Regenerative Glycosylation

Article abstract of DOI:10.1021/acs.joc.7b02768

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 OFox imidates could be conducted in a regenerative fashion. Herein, we extend this study to the synthesis of various glycosidic linkages using different sugar series. The main outcome of this study relates to enhanced yields and/or reduced reaction times of glycosylations. The effect of HOFox-mediated reactions is particularly pronounced in case of unreactive glycosyl donors and/or glycosyl acceptors. A multistep regenerative synthesis of oligosaccharides is also reported.

Full text of DOI:10.1021/acs.joc.7b02768

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Article
Regenerative glycosylation
Yashapal Singh, Tinghua Wang, Scott A. Geringer, Keith John Stine, and Alexei V. Demchenko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02768 • Publication Date (Web): 11 Dec 2017
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The Journal of Organic Chemistry
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Regenerative glycosylation
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Yashapal Singh, Tinghua Wang, Scott A. Geringer, Keith J. Stine, and Alexei V. Demchenko*
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Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University Boulevard, St. Louis, Misꢀ
souri 63121, USA
Glycosylation, catalysis, oligosaccharides, carbohydrates
ABSTRACT: Previously we communicated 3,3ꢀdifluoroxindole (HOFox) – mediated glycosylations wherein 3,3ꢀdifluoroꢀ3Hꢀ
indolꢀ2ꢀyl (OFox) imidates were found to be key intermediates. Both the in-situ synthesis from the corresponding glycosyl broꢀ
mides and activation of the OFox imidates could be conducted in a regenerative fashion. Herein, we extend this study to the syntheꢀ
sis of various glycosidic linkages using different sugar series. The main outcome of this study relates to enhanced yields and/or
reduced reaction times of glycosylations. The effect of HOFoxꢀmediated reactions is particularly pronounced in case of unreactive
glycosyl donors and/or glycosyl acceptors. A multiꢀstep regenerative synthesis of oligosaccharides is also reported.
Introduction
and we managed to achieve reasonable glycosylation rates
between 2 and 4 (2ꢀ3 h) with as little as 10ꢀ25 mol % of
HOFox aglycone to form disaccharide 5 in commendable
yields (Scheme 1). Described herein is a continuation of this
study with the main focus on broadening the scope of this
reaction and its application to a variety of glycosidic linkages
and sugar series.
Complex carbohydrates are paving their ways to a variety of
novel applications, most prominently in the areas of therapeuꢀ
ticꢀagent, diagnosticꢀplatform, and functionalꢀfood developꢀ
ment. Practically all glycans are connected via Oꢀglycosidic
linkages, but the chemical synthesis of these linkages remains
challenging. Many methods for glycoside synthesis have been
developed,1 and a vast majority of all glycosylations reported
in the literature are performed with halides,2 thioglycosides,3
or Oꢀimidates.4ꢀ6 Nevertheless, even these common methods
have drawbacks. For instance, although all thioglycosides and
many halides are stable, their activation requires stoichioꢀ
metric activators. Conversely, Oꢀimidates can be activated
with catalytic amounts of a Lewis acid, but these reactive doꢀ
nors cannot be stored. If not properly controlled, glycosidation
of Oꢀimidates can give poor yields due to competing rapid
hydrolysis. With enhanced understanding of the reaction
mechanism,7ꢀ10 new methods and concepts would be a very
timely addition to the arsenal of methods used for chemical
glycosylation. Versatile new methods making use of stable
precursors that could be activated under catalytic conditions11ꢀ
Scheme 1. A concept of the regenerative glycosylation
13
would be of high significance to supplement other recently
developed concepts that fall into this general category.14ꢀ17
Recently, our laboratory reported Oꢀbenzoxazolyl (OBox)18
and 3,3ꢀdifluoroꢀ3Hꢀindolꢀ2ꢀyl (OFox) imidates.19 While inꢀ
vestigating approaches to the synthesis of OFox imidates, we
discovered that these compounds can be generated and glycoꢀ
sidated in a regenerative fashion in situ. This created the basis
for discovering 3,3ꢀdifluoroxindole (HOFox)ꢀmediated regenꢀ
erative glycosylations wherein the OFox imidates were found
to be key intermediates.19 In our preliminary study we first
reacted thioglycoside 120 with stoichiometric bromine to form
glycosyl bromide 2. The latter can be glycosidated slowly, but
more readily gets converted into highly reactive OFox imidate
3 if HOFox is added. The amount of the reactive glycosyl doꢀ
nor present in the reaction medium can be controlled by the
amount of HOFox added. OFox imidates have reasonable
shelfꢀlife, but are readily activated with various Lewis acids
(5ꢀ10 mol %). Previously, BF3ꢀEt2O was used for this purpose,
Results and Discussion
All glycosyl bromide donors employed in this study were
obtained from the corresponding ethylthio glycosides with
stoichiometric bromine. 3,3ꢀDifluoroxindole aglycone
(HOFox) was obtained in one step from the commercially
available Isatin by reaction with diethylaminosulfur trifluoride
(DAST) in anhydrous CH2Cl2 at room temperature.19,21
A
number of other approaches for the synthesis of HOFox have
been developed.22,23 OꢀImidates can be activated for glycosylaꢀ
tion in the presence of catalytic amounts of TMSOTf,24,25 BF3ꢀ
Et2O,26 pꢀTsOH,27 Bi(OTf)3,28 Yb(OTf)3,29 Sm(OTf)3,29
AgOTf,30 or MeOTf.18 For the further expansion of the regenꢀ
erative glycosylation reaction we chose TMSOTf that is arguꢀ
ably the most commonly used promoter.
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In the first round of experiments, we investigated perꢀ HOFox (0.25 equiv.) disaccharide 15 was obtained in an exꢀ
1
2
3
4
5
6
7
8
benzylated bromides 2, 6 and 8 that were conveniently generꢀ
cellent yield of 98% in only 2 h (Entry 6).
ated from the corresponding ethylthio glycosides20,31,32 by reꢀ
Perꢀacetylated glycosyl bromide donors showed a similar
trend. However, the efficiency of these reactions was hamꢀ
pered by a high propensity of the acetyl protecting groups to
migrate to the hydroxyl of the glycosyl acceptors leading to
poor yields. The latter could be improved in the presence of
SnCl4 as the promoter (results are not shown). All reactions
with perꢀacylated donors were entirely 1,2ꢀtrans stereoselecꢀ
tive due to the participatory effect of the ester substituent at Cꢀ
2.
