Conformationally armed 3,6-tethered glycosyl donors: Synthesis, conformation, reactivity, and selectivity

Article abstract of DOI:10.1021/jo4012464

The reactivity and selectivity of 3,6-tethered glycosyl donors have been studied using acceptors with different steric and electronic characteristics. Eight (four anomeric pairs) 3,6-bridged-glycosyl donors were synthesized in high yields from their common parent sugars. The glycosylation properties were tested using at least three different acceptors and several promoter systems. Thiophenyl 2,4-di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-d- glucopyranoside gave α/β mixtures with standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly β-selective, when using SnCl₂/AgB(C₆F ₅)₄ as the promoter system. Mannosyl donors were highly α-selective despite the altered conformation. Galactosylations using NIS/TfOH were generally α-selective, but more β-selective using the galactosyl fluoride and depending on the acceptor used. Thiophenyl 2-azido-2-deoxy-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-d- glucopyranoside was found to be α-selective. The reactivity of the donors was investigated using competition experiments, and some but not all were found to be highly reactive. Generally it was found that the α-thioglycosides were significantly more reactive than the β; this difference in reactivity was not found for 3,6-anhydro-, armed-(benzylated), or the classic super armed (silylated) donors. A mechanism supporting the unusual observations has been suggested.

Full text of DOI:10.1021/jo4012464

Article
pubs.acs.org/joc
Conformationally Armed 3,6-Tethered Glycosyl Donors: Synthesis,
Conformation, Reactivity, and Selectivity
Mads Heuckendorff, Christian Marcus Pedersen,* and Mikael Bols
Department of Chemistry, University of Copenhagen, DK-2100 Copenhagen Ø, Denmark
S
* Supporting Information
ABSTRACT: The reactivity and selectivity of 3,6-tethered glycosyl donors have been studied using acceptors with different
steric and electronic characteristics. Eight (four anomeric pairs) 3,6-bridged-glycosyl donors were synthesized in high yields from
their common parent sugars. The glycosylation properties were tested using at least three different acceptors and several
promoter systems. Thiophenyl 2,4-di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-glucopyranoside gave α/β mixtures with
standard NIS/TfOH mediated activation, whereas the corresponding fluoride was found to be highly β-selective, when using
SnCl2/AgB(C6F5)4 as the promoter system. Mannosyl donors were highly α-selective despite the altered conformation.
Galactosylations using NIS/TfOH were generally α-selective, but more β-selective using the galactosyl fluoride and depending on
the acceptor used. Thiophenyl 2-azido-2-deoxy-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-glucopyranoside was found to be α-
selective . The reactivity of the donors was investigated using competition experiments, and some but not all were found to be
highly reactive. Generally it was found that the α-thioglycosides were significantly more reactive than the β; this difference in
reactivity was not found for 3,6-anhydro-, armed-(benzylated), or the classic super armed (silylated) donors. A mechanism
supporting the unusual observations has been suggested.
The importance of protective groups in glycosylation
reactions has been realized for decades and was originally
studied by Paulsen,8 who found that benzylated glycosyl donors
are more reactive than acetylated. This was later conceptualized
by Fraser-Reid who invented the armed-disarmed concept,9
which has been of major importance in the development of
efficient oligosaccharide synthesis protocols. Using the
principles described above of higher reactivity of carbohydrate
derivatives with axial O-groups, it is possible to go beyond the
reactivity of armed glycosyl donors by forcing the molecule into
an axial rich conformation. This can be done by introduction of
bulky silyl protective groups trans vicinal to each other.10 Due
to the bulkiness a conformational ring flip is favorable, and
partial or completely flipped sugars are obtained.11 Glyco-
sylation with the all-axial or axial rich donors revealed that they
indeed were superior in reactivity compared with the armed
derivatives.12 Trisaccharide donors could be prepared in a one-
pot one-addition protocol having three thioglycosides present
at the same time competing about the same promoter.10b To
expand the scope of using super armed donors with access to
nonvicinal branching points, tethering of the 3,6-hydroxyl
INTRODUCTION
■
Carbohydrates structures are of crucial importance in every
corner of biology, yet carbohydrates and carbohydrate
analogues are underexplored as pharmaceuticals. One of the
reasons is undoubtedly the comparatively difficult synthesis and
higher complexities of carbohydrates compared to most small
molecules. Many intrinsic properties of carbohydrates are also
poorly understood as they frequently react widely different than
organic molecules with few functionalities.1
One such phenomenon was the difference in hydrolysis rates
of stereoisomeric glycosides,2 e.g., why do galactosides
hydrolyze 5 times faster than glucosides? This was explained
by the recent discovery that there is a de facto difference in
electron-withdrawing effect from the axial and equatorial OH
both in the ground and transition state.3,4 One of the
interesting consequences of this discovery is that it is possible
to increase the hydrolysis rate of a gluco-derivative more than
100-fold by forcing it from a 4C1 chair to a 1C4 chair
conformation.5 This has recently been used to enhance the rate
of hydrolysis of carbohydrate-based biomass.6 We and others
have subsequently been engaged in studying the influence of
stereo electronic effects in the more complicated glycosylation
reactions.7
Received: June 12, 2013
© XXXX American Chemical Society
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a
Scheme 1. Synthesis of the 3,6-Tethered Glycosyl Donors
a
Yields refer to the last step.
groups and the 2,4-hydroxyl groups was investigated using di-
tert-butyl silylene as the bridging reagent. The initial results
demonstrated that the 3,6-tethered donor was highly reactive,
whereas the 2,4-tethering was not.13 Parallel to our
investigations of glycosyl donors having a 3,6-tethering, Yamada
and co-worker developed a synthesis of 3,6-O-(o-xylylene)-
bridged glycosyl fluoride donor,14 originally for the synthesis of
3,6-bridged natural products.15 The synthesis of the donor is
rather complicated, since the bridge can only be installed on the
open chain form of the sugar and hence 13 steps from glucose
are needed. With the donor in hand Yamada and co-workers
discovered that complete β-selectivity was obtained when using
SnCl2/AgB(C6F5)4 as the promoter system.16 It was
furthermore shown that both anomers initially are formed but
epimerize into the strongly favored β, presumable by catalysis
performed by HF formed under the conditions. These recent
results prompted us to expand the ongoing research on
conformationally restricted donors. Herein we presents a
thorough study on 3,6-bridged glycosyl donors, covering the
most common glycopyranoside donors, i.e., gluco-, manno-,
galacto-, and 2-azido-gluco-pyranosides.
little or no effect on the on the outcome of the reactions; hence
this method is generally applicable.
Encouraged by the straightforward and efficient bridging
using di-tert-butyl-silylene ditriflate as the reagent, a number of
other alternative bridging reagents were investigated. As a one-
carbon bridge, to give a six-membered ring, acid-catalyzed
acetal formation was tried using benzaldehyde dimethyl acetal
as the reagent. No product was observed. Introduction of the
acetal under basic conditions was also investigated using α,α-
dibromo toluene as the reagent20 or Rollins reagent,21 but with
no improvement. Introduction of two-, three-, and four-carbon
bridges was also unsuccessfully investigated by using 3,4-
dichloro-cis-cyclobutene,22 3-chloro-2-(chloromethyl)-1-pro-
pene, and α,α′-dibromo-o-xylene respectively. Finally 1,3-
dichloro-1,1,3,3-tetraisopropyldisiloxane was tried, but as
noticed by Yamada, bridging the glucopyranoside is not
straightforward!
The 2-azido-glucosyl donor was synthesized from the known
benzylidene 1323 via a selective reductive opening using
borane−THF complex and dibutylboron triflate as the catalyst
(Scheme 2).24 Separation of the anomers 14 and 15 followed
Scheme 2. Synthesis of 2-Azido 3,6-Tethered Glycosyl
Donors
RESULTS AND DISCUSSION
■
Synthesis of Glycosyl Donors. In preliminary work13,10d it
was demonstrated that the 3,6-bridging can be installed directly
on the readily available phenyl 2,4-di-O-benzyl-1-thio-α-D-
glucopyranoside.17 The initial yields were modest but could be
significantly improved by raising the reaction temperature,
strictly anhydrous conditions, and prolonged reaction time.
Scheme 1 shows the general method for direct 3,6-bridge
formation from the 3,6-diols. Pleased with the easy introduction
and high stability of the di-tert-butylsilylene bridge in the α-
glucopyranoside, we investigated the substrate scope. The 3,6-
diols of the α-18 and β-anomers of mannoside, galactoside, and
glucoside were efficiently synthesized from the corresponding
thioglycosides via a selective 3,6-silylation using TBS-Cl
together with imidazole in DMF, followed by 2,4-benzylation
and subsequent acid-mediated desilylation to the 3,6-diols.19
The diols were then, without further optimization, reacted with
di-tert-butylsilylene ditriflate in 2,6-lutidine at 100 °C for 1−3
hours to give the target 3,6-bridged donors in reasonable yields.
Both the α- and β-donors of different sugars were prepared
effectively, and the configuration of the parent sugars has only
by deacetylation gave the 3,6-diols in high yields. Trans-
formation of the diols into the axial rich bridged compounds 16
and 17 went uneventfully using the standard procedure, giving
the donors in reasonable yields and underlining the generality
of this approach.
In order to investigate Yamada’s method for β-selective
glucosylation14 with this donor system, the corresponding
glycosyl fluorides were synthesized by direct conversion of the
thio-glycosides using DAST and NBS in CH2Cl2.25 No
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Table 1. Coupling Constants, Optical Rotation, and Retention Factor Values for the Eight Thioglycosyl Donors
Rf
pet. ether/CH2Cl2
2:1
H1
H2
H3
H4
H5
H6
H6
C1-H
[α]
7
8
9
6.09 (d,
5.9)
4.04 (m)
4.56 (t, 1.4)
4.04 (m
4.50 (br
s)
4.24 (d 12.7)
4.04 (m)
84.8 (160.5,
4.4)
65.0
0.38
0.65
0.62
0.73
0.49
0.70
0.41
0.78
5.14 (d,
9.2)
3.71 (dd, 9.2, 4.49−4.42 (m) 4.11 (dd, 3.4, 4.04 (m) 4.20−4.08 (m) 3.91 (dd, 12.3, 83.8 (160.4,
10.8
93.1
6.1
0.7)
0.9)
3.0)
4.18−4.13 (m) 3.95 (dd, 12.3, 85.5 (165.0,
2.9) 2.5)
4.25 (dd, 12.4, 3.93 (dd, 12.4, 85.1 (156.6,
0.8) 2.9) 6.0)
4.43 (dd, 13.1, 4.23 (dd, 13.1, 82.8 (160.2,
1.5) 2.3) 5.8)
4.32 (dd, 12.3, 4.19 (dd, 12.3, 85.0 (157.1,
1.5) 2.0) 3.9)
4.22 (dd, 13.2, 4.03 (dd, 13.2, 82.1 (160.8,
2.0) 3.1) 5.7)
4.20 (dd, 12.6, 3.90 (dd, 12.6, 83.4 (160.2,
0.9) 3.3) 4.2)
3.9)
5.65 (d,
4.9)
3.89 (dd, 4.9, 4.52 (m)
3.9)
4.18−4.13
4.42 (br
s)
(m)
10 5.44 (d,
3.96 (t, 5.1)
4.63 (t, 4.8)
4.17 (d, 4.3)
4.08 (d,
2.9)
5.1)
11 6.17 (d,
3.97 (t, 3.0)
4.59 (t, 2.9)
4.33 (dd, 6.7, 4.03 (d,
3.0) 6.6)
2.9
3.2)
12 4.75 (d,
3.79 (dd, 8.5, 4.54 (t, 1.3)
0.9) 1H)
4.10 (dd, 8.2, 4.14 (d,
1.8) 8.2)
−31.0
8.4
8.5)
16 6.06 (d,
3.95−3.91(m) 4.55 (ddd, 2.4, 3.95−3.91(m) 4.35 (br,
4.2)
1.1)
s)
17 5.06 (d,
3.67 (d, 9.8)
4.11 (d, 3.4)
4.50 (d, 3.6)
4.16 (d,
3.1)
41.9
9.8)
degradation of the silylene bridge was observed under these
conditions. All of the fluoride donors were obtained with high
α-selectivity and in good yields.
donors were also recorded at −60 °C. None of the spectra
deviated significantly from the ones recorded at 26 °C, and the
conformations are therefore considered be in the ground state
for the 3,6-bridged system.
Conformation. The 3,6-bridged donors were analyzed in
Glycosylations. With the eight thioglycoside donors (7−
12, 16, and 17) in hand, their properties as glycosyl donors
could be studied. As a standard test three different types of
acceptors were chosen (Figure 1): cyclohexanol 22 (a
detail to determine their conformation, in order to elaborate
3
the influence of the bridge on the ground state structures. JHH
coupling constants were obtained from 1H NMR (see Table 1),
and the approximate vicinal angles were determined on this
basis.26 With this information the ring could be modeled in
Chem3D27 and the structure determined. The glycosyl donors
were all found to resemble a boat conformation, B1,4, or a skew
conformation, 3S1. Donors with α-gluco-stereochemistry (7 and
3
16) resembled a S1 conformation, with a pseudo equatorial
thiophenol avoiding flag-pole interactions with the 4-O-Bn. The
β-anomers (8 and 17) on the other hand resembles an almost
3
perfect B1,4 with a diaxial JH1−H2 coupling constant (9.2 Hz).
The mannosyl donors, 9 and 10, were both found to be in a 3S1
conformation, avoiding unfavorable interactions between the
silylene bridge and the 2-O-benzyl and thiophenol, respectively.
This conformation is in agreement with the observed difference
Figure 1. Glycosyl fluorides and acceptors.
1
(app. 8.5 Hz) in the JC1−H1 couplings, the chemical shifts, and
the 3JH1−H2 couplings (4.9 and 5.1 Hz (α and β); see Table 1).
The α- and β-galactosyl donors (11 and 12) adopts an
approximate B1,4 conformations, which have minimal strain
from steric interactions between the bridge and the now
equatorial 4-O-Bn and the thiophenol, respectively. The
measured optical rotations are consistent with Hudson’s
rule28 with the exception of the 2-azido sugars (16 and 17).
A substantial difference between the retention times (Rf values;
see Table 1) were observed with the α-anomer having the
smallest in all cases. This suggests an unusually big difference in
their respective dipole moments.
secondary nonchiral acceptor), a primary sugar hydroxyl
group 23 (methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside),
and finally a sterically hindered secondary sugar hydroxyl
group on a glycosyl donor 24 (phenyl 2,3,6-tri-O-benzyl-1-thio-
β-D-glucopyranoside) to challenge the reactivity and hence
determine whether the new donor is to be considered super
armed. When the reactivity test failed, then glycosylation was
carried out on a regular 4-hydroxyl acceptor 25 (methyl 2,3,6-
tri-O-benzyl-α-D-glucopyranoside). All donors are activated at
low temperature, in the presence of the acceptor. The reaction
mixture was then allowed to slowly warm to 0 °C, where it was
quenched by adding triethylamine. As the preferred promoter
system NIS/TfOH was chosen due to high yields, clean
reactions, and the formation of I2, which makes it easy to follow
the reaction visually (see Table 2). Preactivation (Ph2SO, Tf2O,
TTBP)30 and Lemieux conditions31 were also tried, but
decomposition of starting material, together with side products
(mainly Friedel−Crafts-type reaction with the 2-O-benzyl32),
and only a small amount of products were observed. The
1
The JC1−H1 couplings are surprisingly similar for all the
anomeric pairs with the mannosyl donors (9 and 10) being the
only pair with a significant difference between them. The
donors with gluco-stereochemistry (7, 8, 16, and 17) have
1
practically the same JCH around 160 Hz and the galacto-pair
(11 and 12) have couplings within a difference of 3 Hz. The
difference usually observed in regular chair conformations
between anomers is around 10 Hz, with the α-anomer
(equatorial H) giving the larger coupling constant. The small
differences observed here suggest a similar C−H bond length
and orientation.29 To eliminate the possibility of having two or
1
selectivity in the glycosylation reactions was determined by H
NMR of the crude reaction mixtures, and all products were
deprotected to confirm the stereochemistry. Table 2
summerizes the glycosylation reactions. In term of selectivity
1
more conformations in a rapid equilibrium, H NMR of all
C
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Table 2. Yields and α/β Ratios for the Glycosylations
no difference between the two anomeric donors was observed;
all glucosylations were slightly α-selective and independent of
donor stereochemistry. Glucosylation on the armed hindered
donor 24 could be performed in a reasonable yield of 64% with
the α-donor 7, but interestingly no glucoside was obtained from
the glucosylation using the β-anomer 8. The β-donor, however,
gave an excellent yield (92%) when using the 4-OH acceptor
25. This demonstrates an unusual big difference in reactivity
between the anomers, with the α being the most reactive and
super armed and the β not (see Table 2).
