A Highly Efficient Glycosidation of Glycosyl Chlorides by Using Cooperative Silver(I) Oxide–Triflic Acid Catalysis

Article abstract of DOI:10.1002/chem.201905576

Following our discovery that silver(I) oxide-promoted glycosylation with glycosyl bromides can be greatly accelerated in the presence of catalytic TMSOTf or TfOH, we report herein a new discovery that glycosyl chlorides are even more effective glycosyl do

Full text of DOI:10.1002/chem.201905576

A Journal of
Accepted Article
Title: A highly efficient glycosidation of glycosyl chlorides using
cooperative silver(I) oxide - triflic acid catalysis
Authors: scott geringer, yashapal singh, daniel hoard, and Alexei V.
Demchenko
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10.1002/chem.201905576
Chemistry - A European Journal
A highly efficient glycosidation of glycosyl chlorides using coopera-
tive silver(I) oxide - triflic acid catalysis
Scott A. Geringer, Yashapal Singh, Daniel J. Hoard, and Alexei V. Demchenko*
Department of Chemistry and Biochemistry, University of Missouri – St. Louis, One University Boulevard, St. Louis,
Missouri 63121, USA
ABSTRACT: Following our discovery that silver(I) oxide-promoted glycosylation with glycosyl bromides can be greatly acceler-
ated in the presence of catalytic TMSOTf or TfOH, reported herein is a new discovery that glycosyl chlorides are even more effec-
tive glycosyl donors under these reaction conditions. The developed reaction conditions work well with a variety of glycosyl chlo-
rides. Both benzoylated and benzylated chlorides were successfully glycosidated, and these reaction conditions were effective in
coupling substrates containing nitrogen and sulfur atoms. Another convenient feature of this glycosylation is that the progress of
this reaction can be monitored by eye, and the completion of the reaction can be judged by the disappearance of characteristic
dark color of Ag2O.
Introduction
cosyl chlorides can be activated with catalytic ferric chlo-
ride.[8] Glycosylation with benzylated donors under these be-
nign reaction conditions was typically completed in a couple
of hours. The activation of electronically deactivated, ben-
zoylated glycosyl chlorides could also be achieved with cata-
lytic ferric chloride. However, these glycosylations were rather
slow (16 h), and the yields remained moderate, typically within
a 60-80% range. Nevertheless, these results were a significant
improvement over other promoters and catalysts that previ-
ously failed to activate those unreactive substrates.
Glycosyl chlorides, once prominent glycosyl donors, have
helped shape the modern synthetic glycochemistry.[1] The
story of chemical glycosylation started with exploration of gly-
cosyl chlorides way back in the late 19th century by Michael.[2]
Those first glycosylations employed per-acetylated glycosyl
chloride as the glycosyl donor for reaction with phenoxide. A
notable advancement of glycosylations with chlorides was
made by Koenigs and Knorr who utilized simple alcohols as
glycosyl acceptors instead of charged nucleophiles.[1a] Those
reactions were conducted in the presence of silver salts as acid
scavengers because the active role of silver salts as promoters
of glycosylation was yet unknown. Only after extensive studies
over the following decades, scientists began appreciating that
silver salts are able to mediate glycosylation by helping disso-
ciate the anomeric carbon-halogen bonds.[3] However, activa-
tion of glycosyl halides commonly requires stoichiometric
amounts of expensive or toxic reagents such as silver(I)[1a, 4] or
mercury(II) salts.[5] Some halides are cumbersome to synthe-
size, store, and apply due to their proclivity to hydrolyze. As a
result, modern glycosyl donors, thioglycosides, trichloroace-
timidates, and others, outshadowed the application of glyco-
syl halides in glycan synthesis.
Over the course of our recent study with glycosyl bromides,
we discovered that slow silver-promoted glycosylations can be
dramatically accelerated in the presence of acid additives.
Thus, glycosylation in the presence of 2.0 equiv of silver(I) ox-
ide that typically requires many hours or even days to com-
plete, became very swift (5-15 min) upon addition of 0.20 equiv
of trimethylsilyl trifluoromethanesulfonate (TMSOTf).[9] An
effort dedicated to studying the reaction mechanism, made it
possible to reduce the amount of Ag2O to only 0.50 equiv and
replace TMSOTf with TfOH.[10] Although we achieved a signif-
icantly improved outcome of the Koenigs-Knorr-like glycosyl-
ation reactions, a few limitations and uncertainties remained.
First, glycosidation of bromide donors containing the nitrogen
atom such as derivatives of glucosamine were very slow and
provided poor yields. This limitation was presumably due to
the competing protonation of the nitrogen atom with TfOH
that led to partial deactivation of the donor. Second, lower re-
action rates and fair product yields were also seen with thio-
glycoside acceptors. This phenomenon was presumably due to
Recently, Ye et al.[6] and Jacobsen et al.[7] largely resurrected
glycosyl chlorides as glycosyl donors by demonstrating that
these compounds can be activated under organocatalytic con-
ditions with urea or thiourea-based catalysts, used along with
stoichiometric additives. We have recently reported that gly-
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10.1002/chem.201905576
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the competing interaction of silver oxide with the sulfur atom
that led to partial deactivation of the promoter system. Addi-
tionally, while glycosidation of supposedly deactivated, ben-
zoylated glycosyl bromides was swift and high-yielding, glyco-
sidation of benzylated glycosyl bromides was much slower
and hence much less efficient.
were equally impressive. Disaccharides 14 and 15 were ob-
tained in 98% and 91% yield, respectively, in 30 min (entries 3
and 4). As clearly evident from our results, we have not seen
any noticeable decline in reaction rates with sterically hin-
dered glycosyl acceptors. While 0.25 equiv TfOH worked uni-
versally for all acceptors investigated, some reactions could be
smoothly driven to completion using as little as 0.15 equiv of
TfOH (data is not shown). All glycosidations of chloride 1 were
completely 1,2-trans diastereoselective due to the assistance of
the neighboring participating group. As expected, glyco-
sidations of benzoylated glycosyl chloride 1 in the presence of
Ag2O only, standard Koenigs-Knorr reaction conditions, were
very sluggish, and only trace amounts of disaccharides were
observed after 48 h. The reaction did not proceed at all in the
presence of TfOH-only proving the cooperative catalysis na-
ture of the activation pathway.
To improve the outcome of this new reaction, we turned our
attention to investigating glycosyl chlorides as donors. Mech-
anistically, the activation of bromides and chlorides would be
similar. As proposed in our previous study, after initial inter-
action of the donor with Ag2O, the resulting species A produce
a strongly ionized species B due to interaction of TfOH
(Scheme 1). This intermediate will rapidly dissociate produc-
ing AgX that precipitates out of the solution. Also produced at
this stage is AgOH that loses water regenerating Ag2O. Water
is then scavenged by molecular sieves present in all of our re-
action. Depending on the protecting group at C-2, glycosyl
cation C will be stabilized either via an acyloxonium (2-O-ben-
zoyl) or oxacarbenium (2-O-benzyl) ion. The subsequent nu-
cleophilic attack of the glycosyl acceptor (ROH) occurs with
regeneration of TfOH that is available for the next catalytic
cycle. Since this reaction is driven by the irreversible for-
mation of the AgX bond, we reasoned that glycosyl chloride
activation would be favored by silver chloride formation.[11]
This could also minimize propensity of silver interact with
other heteroatoms in the system. Reported herein is our study
of glycosyl chlorides using the new acid-catalyzed Koenigs-
Knorr promoter system.