action with bromine in the presence of molecular sieves.33
A
series of reactions between perꢀbenzylated bromides with glyꢀ
cosyl acceptor 434 was performed as depicted in Table 1 (Enꢀ
tries 1ꢀ3). First, a reaction of bromide 2 with acceptor 4 was
performed in presence of TMSOTf (0.08 equiv.) as the activaꢀ
tor and Ag2O (3.0 equiv.) as the HBr scavenger. This sluggish
reaction was stopped after 4 h, and disaccharide 518 was isolatꢀ
ed in 18% yield (α/β = 1/5.4, Entry 1). When essentially the
same reaction was performed in the presence of HOFox cataꢀ
lyst (0.25 equiv.) disaccharide 5 was isolated in 81% yield
(α/β = 1/2.5, Entry 1). The latter reaction was significantly
faster and completed within 2 h. Galactosyl bromide 6 swiftly
reacted with acceptor 4, but the effect of HOFox was negligiꢀ
ble with this highly reactive donor. Irrespectively of whether
the reaction was performed without or with HOFox, disacchaꢀ
ride 716 was rapidly produced in 45 min in a similar yield
(79% or 84%, respectively) with decent βꢀstereoselectivity in
both cases (α/β = 1/18 or 1/10, respectively, Entry 2). The
HOFox catalyst was more efficient in the case of the less reacꢀ
tive mannosyl bromide 8. Thus, the reaction without HOFox
was fairly slow (4 h), but still gave disaccharide 918 in a reꢀ
spectable yield of 74% (α/β > 2.9/1, Entry 3). The same glycoꢀ
sylation in the presence of HOFox (0.25 equiv.) was signifiꢀ
cantly faster (2 h), and disaccharide 9 was obtained in an exꢀ
cellent yield of 94%, albeit with no stereoselectivity (Entry 3).
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The results presented in Entries 1ꢀ6 of Table 1 indicate that
the role of catalytic HOFox is far more significant in the elecꢀ
tronically deactivated, benzoylated, disarmed donors. To exꢀ
plore this further, we also investigated unreactive glucosyl
bromide 1633,37 equipped with the 2ꢀbenzylꢀ3,4,6ꢀtriꢀacetyl,
superꢀdisarming protecting group pattern.38,39 Glycosidation of
bromide donor 16 with glycosyl acceptor 4 without HOFox
produced disaccharide 1737 in a poor yield of 21%. When the
same reaction was performed in the presence of HOFox (0.25
equiv.) disaccharide 17 was obtained in an excellent yield of
95% (Entry 7). It should be noted that both reactions were
quenched after 30 min. In another set of experiments, the reacꢀ
tions were continued for 2.5 h with/without HOFox, but no
observable change in yields of disaccharide 17 was recorded
in either case.
As evident from previous results, HOFox catalyzes reacꢀ
tions of both perꢀbenzylated armed and perꢀbenzoylated disꢀ
armed glycosyl donors. Also noticed was a significantly more
profound effect of the HOFox catalysis on glycosidations of
less reactive disarmed donors. The fact that nearly all reactions
of 2ꢀOꢀbenzylated donors were more stereoselective without
HOFox than those performed in the presence of HOFox has
not remained unnoticed either. To understand the basis for
these effects we turned our focus to screening the effect of the
amount of HOFox on the reactivity of armed and disarmed
donors.40 For this study we chose perꢀbenzylated mannosyl
donor 8 and its perꢀbenzoylated counterpart 14 both of which
provided high yield in the preliminary experiments in the
presence of 25 mol % of HOFox. The study of the effect of
different amounts of HOFox on the reactivity of donors 8 and
14 is summarized in Table 2.
After that, we investigated the effect of HOFox on reactions
of deactivated, perꢀbenzoylated bromides. To endure fair
comparison of the results, perꢀbenzoylated bromides were also
generated from the corresponding Sꢀethyl glycoside precurꢀ
sors35 by the reaction with bromine.33 However, perꢀ
benzoylated bromides can also be obtained from the correꢀ
sponding perꢀbenzoates.36 We were pleased to observe a very
prominent effect of HOFox in all reactions of deactivated
bromides. Thus, glycosidation of perꢀbenzoylated glucosyl
bromide 10 with glycosyl acceptor 4 without HOFox produced
disaccharide 1118 in a poor yield of 35%. When the same reacꢀ
tion was performed in the presence of HOFox (0.25 equiv.)
disaccharide 11 was obtained in a significantly improved yield
of 85% (Table 1, Entry 4). A 1,2ꢀorthoester was also produced
as the side product. Glycosidation of perꢀbenzoylated galactoꢀ
syl bromide donor 12 with glycosyl acceptor 4 without HOFox
produced disaccharide 1318 in 3 h in a poor yield of 19%.
When the same reaction was performed in the presence of
HOFox (0.25 equiv.) disaccharide 13 was obtained in an exꢀ
cellent yield of 90% (Entry 5). No 1,2ꢀorthoester formation
has been detected in this case. The HOFox effect was even
more pronounced with mannosyl bromide donor 14. When the
latter was glycosidated with acceptor 4 without HOFox, disacꢀ
charide 1518 was obtained in a poor yield of 13% after 5 h.
When the same reaction was performed in the presence of
Glycosidation of benzylated mannosyl bromide 8 without
HOFox progressed slowly (4 h) to afford disaccharide 9 in
74% yield (Entry 1). When glycosidation of 8 was performed
in presence of 5 or 10 mol % of HOFox practically identical
results have been obtained. Disaccharide 9 was produced in
excellent yields (92 or 91%, respectively) within 2 h (Entries 2
and 3). These results with perꢀbenzylated donor 8 indicate that
the impact of HOFox is immediately evident even with very
small amounts of the catalyst.
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Table 1. Establishing the benchmark and defining the basic scope of the HOFoxꢀcatalyzed glycosylations
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2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
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Entry
Glycosyl Donor
HOFox (equiv.)
Time
Product
Yield (α/β ratio)
0
0.25
4 h
2 h
18% (1/5.4)
81% (1/2.5)
1a
2
5
0
0.25
0.75 h
0.75 h
79% (1/18)
84% (1/10)
2b
3c
4c
6
7
9
0
0.15
0.25
4 h
2 h
3 h
74% (2.9/1)
94% (1.1/1)
88% (1.2/1)
8
OBz
O
BzO
0
0.25
2.5 h
2.5 h
35% (βꢀonly)
85% (βꢀonly)d
BzO
BzO
Br
10
12
11
13
0
0.25
3 h
3 h
19% (βꢀonly)
90% (βꢀonly)
5b
0
0.25
5 h
2 h
13% (αꢀonly)
98% (αꢀonly)
6a
14
15
OAc
O
AcO
AcO
O
0
0.25
0. 5 h
0. 5 h
21% (9.8/1)
95% (4.3/1)
O
7b
BnO
BnO
BnO
BnO
OMe
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17
a
b
c
d
– TMSOTf (0.08 equiv.); – TMSOTf (0.05 equiv.); – TMSOTf (0.10 equiv.); – the corresponding 1,2ꢀorthoester byꢀproduct was also
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formed
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Increasing the amount of HOFox (25, 50, 75 or 100 mol %) tive glycosyl donors 14 for the synthesis of 1,2ꢀtrans linkages
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3
4
5
6
7
8
did not show any enhancement in the rate of the reaction with
donor 8 nor yields that seemed to reach the plateau (Entries 4ꢀ
7). A gradual decrease of stereoselectivity was observed along
with the increase of HOFox.
and 16 for the synthesis of 1,2ꢀcis linkages along with the set
of standard glycosyl acceptors. This study is summarized in
Table 3. A reaction of the disarmed mannosyl bromide donor
14 with 1ꢀadamantanol 18 in presence of TMSOTf (5 mol %)
without/with HOFox afforded glycoside 19 in excellent yields
of 93/99% (Entry 1). Although the numeric outcome of the
HOFox catalysis may seem negligible in this swift (1 h) reacꢀ
tion, the reaction in the presence of HOFox was notably cleanꢀ
er.