D
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The β-selective procedure developed by Yamada was
performed using the glucosyl fluoride 18, which is obtained
in one step from the thioglucoside 7. Similar to Yamada’s
xylylene bridged donor15 a complete β-selectivity was observed
with the promoter system SnCl2/AgB(C6F5)4 in benzotri-
fluoride (BTF). TLC of the reaction progress suggested that
the α-anomer is initially formed but in time is anomerized to
the thermodynamically more stable β-anomer. This means that
the silylene bridge is an easy accessible alternative to Yamada’s
xylylene bridge. The phenyl 2,3,6-tri-O-benzyl-1-thio-β-D-
glucopyranoside donor was also tried as acceptor, but the
thioglucoside is not compatible the catalytic promoter system.
The mannosyl donors 9 and 10 were investigated in the same
way as the glucosyl donors (7 and 8) and gave excellent yields
and complete α-selectivity with the different acceptors.
Coupling with the armed donor gave the disaccharide donor
in around 70% for both anomers, i.e., both are highly reactive.
Essentially no difference in yields or selectivity was observed
between the anomeric set of donors. Encouraged by the great
shift in selectivity toward the β-anomer when using Yamada’s
procedure, the mannosyl fluoride donor 19 was prepared from
the corresponding thiomannoside 9, and the glycosylation on
the three acceptors was performed. Disappointingly, no β-
product was obtained, but complete α-selectivity and good to
excellent yields. Prolonged reaction time or increased temper-
ature did not change the outcome.
Competition Experiments between Anomers. Due to
the unexpected and pronounced difference in the reactivity of
the bridged donors, a number of competition experiments were
carried out. In order to compare the 3,6-bridged donors with
other more common donor systems, three other anomeric pairs
were synthesized. Classic α- and β- super armed glucosyl
donors (26 and 27) (silylated) were included because of their
conformational resemblance with the bridged donors, both
3
being close to the S1 conformation, but 26 and 27 being
unrestricted. A pair of armed glucosyl donors (28 and 29)
(phenyl 2,3,4,6-tetra-O-benzyl-D-thioglucopyranoside), being in
the 4C1 chairs representing a standard donor type, and finally a
pair of 3,6-anhydro-donors (30 and 31), being 3,6 -tethered,
but without the bulky bridge, were chosen.
With the 14 donors in hand, each pair was activated under
the NIS/TfOH conditions. One equivalent of each donor
competes for 1 equiv of promoter; the acceptor 22 is present in
5 equiv. The competition reactions were analyzed by isolating
the remaining starting material or by NMR of the crude
reaction mixtures. Since the donors have more distinct spectra,
compared with the products, the amount of unreacted donor
was determined by using methyltriphenylsilane as an internal
standard in the NMR spectra (see Scheme 3). In the
Scheme 3. Competition Experiments between Anomeric
a
Pairs of Donors
The galactosyl donors 11 and 12 were found to perform
similarly to the glucosyl donors, giving excellent yields and α-
selectivity, which is slightly higher for these donors and
increases with the steric bulk of the acceptor. As with the
glucosyl donors (7 and 8) only the α-donor was found to be
more reactive than an armed donor 24. The β-donor 12 gave
mixtures with an armed donor, but excellent yield and
selectivity when coupling to the 4-OH acceptor 25. Changing
to the SnCl2/AgB(C5F6)4 promoter system and the galactosyl
fluoride 20 produced a change in product ratios, and a slight β-
selectivity was obtained when using carbohydrate based
acceptors (23 and 25). The equilibrium is however far from
the gluco case, and only a 2:1 (β:α) ratio could be achieved
(Table 2).
The 2-azido donors 16 and 17 were, as expected, significantly
less reactive than the other donors, and therefore no glycoside
formation was observed when using the armed donor 24 as
acceptor. The selectivity was however found to be close to that
observed for the gluco-donors (7 and 8). When the α-donor 16
was used, excellent yields were obtained within the temperature
frame, despite the higher activation temperature. Changing to
the β-donor 17 gave a dramatic decrease in yield, from 99% to
30%, when using the simple cyclohexanol acceptor. This result
could not be improved further by using more promoter or
higher temperatures; unreacted donor remained the major
outcome of the reaction. This again underlines the substantial
difference in reactivity between the anomers. The product ratio
was found to be essentially the same. Shifting to the glycosyl
fluoride 21 and using the SnCl2/AgB(C6F5)4 promotor system,
a complete β-selectivity was observed for the cyclohexanol
acceptor. The selectivity however decreased when using the
carbohydrate acceptors but remained β-selective. The yields
ranged from 84% to 95%. This result suggests that the
anomerization is taking place in all of the reactions described
here, since it is observed with this, the least reactive donor 21,
and therefore the product ratios mirror the thermodynamic
equilibrium.
a
The reactivity is estimated from the amount of remaining donors
1
isolated or observed and quantified by H NMR.
competition experiments with the silylene bridged donors
only the α-anomers (7, 9, 11, 16) were fully consumed and
only a little of the β-anomer (8, 10, 12, 17) (Table 3, entries
1−4). In the reaction with the 2-azido donors a trace of
remaining α-donor could be observed (see Table 3 for the
results).
When the competition experiment was performed between
the classic super armed donors (26 and 27, Figure 2), an almost
1:1 mixture of remaining donors could be observed after the
reaction, i.e., the anomers have similar reactivity in agreement
with earlier studies (Table 3, entry 5).10c Activation of the per-
benzylated (armed) donors gave a 1:3 (α:β) ratio with the α-
Table 3. Ratios of Donor before and after the Competition
Reaction
entry
donor x,x
ratio before
ratio after
1
2
3
4
5
6
7
8
7,8
1/1
1/1
1/1
1/1
1/1
1/1
1/1
1/1
0/0.84
0/0.97
9,10
11,12
16,17
26,27
28,29
30,31
7,26
0/0.93
0.03/0.94
0.52/0.42
0.22/0.66
0.35/0.41
0.18/0.73
E
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armed perbenzylated donor. The difference in anomeric
reactivity is clearly related to the silylene bridge and not only
the conformation, as demonstrated by the glycosylations with
the conventional super armed donors (26 and 27) and the 3,6-
anhydro-donors (30 and 31). None of them show any
significant difference between the anomers (see Table 3).
The difference observed here can be explained by the
conformational limitations introduced by the bulky di-tert-
butylsilylene, which dictate the conformation for the part of the
sugar ring included in the seven-membered tethering. The two
tert-butyl substituents force the C-1 downward due to steric
conflicts, and the conformational freedom is reduced to
3
Figure 2. Donors, besides the 3,6-silylene bridged, used in competition
experiments.
essentially two conformations, the S1 and the B1,4. These
conformations are close to the intermediate oxo-carbenium
ions’ H4 conformation (see Figure 3),33 and since it is locked,
3
the reactivity, i.e., the leaving group ability, of the activated thio-
acetal (sulfonium ion) becomes important. There is not enough
flexibility to provide access to a pseudoaxial sulfonium ion from
the pseudo equatorial and vice versa (see Figure 4).34
anomer 28 being slightly more reactive than the β 29 (Table 3,
entry 6). Finally the 3,6-anhydro donors gave a 1:1 mixture of
unreacted donors, 30 and 31, mirroring a similar reactivity,
despite the 3,6-restricted conformation (Table 3, entry 7). Thus
the silylene bridge donors are special cases with an unpresented
difference in anomeric reactivity.
To clarify whether the bridged super armed donor 7 can
compete or even exceed the reactivity of a classic unrestricted
silylated donors, such as 26, a competition between the two
types was performed (Table 3, entry 8). The donors (26 and 7)
were allowed to compete for the promoter, as described above,
and to our surprise crude NMR revealed that more of the
bridged donor had been consumed. The classic super armed
donor 26 is therefore less reactive than bridged donor 7 (see
Table 3 for the results and Supporting Information for details
and data).
The 3,6-bridged donors (7−12, 16, and 17) demonstrate
some unique and surprising properties. Due to the axial rich
conformation, it was expected that their reactivity would exceed
that of the armed donors, such has been demonstrated with the
super armed donors earlier developed by this group.10 Indeed
the reactivity was superior for all the bridged 3,6-bridged α-
thioglycosides, but surprisingly only the β-manno donor 10
could compete with a conventional armed donor 24. The β-
galacto-donor 12 and β-gluco-donor 8 gave rise to mixtures,
and the reactivity was found to be in the range of that of an
Upon activation the build-up of positive charge on the sulfur
demands electrons to be stabilized. When having the axial/
pseudoaxial configuration at C1, the anti-periplanar electron
pair on O5 can participate as in a classic E1 elimination reaction
(Figure 4).35 This generates the oxocarbenium intermediate
and departure of the phenyl hypoiodothionite. Due to
inefficient overlap this cannot take place when having the
equatorial/pseudoequatorial configuration (Figure 4). The
orientation of O6, which is dictated by the bridge, might also
contribute additionally to the stability of the oxocarbenium
ion.36 Yang and Woerpel have observed this conformation on
dioxocarbenium ions by NMR.37 These observations have also
been supported by theoretical studies.
Release of strain might also be an important contribution to
the increased reactivity of the axial configuration. As mentioned
above flag-pole interactions with the substituents on C4
generate unfavorable steric interactions. The equatorial isomers
on the other hand are in steric conflict with the bridge.
There could be parallels between this proposed mechanism
and what is referred to as the ether effect38 and in some cases
the “reverse anomeric effect”.39 In these “effects” a cationic
substituent on C1 prefers an equatorial position. The axial
Figure 3. Reaction pathway for the glycosyl donors.
F
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Figure 4. α-Anomer is activated faster than the β-anomer because of the optimal anti periplanar orbital alignment for an E1 elimination. To obtain a
1
similar overlap the β-anomer has to approach the C4 conformation, which is sterically highly unfavorable.
aglycon might simply be too reactive40 and hence will
transform into the thermodynamic product, the equatorial
isomer. A similar trend has been observed in studies of the
related glycosyl sulfonium ions by low temperature NMR; only
the equatorial isomers were observed.41
The observed stereoselectivity stems from several contribu-
ting effects. The bridge itself is very sterically demanding and
shields the β-face effectively.42 The effect is enhanced when the
O4 is equatorial and pushes the bridge further toward the
anomeric site, i.e., the galacto-donors (11 and 12) gives more
α-product compared to the donors with gluco-stereochemistry
(7 and 8). The enhanced effect in the galacto donors is
resulting in an increased α-selectivity with increasing acceptor
size.
anomerization conditions. The experiments strongly suggest
that the post-glycosylation anomerization is taking place for all
of the donors, even the disarmed 2-azido donor 21, and the
obtained product ratios are therefore mirroring the thermody-
namic equilibrium between the anomers obtained from
glycosylation with the four glycosyl fluoride donors (18−21)
(12 glycosylations), with the two extremes being the strongly
favored β-glucosides and α-mannosides. The remarkable β-
gluco-selectivity can be explained by the looking at the
3
conformations; the β-anomers prefers a B1,4, whereas a S1 is
more stable for the α due to the flag-pole interactions. As
illustrated in Figure 3 there is only little strain in the B1,4
conformation, and hence it must be more thermodynamically
stable. The galacto stereochemistry reduces the flag-pole
interaction and pushes the bridge toward the β-site, and the
effect diminishes the difference between the anomers. The α-
mannosides are disfavored by the flag-pole interactions, but this
effect is overruled by stereoelectronic effects from the
neighboring O2 and the O5. The interplay between the
anomeric effect and the Δ2 effect43 is acting and stabilizes the
α-anomer. Additionally the B1,4 conformation, favoring the β-
anomer, is disfavored by the steric clash between the bridge and
Normally the attack on the oxocarbenium ion, which directly
produces the chair conformation, is kinetically preferred. Attack
from the opposite site gives a twist-boat conformation, which in
unrestricted donors has to transit to the thermodynamic more
stable chair. In the bridged donor the opposite effect is seen
3
since the more stable ground state conformation is the S1 or
B1,4; both close to the twist boat intermediate. The kinetic
product is therefore the α-anomer (Figure 5).
3
the 2-O-Bn, making the S1 conformation the most stable.
In conclusion, it has been shown that 3,6-bridged glycosyl
donors indeed are more reactive than conventionally armed
glycosyl donors and hence they are super armed. It is now
possible to super arm the most common glycosyl donors with a
3,6-tether, making the concept even more attractive for
oligosaccharide synthesis, especially when a 2−4 or 3−6
branching is desired. The reactivity is strongly dependent on
anomeric configuration, with an axial leaving group being
superior. This has been explained by the need of participation
from the O5 lone pair. When the overlap is poor, such as for
the equatorial isomer, reactivity drops dramatically. The extent
of this effect has not been observed earlier due to conforma-
tionally flexibility and steric in conventional donors. The effect
is for example not seen in a perbenzylated-, 3,6-anhydro, or
classic super armed glucosyl donor, so far only in the 3,6-
bridged donors. Due to the restriction and bulk of the di-tert-
butylsilylene only two ground state conformations are
Figure 5. Exo attack is favored, and the α-anomer is thereby the major
product. The normally disfavored twist boat is the most stable
conformation due to the restriction by the 3,6-bridge.
When the glucosyl fluoride 18 was used as the donor,
complete β-selectivity (using Yamada’s conditions) could be
obtained independent of the acceptor used. When the galacto-
donor 20 was used, an increase in β-product was observed
compared with the NIS/TfOH method, but not to a
synthetically useful extent. Despite the lower reactivity of the
2-azido derivative 21, complete β-selectivity could be obtained
with the cyclohexanol acceptor. The complete α-selectivity in
the mannosylation (with 19) was however unaffected by the
3
observed, the S1 and the B1,4. Anomerization using SnCl2/
AgB(C6F5)4 as the catalyst takes place for all glycosides
presented here, but only the gluco-stereochemistry, and hence
conformation, significantly favors the β-product; α-mannosides
G
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evaporated to dryness. The crude product was purified by flash column
are still thermodynamically favored despite the conformational
changes.
chromatography with petroleum ether as eluent with a gradient of
1
DCM, giving the product as a clear oil. Yield 0.231 g, 59%. H NMR
(500 MHz, chloroform-d) δ 7.74−7.46 (m, 5H), 7.46−7.13 (m, 10H),
6.09 (d, J = 5.9 Hz, 1H, H1), 4.91 (d, J = 11.5 Hz, 1H, benzyl), 4.83−
4.62 (m, 3H, benzyl), 4.56 (t, J = 1.4 Hz, 1H, H3), 4.50 (s, 1H, H5),
4.24 (d, J = 12.7 Hz, 1H, H6), 4.04 (m, 3H, H2, H4, H6), 0.95 (d, J =
12.4 Hz, 18H, TBS). 13C NMR (126 MHz, CDCl3) δ 138.2(ipso),
138.0(ipso), 137.4(ipso), 130.6(Ar), 128.8(Ar), 128.5(Ar), 128.4(Ar),
128.0(Ar), 127.8(Ar), 127.7(Ar), 126.5(Ar), 84.8(C1), 78.0, 75.4,
73.6, 73.2(CH2-benzyl), 71.2(CH2-benzyl), 70.0, 68.3(C6), 28.4-
EXPERIMENTAL SECTION
■
General Methods. All reagents were used as purchased without
further purification. Dry solvents were taken from a solvent
purification system. Glassware used for water-free reactions was
dried for 12 h at 120 °C before use. Columns were packed with silica
gel 60 (230−400 mesh) as the stationary phase. TLC plates (Merck,
60, F254) were visualized by 10% H2SO4 in EtOH and heating until
(CH3), 28.1(CH3), 21.9(C-Si), 21.2(C-Si). [α]rt 65.0° (c 1.0,
1
spots appeared. H NMR and 13C NMR spectra were recorded on a
D
CH2Cl2), HRMS calcd for C34H44O5SSiNa 615.2576, found 615.2570
2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-fluoro-α-D-
glucopyranoside (18). Phenyl 2,4-di-O-benzyl-3,6-O-(di-tert-butylsi-
lylene)-1-thio-α-D-glucopyranoside (0.0593 g, 0.1 mmol) was
dissolved in DCM (2 mL), and the solution was cooled to −15 °C.