Figure 1. Standard glycosyl acceptors 4-7 and thioglyco-
side acceptors 8-11 used in this study
Scheme 1. Activation of glycosyl halides in the presence
of Ag2O/TfOH
Glycosylation of thioglycoside acceptor 8 also proceeded very
smoothly affording disaccharide 16 in 98% yield in 30 min (en-
try 5). This glycosylation reaction represents an important
strategic step because it encompasses selective activation of
one leaving group over another.[14] This approach is commonly
used in expeditious oligosaccharide synthesis[15] because di-
saccharide 16 can be used as the glycosyl donor for subsequent
chain elongation directly. However, glycosylation of thiogly-
coside acceptors was somewhat inefficient in our previous
studies with ferric chloride promoter[8] or with glycosyl bro-
mides as donors.[9-10] In addition, these glycosylations could be
prone to competing aglycone transfer reactions,[16] which was
not observed in this case.
Table 1. Glycosidation of benzoylated glycosyl chlorides
1-3 in the presence of Ag2O and TfOH
Results and Discussion
We first investigated glycosidation of benzoylated glycosyl
chlorides 1-3 (Table 1)[12] with a series of standard glycosyl ac-
ceptors 4-7 (Figure 1).[13] After preliminary screening of the re-
action conditions we determined that the activation of gluco-
syl chloride 1 with 0.50 equiv of silver(I) oxide and 0.25 equiv
of TfOH offers the best combination of rates and yields. As
listed in Table 1, glycosylation of primary acceptor 4 gave di-
saccharide 12 in 98% yield in 30 min (entry 1). These optimized
conditions compare very favorably with those used for the gly-
cosyl bromide activations, 0.50 equiv of silver(I) oxide and
0.35-0.40 equiv of TfOH.[10] Glycosylation of secondary accep-
tors 5-7 gave similar results. Thus, glycosylation of a relatively
unreactive 4OH acceptor 5 afforded disaccharide 13 in 90%
yield in 30 min (entry 2). Glycosylations of acceptors 6 and 7
Donor + Accep-
tor (TfOH equiv)
Entry
Product, Yielda
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1
1 + 4 (o.25)
13
3 + 4 (o.50)
12, 98%
13, 90%
24, 98%
2
3
1 + 5 (o.25)
1 + 6 (o.25)
14
15
3 + 5 (o.50)
3 + 6 (o.50)
25, 98%
26, 98%
14, 98%
15, 91%
4
5
1 + 7 (o.25)
1 + 8 (o.25)
16
3 + 7 (o.50)
27, 99%
a – all yields are isolated yields after column chromatography
16, 98%
With notable success with glucosyl donor 1, we turned our at-
tention to investigating benzoylated chlorides of the D-
galacto and D-manno series, 2 and 3, respectively. Glyco-
sidations of both mannosyl and galactosyl chlorides were
somewhat less efficient under the established reaction condi-
tions for glucosyl chloride 1, 0.50 equiv of silver(I) oxide and
0.25 equiv of TfOH. The reactions were slower, and remained
incomplete, even in prolonged experiments (16 h). After a brief
screening of the reaction conditions, we found that increasing
the amount of TfOH to 0.50 equiv is optimal for driving these
reactions to completion. As in case of glucosyl chloride 1, we
have achieved very effective, rapid, and high-yielding reac-
tions with both primary and secondary glycosyl acceptors. As
listed in Table 1, glycosylation of acceptors 4-7 with galactosyl
chloride 2, produced the respective disaccharides 17-20 in 30
min nearly quantitatively (99% yield in all experiments, en-
tries 6-9). A large-scale glycosylation using 1.0 gram of donor
2 and acceptor 5 was also performed. During this experiment
glycosyl acceptor 5 was completely consumed and disaccha-
ride 18 was obtained in 83% yield.
6
2 + 4 (o.50)
17, 99%
18, 99%
7
2 + 5 (o.50)
2 + 6 (o.50)
8
19, 99%
20, 99%
12
9
2 + 7 (o.50)
2 + 9 (0.50)
To elaborate on our previous success with glycosylating thio-
glycoside acceptor 8 (see entry 5) we investigated other thio-
glycoside acceptors 9-11.[17] Glycosylations of primary thiogly-
coside acceptors 9 and 10 with galactosyl chloride 2 gave
promising results producing the respective disaccharides 21
and 22 in 73-75% yields in 30 min. Glycosylation of a less reac-
tive secondary acceptor 11 led to disaccharide 23 in a moderate
yield of 60% in 1 h. The lower yield, in part, can be attributed
to small amounts of a by-product resulting from a competing
aglycone transfer reaction.[16] Nevertheless, this result favora-
bly compares to inefficient glycosylations of thioglycoside ac-
ceptors in our previous studies with glycosyl bromides as do-
nors.[9-10]
21, 73%
10
11
2 + 10 (0.50)
2 + 11 (0.50)
22, 75%
23, 60%
A very similar outcome was achieved with mannosyl donor 3.
Thus, glycosylation of acceptors 4-7 afforded the correspond-
ing disaccharides 24-27 in 30 min in 98-99% yield (entries 10-
13). These glycosylations were also 1,2-trans selective, and β-
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galactosides and α-mannosides were all obtained with com-
plete diastereoselectivity. As evident from the product yields,
these glycosylations are spot-to-spot, and are practically free
of by-products beyond trace amounts of hemiacetal resulting
from hydrolysis of the donor and 11-linked disaccharide re-
sulting from glycosylation of the hemiacetal. While 0.50 equiv
TfOH worked universally for all acceptors investigated, some
reactions with galactosyl and mannosyl chlorides could be
smoothly driven to completion using as little as 0.25 equiv of
TfOH.
in 30 min (α/β = from 1.3/1 to α-only, entries 9-12). We note
that some reactions between galactosyl and mannosyl chlo-
rides and reactive acceptors could be smoothly driven to com-
pletion using as little as 0.25 equiv of TfOH.
Table 2. Glycosidation of benzylated glycosyl chlorides
28-30 in the presence of Ag2O and TfOH
Having obtained excellent results with all per-benzoylated
chlorides, we turned our attention to investigating per-ben-
zylated chlorides 28-30 (Table 2).[8, 12a-c, 18] It is well established
that the building block reactivity and stereoselectivity can be
modulated through the choice of protecting groups.[19] Ac-
cording to Fraser-Reid’s seminal work on the armed-disarmed
strategy, benzylated (electronically activated, armed) building
blocks are more reactive than their acylated (Bz, disarmed)
counterparts.[20] Our recent discovery that benzylated glycosyl
bromide does not follow this trend when activated in the pres-
ence of Ag+/TMSOTf or TfOH was striking.[9-10] The observed
lower reactivity of benzylated glycosyl bromides resulted in
reduced yields and their glycosidations required longer reac-
tion times to complete.