Table 2. Effect of the catalyst on the rate and the yield of
reactions.
9
Glycosylations of sugar acceptors, which are typically much
slower than those of aliphatic alcohols, were affected by
HOFox much more strongly. Thus, glycosidation of donor 14
with 2ꢀOH acceptor 2034 to form disaccharide 21 was enꢀ
hanced from 27% (no HOFox) to 85% (25 mol % HOFox,
Entry 2). Both reactions were stopped after 3 h. Glycosidation
of donor 14 with 3ꢀOH acceptor 2234 to form disaccharide 2341
was enhanced from 13% (6 h, no HOFox) to 98% (2 h, 25 mol
% HOFox, Entry 3). Glycosidation of donor 14 with 4ꢀOH
acceptor 2434 to form disaccharide 2518 was enhanced from
14% (3 h, no HOFox) to 86% (3 h, 25 mol % HOFox, Entry
4). After this initial success, we investigated benzoylated acꢀ
ceptors that are generally less reactive than their benzylated
counterparts, which often translates into reduced yields.
HOFox catalysis was found very effective in these cases ae
well. Thus, glycosidation of donor 14 with benzoylated 6ꢀOH
acceptor 2642 to form disaccharide 2743 was enhanced from
25% (3 h, no HOFox) to 92% (3 h, 25 mol % HOFox, Entry
5). Glycosidation of donor 14 with sterically hindered and
deactivated C4ꢀOH glycosyl acceptor 2844 to form disacchaꢀ
ride 29 was enhanced from <2% (6 h, no HOFox) to 44% (2 h,
25 mol % HOFox). To improve this result, we conducted these
reactions in the presence of larger quantities of the activator,
o.15 equiv. TMSOTf. In this case, the formation of disacchaꢀ
ride 29 was enhanced from 20% (6 h, no HOFox) to 68% (2 h,
25 mol % HOFox, Entry 6). All reactions with donor 14 were
entirely 1,2ꢀtrans stereoselective due to the participatory effect
of the ester substituent at Cꢀ2.
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14
15
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19
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HOFox
(equiv.)
8ꢀ9, time, yield of
14ꢀ15, time,
Entry
9 (α/β ratio)
yield of 15a
1
2
3
4
5
6
7
0
4 h, 74% (2.9/1)
2 h, 92% (1.1/1)
2 h, 91% (1.4/1)
3 h, 88% (1.2/1)
3 h, 89% (1.2/1)
3 h, 87% (1.1/1)
3 h, 88 % (1.0/1)
5 h, 13%
5 h, 52%
0.05
0.10
0.25
0.50
0.75
1.00
3 h, 90%
2 h, 98%
0.5 h, 98%
0.5 h, 96%
0.5 h, 74%
a disaccharide 15 is obtained as a pure αꢀdiastereomer
The effect of different amounts of HOFox on the reactivity
of donor 14 was more predictable, with a steady decrease of
the reaction time and increase of yields. The glycosylation
reaction without HOFox proceeded slowly and afforded disacꢀ
charide 15 in poor yield (13%) in 5 h (Table 2, Entry 1). A
similar reaction performed with 5 mol % of HOFox produced
disaccharide 15 in a moderate yield (52%) in 5 h (Entry 2).
Increasing the HOFox amount to 10 mol % further decreased
the reaction time. The reaction completed in 3 h and disacchaꢀ
ride 15 was produced in a commendable yield of 90% (Entry
3). Further overall enhancement was achieved in the presence
of 25 mol % of HOFox. Disaccharide 15 was cleanly produced
in 2 h in 98% yield (Entry 4). Further increments in the
amount of HOFox to 50 and 75 mol % also afforded disacchaꢀ
ride in excellent yields, and in these cases the reactions were
even faster (30 min, Entries 4 and 5). When the amount of
HOFox was increased to 100 mol % the reaction was still
swift, but the yield of disaccharide 15 dropped to 74% due to
competing hydrolysis of the OFox imidate intermediate that
was formed in large amounts from the beginning.
After that, we turned our attention to glucosyl bromide 16
equipped with the 2ꢀOꢀbenzylꢀ3,4,6ꢀtriꢀOꢀacyl protecting
group pattern. The glycosylation reactions of glucosyl donor
16 with a variety of glycosyl acceptors were conducted in a
similar fashion to that mentioned earlier. Glycosidation of
donor 16 with 1ꢀadamantanol acceptor 18 to form glycoside
3045 was enhanced from 61% (30 min, no HOFox) to 90% (30
min, 25 mol % HOFox, Entry 7, Table 3). The stereoselectiviꢀ
ty of both reactions was the same, α/β = 10/1. Glycosidation
of donor 16 with 2ꢀOH acceptor 20 to form disaccharide 3137
was enhanced from 26% (45 min, no HOFox) to 92% (45 min,
25 mol % HOFox, Entry 8). The stereoselectivity of both reacꢀ
tions was complete, α-only. Glycosidation of donor 16 with 3ꢀ
OH acceptor 22 to form disaccharide 3237 was enhanced from
27% (no HOFox) to 91% (25 mol % HOFox, Entry 9). The
stereoselectivity of the reaction without HOFox was higher
(α/β = 36/1) than that of the HOFoxꢀcatalyzed reaction (α/β =
20/1). Finally, glycosidation of donor 16 with 4ꢀOH acceptor
24 to form disaccharide 3337 was enhanced from 14% (no
HOFox) to 85% (25 mol % HOFox, Entry 10). The stereoseꢀ
lectivity of both reactions was the same, α/β = 12/1.
After investigating a series of glycosyl donors and optimizaꢀ
tion of the reaction conditions for glycosylation of primary
acceptor 4, we decided to investigate the efficacy of the
HOFox catalysis in application to other glycosyl acceptors.
The reactivity of glycosyl acceptors depends on the nature of
the hydroxyl group i.e. primary or secondary position on sugar
units. The reactivity can also be affected by the electronic
nature of protecting groups and steric hindrance around the
hydroxyl group. For this comparison study we chose unreacꢀ
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Table 3. Glycosidation of donors 14 and 16 with different acceptors in the presence of TMSOTfa
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2
3
4
5
6
7
Entry
Donor
Acceptor (R’’)
HOFox (equiv.)