To the solution was added DAST (0.04 mL, 0.3 mmol), the solution
was stirred for 5 min, and then NBS (0.0463 g, 0.26 mmol) was added
. The reaction was stirred for 1 h while it was slowly allowed to reach 0
°C. The reaction mixture was then transferred to a separation funnel,
washed with satd bicarbonate solution and brine, then dried with
MgSO4, filtered, and evaporated to dryness. The crude compound was
purified by flash column chromatography with petroleum ether as
eluent with a gradient of DCM, giving the product as a clear oil. Yield
500 MHz spectrometer equipped with a cryo probe. Chemical shifts
(δ) are reported in ppm relative to the residual solvent signal (δ = 7.26
1
for H NMR and 77.16 for 13C NMR). High-resolution mass spectral
(HRMS) data were obtained on an electrospray (ESI) time-of-flight
mass spectrometer. Optical rotation data were obtained on a Perkin-
Elmer 341 Polarimeter. NMR assignments were based on COSY and
HSQC NMR experiments.
Phenyl 3,6-Di-O-acetyl-2,4-di-O-benzyl-1-thio-α-D-glucopyr-
anoside. 1,3,6-Tri-O-acetyl-2,4-di-O-benzyl-α/β-D-glucopyranoside
(16.6 g, 0.034 mol) and thiophenol (4.4 mL, 0.043 mol) in 200 mL
dry DCM was cooled to 0 °C, and BF3·Et2O (5.26 mL, 0.043 mol) was
added. The solution was allowed to reach room temperature and was
stirred for 24 h. The reaction was quenched with satd bicarbonate
solution. The mixture was extracted with 1 M HCl, satd bicarbonate
solution, and brine. The organic layer was dried with MgSO4, filtered,
and evaporated to dryness. The crude product was purified by flash
column chromatography with petroleum ether as eluent with a
gradient of EtOAc Recrystallization from methanol gave the product as
white crystals. Yield: 6.76, 38%. 1H NMR (500 MHz, chloroform-d) δ
7.49−7.44 (m, 2H, Ar), 7.38−7.23 (m, 13H, Ar), 5.63 (d, J = 5.5 Hz,
1H, H1), 5.49 (t, J = 9.4 Hz, 1H, H3), 4.73 (d, J = 12.3 Hz, 1H,
benzyl), 4.63−4.52 (m, 3H, benzyl), 4.49 (ddd, J = 10.0, 5.1, 2.1 Hz,
1H, H5), 4.28 (dd, J = 12.0, 5.2 Hz, 1H, H6), 4.20 (dd, J = 12.0, 2.2
Hz, 1H, H6), 3.79 (dd, J = 9.9, 5.5 Hz, 1H, H2), 3.57−3.50 (m, 1H,
H4), 2.02 (s, 3H, Ac), 1.99 (s, 3H, Ac). 13C NMR (126 MHz, CDCl3)
δ 170.7(CO), 169.8(CO), 137.5(ipso), 137.4(ipso), 133.8(ipso),
132.0(Ar), 129.1(Ar), 128.7(Ar), 128.6(Ar), 128.2(Ar), 128.2(Ar),
128.14(Ar), 128.0(Ar), 127.5(Ar), 86.5(C1), 76.9(C2), 76.2(C3),
74.4(CH2-benzyl), 73.9(C3), 72.2(CH2-benzyl), 69.4(C5), 63.1(C6),
1
0.081 g, 81%, H NMR (500 MHz, chloroform-d) δ 7.41−7.38 (m,
2H, Ar), 7.37−7.33 (m, 2H, Ar), 7.33−7.30 (m, 1H, Ar), 7.29 (s, 5H,
Ar), 5.72 (dd, J = 53.2, 5.9 Hz, 1H, H1), 4.80 (d, J = 11.8 Hz, 1H, CH-
benzyl), 4.73 (d, J = 11.7 Hz, 1H, CH-benzyl), 4.68 (d, J = 11.5 Hz,
1H, CH-benzyl), 4.51−4.44 (m, 2H), 4.30−4.26 (m, 1H), 4.23 (dd, J
= 12.7, 1.1 Hz, 1H, H6), 4.06 (s, 1H), 3.97 (ddd, J = 12.7, 3.0, 1.9 Hz,
1H, H6), 3.80 (dd, J = 22.5, 5.8 Hz, 1H, H2), 1.00 (s, 9H, TBS), 0.92
(s, 9H, TBS). 13C NMR (126 MHz, CDCl3) δ 138.1(ipso, Ar),
137.5(ipso, Ar), 128.6(Ar), 128.5(Ar), 128.1(Ar), 128.1(Ar),
127.9(Ar), 127.8(Ar), 109.9 (d, J = 212.3 Hz, C1), 83.3 (d, J = 23.9
Hz, C2), 81.4 (d, J = 4.2 Hz), 74.63−74.62, (broad doublet), 72.7 (d, J
= 8.4 Hz), 72.7(CH2-benzyl), 71.9(CH2-benzyl), 66.7(C6), 28.1-
(CH3), 27.8(CH3), 21.8(C-Si), 21.6(C-Si).13C NMR (126 MHz,
chloroform-d, CH-coupling) δ 109.9 (dddd, J = 212.3, 174.9, 5.2 Hz).
19F NMR (282 MHz, chloroform-d) δ −134.9 (dd, J = 52.6, 23.1 Hz).
[α]rt 34.6° (c 1.0, CHCl3), HRMS calcd for C28H39O5SiFNa =
D
21.2(CH3-Ac), 21.0(CH3-Ac). Mp 143−144 °C, [α]rt 195° (c 1.0,
525.2448, found 525.2444
D
Phenyl 3,6-Di-O-TBS-1-thio-β-D-glucopyranoside. To a sol-
ution of phenyl-1-thio-β-D-glucopyranoside (8.28 g, 0.0304 mol) in
125 mL DMF at 0 °C were added imidazole (7.25 g, 0.106 mol) and
TBSCl (16.0 g, 0.0912 mol). The mixture was stirred overnight at
room temperature and was then quenched with MeOH. The mixture
was added EtOAc and extracted with 1 M HCl, satd bicarbonate
solution, and brine. The organic layer was dried with MgSO4, filtered,
and evaporated to dryness. The crude product was purified by flash
column chromatography with petroleum ether as eluent with a
gradient of DCM, giving the known product as a clear oil. Yield 7.89 g,
52%.
CH2Cl2), HRMS calcd for C30H32O7SNa 559.1766, found 559.1771
Phenyl 2,4-Di-O-benzyl-1-thio-α-D-glucopyranoside (4b).
Phenyl 3,6-di-O-acetyl-2,4-di-O-benzyl-1-thio-α-D-glucopyranoside
(6.7 g, 12.49 mmol) was dissolved in a mixture of 67 mL DCM and
67 mL MeOH. To the solution was added 5 mL of 25% sodium
methoxide solution in methanol. The reaction was stirred until TLC
showed full conversion. The solution was neutralized by adding
Amberlite IR120. The solution was filtered and evaporated to dryness
giving the product as a syrup. Yield 5.65 g, 100%. 1H NMR (500 MHz,
chloroform-d) δ 7.47−7.24 (m, 15H, Ar), 5.60 (d, J = 5.3 Hz, 1H,
H1), 4.94 (d, J = 11.3 Hz, 1H, benzyl), 4.79 (d, J = 11.4 Hz, 1H,
benzyl), 4.72 (d, J = 11.3 Hz, 1H, benzyl), 4.61 (d, J = 11.4 Hz, 1H,
benzyl), 4.20 (dt, J = 9.9, 3.4 Hz, 1H, H5), 4.05 (t, J = 9.2 Hz, 1H,
H3), 3.80−3.72 (m, 2H, H6), 3.69 (dd, J = 9.6, 5.4 Hz, 1H, H2),
3.56−3.50 (m, 1H, H4). 13C NMR (126 MHz, CDCl3) δ 138.4(ipso),
137.4(ipso), 134.1(ipso), 132.2(Ar), 129.2(Ar), 128.7(Ar), 128.7(Ar),
128.4(Ar), 128.4(Ar), 128.3(Ar), 128.1(Ar), 127.6(Ar), 86.4(C1),
79.3(C2), 76.9(C4), 74.8(CH2-benzyl), 74.4(C3), 72.4(CH2-benzyl),
Phenyl 2,4-Di-O-benzyl-1-thio-β-D-glucopyranoside (4a). To
a solution of phenyl 3,6-di-O-TBS-1-thio-β-D-glucopyranoside (7.89 g,
0.0158 mol) in 75 mL DMF at 0 °C were added BnBr (5.62 mL,
0.0473 mol) and NaH (1.9 g, 0.0473 mol). The mixture was stirred
overnight at room temperature and was then quenched with MeOH.
The mixture was added to Et2O and extracted with water, and brine.
The organic layer was dried with MgSO4, filtered, and evaporated to
dryness. The crude product was dissolved in 50 mL MeOH, and a
catalytic amount of TsOH was added. The mixture was refluxed for 2 h
and quenched by adding 3 mL of Et3N. The mixture was evaporated,
and the crude product was purified by flash column chromatography
with petroleum ether as eluent with a gradient of EtOAc, giving the
product as a clear plastic solid. Yield 5.68 g, 80%. The compound can
71.5(C5), 62.0(C6). [α]RT 185° (c 1.0, CH2Cl2), HRMS calcd for
D
C26H28O5SNa 475.1555, found 475.1546
Phenyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-thio-
α-D-glucopyranoside (7). Phenyl 2,4-di-O-benzyl-1-thio-α-D-gluco-
pyranoside (0.3 g, 0.663 mmol) was dissolved in 8 mL of dry 2,6-
lutidine. The solution was added di-tert-butylsilyl ditriflate (0.24 mL,
0.729 mmol) and heated to 100 °C for 4 h. The solution was cooled to
rt, and ethyl acetate was added and then extracted 3 times with 1 M
HCl solution, one time with satd bicarbonate solution, and one time
with brine. The organic layer was dried with MgSO4, filtered, and
1
be crystallized from MeOH giving white crystals. Mp 63−65 °C, H
NMR (500 MHz, chloroform-d) δ 7.56−7.52 (m, 2H, Ar), 7.44−7.31
(m, 13H, Ar), 5.01 (d, J = 10.9 Hz, 1H, CH2-benzyl), 4.85 (d, J = 11.3
Hz, 1H, CH2-benzyl), 4.77−4.69 (m, 3H, CH2-benzyl, H1), 3.92 (ddd,
H
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Article
J = 12.0, 6.2, 2.6 Hz, 1H, H6), 3.82 (tt, J = 8.8, 2.6 Hz, 1H, H3), 3.74
(ddd, J = 12.1, 7.4, 4.9 Hz, 1H, H6), 3.52−3.47 (m, 1H, H4), 3.45−
3.35 (m, 2H, H5, H2), 2.46 (d, J = 2.6 Hz, 1H, OH-2), 1.93 (dd, J =
7.3, 6.4 Hz, 1H, OH-6). 13C NMR (126 MHz, CDCl3) δ 138.2(ipso),
138.09(ipso), 133.56(ipso), 131.86(Ar), 129.23(Ar), 128.78(Ar),
128.74(Ar), 128.36(Ar), 128.28(Ar), 128.21(Ar), 128.18(Ar),
127.86(Ar), 87.25(C1), 81.05(C2), 79.18(C5), 78.70(C3),
77.32(C4), 75.44(CH2-benzyl), 74.90(CH2-benzyl), 62.41(C6).
purified by flash column chromatography with petroleum ether as
eluent with a gradient of DCM, giving the product as a clear oil. Yield
1
0.216 g, 75%, H NMR (300 MHz, chloroform-d) δ 7.46−7.25 (m,
10H, Ar), 5.71 (d, J = 54.7 Hz, 1H, H1), 4.72 (d, J = 11.8 Hz, 1H, CH-
benzyl), 4.66 (d, J = 11.8 Hz, 1H, CH-benzyl), 4.56 (m, 3H), 4.33 (s,
1H), 4.22−4.14 (m, 2H), 4.06−3.95 (m, 1H), 3.92−3.83 (m, 1H),
1.02 (d, J = 1.6 Hz, 9H), 0.94 (d, J = 1.6 Hz, 9H). 13C NMR (126
MHz, CDCl3) δ 138.21, 137.34, 128.71, 128.48, 128.25, 127.94,
127.83, 127.78, 110.83 (d, J = 222.9 Hz), 76.22 (d, J = 35.0 Hz), 75.51,
73.59, 72.22, 70.81, 68.10, 67.52 (d, J = 6.4 Hz), 28.05, 27.90, 21.92,
21.87. 19F NMR (282 MHz, chloroform-d) δ −121.20 (dd, J = 55.3,
[α]rt −3.6° (c 1.0, CHCl3), HRMS calcd for C26H28O5SNa
D
475.1555, found 475.1547
Phenyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-thio-
β-D-glucopyranoside (8). Phenyl 2,4-di-O-benzyl-1-thio-β-D-gluco-
pyranoside (1.0, 2.21 mmol) was dissolved in 10 mL of dry 2,6-
lutidine. To the solution was added di-tert-butylsilyl ditriflate (0.8 mL,
2.43 mmol), and the mixture was heated to 100 °C for 3 h. The
solution was cooled to rt and added to ethyl acetate and was then
extracted 5 times with 1 M HCl solution, one time with satd
bicarbonate solution, and one time with brine. The organic layer was
dried with MgSO4, filtered, and evaporated to dryness. The crude
product was purified by flash column chromatography with petroleum
ether as eluent with a gradient of DCM, giving the product as a clear
18.3 Hz). [α]rt 65.6° (c 1.0, CHCl3), HRMS calcd for
D
C28H39O5SiFNa 525.2448, found 525.2446
Phenyl 3,6-Di-O-TBS-1-thio-β-D-mannopyranoside. To a
solution of phenyl-1-thio-β-D-mannopyranoside (6.17 g, 0.0230 mol)
in 100 mL DMF at 0 °C were added imidazole (3.32 g, 0.0487 mol)
and TBSCl (7.34 g, 0.0487 mol). The mixture was stirred overnight at
room temperature and was then quenched with MeOH. The mixture
was added to EtOAc and extracted with 1 M HCl, satd bicarbonate
solution, and brine. The organic layer was dried with MgSO4, filtered,
and evaporated to dryness. The crude product was purified by flash
column chromatography with petroleum ether as eluent with a
gradient of DCM, giving the product as a clear syrup. Yield 7.02 g,
1
oil. Yield 0.468 g, 37%. H NMR (500 MHz, chloroform-d) δ 7.46−
7.41 (m, 5H, Ar), 7.37−7.29 (m, 5H, Ar), 7.25−7.19 (m, 5H, Ar), 5.14
(d, J = 9.2 Hz, 1H, H1), 4.84 (d, J = 11.6 Hz, 1H, CH2-benzyl), 4.78
(d, J = 11.6 Hz, 1H, CH2-benzyl), 4.67 (d, J = 11.6 Hz, 1H, CH2-
benzyl), 4.49−4.42 (m, 2H, CH2-benzyl, H3), 4.20−4.18 (m, 2H, H5,
H6), 4.11 (dd, J = 3.4, 0.9 Hz, 1H, H4) 3.91 (dd, J = 12.3, 3.0 Hz, 1H,
H6), 3.71 (dd, J = 9.2, 0.7, 1H, H2), 1.00 (s, 9H, TBS), 0.90 (s, 9H,
TBS). 13C NMR (126 MHz, CDCl3) δ 138.34(ipso), 137.75(ipso),
135.27(ipso), 130.95(Ar), 128.88(Ar), 128.53(Ar), 128.44(Ar),
128.22(Ar), 128.08(Ar), 127.97(Ar), 127.81(Ar), 126.99(Ar),
83.75(C1), 82.73(C2), 81.89, 74.93, 73.37(CH2-benzyl), 71.76(CH2-
benzyl), 71.71, 67.56(C6), 28.39(CH3), 27.84(CH3), 21.81(C-Si),
1
62%. H NMR (500 MHz, chloroform-d) δ 7.49 (m, 2H, Ar), 7.30−
7.19 (m, 3H, Ar), 4.82 (t, J = 1.4 Hz, 1H, H1), 4.04−3.99 (m, 1H,
H2), 3.89 (d, J = 5.8 Hz, 2H, H6), 3.73 (td, J = 9.2, 1.9 Hz, 1H, H4),
3.61 (dd, J = 8.7, 3.6 Hz, 1H, H3), 3.32 (dt, J = 9.4, 5.8 Hz, 1H, H5),
2.81 (d, J = 1.9 Hz, 1H,OH4), 2.68 (t, J = 1.6 Hz, 1H, OH2), 0.90 (s,
9H, (CH3)3), 0.88 (s, 9H, (CH3)3), 0.13 (s, 3H, CH3-Si), 0.11 (s, 3H,
CH3-Si), 0.07 (s, 3H, CH3-Si), 0.06 (s, 3H, CH3-Si).13C NMR (126
MHz, CDCl3) δ 135.6(Ar), 130.8(Ar), 129.0(Ar), 127.3(Ar),
86.7(C1), 78.6(C5), 76.3(C3), 73.0(C2), 70.6(C4), 65.2(C6),
26.0((CH3)3), 25.9((CH3)3), 18.4(C-Si)1, 18.3(C-Si), −4.3(CH3-Si),
21.65(C-Si). [α]rt 10.8° (c 1.0, CHCl3), HRMS calcd for
−4.7(CH3-Si), −5.3(CH3-Si), −5.4(CH3-Si). [α]rt −59.5 (c 1.0,
D
D
C34H44O5SSiNa 615.2576, found 615.2569
CHCl3), HRMS calcd for C24H44O5Si2SNa 523.2346, found 523.2341
Phenyl 2,4-Di-O-benzyl-1-thio-β-D-mannopyranoside (5a).