Donor + Accep-
Product, yield,a ratio
Entry
tor (TfOH
equiv)
α/β
Therefore, investigation of benzylated glycosyl chlorides un-
der these reaction conditions appealed to us more than just
broadening the scope of the methodology. A reaction between
glycosyl donor 28 and primary glycosyl acceptor 4 in the pres-
ence of 0.50 equiv of silver(I) oxide and 0.25 equiv of TfOH
afforded disaccharide 31 in 97% yield is only 30 min (α/β = 1.1/1,
Entry 1, Table 2). This result was quite pleasing, particularly in
the light of results previously achieved with the respective glu-
cosyl bromide under similar reaction conditions (18 h, 46%).[9]
The outcome of this reaction also indicates no particular reac-
tivity difference between benzoylated and benzylated chlo-
rides under these reaction conditions. No reactivity difference
was verified by a direct competition experiment between do-
nors 1 and 28. However, it is possible that reducing the equiv-
alence of TfOH or modulating other factors could lead to re-
action conditions under which the reactivity difference could
be observed. Glycosylation of secondary glycosyl acceptors 5-
7 with donor 28 was equally impressive. The corresponding
disaccharides 32-34 were obtained in 95-99% yield in 30 min
(α/β = 1.3-1.5 /1, entries 2-4).
1
28 + 4 (o.25)
28 + 5 (o.25)
31, 97%, α/β = 1.1/1
32, 99%, α/β = 1.5/1
2
3
28 + 6 (o.25)
28 +7 (0.25)
33, 99%, α/β = 1.3/1
34, 95%, α/β = 1.5/1
4
With a notable success with glucosyl donor 28, we turned our
attention to investigating benzylated chlorides of the D-
galacto and D-manno series, 29 and 30, respectively. Again, a
majority of glycosidations of galactosyl and mannosyl chlo-
rides in the presence of 0.25 equiv of TfOH were somewhat
slower, practically stalled after 30 min, and remained incom-
plete even after 16 h. Like in the case of benzoylated chlorides
of these series, increasing the amount of TfOH to 0.50 equiv
was found to be optimal for driving all of these reactions to
completion. Very effective, rapid, and high-yielding reactions
we achieved with both primary and secondary glycosyl accep-
tors. As listed in Table 2, glycosylation of acceptors 4-7 with
galactosyl chloride 29 afforded the respective disaccharides
35-38 in 30 min nearly quantitatively (99% yield in all experi-
ments, α/β = 1.2-4.9/1, entries 5-8). Similarly, glycosylation of
acceptors 4-7 with mannosyl chloride 29 produced the corre-
sponding disaccharides 39-42 in 98% yield in all experiments
5
29+ 4 (0.50)
29 + 5 (0.50)
35, 99%, α/β = 1.2/1
36, 99%, α/β = 2.4/1
6
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First test reaction with 2-phthalimido chloride donor 43
showed that the promoter deactivation could also be the case
with glycosyl chlorides. Reactions with 0.50 or even 1.0 equiv
of Ag2O were incomplete and led to lower product yields. Fur-
ther optimization of our reaction conditions in application to
glycosidation of N-phthaloyl protected glucosamine chloride
43 showed the necessity to increase the amount of Ag2O to 1.50
equiv, whereas 0.50 equiv of TfOH was sufficient. Under these
modified reaction conditions, glycosidation of glycosyl donor
43 with primary acceptor 4 gave disaccharide 46 in 97% yield
in 30 min (entry 1, Table 3). Glycosylations of secondary glyco-
syl acceptors 5-7 with donor 43 were somewhat less efficient.
The corresponding disaccharides 47-49 were obtained in com-
mendable yields of 68-76% in 30 min (entries 2-4). These gly-
cosylations were all completely 1,2-trans stereoselective due to
the participation of the 2-phthalimido group. Prolonged ex-
periments (beyond standard 30 min) did not help to achieve
higher yields.
7
29 + 6 (0.50)
29 + 7 (0.50)
37, 99%, α/β = 2.4/1
38, 99%, α/β = 4.9/1
8
9
30 + 4 (0.50)
30 + 5 (0.50)
Lastly, we investigated glycosidation of sialyl chlorides. Unfor-
tunately, reaction between sialyl donor 44 and galactosyl ac-
ceptor 50 only produced disaccharide 51 in trace amounts,
even in the presence of 2.0 equiv sialyl donor 44 and up to 2
equiv of Ag2O (to donor, entry 5, Table 3). Having attributed
this result to the deactivating nature of the acetamido moi-
ety[24] we turned to investigating the N-acetylacetamido donor
45 because this type of protection is known to enhance the
reactivity of sialyl donors.[25] Glycosylation between 45 (2.0
equiv) and 50 was conducted in the presence of 2.0 equiv Ag2O
and 0.50 equiv TfOH (to donor 45). To prevent competing
eliminations that hamper many types of sialylation reactions,
the reaction was started at -78 °C and after 2 h the reaction
was allowed to slowly warm to rt. As a result, we obtained di-
saccharide 52 in 97% yield in 24 h (α/β = 1/1.7, entry 6). This
result is on a par or even surpasses those obtained with mod-
ern sialyl donors.[23b]
39, 98%, α/β = 1.3/1
10
40, 98%, α only
41, 98%, α only
11
30 + 6 (0.50)
30 + 7 (0.50)
12
Table 3. Glycosidation of 2-phthalimido chloride 43 and
sialyl chlorides 44 and 45 with glycosyl acceptors 4-7 or
50 in the presence of Ag2O and TfOH
42, 98%, α/β =3.6/1
a – all yields are isolated yields after column chromatography
Having obtained excellent results with all per-benzoylated
and per-benzylated chlorides of neutral sugars, we turned our
attention to investigating N-phthaloyl protected glucosamine
chloride 43 (Table 3). This was of particular interest because
previous attempts to glycosidate glucosamine bromides re-
sulted in poor yields and long reaction times. As aforemen-
tioned, this was attributed to the competing protonation of
the nitrogen atom that led to partial deactivation of the donor,
and further attempts to glycosidate glucosamine bromides
were ceased. It has become a common knowledge that 2-ami-
nosugars may have a very different reactivity profile in com-
parison to their neutral sugar counterparts.[21] Glycosidation of
aminosugars often requires different methods specifically de-
signed for these substrates. We also included sialyl chlorides
44 and 45 (Table 3).[22] Being a common aminosugar in mam-
malian and microbial glycans, sialic acids represent a special
case of glycosylation that spans beyond effects of the amino
group functionality.[23] The chemical synthesis of α-sialosides
is considered challenging, and mild methods enhancing the
product yields and suppressing common side reactions (elim-
ination and hydrolysis) are needed.