Time
Product
Yield (α/β ratio)
8
9
0
0.25
1 h
1 h
93% (αꢀonly)
99% (αꢀonly)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
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49
50
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52
53
54
55
56
57
58
59
60
1
14
14
19
18
BnO
O
O
BnO
BnO
0
0.25
3 h
3 h
27% (αꢀonly)
85% (αꢀonly)
OMe
2
BzO
BzO
BzO
O
20
OBz
21
0
0.25
6 h
2 h
13% (αꢀonly)
98% (αꢀonly)
3
4
14
14
22
24
23
25
0
0.25
3 h
3 h
14% (αꢀonly)
86% (αꢀonly)
0
0.25
3 h
3 h
25% (αꢀonly)
92% (αꢀonly)
5
14
14
26
27
0
0.25
6 h
2 h
20% (αꢀonly)
68% (αꢀonly)
6a
28
18
29
30
0
0.25
0.5 h
0.5 h
61% (10/1)
90% (10/1)
7
16
16
0
0.25
0.75 h
0.75 h
26% (αꢀonly)
92% (αꢀonly)
8
9
20
22
31
32
0
0.25
0.75 h
0.75 h
27% (36/1)
91% (20/1)
16
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1
2
3
0
0.25
0.75 h
0.75 h
14% (12/1)
85% (12/1)
10
16
24
4
5
6
33
a TMSOTf (0.15 equiv.)
7
8
9
Encouraged by these results, we decided to investigate the
applicability of this regenerative method to multiꢀstep oligoꢀ
saccharide synthesis. For this endeavor we chose perꢀ
benzoylated galactosyl thioglycosides: compound 3435 as the
precursor for bromide 12 and galactosyl acceptor 35.46 Broꢀ
mination of 34 with bromine produced galactosyl bromide
donor 12 quantitatively. The latter was reacted with acceptor
35 (0.8 equiv.) in the presence of TMSOTf (8 mol %) and
HOFox (25 mol %) to afford 1,2ꢀtransꢀlinked disaccharide
3646 in 84% yield. For comparison, the same reaction in the
absence of HOFox produced disaccharide 36 in only 26%
yield. For the trisaccharide synthesis, bromination of disacchaꢀ
ride 36 with bromine (1.5 equiv.) followed by glycosidation
with acceptor 35 (0.8 equiv.) in the presence of TMSOTf (8
m0l %) and HOFox (25 mol %) afforded 1,2ꢀtransꢀlinked triꢀ
saccharide 37 in 87% yield. Further, bromination of trisacchaꢀ
ride 37 with bromine (1.5 equiv.) followed by glycosidation
with acceptor 35 (0.9 equiv.) in the presence of TMSOTf (0.08
mol %) and HOFox (25 mol %) afforded 1,2ꢀtransꢀlinked
tetrasaccharide 38 in 76% yield.
The HOFoxꢀassisted regenerative glycosylation for oligoꢀ
saccharide synthesis involves the donor and acceptor with the
same leaving group. The concept may look similar to the preꢀ
viously developed twoꢀstep47ꢀ49 or preꢀactivation approaches.50ꢀ
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
52
The similarity is undeniable, but there is a key conceptual
difference. In twoꢀstep or preꢀactivation approaches, glycosyl
donor is entirely converted to a reactive intermediate which is
then reacted with a glycosyl acceptor. This may lead to high
rates of competitive hydrolysis that become more pronounced
at the advanced stages of the synthesis. As a result, a signifiꢀ
cant drop in yields can be observed with the increase in the
size of the oligosaccharides. In the regenerative concept, the
glycosyl bromide donor reacts with a catalytic amount of
HOFox to furnish OFox imidates in a catalytic amount. The
latter is then coupled with the Sꢀethyl glycosyl acceptor to
afford disaccharide. During oligosaccharide synthesis, the
actual reactive species which reacted with Sꢀethyl glycosyl
acceptor are imidates which are obtained in small quantities
and get regenerated only after the first batch has been conꢀ
sumed. We believe, that the regenerative approach helps to
endure that the yields remain high throughout the entire duraꢀ
tion of the oligosaccharides synthesis.
Scheme 2. Oligosaccharide synthesis through regenerative
glycosylation
Conclusions
BzO
OBz
O
Presented herein is our first attempt to extend the HOFoxꢀ
catalyzed regenerative glycosylation to other sugar series and
targets. The versatility of this approach has been demonstrated
in application to the regenerative oligosaccharide synthesis.
The reason why nearly all reactions of 2ꢀOꢀbenzylated donors
were less stereoselective in the presence of HOFox remains
unknown. Further inꢀdepth mechanistic study may help to
explain this phenomenon and provide tools for the enhanceꢀ
ment of the stereoselectivity.
SEt
BzO
34
OBz
Br2, DCM, 0 oC, 15 min, MS 3 A
BzO
OH
O
SEt
12
BzO
OBz
35
Ag2O, HOFox, TMSOTf, 1.5 h
84%
OBz
Further implementation of the OFoxꢀbased regenerative
glycosylation into the HPLCꢀassisted automated oligosacchaꢀ
ride synthesis on solid phases is currently under way in our
laboratories. The regenerative glycosylation has a conservaꢀ
tively estimated threeꢀfold benefit for these reactions. First, the
reactive OFox imidate donor is generated in small amounts,
which helps to minimize side reactions. Second, the OFox
donor is constantly regenerated ensuring continuous feeding of
the system with the “fresh” donor. Third, a stable precursor
can be used, and careful monitoring of glycosylation will enꢀ
sure that only the necessary amounts of reagents is used.
