Bismuth(iii) triflate as a novel and efficient activator for glycosyl halides

Article abstract of DOI:10.1039/d1ob00093d

Presented herein is the discovery that bismuth(iii) trifluoromethanesulfonate (Bi(OTf)₃) is an effective catalyst for the activation of glycosyl bromides and glycosyl chlorides. The key objective for the development of this methodology is to em

Full text of DOI:10.1039/d1ob00093d

Organic &
Biomolecular Chemistry
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PAPER
Bismuth(III) triflate as a novel and efficient
activator for glycosyl halides†
Cite this: Org. Biomol. Chem., 2021,
9, 3220
1
Hayley B. Steber, Yashapal Singh * and Alexei V. Demchenko
*
3
Presented herein is the discovery that bismuth(III) trifluoromethanesulfonate (Bi(OTf) ) is an effective cata-
lyst for the activation of glycosyl bromides and glycosyl chlorides. The key objective for the development
of this methodology is to employ only one promoter in the lowest possible amount and to avoid using
any additive/co-catalyst/acid scavenger except molecular sieves. Bi(OTf)3 works well in promoting the
glycosidation of differentially protected glucosyl, galactosyl, and mannosyl halides with many classes of
glycosyl acceptors. Most reactions complete within 1 h in the presence of only 35% of green and light-
Received 18th January 2021,
Accepted 18th March 2021
DOI: 10.1039/d1ob00093d
rsc.li/obc
3
stable Bi(OTf) catalyst.
The first chemical glycosylations performed by Michael, tion time (even at high temperatures), requirement of additives
1
–3
Fischer, and Koenigs/Knorr helped pave the path to modern that are commonly used in excess, substrate limitations, and,
glycosciences that now encompass many chemical, bio- in some cases, a complex reaction set up is needed.
medical, and industrial aspects of carbohydrates. Glycosyl
In an ongoing effort to develop new glycosylation reactions
halides, once the glycosyl donors of choice to perform both suitable for traditional manual and automated synthetic
single-stage glycosylations and multi-step glycan assembly, approaches, we have recently developed a cooperative concept
started losing dominance due to their instability and some- for the activation of glycosyl halides. Over the course of this
what sluggish activation profile. To address the issues related study, we achieved a dramatic acceleration of a silver(I)-pro-
to the activation of halides, many promoters have been intro- moted glycosylation reaction in the presence of catalytic Lewis
3
–8
9–14
50–52
duced. Traditionally used silver salt
and mercury
salt- or Brønsted acid additive.
As an extension of this effort of
based promoters have been expanded to other metal salts identifying suitable activators, reported herein is our first dedi-
1
1,15–17
11,18–21
22,23
24–26
including cadmium,
zinc,
tin,
indium,
cated study to implement promoters based on other metal salts.
2
7
and iron. The activity of metal salt activators is defined by The substrates of choice for the initial screening were common
their halophilicity; however, the rate of glycosylation can be 2,3,4,6-tetra-O-benzoyl-α-D-glucopyranosyl bromide donor 1
greatly influenced by many other factors.
53
2
8
54
and methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside acceptor 2.
Many metal salt-based promoters for the activation of glyco- After preliminary screening of several halophilic metal salts as
syl halides experience limitations related to their inherent tox- potential promoters for the activation of the bromide leaving
icity, light/air/moisture sensitivity, cost, excess requirement, group, we chose bismuth(III) trifluoromethanesulfonate, Bi
and/or substrate compatibility. As a result, there has been a (OTf)
3
, as a promising candidate for further investigation. Other
O, CuO, CaO, ZnCO , Ni
(acac) , (BiO) CO , Fe(OAc) , and Fe(OTf) , but unfortunately all
notable interest in studying non-metallic promoters including activators considered included Cu
2
3
2
9–34
35–43
44
organic modulators,
halogens,
diarylborinic acid,
2
2
3
3
3
4
5,46
47
48
organocatalysts,
supercritical CO
2
,
and blue light. Most these reagents were practically ineffective as the desired disac-
of the non-metallic activators function with an associative charide was produced in less than 5% under the tested reaction
4
9
45
additive. Recent approaches introduced by Taylor, Ye,
conditions. Good reaction rates and minimal side products
Jacobsen, and Nguyen have largely changed the way glyco- were achieved in the presence of as little as 35 mol% of Bi
syl halides have been activated by providing a catalytic means (OTf) in CH Cl at rt. These, along with the moderate cost, low
4
6
34
3
2
2
to their activation. However, these methods also have certain hygroscopicity, high stability, and greenness of Bi(OTf) , were
3
limitations related to multistep catalyst synthesis, long reac- all important traits of this reaction.
For comparison, silver triflate, arguably the most frequently
used metallic promoter for the activation of glycosyl halides,
has a very high reactivity profile. However, it has to be preacti-
vated and dried directly prior to each application. AgOTf is
highly sensitive towards moisture and light, it must be used in
Department of Chemistry and Biochemistry, University of Missouri – St Louis,
One University Boulevard, St Louis, Missouri 63121, USA.
E-mail: demchenkoa@umsl.edu, satpal04@gmail.com
†
Electronic supplementary information (ESI) available: NMR spectra for all new
and selected known compounds. See DOI: 10.1039/d1ob00093d
excess (2 equiv. or higher), and it frequently requires an associ-
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ative acid scavenger and low temperature conditions. In con- tion in the presence of 90 mg of molecular sieves under other-
trast, glycosidation of bromide 1 with acceptor 2 in the pres- wise identical reaction conditions. As a result, disaccharide 3
3 2 2
ence of 35 mol% of Bi(OTf) in CH Cl in the absence of mole- was obtained in a significantly improved yield of 84% (entry
cular sieves produced the desired disaccharide 3 (entry 1, 3). We have also noted a significant increase in the reaction
5
5
Table 1). The reaction performed at 0 °C was completed in time to 20 h. Further increase of the amount of molecular
.25 h. The isolated yield of disaccharide 3 was rather modest sieves to 120, 150, and 300 mg led to the formation of disac-
1
under these conditions (52%) even though donor 1 has been charide 3 in excellent yields of 92, 93, and 98%, respectively
completely consumed. When the crude reaction mixture was (entries 4–6). At the conclusion of this series of experiments,
subjected to mass spectrometry analysis, several side products we chose to perform subsequent glycosylation reactions in the
were identified. Along with a variety of the hydrolysis products, presence of 120 mg of molecular sieves (4/1, w/w to the donor).
one of the major side products was identified as methyl In our opinion, these reaction conditions offer the best combi-
2
,3,4,6-tetra-O-benzoyl-D-glucopyranoside. The formation of nation between efficiency, sieve amount, and yield. Since this
this compound could be rationalized by the direct inter- reaction required 20 h to complete, we turned our attention to
5
6
molecular acceptor-to-donor aglycone transfer. Alternatively, investigating other factors with the primary purpose of enhan-
methyl glycoside hydrolysis followed by glycosylation of the lib- cing the reaction rates.
erated MeOH could not be excluded due to a relatively high
acidity (TfOH) of the reaction medium. Indeed, along with gly- with toluene showed no noticeable improvement in the rate of
cosylation, TfOH is constantly being produced from Bi(OTf) reaction between compounds 1 and 2, but the yield of disac-
These observations led us to investigating the means for sup- charide 3 was reduced to 67% (entry 7). A notable enhance-
pressing the formation of side products. ment rate was observed for reactions performed in diethyl
2 2
Keeping all other parameters constant, replacing CH Cl
3
.
Practically all chemical glycosylation reactions in modern ether or acetonitrile, reaction solvents known for their ability
times rely on molecular sieves as a desiccant (and acid scaven- to affect the stereoselectivity of glycosylation via participation
ger) to suppress the formation of hydrolyzed by-products. at the anomeric center. While rapid at the beginning, these
When the aforementioned glycosylation (entry 1) was repeated reactions stalled after about 1 h and failed to proceed past this
in the presence of molecular sieves (3 Å, 30 mg, 1/1, w/w to time point. As a result, disaccharide 3 was obtained in 45–50%
donor 1) we noted a slight increase of the yield of disaccharide yield (entries 8 and 9). In contrast, freshly distilled nitro-
3
2
to 57% (entry 2). This result was indicative of the reaction- methane (MeNO ) was very effective in enhancing the rate of
dependence on the presence of molecular sieves. To further the reaction without having any detrimental effect on the reac-
investigate the role of the desiccant, we performed glycosyla- tion yield. Thus, the glycosylation reaction in MeNO smoothly
2
completed within 1 h and disaccharide 3 was isolated in 95%
yield (entry 10). Reaction in MeNO without molecular sieves
2
produced disaccharide 3 in 55% yield (entry 11). Only side pro-
ducts resulted from donor hydrolysis have been observed in
this reaction.
Table 1 Glycosylation of donor 1 (30 mg) and acceptor 2 with varying
the amount of molecular sieves 3 Å and solvent
Over the course of the subsequent experiments, we investi-
gated how modulating the ratios between the reaction solvents
CH Cl and MeNO would affect the reaction time and product
2 2 2
yields (entries 12–14). From this experimentation, we con-
cluded that dichloromethane is a suitable reaction solvent.