To a solution of phenyl 3,6-di-O-TBS-1-thio-β-D-mannopyranoside
(7.02 g, 0.0140 mol) in 100 mL DMF at 0 °C were added BnBr (4.2
mL, 0.0350 mol) and NaH (1.4 g, 0.0350 mol). The mixture was
stirred overnight at room temperature and was then quenched with
MeOH. The mixture was added to Et2O and extracted with water and
brine. The organic layer was dried with MgSO4, filtered, and
evaporated to dryness. The crude product was dissolved in 100 mL
MeOH, and a catalytic amount of TsOH was added. The mixture was
refluxed for 2 h and quenched by adding 5 mL of Et3N. The mixture
was evaporated, and the crude product was purified by flash column
chromatography with petroleum ether as eluent with a gradient of
EtOAc, giving the product as a clear syrup. Yield 4.56 g, 72%. 1H NMR
(500 MHz, chloroform-d) δ 7.52−7.46 (m, 4H), 7.44−7.41 (m, 2H),
7.39−7.28 (m, 9H), 5.01 (d, J = 11.4 Hz, 1H, CH2-benzyl), 4.90 (d, J
= 1.1 Hz, 1H, H1), 4.87−4.80 (m, 2H, CH2-benzyl), 4.71 (d, J = 11.2
Hz, 1H, CH2-benzyl), 4.10 (dd, J = 3.2, 1.1 Hz, 1H, H2), 3.95 (dd, J =
12.0, 2.8 Hz, 1H, H6), 3.81 (dd, J = 12.0, 5.4 Hz, 1H, H6), 3.78 (dd, J
= 9.3, 3.3 Hz, 1H, H3), 3.76−3.72 (m, 1H, H4), 3.37 (ddd, J = 8.4, 5.3,
2.7 Hz, 1H, H5), 2.12(s, 2H). 13C NMR (126 MHz, CDCl3) δ
138.1(ipso), 138.0(ipso), 134.9(ipso), 130.8(Ar), 129.3(Ar),
128.7(Ar), 128.7(Ar), 128.5(Ar), 128.3(Ar), 128.3(Ar), 128.2(Ar),
127.6(Ar), 87.8(C1), 80.6(C2), 79.9(C5), 76.4(CH2-benzyl), 76.1,
Phenyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-thio-
α-D-mannopyranoside (9). Phenyl 2,4-di-O-benzyl-1-thio-α-D-man-
nopyranoside (0.841 g, 1.86 mmol) was dissolved in 10 mL of dry 2,6-
lutidine. To the solution was added di-tert-butylsilyl ditriflate (0.66
mL, 2.04 mmol), and the mixture was heated to 100 °C for 1 h. The
solution was cooled to rt and was then added to ethyl acetate and was
then extracted 3 times with 1 M HCl solution, one time with satd
bicarbonate solution, and one time with brine. The organic layer was
dried with MgSO4, filtered, and evaporated to dryness. The crude
product was purified by flash column chromatography with petroleum
ether as eluent with a gradient of DCM, giving the product as a clear
1
oil. Yield 0.575 g, 53%. H NMR (500 MHz, chloroform-d) δ 7.50−
7.47 (m, 2H), 7.43−7.40 (m, 2H), 7.39−7.35 (m, 2H), 7.34−7.32 (m,
5H), 7.30−7.26 (m, 4H), 7.23−7.19 (m, 1H), 5.65 (d, J = 4.9 Hz, 1H,
H1), 4.70 (d, J = 11.8 Hz, 1H, CH-benzyl), 4.68−4.59 (m, 3H, CH-
benzyl, H3), 4.50 (d, J = 12.1 Hz, 1H, CH-benzyl), 4.42 (s, 1H, H5),
4.18−4.13 (m, 2H, H4, H6), 3.95 (dd, J = 12.3, 2.9 Hz, 1H, H6), 3.89
(dd, J = 4.9, 3.9 Hz, 1H, H2), 1.03 (s, 9H, TBS), 0.94 (s, 9H, TBS).
13C NMR (126 MHz, CDCl3) δ 138.61(Ar ipso), 137.61(Ar(ipso),
136.42(Ar,ipso), 130.15(Ar), 128.87(Ar), 128.67(Ar), 128.39(Ar),
128.11(Ar), 127.93(Ar), 127.78(Ar), 127.61(Ar), 126.51(Ar),
85.54(C1), 76.95(C2), 74.83(C4), 73.75(C5), 71.88(CH2-benzyl),
70.92(CH2-benzyl), 68.67(C3), 68.19(C6), 28.24(CH3), 28.16(CH3),
21.95(C-Si), 21.90(C-Si). [α]rtD 93.1° (c 1.0, CHCl3), HRMS calcd for
C34H44O5SSiNa 615.2576, found 615.2572
75.8, 75.1(CH2-benzyl), 62.6(C6). [α]rt −93.8 (c 1.0, CHCl3),
D
HRMS calcd for C26H28O5SNa 475.1555, found 475.1548
2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-fluoro-α-D-
mannopyranoside (19). Phenyl 2,4-di-O-benzyl-3,6-O-(di-tert-bu-
tylsilylene)-1-thio-α-D-mannopyranoside (0.341 g, 0.575 mmol) was
dissolved in DCM (6 mL), and the solution was cooled to −15 °C. To
the solution was added DAST (0.11 mL, 0.863 mmol), the solution
was stirred for 5 min, and then NBS (0.133 g, 0.748 mmol) was added.
The reaction was stirred for 1 h while it was slowly allowed to reach 0
°C. The reaction mixture was then transferred to a separation funnel,
washed with satd bicarbonate solution and brine, then dried with
MgSO4, filtered, and evaporated to dryness. The crude compound was
Phenyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-thio-
β-D-mannopyranoside (10). Phenyl 2,4-di-O-benzyl-1-thio-β-D-
mannopyranoside (0.858 g, 1.90 mmol) was dissolved in 10 mL of
dry 2,6-lutidine. To the solution was added di-tert-butylsilyl ditriflate
(0.74 mL, 2.28 mmol), and the mixture was heated to 100 °C for 1 h.
The solution was cooled to rt, and then ethyl acetate was added and
extracted 3 times with 1 M HCl solution, one time with satd
bicarbonate solution, and one time with brine. The organic layer was
dried with MgSO4, filtered, and evaporated to dryness. The crude
product was purified by flash column chromatography with petroleum
I
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Article
ether as eluent with a gradient of DCM, giving the product as a clear
oil. Yield 0.626 g, 56%. H NMR (500 MHz, chloroform-d) δ 7.54−
g, 0.05 mol) in 50 mL HMPA was added slowly. The reaction mixture
was stirred for 1 h and then quenched by adding water. The mixture
was diluted with EtOAc, washed three times with water and one time
with brine, dried with MgSO4, filtered, and evaporated to dryness. The
crude compound was subjected to flash column chromatography with
petroleum ether as eluent with a gradient of EtOAc, giving the impure
product as a mixture of anomers (α/β, 4:1). The crude compound was
dissolved in 50 mL of MeOH, and 1 mL of NaOMe solution was
added. The mixture was stirred for 4 h and was then neutralized by
adding Amberlite IR120. The solution was filtered and evaporated to
dryness giving crude phenyl 1-thio-α-D-galactopyranoside, in total 7.1
g. The crude phenyl 1-thio-α-D-galactopyranoside (7.1 g, 0.0261 mol)
was dissolved in 100 mL of dry DMF. The solution was cooled to 0
°C, and then imidazole (3.82 g, 0.0561 mol) and TBSCl (8.45 g,
0.0561 mol) were added. The mixture was stirred overnight, and was
then 5 mL of methanol and 100 mL of EtOAc were added. The
mixture was washed with water, 1 M HCl solution, satd NaHCO3
solution, and brine, then dried with MgSO4, filtered, and evaporated to
dryness. The crude compound was subjected to flash column
chromatography with DCM as eluent giving impure phenyl 3,6-O-di-
tert-butylsilyl-1-thio-α-D-galactopyranoside, 3.83 g. The crude phenyl
3,6-O-di-tert-butylsilyl-1-thio-α-D-galactopyranoside (3.83 g, 0.00765
mol) was dissolved in 50 mL of DMF and cooled to 0 °C, and first
benzylbromide (3.7 mL, 0.0191 mol) and then NaH (0.76 g, 0.0191
mol) were added. The mixture was stirred overnight and then
quenched by adding 5 mL of methanol. The mixture was diluted with
EtOAc, washed with water and brine, then dried with MgSO4, filtered,
and evaporated to dryness. The crude product was dissolved in 50 mL
of methanol, and 0.1 g of TsOH was added. The mixture was refluxed
for 3 h, and then 1 mL of triethylamine was added. The solution was
evaporated, and the crude product was purified by flash column
chromatography with petroleum ether as eluent with a gradient of
EtOAc The product was further purified by recrystallization from
DCM and petroleum ether, giving the product as white crystals. Yield
1
7.46 (m, 4H, Ar), 7.42−7.20 (m, 11H, Ar), 5.44 (d, J = 5.1 Hz, 1H,
H1), 4.86 (d, J = 12.1 Hz, 1H, CH2-benzyl), 4.65 (d, J = 12.1 Hz, 1H,
CH2-benzyl), 4.63 (t, J = 4.8 Hz, 1H, H3), 4.57 (d, J = 12.0 Hz, 1H,
CH2-benzyl), 4.51 (d, J = 12.0 Hz, 1H, CH2-benzyl), 4.25 (dd, J =
12.4, 0.8 Hz, 1H, H6), 4.17 (d, J = 4.3 Hz, 1H, H4), 4.08 (d, J = 2.9
Hz, 1H, H5), 3.96 (t, J = 5.1 Hz, 1H, H2), 3.93 (dd, J = 12.4, 2.9 Hz,
1H, H6), 1.10 (s, 9H, (CH3)3), 0.97 (s, 9H, (CH3)3). 13C NMR (126
MHz, CDCl3) δ 138.7(ipso), 137.4(ipso), 137.0(ipso), 130.2(Ar),
128.8(Ar), 128.7(Ar), 128.3(Ar), 128.3(Ar), 128.0(Ar), 127.5(Ar),
127.4(Ar), 126.4(Ar), 85.1(C1), 81.4(C5), 74.6(C4), 74.2(C2),
72.5(CH2-benzyl), 71.5(CH2-benzyl), 67.9(C6), 67.7(C3), 28.3-
(CH3), 27.9(CH3), 22.2(C-Si), 21.9(C-Si). [α]rt 6.1° (c 1.0,
D
CHCl3), HRMS calcd for C34H44O5SSiNa 615.2576, found 615.2566
Phenyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-thio-
β-D-galactopyranoside (12). Phenyl 2,4-di-O-benzyl-1-thio-β-D-
galactopyranoside (1.24 g, 2.74 mmol) was dissolved in 10 mL of
dry 2,6-lutidine. To the solution was added di-tert-butylsilyl ditriflate
(1 mL, 3.01 mmol), and the mixture was heated to 100 °C for 2 h. The
solution was cooled to rt, and was ethyl acetate was added and
extracted 3 times with 1 M HCl solution, one time with satd
bicarbonate solution, and one time with brine. The organic layer was
dried with MgSO4, filtered, and evaporated to dryness. The crude
product was purified by flash column chromatography with petroleum
ether as eluent with a gradient of DCM, giving the product as a clear
oil. Yield 0.716 g, 44%. 1H NMR (500 MHz, chloroform-d) δ 7.47 (dd,
J = 8.2, 1.3 Hz, 2H, Ar), 7.42−7.23 (m, 13H. Ar), 4.77 (s, 2H, CH2-
benzyl), 4.75 (d, J = 8.5 Hz, 1H, H1), 4.71 (d, J = 12.3 Hz, 1H, CH2-
benzyl), 4.54 (t, J = 1.3 Hz, 1H, H3), 4.45 (d, J = 12.3 Hz, 1H, CH2-
benzyl), 4.32 (dd, J = 12.3, 1.5 Hz, 1H, H6), 4.19 (dd, J = 12.3, 2.0 Hz,
1H, H6), 4.14 (d, J = 8.2, 1H, H5), 4.10 (dd, J = 8.2, 1.8 Hz, 1H, H4),
3.79 (dd, J = 8.5, 0.9 Hz, 1H, H2), 1.10 (s, 9H), 1.03 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 138.0(Ar), 137.7(Ar), 135.5(Ar),
130.9(Ar), 128.9(Ar), 128.6(Ar), 128.0(Ar), 127.9(Ar), 127.2(Ar),
85.0(C1), 84.1(C2), 77.7, 75.4, 72.9(CH2-benzyl), 72.7, 71.5(CH2-
benzyl), 64.8(C6), 28.9(CH3), 28.5(CH3), 22.2(C-Si), 21.7(C-Si).
[α]rtD −31.0° (c 1.0, CHCl3), HRMS calcd for C34H45O5SSi 593.2751,
found 593.2748
2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-fluoro-α,β-D-
galactopyranoside (21). Phenyl 2,4-di-O-benzyl-3,6-O-(di-tert-bu-
tylsilylene)-1-thio-β-D-galactopyranoside (0.533 g, 0.9 mmol) was
dissolved in DCM (9 mL), and the solution was cooled to −15 °C. To
the solution was added DAST (0.2 mL, 1.35 mmol), the solution was
stirred for 5 min, and then NBS (0.208 g, 1.17 mmol) was added. The
reaction was stirred for 1 h while it was slowly allowed to reach 0 °C.