BzO
O
O
BzO
BzO
BzO
O
SEt
BzO
OBz
36
Br2, DCM, 0 oC, 30 min, MS 3 A
87%
35
, Ag2O, HOFox, TMSOTf, 1.5 h
OBz
BzO
BzO
BzO
O
O
BzO
BzO
O
O
O
Experimental
BzO
SEt
BzO
37
OBz
OBz
General remarks. The reactions were performed using
commercial reagents and the ACS grade solvents used for
reactions were purified and dried in accordance with standard
procedures. Column chromatography was performed on silica
gel 60 (70ꢀ230 mesh), reactions were monitored by TLC on
Kieselgel 60 F254. The compounds were detected by examinaꢀ
tion under UV light and by charring with 10% sulfuric acid in
methanol. Solvents were removed under reduced pressure at
Br2, DCM, 0 oC, 45 min, MS 3 A
76 %
35
, Ag2O, HOFox, TMSOTf, 1.5 h
OBz
OBz
BzO
BzO
BzO
O
O
+
O
O
NH4
SEt
BzO
BzO
BzO
BzO
O
O
O
BzO
BzO
o
OBz
<40 C. CH2Cl2 was distilled from CaH2 directly prior to apꢀ
OBz
38
plication. Molecular sieves (3 Å), used for reactions, were
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1
crushed and activated in vacuo at 390 °C for 8 h in the first
+36.9 (c = 2.0, CHCl3); H n.m.r. (300 MHz): δ, 3.45 (s, 3H),
3.68ꢀ3.84 (m, 4H, Hꢀ4,5,6a, 6b), 4.02 (dd, 1H, J2,3 = 9.9 Hz,
1
2
3
4
instance and then for 2ꢀ3 h at 390 °C directly prior to applicaꢀ
tion. Optical rotations were measured at ‘Jasco Pꢀ1020’ polarꢀ
imeter. 1H NMR spectra were recorded at 300 MHz, 13C NMR
Hꢀ2), 4.10 (dd, 1H, J3,4 = 8.4 Hz, Hꢀ3) 4.21 (dd, 1H, J5’,6’a
4.3 Hz, J6’a,6’b = 12.4 Hz, Hꢀ6’a), 4.48ꢀ4.69 (m, 5H, Hꢀ5’, 6’b,
1.5 x CH2Ph), 4.79 (d, 1H, J = 10.7 Hz, ½ CH2Ph), 4.98 (d,
1H, J1,2 = 3.2 Hz, Hꢀ1), 5.08 (dd, 2H, J = 11.4 Hz, CH2Ph),
=
1
2
spectra were recorded at 75 MHz. The H NMR chemical
1
2
shifts are referenced to tetramethyl silane (TMS) for H NMR
5
6
7
8
spectra for solutions in CDCl3. The 13C NMR chemical shifts
are referenced to the central signal of CDCl3 (δC = 77.00 ppm)
for solutions in CDCl3. Mass analysis was performed in a Waꢀ
ters Synapt G2 HDMS mass spectrometer with 10,000 resoluꢀ
tion, calibrated with CsI clusters in the mass range of 100 to
3000 m/z. The sample was infused using a syringe pump at a
flow rate of 500 nL/minute directly to the nano ESI source
operated in positive mode. Conditions: Capillary voltage 2.0
kV, cone 20 V, extraction cone 2 V, source temperature 30 oC.
5.22 (d, 1H, J1’,2’ = 1.5 Hz, Hꢀ1’), 5.78 (dd, 1H, J2’,3’ = 3.2 Hz,
Hꢀ2’), 5.94 (dd, 1H, J3’,4’ = 10.2 Hz, Hꢀ3’), 6.09 (dd, 1H, J4’,5’
= 10.2 Hz, Hꢀ4’), 7.10ꢀ8.13 (m, 35H, aromatic), ppm; 13C
n.m.r. (75 MHz): δ, 55.3, 62.3, 66.4, 68.3, 68.9, 69.9, 70.2,
70.5, 73.5, 74.9, 75.1, 75.7, 78.1, 80.4, 94.5, 96.2, 127.2 (x 2),
127.4, 127.7(x 2), 127.8 (x 2), 127.9(x 2), 128.3 (x 4), 128.4
(x 9), 128.5(x 2), 128.8, 129.0, 129.2, 129.7 (x 5), 129.8(x 2),
129.9, 132.9, 133.1, 133.3, 133.5, 137.8, 137.9, 138.4, 165.3
(x 3), 166.0 ppm; HRꢀES MS [M+NH4]+ calculated for
[C62H58O15 + NH4]+ 1060.4114, found 1060.4126.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
A typical glycosylation procedure and the synthesis of
glycosides. A thioglycoside precursor (0.022 ꢀ 0.047 mmol)
and freshly activated molecular sieves (3 Å, 100ꢀ150 mg) in
CH2Cl2 (1 ꢀ 1.5 mL) was stirred under argon for 1 h at rt. Br2
(1.3 equiv. or as indicated in tables and Scheme 2) was added
Methyl
4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀ
mannopyranosyl)ꢀ2,4,6ꢀtriꢀOꢀbenzoylꢀαꢀDꢀglucopyranoside
(29). The title compound was obtained from mannosyl donor
14 and acceptor 28 by glycosylation method described earlier
in 68% yield as a white amorphous solid. Analytical data for
αꢀ29: Rf = 0.60 (ethyl acetate/toluene, 15/85. v/v); [α]D22 +27.1
o
at 0 C and the resulting mixture was stirred for 15 min or as
mentioned in Scheme 2. Solvent was removed under the reꢀ
duced pressure and the residue was dried in vacuo for 1 h.
Silver oxide (3 equiv.), glycosyl acceptor (0.018 ꢀ 0.037
mmol) and HOFox (0ꢀ1.0 equiv.) were added and the resulting
solid was additionally dried in vacuo for 1 h. CH2Cl2 (1.5 mL)
was added and the resulting mixture was stirred for 30 min at
rt. The mixture was cooled to 0 oC, TMSOTf (0.05ꢀ0.15
equiv.) was added, and the resulting mixture was stirred for
the time specified in tables and Scheme 2. The solids were
filteredꢀoff through a pad of Celite and rinsed successively
with CH2Cl2. The combined filtrate (~40 mL) was washed
with 1% aq. NaOH (10 mL) and water (2 x 10 mL). The orꢀ
ganic phase was separated, dried with MgSO4, and concentratꢀ
ed in vacuo. The residue was purified by column chromatogꢀ
raphy on silica gel (ethyl acetate ꢀ hexane gradient elution) to
afford a glycoside derivative in yields listed in tables and
Scheme 2. Anomeric ratios (if applicable) were determined by
1
(c = 1.2, CHCl3); H n.m.r. (300 MHz): δ, 3.48 (s, 3H), 4.28ꢀ
4.41 (m, 3H, Hꢀ4, 5, 6’a), 4.46ꢀ4.54 (m, 1H, J5’,6’b = 2.3 Hz, Hꢀ
5’), 4.58 (dd, 1H, J6’a,6’b = 12.3 Hz, Hꢀ6’b), 4.72 (dd, 1H, J6a,6b
= 11.8 Hz, Hꢀ6), 4.87 (br d, 1H, Hꢀ6b), 5.15 (dd, 1H, J2,3
=
10.1 Hz, Hꢀ2), 5.20 (d, 1H, J1,2 = 3.6 Hz, Hꢀ1), 5.42 (d, 1H,
J1’,2’ = 1.7 Hz, Hꢀ1’), 5.47 (dd, 1H, J2’,3’ = 3.1 Hz, Hꢀ2’), 5.86
(dd, 1H, J3’,4’ = 10.2 Hz, Hꢀ3’), 6.05 (dd, 1H, J4’,5’ = 10.1 Hz,
Hꢀ4’), 6.22 (br dd, 1H, J3,4 = 9.9 Hꢀ3), 7.08ꢀ8.15 (m, 35H,
aromatic) ppm; 13C n.m.r. (75 MHz): δ, 55.5, 62.3, 63.1, 66.3,
68.2, 69.2, 70.2 (x 2), 72.1, 72.4, 75.8, 96.8, 99.1, 128.0 (x 3),
128.2 (x 4), 128.4 (x 5), 128.6 (x 3), 128.8, 128.9 (x 3), 129.0,
129.4, 129.6 (x 2), 129.7 (x 4), 129.8 (x 5), 129.9 (x 3), 132.9
(x 2), 133.0, 133.1, 133.4 (x 3), 164.2, 165.1, 165.3 (x 2),
165.9,166.0 ,166.2 ppm; HRꢀES MS [M+NH4]+ calculated for
[C62H52O18 + NH4]+ 1102.3492, found 1102.3503.
Ethyl
Oꢀ(2,3,4ꢀTriꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀ
1
comparison of the integral intensities of relevant signals in H
(1→6)ꢀOꢀ(2,3,4ꢀtriꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀ
(1→6)ꢀ2,3,4ꢀtriꢀOꢀbenzoylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside
(37). The title compound was obtained from mannosyl donor
36 and acceptor 35 by glycosylation method described earlier
in 87% yield as a colorless amorphous solid. Analytical data
NMR spectra.
1ꢀAdamantyl
2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀ
mannopyranoside (19). The title compound was obtained
from mannosyl donor 14 and acceptor 18 by glycosylation
method described earlier in 99% yield as a thick transparent
syrup. Analytical data for αꢀ19: Rf = 0.62 (ethyl aceꢀ
tate/hexane, 25/75, v/v); [α]D21 ‒65.9 (c = 1 , CHCl3); 1H n.m.r.
(300 MHz): δ, 1.54ꢀ2.16 (m, 15H, 1ꢀadamantyl), 4.48 (dd, 1H,
J5,6a = 6.0 Hz, J6a,6b = 12.4 Hz, Hꢀ6a), 4.60ꢀ4.69 (m, 2H, Hꢀ
5,6b), 5.98 (dd, 1H, J2,3 = 2.5 Hz, J3,4 = 10.0 Hz, Hꢀ3), 6.05
(dd, 1H, J4,5 = 10.1 Hz, Hꢀ4), 7.12ꢀ8.14 (m, 20H, aromatic)
ppm; 13C n.m.r. (75 MHz): δ, 30.6 (x 3), 36.1 (x 3), 42.3 (x 3),
63.4, 67.3, 68.4, 70.2, 72.2, 76.0, 90.9, 128.2 (x 2), 128.3 (x
2), 128.4 (x 2), 128.5 (x 2), 129.0, 129.1, 129.5, 129.7 (x 4),
129.8 (x 5), 133.0, 133.1, 133.4 (x 2), 165.5, 162.6, 162.7,
22
for 37: Rf = 0.57 (ethyl acetate/toluene, 12/88, v/v); [α]D
1
+150.2 (c = 1.5, CHCl3); H n.m.r. (300 MHz): δ, 1.14 (t, 3H,
3J = 7.4 Hz, ꢀCH3), 2.50ꢀ2.72 (m, 2H, ꢀCH2ꢀ), 3.58ꢀ4.30 (m,
9H, Hꢀ5, 5’, 5’’, 6a, 6a’, 6a’’, 6b, 6b’, 6b’’), 4.63ꢀ4.81 (3d,
3H, Hꢀ1, 1’, 1’’), 5.45ꢀ5.60 (m, 3H, Hꢀ3, 3’, 3’’), 5.63ꢀ5.79
(m, 3H, Hꢀ2, 2’, 2’’), 5.84ꢀ5.97 (m, 3H, Hꢀ4, 4’, 4’’) 7.17ꢀ8.12
(m, 50H, aromatic) ppm; 13C n.m.r. (75 MHz): δ, 14.7, 24.1,
61.4, 66.2, 67.5, 67.7, 67.8, 68.2, 68.7, 69.7 (x 2), 71.0, 71.5,
71.6, 72.4, 72.6, 76.6, 83.8, 100.6, 100.9, 128.1 (x 2), 128.2 (x
4), 128.3 (x 4), 128.4 (x 5), 128.5 (x 5), 128.6 (x 2), 128.7,
128.8, 128.9 (x 2), 129.1, 129.2 (x 3), 129.3, 129.6 (x 4),
129.7 (x 4), 129.8 (x 4), 129.9 (x 2), 130.0 (x 3), 130.1 (x 2) ,
133.0, 133.2 (x 6), 133.3, 133.4, 133.5, 164.9, 165.1 (x 2),
165.2, 165.3 (x 2), 165.4, 165.5 (x 2), 165.7 ppm; HRꢀES MS
[M+NH4]+ calculated for [C90H76O25S + NH4]+ 1606.4735,
found 1606.4744.
166.2 ppm; HRꢀES MS [M+NH4]+ calculated for [C44H42O10
NH4]+ 748.3116, found 748.3146.
+
Methyl
2ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀαꢀDꢀ
mannopyranosyl)ꢀ3,4,6ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(21). The title compound was obtained from mannosyl donor
14 and acceptor 20 by glycosylation method described earlier
in 85% yield as a white amorphous solid. Analytical data for
Ethyl
Oꢀ(2,3,4ꢀTriꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀ
(1→6)ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀ
(1→6)ꢀOꢀ(2,3,4ꢀtriꢀOꢀbenzoylꢀβꢀDꢀgalactopyranosyl)ꢀ
22
αꢀ24: Rf = 0.83 (ethyl acetate/hexanes, 35/65, v/v); [α]D
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Page 8 of 10
(1→6)ꢀ2,3,4ꢀtriꢀOꢀbenzoylꢀ1ꢀthioꢀβꢀDꢀgalactopyranoside
solid. The analytical data for the title compound was in acꢀ
cordance to that reported previously.18
1
2
3
4
5
6
7
8
(38). The title compound was obtained from mannosyl donor
37 and acceptor 35 by glycosylation method described earlier
in 76% yield as a colorless amorphous solid. Analytical data
Methyl
6ꢀOꢀ(3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀOꢀbenzylꢀαꢀDꢀ
glucopyranosyl)ꢀ2,3,4ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(17). The title compound was obtained from donor 16 and
acceptor 4 by typical glycosylation method in 21% (α/β =
9.8/1) with no HOFox and 95% (α/β = 4.3/1) with 25 mol %
HOFox as a clear film. The analytical data for the title comꢀ
pound was in accordance to that reported previously.37
22
for 38: Rf = 0.48 (ethyl acetate/toluene, 12/88, v/v); [α]D
+111.1 (c = 1 , CHCl3); 1H n.m.r. (300 MHz): δ, 1.13 (t, H, J
3
= 7.5 Hz, ꢀCH3), 2.46ꢀ2.71 (m, 2H, ꢀCH2ꢀ), 3.22ꢀ4.26 (m, 12H,
Hꢀ5, 5’, 5’’, 5’’’, 6a, 6a’, 6a’’, 6a’’’, 6b, 6b’, 6b’’, 6b’’’),
4.42ꢀ4.83 (4 d, 4H, Hꢀ1, 1’, 1’’, 1’’’), 5.38ꢀ5.77 (m, 8H, Hꢀ2,
2’, 2’’, 2’’’, 3, 3’, 3’’, 3’’’), 5.84ꢀ5.97 (m, 4H, Hꢀ4, 4’, 4’’,
4’’’), 7.12ꢀ8.13 (m, 65H, aromatic) ppm; 13C n.m.r. (75 MHz):
δ, 14.7, 24.1, 61.2, 66.1 (x 2), 67.5, 67.6, 67.7 (x 2), 68.2,
68.7, 69.7, 69.8 (x 2), 70.9, 71.5, 71.6, 71.7, 72.1 (x 2), 72.7,
76.6, 83.8, 100.7 (x 2), 100.9, 128.1 (x 5), 128.2 (x 6), 128.3
(x 5), 128.4 (x 6), 128.5 (x 3), 128.6 (x 2), 128.7, 128.8, 128.9,
129.0 (x 4), 129.1, 129.2 (x 4), 129.3 (x 2), 129.5, 129.7 (x 8),
129.8 (x 7), 129.9 (x 2), 130.0 (x 2), 130.1 (x 4) , 133.0 (x 2),
133.1 (x 4), 133.2 (x 5) 133.3, 133.4, 164.9, 165.0 (x 2), 165.1
(x 2), 165.2, 165.3 (x 2), 165.4 (x 2), 165.5 (x 2), 165.7 ppm;
HRꢀES MS [M+NH4]+ calculated for [C117H98O33S + NH4]+
2080.6049, found 2080.6047.
