Stereocontrolled α-Galactosylation under Cooperative Catalysis

Article abstract of DOI:10.1021/acs.joc.0c01279

A recent discovery of a cooperative catalysis comprising a silver salt and an acid led to a dramatic improvement in the way glycosyl halides are glycosidated. Excellent yields have been achieved, but the stereoselectivity achieved with 2-O-benzylated donors was poor. Reported herein is our first attempt to refine the stereoselectivity of the cooperatively catalyzed galactosylation reaction. Careful optimization of the reaction conditions along with studying effects of the remote protecting groups led to excellent stereocontrol of α-galactosylation of a variety of glycosyl acceptors with differentially protected galactosyl donors.

Full text of DOI:10.1021/acs.joc.0c01279

pubs.acs.org/joc
Article
Stereocontrolled α‑Galactosylation under Cooperative Catalysis
Melanie Shadrick, Yashapal Singh, and Alexei V. Demchenko*
Cite This: https://dx.doi.org/10.1021/acs.joc.0c01279
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A recent discovery of a cooperative catalysis
comprising a silver salt and an acid led to a dramatic improvement
in the way glycosyl halides are glycosidated. Excellent yields have
been achieved, but the stereoselectivity achieved with 2-O-
benzylated donors was poor. Reported herein is our first attempt
to refine the stereoselectivity of the cooperatively catalyzed
galactosylation reaction. Careful optimization of the reaction
conditions along with studying effects of the remote protecting
groups led to excellent stereocontrol of α-galactosylation of a
variety of glycosyl acceptors with differentially protected galactosyl
donors.
these significant advancements, completely stereocontrolled
1,2-cis glycosylation remains a notable challenge in chemical
synthesis.8
INTRODUCTION
■
Construction of the biologically relevant glycans has been a
great challenge since the first chemical glycosidations of
glycosyl halides performed by Michael,1 Koenigs−Knorr,2 and
Fischer.3 A rigorous study of chemical glycosylation gave
straightforward access to many 1,2-trans glycosidic linkages
that can be reliably achieved with the aid of a neighboring
participating ester group at C-2.4−7 Conversely, there is no
universal method for installing 1,2-cis glycosidic linkages.8
Early work by Helferich, Zemplen, and others has enhanced
our understanding of the synthesis of 1,2-cis glycosides with
glycosyl halides as donors.9−12 However, these studies did not
lead to practical application in the synthesis of complex
oligosaccharides. Since then, many improvements for the
construction of 1,2-cis glycosides with glycosyl halides have
emerged: employing bases as acid scavengers,2,13−16 alcohol-
ysis of glycosyl halides with or without halide additives,17−19
halide-ion catalyzed glycosylation,20−22 conversion of anomeric
halides to positively charged leaving groups,23,24 β- to α-
glycoside anomerization,25−27 in situ generation and glyco-
sylation of glycosyl bromides from thioglycosides,28 bromine-
promoted glycosylation,29,30 etc.
Due to their general instability, low reactivity profile, and the
requirement for excess toxic reagents for their activation,
glycosyl halides have been superseded by other glycosyl donors
at the forefront of modern oligosaccharide synthesis. In recent
years, imidates, thioglycosides, and phosphates were found to
be more advantageous.8 Many current methods employed for
1,2-cis glycosylation rely on these glycosyl donors in
combination with other effects including steric factors,31,32
remote participation,33−37 chiral auxiliaries,38−41 H-bond-
mediated aglycone delivery (HAD),42 modification of
catalysts,43−45 or glycosylation modulators.46,47 In spite of
Recently, glycosyl chlorides have been progressively gaining
interest after Ye48 and Jacobsen49 reported organocatalyzed
activation for the α- and β-stereoselective glycosidation,
respectively. A new method for highly stereoselective 1,2-cis
glycosylation with glycosyl bromides has also been recently
reported.16 However, glycosidation of glycosyl halides may be
very slow, even at elevated temperatures. Recently, our group
has introduced a cooperative catalysis approach for the
activation of glycosyl halides.50 An acid and a silver salt
applied together have changed the fate of glycosyl halides by
leading to a drastically reduced glycosylation reaction time to
as low as 2 min and a dramatic increase in the yields of
glycosides.51 However, our previous cooperatively catalyzed
reactions were nonstereoselective, and reported herein is our
first attempt to investigate 1,2-cis α-stereoselective galactosy-
lation.
RESULTS AND DISCUSSION
■
In the effort to investigate 1,2-cis stereoselective glycosylation
we chose to focus on galactosyl bromide donors. One of the
driving forces for this selection is the fact that the HAD
method that gives excellent syn-selectivity in application to β-
mannosides52 and α-glucosides53 cannot be applied to α-
Special Issue: A New Era of Discovery in Carbohy-
drate Chemistry
Received: May 28, 2020
https://dx.doi.org/10.1021/acs.joc.0c01279
© XXXX American Chemical Society
J. Org. Chem. XXXX, XXX, XXX−XXX
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
galactosides because all remote substituents are pointing
upward (anti). Another motivation to investigate α-galactosy-
lation was due to the very unexpected β-stereoselectivity
observed in our recent work with galactosyl bromides.50
Glycosidation of per-benzoylated bromide 2a generated from
the corresponding thioglycoside 1a with glycosyl acceptor 354
provided disaccharide 4a with complete β-stereoselectivity due
to the participation of a 2-O-benzoyl neighboring group (Table
1, entry 1). This glycosylation was performed in the presence
improving the stereoselectivity. Previous studies demonstrated
that acyl groups at various remote positions may have a
profound effect on the stereoselectivity of glycosylation.55−58
To understand the effects of remote substituents on
cooperatively catalyzed galactosylations, we obtained thiogly-
cosides 1c and 1d, equipped with a 6-OBz and 4-OBz
substituent, respectively. The corresponding galactosyl bro-
mides 2c and 2d were generated in situ and activated in the
presence of Ag2O (3.0 equiv) and TMSOTf (0.25 equiv).
Glycosidation of 6-OBz bromide 2c with acceptor 3 was largely
disappointing because it produced disaccharide 4c in a good
yield of 84% albeit preferential β-stereoselectivity (α/β = 1:3.0,
entry 4). Encouragingly, galactosyl bromide 2d afforded
disaccharide 4d56 in 80% yield with a marginal shift toward
α-stereoselectivity (α/β = 2.9:1, entry 5). From these results, it
was apparent that only the benzoyl group at the C-4 position
offers a promising structural feature for the galactosyl donor
favoring α-1,2-cis stereoselectivity.
Table 1. Comparative Glycosidation of Galactosyl Bromides
2a−d and Optimization of the Reaction Conditions
To enhance the utility of this galactosylation we then
endeavored to optimize the reaction conditions bearing the
following considerations. We note that some reactions were
accompanied by a competing silyl transfer to the glycosyl
acceptor that explains compromised yields of disaccharides
seen in a number of experiments. Hence, we replaced
TMSOTf with trifluoromethanesulfonic acid (TfOH), which
provided comparable results in our previous study,51 to avoid
the silyl transfer side reaction. All previous reactions were
conducted at 0 °C followed by slowly bringing the reaction
temperature to ambient. Hence, we wondered if modifying the
reaction temperature would offer a better means for the
stereocontrol. After preliminary screening, we found that the
reaction of galactosyl bromide 2d with glycosyl acceptor 3 in
the presence of Ag2O (3.0 equiv) and TfOH (0.15 equiv) at
−10 °C affords disaccharide 4d in 72% yield with a further
improved α-stereoselectivity (α/β = 5.0:1, entry 6). A decrease
in temperature to −30 °C produced disaccharide 4d in a
respectable yield and even higher stereoselectivity (82%, α/β =
11:1, entry 7). Further cooling to −50 °C (or −70 °C) did not
enhance the stereoselectivity but led to a decreased yield (67%,
α/β = 11:1, entry 8).
We then endeavored to change the source of the silver
promoter and replaced silver(I) oxide with silver(I) sulfate
(Ag2SO4). After preliminary screening, we noticed that the
same stereoselectivity albeit with a much higher yield could be
achieved in the presence of only 1.0 equiv of Ag2SO4, along
with 0.20 equiv of TfOH. Thus, disaccharide 4d was produced
in an excellent yield of 95% and high stereoselectivity (α/β =
11:1, entry 9). This reaction was much slower than the
previous experiments. As a matter of fact, it was not proceeding
at −30 °C during the initial 5 h. When the external cooling was
removed, the reaction required an additional 13 h to complete.
The subsequent experiment was performed with a larger
amount of Ag2SO4 (1.50 equiv) and at higher reaction
temperature (−10 °C). As a result, disaccharide 4d was
produced in only 1 h in an excellent yield of 92% and with a
similar stereoselectivity (α/β = 11.5:1, entry 10). A further
increase in the starting reaction temperature to 0 °C followed
by warming to room temperature produced disaccharide 4d in
a similar yield, but the stereoselectivity dropped (87%, α/β =
6.0:1, entry 11). Nevertheless, we chose this latter experiment
as the benchmark for our subsequent study. This choice was
driven by experimental convenience as opposed to low
Product,
Entry Donor
Conditions
yield, α/β
150
250
3
2a
2b
2b
2c
2d
2d
2d
2d
2d
2d
2d
Ag2O (3.0 equiv), TMSOTf (0.25 equiv),
0 °C→rt, 10 min
Ag2O (3.0 equiv), TMSOTf (0.10 equiv),
0 °C→rt, 15 min
Ag2O (3.0 equiv), TMSOTf (0.25 equiv),
0 °C→rt, 15 min
Ag2O (3.0 equiv), TMSOTf (0.25 equiv),
4a, 99%,
β-only
4b, 96%,
1:20
4b, 71%,
1.0:1
4c, 84%,
1:3.0
4
0 °C→rt, 1 h
5
Ag2O (3.0 equiv), TMSOTf (0.25 equiv), 0 4d, 80%,
°C→rt, 3 h 2.9:1
Ag2O (3.0 equiv), TfOH (0.15 equiv), −10 4d, 72%,
6
°C, 1.5 h
5.0:1
4d, 82%,
11:1
4d, 67%,
11:1
4d, 95%,
11:1
4d, 92%,
11.5:1
4d, 87%,
6.0:1
7
Ag2O (3.0 equiv), TfOH (0.15 equiv),
−30 °C, 2 h
8
Ag2O (3.0 equiv), TfOH (0.20 equiv),
−50 °C, 3 h
9
Ag2SO4 (1.0 equiv), TfOH (0.20 equiv),
−30 °C → rt, 18 h
Ag2SO4 (1.5 equiv), TfOH (0.20 equiv),
10
11
−10 °C, 1 h
Ag2SO4 (1.5 equiv), TfOH (0.20 equiv),
0 °C→rt, 1 h
of Ag2O (3.0 equiv) and TMSOTf (0.25 equiv).50 However,
when galactosyl bromide 2b generated from per-benzylated
thioglycoside precursor 1b, was coupled with glycosyl acceptor
3, rather unexpectedly disaccharide 4b was obtained in 96%
yield with a nearly complete β-stereoselectivity (α/β = 1:20,
entry 2). This glycosylation was performed in the presence of
Ag2O (3.0 equiv) and TMSOTf (0.10 equiv).50 With a general
idea of developing universal reaction conditions that would be
applicable to all kinds of substrates, we repeated glycosidation
of 2b in the presence of Ag2O (3.0 equiv) using the larger
amount of TMSOTf (0.25 equiv). Strikingly, increasing the
amount of TMSOTf resulted in a complete loss of stereo-
selectivity and a significant reduction of the yield of 4b that
dropped to 71% (entry 3).
Methods for enhancing α-stereoselectivity of galactosylation
exist. Among these, utilizing the remote protecting group
participation appealed to us as a promising next step toward
B
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
temperature experiments that are more tedious to set up and
maintain.
Table 3. Expanding the Scope of Glycosidation of Donors 2f
and 2g with Acceptors 5−9
Under the established reaction conditions, with the addition
Ag2SO4 (1.5 equiv) and TfOH (0.20 equiv) and a starting
reaction temperature of 0 °C which was allowed to warm to
room temperature, whereas 4-OBz donor 4d showed good
stereoselectivity (α/β = 6.0:1, Table 2, entry 1), galactosyl
Table 2. Comparative Glycosidation of Galactosyl Bromides
2b−g under Optimized Reaction Conditions
Entry
Donor
Time
1 h
1.5 h
1 h
1 h
30 min
2 h
Product, yield, α/β
1
2
3
4
5
6
2d (4-OBz)
2b (all-OBn)
2c (6-OBz)
2e (3,4,6-OBz)
2f (4,6-OBz)
2g (3,4-OBz)
4d, 87%, 6.0:1
4b, 87%, 1:1.2
4c, 75%, 1:2.7
4e, 97%, α-only
4f, 93%, 33:1
4g, 96%, α-only
Figure 1. Standard glycosyl acceptors 5−9 for broadening the scope
of α-galactosylation
bromides 2b and 2c failed. Thus, per-OBn bromide 2b and 6-
OBz bromide 2c produced the respective disaccharides 4b and
4c in good yields albeit with preferential β-stereoselectivity (α/
β = 1/1.2−2.7, entries 2 and 3). These results reinforce our
previous assumption that the 4-OBz group is essential for
achieving preferential α-stereoselectivity. To elaborate on this,
we obtained a further series of differentially polybenzoylated
ethylthio galactosides 1e−g. The corresponding bromides were
then generated in situ followed by their glycosidation with
acceptor 3. Galactosyl bromide donor 2e equipped with three
benzoyl substituents at C-3, -4, and -6 provided disaccharide
4e in 97% yield with complete α-stereoselectivity (entry 4).
Although galactosyl bromide 2e is equipped with the
electronically superdisarming protecting group pattern,59 the
reaction readily completed within 1 h. Glycosidation of 4,6-
OBz galactosyl bromide 2f was faster, and the corresponding
disaccharide 4f was smoothly produced in only 30 min in 93%
yield and with nearly complete stereoselectivity (α/β = 33/1,
entry 5). Glycosidation of 3,4-OBz galactosyl bromide 2g was
slower (2 h), but the corresponding disaccharide 4g was
smoothly produced in 96% yield with complete α-stereo-
selectivity (entry 6).
C
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
°C. Molecular sieves (3 Å) used for reactions were crushed and
activated under vacuum for 8 h at 390 °C in the first instance, and
then for 2−3 h at 390 °C directly prior to application. Optical
Excellent yields and α-stereoselectivity achieved with
galactosyl bromide donors 2e−g and primary glucosyl acceptor
3 prompted us to broaden the scope of the cooperatively
catalyzed 1,2-cis glycosylation. For this study, we selected
dibenzoylated galactosyl bromides 2f and 2g due to the ease of
their preparation from the corresponding cyclic acetal/ketal-
protected precursors. We also chose a series of glycosyl
acceptors including secondary alcohols 5−754 and primary
alcohols of differential reactivity, highly reactive diacetone
galactose 8, and electronically deactivated compound 960
(Figure 1). Results for reactions between glycosyl donors 2f
and 2g and different glycosyl acceptors 5−9 are listed in Table
3. Glycosylation between donor 2f and 2-OH acceptor 5 was
very efficient in the presence of Ag2SO4 (1.5 equiv) and TfOH
(0.20 equiv) at 0 °C to rt. As a result, disaccharide 10 was
obtained in 3 h in 91% yield and with complete α-
stereoselectivity (entry 1). Glycosidation of donor 2f with
the less reactive 3- and 4-OH acceptors 6 and 7 was slower,
and to enhance the utility we increased the amount of TfOH
to 0.40 equiv. As a result, disaccharides 11 and 12 were
obtained in 6 h in 73% and 49% yield, respectively, with
complete α-stereoselectivity in both cases (entries 2 and 3).
Glycosidations of donor 2f with differently protected
primary acceptors were performed using 0.20 equiv of
TfOH. Under these reaction conditions, diacetone galactose
acceptor 8 gave disaccharide 1358 in 68% yield and good α-
selectivity (α/β = 11/1, entry 4). Glycosylation of a much less
reactive benzoylated 6-OH acceptor 9 with donor 2f gave
disaccharide 14 in 87% yield and with complete α-stereo-
selectivity (entry 5). A practically identical trend was observed
during glycosylations with 3,4-OBz protected bromide 2g
(Table 3). All glycosylations were rather swift (2−6 h), and the
respective disaccharide derivatives 15−19 were produced in
good yields of 65−97% with practically complete stereo-
selectivity in all cases (α/β > 25/1 to α-only, entries 6−10).
In conclusion, combined effects of the cooperative catalysis
and remote participation of benzoyl groups led us to develop a
powerful new method for stereocontrolled α-galactosylation.
This method has the following four (conservatively estimated)
advantages in comparison with the known methods. First, the
ease of the synthesis of glycosyl donors and a rapid in situ
conversion to the corresponding bromides. Second, no
specialized protecting groups are required; only altering
positions of common benzyl and benzoyl groups provide
high to exclusive α-stereoselectivity. Third, the reaction
duration is relatively short, and the reaction can be conducted
at ambient temperature without losing stereoselectivity.
Fourth, promoter systems are stable, not environment
sensitive, and commonly available. Further development of
the methodology and its application to the stereoselective
synthesis of biologically relevant molecules are currently
underway in our laboratory.
1
rotations were measured by a Jasco P2000 polarimeter. H and 13C
NMR spectra were recorded in CDCl3 at 300 and 75 MHz,
respectively. 1H NMR was calibrated to tetramethylsilane (TMS, δH =
0 ppm) in CDCl3. 13C NMR was calibrated to the central signal of
CDCl3 (δC = 77.00 ppm) in CDCl3. HRMS analysis was performed
using an Agilent 6230 ESI TOF LC/MS mass spectrometer.
Synthesis of Thioglycoside Donors. Ethyl 2,3,4,6-Tetra-O-
benzoyl-1-thio-β-D-galactopyranoside (1a). 1a was synthesized as
previously reported,61 and its analytical data were in accordance with
those reported previously.61
Ethyl 2,3,4,6-Tetra-O-benzyl-1-thio-β-D-galactopyranoside (1b).
1b was synthesized as previously reported,28 and its analytical data
were in accordance with those reported previously.28
Ethyl 6-O-Benzoyl-2,3,4-tri-O-benzyl-1-thio-β-D-galacto-
pyranoside (1c). A solution of ethyl 2,3,4-tri-O-benzyl-1-thio-β-D-
galactopyranoside (20,62 2.34 g, 4.73 mmol) in pyridine (40 mL) was
cooled to 0 °C. Benzoyl chloride (0.82 mL, 7.09 mmol) was added
dropwise followed by the addition of 4-dimethylaminopyridine
(DMAP, 115.6 mg, 0.95 mmol), the external cooling was removed,
and the resulting mixture was stirred under argon for 16 h at rt.
Afterward, the reaction was quenched with MeOH (∼10 mL), the
volatiles were removed under reduced pressure, and the residue was
coevaporated with toluene (4 × 10 mL). The resulting residue was
dissolved in CH2Cl2 (∼40 mL) and washed with 1 N aq. HCl (15
mL), sat. aq. NaHCO3 (15 mL), and water (2 × 15 mL). The organic
phase was separated, dried with MgSO4, and concentrated under
reduced pressure. The residue was purified by column chromatog-
raphy on silica gel (ethyl acetate−hexane 10% gradient elution) to
afford the title compound as a white amorphous solid (2.25 g, 3.75
mmol, 80% yield). Analytical data for 1c: Rf1= 0.65 (EtOAc/hexanes,
3/7, v/v); [α]23 −13.2 (c = 1.0, CHCl3); H NMR (CDCl3 at 300
D
MHz): δ 7.99−7.88 (m, 2H, aromatic), 7.62−7.50 (m, 1H, aromatic),
2
7.48−7.15 (m, 17H, aromatic), 5.01 (d, 1H, J = 11.7 Hz, CHPh),
4.90 (d, 1H, 2J = 10.2 Hz, CHPh), 4.77 (dd, 4H, 4 × CHPh), 4.54−
4.42 (m, 2H, J1,2 = 9.7, J6a,6b = 11.2 Hz, H-1, 6a), 4.31 (dd, 1H, H-6b),
3.93−3.82 (m, 2H, J2,3 = 9.3 Hz, H-2, 4), 3.70 (m, 1H, J5,6a = 6.9, J5,6b
= 6.0 Hz, H-5), 3.61 (dd, 1H, J3,4 = 2.8 Hz, H-3), 2.85−2.63 (m, 2H,
SCH2CH3), 1.29 (t, 3H, SCH2CH3) ppm; 13C{1H} NMR (CDCl3 at
75 MHz): δ, 166.1, 138.2, 138.1 (×2), 133.1 129.7, 129.6 (×3), 128.4
(×2), 128.3 (×5), 128.2 (×2), 127.8, 127.7 (×2), 127.6 (×3), 85.3,
84.1, 78.4, 75.9, 75.8, 74.3, 73.2 (×2), 63.5, 24.9, 15.1 ppm; HR-FAB
MS [C36H38O6SNa]+ calcd for 621.2281, found 621.2290.