The reaction mixture was then transferred to a separation funnel,
washed with satd bicarbonate solution and brine, then dried with
MgSO4, filtered, and evaporated to dryness. The crude compound was
purified by flash column chromatography with petroleum ether as
eluent with a gradient of DCM, giving the product as a clear oil. Yield
0.335 g, 74% (α/β, 30/1), 1H NMR (500 MHz, chloroform-d) δ
7.46−7.34 (m, 10H, Ar), 5.82 (dd, J = 53.4, 5.0 Hz, 1H, H1), 4.79 (d, J
= 12.0 Hz, 1H), 4.75 (s, 2H), 4.59−4.53 (m, 2H), 4.46−4.38 (m, 2H),
4.29−4.24 (m, 1H), 4.17 (dd, J = 12.6, 2.8 Hz, 1H), 3.94 (dd, J = 22.1,
5.0 Hz, 1H, H2), 1.06 (s, 9H, TBS), 1.00 (s, 9H, TBS). 13C NMR
(126 MHz, CDCl3) δ 137.5(ipso), 137.4(ipso), 128.6(Ar), 128.5(Ar),
128.5(Ar), 128.1(Ar), 128.0(Ar), 127.9(Ar),110.1 (d, J = 214.3 Hz,
H1), 104.3 (d, J = 232.9 Hz, H1), 83.2 (d, J = 25.2 Hz, C2), 79.1 (d, J
= 22.3 Hz, C2), 76.0 (d, J = 5.1 Hz), 75.0, 74.6 (d, J = 3.4 Hz), 73.2 (d,
J = 1.4 Hz), 73.0 (d, J = 7.7 Hz), 73.0, 72.1, 71.8, 71.6, 71.6, 71.5,
63.78, 63.5, 28.6(CH3), 28.4(CH3), 28.4(CH3), 28.2(CH3), 22.2(C-
Si), 22.2(C-Si), 21.5(C-Si), 21.3(C-Si). 19F NMR (282 MHz,
chloroform-d) δ −135.3 (dd, J = 52.1, 19.6 Hz), −142.4 (dd, J =
56.0, 18.8 Hz). HRMS calcd for C28H39O5SiFNa 525.2448, found
525.2442
1
1.74 g, 7.8%, H NMR (500 MHz, chloroform-d) δ 7.56−7.25 (m,
15H), 5.82 (d, J = 5.3 Hz, 1H, H1), 4.96 (d, J = 11.6 Hz, 1H, CH2-
benzyl), 4.84 (d, J = 11.2 Hz, 1H, CH2-benzyl), 4.70 (d, J = 11.6 Hz,
1H, CH2-benzyl), 4.61 (d, J = 11.1 Hz, 1H, CH2-benzyl), 4.36−4.30
(m, 1H, H5), 4.23 (dd, J = 10.0, 5.3 Hz, 1H, H2), 4.05 (dd, J = 10.0,
3.1 Hz, 1H, H3), 3.97 (dd, J = 3.1, 1.3 Hz, 1H, H4), 3.77 (dd, J = 11.5,
6.7 Hz, 1H, H6), 3.57 (dd, J = 11.5, 4.9 Hz, 1H, H6), 2.55 (s, 1H,
OH), 1.58 (s, 1H, OH). 13C NMR (126 MHz, CDCl3) δ 138.2(Ar
ipso), 137.5(Ar ipso), 134.0(Ar ipso), 132.1(Ar), 129.2(Ar),
128.7(Ar), 128.7(Ar), 128.6(Ar), 128.5(Ar), 128.4(Ar), 128.2(Ar),
127.5(Ar), 86.7(C1), 76.8(C2), 75.9(C4), 75.1(CH2-benzyl),
72.3(CH2-benzyl), 71.6, 71.5, 62.5(C6). Mp 108−109 °C, [α]rt
D
169.2° (c 1.0, CHCl3), HRMS calcd for C26H28O5SNa 475.1555,
found 475.1554
Phenyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-1-thio-
α-D-galactopyranoside (12). Phenyl 2,4-di-O-benzyl-1-thio-α-D-
galactopyranoside (1.00 g, 2.21 mmol) was dissolved in 10 mL of
dry 2,6-lutidine. To the solution was added di-tert-butylsilyl ditriflate
(0.8 mL, 2.43 mmol), and the mixture was heated to 100 °C for 2 h.
The solution was cooled to rt, and then added ethyl acetate was added
and extracted 3 times with 1 M HCl solution, one time with satd
bicarbonate solution, and one time with brine. The organic layer was
dried with MgSO4, filtered, and evaporated to dryness. The crude
product was purified by flash column chromatography with petroleum
ether as eluent with a gradient of DCM, giving the product as a clear
1
oil. Yield 0.618 g, 47%. H NMR (500 MHz, chloroform-d) δ 7.51−
7.47 (m, 2H, Ar), 7.39−7.26 (m, 12H, Ar), 7.23−7.18 (m, 1H, Ar),
6.17 (d, J = 3.2 Hz, 1H, H1), 4.75 (d, J = 11.4 Hz, 1H, CH2-benzyl),
4.65 (d, J = 11.4 Hz, 2H, CH2-benzyl), 4.59 (t, J = 2.9 Hz, 1H, H3),
4.51 (d, J = 12.1 Hz, 1H, CH2-benzyl), 4.43 (dd, J = 13.1, 1.5 Hz, 1H,
H6), 4.33 (dd, J = 6.7, 3.0 Hz, 1H, H4), 4.23 (dd, J = 13.1, 2.3 Hz, 1H,
H6), 4.03 (d, J = 6.6 Hz, 1H, H5), 3.97 (t, J = 3.0 Hz, 1H, H2), 1.07
(s, 9H, (CH3)3), 0.91 (s, 9H, (CH3)3). 13C NMR (126 MHz, CDCl3)
δ 137.8(ipso), 137.6(ipso), 135.6(ipso), 130.1(Ar), 128.9(Ar),
128.6(Ar), 128.5(Ar), 128.3(Ar), 128.1(Ar), 128.1(Ar), 128.0(Ar),
126.7(Ar), 82.8(C1), 81.2(C2), 75.5(C5), 74.0(CH2-benzyl),
Phenyl 2,4-Di-O-benzyl-1-thio-α-D-galactopyranoside (6b).
Thiophenol (0.1 mol, 10.3 mL) in 50 mL of HMPA was cooled to 0
°C, and NaH (0.15 mol, 6 g) was added. The solution was stirred for 5
min. Then 2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside chloride (18.34
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73.8(C4), 71.0(C2), 70.9(CH2-benzyl), 66.1(C6), 29.4((CH3)3),
2-Azido-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-2-deoxy-1-
fluoro-α-D-glucopyranoside (21). Phenyl 2-azido-4-O-benzyl-3,6-
O-(di-tert-butylsilylene)-2-deoxy-1-thio-α-D-glucopyranoside (0.570 g,
1.08 mmol) was dissolved in DCM (10 mL), and the solution was
cooled to −15 °C. To the solution was added DAST (0.21 mL, 1.62
mmol), the solution was stirred for 5 min, and then NBS (0.256 g,
1.44 mmol) was added. The reaction was stirred for 1 h while it was
slowly allowed to reach 0 °C. The reaction mixture was then
transferred to a separation funnel, washed with satd bicarbonate
solution and brine, then dried with MgSO4, filtered, and evaporated to
dryness. The crude compound was purified by flash column
chromatography with petroleum ether as eluent with a gradient of
28.3((CH3)3), 23.2(C-Si), 21.0(C-Si). [α]rt 2.9° (c 1.0, CHCl3),
D
HRMS calcd for C34H44O5SSiNa 615.2576, found 615.2571
Phenyl 3-O-Acetyl-2-azido-4-O-benzyl-2-deoxy-1-thio-α,β-D-
glucopyranoside. Phenyl 3-O-acetyl-2-azido-4,6-O-benzylidene-2-
deoxy-1-thio-α,β-D-glucopyranoside (5 g, 0.0117 mol) was dissolved
in 121.5 mL of 1 M BH3·THF at 0 °C. The mixture was stirred for 5
min, and then 12.2 mL of 1 M Bu2BOTf in DCM was added. The
reactions was stirred for 2 h, and then 6 mL Et3N was added followed
by addition of methanol. The reaction mixture was co-distilled with
methanol 3 times and then purified by flash column chromatography
with petroleum ether as eluent with a gradient of EtOAc giving the
known products (β:1.15, α:3.01 g, α/β: 0.589), total 4.75 g, 95%.
Phenyl 2-Azido-4-O-benzyl-(di-tert-butylsilylene)-2-deoxy-
1-thio-α-D-glucopyranoside (16). Phenyl 3-O-acetyl-2-azido-4-O-
benzyl-2-deoxy-1-thio-α-D-glucopyranoside (3.01 g, 7.0 mmol) was
dissolved in 50 mL of dry methanol. To the solution was added 2 mL
of 25% sodium methoxide solution in methanol. The reaction was
stirred until TLC showed full conversion. The solution was neutralized
by adding Amberlite IR120. The solution was filtered and evaporated
to dryness, giving the product as a white solid. The white solid (1.0 g,
2.58 mmol) was dissolved in 10 mL of dry 2,6-lutidine. To the solution
was added di-tert-butylsilyl ditriflate (0.92 mL, 2.84 mmol), and the
mixture was heated to 100 °C for 2 h. The solution was cooled to rt,
and then ethyl acetate was added and extracted 3 times with 1 M HCl
solution, one time with satd bicarbonate solution, and one time with
brine. The organic layer was dried with MgSO4, filtered, and
evaporated to dryness. The crude product was purified by flash
column chromatography with petroleum ether as eluent with a
gradient of DCM, giving the product as a clear oil. Yield: 0.631 g, 46%,
1H NMR (500 MHz, chloroform-d) δ 7.58−7.53 (m, 2H, Ar), 7.43−
1
DCM, giving the product as a clear oil. Yield 0.246 g, 52%, H NMR
(500 MHz, chloroform-d) δ 7.39−7.30 (m, 5H, Ar), 5.62 (dd, J = 53.1,
6.3 Hz, 1H, H1), 4.67 (d, J = 11.9 Hz, 1H, CH2-benzyl), 4.52 (d, J =
11.9 Hz, 1H, CH2-benzyl), 4.40 (t, J = 4.1 Hz, 1H), 4.26 (d, J = 3.0
Hz, 1H), 4.21 (dd, J = 12.8, 1.1 Hz, 1H), 4.03 (t, J = 2.8 Hz, 1H), 3.92
(ddd, J = 12.8, 3.2, 1.9 Hz, 1H), 3.75 (dd, J = 23.0, 6.3 Hz, 1H, H2),
0.99 (s, 9H, TBS), 0.89 (s, 9H, TBS).13C NMR (126 MHz, CDCl3) δ
136.8(ipso), 128.7(Ar), 128.3(Ar), 128.0(Ar), 108.2 (d, J = 212.9 Hz,
C1), 81.3 (d, J = 3.8 Hz), 73.5 (d, J = 1.4 Hz), 73.2 (d, J = 7.0 Hz),
72.2(CH2-benzyl), 66.6 (d, J = 24.7 Hz, C2), 66.4(C6), 27.9(CH3),
27.6(CH3), 21.6(C-Si), 21.4(C-Si). 19F NMR (282 MHz, chloroform-
d) δ −134.8 (dd, J = 52.7, 23.5 Hz). [α]rt 59.4° (c 1.0, CHCl3),
D
HRMS calcd for C21H32FN3O4SiNa 460.2044, found 460.2032
Phenyl 3,6-Anhydro-2,4-di-O-benzyl-1-thio-α-D-glucopyra-
noside (30). Phenyl 2,4-di-O-benzyl-1-thio-α-D-glucopyranoside
(0.223 g, 0.492 mmol) was dissolved in 5 mL of dry pyridine, and
then TsCl (0.10 g, 0.541 mmol) was added. The reaction was stirred
for 3 days, then diluted with ethyl acetate, and extracted 3 times with 1
M HCl solution, one time with satd bicarbonate solution, and one
time with brine. The organic layer was dried with MgSO4, filtered, and
evaporated to dryness. The compound was dissolved in 5 mL of DMF,
and NaH (0.022 g, 0.541 mmol) was added. The reaction was stirred
for 3 h, quenched with water, and diluted with ethyl acetate. The
mixture was washed 3 times with water and one time with brine. The
organic layer was dried with MgSO4, filtered, and evaporated to
dryness. The crude compound was purified by flash column
chromatography with petroleum ether as eluent with a gradient of
7.25 (m, 8H, Ar), 6.06 (d, J = 4.2 Hz, 1H, H1), 4.75 (d, J = 12.6 Hz,
1H, CH2-benzyl), 4.71 (d, J = 12.6 Hz, 1H, CH2-benzyl), 4.55 (ddd, J
= 2.4, 1.1 Hz, 1H, H3), 4.35 (s, 1H, H5), 4.22 (dd, J = 13.2, 2.0 Hz,
1H, H6), 4.03 (dd, J = 13.2, 3.1 Hz, 1H, H6), 3.95−3.91 (m, 2H, H2,
H4), 0.91 (s, 9H, TBS), 0.89 (s, 9H, TBS). 13C NMR (126 MHz,
CDCl3) δ 137.4(ipso), 135.3(ipso), 131.3(Ar), 128.0(Ar), 128.7 (Ar),
128.2(Ar), 127.3(Ar), 82.1(C1), 76.4, 72.4, 71.7(CH2-benzyl), 70.8,
68.3(C6), 61.6(C2), 28.7(CH3), 28.0(CH3), 21.9(C-Si), 21.0(C-Si).
[α]rt 8.4° (c 1.0, CHCl3), HRMS calcd for C27H37N3O4SSiNa
EtOAc, giving the product as a white solid. Yield: 106 mg, 50%, H
1
D
550.2172, found 550.2172
NMR (500 MHz, chloroform-d) δ 7.67−7.55 (m, 2H, Ar), 7.56−7.48
(m, 2H, Ar), 7.47−7.22 (m, 11H, Ar), 5.65 (d, J = 3.9 Hz, 1H, H1),
4.90 (d, J = 11.6 Hz, 1H, CH2-benzyl), 4.77 (d, J = 12.0 Hz, 1H, CH2-
benzyl), 4.73 (d, J = 11.6 Hz, 1H, CH2-benzyl), 4.65 (d, J = 12.0 Hz,
1H, CH2-benzyl), 4.50 (t, J = 2.9 Hz, 1H), 4.37 (t, J = 4.7 Hz, 1H),
4.22 (d, J = 10.7 Hz, 1H, H6), 3.93 (dd, J = 10.7, 3.1 Hz, 1H, H6),
3.90−3.83 (m, 2H, H2). 13C NMR (126 MHz, CDCl3) δ 138.0(ipso),
138.0(ipso), 136.2(ipso), 130.5(Ar), 128.9(Ar), 128.4(Ar), 128.3(Ar),
128.0(Ar), 128.0(Ar), 127.8(Ar), 127.6(Ar), 126.9(Ar), 84.3(C1),
78.4, 76.1, 75.1, 74.7(CH2-benzyl), 72.2(CH2-benzyl), 71.0, 68.6(C6).
Phenyl 2-Azido-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-2-
deoxy-1-thio-β-D-glucopyranoside (17). Phenyl 3-O-acetyl-2-
azido-4-O-benzyl-2-deoxy-1-thio-β-D-glucopyranoside (1.15 g, 2.68
mmol) was dissolved in 50 mL of dry methanol. To the solution
was added 2 mL of 25% sodium methoxide solution in methanol. The
reaction was stirred until TLC showed full conversion. The solution
was neutralized by adding Amberlite IR120. The solution was filtered
and evaporated to dryness, giving the product as a white solid. The
white solid was dissolved in 10 mL of dry 2,6-lutidine. To the solution
was added di-tert-butylsilyl ditriflate (0.81 mL, 2.47 mmol), and the
mixture was heated to 100 °C for 2 h. The solution was cooled to rt,
and then ethyl acetate was added and extracted 3 times with 1 M HCl
solution, one time with satd bicarbonate solution, and one time with
brine. The organic layer was dried with MgSO4, filtered, and
evaporated to dryness. The crude product was purified by flash
column chromatography with petroleum ether as eluent with a
gradient of DCM, giving the product as a clear oil. Yield: 0.474 g, 40%,
1H NMR (500 MHz, chloroform-d) δ 7.56−7.52 (m, 2H, Ar), 7.40−
Mp 115−117 °C, [α]rt 64.2° (c 1.0, CHCl3), HRMS calcd for
D
C26H26O4SNa 457.1449, found 457.1446
Phenyl 3,6-Anhydro-2,4-di-O-benzyl-1-thio-β-D-glucopyra-
noside (31). Phenyl 2,4-di-O-benzyl-1-thio-β-D-glucopyranoside
(0.211 g, 0.466 mmol) was dissolved in 5 mL of dry pyridine, and
then TsCl (0.098 g, 0.513 mmol) was added. The reaction was stirred
for 3 days, then diluted with ethyl acetate, and extracted 3 times with 1
M HCl solution, one time with satd bicarbonate solution, and one
time with brine. The organic layer was dried with MgSO4, filtered, and
evaporated to dryness. The compound was dissolved in 5 mL of DMF,
and NaH (0.020 g, 0.513 mmol) was added. The reaction was stirred
for 3 h, quenched with water, and diluted with ethyl acetate. The
mixture was washed 3 times with water and one time with brine. The
organic layer was dried with MgSO4, filtered, and evaporated to
dryness. The crude compound was purified by flash column
chromatography with petroleum ether as eluent with a gradient of
7.30 (m, 8H, Ar), 5.06 (d, J = 9.8 Hz, 1H, H1), 4.71 (d, J = 12.0 Hz,
1H, CH2-benzyl), 4.54 (d, J = 12.0 Hz, 1H, CH2-benzyl), 4.50 (d, J =
3.6 Hz, 1H, H4), 4.20 (dd, J = 12.6, 0.9 Hz, 1H, H6), 4.16 (d, J = 3.1
Hz, 1H, H5), 4.11 (d, J = 3.4 Hz, 1H, H3), 3.90 (dd, J = 12.6, 3.3 Hz,
1H, H6), 3.67 (d, J = 9.7 Hz, 1H, H2), 1.01 (s, 9H, TBS), 0.91 (s, 9H,
TBS). 13C NMR (126 MHz, CDCl3) δ 137.2(ipso), 133.8(ipso),
132.1(Ar), 129.1(Ar), 128.7(Ar), 128.3(Ar), 128.2(Ar), 127.9(Ar),
83.4(C1), 82.0, 73.9, 73.0, 72.2(CH2-benzyl), 67.4(C6), 65.5(C2),
1
EtOAc, giving the product as a syrup. Yield: 126 mg, 62%, H NMR
28.3(CH3), 27.7(CH3), 21.8(C-Si), 21.6(C-Si). [α]rt 41.9° (c 1.0,
(500 MHz, chloroform-d) δ 7.56−7.53 (m, 2H, Ar), 7.45−7.27 (m,
13H, Ar), 5.71 (d, J = 5.4 Hz, 1H, H1), 4.82−4.78 (m, 2H, CH2-
benzyl), 4.71 (d, J = 11.8 Hz, 1H, CH2-benzyl), 4.66 (d, J = 11.5 Hz,
D
CHCl3), HRMS calcd for C27H37N3O4SSiNa 550.2172, found
550.2167
K
dx.doi.org/10.1021/jo4012464 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1H, CH2-benzyl), 4.46 (t, J = 2.8 Hz, 1H), 4.37 (dd, J = 5.2, 1.8 Hz,
1H), 4.19 (d, J = 10.0 Hz, 1H, H6), 4.08−4.04 (m, 1H), 3.86−3.81
(m, 2H, H2, H6). 13C NMR (126 MHz, CDCl3) δ 137.9(ipso),
137.5(ipso), 134.6(ipso), 131.6(Ar), 128.9(Ar), 128.5(Ar), 128.5(Ar),
128.1(Ar), 128.1(Ar), 128.0(Ar), 127.9(Ar), 127.3(Ar), 82.4(C2),
82.4(C1), 76.7, 73.5, 72.9, 72.9(CH2-benzyl), 72.5(CH2-benzyl),
(s, 1H), 4.48 (d, J = 8.2 Hz, 1H), 4.19 (dd, J = 12.2, 1.0 Hz, 1H), 4.11
(d, J = 2.0 Hz, 2H), 4.04 (d, J = 2.7 Hz, 1H), 3.95 (dd, J = 12.2, 2.9
Hz, 1H), 3.69 (d, J = 6.5 Hz, 1H), 3.63 (tt, J = 9.3, 3.8 Hz, 2H), 1.92
(s, 2H), 1.76 (s, 2H), 1.55 (s, 1H), 1.49−1.36 (m, 2H), 1.36−1.21 (m,
4H), 1.03 (s, 9H), 0.94 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
139.2, 138.0, 128.5, 128.3, 128.1, 127.9, 127.7, 127.4, 100.2, 83.5, 80.1,
76.9, 75.2, 72.8, 72.6, 71.7, 67.5, 34.0, 32.4, 28.4, 27.9, 25.9, 24.3, 24.3,
21.9, 21.7. [α]rtD 8.2° (c 1.0, CH2Cl2), HRMS calcd for C34H50O6SiNa
605.3274, found 605.3278
71.6(C6). [α]rt −41.1° (c 1.0, CHCl3), HRMS calcd for
D
C26H26O4SNa 457.1449, found 457.1440
General Glycosylation Procedures. Typical NIS/TfOH-pro-
moted glycosylation procedure: A mixture of glycosyl donor (0.10
mmol), glycosyl acceptor (0.11 mmol), and freshly activated molecular
sieves (3 Å, 100 mg) in DCM (4 mL) was stirred under argon for 1 h.
The solution was cooled to −78 °C, and NIS (0.11 mmol) and TfOH
(0.010 mmol) were added. The reaction was slowly allowed to reach 0
°C. Upon completion, the reaction was quenched by adding
triethylamine. The solid was filtered off, and the filtrate was washed
with 1 M HCl, satd bicarbonate solution, 10% Na2S2O3, and brine.
The organic layer was dried with MgSO4 and concentrated in vacuo.
The residue was purified by flash column chromatography to afford
the corresponding saccharide. Anomeric ratios were measured by
Cyclohexyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-
1
glucopyranoside. H NMR (500 MHz, chloroform-d) δ 7.31 (m,
4H), 7.26−7.14 (m, 6H), 5.27 (d, J = 5.4 Hz, 1H), 4.75 (d, J = 12.2
Hz, 1H), 4.62 (d, J = 12.5 Hz, 1H), 4.56 (d, J = 12.2 Hz, 1H), 4.51 (d,
J = 12.5 Hz, 1H), 4.33 (d, J = 2.9 Hz, 1H), 4.08 (s, 1H), 4.04 (dd, J =
12.4, 1.5 Hz, 1H), 3.83 (d, J = 2.6 Hz, 1H), 3.78 (dd, J = 12.4, 2.8 Hz,
1H), 3.65 (d, J = 5.4 Hz, 1H), 3.58 (tt, J = 9.4, 3.8 Hz, 1H), 1.86 (s,
2H), 1.69 (s, 2H), 1.50−1.41 (m, 2H), 1.31 (q, J = 12.4, 11.0 Hz, 1H),
1.19 (td, J = 28.2, 26.9, 11.1 Hz, 4H), 0.84 (s, 9H), 0.79 (s, 9H). 13C
NMR (126 MHz, CDCl3) δ 139.0, 138.6, 128.4, 128.3, 128.0, 127.9,
127.7, 127.4, 93.2, 77.2, 75.4, 74.7, 74.0, 72.4, 71.6, 71.2, 68.4, 33.5,
integration of the anomeric protons from H NMR of crude product
31.7, 28.3, 28.2, 25.9, 24.5, 24.3, 21.9, 21.3. [α]rt 50.3° (c 1.0,
1
D
mixtures. The anomeric configuration of conformationally changed
sugars was checked by first deprotection of silyl groups with TBAF and
then 1H NMR to measure the coupling constants between H1 and H2.
Typical SnCl2/AgB(C6F5)4 promoted glycosylation procedure: A
mixture of SnCl2(0.02 mmol), AgB(C6F5)4 (0.02 mmol), and
molecular sieves (5 Å, 300 mg) was dissolved in 2 mL of BTF.
Then the glycosyl donor (0.1 mmol) and the glycosyl acceptor were
added (0.11 mmol). The reaction was stirred upon completion and
quenched with satd bicarbonate solution. The solids was filtered of and
washed with ethyl acetate, and the organic layer was washed with water
and brine. The organic layer was dried with MgSO4 and concentrated
in vacuo. The residue was purified by flash column chromatography to
afford the corresponding saccharide.
CH2Cl2), HRMS calcd for C34H50O6SiNa 605.3274, found 605.3277
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-β-D-glucopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.41−7.21 (m, 25H), 5.03 (d, J
= 10.9 Hz, 1H), 4.97 (d, J = 6.7 Hz, 1H), 4.89−4.80 (m, 4H), 4.75 (d,
J = 11.7 Hz, 1H), 4.71−4.66 (m, 2H), 4.64−4.59 (m, 2H), 4.49 (d, J =
3.4 Hz, 1H), 4.44 (d, J = 11.4 Hz, 1H), 4.18 (d, J = 12.7 Hz, 1H),
4.12−4.02 (m, 4H), 3.95 (dd, J = 12.3, 3.0 Hz, 1H), 3.85−3.79 (m,
1H), 3.75 (dd, J = 11.2, 5.6 Hz, 2H), 3.54 (ddt, J = 9.1, 5.9, 2.9 Hz,
2H), 3.36 (s, 3H), 1.02 (s, 9H), 0.96 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 139.0, 138.8, 138.5, 138.3, 137.8, 128.6, 128.5, 128.4, 128.3,
128.2, 128.09, 128.0, 128.0, 127.8, 127.8, 127.7, 127.7, 127.5, 102.3,
98.0, 83.6, 82.3, 80.5, 80.0, 78.2, 75.8, 75.3, 75.0, 73.4, 72.8, 72.3, 71.7,
70.6, 68.6, 67.3, 55.3, 28.3, 27.9, 21.8, 21.7. [α]rt 20.9° (c 1.0,
Anomeric ratios were measured by integration of the anomeric
D
1
protons from H NMR of crude product mixtures.
CH2Cl2), HRMS calcd for C56H70O11SiNa 969.4585, found 969.4591
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α,β-D-glucopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.50−7.12 (m, Ar), 5.35 (d, J =
5.8 Hz), 5.04 (d, J = 10.9 Hz), 4.98 (d, J = 7.0 Hz), 4.95 (d, J = 7.0
Hz), 4.89 (d, J = 11.1 Hz), 4.86−4.77 (m), 4.75−4.67 (m), 4.64−4.53
(m), 4.47 (d, J = 11.5 Hz), 4.24−3.86 (m), 3.80−3.68 (m), 3.38 (s),
3.36 (s), 3.31 (dd, J = 9.6, 3.5 Hz), 1.04 (s), 1.01 (s), 0.97 (s), 0.97 (s).
13C NMR (126 MHz, CDCl3) δ 139.2, 139.1, 139.0, 138.9, 138.7,
138.4, 138.2, 138.0, 137.7, 128.5, 128.4, 128.3, 128.2, 128.2, 128.1,
128.1, 128.0, 128.0, 127.9, 127.8, 127.8, 127.7, 127.7, 127.6, 127.6,
127.5, 127.5, 127.4, 127.3, 127.3, 102.3, 98.2, 97.9, 96.5, 83.5, 82.2,
82.0, 80.4, 80.1, 79.9, 78.1, 77.6, 77.3, 77.2, 77.1, 76.8, 75.7, 75.4, 75.2,
74.9, 74.8, 74.6, 74.3, 73.4, 73.3, 72.7, 72.2, 71.7, 71.5, 70.5, 70.3, 70.2,
68.5, 68.1, 67.6, 67.2, 55.2, 55.1, 28.2, 28.1, 27.8, 21.8, 21.4.
The anomeric configuration of conformationally changed sugars was
checked by first deprotection of silyl groups with TBAF and then H
NMR to measure the coupling constants between H1 and H2.
Competion Experiments. A mixture of the two glycosyl donors
(0.10 mmol each), cyclohexanol (0.50 mmol), and freshly activated
molecular sieves (3 Å, 100 mg) in DCM (4 mL) was stirred under
argon for 1 h. The solution was cooled to −78 °C, and NIS (0.10
mmol) and TfOH (0.010 mmol) were added. The reaction was slowly
allowed to reach 0 °C. The reaction was quenched by adding
triethylamine. The mixture was diluted with CH2Cl2, the solid was
filtered off, and the filtrate was washed with 1 M HCl, satd bicarbonate
solution, 10% Na2S2O3, and brine. The organic layer was dried with
MgSO4 and concentrated in vacuo. The donors were isolated by
purifying the crude mixture by flash column chromatography. In cases
where purification of starting material or products was impossible, then
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
1
the yields were measured by H NMR. This was done by taking the
tert-butylsilylene)-β-D-glucopyranosyl)-1-thio-β-D-glucopyra-
1
two donors (0.10 mmol each) and 0.10 mmol of Ph3SiMe as internal
standard, which were dissolved in CDCl3, and measuring the ratios of
noside. H NMR (500 MHz, chloroform-d) δ 7.49 (dd, J = 8.1, 1.5
Hz, 2H), 7.39−6.97 (m, 28H), 5.05 (d, J = 7.3 Hz, 1H), 5.02 (d, J =
11.2 Hz, 1H), 4.72 (d, J = 11.7 Hz, 1H), 4.67−4.52 (m, 6H), 4.47 (d, J
= 11.9 Hz, 1H), 4.35−4.27 (m, 4H), 4.15 (d, J = 12.0 Hz, 1H), 4.05 (s,
1H), 3.91 (d, J = 12.5 Hz, 1H), 3.84 (dd, J = 14.3, 5.1 Hz, 4H), 3.76
(d, J = 9.0 Hz, 1H), 3.68 (dd, J = 12.6, 3.0 Hz, 1H), 3.62−3.52 (m,
2H), 3.43−3.34 (m, 2H), 0.81 (s, 1H, 9H), 0.78 (s, 1H, 9H). 13C
NMR (126 MHz, CDCl3) δ 139.3, 138.9, 138. 5, 138. 3, 137.7, 133.8,
132.2, 129.0, 128.5, 128.5, 128.4, 128.4, 128.2, 128.0, 128.0, 128.0,
127.8, 127.8, 127.7, 127.5, 127.4, 127.3, 127.2, 101.4, 87.1, 84.8, 84.4,
80.8, 80.4, 79.4, 78.9, 75.7, 75.5, 75.3, 72.8, 72.6, 72.4, 71.7, 68.3, 67.1,
1
donors compared to Ph3SiMe by H NMR. Then the solvent was
evaporated, and the procedure as described above was followed. After
1
workup another H NMR was recorded of the crude mixture, and
comparison of the ratios of donors before and after gave the yields.
General Deprotection Procedure. The compound (0.10 mmol)
was dissolved in 1 mL of THF, and then 1 M TBAF solution in THF
(0.2 mL, 0.20 mmol) was added. The solution was stirred until the
reaction was finished (checked by TLC). The reaction mixture was
subjected to aqueous workup with brine, dried with MgSO4, and
concentrated in vacuo. The crude compound was purified by flash
column chromatography to afford the corresponding deprotected
compound.