Donor + Acceptor
(Ag2O equiv)
Product, yield,a ratio
Entry
α/β
1
43 + 4 (1.5)
43 + 5 (1.5)
46, 97%
2
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Chemistry - A European Journal
47, 76%
rotations were measured using a Jasco polarimeter. 1H-NMR
spectra were recorded in CDCl3 at 300 or 600 MHz, 13C-NMR
spectra were recorded in CDCl3 at 75 or 151 MHz. Accurate
mass spectrometry determinations were preformed using Ag-
ilent 6230 ESI TOF LCMS mass spectrometer
3
43 +6 (1.5)
43 +7 (1.5)
48, 72%
49, 68%
Synthesis of Glycosyl Donors
2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl chloride (1)
was obtained from 2,3,4,6-tetra-O-benzoyl-D-glucopyra-
nose[26] as described previously,[8] and its analytical data for
were the same as those reported previously.[12a, b]
4
2,3,4,6-Tetra-O-benzoyl-α-D-galactopyranosyl chloride
(2). Thionyl chloride (294 mg, 2.47 mmol) was added drop-
wise to a solution of 2,3,4,6-tetra-O-benzoyl-D-galactopyra-
nose[27] (705 mg, 1.24 mmol) in 1,2-dichloroethane (10 mL) con-
taining N,N-dimethylformamide (0.5 mL) and the resulting
mixture was stirred under argon for 20 min at 0 °C. After that,
the volatiles were removed under reduced pressure. The resi-
due was dissolved in a mixture of ethyl acetate/hexane (25 mL,
1/1, v/v) and filtered through a pad of silica gel (10 g). The pad
of silica gel was additionally eluted with a mixture of ethyl ac-
etate and hexane (75 mL, 1/1, v/v) and the combined eluate was
concentrated in vacuo to afford the title compound as color-
less foam in 94% yield (681 mg, 1.11 mmol). Analytical data for
2 were essentially the same as reported previously.[12c]
5b
44 + 50 (2.0)
45 + 49 (2.0)
51, traces
6b
52, 97%, α/β = 1/1.7
a – all yields are isolated yields after column chromatography;
b - performed at –72 oC (2 h), then at rt for 22 h
2,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl chloride
(3). A mixture of oxalyl chloride (820 mg, 1.48 mmol) in di-
chloromethane (6.0 mL) and added dropwise to a solution of
2,3,4,6-tetra-O-benzoyl-D-mannopyranose[28] (1.28 g, 2.15
mmol) in dichloromethane (20 mL) containing N,N-dimethyl-
formamide (0.7 mL) and the resulting mixture was stirred un-
der argon for 1.5 h at 0 °C. After that, the volatiles were re-
moved under reduced pressure. The residue was dissolved in
a mixture of ethyl acetate/ hexane (30 mL, 1/1, v/v) and filtered
through a pad of silica gel (15 g). The pad of silica gel was ad-
ditionally eluted with a mixture of ethyl acetate and hexane
(90 mL, 1/1, v/v) and the combined eluate was concentrated in
vacuo to afford the title compound as colorless foam in 94%
yield (1.19 g, 1.77 mmol). Analytical data for 3 were essentially
the same as that reported previously.[29]
In conclusion, this study showed how glycosyl chlorides can
be activated in a similar manner as glycosyl bromides using
0.50 equiv of Ag2O and 0.25-0.50 equiv of TfOH. Efficient gly-
cosylations of benzoylated glucosyl, galactosyl, and mannosyl
chlorides have all been performed with a variety of differently
protected primary and secondary acceptors providing high
yields and fast reaction times. Furthermore, glycosidations of
benzylated glucosyl, galactosyl, and mannosyl chlorides have
been performed with similar efficiency. Lastly, nitrogen con-
taining glucosamine and sialic acid chlorides were also suc-
cessfully glycosidated, but these reactions required excess sil-
ver oxide. Another convenient feature of this glycosylation is
that the progress of this reaction can be monitored by eye, and
the completion of the reaction can be judged by the disappear-
ance of characteristic dark color of Ag2O. This is because since
only the minimal amount of Ag2O is used to catalyze this re-
action, it gets entirely converted in AgCl, which is a white crys-
talline solid. Attempts to improve the stereoselectivity of gly-
cosidation of glycosyl bromides and chlorides using the silver
salts and TfOH promoter system are currently underway in
our laboratory.
2,3,4,6-Tetra-O-benzyl-α-D-glucopyranosyl chloride (28)
was obtained from 2,3,4,6-tetra-O-benzyl-D-glucopyranose[30]
as described previously,[8] and its analytical data for were the
same as those reported previously.[12b]
2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl
chloride
(29) was obtained from 2,3,4,6-tetra-O-benzyl-D-galactopyra-
nose[31] as described previously,[8] and its analytical data were
the same as those reported previously.[12c]
Experimental
2,3,4,6-Tetra-O-benzyl-α-D-mannopyranosyl
chloride
General. Column chromatography was performed on silica gel
60 (70-230 mesh), reactions were monitored by TLC on Kie-
selgel 60 F254. The compounds were detected by examination
under UV light and by charring with 10% sulfuric acid in meth-
anol. Solvents were removed under reduced pressure at <40
°C. CH2Cl2 and ClCH2CH2Cl (1,2-DCE) were distilled from
CaH2 directly prior to application. Pyridine was dried by re-
fluxing with CaH2 and then distilled and stored over molecular
sieves (3 Å). Anhydrous DMF was used as it is. Molecular
sieves (3 Å or 4 Å), used for reactions, were crushed and acti-
vated in vacuo at 390 °C during 8 h in the first instance and
then for 2-3 h at 390 °C directly prior to application. Optical
(30) was obtained from 2,3,4,6-tetra-O-benzyl-D-mannopyra-
nose[32] as described previously,[8] and its analytical data were
the same as those reported previously.[18b]
3,4,6-Tri-O-benzoyl-2-deoxy-2-phthalimido-β-D-gluco-
pyranosyl chloride (43). Thionyl chloride (0.45 g, 3.76
mmol) was added dropwise to a solution of 3,4,5-tri-O-
benzoyl-2-deoxy-2-phthalimido-D-glucopyranose[33] (1.17 g,
1.88 mmol) in dichloroethane (70 mL) containing DMF (5.0
mL) and the resulting mixture was stirred under argon for 1 h
at 0 °C. The volatiles were then removed under reduced
pressure. The residue was dissolved in a mixture of ethyl
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10.1002/chem.201905576
Chemistry - A European Journal
acetate/ hexane (50 mL, 1/1, v/v) and passed through a pad of
silica gel (25 g). The pad of silica gel was additionally eluted
with a mixture of ethyl acetate/ hexane (75 mL, 1/1, v/v) and
the combined eluate was concentrated under reduced
pressure to afford the title compound as a white foam in 87%
yield (1.05 g, 1.64 mmol). Analytical data for 43: Rf = 0.70 (ethyl
acetate/hexane, 1/1, v/v); [α]D21 61.3 (c 3.2, CHCl3); 1H NMR (300
MHz, CDCl3): δ 8.07 (d, J = 7.6 Hz, 2H, aromatic), 7.95 – 7.65
(m, 8H, aromatic), 7.62 – 7.39 (m, 5H, aromatic), 7.38 – 7.19
obtained from donor 1 and acceptor 5[13a] under the general
glycosylation method as a colorless foam in 90% yield. Analyt-
ical data for 13 was in accordance with that previously re-
ported.[36]
Methyl
3-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyra-
nosyl)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (14) was
obtained from donor 1 and acceptor 6[13a] under the general
glycosylation method as a colorless foam in 98% yield. Analyt-
ical data for 14 was in accordance with that previously re-
ported.[13a]
(m, 4H, aromatic), 6.41 (d, J1,2 = 9.3 Hz, 1H, H-1), 6.29 (dd, J3,4
9.7 Hz, 1H, H-3), 5.81 (dd, J4,5 =10.1 Hz, 1H, H-4), 4.80 (dd, J2,3
=
=
9.9 Hz, 1H, H-2), 4.68 (dd, J6a,6b = 12.4, 1H, H-6a), 4.53 (dd, 1H,
H-6b), 4.38 (m, J5,6a = 2.5 Hz, J5,6b = 4.8 Hz, 1H, H-5) ppm; 13C
NMR (75 MHz, CDCl3): δ 166.2, 165.6, 165.1, 134.5, 133.6, 133.5,
133.3, 131.2, 129.9 (x4), 129.8 (x3), 129.5, 128.5 (x7), 128.4 (x3),
128.3, 123.9 (x2), 85.8, 76.0, 71.0, 69.3, 62.8, 57.8 ppm; HRMS
[M+Na]+ calcd for C35H26ClNO9Na 662.1188, found 662.1201.
Methyl
2-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyra-
nosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (15) was
obtained from donor 1 and acceptor 7[13a] under the general
glycosylation method as a colorless foam in 91% yield. Analyt-
ical data for 15 was in accordance with that previously re-
ported.[37]
Methyl (4,7,8,9-tetra-O-acetyl-5-acetamido-3,5-dideoxy-
Ethyl 6‐O‐(2,3,4,6‐tetra‐O‐benzoyl‐β‐D‐glucopyranosyl)‐
2,3,4‐tri‐O‐benzoyl‐1‐thio‐β‐D‐glucopyranoside (16) was
obtained from donor 1 and acceptor 8[13b] under the general
glycosylation method as a colorless foam in 98% yield. Analyt-
ical data for 16 was in accordance with that previously re-
ported.[38]
β-D-glycero-D-galacto-non-2-ulopyranosyl
chlo-
ride)onate (44) was obtained from methyl (2,4,7,8,9-penta-
O-acetyl-5-acetamido-3,5-dideoxy-D-glycero-D-galacto-non-
2-ulopyranos)onate[34] as described previously,[22a] and its an-
alytical data was in accordance with that previously re-
ported.[22b]
Methyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (17) was
obtained from donor 2 and acceptor 4 under the general gly-
cosylation method as a colorless foam in 99% yield. Analytical
data for 17 was in accordance with that previously reported.[39]
Methyl (4,7,8,9-tetra-O-acetyl-5-(N-acetyl)acetamido-3,5-
dideoxy-β-D-glycero-D-galacto-non-2-ulopyranosyl
chloride)onate (45) was obtained from methyl (2,4,7,8,9-
penta-O-acetyl-5-(N-acetyl)acetamido-3,5-dideoxy-D-glyc-
ero-D-galacto-non-2-ulopyranos)onate[35] as described previ-
ously, and its analytical data was in accordance with that pre-
viously reported.[22c]
Methyl
4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
nosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (18) was
obtained from donor 2 and acceptor 5 under the general gly-
cosylation method as a colorless foam in 99% yield. Analytical
data for 18 was in accordance with that previously reported.[37]
Synthesis of Disaccharides
General procedure for glycosylations in the presence of
Ag2O and TfOH. A mixture of a glycosyl donor (0.05 mmol),
glycosyl acceptor (0.035 mmol), and freshly activated
molecular sieves (3 Å, 150 mg) in CH2Cl2 (1.0 mL) was stirred
under argon for 1 h at rt. The mixture was cooled to 0 °C, Ag2O
(0.025 mmol) was added and the resulting mixture was stirred
under argon for 10 min at 0 °C. TfOH (0.25 or 0.50, see Tables)
was added and the reaction mixture was stirred under argon
for 30 min at 0 °C. After that, the solid was filtered off and
washed sucessively with CH2Cl2. The combined filtrate (~40
mL) was washed with saturated aq. NaHCO3. (10 mL). The
organic phase was separated, dried with magnesium sulfate,
and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (ethyl acetate – toluene
gradient elution) to afford the respective disaccharides in
yields and stereoselectivites listed in Tables and below.
Anomeric ratios (or anomeric purity) were determined by
comparison of the integral intensities of relevant signals in 1H
NMR spectra.
Methyl
3-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
nosyl)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (19) was
obtained from donor 2 and acceptor 6 under the general gly-
cosylation method as a colorless foam in 99% yield. Analytical
data for 19 was in accordance with that previously reported.[40]
Methyl
2-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
nosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (20) was
obtained from donor 2 and acceptor 7 under the general gly-
cosylation method as a colorless foam in 99% yield. Analytical
data for 20 was in accordance with that previously reported.[40]
Tolyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
nosyl)-2,3,6-tri-O-benzoyl-1-thio-β-D-glucopyranoside
(21) was obtained from donor 2 and acceptor 9[17a] under the
general glycosylation method as a colorless foam in 73% yield.
Analytical data for 21: Rf = 0.72 (ethyl acetate/toluene, 1/4,
v/v); [α]D 63.6 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ
8.06 (m, 4H, aromatic), 7.94 (m, 4H, aromatic), 7.87 – 7.69 (m,
23
1
6H, aromatic), 7.67 – 7.04 (m, 26H, aromatic), 6.00 (dd, J4’,5’
=
Methyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyra-
3.1 Hz, 1H, H-4’), 5.81 (dd, J2’,3’ = 8.0 Hz, 1H, H-2’), 5.74 (dd, J4,5
= 9.5 Hz, 1H, H-4), 5.58 (dd, J3’,4’ = 10.4 Hz, 1H, H-3’), 5.30 (dd,
J2,3 = 9.7 Hz, 1H, H-2), 5.26 (dd, J3,4 = 9.4 Hz, 1H, H-3), 5.03 (d,
J1’,2’ = 8.0 Hz, 1H, H-1’), 4.80 (d, J1,2 = 9.9 Hz, 1H, H-1), 4.60 (dd,
1H, H-6b’), 4.39 (dd, J6a’,6b’ = 11.2 Hz, 1H, H-6a’), 4.28 (dd, J5’,6a'
= 6.6, J5’,6b’ = 6.4Hz, 1H, H-5’), 4.12 – 3.91 (m, 3H, H-5, 6a, 6b),
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (12) was
obtained from donor 1 and acceptor 4[13a] under the general
glycosylation method as a colorless foam in 98% yield. Analyt-
ical data for 12 was in accordance with that previously re-
ported.[36]
1
3
2.30 (s, 3H, CH3) ppm; C NMR (75 MHz, CDCl3): δ 166.1, 165.7,
165.6, 165.4 (x2), 165.0, 138.9, 134.0 (x2), 133.6 (x2), 133.4, 133.3
Methyl
4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyra-
nosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (13) was
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10.1002/chem.201905576
Chemistry - A European Journal
(x3), 130.1 (x3), 129.9 (x6), 129.8 (x3), 129.4 (x2), 129.3, 129.0,
128.8 (x2), 128.7 (x2), 128.6 (x5), 128.5 (x4), 128.4 (x6), 128.3 (x4),
127.5, 101.6, 85.9, 78.7, 74.1, 71.8, 71.4, 70.4, 69.7, 69.4, 68.3, 68.1,
61.9, 21.2 ppm; HRMS [M+Na]+ calcd for C68H56O17SNa
1199.3130, found 1199.3150.
Methyl
3-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyra-
nosyl)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (26) was
obtained from donor 3 and acceptor 6 under the general gly-
cosylation method as a colorless foam in 98% yield. Analytical
data for 26 was in accordance with that previously reported.[41]
Phenyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
Methyl
2-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyra-
nosyl)-2,3,4-tri-O-benzyl-1-thio-β-D-glucopyranoside
(22) was obtained from donor 2 and acceptor 10[17b] under the
general glycosylation method as a colorless foam in 75% yield.
Analytical data for 22: Rf = 0.73 (ethyl acetate/toluene, 1/4,
nosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (27) was
obtained from donor 3 and acceptor 7 under the general gly-
cosylation method as a colorless foam in 98% yield. Analytical
data for 27 was in accordance with that previously reported.[41]
23
1
v/v); [α]D 55.6 (c 1.0, CHCl3); H NMR (300 MHz, CDCl3): δ
8.07 (m, 4H, aromatic), 7.82 (m, 4H, aromatic), 7.69 – 7.02 (m,
32H, aromatic), 5.97 (dd, J4’,5’ = 3.0 Hz, 1H, H-4’), 5.85 (dd, J2’,3’
= 10.3 Hz, 1H, H-2’), 5.53 (dd, J3’,4’ = 3.3 Hz, 1H, H-3’), 4.88 (d,
J1’,2’ = 7.8 Hz, 1H, H-1’), 4.78 (dd, 2J = 10.6 Hz, 2H, CH2Ph), 4.71
(dd, 2J = 10.6 Hz, 2H, CH2Ph) 4.65 (dd, 1H, H-6b’) 4.63 (dd, 2J
= 11.0 Hz, 2H, CH2Ph) 4.62 (dd, J2,3 = 9.6 Hz, 1H, H-2), 4.44 (d,
J1,2 = 10.1 Hz, 1H, H-1), 4.41 (dd, J6a’,6b’ = 7.0 Hz, 1H, H-6a’), 4.22
(dd, 1H, H-6b), 4.20 (dd, 1H, H-5’), 3.89 (dd, J6a,6b = 11.4, 1H, H-
6a), 3.61 (dd, J3,4 = 8.7 Hz, 1H, H-3), 3.49 (m, J5,6a = J5,6b = 4.6
Hz, 1H, H-5), 3.43 (dd, J4,5 = 8.2 Hz, 1H, H-4), 3.40 (dd, J2,3 = 9.1
Hz, 1H, H-2) ppm; 13C NMR (75 MHz, CDCl3): δ 166.1, 165.6,
165.2, 138.3, 138.0, 137.8, 133.6, 133.4 (x2), 133.2 (x2), 130.1, 129.9
(x4), 129.8, 129.5, 129.3, 129.2 (x2), 129.1 (x3), 128.8, 128.7 (x2),
128.6 (x2), 128.5 (x6), 128.4 (x4), 128.3 (x5), 128.0, 127.9 (x2),
127.8 (x2), 125.4, 101.3, 87.2, 86.6, 80.4, 78.9 (x2), 77.4, 75.8, 75.5,
75.0, 71.8, 71.3, 69.7, 68.1, 67.5, 61.9, 21.5 ppm; HRMS [M+Na]+
calcd for C67H60O14SNa 1143.3596, found 1043.3608.
Methyl
2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-glucopyranosyl)-α-D-glucopyranoside (31) was ob-
tained from donor 28 and acceptor 4 under the general glyco-
sylation method as a colorless foam in 97% yield (α/β = 1.1/1).
Analytical data for 31 was in accordance with that previously
reported.[42]
Methyl
2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-glucopyranosyl)-α-D-glucopyranoside (32) was ob-
tained from donor 28 and acceptor 5 under the general glyco-
sylation method as a colorless foam in 99% yield (α/β = 1.5/1).
Analytical data for 32 was in accordance with that previously
reported.[43]
Methyl
2,4,6-tri-O-benzyl-3-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-glucopyranosyl)-α-D-glucopyranoside (33) was ob-
tained from donor 28 and acceptor 6 under the general glyco-
sylation method as a colorless foam in 99% yield (α/β = 1.3/1).
Analytical data for 33 was in accordance with that previously
reported.[44]
Ethyl
4-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyra-
nosyl)-2,3,6-tri-O-benzyl-1-thio-β-D-glucopyranoside
(23) was obtained from donor 2 and acceptor 11[17c] under the
general glycosylation method as a colorless foam in 60% yield.
Analytical data for 23: Rf = 0.70 (ethyl acetate/toluene, 1/4,
Methyl
3,4,6-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-glucopyranosyl)-α-D-glucopyranoside (34) was ob-
tained from donor 28 and acceptor 7 under the general glyco-
sylation method as a colorless foam in 95% yield (α/β = 1.5/1).
Analytical data for 34 was in accordance with that previously
reported.[45]
23
v/v); [α]D 3.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3): δ
8.10-7.7o (m, 8H, aromatic), 7.65 – 7.04 (m, 27H, aromatic),
5.86 (br. d, 1H, H-4’), 5.72 (dd, J2’,3’ = 8.5 Hz, 1H, H-2’), 5.39 (dd,
2
J3’,4’ = 3.2 Hz, 1H, H3’), 5.07 (dd, J = 11.1 Hz, 2H, CH2Ph), 4.97
Methyl
2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-
2
(d, J1’,2’ = 7.9 Hz, 1H, H-1’), 4.77 (dd, J = 10.3 Hz, 2H, CH2Ph),
α/β-D-galactopyranosyl)-α-D-glucopyranoside (35) was
obtained from donor 29 and acceptor 4 under the general gly-
cosylation method as a colorless foam in 99% yield (α/β =
1.2/1). Analytical data for 35 was in accordance with that pre-
viously reported.[46]
2
4.55 (dd, J = 10.0 Hz, 2H, CH2Ph), 4.40 (dd, 1H, H-6b’), 4.38
(d, J1,2 = 11.6 Hz, 1H, H-1), 4.19 (dd, J6a,6b = 9.4 Hz, 1H, H-6a’) 4.14
(dd, J4,5 = 9.4 Hz, H-4), 3.94 (m, J5’,6a = J5’,6b = 6.6 Hz, 1H, H-5’),
3.75-3.54 (m, 3H, H-3, 6a, 6b), 3.41 (dd, J2,3 = 9.2 Hz, 1H, H-2),
3.24 (dd, 1H, H-5), 2.78 – 2.56 (m, 2H, SCH2CH3), 1.28 (t, J = 7.0
Hz, 3H, SCH2CH3) ppm; 13C NMR (151 MHz, CDCl3): δ 165.8,
165.4 (x2), 164.9, 139.0, 138.1, 138.0, 133.4 (x2), 133.3, 133.2, 129.8
(x5), 129.7 (x2), 129.6 (x2), 129.5, 129.1, 129.0, 128.8, 128.6 (x2),
128.5 (x3), 128.4 (x2), 128.3 (x2), 128.2 (x3), 128.1 (x2), 128.0 (x2),
127.7, 127.3 (x2), 100.3, 85.1, 84.4, 81.0, 78.6, 76.5, 75.5, 75.3, 73.5,
71.8, 71.1, 70.4, 67.9 (x2), 61.4, 24.8, 15.1 ppm; HRMS [M+Na]+
calcd for C63H60O14SNa 1095.3596, found 1095.3609.