However, the rate of the reaction was low and 18–24 h were
still needed for complete consumption of the glycosyl
bromide. In terms of reactivity, yield of glycosides, and sup-
pressing sides products, nitromethane seems a better choice
among the investigated solvents. However, nitromethane alone
is often a poor solvent for sugars. To develop a universal
solvent system that would be suitable for most donor acceptor
combinations, we concluded that MeNO /CH Cl (7/3, v/v)
offers an optimal balance between solubility, rates, and yields.
Therefore, this solvent combination was chosen as the stan-
dard reaction solvent system for future experimentations.
Having optimized the basic reaction conditions, we
3
extended Bi(OTf) -promoted reactions to glycosidation of
donor 1 with various glycosyl acceptors 4–14 depicted in Fig. 1.
Entry MS 3 Å (mg) Solvent
Time (h) Yield of 3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
—
30
90
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
1.25
2
52%
57%
84%
92%
93%
98%
67%
45%
50%
95%
55%
96%
98%
98%
2
2
2
20
20
20
20
20
1
120
150
300
120
120
120
120
—
Toluene
Et
2
O
MeCN
MeNO
MeNO
MeNO
MeNO
MeNO
1
1
1
0
1
2
3
4
2
2
2
2
2
Glycosylation reactions of less reactive standard secondary gly-
120
120
120
/CH
/CH
/CH
2
Cl
2
Cl
2
Cl
2
2
2
, 1/4, v/v 20
, 1/1, v/v 20
, 7/3, v/v
5
4
cosyl acceptors 4–6 with glucosyl bromide 1 were rapid and
5
4,55
1
efficient affording the respective disaccharides 15–17
in
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Table 2 Glycosidation of donor 1 with acceptors 4–14
Entry
1
ROH
Time
1 h
Products, yield
4
2
3
5
6
40 min
1 h
Fig. 1 Glycosyl acceptors used in this study.
4
0–60 min in 92–94% (entries 1–3, Table 2). These and follow-
ing reactions were exclusively 1,2-trans-stereoselective due to
the participatory effect of the benzoyl ester group at C-2 of
donor 1.
4
5
7
8
2 h
1 h
Further, the compatibility of the reaction conditions
towards the acid-labile protecting groups was investigated by
performing glycosylation reactions with benzylidene-protected
5
7
acceptor 7 and isopropylidene-protected acceptor 8. The gly-
cosylations proceeded smoothly and produced the respective
5
8–60
61
disaccharides 18
and 19
in 1–2 h in 85–86% yield
(
entries 4 and 5). Glycosylation of electronically deactivated
a
6
2
6
9
15 min
benzoylated glycosyl acceptor 9 was also swift and efficient,
but only if carried out in the presence of the increased amount
of Bi(OTf)
3 2
(0.5 equiv.) and in neat MeNO . As a result, the
6
3
corresponding disaccharide 20 was obtained in 85% yield in
1
5 min (entry 6).
A selective activation approach was then undertaken to
b
6
4
7
10
11
12
45 min
6
5
activate glycosyl bromide 1 over thioglycoside acceptors 10
and 11. These efforts still need improvement, and the
respective disaccharides 21
6
6
6
7
68
and 22
were isolated in
1
6–42% yield (entries 7 and 8). It should be noted that these
c
8
1 h
disaccharides equipped with the anomeric leaving group can
be used as glycosyl donors for subsequent chain elongation
directly. A lower efficiency of these reactions in comparison to
that of glycosylation of standard acceptors was attributed to
the competing aglycone transfer. Presumably, this side reac-
tion is accelerated due to interaction of the thiophilic bismuth
cation with the anomeric sulfur atom of the glycosyl acceptor.
Aliphatic glycosyl acceptors, secondary alcohol cholesterol 12
and tertiary 1-adamantanol 13 were then studied. These glyco-
5
6
9
2.5 h
6
9
70
sylations produced corresponding glycosides 23 and 24 in
7% and 96% yield, respectively (entries 9 and 10). Note that
reaction in neat CH Cl was found to be superior for glycosyl
acceptor 13. Finally, to execute multiple glycosylations to
7
2
2
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Table 2 (Contd.)
purpose of this study was to further explore the scope of this
reaction, determine compatibility with other classes of pro-
tecting groups, and to access its applicability to the assembly
of complex glycans. Benzylated glycosyl acceptor 2 was
chosen as a nucleophile for this study. The first series of
experiments was conducted with glycosyl bromide donors
bearing disarming protection (benzoyl group). Benzoylated
glucosyl donor 1 was supplemented with benzoylated galacto-
7
2
73
syl bromide 26 and mannosyl bromide 27. In comparison
with the benchmark experiment involving bromide 1 and
acceptor 2 that produced disaccharide 3 in 45 min in 98%
yield (entry 1, Table 3), donors 26 and 27 provided a very
similar outcome. Thus, glycosylation of acceptor 2 with
Entry
ROH
Time
20 h
Products, yield
d
10
13
7
4
donors 26 and 27 swiftly produced disaccharides 37 and
6
3
38
in 30 min in 97% and 92% yield, respectively (entries 2
and 3).
We then moved on to investigating the glycosylation reac-
e
11
14
2 h
tions with per-benzylated (armed) glycosyl bromides that were
generated from the corresponding ethyl thioglycoside precur-
sors by reaction with bromine directly prior to application
after treatment with stoichiometric molecular bromine.
Glycosidation of armed glucosyl bromide generated from thio-
a
Deviations from standard reaction conditions: Performed in the pres-
75
76
b
glycoside 28 afforded disaccharide 39 in 71% in 15 min
entry 4). The lower yield of 39 in comparison to those seen for
ence of 0.5 equiv. Bi(OTf)
3
in neat MeNO2. Performed in the presence
of 0.5 equiv. Bi(OTf)3. Performed in the presence of 0.6 equiv. Bi
c
(
d
e
(
2
OTf)3. Performed in neat CH Cl2. Performed with 0.4 equiv. of reactions with benzoylated bromides could be attributed to
acceptor at 0 °C for 5 min and then increased to rt.
competitive hydrolysis and the formation of the 1,6-anhydro
derivative. Galactosyl and mannosyl bromides generated from
3
7,77
78
the respective thioglycoside precursors 29
and 30 gave
7
9
80
rise to disaccharides 40
and 41
in 78 and 91% yield,
access branched structures in one pot, we conducted glycosyla-
7
1
respectively (entries 5 and 6). The armed glycosyl bromide
donors generated from thioglycoside precursors 28–30 pro-
duced disaccharides in poor stereoselectivity with α/β ratio
ranging within 1/1.1–1.5 due to the lack of stereodirecting
factors.
tion of benzylated 4,6-diol acceptor 14. This reaction pro-
duced trisaccharide 25 in 41% yield (entry 11).
After the successful construction of a variety of glycosidic
linkages from donor 1, we explored the glycosylation reaction
with other classes of glycosyl donors depicted in Fig. 2. The
Following the efficient glycosylation reactions of various gly-
cosyl bromide donors with the newly discovered metal salt, we
8
1
82
investigated glycosyl chloride donors 31
and 32.
Glycosidation under the standard reaction conditions was also
smooth and efficient in producing disaccharides 37 and 40 in
15 min in 93% and 97% yield, respectively (entries 7 and 8).
Glycosidation of differentially protected glycosyl bromide
donors obtained from thioglycosides 33–35 was then
attempted to understand the compatibility of the new acti-
vation conditions with various protecting and functional
groups. Of particular interest were aminosugars and temporary
protecting groups (TBDMS and Lev) that are commonly used
in glycan synthesis. These glycosylations were smooth and
efficient producing disaccharides 42–44 in 73–93% yield
(
entries 9–11). Finally, glycosidation of the L-series sugar,
8
3
84
rhamnosyl bromide donor 36, afforded disaccharide 45 in
79% yield (entry 12).
3
In conclusion, Bi(OTf) was found to be an effective metal
salt capable of the activation of glycosyl bromides and chlor-
ides. Successful glycosidation of per-benzoylated glucosyl
bromide was carried out with a variety of glycosyl acceptors,
and these reactions were relatively high yielding with swift
Fig. 2 Glycosyl donors used in this study.
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Table 3 (Contd.)
Table 3 Glycosylation of acceptor 2 with various donors
Entry
8
Donor
Time
Product, yield, ratio α/β
Entry
1
Donor
Time
Product, yield, ratio α/β
32
15 min
1
45 min
2
3
26
27
30 min
30 min
9
33
10 min
1
1
1
0
1
2
34
35
36
1 h
1 h
4
5
28
29
15 min
30 min
15 min
6
7
30
31
25 min
15 min
reaction times. Additionally, glycosidations of benzylated/ben-
zoylated glucosyl, galactosyl, and mannosyl bromides, along
with benzylated/benzoylated galactosyl chlorides and a few
differentially protected building blocks have been performed
with high efficiency. This glycosylation method is favorable
due to the low mol % of green and light-stable Bi(OTf)3
required. One current limitation of this reaction is the use of
thioglycoside acceptors that showed propensity to undergo
the competing aglycone transfer reaction, which is not
uncommon under other reaction conditions. Further investi-
gation of this reaction is currently underway in our
laboratory.