Methyl 2,4,6ꢀtriꢀOꢀbenzylꢀ3ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀ
αꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (23). The title
compound was obtained from donor 14 and acceptor 22 by
typical glycosylation method in 13% (αꢀonly) with no HOFox
and 98% (αꢀonly) with 25 mol % HOFox as white amorphous
solid. The analytical data for the title compound was in acꢀ
cordance to that reported previously.41
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Methyl 2,3,6ꢀtriꢀOꢀbenzylꢀ4ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀ
αꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (25). The title
compound was obtained from donor 14 and acceptor 24 by
typical glycosylation method in 14% (αꢀonly) with no HOFox
and 86% (αꢀonly) with 25 mol % HOFox as a white amorꢀ
phous solid. The analytical data for the title compound was in
accordance to that reported previously.18
Methyl 6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀβꢀDꢀglucopyranosyl)ꢀ
2,3,4ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside (5). The title comꢀ
pound was obtained from donor 2 and acceptor 4 by typical
glycosylation method in 18%, (α/β = 1/5.4) with no HOFox
and 81% (α/β = 1/2.5) with 25 mol % HOFox as a white
amorphous solid. The analytical data for the title compound
was in accordance to that reported previously.18
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀ
αꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (27). The title
compound was obtained from donor 14 and acceptor 26 by
typical glycosylation method in 25% (αꢀonly) with no HOFox
and 92% (αꢀonly) with 25 mol % HOFox as a white amorꢀ
phous solid. The analytical data for the title compound was in
accordance to that reported previously.43
Methyl
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀβꢀDꢀ
galacopyranosyl)ꢀ2,3,4ꢀtriꢀOꢀbenzylꢀαꢀDꢀ glucopyranoside
(7). The title compound was obtained from donor 6 and accepꢀ
tor 4 by typical glycosylation method in 79% (α/β = 1/18) with
no HOFox and 81% (α/β = 1/10) with 25 mol % HOFox as a
white amorphous solid. The analytical data for the title comꢀ
pound was in accordance to that reported previously.16
1ꢀAdamantyl
3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀOꢀbenzylꢀαꢀDꢀ
glucopyranoside (30). The title compound was obtained from
donor 16 and acceptor 18 by typical glycosylation method in
61% (α/β = 10/1) with no HOFox and 92% (α/β = 10/1) with
25 mol % HOFox as a clear film. The analytical data for the
title compound was in accordance to that reported
previously.45
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀαꢀ
Dꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (9). The title
compound was obtained from donor 8 and acceptor 4 by typiꢀ
cal glycosylation method in 74% (α/β = 2.9/1) with no HOFox
and 94% (α/β = 1.1/1) with 15 mol % of HOFox as a white
amorphous solid. The analytical data for the title compound
was in accordance to that reported previously.18
Methyl
2ꢀOꢀ(3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀOꢀbenzylꢀαꢀDꢀ
glucopyranosyl)ꢀ3,4,6ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(31). The title compound was obtained from donor 16 and
acceptor 20 by typical glycosylation method in 26% (α only)
with no HOFox and 92% (αꢀonly) with 25 mol % HOFox as a
clear film. The analytical data for the title compound was in
accordance to that reported previously.37
Methyl
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀ
glucopyranosyl)ꢀ2,3,4ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(11). The title compound was obtained from donor 10 and
acceptor 4 by typical glycosylation method in 35% (β only)
with no HOFox and 94% (β only) with 25 mol % HOFox as a
white amorphous solid. The analytical data for the title comꢀ
pound was in accordance to that reported previously.18
Methyl
3ꢀOꢀ(3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀOꢀbenzylꢀαꢀDꢀ
glucopyranosyl)ꢀ2,4,6ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(32). The title compound was obtained from donor 16 and
acceptor 22 by typical glycosylation method in 27% (α/β =
36/1) with no HOFox and 91% (α/β = 20/1) with 25 mol %
HOFox as a clear film. The analytical data for the title comꢀ
pound was in accordance to that reported previously.37
Methyl
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀβꢀDꢀ
galactopyranosyl)ꢀ2,3,4ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(13). The title compound was obtained from donor 12 and
acceptor 4 by typical glycosylation method in 19% (β only)
with no HOFox and 90% (β only) with 25 mol % HOFox as a
white amorphous solid. The analytical data for the title comꢀ
pound was in accordance to that reported previously.18
Methyl
4ꢀOꢀ(3,4,6ꢀtriꢀOꢀacetylꢀ2ꢀOꢀbenzylꢀαꢀDꢀ
glucopyranosyl)ꢀ2,3,6ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(33). The title compound was obtained from donor 16 and
acceptor 22 by typical glycosylation method in 14% (α/β =
12/1) with no HOFox and 85% (α/β = 12/1) with 25 mol %
HOFox as a clear film. The analytical data for the title comꢀ
pound was in accordance to that reported previously.37
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzoylꢀ
αꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (15). The title
compound was obtained from donor 14 and acceptor 4 by typꢀ
ical glycosylation method in 13% (αꢀonly) with no HOFox and
98% (αꢀonly) with 25 mol % HOFox as a white amorphous
Methyl 2ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀbenzylꢀβꢀDꢀglucopyranosyl)ꢀ
3,4,6ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside (40). The title comꢀ
pound was obtained from donor 3920 and acceptor 20 by typiꢀ
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The Journal of Organic Chemistry
(12) McKay, M. J.; Nguyen, H. M. ACS Catal. 2012, 2, 1563.
cal glycosylation method in 11% (α/β = 1/5.4) with no HOFox
(13) Williams, R.; Galan, M. C. Eur. J. Org. Chem. 2017, 6247.
(14) Goswami, M.; Ellern, A.; Pohl, N. L. Angew. Chem. Int. Ed. Engl.