Methyl
2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-galactopyranosyl)-α-D-glucopyranoside (36) was
obtained from donor 29 and acceptor 5 under the general gly-
cosylation method as a colorless foam in 99% yield (α/β =
2.4/1). Analytical data for 36 was in accordance with that pre-
viously reported.[47]
Methyl
2,4,6-tri-O-benzyl-3-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-galactopyranosyl)-α-D-glucopyranoside (37) was
obtained from donor 29 and acceptor 6 under the general gly-
cosylation method as a colorless foam in 99% yield (α/β =
2.4/1). Analytical data for 37 was in accordance with that pre-
viously reported.[48]
Methyl
6-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyra-
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (24) was
obtained from donor 3 and acceptor 4 under the general gly-
cosylation method as a colorless foam in 98% yield. Analytical
data for 24 was in accordance with that previously reported.[37]
Methyl
3,4,6-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-
Methyl
4-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyra-
α/β-D-galactopyranosyl)-α-D-glucopyranoside (38) was
obtained from donor 29 and acceptor 7 under the general gly-
cosylation method as a colorless foam in 99% yield (α/β =
4.9/1). Analytical data for 38 was in accordance with that pre-
viously reported.[49]
nosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (25) was
obtained from donor 3 and acceptor 5 under the general gly-
cosylation method as a colorless foam in 98% yield. Analytical
data for 25 was in accordance with that previously reported.[36]
This article is protected by copyright. All rights reserved.

10.1002/chem.201905576
Chemistry - A European Journal
Methyl
2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-
matic), 7.53 – 7.37 (m, 3H, aromatic,), 7.37 – 7.20 (m, 15H, aro-
matic), 7.20 – 7.10 (m, 6H, aromatic), 6.43 (dd, J3’,4’ = 9.6 Hz,
1H, H-3’), 6.01 (d, J1’,2’ = 8.3 Hz, 1H, H-1’), 5.70 (dd, 1H, H-4’),
α/β-D-mannopyranosyl)-α-D-glucopyranoside (39) was
obtained from donor 30 and acceptor 4 under the general gly-
cosylation method as a colorless foam in 98% yield (α/β =
1.3/1). Analytical data for 39 was in accordance with that pre-
viously reported.[50]
2
2
5.06 (d, J = 11.2 Hz, 1H, CHPh), 4.86 (dd, J = 12.6 Hz, 2H,
CH2Ph), 4.61 (dd, J2’,3’ = 10.7 Hz, 1H, H-2’), 4.51 (dd, J6a’,6b’ = 12.0
Hz, 1H, H-6a’), 4.44 (dd, 2J = 9.0 Hz, 2H, CH2Ph), 4.40 (dd, 1H,
H-6b’), 4.38 (dd, J3’,4’ = 12.2 Hz, 1H, H-3), 4.37 (d, 1H, CHPh),
4.17 (dd, J5’,6a’ = 3.1 Hz, 1H, H-5’), 4.13 (d, J1,2 = 6.0 Hz, 1H, H-1),
Methyl 2,3,6-tri-O-benzyl-4-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-α-D-glucopyranoside (40) was ob-
tained from donor 30 and acceptor 5 under the general glyco-
sylation method as a colorless foam in 98% yield. Analytical
data for 40 was in accordance with that previously reported.[51]
2
3.84 (d, J = 12.6 Hz, 1H, CHPh), 3.67-3.43 (m, 4H, H-4, 5, 6a,
6b), 3.23 (dd, J2,3 = 9.6 Hz, 1H, H-2), 3.08 (s, 3H, OCH3) ppm;
13C NMR (151 MHz, CDCl3): δ 166.3, 165.8, 165.4, 138.8, 138.5,
138.1, 133.5, 133.4, 133.0 (x8), 129.9, 129.1, 128.9, 128.6 (x3), 128.52
(x10), 128.4 (x3), 128.4 (x3), 128.3 (x2), 128.2, 128.1 (x4), 127.8,
127.6, 98.5, 97.7, 81.0, 78.7, 76.0, 74.9, 74.0, 73.6, 71.7, 71.1, 70.8,
69.6, 68.7, 63.5, 56.0, 55.0 ppm; HRMS [M+Na]+ calcd for
C63H57NO15Na 1090.3620 found 1090.3617.
Methyl 2,4,6-tri-O-benzyl-3-O-(2,3,4,6-tetra-O-benzyl-α-
D-mannopyranosyl)-α-D-glucopyranoside (41) was ob-
tained from donor 30 and acceptor 6 under the general glyco-
sylation method as a colorless foam in 98% yield. Analytical
data for 41 was in accordance with that previously reported.[52]
Methyl 2-O-(3,4,6-tri-O-benzoyl-2-deoxy-2-phthalimido-
β-D-glucopyranosyl)-3,4,6-tri-O-benzyl-α-D-glucopyra-
noside (49) was obtained from donor 43 and acceptor 7 under
the general glycosylation method using Ag2O (1.50 equiv) and
TfOH (0.50 equiv) as a colorless foam in 68% yield. Analytical
Methyl
3,4,6-tri-O-benzyl-2-O-(2,3,4,6-tetra-O-benzyl-
α/β-D-mannopyranosyl)-α-D-glucopyranoside (42) was
obtained from donor 30 and acceptor 7 under the general gly-
cosylation method as a colorless foam in 98% yield (α/β =
3.6/1). Analytical data for 42 was in accordance with that pre-
viously reported.[45]
21
data for 49: Rf = 0.65 (ethyl acetate/toluene, 1/4, v/v); [α]D
1
72.1 (c 2.35, CHCl3); H NMR (300 MHz, CDCl3): δ 8.12 – 8.02
(m, 2H, aromatic), 7.94 – 7.88 (m, 2H, aromatic), 7.76 – 7.65
(m, 2H, aromatic), 7.60 – 7.08 (m, 21H, aromatic), 7.08 – 6.95
(m, 3H, aromatic), 6.84 (m, 4H, aromatic), 6.23 (dd, J3’,4’ = 9.7
Hz, 1H, H-3’), 5.84 (d, J1’,2’ = 8.4 Hz, 1H, H-1’), 5.72 (dd, J4’,5’ = 9.7
Hz, 1H, H-4’), 5.10 (d, J1,2 = 3.3 Hz, 1H, H-1), 4.77 (dd, J2’,3’ = 10.6
Hz, 1H, H-2’), 4.72 (dd, J6a’,6b’ = 11.6 Hz, 1H, H-6a’), 4.53 (dd, 2J
Methyl 6-O-(3,4,6-tri-O-benzoyl-2-deoxy-2-phthalimido-
β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyra-
noside (46) was obtained from donor 42 and acceptor 4 under
the general glycosylation method using 1.0 equiv of Ag2O and
0.5 equiv of TfOH as a colorless foam in 97% yield. Analytical
data for 46 was in accordance with that previously reported.[53]
2
= 12.1 Hz, 2H, CH2Ph), 4.44 (dd, 1H, H-6b’), 4.40 (dd, J = 12.1
Hz, 2H, CH2Ph), 4.39 (s, 2H, CH2Ph), 4.28 (ddd, J5’,6a’ = 2.7 Hz,
J5’,6b’ = 5.0 Hz, 1H, H-5’), 3.85 (dd, J3,4 = 8.7 Hz, 1H, H-3), 3.73
(dd, J2,3 = 9.8 Hz, 1H, H-3), 3.72 - 3.54 (m, 3H, H-5, 6a, 6b), 3.57
(dd, J4,5 = 10.7 Hz, 1H, H-4), 3.32 (s, 3H, OCH3) ppm; 13C NMR
(151 MHz, CDCl3): δ 166.0, 165.6, 165.1, 138.5, 138.0 (x2), 133.8,
133.4, 133.2 (x2), 129.8 (x5), 129.7 (x3), 129.4, 128.8, 128.5, 128.4
(x4), 128.3 (x3), 128.2 (x2), 128.12 (x3), 127.9 (x5), 127.8 (x4),
127.6, 127.5, 126.5, 126.0 (x2), 100.1, 99.2, 82.9, 80.3, 77.7, 74.9,
74.6, 73.5, 72.2, 71.2, 69.9, 69.8, 68.5, 63.0, 55.2, 54.8; HRMS
[M+Na]+ calcd for C63H57NO15Na 1090.3620 found 1090.3615.