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under reduced pressure. The residue was purified by column
chromatography on silica gel (ethyl acetate – hexane gradient
elution) and crystallization (diethyl ether–hexane) to afford the
Experimental section
General
Column chromatography was performed on silica gel 60 title compound as white crystals in 86% yield (12.32 g).
(
6
70–230 mesh), reactions were monitored by TLC on Kieselgel Analytical data for 33: R = 0.66 (ethyl acetate/hexane, 1/4, v/v);
f
2
0
0 F254. The compounds were detected by examination under m. p. 101.7–102.9 °C (diethyl ether–hexane); [α] + 17.4 (c =
D
1
UV light and by charring with 10% sulfuric acid in methanol. 1.0, CHCl
3
); H NMR (300 MHz, CDCl
3
): δ 8.05, 7.99 (2 d, 4H,
Solvents were removed under reduced pressure at <40 °C. aromatic), 7.20–7.63 (m, 11H, aromatic), 5.67 (dd, 1H, J = 9.6
2
,3
2
CH
application. Molecular sieves (3 Å) used for reactions were
crushed and activated in vacuo at 390 °C for 8 h in the first (dd, 1H, J3,4 = 1.0 Hz, H-3), 3.92 (m, 1H, J5,6a = 6.8, J5,6b
instance and then for 2–3 h at 390 °C directly prior to appli- 5.6 Hz, H-5), 3.87 (br d, 1H, J4,5 = 1.9 Hz, H-4), 2.72 (m, 2H,
2
Cl
2
and MeNO
2
were distilled from CaH
2
directly prior to Hz, H-2), 4.90 (dd, 2H, J = 11.4 Hz, CH
2
Ph), 4.45–4.60 (m, 2H,
J
1,2 = 9.6, J6a,6b = 11.3 Hz, H-1, 6a), 4.42 (dd, 1H, H-6b), 4.02
=
t
cation. Optical rotations were measured using a Jasco P-1020 SCH
2
), 1.22 (t, 3H, SCH
2
CH
3
), 0.80 (s, 9H, Si Bu), 0.13, −0.06 (2
polarimeter. H NMR spectra were recorded in CDCl at s, 6H, SiMe ) ppm; C NMR (75 MHz, CDCl ): δ 166.3, 165.4,
1
13
3
2
3
1
3
3
7
00 MHz and C NMR spectra were recorded in CDCl
5 MHz. Accurate mass spectrometry determinations were pre- (×2), 128.4 (×4), 128.0 (×2), 127.7, 83.9, 77.1, 76.4, 75.7, 75.1
(×2), 71.0, 63.9, 25.6 (×3), 24.1, 15.0, −3.9, −5.0 ppm; HR-FAB
3
at 138.4, 133.3, 133.1, 130.3, 129.9 (×2), 129.8, 129.7 (×2), 128.5
formed using Agilent 6230 ESI TOF LCMS mass spectrometer.
+
Synthesis of glycosyl halide donors and thioglycoside precur- MS [M + Na] calcd for C35
44 7
H O SSiNa 659.2475, found
sors. 2,3,4,6-Tetra-O-benzoyl-α-D-glucopyranosyl bromide (1) 659.2465.
was obtained from 1,2,3,4,6-penta-O-benzoyl-D-glucopyranose
Ethyl 4,6-di-O-benzyl-2-deoxy-3-O-levulinoyl-2-phthalimido-
8
5
as reported previously. The analytical data for 1 was in 1-thio-β-D-glucopyranoside (34). Levulinic acid (0.336 g,
5
3
accordance with that previously reported.
2.90 mmol), N,N‘-diisopropylcarbodiimide (DIC, 0.449 mL,
2
,3,4,6-Tetra-O-benzoyl-α-D-galactopyranosyl bromide (26) 2.90 mmol) and dimethylaminopyridine (DMAP, 35.0 mg,
was obtained from 1,2,3,4,6-penta-O-benzoyl-D-galactopyranose 0.29 mmol, 0.20 equiv.) were added to a solution of ethyl 4,6-
8
6
91
as reported previously. The analytical data for 26 was in di-O-benzyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside
7
2
accordance with that previously reported.
(47, 0.773 g, 1.45 mmol) in dry DCM (1.0 mL) and the resulting
2
,3,4,6-Tetra-O-benzoyl-α-D-mannopyranosyl bromide (27) mixture was stirred under argon for 3 h at rt. After that, the
was obtained from 1,2,3,4,6-penta-O-benzoyl-D-mannpyranose reaction mixture was diluted with DCM (∼100 mL), washed
8
7
as reported previously. The analytical data for 27 was in with saturated aq. NaHCO (2 × 25 mL) and water (2 × 25 mL).
3
7
3
accordance with that previously reported.
2 4
The organic layer was separated, dried over Na SO , and con-
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-glucopyranoside (28) centrated under reduced pressure. The residue was purified by
7
5
was obtained as reported previously.
column chromatography on silica gel (ethyl acetate-hexane gra-
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-β-D-galactopyranoside (29) dient elution) and crystallization (diethyl ether) to afford the
37,77
was obtained as reported previously.
title compound as white crystalline solid in 91% yield (0.83 g).
Ethyl 2,3,4,6-tetra-O-benzyl-1-thio-α-D-mannopyranoside (30) Analytical data for 34: R = 0.24 (ethyl acetate/hexane, 35/65,
f
7
8
20
was obtained as reported previously.
v/v); m.p. 133.2–133.8 °C (diethyl ether); [α] + 17.7 (c = 1.0,
); H NMR (300 MHz, CDCl
7.68–7.76 (m, 2H, aromatic), 7.15–7.42 (m, 10H, aromatic),
D
1
2
,3,4,6-Tetra-O-benzoyl-α-D-galactopyranosyl chloride (31) CHCl
was obtained from 2,3,4,6-tetra-O-benzoyl-D-galactopyranose
3
3
): δ 7.85 (br s, 2H, aromatic),
8
8
5
2
as reported previously. The analytical data for 31 was in 5.87 (dd, 1H, J3,4 = 9.4 Hz, H-3), 5.44 (d, 1H, J1,2 = 10.6 Hz,
8
1
accordance with that previously reported.
H-1), 4.52–4.72 (m, 4H, 2 × CH
2
Ph), 4.32 (dd, 1H, J2,3 =
2
,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl chloride (32) 10.4 Hz, H-2), 3.69–3.90 (m, 4H, H-4, 5, 6a, 6b), 2.57–2.80 (m,
8
9
was obtained from 2,3,4,6-tetra-O-benzyl-D-galactopyranose
as reported previously. The analytical data for 32 was in 1.21 (t, 3H, J = 7.4 Hz, SCH
accordance with that previously reported.
2H, SCH
2
), 2.15–2.53 (m, 4H, CH
CH
CDCl ): δ 205.6, 171.8, 167.8, 167.5, 138.0, 137.9, 134.0, 133.9,
2
CH
2 3
), 1.91 (s, 3H, COCH ),
2
7
13
2
3
) ppm; C NMR (75 MHz,
8
1,82
3
Ethyl 2,6-di-O-benzoyl-4-O-benzyl-3-O-tert-butyldimethylsilyl- 131.6, 131.5, 128.3 (×4), 127.8 (×2), 127.7 (×2), 127.6 (×2),
1
3
-thio-β-D-galactopyranoside (33). Benzoyl chloride (3.93 mL, 123.5, 123.4, 80.8, 79.1, 76.4, 74.5, 74.00, 73.4, 68.6, 54.0, 37.5,
+
3.78 mmol) was added to a solution of ethyl 2-O-benzoyl-4-O- 29.4, 27.7, 24.1, 14.9 ppm; HR-FAB MS [M + Na] calcd for
9
0
benzyl-3-O-tert-butyldimethylsilyl-1-thio-β-D-galactopyranoside
C
35
H
37NO
8
SNa 654.2138, found 654.2140.