Ethyl 4-O-Benzoyl-2,3,6-tri-O-benzyl-1-thio-β-D-galacto-
pyranoside (1d). A solution of ethyl 2,3,6-tri-O-benzyl-1-thio-β-D-
galactopyranoside (21,63 1.50 g, 3.03 mmol) in pyridine (20 mL) was
cooled to 0 °C. Benzoyl chloride (0.53 mL, 4.55 mmol) was added
dropwise followed by addition of DMAP (74.5 mg, 0.61 mmol), the
external cooling was removed, and the resulting mixture was stirred
under argon for 16 h at rt. Afterward, the reaction was quenched with
MeOH (∼5 mL), the volatiles were removed under reduced pressure,
and the residue was coevaporated with toluene (3 × 5 mL). The
resulting residue was dissolved in CH2Cl2 (∼20 mL) and washed with
1 N aq. HCl (8 mL), sat. aq. NaHCO3 (8 mL), and water (2 × 8 mL).
The organic phase was separated, dried with MgSO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (ethyl acetate−hexane 10%
gradient elution) to afford the title compound as a white amorphous
solid (1.63 g, 2.73 mmol, 90% yield). Analytical data for 1d: Rf = 0.60
(EtOAc/hexanes, 3/7, v/v); [α]23D +13.0 (c = 1.0, CHCl3); 1H NMR
(CDCl3 at 300 MHz): δ 8.16−8.05 (m, 2H, aromatic), 7.59−7.14 (m,
EXPERIMENTAL SECTION
■
General. The reactions were performed using commercially
available reagents. CH2Cl2 used for reactions was distilled from
CaH2 prior to the application. Other ACS-grade solvents used for
reactions were purified and dried according to standard procedures.
Prior to the initial application, silver salts were coevaporated with
toluene (×2), dried in vacuo in the dark. Column chromatography was
performed on silica gel 60 (70−230 mesh); reactions were monitored
using Thin-Layer Chromatography (TLC) on Kieselgel 60 F254. TLC
was examined under UV light and by charring with 10% sulfuric acid
in methanol. Solvents were removed under reduced pressure at <40
2
18H, aromatic), 5.90 (br. d, 1H, H-4), 4.77 (dd, 2H, J = 10.2 Hz,
CH2Ph), 4.70 (dd, 2H, 2J = 11.4 Hz, CH2Ph), 4.54 (d, 1H, J1,2 = 9.1
2
Hz, H-1), 4.47 (dd, 2H, J = 11.7 Hz, CH2Ph), 3.84 (m, 1H, J5,6a
=
J
5,6b = 6.5 Hz, H-5), 3.72 (dd, 1H, J2,3 = 3.1 Hz, H-2), 3.71−3.59 (m,
2H, J6a,6b = 9.4 Hz, H-3, 6a), 3.53 (dd, 1H, H-6b), 2.79 (m, 2H,
SCH2CH3), 1.34 (t, 3H, SCH2CH3) ppm; 13C NMR (CDCl3 at 75
MHz): δ 165.6, 137.9, 137.6, 137.4, 133.1, 129.9 (×2), 129.7, 128.4
D
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(×4), 128.3 (×5), 128.2, 128.0 (×2), 127.8 (×2), 127.7 (×2), 127.6,
85.3, 81.0, 77.6, 75.9, 75.8, 73.6, 71.6, 68.2, 67.3, 24.8, 15.0 ppm; HR-
FAB MS [C36H38O6SNa]+ calcd for 621.2297, found 621.2290.