2013, 52, 8441.
(15) Park, Y.; Harper, K. C.; Kuhl, N.; Kwan, E. E.; Liu, R. Y.;
Jacobsen, E. N. Science 2017, 355, 162.
(16) Vibhute, A. M.; Dhaka, A.; Athiyarath, V.; Sureshan, K. M.
Chem. Sci. 2016, 7, 4259.
(17) Sun, L.; Wu, X.; Xiong, D. C.; Ye, X. S. Angew. Chem. 2016, 55,
8041.
(18) Nigudkar, S. S.; Parameswar, A. R.; Pornsuriyasak, P.; Stine, K.
J.; Demchenko, A. V. Org. Biomol. Chem. 2013, 11, 4068.
(19) Nigudkar, S. S.; Stine, K. J.; Demchenko, A. V. J. Am. Chem.
Soc. 2014, 136, 921.
(20) Andersson, F.; Fugedi, P.; Garegg, P. J.; Nashed, M. Tetrahedron
Lett. 1986, 27, 3919.
(21) Torres, J. C.; Garden, S. J.; Pinto, A. C. Tetrahedron 1999, 55,
1881.
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(23) Yu, L.ꢀC.; Gu, J.ꢀW.; Zhang, S.; Zhang, X. J. Org. Chem 2017,
82, 3943.
(24) Schmidt, R. R. Angew. Chem. Int. Edit. Engl. 1986, 25, 212.
(25) Morelli, L.; Bernardi, A.; Sattin, S. Carbohydr. Res. 2014, 390,
33.
(26) Schmidt, R. R.; Jung, K. H. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New York,
1997, p 283.
(27) Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl. 1980, 19,
731.
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Lett. 2006, 47, 2595.
1
2
3
4
5
6
7
8
and 80% (α/β = 1/1.3) with 25 mol % HOFox as a white
amorphous solid. The analytical data for the title compound
was in accordance to that reported previously.18
Methyl 6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀglucopyranosyl)ꢀ
2,3,4,ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside (42). The title
compound was obtained from donor 41 and acceptor 4 by typꢀ
ical glycosylation method in 38% (βꢀonly) with no HOFox and
31% (βꢀonly) with 25 mol % HOFox as a white amorphous
solid. The analytical data for the title compound was in acꢀ
cordance to that reported previously.18
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
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52
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55
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57
58
59
60
Methyl
6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀacetylꢀβꢀDꢀ
galactopyranosyl)ꢀ2,3,4ꢀtriꢀOꢀbenzylꢀαꢀDꢀglucopyranoside
(44). The title compound was obtained from donor 43 and
acceptor 4 by typical glycosylation method in 16% (β only)
with no HOFox and 30% (βꢀonly) with 25 mol % HOFox as a
clear film. The analytical data for the title compound was in
accordance to that reported previously.16
Methyl 2,3,4ꢀtriꢀOꢀbenzylꢀ6ꢀOꢀ(2,3,4,6ꢀtetraꢀOꢀacetylꢀ2ꢀ
αꢀDꢀmannopyranosyl)ꢀαꢀDꢀglucopyranoside (46). The title
compound was obtained from donor 45 and acceptor 4 by typꢀ
ical glycosylation method in <5% with no HOFox and 30%
(αꢀonly along with the corresponding 1,2ꢀorthoester) with 25
mol % HOFox as a clear film. The analytical data for the title
compound was in accordance to that reported previously.16
(29) Adinolfi, M.; Barone, G.; Guariniello, L.; Iadonisi, A.
Tetrahedron Lett. 2000, 41, 9005.
(30) Du, Y.; Wei, G.; Linhardt, R. J. Tetrahedron Lett. 2003, 44, 6887.
(31) Weïwer, M.; Sherwood, T.; Linhardt, R. J. J. Carbohydr. Chem.
2008, 27, 420.
(32) Wang, C.; Sanders, B.; Baker, D. C. Can. J. Chem. 2011, 89, 959.
(33) Kaeothip, S.; Yasomanee, J. P.; Demchenko, A. V. J. Org. Chem.
2012, 77, 291.
(34) Ranade, S. C.; Kaeothip, S.; Demchenko, A. V. Org. Lett. 2010,
12, 5628.
(35) Sail, D.; Kovac, P. Carbohydr. Res. 2012, 357, 47.
(36) Lemieux, R. U. In Methods in Carbohydrate Chemistry; Whistler,
R. L., Wolform, M. L., Eds.; Academic Press Inc.: New York and
London, 1963; Vol. 2, p 226.
(37) Nigudkar, S. S.; Wang, T.; Pistorio, S. G.; Yasomanee, J. P.;
Stine, K. J.; Demchenko, A. V. Org. Biomol. Chem. 2017, 15,
348.
(38) Kamat, M. N.; Demchenko, A. V. Org. Lett. 2005, 7, 3215.
(39) Mydock, L. K.; Kamat, M. N.; Demchenko, A. V. Org. Lett.
2011, 13, 2928.
(40) Bandara, M. D.; Yasomanee, J. P.; Demchenko, A. V. In Selective
Glycosylations: Synthetic Methods and Catalysts; Bennett, C. S.,
Ed.; Wiley: 2017, p 29.
(41) Baek, J. Y.; Lee, B.ꢀY.; Pal, R.; Lee, W.ꢀY.; Kim, K. S.
Tetrahedron Lett. 2010, 51, 6250.
(42) Zhang, F.; Zhang, W.; Zhang, Y.; Curran, D. P.; Liu, G. J. Org.
Chem. 2009, 74, 2594.
(43) Mishra, B.; Neralkar, M.; Hotha, S. Angew. Chem. Int. Ed. 2016,
55, 7786.
(44) Bandara, M. D.; Yasomanee, J. P.; Rath, N. P.; Pedersen, C. M.;
Bols, M.; Demchenko, A. V. Org. Biomol. Chem. 2017, 15, 559.
(45) Kowalska, K.; Pedersen, C. M. Chem. Commun. 2017, 53, 2040.
(46) Pornsuriyasak, P.; Demchenko, A. V. Tetrahedron: Asymmetry
2005, 16, 433.
(47) Nicolaou, K. C.; Ueno, H. In Preparative Carbohydrate
Chemistry; Hanessian, S., Ed.; Marcel Dekker, Inc.: New York,
1997, p 313.
(48) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661.
(49) Smoot, J. T.; Demchenko, A. V. Adv. Carbohydr. Chem.
Biochem. 2009, 62, 161.
ASSOCIATED CONTENT
Supporting Information. H and 13C NMR spectra for all new
compounds have been supplied as the Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.”
1
AUTHOR INFORMATION
Corresponding Author
* Alexei V. Demchenko. Eꢀmail: demchenkoa@umsl.edu
Author Contributions
The manuscript was written through contributions of all authors. /
All authors have given approval to the final version of the manuꢀ
script.
Funding Sources
This work was supported by grants from the National Institute of
General Medical Sciences (GM111835 and GM120673).
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