Ethyl 6-O-benzoyl-4-O-benzyl-2-deoxy-3-O-levulinoyl-2-phtha-
mixture was stirred under argon for 4 h at rt. Methanol limido-1-thio-β-D-glucopyranoside (35). Benzoyl chloride
∼5 mL) was added dropwise, the volatiles were removed under (3.63 mL, 31.24 mmol) was added to a solution of ethyl 4-O-
reduced pressure and the residue was co-evaporated with benzyl-3-O-tert-butyldimethylsilyl-2-deoxy-2-phthalimido-1-thio-
(
46, 12.0 g, 22.52 mmol) in pyridine (50 mL) and the resulting
(
9
1
toluene (3 × 40 mL). The resulting residue was diluted with β-D-glucopyranoside (48, 5.81 g, 10.42 mmol) in pyridine
CH Cl (∼500 mL) and washed with 1 N aq. HCl (50 mL), sat. (40 mL) and the resulting mixture was stirred under argon for
aq. NaHCO (50 mL), and water (2 × 50 mL). The organic 12 h at rt. Methanol (∼5 mL) was added dropwise, the volatiles
phase was separated, dried over Na SO , and concentrated were removed under reduced pressure and the residue was co-
2
2
3
2
4
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evaporated with toluene (3 × 20 mL). The resulting residue was solution of compound 50 (1.00 g, 1.83 mmol) in dry DCM
diluted with CH Cl (∼300 mL) and washed with 1 N aq. HCl (25 mL) and the resulting mixture was stirred under argon for
2
2
(
50 mL), sat. aq. NaHCO
organic phase was separated, dried over Na
trated under reduced pressure. The residue was purified by and water (2 × 25 mL). The organic layer was separated, dried
column chromatography on silica gel (ethyl acetate–CH Cl over Na SO , and concentrated under reduced pressure. The
hexane gradient elution) to afford 6-O-benzoyl-4-O-benzyl-3-O- residue was purified by column chromatography on silica gel
tert-butyldimethylsilyl-2-deoxy-2-phthalimido-1-thio-β-D-gluco- (ethyl acetate-hexane gradient elution) to afford the title com-
pyranoside (49) as a white foam in 94% yield (6.46 g). pound (35) as a white foam in 94% yield (1.11 g). Analytical
3
(50 mL), and water (2 × 50 mL). The 3 h at rt. The reaction mixture was then diluted with DCM
2
SO , and concen- (∼100 mL) and washed with saturated aq. NaHCO (2 × 25 mL)
4
3
2
2
–
2
4
2
0
Analytical data for 49: R
f
= 0.54 (ethyl acetate/hexane, 1/3, v/v); data for 35: R
f
= 0.37 (ethyl acetate/hexane, 2/3, v/v); [α] + 25.5
D
2
0
1
1
[α] + 37.2 (c = 1.0, CHCl ); H NMR (300 MHz, CDCl ): δ 8.06 (c = 1.0, CHCl ); H NMR (300 MHz, CDCl ): δ 8.06 (d, 2H, J =
D
3
3
3
3
(d, 2H, J = 7.3 Hz, aromatic), 7.87 (br s, 2H, aromatic), 7.6 Hz, aromatic), 7.87 (br s, 2H, aromatic), 7.69–7.78 (m, 2H,
7
7
.71–7.79 (m, 2H, aromatic), 7.54–7.63 (m, 1H, aromatic), aromatic), 7.56–7.65 (m, 1H, aromatic), 7.44–7.53 (m, 2H, aro-
.42–7.52 (m, 2H, aromatic), 7.19–7.34 (m, 5H, aromatic), 5.39 matic), 7.16–7.32 (m, 5H, aromatic), 5.95 (dd, 1H, J3,4 = 9.8 Hz,
2
(d, 1H, J1,2 = 10.5 Hz, H-1), 4.86 (d, 1H, J = 11.4 Hz, CHPh), H-3), 5.52 (d, 1H, J1,2 = 10.5 Hz, H-1), 4.59–4.74 (m, 3H, H-6a,
4
(
1
.49–4.71 (m, 3H, J3,4 = 8.7 Hz, J6a,6b = 12 Hz, H-3, 6a), 4.40 CH
dd, 1H, H-6b), 4.31 (dd, 1H, J2,3 = 10.2 Hz, H-2), 3.82–3.91 (m, = 10.4 Hz, H-2), 3.91–4.00 (m, 1H, J5,6a = 4.5 Hz, H-5), 3.83 (dd,
H, J5,6a = 2.0, J5,6b = 4.7 Hz, H-5), 3.60 (dd, 1H, J4,5 = 8.7 Hz, 1H, J4,5 = 9.0 Hz, H-4), 2.56–2.76 (m, 2H, SCH ), 2.22–2.55 (m,
H-4), 2.49–2.73 (m, 2H, SCH ), 1.15 (t, 3H, J = 7.4 Hz, 4H, CH CH ), 1.91 (s, 3H, COCH ), 1.18 (t, 3H, J = 7.4 Hz,
SCH CH ), 0.75 (s, 9H, Si Bu), −0.20, −0.40 (2 s, 6H, SiMe ) SCH CH ) ppm; C NMR (75 MHz, CDCl ): δ 205.5, 171.9,
2
Ph), 4.52 (dd, 1H, J6a,6b = 12.0 Hz, H-6b), 4.35 (dd, 1H, J2,3
2
2
2
2
3
t
13
2
3
2
2
3
3
1
3
ppm; C NMR (75 MHz, CDCl
3
): δ, 168.6, 167.6, 166.1, 137.4, 167.8, 167.5, 166.1, 137.2, 134.1, 133.9, 133.1, 131.5, 129.7,
34.2, 133.0, 131.9, 131.5, 129.8, 129.6 (×2), 128.3 (×4), 127.7, 129.6 (×2), 128.4 (×3), 128.3 (×2), 127.9 (×3), 123.6, 123.5, 81.0,
27.3 (×3), 123.6, 123.2, 80.9, 80.1, 77.2, 75.0, 73.4, 63.6, 55.6, 77.1, 76.4, 74.6, 74.1, 63.4, 54.0, 37.5, 29.3, 27.7, 24.4,
1
1
2
+
9
5.6 (×3), 24.1, 17.6, 14.9, −4.2, −4.6 ppm; HR-FAB MS [M + 14.9 ppm; HR-FAB MS [M + Na] calcd for C35H35NO SNa
+
Na] calcd for C36
H
43NO
7
SSiNa 684.2427, found 684.2434.
668.1930, found 668.1939.
BF -Et O (1.23 mL, 9.97 mmol) was added to a solution of
2,3,4-Tri-O-benzoyl-α-L-rhamnopyranosyl bromide (36) was
3
2
9
2
compound 49 (6.0 g, 9.06 mmol) in dry CH
3
CN (50 mL) and obtained from 1,2,3,4-tetra-O-benzoyl-L-rhamnopyranose as
the resulting mixture was stirred under argon for 2 h 45 min at reported previously. The analytical data for 36 was in accord-
8
3,92
0
2
°C. Additional CH CN (25 mL) and BF -Et O (0.33 mL, ance with that previously reported.
3 3 2
.72 mmol) were added, and the reaction mixture was stirred
Synthesis of oligosaccharides
General method A.
for additional 15 min at 0 °C. After that, the reaction was
quenched with sat. aq. NaHCO (5 mL), and the volatiles were
A
mixture of glycosyl donor
3
removed under reduced pressure. The residue was diluted with (0.046 mmol), glycosyl acceptor (0.036 mmol), and freshly acti-
CH Cl (∼300 mL) and washed with brine (2 × 70 mL). The vated molecular sieves (3 Å, 120 mg) in MeNO and CH Cl
organic phase was separated, dried over Na SO , and concen- (1.0 mL, 7/3, v/v) was stirred under argon for 1 h at rt. The
2
2
2
2
2
2
4
3
trated under reduced pressure. The residue was purified by mixture was cooled to 0 °C, Bi(OTf) (0.016 mmol) was added,
column chromatography on silica gel (ethyl acetate-hexane gra- and the resulting mixture was stirred for the time specified in
dient elution) to give ethyl 6-O-benzoyl-4-O-benzyl-2-deoxy-2- Tables at 0 °C. After that, the solids were filtered off through a
phthalimido-1-thio-β-D-glucopyranoside (50) as a white foam in pad of Celite and rinsed successively with CH
2 2
Cl . The com-
8
6% yield (4.26 g). Analytical data for 50: R = 0.59 (ethyl bined filtrate (∼40 mL) was washed with water (2 × 10 mL).
f
2
0
1
acetate/hexane, 2/3, v/v); [α] + 10.2 (c = 1.0, CHCl ); H NMR The organic phase was separated, dried with MgSO , and con-
D
3
4
(
300 MHz, CDCl
s, 2H, aromatic), 7.69–7.77 (m, 2H, aromatic), 7.56–7.64 (m, column chromatography on silica gel (ethyl acetate – hexane or
H, aromatic), 7.44–7.53 (m, 2H, aromatic), 7.19–7.35 (m, 5H, toluene gradient elution) to afford the corresponding glyco-
aromatic), 5.37 (d, 1H, J1,2 = 10.4 Hz, H-1), 4.63–4.81 (m, 3H, sides in yields and stereoselectivities listed in Tables and
3
): δ 8.07 (d, 2H, J = 7.6 Hz, aromatic), 7.85 (br centrated under reduced pressure. The residue was purified by
1
H-6b, CH
2
Ph), 4.49–4.62 (m, 2H, J3,4 = 9.3 Hz, H-3, 6a), 4.28 below. Anomeric ratios (or anomeric purity) were determined
(
1
dd, 1H, J2,3 = 10.4 Hz, H-2), 3.81–3.91 (m, 1H, H-5), 3.64 (dd, by comparison of the integral intensities of relevant signals in
1
H, J4,5 = 9.3 Hz, H-4), 2.54–2.77 (m, 2H, -SCH
2
), 2.25 (br s, 1H,
H NMR spectra.
13
OH), 1.18 (t, 3H, J = 7.4 Hz, SCH
2
CH
3
) ppm; C NMR
General method B. A mixture of thioglycoside precursor
(75 MHz, CDCl ): δ, 168.2, 167.9, 166.2, 137.5, 134.1, 133.1, (0.048–0.051 mmol) and freshly activated molecular sieves
3
1
31.4 (×2), 129.7, 129.6 (×2), 128.6 (×3), 128.3 (×2), 128.1, 128.0 (3 Å, 120 mg) in CH
2
Cl
2
(1.0 mL) was stirred under argon for
(1.3 equiv.) was
4.9 ppm; HR-FAB MS [M + Na] calcd for C H NO SNa added dropwise, and the resulting mixture was stirred for
(×2), 123.7, 123.2, 81.1, 79.0, 77.1 75.0, 72.9, 63.7, 55.7, 24.2, 1 h at rt. The mixture was cooled to 0 °C, Br
2
+
1
5
3
0
29
7
70.1562, found 570.1571.
15 min at 0 °C. The volatiles were then removed under reduced
Levulinic acid (0.424 g, 3.65 mmol), DIC (0.566 mL, pressure, and the residue was dried in vacuo for 1 h. Glycosyl
.65 mmol) and DMAP (44.0 mg, 0.36 mmol) were added to a acceptor (0.038–0.041 mmol) was added and the resulting
3
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2
mixture was dried in vacuo for an additional 30 min. MeNO
2
4.64 (d, 1H, J = 12.2 Hz, CHPh), 4.54–4.32 (m, 6H, J3,4 = 9.7
and CH Cl (1.0 mL, 7/3, v/v) were added, the resulting Hz, H-3, H-6a′, 6b′, 3 × CHPh), 4.26 (d, 1H, J1,2 = 3.4 Hz, H-1),
2
2
mixture was cooled to 0 °C, Bi(OTf)
cated in Tables) was added, and the reaction mixture was 6b), 3.32 (dd, 1H, J2,3 = 9.6 Hz, H-2), 3.22 (s, 3H, OCH
stirred under argon for the time specified in Tables at 0 °C. Methyl 2-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-
After that, the solids were filtered off through a pad of Celite 3,4,6-tri-O-benzyl-α-D-glucopyranoside (17) was obtained from
3
(0.35 equiv. or as indi- 4.14–4.10 (m, 2H, H-5′, CHPh), 3.65–3.51 (m, 4H, H-4, 5, 6a,
3
) ppm.
5
4
and rinsed successively with CH
∼40 mL) was washed with water (2 × 10 mL). The organic method A in 94% yield (β only) as a white amorphous solid.
phase was separated, dried with MgSO , and concentrated The analytical data for 17 was in accordance with that pre-
under reduced pressure. The residue was purified by column viously reported. δ
2
Cl
2
. The combined filtrate donor 1 and acceptor 6
under the general glycosylation
(
4
5
4,55
1
H
NMR (300 MHz, CDCl
3
):
chromatography on silica gel (ethyl acetate–hexane or toluene 8.05–6.95 ppm (m, 35H, aromatic), 5.90 (dd, 1H, J3′,4′ = 9.6 Hz,
gradient elution) to afford the corresponding glycosides in H-3′), 5.73–5.68 (m, 2H, H-2′, 4′), 5.16 (d, 1H, J1′,2′ = 7.7 Hz,
yields and stereoselectivities listed in Tables and below. H-1′), 5.05 (d, 1H, J1,2 = 3.4 Hz, H-1), 4.74–4.69 (dd, 1H, H-6a′),
Anomeric ratios (or anomeric purity) were determined by com- 4.64–4.55 (m, 3H, 3 × CHPh), 4.50–4.35 (m, 4H, H-6b′, 3 ×
1
parison of the integral intensities of relevant signals in
NMR spectra.
H
CHPh), 4.16–4.13 (m, 1H, J5′,6a′ = 1.5, J5′,6b′ = 4.8 Hz, H-5′), 3.92
(dd, 1H, J3,4 = 9.4 Hz, H-3), 3.95–3.88 (dd, 1H, J2,3 = 3.4 Hz,
Methyl
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)- H-2), 3.82–3.58 (m, 4H, H-4, 5, 6a, 6b), 3.35 (s, 3H, OCH3)
2
,3,4-tri-O-benzyl-α-D-glucopyranoside (3) was obtained from ppm.
5
4
donor 1 and acceptor 2
under the general glycosylation
Methyl 3-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-2-O-
(18) was
The analytical data for 3 was in accordance with that pre- obtained from donor 1 and acceptor 7 under the general gly-
method A in 98% yield (β only) as a white amorphous solid. benzyl-4,6-O-benzylidene-α-D-glucopyranoside
5
7
5
5 1
viously reported. H NMR (300 MHz, CDCl
3
): δ 7.90–7.03 (m, cosylation method A in 86% yield (β only) as a white amor-
3
5H, aromatic), 5.89 (dd, 1H, J3′,4′ = 9.6 Hz, H-3′), 5.68 (dd, 1H, phous solid. The analytical data for 18 was in accordance with
5
8–60 1
J4′,5′ = 9.7 Hz, H-4′), 5.60 (dd, 1H, J2′,3′ = 9.6 Hz, H-2′), 4.89 (d, that previously reported.
H NMR (300 MHz, CDCl
3
): δ
2
1
H, J = 10.9 Hz, CHPh), 4.82 (d, 1H, J1′,2′ = 7.8 Hz, H-1′), 4.73 7.98–7.78 (m, 8H, aromatic), 7.53–7.22 (m, 22H, aromatic),
2
2
(d, 1H, J = 12.2 Hz, CHPh), 4.67 (d, 1H, J = 11.1 Hz, CHPh), 5.88 (dd, 1H, H-3′), 5.72–5.62 (m, 2H, J2′,3′ = 9.6 Hz, H-2′, 4′),
4
.63–4.57 (m, 2H, CH Ph), 4.54–4.46 (m, 3H, H-1, 6a′, 6b′), 4.27 5.55 (s, 1H, >CHPh), 5.23 (d, 1H, J1′,2′ = 7.7 Hz, H-1′), 4.58 (d,
2
2
2
(
d, 1H, J = 11.1 Hz, CHPh), 4.15 (m, 1H, H-5′), 4.11–4.08 (m, 1H, J = 12.7 Hz, CHPh), 4.49 (dd, 1H, J6a′,6b′ = 12.3 Hz, H-6a′),
H, H-6a), 3.88 (dd, 1H, J3,4 = 9.3 Hz, H-3), 3.77–3.70 (m, 2H, 4.32–4.16 (m, 5H, J1,2 = 3.6, H-1, 3, 6a, 6b′, CHPh), 3.98–3.93
H-5, 6b), 3.43 (dd, 1H, J2,3 = 9.6, J1,2 = 3.6 Hz, H-2), 3.36 (dd, (m, 1H, J5′,6b′ = 3.4 Hz, H-5′), 3.80–3.57 (m, 3H, H-4, 5, 6b), 3.41
1
1
H, J4,5 = 9.3 Hz, H-4), 3.20 (s, 3H, OCH
Methyl 4-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-
,3,6-tri-O-benzyl-α-D-glucopyranoside (15) was obtained from O-isopropylidene-α-D-galactopyranose (19) was obtained from
3
) ppm.
(dd, 1H, J2,3 = 9.1 Hz, H-2), 3.26 (s, 3H, OCH
3
) ppm.
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-1,2:3,4-di-
2
5
4
donor 1 and acceptor 4 under the general glycosylation donor 1 and acceptor 8 under the general glycosylation
method A in 92% yield (β only) as an off-white amorphous method A in 85% yield (β only) as an off-white amorphous
solid. The analytical data for 15 was in accordance with that solid. The analytical data for 19 was in accordance with that
5
4,55
1
61 1
previously reported.
H
NMR (300 MHz, CDCl
.97–7.17 (m, 35H, aromatic), 5.59 (dd, 1H, J3′,4′ = 9.5 Hz, H-3′), (m, 8H, aromatic), 7.57–7.25 (m, 12H, aromatic), 5.90 (dd, 1H,
.55 (dd, 1H, J2′,3′ = 9.6 Hz, H-2′), 5.46 (dd, 1H, J4′,5′ = 8.0 Hz, 3′,4′ = 9.6 Hz, H-3′), 5.68 (dd, 1H, H-4′), 5.54 (dd, 1H, J2′,3′ = 9.6
3
):
δ
previously reported.
3
H NMR (300 MHz, CDCl ): δ 8.04–7.81
7
5
J
2
H-4′), 5.06 (d, 1H, J = 11.2 Hz, CHPh), 4.81–4.75 (m, 3H, 3 × Hz, H-2′), 5.42 (d, 1H, J1,2 = 5.0 Hz, H-1), 5.05 (d, 1H, J1′,2′ = 7.8
CHPh), 4.75 (d, 1H, J1′,2′ = 8.1 Hz, H-1′), 4.60 (d, 1H, J = 12.2 Hz, H-1′), 4.65 (dd, 1H, J6a′,6b′ = 12.2 Hz, H-6a′), 4.51–4.41 (m,
2
Hz, CHPh), 4.54 (d, 1H, J1,2 = 3.5 Hz, H-1), 4.41 (dd, 1H, J6a′,6b′ 2H, H-3, 6b′), 4.23–4.15 (m, 2H, J5′,6b′ = 3.2 Hz, H-2, 5′), 4.10
2
=
1
3
3
6
12.1 Hz, H-6a′), 4.33 (d, 1H, J = 12.2 Hz, CHPh), 4.27 (dd, (dd, 1H, J4,5 = 8.1 Hz, H-4), 4.02 (dd, 1H, J6a,6b = 9.3 Hz, H-6a),
H, H-6b′), 3.94 (dd, 1H, H-4), 3.88 (dd, 1H, J3,4 = 9.4 Hz, H-3), 3.91–3.82 (m, 2H, J5,6b = 2.4 Hz, H-5, 6b), 1.37, 1.24, 1.21, 1.19
.71–3.68 (m, 2H, J5′,6a′ = 3.6, J5′,6b′ = 5.0 Hz, H-5′, 6a), (4 s, 12H, 4 × CH ) ppm.
