–4.90 (m, 2H, H-
2
1
1, = CH2Ph), 5.42 (dd, 1H, J4,5 =9.8 Hz, H-4), 7.05–8.10 (m, 23H, ar-
2
omatic), 8.72 ppm (d, 1H, J=4.1 Hz, aromatic); 13C NMR: d=68.9,
69.0, 69.4, 72.1, 73.4, 73.7, 75.6, 79.5, 79.9, 95.7, 125.8, 127.1, 127.5,
127.6, 128.0 (”3), 128.1 (”2), 128.2 (”3), 128.3 (”4), 128.6 (”4),
128.8 (”2), 137.1, 137.2, 138.0, 138.2, 138.6, 147.8, 149.9,
164.2 ppm; HR FAB MS [M+H]+ calcd for C40H40O7N 646.2805,
found 646.2841.
v); ½aŠ28 = +30.9 (c=1.0, CHCl3); 1H NMR: d=3.41 (s, 3H, OCH3),
D
3.44 (dd, 1H, J1,2 =3.6 Hz, J2,3 =9.6 Hz, H-2), 3.47–3.60 (m, 2H, H-6a’,
6b’), 3.64–3.72 (m, 2H, H-2’, 4), 3.74–3.93 (m, 3H, H-5, 6a, 6b), 4.00
(dd, 1H, J3,4 =9.2 Hz, H-3), 4.19 (m, 1H, H-5’), 4.37–4.65 (m, 6H, H-1,
21= CH2Ph), 4.73 (d, 2H, 2J=11.5 Hz, CH2Ph), 4.90 (dd, 2H, 2J=
2
11.0 Hz, CH2Ph), 4.96 (d, 1H, 2J=11.2 Hz, = CH2Ph), 5.12 (d, 1H,
1
2
J
J
1’,2’ =3.5 Hz, H-1’), 5.55 (dd, 1H, J4’,5’ =9.8 Hz, H-4’), 5.93 (dd, 1H,
3’,4’ =9.7 Hz, H-3’), 7.00–8.10 (m, 33H, aromatic), 8.67 ppm (d, 1H,
Isopropyl 2,3,6-tri-O-benzyl-4-O-picoloyl-d-glucopyranoside (24):
The title compound was obtained by method D as a colorless
syrup from donor 1b and isopropanol (23, 50 mm) in 47% yield
(a/b=13:1). Analytical data for a-24: Rf =0.57 (acetone/toluene,
J=3.9 Hz, aromatic); 13C NMR: d=55.4, 66.2, 68.5, 68.7, 70.6, 70.8,
72.3 (”2), 73.6, 73.8, 75.3, 75.9, 76.6, 77.8, 80.0, 82.4, 97.2, 98.3,
125.5, 127.1, 127.7 (”2), 127.9, 128.0 (”2), 128.1 (”7), 128.3 (”2),
128.4 (”3), 128.5 (”6), 128.6 (”4), 130.0 (”3), 133.1, 137.1, 137.8 (”
2), 138.3, 138.7, 139.1, 147.4, 150.2, 163.8, 166.0 ppm; HR FAB MS
[M+H]+ calcd for C61H62NO13 1016.4221, found 1016.4213.
1
1:4, v/v); H NMR: d=1.17 (m, 6H, 2”CH3), 3.43–3.52 (m, 2H, H-6a,
6b), 3.58 (dd, 1H, J2,3 =9.5 Hz, H-2), 3.85 (m, 1H, OCH(CH3)2), 4.10–
2
4.5 (m, 2H, H-3, 5), 4.38 (dd, 2H, J=11.9 Hz, CH2Ph), 4.66 (dd, 2H,
2
2J=12.1 Hz, CH2Ph), 4.70 (dd, 2H, J=11.3 Hz, CH2Ph), 4.80 (d, 1H,
Methyl 2,3,4-tri-O-benzyl-6-O-(3,6-di-O-benzoyl-2-O-benzyl-4-O-
picoloyl-a-d-glucopyranosyl)-a-d-glucopyranoside (18): The title
compound was obtained by method D as a white amorphous solid
from donor 1i and acceptor 2 in 73% yield and complete stereose-
lectivity. Analytical data for 18: Rf =0.52 (acetone/toluene, 1:4, v/v);
J1,2 =3.8 Hz, H-1), 5.37 (dd, 1H, J4,5 =10.0 Hz, H-4), 6.90–8.10 (m,
18H, aromatic), 8.68 ppm (d, 1H, J=3.5 Hz, aromatic); 13C NMR:
d=21.5, 23.5, 68.7, 69.0, 70.0, 72.3, 73.5, 73.7, 75.6, 79.6, 79.9, 95.4,
125.9, 127.1, 127.4, 127.5, 127.9 (”2), 128.0 (”2), 128.1, 128.3 (”4),
128.4 (”2), 128.7 (”3), 129.9, 137.3, 138.0, 138.4, 138.7, 149.9 ppm;
HR FAB MS [M+H]+ calcd for C36H40O7N 598.2805, found 598.2837.
½aŠ27 = +51.5 (c=1.0, CHCl3); 1H NMR: d=3.32 (dd, 1H, J1,2
=
D
Chem. Eur. J. 2015, 21, 6572 – 6581
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Full Paper
Zhu, R. R. Schmidt, in Handbook of Chemical Glycosylation (Ed.: A. V.
Demchenko), Wiley-VCH, Weinheim, 2008, pp. 143–185; d) W. Szeja, G.
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Acknowledgements
This work was supported by awards from the NSF (CHE-
1058112) and Mizutani Foundation for Glycosciences (130057).
J.P.Y. is indebted to the UM–St. Louis Graduate School for
awarding her with the Dissertation Fellowship. We thank the
NSF for a grant (CHE-0959360) to purchase the 600 MHz NMR
spectrometer used in this work. Dr. Winter and Mr. Kramer
(UM–St. Louis) are thanked for HRMS determinations.
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Published online on March 12, 2015
Chem. Eur. J. 2015, 21, 6572 – 6581
www.chemeurj.org
6581
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim