OFox imidates as versatile glycosyl donors for chemical glycosylation

Article abstract of DOI:10.1039/c6ob02230h

Previously we communicated 3,3-difluoroxindole (HOFox)-mediated glycosylations wherein 3,3-difluoro-3H-indol-2-yl (OFox) imidates were found to be key intermediates. Both the in situ synthesis from the corresponding glycosyl bromides and activation of the

Full text of DOI:10.1039/c6ob02230h

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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OFox imidates as versatile glycosyl donors for chemical glycosylation†,‡
Swati S. Nigudkar,a Tinghua Wang,a Salvatore G. Pistorio,a Jagodige P. Yasomanee,a Keith J. Stine,a and
Alexei V. Demchenkoa,*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Previously we communicated 3,3-difluoroxindole (HOFox) –
mediated glycosylations wherein 3,3-difluoro-3H-indol-2-yl
(OFox) imidates were found to be key intermediates. Both the
corresponding bromide 1214 in 80% yield (entry 7). The
formation of OFox imidates in all cases was confirmed by
detecting changes in the 19F NMR signals from -112.4 ppm for
in-situ synthesis from the corresponding glycosyl bromides 60 3,3-difluoro-2-oxindole to -121 to -122 ppm for the coupled
10 and activation of the OFox imidates could be conducted in a
regenerative fashion. Herein, we extend this study with the
main focus on the synthesis of various OFox imidates and
their investigation as glycosyl donors for chemical 1,2-cis and
1,2-trans glycosylation.
product.15 Interestingly, the formation of side products such as N-
glycosides or 1,2-dehydro derivatives (glycals) seen in other
imidate syntheses16 was practically absent in the case of OFox
imidates.
65 Table 1. Synthesis of 3,3-difluoro-3H-indol-2-yl (OFox) imidates
15
Practically all complex carbohydrates are connected via O-
glycosidic linkages, but obtaining these linkages by chemical
methods remains challenging. Many methods for glycoside
synthesis have been developed.1 However, the complexity of
glycosylation reactions constantly calls for further improvement.2
20
A
majority of all glycosylations are performed with
thioglycosides3 and O-trichloroacetimidates (TCAI),4 but N-
phenyl trifluoroacetimidates (PTFAI) introduced by Yu and co-
workers5 have also been gaining a considerable niche amongst
methods used for chemical glycosylation. Inspired by excellent
Product (yield,
α/β ratio)
Entry
1
Precursor
Conditions
HOFox, Ag2O,
DIPEA, toluene, rt,
6 h
25 results achieved with the PTFAI donors, we decided to
investigate the 3,3-difluoro-3H-indol-2-yl (OFox) leaving group
that represents a hybrid structure between PTFAI and S/O-
benzoxazolyl (SBox/OBox) leaving groups developed by our
laboratory.6 While investigating approaches to the synthesis of
30 OFox imidates, we discovered that these new compounds can be
generated and glycosylated in a regenerative fashion in situ. This
created the basis to exploring 3,3-difluoroxindole (HOFox)-
mediated regenerative glycosylations wherein the OFox imidates
were found to be key intermediates.7 Described herein is a
35 continuation of this study with the main focus on the synthesis of
various OFox imidates and their investigation as glycosyl donors
for chemical glycosylation.
1
5 (80%, α only)
6 (75%, α only)
HOFox, Ag2O,
DIPEA, CH2Cl2, rt,
10 h
2
3
4
2
3
BzO
i) 33% HBr/AcOH,
CH2Cl2; ii) HOFox,
Ag2O, DIPEA,
CH2Cl2, 0 oC to rt,
6 h
OBz
O
OFox
BzO
BzO
7 (75%, β only)
i) 33% HBr/AcOH,
CH2Cl2, ii) HOFox,
Ag2O, DIPEA,
3,3-Difluoroxindole aglycone (HOFox) can be synthesized
from the commercially available Isatin with diethylaminosulfur
40 trifluoride (DAST) in anhydrous CH2Cl2 at room temperature,7-8
but there is a variety of approaches that might be suitable as
well.9 Based on previous syntheses of imidates and thioimidates
of similar structure we decided to react HOFox with different
glycosyl halides (110 or 2,11 X = Br, Table 1) that were used either
45 directly or obtained in situ from the corresponding benzoates (3
or 4, X = Bz). It was observed that all anomeric substitutions
proceeded stereoselectively providing either 1,2-trans or 1,2-cis-
linked OFox imidates 5-8 in 75-84% yields (entries 1-4, Table 1).
Also investigated was the synthesis using hemiacetal 912 (X =
50 OH) as the starting material. This transformation was performed
via the corresponding chloride (X = Cl) and resulted in the
formation of per-benzylated OFox imidate 10 in 62% yield (entry
5). We also demonstrated that thioglycoside 1113 can be
converted into OFox imidate 10 in 95% yield in the presence of
55 N-iodosuccinimide (entry 6). The synthesis of 2-benzyl-3,4,6-tri-
O-acetylated OFox imidate 13 was performed from the
CH2Cl2, rt, 2.5 h
4
9
8 (84%, α only)
i) SOCl2, DMF,
CH2Cl2; ii) HOFox,
Ag2O, DIPEA,
5
6
CH2Cl2, rt, 8 h
10 (62%, 10/1)
10 (95%, 9.0/1)
NIS, HOFox,
CH2Cl2, rt, 1 h
11
HOFox, Ag2O,
DIPEA, CH2Cl2, 0
oC, 40 min
7a
13 (80%, β only)
12
a
– reactions at rt for prolonged time (5 h) lead to the exclusive
formation of the corresponding α-linked OFox imidate (81% yield)
70
With success in synthesizing a variety of OFox imidates, we
turned our attention to studying the glycosidation of per-acylated
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compounds 5-8 with selected representative glycosyl acceptors
14-17. A majority of leaving groups in carbohydrate chemistry,
even the most reactive ones, would not depart on their own.
Instead, the leaving group departure is typically affected via the
interaction with electrophilic promoters. Resultantly, the leaving
group ability is enhanced and it departs as neutral species or a
complex.2c For the glycosyl imidate series, the activation can
take place either directly, via the anomeric atom (oxygen or
sulfur), or remotely, via the nitrogen atom as depicted in Figure 1.
presence of TMSOTf gave low yields for the formation of the
corresponding disaccharide (<50% yield).
Table 2. Glycosylation with per-benzoylated OFox donors 6-8
5
50
Entry
1
Donor
Acceptor
Product (yield)
10 For instance, it has become common knowledge that TCAI
donors are activated via the remote nitrogen.2c
Figure 1. Direct vs. remote activation of S- and O-imidates
6
14
15
16
18 (94%)
19 (86%)
2
3
6
6
20 (93%)
4
6
15
In principle, the activation mode can be determined by means
of isolation and characterization of the departed aglycone that
represents the leaving group-promoter conjugate. As previously
shown in our laboratory, S-thiazolinyl donors are activated via
the remote nitrogen.17 In strong contrast, bicyclic leaving groups
17
14
21 (90%)
20 SBox or OBox are activated via the anomeric sulfur or oxygen
atom, respectively (Figure 1).18 This is due to the propensity of
the benzoxazolyl group to retain the aromaticity of its
heterocyclic ring, which otherwise would have been disrupted if
the activation were taking place via the endocyclic nitrogen. In
25 regards to the OFox imidates, the five-membered ring is non-
aromatic, therefore, our working hypothesis was that the
activation of the OFox leaving group takes place via the remote
nitrogen atom. However, regardless of the activator used (vide
infra), the isolation of the departed leaving group as an elusive
30 OFox-promoter conjugate was proven impossible at this stage.
All glycosylation reactions with OFox imidates, even deactivated
per-O-benzoylated ones, were completed in a matter of minutes
in the presence of a catalytic amount of the promoter. Instead,
only “free” HOFox could be isolated from the reaction medium
35 because the departed aglycone would release the activator
creating the basis for exploring the HOFox mediated regenerative
glycosylation disclosed previously.7
It has been previously demonstrated that the activation of O-
imidoyl glycosyl donors TCAI, PTFAI, OBox) can be
40 accomplished in the presence of the catalytic amount of
promoters including TMSOTf,19 BF3-Et2O,20 p-TsOH,21
Bi(OTf)3,22 Yb(OTf)3,23 Sm(OTf)3,23 AgOTf,24 MeOTf,6b Among
these, TMSOTf is arguably the most commonly used promoter.
Hence, our initial focus has been centered on examining the effect
45 of this activator on OFox glycosides. Unfortunately, the reaction
of per-acetylated OFox donor 5 with glycosyl acceptor 1425 in the
5
6
7
7
22 (98%)
23 (98%)
15
14
7
8
8
8
24 (93%)
25 (90%)
15
We note that the low yield is mainly attributed to high rates of
the competing acetyl migration to the C-6 of the glycosyl
55 acceptor. Similarly to our previous study with OBox imidates,6b
we were able to overcome this issue by performing this
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60 Table 3. TMSOTf-promoted glycosidation of OFox donor 10 with
acceptors 14-17, 26-28.
glycosylation reaction using SnCl4 as an activator. This reaction
led to the formation of the corresponding disaccharide in a
respectable 80% yield. Nevertheless, to avoid complications
related to the competing acetyl migration, further study was
conducted with per-benzoylated OFox imidates of the D-gluco,
5
D-galacto, and D-manno series (6-8).