3
.50–3.47 (m, 1H, H-5), 3.46–3.39 (m, 2H, J2,3 = 9.1 Hz, H-2,
Methyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzoyl-β-D-
glucopyranosyl)-α-D-glucopyranoside (20) was obtained from
b), 3.27 (s, 3H, OCH ) ppm.
Methyl
3
6
2
3-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)- donor 1 and acceptor 9
under the general glycosylation
2
,4,6-tri-O-benzyl-α-D-glucopyranoside (16) was obtained from method A in 85% yield (β only) as a white amorphous solid.
5
4
donor 1 and acceptor 5
under the general glycosylation The analytical data for 20 was in accordance with that pre-
6
3 1
method A in 93% yield (β only) as a white amorphous solid. viously reported. H NMR (300 MHz, CDCl
3
): δ 8.01–7.78 (m,
The analytical data for 16 was in accordance with that pre- 14H, aromatic), 7.52–7.26 (m, 21H, aromatic), 6.07 (dd, 1H, J3,4
5
4,55 1
viously reported.
m, 35H, aromatic), 5.94 (dd, 1H, J3′,4′ = 9.6 Hz, H-3′), 5.72 (dd,
H, J4′,5′ = 9.7 Hz, H-4′), 5.65 (dd, 1H, J2′,3′ = 9.7 Hz, H-2′), 5.51 1H, J4,5 = 9.9 Hz, H-4), 5.09 (dd, 1H, J2,3 = 10.2 Hz, H-2), 4.97
H NMR (300 MHz, CDCl ): δ 8.02–7.07 = 9.8 Hz, H-3), 5.93 (dd, 1H, J3′,4′ = 9.6 Hz, H-3′), 5.67 (dd, 1H,
3
(
1
J4′,5′ = 9.7 Hz, H-4′), 5.57 (dd, 1H, J2′,3′ = 9.5 Hz, H-2′), 5.32 (dd,
2
(
d, 1H, J1′,2′ = 8.0 Hz, H-1′), 5.11 (d, 1H, J = 10.7 Hz, CHPh), (d, 1H, J1′,2′ = 7.9 Hz, H-1′), 4.93 (d, 1H, J1,2 = 3.5 Hz, H-1), 4.60
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dd, 1H, J6a′,6b′ = 12.0 Hz, H-6a′), 4.46 (dd, 1H, J5′,6a′ = 4.9 Hz,
Organic & Biomolecular Chemistry
(
Methyl 4,6-di-O-(2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl)-
H-6b′), 4.22–4.09 (m, 3H, J5′,6b′ = 2.6 Hz, H-5, 5′, 6a), 3.79 (dd, 2,3-di-O-benzyl-α-D-glucopyranoside (25) was obtained from
7
1
1
H, J6a,6b = 7.8 Hz, J5,6a = 3.4 Hz, H-6b), 2.94 (s, 3H, OCH
ppm.
Ethyl 2,3,4-tri-O-benzoyl-6-O-(2,3,4,6-tetra-O-benzoyl-β-D-glu- Analytical data for 25: R = 0.36 (ethyl acetate/hexane, 35/65,
3
)
donor 1 and acceptor 14
under the general glycosylation
method A in 41% yield (β only) as a white amorphous solid.
f
2
3
1
3 3
copyranosyl)-1-thio-β-D-glucopyranoside (21) was obtained v/v); [α] + 26.8 (c 1.0, CHCl ); H NMR (300 MHz, CDCl ): δ
D
6
5
from donor 1 and acceptor 10 under the general glycosyla- 8.12–7.77 (m, 16H, aromatic), 7.62–7.21 (m, 34H, aromatic),
tion method A in 16% yield (β only) as an off-white amorphous 5.75 (dd, 1H, J3′,4′ = 9.5 Hz, H-3′), 5.66 (dd, 1H, J3″,4″ = 9.7 Hz,
solid. The analytical data for 21 was in accordance with that H-3″), 5.59–5.53 (m, 2H, H-4′, 4″), 5.50–5.43 (m, 2H, J2′,3′ = 9.5,
6
7 1
previously reported.
H NMR (300 MHz, CDCl
3
): δ 8.02–7.23
J
2″,3″ = 9.7 Hz, H-2′, 2″), 4.90 (dd, 2H, CH
2
Ph), 4.63 (d, 1H, J1′,2′
= 7.6 Hz, H-1′), 4.59 (d, 1H, J = 10.0 Hz, CHPh), 4.49–4.38 (m,
.5 Hz, H-3′), 5.63 (dd, 1H, J4,5 = 9.7 Hz, H-4), 5.51 (dd, 1H, J2,3 4H, J1,2 = 3.4 Hz, H-1, 6a′, 6b′, CHPh), 4.32 (d, 1H, J1″,2″ = 7.5
9.7 Hz, H-2), 5.40 (dd, 1H, J2′,3′ = 9.7 Hz, H-2′), 5.31 (dd, 1H, Hz, H-1″), 4.07 (dd, 1H, J6a″,6b″ = 12.7 Hz, H-6a″), 3.99 (dd, 1H,
2
(m, 35H), 5.88 (dd, 1H, J3,4 = 9.6 Hz, H-3), 5.81 (dd, 1H, J3′,4′
=
9
=
J4′,5′ = 9.7 Hz, H-4′), 4.99 (d, 1H, J1,2 = 7.8 Hz, H-1), 4.65 (d, 1H, H-6b″), 3.91–3.83 (m, 2H, J3,4 = 10.7 Hz, H-3, 6a), 3.66–3.60 (m,
J1′,2′ = 10.0 Hz, H-1′), 4.58 (dd, 1H, J6a,6b = 12.1 Hz, H-6a), 4.40 3H, H-5, 5′, 6b′), 3.56 (dd, 1H, J4,5 = 3.7 Hz, H-4), 3.38 (dd, 1H,
(
dd, 1H, H-6b), 4.13–3.83 (m, 4H, J5,6a = 3.0, J5,6b = 5.0 Hz, H-5, 2,3 = 9.4 Hz, H-2), 3.30 (m, 1H, J5″,6a″ = 2.0, J5″,6b″ = 3.6 Hz,
J
1
3
H-5′, 6a′, 6b′), 2.52 (m, 2H, SCH CH ), 1.10 (t, 3H, SCH CH ) H-5″), 3.18 (s, 3H, OCH ) ppm; C NMR (75 MHz, CDCl ): δ
2
3
2
3
3
3
ppm.
p-Tolyl
glucopyranosyl)-1-thio-β-D-glucopyranoside (22) was obtained 129.7 (×4), 129.6 (×5), 129.3, 129.2, 129.1 (×2), 128.9, 128.8,
166.1 166.0, 165.5 (×2), 165.4, 165.3, 165.2, 164.8, 138.2, 137.9,
2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzoyl-β-D- 133.4, 133.3, 133.2 (×2), 133.0 (×3), 132.9, 130.0, 129.8 (×4),
6
6
from donor 1 and acceptor 11 under the general glycosyla- 128.5 (×2), 128.4 (×6), 128.3 (×6), 128.2 (×4), 128.1 (×3), 128.0
tion method A in 42% yield (β only) as a white amorphous (×3), 127.9, 127.4 (×3), 127.1, 101.6, 101.5, 97.9, 80.0, 79.6,
solid. The analytical data for 22 was in accordance with that 79.2, 74.5, 73.6, 73.2, 72.9, 72.6, 72.3, 72.2, 71.8, 69.7, 69.2,
6
8 1
+
previously reported.
m, 39H, aromatic), 5.84 (dd, 1H, J3′,4′ = 9.6 Hz, H-3′), 5.67 (dd, for C89
H, J4′,5′ = 9.6 Hz, H-4′), 5.58 (dd, 1H, J2′,3′ = 9.6 Hz, H-2′), 4.93 Methyl
3
H NMR (300 MHz, CDCl ): δ 7.93–7.09 68.9, 68.3, 63.5, 62.4, 55.4 ppm; HR-FAB MS [M + Na] calcd
(
1
H
78
O
24Na 1553.4781, found 1553.4755.