Methyl 4-O-(3,4,6-tri-O-benzoyl-2-deoxy-2-phthalimido-
β-D-glucopyranosyl)-2,3,6-tri-O-benzyl-α-D-glucopyra-
noside (47) was obtained from donor 42 and acceptor 5 under
the general glycosylation method using Ag2O (1.50 equiv) and
TfOH (0.50 equiv) as a colorless foam in 76% yield. Analytical
data for 47: Rf = 0.60 (ethyl acetate/toluene, 1/4, v/v); [α]D21 31.1
(c 2.05, CHCl3); 1H NMR (300 MHz, CDCl3): δ 8.04 – 7.93 (m,
2H, aromatic), 7.88 – 7.78 (m, 2H, aromatic), 7.75 – 7.69 (m,
2H, aromatic), 7.69 – 7.59 (m, 2H, aromatic), 7.55 – 7.12 (m,
26H, aromatic), 6.16 (dd, J3’,4' = 9.3 Hz, 1H, H-3’), 5.77 (d, J1’,2’
=
8.4 Hz, 1H, H-1’), 5.60 (dd, J4’,5’ = 9.7 Hz, 1H, H-4’), 4.98 (dd, 2J
= 11.8 Hz, 2H, CH2Ph), 4.60 (dd, 2J = 12.2 Hz, 2H, CH2Ph), 4.51
(dd, J2’,3’ = 10.7 Hz, 1H, H-2’) 4.50 (d, J1,2 = 3.0 Hz, 1H, H-1), 4.44
(dd, 2J = 2.7 Hz, 2H, CH2Ph), 4.34 (dd, J6a’,6b’ = 12.2, 1H, H-6a’),
4.14 (dd, 1H, H-6b’), 4.08 (dd, J4,5 = 9.2 Hz, 1H, H-4), 3.90 (dd,
J3,4 = 9.2 Hz, 1H, H-3), 3.70 – 3.53 (m, J5’,6b’ = 3.3 Hz, 2H, H-5,
5’), 3.53 – 3.47 (m, 2H, H-6a, 6b), 3.43 (dd, J2,3 = 9.5 Hz, 1H, H-
2), 3.26 (s, 3H, OCH3) ppm;13C NMR (151 MHz, CDCl3): δ 166.2,
165.9, 165.2, 139.6, 138.5, 138.4, 133.5, 133.5, 133.1, 130.0 (x6), 129.9
(x4), 129.1, 128.7, 128.5 (x12), 128.4 (x3), 128.2 (x3), 127.9, 127.6
(x3), 127.3, 127.2 (x3), 98.4, 97.6, 80.3, 79.5, 75.7, 75.0, 73.7, 73.0,
71.9, 71.4, 70.4, 69.5, 68.5, 63.2, 55.8, 55.5 ppm; HRMS [M+Na]+
calcd for C63H57NO15Na 1090.3620, found 1090.3627.
1,2:3,4-Di-O-isopropylidene-6-O-[methyl (4,7,8,9-tetra-O-
acetyl-5-(N-acetyl)acetamido-3,5-dideoxy-D-glycero-α-D-
galacto-non-2-ulo-pyranosyl)onate]-α-D-galactopyra-
nose (52) A mixture of a glycosyl donor 45[22c] (29.5 mg, 0.053
mmol), glycosyl acceptor 50 (6.8 mg, 0.026 mmol), and freshly
activated molecular sieves (3 Å, 150 mg) in CH2Cl2 (1.0 mL) was
stirred under argon for 1 h. The mixture was cooled to -78 °C,
Ag2O (24.8 mg, 0.11 mmol) was added, and the resulting
mixture was stirred for 10 min. TfOH (4.0 mg, 0.027 mmol)
was then added, and the resulting mixture was stirred under
argon for 2 h at -78 °C. After that, the reaction mixture was
allowed to warm to rt over the course of 6 h and left stirring
for additional 16 h at rt. The solid was filtered off and washed
sucessively with CH2Cl2. The combined filtrate (~40 mL) was
washed with saturated NaHCO3 (10 mL). The organic phase
was separated, dried with magnesium sulfate, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (acetone – hexane gradient
elution) to give the title compound as a clear syrup in 97%
yield (19.6 mg, 0.025 mmol). Analytical data for 52 was in
accordance with that previously reported.[54]
Methyl 3-O-(3,4,6-tri-O-benzoyl-2-deoxy-2-phthalimido-
β-D-glucopyranosyl)-2,4,6-tri-O-benzyl-α-D-glucopyra-
noside (48) was obtained from donor 43 and acceptor 6 under
the general glycosylation method using Ag2O (1.50 equiv) and
TfOH (0.50 equiv) as a colorless foam in 72% yield. Analytical
data for 48: Rf = 0.60 (ethyl acetate/toluene, 1/4, v/v); [α]D21 6.4
(c 2.34, CHCl3); 1H NMR (300 MHz, CDCl3): δ 7.97 (m, 2H, ar-
omatic), 7.91-7.76 (m, 6H, aromatic), 7.75 – 7.64 (m, 2H, aro-
This article is protected by copyright. All rights reserved.

10.1002/chem.201905576
Chemistry - A European Journal
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ASSOCIATED CONTENT
Supporting Information
NMR spectra for all new and selected known compounds. This
material is available free of charge via the Internet at
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AUTHOR INFORMATION
Corresponding Author
[23] a) G. J. Boons and A. V. Demchenko, Chem. Rev. 2000, 100, 4539-
4565; b) C. De Meo and B. T. Jones, Adv. Carbohydr. Chem. Biochem.
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[24] C. De Meo and U. Priyadarshani, Carbohydr. Res. 2008, 343, 1540-
1552.
* Department of Chemistry and Biochemistry, University of
Missouri – St. Louis, One University Boulevard, St. Louis, Mis-
souri 63121, USA; demchenkoa@umsl.edu
Author Contributions
[25] A. V. Demchenko and G. J. Boons, Tetrahedron Lett. 1998, 39, 3065-
3068.
The manuscript was written through contributions of all au-
thors. / All authors have given approval to the final version of
the manuscript.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
This work was supported by the NSF (CHE-1800350) and the
National Institute of General Medical Sciences (GM111835).
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