All glycosylations
summarized in Table 2 proceeded smoothly in the presence of
TMSOTf (0.1 equiv. to donor), completed in minutes and
provided excellent yields for the formation of disaccharides 18-25
10 (86% and higher). Complete 1,2-trans stereoselectivity due to the
participatory effect of the 2-O-benzoyl substituent was recorded
in each case.
Entry
1
Acceptor
Product (yield, α/β ratio)
We were then bound to extend the scope of the OFox
glycosylation methodology to per-benzylated OFox imidate 10
15 with the intention of gaining access to 1,2-cis glycosidic linkage.
For this study, we chose TMSOTf as the promoter and a set of
structurally diverse glycosyl acceptors (14-17, 26-28) ranging
from highly reactive primary alcohols to sterically hindered
and/or less reactive alcohols. All reactions were performed at -78
20 oC due to the anticipated high reactivity of 10. The results of this
study are summarized in Table 3. Glycosidation of donor 10 with
primary acceptor 14 gave glycoside 29 in 94% yield and a nearly
complete β-selectivity (α/β = 1/24, entry 1). Reactions with
secondary acceptors 1525 and 1625 were still β-selective and
25 disaccharides 30 and 31 were obtained in high yields over 90%
and moderate selectivity (up to α/β = 1/4-6, entries 2 and 3).
Along similar lines, glycosylations with other primary acceptors
17 and 2626 as well as more sterically hindered alcohols,
cholesterol 27 and adamantanol 28, were all β-selective. The
30 respective products 32-35 were obtained in high yields (85-89%)
and high 1,2-trans selectivity (up to complete β, entries 4-7). It is
noteworthy that the high β-selectivity obtained from glycosyl
donors without the neighboring participating acyl group is
relatively rare. While rather unexpected, these glycosylations
35 indicate that OFox glycosyl donor 10 can be used to obtain β-
linked glycosides in high yields and selectivities.
14
15
16
29 (94%, 1/24)a
30 (94%, 1/4.0)a
2
3
31 (90%, 1/6.0)a
4
17
26
32 (85%, 1/12)a
5
6
Encouraged by the high selectivity and overall high reactivity
of OFox imidates, we decided to explore the effect that different
experimental conditions and factors may have on
40 stereoselectivity. The effect of solvents on the stereoselectivity
of glycosylation has been studied for a long time and resulted in a
good level of understanding of the modes by which solvents may
affect the reaction. For instance, it has been shown that nitrilic
solvents strongly favor the formation of equatorial (β-D)
45 glycosides, whereas ethereal solvents are often beneficial for the
synthesis of axial (α-D) glycosides.27 As aforementioned,
glycosylation of per-O-benzylated OFox donor 10 with primary
glycosyl acceptor 14 in the presence of TMSOTf (10 mol %) at -
33 (89%, 1/11)a
27
28
34 (86%, β only)
7
o
78 C produced disaccharide 29 in 94% yield and excellent β-
50 selectivity (α/β = 1/24, entry 1, Table 3). A similar result was
obtained with the reduced amount of TMSOTf to 5 mol % (entry
1, Table 4). With the exploration of the solvent effect on the
stereoselectivity of glycosidation of OFox donors in mind, the
reaction in CH2Cl2 (entry 1) was chosen as the benchmark. Along
55 this study, we also investigated the temperature effect of
glycosylation with OFox imidates with the anticipation that low
temperatures will favor the equatorial (kinetic) product, whereas
high temperature would be beneficial for axial (thermodynamic)
product.
35 (88%, 1/23)
a
– the β-selectivity of these reactions could be further enhanced by
using EtCN as the reaction solvent (vide infra)
65
Glycosylation of per-O-benzylated OFox donor 10 with
primary glycosyl acceptor 14 in the presence of TMSOTf (5 mol
%) at -40 C produced disaccharide 29 in an excellent yield of
o
94%, but the β-selectivity was significantly reduced (α/β = 1/8.0,
70 entry 2, Table 4). A similar glycosylation of per-O-benzylated
OFox donor 10 performed at rt produced disaccharide 29 in an
excellent yield of 93%, but practically no stereoselectivity (α/β =
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1/1.2, entry 3, Table 4). The β-selectivity was enhanced by
changing the reaction solvent from CH2Cl2 to CH3CN. Under
these reaction conditions disaccharide 29 was obtained in 87%
yield (α/β = 1/14, entry 4). Interestingly, when a solvent mixture
the activation of OFox imidate 10 using other promoters is
summarized in Table 5. Glycosylation using TMSOTf as the
promoter has been used as the benchmark (entry 1). Using BF3-
Et2O, Cu(OTf)2 or MeOTf as promoters gave very comparable
5
of CH2Cl2/CH3CN (1/2, v/v) was used a decreased in 45 results (entries 2-4) to those achieved with TMSOTf. All of these
stereoselectivity in comparison to the results achieved with both
of these solvents individually was recorded (α/β = 1/6.0, entry 5).
reactions proceeded with a nearly complete β-selectivity for the
formation of disaccharide 29, which is rather uncommon for
benzylated glycosyl donors.
Table 4. The solvent and temperature effects on glycosidation of
OFox donor 10.
When metal salt-based promoters AgOTf or PdCl2 were used,
50 the reactions became much slower, did not proceed to completion
even in 24-36 h (entries 5 and 6). Bi(OTf)3-promoted reactions
were swift (entry 7), but the stereoselectivity has dropped in all
cases of metal promoter-based activations. To reinforce this
finding further, we were curious to investigate whether OFox
55 imidate 10 is capable of providing α-stereoselectivity. For this
purpose we chose trimethylsilyl perchlorate (TMSClO4) as an
activator because our independent study showed that perchlorates
typically outperform other counter ions and provide superior α-
selectivity.28 Thus, reaction in the presence of TMSClO4 in
60 diethyl ether gave disaccharide 29 in 75% yield in enhanced α-
selectivity (α/β = 5.0/1, entry 9). A similar stereoselectivity albeit
a reduced yield was achieved using diethyl ether/1,4-dioxane
(1/1, v/v) as a solvent mixture (not shown).
10
Yield of
29
Entry
Solvent
Temp
α/β ratio
CH2Cl2
CH2Cl2
-78 oC
-40 oC
rt
94%
1/24
1/8.0
1/1.2
1/14
1/6.0
1
2
3
4
5
97%
93%
87%
96%
CH2Cl2
-40 oC
-40 oC
Table 5. The effect of promoter on the stereoselectivity of
CH3CN
65
glycosidation of OFox donor 10.
CH2Cl2/CH3CN (1/2, v/v)
CH2Cl2/CH3CN/EtCN
(1/2/1, v/v/v)
6
-78 oC
99%
β only
EtCN
Et2O
Et2O
-78 oC
-78 oC
50 oC
99%
84%
81%
β only
1/5.0
1.6/1
7
8
9
Yield of
29
The use of acetonitrile as the reaction solvent has its
limitations because the reactions cannot be cooled below -40 C.
Entry
Promoter (equiv.)
Temp, time
-78 oC, 5 min
-78 oC, 5 min
-78 oC, 5 min
α/β ratio
1/24
o
15 Therefore, to achieve direct comparison of excellent β-selectivity
(α/β = 1/24, entry 1) obtained in CH2Cl2 at -78 oC we
incorporated propionitrile (EtCN) in our study. To our delight,
when CH3CN was used either as an additive or neat, disaccharide
29 was obtained in a nearly quantitative yield and complete β-
20 stereoselectivity (entries 6 and 7). Along similar lines, the effect
of diethyl ether as the reaction solvent was also investigated.
Since diethyl ether favors the formation of α-glucosides, we
observed reduced β-stereoselectivity in reactions at -78 oC (α/β =
1/5.0, entry 8). The same reaction performed at higher
TMSOTf (0.05
equiv.)
1
2
3
4
94%
BF3-OEt2 (0.1
equiv.)
93%
97%
91%
1/20
Cu(OTf)2 (0.2
equiv.)
β only
1/>25
-78 oC, 10
min
MeOTf (0.2 equiv.)
5
6
7
AgOTf (0.5 equiv.)
PdCl2 (0.3 equiv.)
rt, 24 h
71%
57%
85%
1/1.6
1/1.7
1/7
rt, 36 h
o
25 temperatures of 50 C, gave disaccharide 29 with preferential α-
Bi(OTf)3 (0.1 equiv.) -78 oC, 5 min
stereoselectivity (α/β = 1.6/1, entry 9). A similar result was
obtained using THF as the reaction solvent (not shown).
TMSClO4 (0.1
rt, 5 min
8a
75%
5.0/1
equiv.)a
With the establishment of the effect of EtCN on
stereoselectivity, we decided to reevaluate reactions performed
30 earlier, particularly those where somewhat lower β-
stereoselectivity was recorded, Table 3, entries 2-6 in particular.
Thus, the synthesis of 30 yielded enhanced α/β selectivity from
1/4.0 to 1/12; 31 from 1/6.0 to 1/15; 32 from 1/12 to β-only; and
33 from 1/11 to 1/18 with practically the same yield.
A result of this study confirmed that OFox imidates adequately
respond to the solvent and temperature effects. A similar trend to
that established for other classes of glycosyl donors was also
observed herein. As an expansion of this study, we decided to
investigate whether other Lewis acid activators would provide
a – Et2O was used as the reaction solvent
As a result of the preliminary screening of reaction conditions;
70 we conclude that reactions in the presence of 5 mol % of
TMSOTf in either CH2Cl2 or EtCN at -78 oC are the most
effective reaction conditions for glycosidation of OFox imidate
10. Since per-benzylated OFox donor 10 was β-selective, in the
expansion of our studies we decided to investigate whether other
75 common O-imidates behave similarly under essentially the same
reaction conditions. For these studies we acquired similarly
protected TCAI and PTFAI 36 and 37, respectively.
35
40 further enhancement of the methodology. A study dedicated to
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Glycosidations of 10 with acceptor 14 in the presence of
TMSOTf either at -78 C or ambient temperature were used as
acceptors. For instance, 4-OH acceptor 15 also provided complete
α-stereoselectivity, but the corresponding disaccharide 39 was
isolated in a modest yield of 70% (entry 3). The outcome of this
coupling could be improved by using excess donor 13 (1.8 equiv.
o
the benchmark (entries 1 and 2, Table 6). Coupling of all three
glycosyl donors 10, 36,29 and 375a with acceptor 14 produced
5
disaccharide 29 in 5 min at either temperature in comparable 50 in respect to the acceptor) necessary to overcome the mismatch
yields and stereoselectivities. Comparable results were obtained
in BF3-OEt2 promoted glycosylations (not shown). Nevertheless,
the highest β-stereoselectivity amongst all was achieved with
OFox donor 10 at -78 oC (entry 1).
between the highly reactive OFox donor and hindered 4-OH
acceptor. As a result, disaccharide 39 was obtained in 99% yield,
still with complete α-stereoselectivity (entry 4). Upon further
exploration of this approach, we noticed that other, more reactive
55 glycosyl acceptors may lead to a reduced stereoselectivity. Thus,
glycosylation of 3-OH acceptor 40 produced disaccharide 41 in
79% yield an a reduced stereoselectivity of α/β = 10/1 (entry 5).
Since all reactions with the OFox imidate donors are quite swift,
we assumed that slowing the reaction would help to gain a better
60 control of the outcome in general, and stereoselectivity in
particular. This was attempted by diluting the reaction mixture.
All previous reactions have been performed under the standard
dilution, typical for glycosylation reactions, 50 mM concentration
of the donor. Since the donor-acceptor ratio may vary, we
65 standardized the reaction conditions by maintaining the
concentration of the glycosyl acceptor, 45 mM for glycosylations
with 1.1 equiv. excess of the donor. When the glycosylation
between donor 13 and acceptor 40 was performed at 9 mM
concentration of the latter, five-fold dilution in respect to the
70 standard conditions used previously, a significant enhancement of
stereoselectivity was recorded. Thus, disaccharide 41 was
obtained in 72% yield and α/β = 20/1 (entry 6). The impact of the
five-fold dilution on the reaction rate was modest, but the
reaction did not proceed to completion, and the unreacted
75 acceptor 40 was still remaining even after 18 h. This was
addressed by upping the amount of the donor to 1.5 equiv. As a
result, disaccharide 41 was obtained in 80% yield, and excellent
stereoselectivity was maintained (α/β = 21/1, entry 7).
10
Table 6. Comparative investigation of glycosylations with O-
imidates 10, 36, and 37.
Donor
10
Temp.
-78 oC
rt
Yield of 29
94%
Ratio, α/β
1/24
Entry
1
2
3
4
5
6
93%
1/1.2
10
-78 oC
92%
1/15
36
rt
94%
4.0/1
36
-78 oC
rt
70%
1/4.4
37
91%
1/2.2
37
15
Since per-benzylated OFox donor 10 was generally very β-
selective, in the expansion of our studies to obtaining 1,2-cis
glycosides we wanted to investigate whether OFox imidates with
other protecting groups would be more suitable for our purpose.
For instance, we were particularly interested in investigating
Further drop in stereoselectivity was observed with the highly
80 reactive primary acceptor 14. Under normal concentration (45
mM of 14) disaccharide 42 was obtained in 88% with very poor
stereoselectivity α/β = 1.7/1 (entry 8). Repeating this reaction at
low concentration (9 mM of 14) immediately boosted
stereoselectivity to α/β = 6.0/1 and disaccharide 42 was isolated
85 in 78% yield (entry 9). Since this five-fold dilution had
practically no effect on the rate of the reaction, we continued
experimenting and performed the coupling at 4.5 mM
concentration of acceptor 14. Again, no visible rate reduction was
detected and disaccharide 42 was isolated in 86% with further
20 glycosyl donors with the superdisarming 2-O-benzyl-3,4,6-tri-O-
acyl protecting group pattern. In the unrelated study,
thioglycoside donors equipped with this protecting group pattern
allowed us to obtaining complete α-selectivities, whereas
glycosyl donors with multiple benzyl groups gave much lower
25 stereoselectivity.30 For this purpose, OFox imidate 13 was
subjected to exploratory glycosylations. Since both α-13 and β-13
could be obtained individually (vide supra), first we wanted to
look into the possible effect of the anomeric group orientation on
the stereoselectivity of glycosylations. As a result of this
30 experimentation, we determined that either α-13 or β-13 is
capable of providing the corresponding disaccharide 38 in a
practically identical yield of 88-89%. Most noteworthy, complete
α-stereoselectivity was achieved in both cases (Table 7, entries 1
and 2). In this context, although perbenzylated OFox donor 10
35 was used as the anomeric mixture (α/β = 10/1), a test reaction
with pure α-10 gave essentially the same result: disaccharide 29
was obtained in 94% yield with excellent selectivity of α/β =
1/24. This study helps to exclude the uncertainty arising from the
impact of the differential anomeric orientation between donors 10
40 (used as α-mainly) and donor 13 that is used as β-only due to the
readiness of its synthesis. Irrespective of the orientation of the
OFox group of the glycosyl donor, essentially the same
stereoselectivity was achieved.
90 enhancement in stereoselectivity α/β
= 9.0/1 (entry 10).
Experiments with further dilution (up to 1.5 mM of 14) required
the increased amount of donor 13 (1.5 equiv.) to maintain high
rates and yields. As a result, disaccharide 42 was obtained in 30
min in 95% yield with an improved stereoselectivity α/β = 12/1
95 (entry 11). Finally, we investigated glycosyl acceptor 26 with the
anticipation that the decreased nucleophilicity due to multiple
ester protecting groups would help to obtain high
stereoselectivity. Indeed, glycosylation of 26 under the regular
concentration conditions gave disaccharide 43 in 89% α/β = 5.2/1
100 (entry 12), which was
a
three-fold enhancement for
stereoselectivity obtained with acceptor 14 under the same
reaction conditions (compare with entry 8). This outcome could
be further improved in high dilution conditions, 9 mM of 26,
which led to the formation of disaccharide 43 in 96% yield and
105 excellent stereoselectivity α/β = 18/1 (entry 13).
Being encouraged by excellent stereoselectivity achieved with
45 2-OH acceptor 16, we moved on to explore other glycosyl
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Table 7. Investigation of the stereoselectivity of glycosidation of
OFox donor 13
Interestingly, further dilution led to decreased stereoselectivity,
thus, reaction performed at 4.5 mM of 26 gave disaccharide 43
with selectivity α/β = 7.2/1 (no details are provided). In a further
10 attempt to enhance the stereoselectivity, we also explored the
solvent effect on the glycosylations with donor 13. However, the
effect of reaction solvents that typically favor the formation of
axially oriented products, such as 1,4-dioxane, diethyl ether, THF
or toluene, used either neat or in combination with halogenated
15 solvents, dichloromethane, 1,2-dichloroethane or chloroform was
negligible (no details have been provided).
13
Entry
ROH (conc.)
Product (time, yield, α/β ratio)
(equiv.)
For conducting the comparative hydrolytic stability studies,
per-benzoylated OFox glycosyl donor 6 was compared with
2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate
31
20 446b,
and 2,3,4,6-tetra-O-benzoyl-α,β-D-glucopyranosyl N-
1
1.10
phenyltrifluoroacetimidate 45.5a These studies summarized in
Table 8 were performed in the presence of various Lewis acids in
wet ClCH2CH2Cl and quantitative estimates were made at 1, 16
and 24 h time points and are based on the accumulation of
25 2,3,4,6-tetra-O-benzoyl-D-glucopyranose 46, as observed by
TLC. Thus, in the presence of BF3-OEt2 as the activator OFox
imidate 6 underwent a nearly quantitative hydrolysis in 1 h,
whereas TCAI 44 and PTFAI 45 counterparts showed 50% and
40% hydrolysis, respectively, in 1h of reaction (Table 8, entries
30 1-3). Imidates 44 and 45 were still present even after 24 h.
On the other hand, practically no hydrolysis in cases of all
three imidates took place in the presence of Bi(OTf)3 (0.1 equiv.,
entries 4-6). In a similar series of experiments, we determined
that PTFAI 45 showed the highest stability in comparison with
35 the OFox donor 6 and TCAI counterpart 44 under MeOTf-
mediated activation conditions (entries 7-9). Conversely, we
found out that under PdCl2 mediated reactions OFox donor 6
shows the highest stability followed by TCAI donor 44 with
PTFAI counterpart 45 being the least stable (entries 10-12).