6-O-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyl)-
(d, 1H, J1′,2′ = 7.8 Hz, H-1′), 4.86–4.80 (m, 2H, 2 × CHPh), 2,3,4-tri-O-benzyl-α-D-glucopyranoside (37) was obtained from
4
.74–4.39 (m, 7H, H-1, 6a′, 6b′, 4 × CHPh), 4.13 (d, 1H, J6a,6b
=
donor 26 and acceptor 2 under the general glycosylation
1
1.4 Hz, H-6a), 3.87–3.82 (m, 1H, H-5′), 3.85 (dd, 1H, H-6b), method A in 97% yield (β only) as a white amorphous solid.
3
.57 (dd, 1H, J3,4 = 8.3 Hz, H-3), 3.42–3.33 (m, 3H, J5,6a = 4.2 The analytical data for 37 was in accordance with that pre-
7
4 1
Hz, H-2, 4, 5), 2.34 (s, 3H, CH
3
) ppm.
3
viously reported. H NMR (300 MHz, CDCl ): δ 8.09–7.11 (m,
(
3β)-Cholest-5-en-3-yl 2,3,4,6-tetra-O-benzoyl-β-D-glucopyra- 35H, aromatic), 5.97 (d, 1H, J4′,5′ = 2.7 Hz, H-4′), 5.85, (dd, 1H,
noside (23) was obtained from donor 1 and acceptor 12 under 2′,3′ = 10.4 Hz, H-2′), 5.60 (dd, 1H, J3′,4′ = 3.5 Hz, H-3′) 4.90 (d,
the general glycosylation method A in 77% yield (β only) as a 1H, J = 10.9 Hz, CHPh), 4.76 (d, 1H, J1′,2′ = 8.0 Hz, H-1′), 4.72
J
2
2
2
white solid. The analytical data for 23 was in accordance with (d, 1H, J = 12.0 Hz, CHPh), 4.69 (d, 1H, J = 10.9 Hz, CHPh),
6
9 1
2
that previously reported.
7
H NMR (300 MHz, CDCl
3
): δ 8.01, 4.67 (dd, 1H, J6a′,6b′ = 11.3 Hz, H-6a′), 4.58 (d, 1H, J = 12.0 Hz,
.96, 7.90 and 7.84 (4 d, 8H, aromatic), 7.57–7.26 (m, 12H, aro- CHPh), 4.56 (d, 1H, J = 11.2 Hz, CHPh), 4.51 (d, 1H, J1,2 = 3.5
matic), 5.90 (dd, 1H, J3,4 = 9.7 Hz, H-3), 5.63 (dd, 1H, H-4), 5.50 Hz, H-1), 4.40 (dd, 1H, H-6b′), 4.38 (d, 1H, J = 11.2 Hz, CHPh),
dd, 1H, J2,3 = 9.7 Hz, H-2), 5.22 (d, 1H), 4.94 (d, 1H, J1,2 = 7.9 4.24–4.19 (m, 1H, J5′,6a′ = 6.4, J5’,6b′ = 6.8 Hz, H-5′), 4.21 (dd,
Hz, H-1), 4.60 (dd, 1H, J6a,6b = 12.0 Hz, H-6a), 4.52 (dd, 1H, 1H, J6a,6b = 12.7 Hz, H-6a), 3.89 (dd, 1H, J3,4 = 9.2 Hz, H-3),
H-6b), 4.18–4.12 (m, 1H, J5,6a = 3.3, J5,6b = 5.9 Hz, H-5), 3.53 3.77–3.74 (m, 2H, J5,6a = 4.2 Hz, H-5, H-6b), 3.40 (dd, 1H, J2,3
2
2
(
=
3
(m, 1H), 2.17–2.16 (m, 2H), 2.02–1.69 (m, 2H), 1.60–1.57 (m, 9.6 Hz, H-2), 3.38 (dd, 1H, H-4), 3.20 (s, 3H, OCH ) ppm.
1
H), 0.91 (d, 3H, J = 6.5 Hz), 0.89 (s, 3H), 0.87 (d, 3H, J = 6.6
Methyl 6-O-(2,3,4,6-tetra-O-benzoyl-α-D-mannopyranosyl)-
2,3,4-tri-O-benzyl-α-D-glucopyranoside (38) was obtained from
Hz), 0.86 (d, 3H, J = 6.6 Hz), 0.65 (s, 3H) ppm.
-Adamantyl
24) was obtained from donor 1 and acceptor 13 under the method A in 92% yield (α only) as a white amorphous solid.
general glycosylation method A in 96% yield (β only) as a The analytical data for 38 was in accordance with that pre-
1
2,3,4,6-tetra-O-benzoyl-β-D-glucopyranoside donor 27 and acceptor 2 under the general glycosylation
(
6
3 1
white solid. The analytical data for 24 was in accordance viously reported. H NMR (300 MHz, CDCl
with that previously reported.
8
5
3
): δ 8.09–7.25 (m,
): δ 35H, aromatic), 6.07 (dd, 1H, J4′,5′ = 10.0 Hz, H-4′), 5.86 (dd,
.03–7.90 (m, 8H, aromatic), 7.85–7.26 (m, 12H, aromatic), 1H, J3′,4′ = 3.1 Hz, H-3′), 5.72 (dd, 1H, J2′,3′ = 1.7 Hz, H-2′), 5.15
.92 (dd, 1H, J3,4 = 9.6 Hz, H-3), 5.55 (dd, 1H, J4,5 = 10.0 Hz, (d, 1H, J1′,2′ = 1.5 Hz, H-1′), 5.00 (dd, 2H, CH Ph), 4.84–4.78 (m,
7
0 1
H NMR (300 MHz, CDCl
3
2
H-4), 5.49 (dd, 1H, J2,3 = 8.0 Hz, H-2), 5.13 (d, 1H, J1,2 = 7.9 2H, 2 × CHPh), 4.70–4.61 (m, 4H, J1,2 = 3.6 Hz, H-1, 6a′,
Hz, H-1), 4.59 (dd, 1H, J6a,6b = 11.9 Hz, H-6a), 4.48 (dd, 1H, CH Ph), 4.40–4.35 (m, 1H, J = 4.3 Hz, H-5′), 4.30 (dd, 1H,
2
5′,6a′
H-6b), 4.19 (ddd, 1H, J5,6a = 3.0 Hz, J5,6b = 7.1 Hz, H-5), 2.02 H-6b′), 4.03 (dd, 1H, J3,4 = 9.2 Hz, H-3), 3.96–3.91 (dd, 1H,
s, 3H), 1.82 (d, 3H, J = 11.3 Hz), 1.63 (d, 3H, J = 11.4 Hz), H-6a), 3.88–3.78 (m, 2H, J5,6a = 4.9 Hz, H-5, 6b), 3.58–3.49 (m,
(
1
.50 (dd, 6H) ppm.
2H, J4,5 = 9.3 Hz, H-2, 4), 3.45 (s, 3H, OCH ) ppm.
3
3228 | Org. Biomol. Chem., 2021, 19, 3220–3233
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Methyl 6-O-(2,3,4,6-tetra-O-benzyl-D-glucopyranosyl)-2,3,4- 5H, J3,4 = 9.2 Hz, H-3, 4′, 5′, 6a′, 6b′), 3.66–3.62 (m, 2H, H-5,
tri-O-benzyl-α-D-glucopyranoside (39) was obtained from donor 6a), 3.38 (dd, 1H, J2,3 = 9.7 Hz, H-2), 3.26 (dd, 1H, J4,5 = 9.2 Hz,
2
7
8 and acceptor 2 under the general glycosylation method B in H-4), 3.13 (s, 3H, OCH
3
), 2.20–2.45 (m, 4H, CH
2 2
CH ), 1.91 (s,
1
3
1% yield (α/β = 1/1.5) as a white amorphous solid. The 3H, COCH
3
) ppm; C NMR (75 MHz, CDCl ): δ 205.7, 172.0,
3
analytical data for 39 was in accordance with that previously 168.2, 167.5, 138.7, 138.2 138.1, 137.9, 137.8, 133.8, 131.5,
7
6 1
reported.
aromatic), 4.98–4.35 (m, 15H), 4.34 (d, 1H, J1′,2′ = 7.7 Hz, H-1′), (×4), 127.8 (×3), 127.7 (×5), 127.6, 123.4, 98.2, 97.9, 81.9, 79.7,
.20–3.42 (m, 12H), 3.35–3.32 (2 s, 6H, 2 × OCH ) ppm. 77.7, 75.8, 75.1, 74.8, 74.6, 73.5 (×2), 73.4, 73.3, 69.3, 68.6 (×2),
3
H NMR (300 MHz, CDCl ): δ 7.32–7.16 (m, 35H, 128.5 (×2), 128.4 (×6), 128.3 (×2), 128.2 (×2), 128.0 (×3), 127.9
4
3
+
Methyl 6-O-(2,3,4,6-tetra-O-benzyl-D-galactopyranosyl)-2,3,4- 54.9, 37.6, 29.8, 29.5, 27.8 ppm; HRMS [M + Na] calcd for
+
tri-O-benzyl-α-D-glucopyranoside (40) was obtained from donor [C61
H
63NO14Na] 1056.4146 found 1056.4164.
Methyl 6-O-(6-O-benzoyl-4-O-benzyl-2-deoxy-3-O-levulinoyl-
7% yield (α/β = 1/1.1) as a white amorphous solid. The 2-phthalimido-β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-gluco-
3
9
2 and acceptor 2 under the general glycosylation method A in
analytical data for 40 was in accordance with that previously pyranoside (44) was obtained from donor 35 and acceptor 2 by
7
9 1
reported.