28.2, 28.0, 21.8, 21.2. [α]rt 11° (c 1.0, CH2Cl2), HRMS calcd for
D
C61H72O10SSiNa 1047.4513, found 1047.4489
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α-D-glucopyranosyl)-1-thio-β-D-glucopyra-
Cyclohexyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-β-D-
1
1
glucopyranoside. H NMR (500 MHz, chloroform-d) δ 7.45−7.41
noside. H NMR (300 MHz, chloroform-d) δ 7.60 (dd, J = 7.9, 1.7
(m, 2H), 7.38−7.28 (m, 8H), 4.99 (d, J = 6.5 Hz, 1H), 4.88 (d, J =
11.9 Hz, 1H), 4.75 (d, J = 9.0 Hz, 1H), 4.73 (d, J = 8.7 Hz, 1H), 4.49
Hz, 2H), 7.39−7.06 (m, 28H), 5.96 (d, J = 6.5 Hz, 1H), 4.93 (d, J =
11.3 Hz, 1H), 4.88 (d, J = 10.2 Hz, 1H), 4.72−4.56 (m, 6H), 4.55−
L
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The Journal of Organic Chemistry
Article
4.39 (m, 5H), 4.35 (d, J = 3.1 Hz, 1H), 4.20 (s, 1H), 4.11−4.02 (m,
2H), 3.98 (dd, J = 12.4, 1.3 Hz, 1H), 3.91 (d, J = 2.7 Hz, 1H), 3.85
(dd, J = 10.8, 1.8 Hz, 1H), 3.77 (t, J = 8.8 Hz, 1H), 3.73−3.64 (m,
2H), 3.60−3.50 (m, 2H), 0.88 (s, 9H), 0.85 (s, 9H). 13C NMR (126
MHz, CDCl3) δ 139.0, 138.3, 138.2, 138.1, 133.8, 132.1, 129.0, 128.6,
128.5, 128.4, 128.3, 128.3, 128.1, 127.9, 127.7, 127.6, 127.5, 127.4,
127.2, 94.3, 87.5, 87.2, 81.2, 79.1, 75.2, 75.1, 74.4, 74.1, 73.2, 72.4,
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α-D-mannopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.47−7.43 (m, 2H, Ar), 7.42−
7.25 (m, 21H, Ar), 7.22−7.19 (m, 2H, Ar), 5.10 (d, J = 3.5 Hz, 1H),
5.03 (d, J = 10.9 Hz, 1H), 4.87−4.80 (m, 3H), 4.74−4.67 (m, 4H),
4.66 (d, J = 3.5 Hz, 1H), 4.60 (t, J = 3.9 Hz, 1H), 4.50 (d, J = 12.1 Hz,
1H), 4.46 (d, J = 12.1 Hz, 1H), 4.10−4.01 (m, 5H), 3.85 (t, J = 3.6 Hz,
1H), 3.84−3.80 (m, 1H), 3.77 (td, J = 12.0, 11.3, 2.1 Hz, 2H), 3.68−
3.62 (m, 1H), 3.56 (dd, J = 9.6, 3.5 Hz, 1H), 3.37 (s, 3H, OMe), 1.07
(s, 9H, TBS), 0.96 (s, 9H, TBS).13C NMR (126 MHz, CDCl3) δ
139.0, 138.8, 138.8, 138.4, 137.7, 128.5, 128.4, 128.3, 128.1, 128.0,
128.0, 128.0, 127.8, 127.6, 127.5, 127.5, 101.4, 98.0, 82.2, 80.2, 78.0,
76.7, 75.7, 74.8, 74.8, 74.4, 73.4, 71.9, 70.7, 70.0, 68.8, 68.3, 66.6, 55.1,
72.2, 71.7, 69.5, 69.1, 68.0, 28.2, 28.1, 21.8, 21.4. [α]rt 29° (c 1.0,
D
CH2Cl2), HRMS calcd for C61H72O10SSiNa 1047.4513, found
1047.4523
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-β-D-glucopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.37−7.04 (m, 25H), 5.02 (d, J
28.3, 28.2, 21.9, 21.8. [α]rt 50.6° (c 1.0, CHCl3), HRMS calcd for
D
= 7.2 Hz, 1H), 4.98 (d, J = 11.1 Hz, 1H), 4.71 (m, 2H), 4.68−4.59 (m,
2H), 4.53−4.45 (m, 2H), 4.41 (d, J = 11.9 Hz, 1H), 4.34−4.24 (m,
3H), 4.12 (d, J = 11.9 Hz, 1H), 4.06 (s, 1H), 3.95−3.78 (m, 5H), 3.67
(dd, J = 12.5, 2.9 Hz, 1H), 3.65−3.60 (m, 1H), 3.61−3.56 (m, 1H),
3.51 (dd, J = 10.6, 1.8 Hz, 1H), 3.41 (dd, J = 9.3, 3.8 Hz, 1H), 3.28 (s,
3H), 0.85 (s, 9H), 0.78 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
139.7, 138.5, 138.5, 138.5, 137.6, 128.4, 128.3, 128.1, 128.0, 128.0,
127.9, 127.8, 127.7, 127.6, 127.2, 127.1, 101.4, 98.3, 84.5, 80.7, 80.2,
79.4, 79.0, 75.6, 75.2, 73.72, 72.8, 72.5, 71.7, 70.3, 67.8, 67.1, 55.3,
C56H70O11SiNa 969.4585, found 969.4543
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α-D-mannopyranosyl)-1-thio-β-D-glucopyra-
noside. 1H NMR (500 MHz, chloroform-d) δ 7.65−7.63 (m, 2H, Ar),
7.47−7.20 (m, 28H, Ar), 5.66 (d, J = 2.8 Hz, 1H), 4.93−4.90 (m, 2H),
4.85 (d, J = 10.1 Hz, 1H), 4.74 (d, J = 9.9 Hz, 2H), 4.69 (d, J = 11.6
Hz, 1H), 4.62−4.56 (m, 4H), 4.58−4.48 (m, 3H), 4.17 (s, 1H), 4.14
(d, J = 4.7 Hz, 1H), 4.09−4.04 (m, 1H), 4.01 (d, J = 11.5 Hz, 1H),
3.91−3.85 (m, 4H), 3.80 (t, J = 8.8 Hz, 1H), 3.73 (dd, J = 12.1, 2.8 Hz,
1H), 3.62−3.56 (m, 2H), 0.99 (s, 9H, TBS), 0.94 (s, 9H, TBS). 13C
NMR (126 MHz, CDCl3) δ 138.8, 138.7, 138.2, 138.1, 137.7, 133.9,
132.0, 129.0, 128.6, 128.5, 128.4, 128.3, 128.3, 128.2, 128.2, 128.1,
127.9, 127.8, 127.87, 127.5, 127.5, 127.4, 127.3, 100.8, 87.6, 87.4, 81.0,
79.3, 78.0, 75.5, 75.4, 74.4, 74.3, 73.5, 72.1, 71.1, 70.5, 69.5, 68.6, 67.3,
28.2, 28.0, 21.8, 21.2. [α]rt 33.3° (c 1.0, CH2Cl2), HRMS calcd for
D
C56H70O11SiNa 969.4585, found 969.4572
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α,β-D-glucopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.40−7.07 (m), 6.00−5.93 (d, J
28.2, 27.9, 21.9. [α]rt 43.3° (c 1.0, CHCl3), HRMS calcd for
= 6.6), 5.06 (d, J = 7.2 Hz), 5.00 (d, J = 11.0 Hz), 4.75 (dd, J = 11.4,
3.1 Hz), 4.71−4.31 (m), 4.16 (d, J = 11.9 Hz), 4.10 (s), 4.08−4.01
(m,), 3.98−3.96 (m), 3.96−3.91 (m), 3.89−3.84 (m), 3.82 (d, J = 2.3
Hz), 3.79−3.75 (m), 3.72 (dd, J = 12.5, 2.9 Hz), 3.68 (d, J = 6.6 Hz),
3.62 (d, J = 7.3 Hz), 3.60−3.52 (m), 3.45 (dd, J = 9.3, 3.7 Hz), 3.33
(s), 3.33 (s), 0.89 (s), 0.85 (s), 0.82 (s), 0.80 (s). 13C NMR (126
MHz, CDCl3) δ 139.7, 138.7, 138.7, 138.5, 138.5, 138.5, 138.4, 138.3,
138.1, 137.6, 128.6, 128.5, 128.4, 128.4, 128.3, 128.3, 128.3, 128.2,
128.2, 128.1, 128.0, 127.9, 127.8, 127.7, 127.6, 127.5, 127.3, 127.2,
127.1, 127.0, 101.4, 98.3, 97.8, 94.2, 84.5, 82.7, 80.7, 80.2, 79.4, 79.0,
76.9, 75.6, 75.2, 75.1, 74.3, 73.9, 73.7, 73.4, 73.0, 72.8, 72.7, 72.5, 72.4,
72.3, 71.6, 71.6, 70.3, 69.7, 69.7, 68.9, 68.0, 67.8, 67.1, 55.3, 55.1, 28.2,
28.2, 28.1, 28.0, 21.8, 21.8, 21.4, 21.2. HRMS calcd for C56H70O11SiNa
969.4585, found 969.4582
D
C61H72O10SSiNa 1047.4513, found 1047.4522
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-(di-tert-bu-
tylsilylene)-α-D-mannopyranosyl)-α-D-glucopyranoside. 1H
NMR (500 MHz, chloroform-d) δ 7.39−7.20 (m, 25H), 5.68 (d, J
= 2.8 Hz, 1H), 4.92 (d, J = 10.0 Hz, 1H), 4.84 (d, J = 10.0 Hz, 1H),
4.79 (d, J = 12.0 Hz, 1H), 4.69−4.59 (m, 6H), 4.56−4.42 (m, 7H),
4.09−3.97 (m, 6H), 3.94 (d, J = 11.9 Hz, 1H), 3.88−3.81 (m, 4H),
3.76−3.69 (m, 1H), 3.65−3.57 (m, 2H), 3.43 (s, 3H), 0.96 (s, 9H),
0.90 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 138.8, 138.6, 138.65,
137.8, 128.6, 128.5, 128.4, 128.4, 128.3, 128.3, 128.1, 1287.0, 127.8,
127.5, 127.4, 127.3, 127.2, 100.9, 98.1, 82.7, 80.4, 78.0, 75.4, 74.4, 74.3,
73.5, 73.4, 72.1, 71.6, 70.6, 70.0, 69.5, 68.6, 67.5, 55.3, 28.2, 27.9, 21.9.
[α]rt 42.0° (c 1.0, CHCl3), HRMS calcd for C56H70O11SiNa
D
969.4585, found 969.4582
Cyclohexyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-
mannopyranoside. 1H NMR (500 MHz, chloroform-d) δ 7.47−7.43
(m, 2H, Ar), 7.39−7.28 (m, 8H, Ar), 5.23 (d, J = 4.1 Hz, 1H, H1),
4.76 (d, J = 12.0 Hz, 1H, CH-benzyl), 4.72 (d, J = 12.0 Hz, 1H, CH-
benzyl), 4.60 (d, J = 12.4 Hz, 1H, CH-benzyl), 4.58 (t, J = 3.9 Hz, 1H,
H3), 4.55 (d, J = 12.4 Hz, 1H, CH-benzyl), 4.18−4.13 (m, 2H), 4.09
(d, J = 4.2 Hz, 1H, H4), 3.92−3.88 (m, 1H, H6), 3.78 (t, J = 3.9 Hz,
1H, H2), 3.66 (td, J = 9.4, 4.7 Hz, 1H, H5), 1.99−1.90 (m, 2H), 1.83−
1.72 (m, 2H), 1.61−1.53 (m, 1H), 1.53−1.19 (m, 6H), 1.07 (s, 9H,
TBS), 0.95 (s, 9H, TBS). 13C NMR (126 MHz, CDCl3) δ 139.2(ipso,
Ar), 138.0(ipso, Ar), 128.6(Ar), 128.3(Ar), 128.0(Ar), 127.9(Ar),
127.6(Ar), 127.4(Ar), 98.7(C1), 77.4(C2), 75.5(C5), 75.0(C4), 74.2,
71.7(CH2-benzyl), 71.2(CH2-benzyl), 69.6(C3), 68.5(C6), 33.8, 32.0,
28.3(CH3), 28.3(CH3), 25.89, 24.5, 24.2, 21.9(C-Si), 21.7(C-Si).
[α]rtD 58.3° (c 1.0, CHCl3), HRMS calcd for C34H50O6SiNa 605.3274,
found 605.3267
Cyclohexyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-β-D-
1
galactopyranoside. H NMR (500 MHz, chloroform-d) δ 7.41−
7.27 (m, 10H, Ar), 4.74−4.65 (m, 3H, benzyl), 4.63 (d, J = 6.0 Hz,
1H, H1), 4.41 (d, J = 12.3 Hz, 2H), 4.30 (dd, J = 12.1, 1.4 Hz, 1H,
H6), 4.11 (dd, J = 12.1, 2.3 Hz, 1H, H6), 4.03 (d, J = 8.1 Hz, 1H), 3.97
(dd, J = 8.2, 1.9 Hz, 1H), 3.70 (dd, J = 6.0, 0.9 Hz, 1H, H2), 3.56 (tt, J
= 9.1, 3.8 Hz, 1H), 1.84 (m), 1.72 (m), 1.41−1.16 (m), 1.01 (s, 9H),
0.97 (s, 9H). 13C NMR (126 MHz, CDCl3) δ 138.6, 137.9, 128.5,
128.5, 127.9, 127.8, 127.7, 127.6, 100.2(C1), 84.2(C2), 76.5, 76.00,
75., 73.3, 72.2(CH2-benzyl), 71.4(CH2-benzyl), 64.6(C6), 33.7 32.0,
28.8, 28.6, 25.9, 24.2, 24.1, 22.2, 21.7. [α]rt −4.7° (c 1.0, CHCl3),
D
HRMS calcd for C34H50O6SiNa 605.3274, found 605.3260
Cyclohexyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α-D-
1
galactopyranoside. H NMR (500 MHz, chloroform-d) δ 7.42−
7.29 (m, 10H), 5.25 (d, J = 5.2 Hz, 1H, H1), 4.78−4.70 (m, 2H), 4.63
(d, J = 12.0 Hz, 1H), 4.54−4.46 (m, 5H), 4.39 (dd, J = 12.4, 1.0 Hz,
1H, H6), 4.09 (dd, J = 12.4, 2.7 Hz, 1H, H6), 3.97 (d, J = 6.6 Hz, 1H),
3.87 (dd, J = 5.3, 0.9 Hz, 1H, H2), 3.68−3.58 (m, 2H), 1.93 (d, J =
10.8 Hz, 1H), 1.84 (d, J = 13.3 Hz, 1H), 1.75 (s, 1H), 1.56 (s, 0H),
1.47−1.18 (m, 6H), 1.02 (s, 7H), 0.96 (s, 8H). 13C NMR (126 MHz,
CDCl3) δ 138.3, 138.2, 128.5, 128.4, 128.0, 128.0, 127.8, 127.7,
93.8(C1), 79.7(C2), 76.0, 75.3, 72.9, 72.7, 71.8, 71.3, 64.6(C6), 33.4,
Cyclohexyl 2,4-Di-O-benzyl-3,6-O-(di-tert-butylsilylene)-α/β-
1
D-mannopyranoside. H NMR (500 MHz, chloroform-d) δ 7.47−
7.26 (m), 5.22 (d, J = 4.1 Hz), 5.11 (d, J = 3.4 Hz), 4.83 (d, J = 12.2
Hz), 4.75 (d, J = 12.0 Hz), 4.73−4.69 (m), 4.64 (d, J = 11.8 Hz),
4.61−4.52 (m), 4.15 (dd, J = 6.4, 1.6 Hz), 4.15−4.11 (m), 4.08 (d, J =
4.2 Hz), 3.92−3.84 (m), 3.77 (t, J = 3.9 Hz), 3.64 (td, J = 9.4, 4.7 Hz),
1.93 (b,s), 1.77 (b,s), 1.56 (b, s), 1.45−1.23 (m), 1.06 (s), 1.02 (s),
0.94 (s), 0.94 (s). 13C NMR (126 MHz, CDCl3) δ 139.2, 138.9, 138.0,
137.8, 128.6, 128.6, 128.4, 128.3, 128.3, 128.0, 128.0, 127.9, 127.7,
127.6, 127.6, 127.5, 127.4, 100.5, 98.7, 77.5, 77.3, 75.5, 75.0, 74.7, 74.2,
72.0, 71.7, 71.2, 71.0, 69.6, 69.5, 68.9, 68.5, 68.4, 33.8, 32.1, 28.3, 28.3,
28.2, 28.2, 25.9, 24.5, 24.3, 21.9, 21.9, 21.9, 21.8.