16 (45 mM)
16 (45 mM)
38 (15 min, 88%, α only)
38 (15 min, 89%, α only)
2
3
1.10a
1.10
15 (45 mM)
15 (45 mM)
39 (5 min, 70%, α only)
39 (5 min, 99%, α only)
4
5
1.80
1.10
40 (45 mM)
41 (5 min, 79%, 10/1)
41 (18 h, 72%, 20/1)b
6
7
1.10
1.50
40 (9 mM)
40 (9 mM)
40 Conclusions
41 (5 min, 80%, 21/1)
A new class of compounds, OFox imidates, with various
protecting groups have been synthesized in high yields from a
variety of precursors. The OFox imidates are very reactive and
depending on the protecting groups employed are suitable as
45 glycosyl donors for the synthesis of 1,2-cis and 1,2-trans
glycosides. These glycosylations show notable features such as
operational simplicity, rapid reaction times, high yields and
excellent stereocontrol in presence of Lewis acids used in
catalytic amounts. Achieving high levels of β-stereoselectivity
50 with per-benzylated OFox donors is an uncommon event in
carbohydrate chemistry and the use of propionitrile as the
reaction solvent can further enhance the stereoselectivity
suggesting the solvent participation during glycosylation. High α-
selectivities could also be achieved by using OFox of the
55 superdisarmed series, particularly at high dilution conditions.
This study complements a new regenerative concept for chemical
glycosylation that proceeds via reactive glycosyl OFox
intermediates and activation thereof in the catalytic fashion in
situ. Very recently, we reported a high utility of donor 6 in
60 HPLC-assisted automated oligosaccharide synthesis, which,
however, was outperformed by more traditional TCAI imidates
and showed similar efficacy to that of phosphates.32 The
exploration of both glycosylation pathways in application to the
synthesis of oligosaccharides in solution and using solid-phases is
65 currently underway in our laboratory.
8
1.10
14 (45 mM)
42 (5 min, 88%, 1.7/1)
42 (5 min, 78%, 6.8/1)
9
1.10
1.10
1.50
14 (9 mM)
14 (4.5 mM)
14 (1.5 mM)
10
11
42 (5 min, 86%, 9.0/1)
42 (30 min, 95%, 12/1)
12
1.10
1.10
26 (45 mM)
26 (9.0 mM)
43 (5 min, 89%, 5.2/1)
13
43 (10 min, 96%, 18/1)
a
b
5
– α-configured OFox donor (α-13) was used for comparison; – the
reaction did not go to completion even after 18 h
6
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DOI: 10.1039/C6OB02230H
40 Celite and rinsed successively with CH2Cl2. The combined filtrate
(~40 mL) was washed with 1% aq. NaOH (2 x 15 mL) and water (2 x
15 mL). The organic phase was separated, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexanes gradient elution)
45 to afford the corresponding OFox imidates 5, 6 or 13 in yields listed
in Table 1.
Table 8. Comparative hydrolytic stability study of OFox imidates,
TCAI, and PTFAI.
Method B.
A typical procedure for the preparation from
pentabenzoates via glycosyl bromides. A 33% solution of HBr in
AcOH (0.10 mL, 1.7 mmol) was added to a solution of a 1,2,3,4,6-
50 penta-O-benzoyl-D-galacto or mannopyranose (3 or 4, 100 mg, 0.14
mmol) in dry CH2Cl2 (0.2 mL) and the resulting mixture was stirred
under argon for 2-4 h at rt. The reaction mixture was then diluted
with CH2Cl2 (~40 mL) and washed with cold sat. aq. NaHCO3 (2 x
15 mL) and cold water (2 x 15 mL). The organic phase was
55 separated, dried with MgSO4, and concentrated in vacuo. The residue
containing crude glycosyl bromide (0.14 mmol) was dried under high
vacuum for 4 h. After that, freshly activated molecular sieves (3 Å)
and dry CH2Cl2 (1.4 mL) were added and the resulting mixture was
% of hemiacetal 46 formed
after
Entry
Donor
Conditions
1 h
16 h
24 h
---
1
2
BF3-Et2O (0.1 equiv.)
BF3-Et2O (0.1 equiv.)
BF3-Et2O (0.1 equiv.)
Bi(OTf)3 (0.1 equiv.)
Bi(OTf)3 (0.1 equiv.)
Bi(OTf)3 (0.1 equiv.)
MeOTf (1.0 equiv.)
MeOTf (1.0 equiv.)
MeOTf (1.0 equiv.)
PdCl2 (0.1 equiv.)
quant.
---
60
50
0
6
50
40
0
60
44
45
6
3
50
stirred under argon for 1 h at rt. The resulting mixture was cooled to
4
0
o
60 0 C in case of galactosyl bromide (rt for mannosyl bromide). 3,3-
5
0
0
0
44
45
6
Difluorooxindole (26.7 mg, 0.16 mmol), Ag2O (99.2 mg, 0.43 mmol)
and DIPEA (37.4 μL, 0.21 mmol) were added and the resulting
mixture was stirred for 2.5-6 h as indicated in Table 1. The solids
were filtered off through a pad of Celite and rinsed successively with
65 CH2Cl2. The combined filtrate (~40 mL) was washed with 1% aq.
NaOH (2 x 15 mL) and water (2 x 15 mL). The organic phase was
separated, dried with MgSO4, and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (ethyl acetate-
hexanes gradient elution) to afford the corresponding OFox imidates
70 7 or 8 in yields listed in Table 1.
6
0
0
0
7
0
quant.
0
---
8
0
20
44
45
6
9
0
0
0
10
11
12
0
0
50
PdCl2 (0.1 equiv.)
0
10
70
quant.
quant.
44
45
PdCl2 (0.1 equiv.)
0
Method C. A typical procedure for the preparation from hemiacetals
via glycosyl chlorides. SOCl2 (81.1 μL, 1.11 mmol) was added
dropwise to a solution of hemiacetal 9 (0.20 g, 0.37 mmol) in dry
CH2Cl2 (2.0 mL) and dry DMF (14.3 μL) and the resulting mixture
75 was stirred under argon for 7 h at rt. Upon completion, the reaction
mixture was diluted with CH2Cl2 (~30 mL) and washed with sat. aq.
NaHCO3 (2 x 15 mL) and cold water (2 x 15 mL). The organic phase
was separated, dried with MgSO4, and concentrated in vacuo. The
residue containing crude glycosyl halide (0.37 mmol) was dried
80 under high vacuum for 4 h. Freshly activated molecular sieves (3 Å,
600 mg) and dry CH2Cl2 (2.0 mL) were added and the resulting
mixture was stirred under argon for 1 h at rt. After that, 3,3-
difluorooxindole (69 mg, 0.41 mmol), Ag2O (258 mg, 1.11 mmol),
and diisopropylethylamine (DIPEA, 97 μL, 0.56 mmol) were added
85 and the resulting mixture was stirred for 8 h. The solids were filtered
off through a pad of Celite and rinsed successively with CH2Cl2. The
combined filtrate (~40 mL) was washed with 1% aq. NaOH (2 x 15
mL) and water (2 x 15 mL). The organic phase was separated, dried
with MgSO4, and concentrated in vacuo. The residue was purified by
90 column chromatography on silica gel (ethyl acetate-hexanes gradient
elution) to afford the corresponding OFox imidate 10 in 62% yield.
5
Experimental
General. The reactions were performed using commercial reagents
and the ACS grade solvents used for reactions were purified and
dried in accordance with standard procedures.
chromatography was performed on silica gel 60 (70-230 mesh),
Column
10 reactions were monitored by TLC on Kieselgel 60 F254. The
compounds were detected by examination under UV light and by
charring with 10% sulfuric acid in methanol. Solvents were removed
under reduced pressure at <40 C. CH2Cl2 and 1,2-dichloromethane
o
(DCE) were distilled from CaH2 directly prior to application.
15 Molecular sieves (3 or 4 Å), used for reactions, were crushed and
activated in vacuo at 390 °C for 8 h in the first instance and then for
2-3 h at 390 °C directly prior to application. Optical rotations were
measured at ‘Jasco P-1020’ polarimeter. 1H NMR spectra were
recorded at 300, 500 or 600 MHz, 13C NMR spectra were recorded at
1
20 75, 125 or 150 MHz. The H NMR chemical shifts are referenced to
the signal of the residual CHCl3 (δH = 7.27 ppm) for solutions in
CDCl3. The 13C NMR chemical shifts are referenced to the central
signal of CDCl3 (δC = 77.23 ppm) for solutions in CDCl3. The 19F
NMR chemical shifts are referenced to CFCl3 (δF = 0 ppm) for
25 solutions in CDCl3. HRMS determinations were made with the use of
a mass spectrometer with FAB ionization and ion-trap detection.
Method D.
A typical procedure for the preparation from
thioglycosides. A mixture of thioglycoside 11 (29 mg, 0.05 mmol)
and freshly activated molecular sieves (4 Å, 100 mg) in dry CH2Cl2
95 (1.0 mL) was stirred under argon for 1 h at rt. After that, N-
iodosuccinimide (NIS, 22.4 mg, 0.10 mmol) was added and the
resulting mixture was stirred for 10 min. HOFox (8.55 mg, 0.05
mmol) was added and the reaction mixture was stirred for 1h at rt.
The solids were filtered off through a pad of Celite and rinsed
100 successively with CH2Cl2. The combined filtrate (~20 mL) was
washed with NaHCO3 (5 mL) and water (2 x 5 mL). The organic
phase was separated, dried with MgSO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(ethyl acetate-hexanes gradient elution) to afford OFox imidate 10 in
105 95% yield.
Synthesis of 3,3-difluoroxindole (HOFox, 3,3-difluoroindolin-2-
one). HOFox was obtained from Isatin and DAST as previously
described. Analytical data were in accordance with that previously
30 reported.8
Synthesis of glycosyl donors
Method A. A typical procedure for the preparation from glycosyl
bromides. A mixture of a glycosyl bromide (1, 2 or 12, 0.15 mmol)
and freshly activated molecular sieves (3 Å, 300 mg) in dry CH2Cl2
35 (1.0 mL) or toluene (1.0 mL) was stirred under argon for 1 h at rt.
After that, 3,3-difluorooxindole (25.7 mg, 0.15 mmol), Ag2O (105
mg, 0.45 mmol), and DIPEA (39.7 μL, 0.23 mmol) were added and
the resulting mixture was stirred for 40 min - 10 h at the temperature
indicated in Table 1. The solids were filtered off through a pad of
3,3-Difluoro-3H-indol-2-yl
2,3,4,6-tetra-O-acetyl-α-D-
glucopyranoside (5). The title compound was obtained from
2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide 110 by Method A
in 62% yield as a white foam. Analytical data for 5: Rf = 0.42 (ethyl
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21
1
acetate/ hexanes, 1/1, v/v); [α]D +5.2 (c = 1.0, CHCl3); H n.m.r.
75.2, 75.3, 79.4, 81.5, 99.8, 117.4, 120.4, 123.3, 125.7, 127.8, 127.9,
128.0 (x 4), 128.0 (x 2), 128.1 (x 7), 128.6 (x 8), 133.6, 137.9, 138.0,
138.2, 138.8 ppm; 19F n.m.r.: δ, -121.3 (s, 2F, CF2) ppm; HR-FAB
MS [M+Na]+ calculated for C42H39F2NO6Na+ 714.2643, found
(300 MHz): δ, 1.96, 1.97, 1.98, 2.01 (4 s, 12H, 4 x COCH3), 3.95 (m,
1H, H-5), 4.15 (dd, 1H, J5,6a = 2.3 Hz, J6a,6b = 12.5 Hz, H-6a), 4.30
(dd, 1H, J5,6b = 4.3 Hz, H-6b), 5.17-5.32 (m, 3H, H-2, 3, 4), 5.95 (m,
5
1H, H-1), 7.14-7.40 (m, 4H, aromatic) ppm; 13C n.m.r. (75 MHz): δ, 75 714.2645.
20.4, 20.6 (x 2), 20.7, 61.4, 67.6, 70.3, 72.4, 72.9, 96.6, 120.5 (x 2),
123.3 (x 2), 126.2, 126.8, 133.6, 150.0, 169.3, 169.4, 170.2, 170.8
3,4,6-Tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl bromide (12).
The title compound was obtained from 1,3,4,6-tetra-O-acetyl-2-O-
benzyl-D-glucopyranose33 in 90% yield as a white foam as previously
described.14 Analytical data for 12: Rf = 0.43 (ethyl acetate/hexanes,
80 2/3, v/v); 1H n.m.r. (300 MHz): δ, 1.96, 1.98, 2.00 (3s, 9H, 3 x
COCH3), 3.57 (dd, 1H, J2,3 = 9.6 Hz, H-2), 4.12 (m, 1H, J5,6a = 4.1
a
b
ppm; 19F n.m.r.: δ, -122.4 (s, 1F, CF2 ), -122.3 (s, 1F, CF2 ) ppm; HR-
FAB MS [M+H]+ calculated for C22H23F2NO10 500.1290, found
10 500.1361.
3,3-Difluoro-3H-indol-2-yl
2,3,4,6-tetra-O-benzoyl-α-D-
glucopyranoside (6). The title compound was obtained from
2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl bromide 211 by Method
A in 75% yield as a pale yellow foam. Analytical data for 6: Rf = 0.41
Hz, H-6a), 4.22 (m, 1H, H-5), 4.27 (dd, 1H, J5,6b = 4.0 Hz, J6a,6b
=
=
12.6 Hz, 6b), 4.63 (dd, 2H, 2J = 12.3 Hz, CH2Ph), 5.06 (dd, 1H, J4,5
9.8 Hz, H-4), 5.48 (dd, 1H, J3,4 = 9.5 Hz, H-3), 6.34 (d, 1H, J1,2 = 3.9
15 (ethyl acetate/hexanes, 3/7, v/v); [α]D +45.8 (c = 1.0, CHCl3); H 85 Hz, H-1) ppm; 13C n.m.r. (75 MHz): δ, 20.8, 20.9 (x 2), 61.3, 67.3,
23
1
n.m.r. (300 MHz): δ, 4.48 (dd, 1H, J5,6a = 4.7 Hz, J6a,6b = 12.4 Hz, H-
6a), 4.64 (m, 2H, J5,6b = 2.3 Hz, H-5, 6b), 5.69 (dd, 1H, J2,3 = 10.2
Hz, H-2), 5.83 (dd, 1H, J4,5 = 10.0 Hz, H-4), 6.31 (dd, 1H, J3,4 = 10.0
Hz, H-3), 6.82 (d, 1H, J1,2 = 3.7 Hz, H-1), 7.05-7.99 (m, 24H,
20 aromatic) ppm; 13C n.m.r. (75 MHz): δ, 62.4, 68.6, 70.1, 70.3, 70.6,
94.8, 120.6, 123.2, 126.0, 126.5, 128.3, 128.4 (x 2), 128.4 (x 2),
128.5 (x 4), 128.6 (x 2), 128.8, 129.1, 129.5, 129.7 (x 2), 129.8 (x 2),
130.0 (x 4), 133.1, 133.4, 133.5, 133.6, 133.7, 150.1, 165.2, 165.5,
72.2 (x 2), 72.9, 76.5, 89.2, 128.1 (x 2), 128.5, 128.8 (x 2), 137.0,
169.9, 170.1, 170.7 ppm; HR-FAB MS [M+Na]+ calculated for
C19H23BrO8Na+ 481.0474, found 481.0483.
3,3-Difluoro-3H-indol-2-yl
3,4,6-tri-O-acetyl-2-O-benzyl-β-D-
90 glucopyranoside (β-13). The title compound was obtained from 12
o
by Method A at 0 C in 80% yield as a white foam. Analytical data
for β-13: Rf = 0.39 (ethyl acetate/hexanes, 2/3, v/v); [α]D26 +13.7 (c =
165.6, 166.0 ppm; 19F n.m.r.: δ, -121.8 (s, 1F, CF2 ), -121.6 (s, 1F,
a
1
1.0, CHCl3); H n.m.r. (300 MHz): δ, 1.95, 2.03, 2.07 (3s, 9H, 3 x
25 CF2 ) ppm; HR-FAB MS [M+Na]+ calculated for C42H31F2NO10Na+
b
COCH3), 3.80 (dd, 1H, J2,3 = 7.9 Hz, H-2), 3.95 (m, 1H, H-5), 4.14
770.1813, found 770.1800.
95 (dd, 1H, J5,6a = 2.3 Hz, J6a,6b = 12.5 Hz, H-6a), 4.34 (dd, 1H, J5,6b
=
4.4 Hz, H-6b), 4.74 (dd, 2H, 2J = 11.6 Hz, CH2Ph), 5.11 (dd, 1H, J4,5
3,3-Difluoro-3H-indol-2-yl
galactopyranoside (7). The title compound was obtained from
1,2,3,4,6-penta-O-benzoyl-D-galactopyranose 3 by Method B in 75%
2,3,4,6-tetra-O-benzoyl-β-D-
= 9.5 Hz, H-4), 5.27 (dd, 1H, J3,4 = 9.2 Hz, H-3), 5.94 (d, 1H, J1,2 =
7.8 Hz, H-1), 7.18-7.49 (m, 9H, aromatic) ppm; 13C n.m.r. (75 MHz):
δ, 20.7 (x 2), 20.8, 61.5, 67.9, 72.6, 73.6, 74.7, 77.6, 99.1, 120.6,
30 yield as a white foam. Analytical data for 7: Rf = 0.39 (ethyl acetate/ 100 123.3, 126.2, 128.1 (x 2), 128.3 (x 3), 128.5 (x 3), 133.7, 137.1,
hexanes, 3/7, v/v); [α]D22 +2.7 (c = 1.0, CHCl3); 1H n.m.r. (300 MHz):
δ, 4.51 (dd, 1H, J5,6a = 5.9 Hz, J6a,6b = 10.6 Hz, H-6a), 4.63 (m, 1H,
H-5), 4.72 (dd, 1H, J5,6b = 6.6 Hz, H-6b), 5.75 (dd, 1H, J3,4 = 3.4 Hz,
H-3), 6.11 (m, 2H, H-2, 4), 6.34 (d, 1H, J1,2 = 7.8 Hz, H-1), 7.14-8.14
35 (m, 24H, aromatic) ppm; 13C n.m.r. (75 MHz): δ, 61.8, 67.6, 68.9,
71.4, 72.7, 97.4, 120.4, 123.6, 124.7, 125.4, 128.3, 128.6 (x 4), 128.7,
128.8, 128.9 (x 2), 129.0, 129.2 (x 2), 129.4, 129.9 (x 9), 130.1 (x 2),
133.3, 133.5, 133.6, 133.8, 165.1, 165.5 (x 2), 166.0 ppm; 19F n.m.r.:
δ, -122.2 (s, 2F, CF2); HR-FAB MS [M+Na]+ calculated for
40 C42H31F2NO10Na+ 770.1813, found 770.1791.
150.3, 169.7, 170.0, 170.7 ppm; 19F n.m.r.: δ, -122.0 (d, 2F, CF2)
ppm; HR-FAB MS [M+Na]+ calculated for C27H27F2NO9Na+
570.1552, found 570.1562.
3,3-Difluoro-3H-indol-2-yl
3,4,6-tri-O-acetyl-2-O-benzyl-α-D-
105 glucopyranoside (α-13). The title compound was obtained from
3,4,6-tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl bromide 12 by
Method A at rt in 81% yield as a white foam. Analytical data for α-
13: Rf = 0.38 (ethyl acetate/hexanes, 2/3, v/v); [α]D25 +101.4 (c = 1.0,
CHCl3); 1H n.m.r. (300 MHz): δ, 2.02, 2.03, 2.05 (3 s, 9H, 3 x
110 COCH3), 3.81 (dd, 1H, J2,3 = 9.9 Hz, H-2), 4.06 (dd, 1H, J5,6a = 2.0
3,3-Difluoro-3H-indol-2-yl
2,3,4,6-tetra-O-benzoyl-α-D-
Hz, J6a,6b = 12.4 Hz, H-6a), 4.18 (m, 1H, H-5), 4,29 (dd, 1H, J5,6b =
mannopyranoside (8). The title compound was obtained from
1,2,3,4,6-penta-O-benzoyl-D-mannopyranose 4 by Method B in 84%
yield as a white foam. Analytical data for 8: Rf = 0.43 (ethyl
4.1 Hz, H-6b), 4.67 (s, 2H, CH2Ph), 5.11 (dd, 1H, J4,5 = 10.0 Hz, H-
4), 5.57 (d, 1H, J3,4 = 9.7 Hz, H-3), 6.45 (d, 1H, J1,2 = 3.5 Hz, H-1),
7.17-7.40 (m, 9H, aromatic) ppm; 13C n.m.r. (75 MHz): δ, 20.7 (x 2),
45 acetate/hexanes, 3/7, v/v); [α]D21 -5.3 (c = 1.0, CHCl3); 1H n.m.r. (300 115 20.8, 61.4, 67.8, 69.8, 71.4, 73.3, 75.7, 95.0, 120.4, 123.3, 125.9,
MHz): δ, 4.52 (dd, 1H, J5,6a = 4.4 Hz, J6a,6b = 12.1 Hz, H-6a), 4.62 (m,
1H, H-5), 4.70 (dd, 1H, J5,6b = 2.2 Hz, H-6b), 6.02 (dd, 1H, J2,3 = 3.3
Hz, H-2), 6.07 (dd, 1H, J3,4 = 10.0 Hz, H-3), 6.24 (dd, 1H, J4,5 = 10.0
Hz, H-4), 6.64 (d, 1H, J1,2 = 1.7 Hz, H-1), 7.16-8.09 (m, 24H,
50 aromatic) ppm; 13C n.m.r. (75 MHz): δ, 62.5, 66.2, 69.0, 69.6, 71.5,
96.0, 121.0, 123.5, 125.5, 126.4, 126.8, 128.4, 128.5 (x 2), 128.6 (x
2), 128.7 (x 2), 128.8, 128.9 (x 2), 128.9, 129.0, 129.2, 129.8, 129.9
(x 2), 130.0 (x 2), 130.1 (x 4), 133.2, 133.6, 133.8, 134.0, 138.1,
126.8, 127.9 (x 3), 128.2, 128.6 (x 3), 133.5, 137.2, 150.4, 168.7,
169.8, 170.1 ppm; 19F n.m.r.: δ, -121.6 (s, 1F, CF2 ), -121.5 (s, 1F,
a
CF2 ); HR-FAB MS [M+Na]+ calculated for C27H27F2NO9Na+
b
570.1552, found 570.1569.
120 2,3,4,6-Tetra-O-benzyl-α/β-D-glucopyranosyl
trichloroacetimidate (36). The title compound was obtained from
2,3,4,6-tetra-O-benzyl-D-glucopyranose 912 in 62% yield as a white
165.2, 165.5, 165.6, 166.1 ppm; 19F n.m.r.: δ, -121.8 (s, 1F, CF2 ), -
a
foam as previously described.29 Analytical data for α-36: Rf = 0.43
55 121.5 (s, 1F, CF2 ); HR-FAB MS [M+Na]+ calculated for
b
1
(ethyl acetate/hexanes, 1/4 v/v); H n.m.r. (300 MHz): δ, 3.67 (dd,
C42H31F2NO10Na+ 770.1813, found 770.1814.
125 1H, J6a,6b = 10.9 Hz, H-6a), 3.74-3.80 (m, 3H, H-2, 4, 6b), 3.99 (m,
1H, J5,6a = 1.9 Hz, H-5), 4.05 (dd, 1H, J32,4 = 9.4 Hz, H-3), 4.53 (dd,
2
3,3-Difluoro-3H-indol-2-yl
2,3,4,6-tetra-O-benzyl-α/β-D-
2H, J = 12.0 Hz, CH2Ph), 4.71 (dd, 2H, J = 11.7 Hz, CH2Ph), 4.73
2
2
glucopyranoside (10). The title compound was obtained from
(dd, 2H, J = 10.7 Hz, CH2Ph), 4.84 (dd, 2H, J = 10.6 Hz, CH2Ph),
6.50 (d, 1H, J1,2 = 3.4 Hz, H-1), 7.12-7.33 (m, 20H, aromatic), 8.57
2,3,4,6-tetra-O-benzyl-D-glucopyranose 912 by Method C in 62%
60 yield (α/β = 10/1) as a white foam. The title compound was also 130 (s, 1H, NH) ppm; 13C n.m.r. (75 MHz): δ, 68.1, 73.0, 73.2, 73.6, 75.5,
obtained
from
ethyl
2,3,4,6-tetra-O-benzyl-1-thio-β-D-
75.8, 79.5, 81.5, 91.4, 94.5, 127.8 (x 3), 127.9 (x 2), 128.0, 128.1 (x
2), 128.2 (x 4), 128.5 (x 5), 128.6 (x 4), 137.9, 138.1, 138.2, 138.7,
161.4 ppm; HR-ESI MS [M+Na]+ calculated for C36H36Cl3NO6Na+
706.1506, found 706.1500.
glucopyranoside 1113 by Method D in 95% yield (α/β = 1/9.0).
Analytical data for α-10: Rf = 0.43 (ethyl acetate/hexanes, 1/4, v/v);
1H n.m.r. (300 MHz): δ, 3.66 (dd, 1H, J5,6a = 1.8 Hz, J6a,6b = 10.9 Hz,
65 H-6a), 3.79 (dd, 1H, J2,3 = 9.3 Hz, H-2), 3.79 (dd, 1H, J5,6b = 3.3 Hz,
H-6b), 3.83 (dd, 1H, J4,5 = 9.3 Hz, H-4), 4.01 (m, 1H, H-5), 4.13 (dd,
1H, J3,4 = 9.3 Hz, H-3), 4.52 (dd, 2H, 2J = 12.0 Hz, CH2Ph), 4.69 (dd,
135 2,3,4-Tri-O-benzyl-α,β-D-glucopyranosyl
N-
phenyltrifluoroacetimidate (37). The title compound was obtained
from 2,3,4,6-tetra-O-benzyl-D-glucopyranose 912 by adapting
previously published procedure.5a K2CO3 (55 mg, 0.55 mmol) in
acetone (1.5 mL) was added to a mixture of 9 (150 mg, 0.28 mmol)
2
2
2H, J = 10.5 Hz, CH2Ph), 4.73 (s, 2H, CH2Ph), 4.93 (dd, 2H, J =
10.9 Hz, CH2Ph), 6.50 (d, 1H, J1,2 = 3.3 Hz, H-1), 7.11-7.42 (m, 24H,
70 aromatic) ppm; 13C n.m.r. (75 MHz): δ, 68.1, 73.2, 73.5, 73.6 (x 2),
8
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C6OB02230H
and 2,2,2,-trifluoro-N-phenylethanimidoyl chloride (89.4 μL, 0.55
Analytical data for 19 were essentially the same as reported
mmol) and the resulting mixture was stirred for 3 h at rt. The solids
were filtered off through a pad of Celite and the solvent was
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexanes gradient elution)
to afford the title compound in 72% yield as a white amorphous solid.
Analytical data for β-37: Rf = 0.5 (ethyl acetate/hexanes, 1/4, v/v); 1H
n.m.r. (500 MHz): δ, 3.56-3.95 (m, 6H, H-2, 3, 4, 5, 6a, 6b), 4.58 (dd,
previously.25
70 Methyl 2-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-3,4,6-
tri-O-benzyl-α-D-glucopyranoside (20). The title compound was
obtained from donor 6 and acceptor 1625 as a clear film in 93% yield.
Analytical data for 20 were essentially the same as reported
previously.25
5
2
2
2H, J = 9.5 Hz, CH2Ph), 4.69 (dd, 2H, J = 12.2 Hz, CH2Ph), 4.88
10 (s, 2H, CH2Ph), 5.00 (dd, 2H, 2J = 10.2 Hz, CH2Ph), 5.74 (d, 1H, J1,2
= 8.0 Hz, H-1), 6.78-7.50 (m, 25H, aromatic); 13C n.m.r. (75 MHz):
δ, 73.6, 75.3, 75.4, 75.8 (x 2), 75.9 (x 2), 75.8, 81.1, 84.7, 119.5,
124.5, 127.9, 128.0 (x 2), 128.1 (x 3), 128.2 (x 3), 128.4 (x 2), 128.6
(x 6), 128.7 (x 6), 128.9 (x 2), 137.9, 138.1 (x 2), 138.5, 143.6 ppm;
15 HR-FAB MS [M+Na]+ calculated for C42H40F3NO6Na+ 734.2705,
found 734.2720.
75 6-O-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (21). The title compound was
obtained from donor 6 and acceptor 17 in 90% yield. Analytical data
for 21 were essentially similar as reported previously.16a
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-2,3,4-
80 tri-O-benzyl-α-D-glucopyranoside (22). The title compound was
obtained from donor 7 and acceptor 1425 as a clear film in 98% yield.
Analytical data for 22 were essentially the same as reported
previously.34
2,3,4,6-Tetra-O-benzoyl-α-D-glucopyranosyl trichloroacetimidate
(44). The title compound was obtained from 2,3,4,6-tetra-O-benzoyl-
D-glucopyranose 46 in 83% yield as a white foam as previously
20 described.31 Analytical data for 44 was in accordance with that
reported previously.6b
Methyl 4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-2,3,6-
85 tri-O-benzyl-α-D-glucopyranoside (23). The title compound was
obtained from donor 7 and acceptor 1525 as a clear film in 98% yield.
Analytical data for 23 were essentially the same as reported
previously.16a
2,3,4,6-Tetra-O-benzoyl-α-D-glucopyranosyl
N-
phenyltrifluoroacetimidate (45). The title compound was obtained
from 2,3,4,6-tetra-O-benzoyl-D-glucopyranose 46 by adapting the
25 previously published procedure.5a K2CO3 (0.54 g, 5.46 mmol) in
acetone (20 mL) was added to a mixture of 46 (2.17 g, 3.64 mmol)
and 2,2,2,-trifluoro-N-phenylethanimidoyl chloride (0.7 mL, 4.37
mmol) and the resulting mixture was stirred for 5 h at rt. The solids
were filtered off through a pad of Celite and the solvent was
30 concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate-hexanes gradient elution)
to afford the title compound in 86% yield as a white foam. Analytical
data for α-45: Rf = 0.5 (ethyl acetate/hexanes, 3/7, v/v); [α]D27 +49.4
(c= 1.0, CHCl3); 1H n.m.r. (500 MHz): δ, 4.51 (dd, 1H, J5,6a = 4.4 Hz,
35 J6a,6b = 12.5 Hz, H-6a), 4.69 (m, 1H, H-5), 4.77 (dd, 1H, J5,6b = 1.8
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-2,3,4-
90 tri-O-benzyl-α-D-glucopyranoside (24). The title compound was
obtained from donor 8 and acceptor 1425 as a clear film in 93% yield.
Analytical data for 24 were essentially the same as reported
previously.16a
Methyl 4-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-2,3,6-
95 tri-O-benzyl-α-D-glucopyranoside (25). The title compound was
obtained from donor 8 and acceptor 1525 as a clear film in 90% yield.
Analytical data for 25 were essentially the same as reported
previously.35
Hz, H-6b), 5.67 (dd, 1H, J2,3 = 10.3 Hz, H-2), 5.93 (dd, 1H, J4,5
=
10.1 Hz, H-4), 6.30 (m, 3H, H-3, aromatic), 6.92 (d, 1H, J1,2 = 3.6
Hz, H-1), 7.00-8.15 (m, 25H, aromatic) ppm; 13C n.m.r. (125 MHz):
δ, 62.4, 68.6, 70.0, 70.5, 70.8, 92.3, 119.1, 124.4, 128.6 (x 2), 128.7
40 (x 5), 128.8 (x 5), 128.9, 129.7, 129.9 (x 2), 130.0 (x 8), 133.3, 133.4,
133.7, 133.8, 142.8, 143.0, 165.2, 165.4, 165.7, 166.1; 19F n.m.r.: δ, -
65.51 (s, 3F, CF3) ppm; HR-FAB MS [M+Na]+ calculated for
C42H32F3NO10Na+ 790.1876, found 790.1886.
Methyl
2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-β-D-
100 glucopyranosyl)-α-D-glucopyranoside (29). The title compound
was obtained from donor 10 and methyl 2,3,4-tri-O-benzyl-α-D-
glucopyranoside 1425 in 57-99% yield (α/β ranging from 5.0/1 to β-
only, see Tables). Analytical data for 29 was in accordance with that
reported previously.36
105 Methyl
2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-D-
Synthesis of disaccharides
glucopyranosyl)-α-D-glucopyranoside (30). The title compound
was obtained from donor 10 and methyl 2,3,6-tri-O-benzyl-α-D-
glucopyranoside 1525 in CH2Cl2 or EtCN in 94% (α/β = 1/4) or 92%
yield (α/β = 1/12), respectively. Analytical data for 30 was in
110 accordance with that reported previously.37
45 A typical glycosylation procedure and the synthesis of glycosides.
A mixture of glycosyl donor (0.11 mmol or as indicated in Tables),
glycosyl acceptor (0.10 mmol), and freshly activated molecular
sieves (3 or 4 Å, 90 mg) in CH2Cl2 (0.5 mL) or other solvent or
amount required for high dilution experiments as indicated in Tables
50 was stirred under argon for 1 h at rt. The mixture was cooled to -78
oC or other temperature as indicated in Tables, promoter (0.0055-0.11
mmol) was added, and the resulting mixture was stirred for the time
as indicated in Tables. The solids were filtered off through a pad of
Celite and rinsed successively with CH2Cl2. The combined filtrate
55 (~40 mL) was washed with 1% aq. NaOH (2 x 10 mL) and water (2 x
10 mL). The organic phase was separated, dried with MgSO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (ethyl acetate - hexane gradient elution)
to afford a glycoside derivative in yields listed in Tables.
Methyl 2-O-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3,4,6-tri-
O-benzyl-α-D-glucopyranoside (31). The title compound was
obtained by Method A from donor 10 and methyl 3,4,6-tri-O-benzyl-
α-D-glucopyranoside 1625 in CH2Cl2 or EtCN in 90% (α/β = 1/6.0) or
115 88% yield (α/β = 1/15), respectively. Analytical data for 31 was in
accordance with that reported previously.16a
6-O-(2,3,4,6-Tetra-O-benzyl-β-D-glucopyranosyl)-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose (32). The title compound was
obtained by Method
A from donor 10 and 1,2:3,4-di-O-
120 isopropylidene-α-D-galactopyranose 17 in CH2Cl2 or EtCN as a clear
film in 85% yield (α/β = 1/12) or 89% yield (β only), respectively.
Analytical data for 32 was in accordance with that reported
previously.38
60 Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-2,3,4-
tri-O-benzyl-α-D-glucopyranoside (18). The title compound was
obtained from donor 6 and acceptor 1425 as a clear film in 94% yield.
Analytical data for 18 were essentially the same as reported
previously.25
Methyl
2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzyl-D-
125 glucopyranosyl)-α-D-glucopyranoside (33). The title compound
was obtained from donor 10 and methyl 2,3,4-tri-O-benzoyl-α-D-
glucopyranoside 2626 in CH2Cl2 or EtCN as a clear film in 89% yield
(α/β = 1/11) or 87% yield (α/β = 1/18), respectively. Analytical data
for 33 was in accordance with that reported previously.37
65 Methyl 4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-2,3,6-
tri-O-benzyl-α-D-glucopyranoside (19). The title compound was
obtained from donor 6 and acceptor 1525 as a clear film in 86% yield.
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DOI: 10.1039/C6OB02230H
(3β)-Cholest-5-en-3-yl
2,3,4,6-tetra-O-benzyl-β-D-
65 3.
4.
W. Zhong and G.-J. Boons, in Handbook of Chemical
Glycosylation, ed. A. V. Demchenko, Wiley-VCH, Weinheim,
Germany, 2008, pp. 261-303.
X. Zhu and R. R. Schmidt, in Handbook of Chemical
Glycosylation, ed. A. V. Demchenko, Wiley-VCH, Weinheim,
Germany, 2008, pp. 143-185.
glucopyranoside (34). The title compound was obtained from donor
10 and (3β)-cholest-5-en-3-ol 27 as a white amorphous solid in 86%
yield (β-only). Analytical data for 34 was in accordance with that
reported previously.39
5
70
1-Adamantyl
2,3,4,6-tetra-O-benzyl-D-glucopyranoside (35).
5.
a) B. Yu and H. Tao, Tetrahedron Lett., 2001, 42, 2405-2407;
b) B. Yu and J. Sun, Chem. Commun., 2010, 46, 4668-4678.
a) A. V. Demchenko, N. N. Malysheva and C. De Meo, Org.
Lett., 2003, 5, 455-458; b) S. S. Nigudkar, A. R. Parameswar,
P. Pornsuriyasak, K. J. Stine and A. V. Demchenko, Org.
Biomol. Chem., 2013, 11, 4068-4076.
S. S. Nigudkar, K. J. Stine and A. V. Demchenko, J. Am.
Chem. Soc., 2014, 136, 921-923.
J. C. Torres, S. J. Garden and A. C. Pinto, Tetrahedron, 1999,
55, 1881-1892.
The title compound was obtained from donor 10 and 1-adamantol 28
as a white amorphous solid in 88% yield (α/β = 1/23). Analytical data
for 35 was in accordance with that reported previously.39
6.
75
10 Methyl 2-O-(3,4,6-tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl)-
3,4,6-tri-O-benzyl-α-D-glucopyranoside (38). The title compound
was obtained from donor α-13 or donor β-13 and acceptor 1625 as a
clear film in 89% or 88% yield (α only), respectively. Analytical data
for 38 was in accordance with that reported previously.16a
7.
8.
80
9.
J. Zhu, W. Zhang and J. Hu, J. Org. Chem., 2010, 75, 5505-
5512.
15 Methyl 4-O-(3,4,6-tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl)-
2,3,6-tri-O-benzyl-α-D-glucopyranoside (39). The title compound
was obtained from donor 13 and acceptor 1525 as a clear film in 70%
or 99% yield (α only). Analytical data for 39 was in accordance with
that reported previously.16a
10.
R. U. Lemieux, in Methods in Carbohydrate Chemistry, eds.
R. L. Whistler and M. L. Wolform, Academic Press Inc., New
York and London, 1963, vol. 2, pp. 221-222.
R. U. Lemieux, in Methods in Carbohydrate Chemistry, eds.
R. L. Whistler and M. L. Wolform, Academic Press Inc., New
York and London, 1963, vol. 2, pp. 226-228.
J. Dinkelaar, M. D. Witte, L. J. van den Bos, H. S. Overkleeft
and G. A. van der Marel, Carbohydr. Res., 2006, 341, 1723-
1729.
F. Andersson, P. Fugedi, P. J. Garegg and M. Nashed,
Tetrahedron Lett., 1986, 27, 3919-3922.
S. Brennan and P. A. Finan, J. Chem. Soc., C, 1970, 1742-
1744.
N. Boechat, W. B. Kover, M. M. Bastos, A. C. Pinto, L. C.
Maciel, L. M. U. Mayer, F. S. Q. d. Silva and M. S. L. Arruda,
J. Braz. Chem. Soc., 2008, 19, 445-457.
a) P. Pornsuriyasak and A. V. Demchenko, Chem. Eur. J.,
2006, 12, 6630-6646; b) S. J. Hasty and A. V. Demchenko,
Chem. Heterocycl. Compd., 2012, 48, 220-240.
S. Kaeothip, P. Pornsuriyasak, N. P. Rath and A. V.
Demchenko, Org. Lett., 2009, 11, 799-802.
M. N. Kamat, N. P. Rath and A. V. Demchenko, J. Org.
Chem., 2007, 72, 6938-6946.
a) R. R. Schmidt, Angew. Chem. Int. Edit. Engl., 1986, 25,
212-235; b) L. Morelli, A. Bernardi and S. Sattin, Carbohydr.
Res., 2014, 390, 33-41.
R. R. Schmidt and K. H. Jung, in Preparative Carbohydrate
Chemistry, ed. S. Hanessian, Marcel Dekker, Inc., New York,
1997, pp. 283-312.
R. R. Schmidt and J. Michel, Angew. Chem., Int. Ed. Engl.,
1980, 19, 731-732.
M. Adinolfi, A. Iadonisi, A. Ravida and S. Valerio,
Tetrahedron Lett., 2006, 47, 2595-2599.
M. Adinolfi, G. Barone, L. Guariniello and A. Iadonisi,
Tetrahedron Lett., 2000, 41, 9005-9008.
Y. Du, G. Wei and R. J. Linhardt, Tetrahedron Lett., 2003, 44,
6887-6890.
S. C. Ranade, S. Kaeothip and A. V. Demchenko, Org. Lett.,
2010, 12, 5628-5631.
F. Zhang, W. Zhang, Y. Zhang, D. P. Curran and G. Liu, J.
Org. Chem., 2009, 74, 2594-2597.
S. S. Nigudkar and A. V. Demchenko, Chem. Sci., 2015, 6,
2687–2704.
85
90
11.
12.
20 Methyl 3-O-(3,4,6-tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl)-
2,4,6-tri-O-benzyl-α-D-glucopyranoside (41). The title compound
was obtained from donor 13 and acceptor 4025 as a clear film in 72-
80% yield (α/β = 10-21/1). Analytical data for 41 was in accordance
with that reported previously.40
13.
14.
15.
25 Methyl 6-O-(3,4,6-tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl)-
2,3,4-tri-O-benzyl-α-D-glucopyranoside (42). The title compound
was obtained from donor 13 and acceptor 1425 as a clear film in 78-
95% yield (α/β = 1.7-12/1). 1H n.m.r. (300 MHz): δ, 1.96, 1.97, 2.00
(3s, 9H, 3 x COCH3), 3.35 (s, 3H, OCH3), 3.37-3.42 (m, 1H, H-2),
30 3.48 (dd, 1H, J2’,3’ = 9.9 Hz, H-2’), 3.56 (dd, 1H, J4,5 = 9.4 Hz, H-4),
3.61-3.81 (m, 3H, H-5, 6a, 6b), 3.89-4.01 (m, 3H, J5’,6b’ = 4.4 Hz, H-
3, 5’, 6a’), 4.14 (dd, 1H, J6a’,6b’ = 12.5 Hz, H-6b’), 4.45–4.82 (m, 7H,
H-1, 3 x CH2Ph), 4.85-4.98 (m, 4H, J1’,2’ = 3.5 Hz, H-1’, 4’, CH2Ph),
5.39 (dd, J3’,4’ = 9.7 Hz, 1H, H-3’), 7.16-7.36 (m, 20H, aromatic)
35 ppm; 13C n.m.r. (150 MHz): δ, 21.0, 55.4, 62.1, 66.4, 67.3, 68.8, 70.5,
71.9, 72.5, 73.5, 75.2, 75.9, 76.6, 77.8, 80.0, 82.3, 97.0, 98.2, 127.8
(x 3), 127.9 (x 3), 128.1 (x 3), 128.2 (x 3), 128.6 (x 3), 137.9, 138.3,
138.6, 138.9, 170.3, 170.6, 170.8. The remaining analytical data for
42 was in accordance with that reported previously.16a
95
16.
100
105
110
115
17.
18.
19.
20.
40 Methyl 6-O-(3,4,6-tri-O-acetyl-2-O-benzyl-α-D-glucopyranosyl)-
2,3,4-tri-O-benzoyl-α-D-glucopyranoside (43). The title compound
was obtained from donor 13 and acceptor 2626 as a clear film in 89-
96% yield (α/β = 5.2-18/1). Analytical data for 43 was in accordance
with that reported previously.18
21.
22.
23.
24.
45 Notes and references
a Department of Chemistry and Biochemistry, University of Missouri – St.
Louis, One University Boulevard, St. Louis, Missouri 63121, USA; E-
mail: demchenkoa@umsl.edu
120 25.
26.
† Electronic Supplementary Information (ESI) available: 1H and 13C
50 NMR spectra for all new compounds. See DOI: 10.1039/b000000x/
‡ This work was supported by grants from the National Institute of
General Medical Sciences (GM111835 and GM120673). We thank Dr.
Rensheng Luo (UM – St. Louis) for help with acquiring spectral data
using 600 MHz NMR spectrometer that was purchased thanks to the NSF
55 (award CHE-0959360). Dr. Winter and Mr. Kramer (UM – St. Louis) are
thanked for HRMS determinations.
27.
125
28.
S. J. Hasty, S. C. Ranade and A. V. Demchenko, Reports Org.
Chem., 2014, 4, 1-10.
R. Schmidt, R. and M. Stumpp, Liebigs Ann. Chem., 1983,
1249-1256.
S. Kaeothip, J. P. Yasomanee and A. V. Demchenko, J. Org.
Chem., 2012, 77, 291-299.
K. Egusa, S. Kusumoto and K. Fukase, Eur. J. Org. Chem.,
2003, 2003, 3435-3445.
S. G. Pistorio, S. S. Nigudkar, K. J. Stine and A. V.
Demchenko, J. Org. Chem., 2016, 81, 8796−8805.
G. Excoffier, D. Y. Gagnaire and M. R. Vignon, Carbohydr.
Res., 1976, 46, 215-226.
29.
130 30.
31.
1.
X. Zhu and R. R. Schmidt, Angew. Chem. Int. Ed., 2009, 48,
1900-1934.
60 2.
a) D. Crich, Acc. Chem. Res., 2010, 43, 1144-1153; b) D.
Crich, J. Org. Chem., 2011, 76, 9193-9209; c) S. C. Ranade
and A. V. Demchenko, J. Carbohydr. Chem., 2013, 32, 1-43;
d) L. K. Mydock and A. V. Demchenko, Org. Biomol. Chem.,
2010, 8, 497-510.
32.
135
33.
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DOI: 10.1039/C6OB02230H
34.
35.
J. Tatai and P. Fugedi, Org. Lett., 2007, 9, 4647-4650.
K. S. Kim, D. B. Fulse, J. Y. Baek, B. Y. Lee and H. B. Jeon,
J. Am. Chem. Soc., 2008, 130, 8537-8547.
36.
a) B. A. Garcia and D. Y. Gin, J. Am. Chem. Soc., 2000, 122,
4269-4279; b) H. M. Nguyen, Y. N. Chen, S. G. Duron and D.
Y. Gin, J. Am. Chem. Soc., 2001, 123, 8766-8772.
T. J. Boltje, J.-H. Kim, J. Park and G.-J. Boons, Org. Lett.,
2011, 13, 284-287.
5
37.
38.
E. J. Grayson, S. J. Ward, A. L. Hall, P. M. Rendle, D. P.
Gamblin, A. S. Batsanov and B. G. Davis, J. Org. Chem.,
2005, 70, 9740-9754.
10
39.
E. A. Mensah, J. M. Azzarelli and H. M. Nguyen, J. Org.
Chem., 2009, 74, 1650-1657.
40.
S. Kaeothip, S. J. Akins and A. V. Demchenko, Carbohydr.
Res., 2010, 345, 2146-2150.
15
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