H NMR (300 MHz, CDCl ): δ 7.33–7.24 (m, 35H, general method B in 79% yield (β-only) as a white foam.
3
aromatic), 4.99–4.33 (m, 15H), 4.32 (d, 1H, J1′,2′ = 7.6 Hz, H-1′), Analytical data for 44: R
f
= 0.60 (ethyl acetate/hexane, 45/55,
2
3
1
4
.16–3.41 (m, 12H), 3.28 (2 s, 6H, 3 × OCH
Methyl 6-O-(2,3,4,6-tetra-O-benzyl-D-mannopyranosyl)-2,3,4- 8.06 (d, 2H, J = 7.5 Hz, aromatic), 7.77–7.21 (m, 25H, aromatic),
tri-O-benzyl-α-D-glucopyranoside (41) was obtained from donor 7.01–6.99 (dd, 2H, J = 3.1 Hz, aromatic), 5.89 (dd, 1H, J3′,4′ = 8.8
3
) ppm.
D
3 3
v/v); [α] + 33.7 (c 1.0, CHCl ); H NMR (300 MHz, CDCl ): δ
2
3
0 and acceptor 2 under the general glycosylation method B in Hz, H-3′), 5.46 (d, 1H, J1′,2′ = 8.5 Hz, H-1′), 4.83 (d, 1H, J = 10.8
9
1% yield (α/β = 1/1.4) as an off-white amorphous solid. The Hz, CHPh), 4.72–4.51 (m, 7H, H-6a′, 6b′, 5 × CHPh), 4.39–4.35
analytical data for 41 was in accordance with that previously (m, 3H, J1,2 = 3.4 Hz, H-1, 2′, CHPh), 4.11–4.05 (m, 2H, H-6b,
8
0 1
reported.
3
H NMR (300 MHz, CDCl ): δ 7.40–7.12 (m, 35H, CHPh), 3.93 (m, 1H, H-5′), 3.87–3.78 (m, 2H, J3,4 = 8.9 Hz, H-3,
aromatic), 5.04–4.41 (m, 16H), 4.18–3.36 (m, 12H), 3.32–3.30 (2 4′), 3.68–3.61 (m, 2H, H-5, 6a), 3.37 (dd, 1H, J2,3 = 9.7 Hz, H-2),
s, 6H, 2 × OCH
3
) ppm.
3.23 (dd, 1H, J4,5 = 9.6 Hz, H-4), 3.11 (s, 3H, OCH
3
), 2.48–2.29
1
3
Methyl
6-O-(2,6-di-O-benzoyl-4-O-benzyl-3-O-tert-butyldi- (m, 4H, CH
2
CH ), 1.91 (s, 3H, COCH ) ppm;
2
3
C NMR
methylsilyl-β-D-galactopyranosyl)-2,3,4-tri-O-benzyl-α-D-gluco- (75 MHz, CDCl ): δ 205.7 (×2), 172.0 (×2), 166.2, 138.7, 138.1,
3
pyranoside (42) was obtained from donor 33 and acceptor 2 137.7, 137.3, 133.9, 133.2, 131.4, 129.8 (×3), 128.5 (×7), 128.4
by general method A in 93% yield (β-only) as a white foam. (×3), 128.3 (×3), 128.1 (×3), 128.0 (×6), 127.9 127.7 (×3), 127.6,
Analytical data for 42: R = 0.60 (ethyl acetate/toluene, 12/88, 123.4, 98.3, 97.9, 81.9, 79.6, 76.6, 75.7, 74.8, 74.7, 73.4 (×2),
f
2
3
1
v/v); [α]D + 25.3 (c 1.0, CHCl
.98 (m, 4H, aromatic), 7.58–7.23 (m, 26H, aromatic), 7.11 Na] calcd for [C61
dd, 2H, aromatic), 5.66 (dd, 1H, J = 8.6 Hz, H-2′), 5.11 (d, Methyl 6-O-(2,3,4-tri-O-benzoyl-α-L-rhamnopyranosyl)-2,3,4-
3 3
); H NMR (300 MHz, CDCl ): δ 73.2, 69.2, 68.6, 63.4, 54.9, 37.6, 29.5, 27.8 ppm; HRMS [M +
+
+
7
(
H61NO15Na] 1070.3939 found 1070.3954.
2
′,3′
2
2
1
4
×
H, J = 11.3 Hz, CHPh), 4.87 (d, 1H, J = 11.0 Hz, CHPh), tri-O-benzyl-α-D-glucopyranoside (45) was obtained from donor
.71–4.35 (m, 10H, J1,2 = 3.3, J1′,2′ = 8.6 Hz, H-1, 1′, 6a′, 6b′, 3 36 and acceptor 2 under the general glycosylation method A in
CH Ph), 4.12 (m, 1H, H-6b), 3.97 (br d, 1H, H-3′), 3.89–3.82 79% yield (α only) as a white foam. The analytical data for 47
2
8
4 1
(
m, 3H, J2,3 = 10.1 Hz, H-3, 4′, 5′), 3.68–3.60 (m, 2H, H-5, 6a), was in accordance with that previously reported.
H NMR
3
.39–3.29 (m, 2H, H-2, 4), 3.13 (s, 3H, OCH ), 0.79 (s, 9H, (300 MHz, CDCl ): δ 8.08 (d, 2H, J = 7.6 Hz, aromatic), 7.97 (d,
3
3
t
13
Si Bu), 0.12, −0.06 (2 s, 6H, SiMe ) ppm; C NMR (75 MHz, 2H, J = 7.6 Hz, aromatic), 7.81 (d, 2H, J = 7.7 Hz, aromatic),
2
CDCl
3
): δ 166.3, 165.0, 138.9, 138.3 (×2), 138.2, 133.2, 132.9, 7.61–7.23 (m, 24H, aromatic), 5.80 (dd, 1H, J3′,4′ = 10.1 Hz,
1
1
1
6
−
30.2, 129.9, 129.8 (×2), 129.6 (×2), 128.5 (×2), 128.4 (×4), H-3′), 5.67–5.60 (m, 2H, J2′,3′ = 3.4 Hz, J4′,5′ = 9.9 Hz, H-2′, 4′),
28.3 (×5), 128.1 (×4), 127.9 (×3), 127.8, 127.7 (×2), 127.6, 5.05–4.93 (m, 3H, J1′,2′ = 5.3 Hz, H-1′, CH Ph), 4.87–4.81 (m,
2
2 2
27.5, 101.6, 97.7, 82.0, 80.0, 75.5, 75.1, 74.7, 73.3, 72.5, 69.5, 2H, CH Ph), 4.72–4.61 (m, 3H, J1,2 = 2.9 Hz, H-1, CH Ph), 4.16
7.8, 63.7, 54.9 (×2), 29.8, 25.6 (×3), 17.9 (×2), −3.9, (m, 1H, J5′,6′ = 6.2 Hz, H-5′), 4.05 (dd, 1H, J3,4 = 9.4 Hz, H-3),
+
+
5.0 ppm; HRMS [M + Na] calcd for [C H O SiNa]
3.97–3.94 (m, 1H, H-6a), 3.86 (m, 1H, H-5), 3.65–3.52 (m, 3H,
2,3 = 9.2 Hz, J4,5 = 10.3 Hz, H-2, 4, 6b), 3.46 (s, 3H, OCH ), 1.31
Methyl 6-O-(4,6-di-O-benzyl-2-deoxy-3-O-levulinoyl-2-phtha- (d, 3H, H-6′) ppm.
6
1
70 13
1
061.4483 found 1061.4500.
J
3
limido-β-D-glucopyranosyl)-2,3,4-tri-O-benzyl-α-D-glucopyrano-
side (43) was obtained from donor 34 and acceptor 2 by
general method B in 73% yield (β-only) as a white foam.
Conflicts of interest
Analytical data for 43: R = 0.60 (ethyl acetate/hexane, 1/1, v/v);
f
There are no conflicts to declare.
2
3
1
[
α] + 30.6 (c 1.0, CHCl
3
); H NMR (300 MHz, CDCl
3
): δ
D
7
.75–7.18 (m, 27H, aromatic), 7.01 (dd, 2H, J = 3.2 Hz, aro-
matic), 5.82 (dd, 1H, J3 = 8.3 Hz, H-3′), 5.40 (d, 1H, J1′,2′ = 8.5
′,4′
2
Acknowledgements
Hz, H-1′), 4.85 (d, 1H, J = 10.8 Hz, CHPh), 4.73–4.53 (m, 7H, 7
2
×
CHPh), 4.42–4.27 (m, 3H, J1,2 = 3.5, J2′,3′ = 9.6, J = 10.6 Hz, This work was supported by grants from the NIGMS
H-1, 2′, CHPh), 4.15–4.10 (m, 2H, H-6b, CHPh), 3.87–3.74 (m, (GM111835) and the NSF (CHE-1058112).
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6
1
-glycosides and related compounds, Chem. Pharm. Bull.,
994, 42, 1479–1484.
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