31.9, 28.8, 28.4, 25.8, 24.5, 24.2, 22.5, 21.3. [α]rt 15.5° (c 1.0,
D
CHCl3), HRMS calcd for C34H50O6SiNa 605.3274, found 605.3273
Methyl 2,3,4-Tri-O-benzyl-6-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α,β-D-galactopyranosyl)-α-D-glucopyrano-
side. 1H NMR (500 MHz, chloroform-d) δ 7.40−7.23 (m), 5.25 (d, J
= 5.1 Hz, 1H), 5.00 (d, J = 10.9 Hz, 1H), 4.83 (d, J = 10.9 Hz), 4.80−
M
dx.doi.org/10.1021/jo4012464 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4.68 (m), 4.60 (dd, J = 22.2, 11.9 Hz), 4.55−4.51 (m), 4.50−4.44 (m),
4.42 (dd, J = 7.5, 2.6 Hz), 4.35 (d, J = 11.6 Hz), 4.08 (dd, J = 12.5, 2.6
Hz), 4.03 (d, J = 4.4 Hz), 4.02−3.99 (m), 3.99−3.94 (m), 3.92 (dd, J =
5.1, 1.2 Hz), 3.80−3.73 (m), 3.58−3.52 (m), 3.39 (dd, J = 9.6, 3.6
Hz), 3.36 (s), 3.32 (s), 1.04 (s), 1.03 (s), 1.02 (s), 0.99 (s). 13C NMR
(126 MHz, CDCl3) δ 138.9, 138.8, 138.4, 138.4, 138.2, 138.2, 137.6,
128.5, 128.4, 128.4, 128.3, 128.3, 128.0, 127.9, 127.9, 127.7, 127.7,
127.6, 127.6, 127.5, 102.32, 97.9, 97.0, 96.4, 84.0, 82.1, 82.0, 80.1, 79.9,
79.5, 78.2, 77.9, 75.8, 75.7, 75.6, 75.3, 75.0, 74.9, 74.8, 73.3, 72.7, 72.5,
72.2, 72.1, 71.7, 71.3, 70.9, 70.3, 70.0, 68.5, 67.6, 64.5, 64.3, 55.1, 55.1,
28.7, 28.6, 28.4, 28.3, 22.4, 21.2. HRMS calcd for C56H70O11SiNa
969.4585, found 969.4578
28.5(CH3), 28.1(CH3), 25.8, 24.0, 23.8(C-Si), 21.9(C-Si), 21.6. [α]rt
56.6° (c 1.0, CHCl3), HRMS calcd for C27H43N3O5SiNa 540.2870,
found 540.2870
D
Cyclohexyl 2-Azido-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-
2-deoxy-1-thio-β-D-glucopyranoside. 1H NMR (500 MHz,
chloroform-d) 7.38−7.28 (m, 5H, Ar), 4.94 (d, J = 7.1 Hz, 1H,
H1), 4.68 (d, J = 11.9 Hz, 1H, CH2-benzyl), 4.49 (d, J = 11.9 Hz, 1H,
CH2-benzyl), 4.30 (d, J = 3.5 Hz, 1H, H3), 4.14 (dd, J = 12.3, 1.1 Hz,
1H, H6), 4.08 (d, J = 2.5 Hz, 1H, H5), 3.95 (d, J = 3.2 Hz, 1H, H4),
3.86 (dd, J = 12.3, 3.0 Hz, 1H, H6), 3.65 (d, J = 7.1 Hz, 1H, H2), 3.61
(td, J = 9.4, 4.7 Hz, 2H), 1.94−1.83 (m, 2H), 1.79−1.70 (m, 2H),
1.56−1.47 (m, 2H), 1.47−1.36 (m, 2H), 1.30−1.20 (m, 3H), 0.98 (s,
9H, TBS), 0.88 (s, 9H, TBS). 13C NMR (126 MHz, CDCl3) δ 137.5,
128.7, 128.2, 128.1, 98.7, 80.3, 77.4, 74.5, 72.7, 72.1, 67.3, 66.3, 33.9,
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-β-D-galactopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.48 (d, J = 7.1 Hz, 2H), 7.41−
32.3, 28.3, 27.8, 25.8, 24.4, 24.4, 21.8, 21.7.[α]rtD 23.6° (c 1.0, CHCl3),
́
HRMS calcd for C27H43N3O5SiNa 540.2870, found 540.2861
Methyl 2,3,4-Tri-O-benzyl-6-O-(2-azido-4-O-benzyl-3,6-O-
(di-tert-butylsilylene)-2-deoxy-α,β-D-glucopyranosyl)-α-D-glu-
7.23 (m, 21H), 7.20−7.16 (m, 2H), 5.03 (d, J = 10.7 Hz, 1H), 4.82 (d,
J = 10.7 Hz, 1H), 4.78 (d, J = 12.2 Hz, 1H), 4.74 (d, J = 11.4 Hz, 1H),
4.70 (d, J = 6.9 Hz, 1H), 4.62 (d, J = 3.0 Hz, 1H), 4.59 (d, J = 1.9 Hz,
1H), 4.58−4.55 (m, 1H), 4.40 (d, J = 2.3 Hz, 1H), 4.36 (d, J = 12.1
Hz, 1H), 4.32 (d, J = 12.1 Hz, 1H), 4.27 (d, J = 12.1 Hz, 1H), 4.20 (d,
J = 11.2 Hz, 1H), 4.05−3.98 (m, 2H), 3.95 (d, J = 3.5 Hz, 1H), 3.93−
3.91 (m, 1H), 3.89 (d, J = 9.1 Hz, 1H), 3.86−3.81 (m, 1H), 3.79 (dd, J
= 8.1, 2.3 Hz, 1H), 3.77 (s, 1H), 3.75 (s, 1H), 3.72 (ddd, J = 9.9, 3.3,
1.6 Hz, 1H), 3.58 (dd, J = 10.6, 1.6 Hz, 1H), 3.52 (dd, J = 9.3, 3.6 Hz,
1H), 3.40 (s, 3H), 1.02 (s, 9H), 1.00 (s, 9H). 13C NMR (126 MHz,
CDCl3) δ 139.5, 138.5, 138.4, 138.0, 137.5, 128.5, 128.5, 128.3, 128.3,
128.2, 128.1, 128.0, 127.9, 127.4, 127.3, 101.5, 98.3, 84.7, 80.1, 79.9,
79.2, 75.8, 75.6, 75.3, 73.7, 73.0, 72.6, 71.9, 71.5, 70.1, 68.2, 63.6, 55.4,
1
copyranoside. H NMR (500 MHz, chloroform-d) δ 7.45−7.24 (m,
Ar), 5.50 (d, J = 5.0 Hz), 5.05−4.98 (m), 4.94 (d, J = 11.1 Hz), 4.92−
4.80 (m), 4.78 (d, J = 11.2 Hz), 4.73−4.67 (m), 4.65 (d, J = 6.5 Hz),
4.63−4.56 (m), 4.49 (d, J = 11.9 Hz), 4.43 (s), 4.38 (d, J = 3.5 Hz),
4.22−4.00 (m), 3.91−3.72 (m), 3.69 (d, J = 7.1 Hz), 3.59 (d, J = 3.5
Hz), 3.56 (dd, J = 7.3, 4.4 Hz), 3.53−3.47 (m), 3.41 (s, OMe), 3.39 (s,
OMe), 1.00 (s, TBS), 0.96 (s, TBS), 0.92 (s, TBS), 0.88 (s, TBS). 13C
NMR (126 MHz, CDCl3) δ 138.9, 138.8, 138.4, 138.3, 138.2, 137.4,
137.2, 128.5, 128.5, 128.5, 128.4, 128.4, 128.4, 128.4, 128.3, 128.2,
128.1, 128.1, 128.0, 127.9, 127.9, 127.7, 127.7, 127.6, 127.5, 127.5,
100.9, 98.2, 97.9, 96.0, 82.1, 82.0, 80.4, 90.0, 79.9, 78.1, 77.6, 75.7,
75.6, 75.4, 74.9, 74.8, 74.2, 73.5, 73.3, 72.9, 72.6, 72.0, 71.5, 71.2, 70.4,
70.1, 68.7, 67.9, 67.4, 67.0, 66.6, 60.3, 55.1, 28.3, 28.1, 28.0, 27.7, 21.8,
21.7, 21.5, 21.0. HRMS calcd for C49H63N3O10SiNa 904.4180, found
904.4183
28.7, 28.6, 22.4, 21.2. [α]rt 6.0° (c 1.0, CHCl3), HRMS calcd for
D
C56H70O11SiNa 969.4585, found 969.4592
Methyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α-D-galactopyranosyl)-α-D-glucopyranoside.
1H NMR (500 MHz, chloroform-d) δ 7.40−7.26 (m, 25H), 5.97 (d, J
Methyl 2,3,6-Tri-O-benzyl-4-O-(2-azido-4-O-benzyl-3,6-O-
= 5.9 Hz, 1H), 5.06 (d, J = 11.2 Hz, 1H), 4.76 (d, J = 12.0 Hz, 1H),
4.70 (dd, J = 11.7, 5.4 Hz, 3H), 4.65−4.61 (m, 2H), 4.54 (s, 2H),
4.50−4.42 (m, 4H), 4.38 (d, J = 12.0 Hz, 1H), 4.31 (dd, J = 7.5, 2.6
Hz, 1H), 4.20 (d, J = 12.0 Hz, 1H), 4.10−3.92 (m, 5H), 3.86−3.82
(m, 1H), 3.76 (dt, J = 9.6, 2.7 Hz, 2H), 3.63−3.56 (m, 3H), 3.41 (s,
3H), 1.02 (s, 9H), 0.97 (s, 9H). 13C NMR (126 MHz, CDCl3) δ
138.6, 138.1, 137.9, 137.9, 137.8, 128.5, 128.4, 128.4, 128.4, 128.3,
128.2, 128.0, 127.9, 127.8, 127.7, 127.5, 127.4, 127.3, 127.1, 97.7, 95.1,
82.3, 80.4, 79.8, 74.9, 74.6, 73.3, 72.9, 72.0, 71.7, 71.5, 70.7, 69.5, 69.1,
64.1, 55.2, 28.6, 28.4, 22.3, 21.2. [α]rtD 14.7.0° (c 1.0, CHCl3), HRMS
calcd for C56H70O11SiNa 969.4585, found 969.4584
(di-tert-butylsilylene)-2-deoxy-α,β-D-glucopyranosyl)-α-D-glu-
1
copyranoside. H NMR (500 MHz, chloroform-d) δ 7.49−7.26 (m,
Ar), 5.96 (d, J = 6.4 Hz,), 5.13 (d, J = 11.1 Hz), 5.05−5.03 (m), 5.01
(d, J = 11.4 Hz), 4.89 (d, J = 11.4 Hz), 4.82 (d, J = 11.1 Hz), 4.78 (d, J
= 12.1 Hz), 4.74 (d, J = 12.2 Hz), 4.71−4.64 (m), 4.64−4.45 (m),
4.42−4.38 (m), 4.33 (d, J = 3.2 Hz), 4.12 (m), 4.05 (dd, J = 10.8, 3.8
Hz), 4.02−3.82 (m), 3.78 (dd, J = 10.8, 1.7 Hz), 3.72 (dd, J = 10.7, 1.9
Hz), 3.70−3.64 (m), 3.64−3.58 (m), 3.55 (dd, J = 9.2, 3.6 Hz), 3.42
(s, OMe), 3.41 (s, OMe), 3.35 (d, J = 6.4 Hz), 0.94 (s, TBS), 0.87 (s,
TBS), 0.86 (s, TBS), 0.84 (s, TBS).13C NMR (126 MHz, CDCl3) δ
139.5, 138.7, 138.5, 138.3, 138.2, 138.1, 137.5, 137.0, 128.5, 128.5,
128.4, 128.2, 128.2, 128.1, 128.0, 128.0, 128.0, 128.9, 128.8, 127.8,
127.6, 127.4, 127.4, 127.3, 127.3, 127.1, 127.0, 100.3, 98.1, 97.8, 95.5,
82.3, 80.5, 80.3, 79.9, 79.6, 78.4, 75.5, 74.9, 74.5, 74.3, 74.1, 73.7, 73.5,
73.2, 73.2, 73.0, 72.4, 71.7, 70.8, 69.8, 69.7, 68.8, 68.3, 67.7, 67.5, 66.8,
60.3, 55.3, 28.0, 28.0, 27.7, 21.7, 21.6, 21.2, 21.1. HRMS calcd for
C49H63N3O10SiNa 904.4180, found 904.4185
Phenyl 2,3,6-Tri-O-benzyl-4-O-(2,4-di-O-benzyl-3,6-O-(di-
tert-butylsilylene)-α-D-galactopyranosyl)-1-thio-β-D-glucopyra-
1
noside. H NMR (500 MHz, chloroform-d) δ 7.63−7.58 (m, 2H),
7.40−7.19 (m, 26H), 7.15 (dd, J = 7.2, 2.2 Hz, 2H), 5.89 (d, J = 5.9
Hz, 1H, H1), 4.92 (d, J = 11.3 Hz, 1H), 4.88 (d, J = 10.2 Hz, 1H),
4.71−4.59 (m, 4H), 4.55−4.42 (m, 6H), 4.29 (dd, J = 7.6, 2.7 Hz,
1H), 4.25 (d, J = 12.0 Hz, 1H), 4.09−4.02 (m, 2H), 3.98 (dd, J = 12.4,
2.6 Hz, 1H), 3.82−3.79 (m, 1H), 3.72−3.65 (m, 2H), 3.57−3.51 (m,
2H), 3.48 (ddd, J = 9.6, 4.2, 1.9 Hz, 1H), 1.01 (s, 9H), 0.94 (s, 9H).
13C NMR (126 MHz, CDCl3) δ 138.5, 138.3, 138.0, 138.0, 137.9,
132.1, 129.1, 128.6, 128.5, 128.5, 128.4, 128.3, 128.1, 128.0, 127.9,
127.9, 127.9, 127.6, 127.6, 127.6, 127.4, 127.2, 95.2, 87.2, 87.1, 80.9,
79.9, 78.8, 75.2, 74.8, 74.4, 73.5, 72.6, 72.2, 71.7, 71.5, 70.8, 69.2, 64.3,
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
28.7, 28.4, 22.4, 21.2. [α]rt 3.6° (c 1.0, CHCl3), HRMS calcd for
D
C61H72O10SSiNa 1047.4513, found 1047.4511
AUTHOR INFORMATION
■
Cyclohexyl 2-Azido-4-O-benzyl-3,6-O-(di-tert-butylsilylene)-
2-deoxy-1-thio-α-D-glucopyranoside. 1H NMR (500 MHz,
chloroform-d) δ 7.41−7.30 (m, 5H, Ar), 5.60−5.58 (d, J = 4.8, 1H,
H1), 4.72 (d, J = 12.6 Hz, 1H, CH2-benzyl), 4.65 (d, J = 12.6 Hz, 1H,
CH2-benzyl), 4.43−4.41 (m, 1H), 4.22 (br s, 1H), 4.19 (dd, J = 12.7,
1.7 Hz, 1H, H6), 3.94 (dd, J = 12.7, 2.9 Hz, 1H, H6), 3.89 (d, J = 2.8
Hz, 1H), 3.76 (tt, J = 8.7, 3.7 Hz, 1H), 3.54 (d, J = 4.8 Hz, 1H, H2),
1.92 (m, 2H), 1.80 (m, 2H), 1.54 (m, 2H), 1.45 (m, 1H), 1.31 (m,
5H), 0.99 (s, 9H, TBS), 0.89 (s, 9H, TBS). 13C NMR (126 MHz,
CDCl3) δ 137.8(ipso), 128.6(Ar), 128.1(Ar), 128.0(Ar), 93.2(C1),
75.8, 75.2, 72.8, 71.8, 71.5(CH2-benzyl), 68.3(C6), 60.9, 33.3, 31.5,
Corresponding Author
*E-mail: cmp@chem.ku.dk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank FTP for supporting this work and Christian Tortzen
for help with low temperature NMR.
N
dx.doi.org/10.1021/jo4012464 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(20) Crich, D.; Pedersen, C. M.; Bowers, A. A.; Wink, D. J. J. Org.
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