Ethyl 3,4,6-Tri-O-benzoyl-2-O-benzyl-1-thio-β-D-galacto-
pyranoside (1e). A solution of ethyl 2-O-benzyl-1-thio-β-D-galacto-
pyranoside (22,64 1.17 g, 3.72 mmol) in pyridine (20 mL) was cooled
to 0 °C. Benzoyl chloride (2.59 mL, 22.33 mmol, 6.0 equiv) was
added dropwise, followed by the addition of DMAP (90.4 mg, 0.74
mmol, 0.2 equiv). The external cooling was removed, and the
resulting mixture was stirred under argon for 16 h at rt. Afterward, the
reaction was quenched with MeOH (∼8 mL), the volatiles were
removed under reduced pressure, and the residue was coevaporated
with toluene (3 × 5 mL). The resulting residue was dissolved in
CH2Cl2 (∼30 mL) and washed with 1 N aq. HCl (10 mL), sat. aq.
NaHCO3 (10 mL), and water (2 × 10 mL). The organic phase was
separated, dried with MgSO4, and concentrated under reduced
pressure. The residue was purified by column chromatography on
silica gel (ethyl acetate−hexane 10% gradient elution) to afford the
title compound as a white amorphous solid (2.28 g, 3.64 mmol, 98%).
removed under reduced pressure, and the residue was coevaporated
with toluene. The resulting residue was dissolved in CH2Cl2 (∼40
mL) and washed with 1 N aq. HCl (15 mL), sat. aq. NaHCO3 (15
mL), and water (2 × 15 mL). The organic phase was separated, dried
with MgSO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (ethyl acetate−
hexane 10% gradient elution) to afford the title compound as a clear
syrup (4.22 g, 6.89 mmol, 90%). Analytical data for 1g: Rf = 0.75
(EtOAc/hexanes, 3/7, v/v); [α]23 +126.0 (c = 1.0, CHCl3); 1H
D
NMR (CDCl3 at 300 MHz): δ 8.06−7.93 (m, 2H, aromatic), 7.86−
7.74 (m, 2H, aromatic), 7.61 (d, 1H, aromatic), 7.53−7.42 (m, 3H,
aromatic), 7.37−7.05 (m, 12H, aromatic), 5.88 (d, 1H, H-4), 5.43
(dd, 1H, J3,4 = 3.4 Hz, H-3), 4.83 (d, 1H, 2J = 10.6 Hz, CHPh), 4.69
(d, 1H, J1,2 = 9.7 Hz, H-1), 4.61 (d, 1H, 2J = 10.6 Hz, CHPh), 4.51 (d,
1H, 2J = 11.8 Hz, CHPh), 4.40 (d, 1H, 2J = 11.8 Hz, CHPh), 4.04 (m,
1H, J5,6a = 6.2 Hz, H-5), 3.89 (dd, 1H, J2,3 = 9.6 Hz, H-2), 3.72−3.48
(m, 2H, H-6a, 6b), 2.93−2.76 (m, 2H, SCH2CH3), 1.38 (t, 3H,
SCH2CH3) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ 165.4 (×2),
137.5, 137.3, 133.3, 133.0, 129.8 (×3), 129.6 (×3), 129.5, 128.4 (×2),
128.3 (×2), 128.2 (×5), 127.7 (×3), 127.6, 85.7, 76.4, 76.0, 75.5,
74.7, 73.5, 68.9, 68.0, 25.3, 15.0 ppm; HR-FAB MS [C36H36O7S +
Na]+ calcd for 635.2074, found 635.2078.
Synthesis of Disaccharides. A General Procedure for
Bromination of Thioglycosides followed by Glycosylation. A
mixture containing a thioglycoside precursor (0.047−0.050 mmol),
which was dried in vacuo for 45 min, and activated molecular sieves (3
Å, 90 mg) in freshly distilled CH2Cl2 (1.0 mL) was stirred under
argon for 30 min at rt. The resulting mixture was cooled to 0 °C, Br2
(0.062−0.065 mmol, 1.3 equiv) was added, and the reaction mixture
was stirred under argon for 15 min at 0 °C. Afterward, the volatiles
were removed under reduced pressure, and the residue was dried in
vacuo for 30 min. A silver salt (1.50 equiv) and a glycosyl acceptor
(0.038−0.040 mmol, 0.80 equiv) were added, and the resulting
mixture was dried in vacuo for 1.5 h. Freshly distilled CH2Cl2 (1.0
mL) was added, and the resulting mixture was stirred under argon for
10 min at rt. The mixture was cooled to the temperature specified in
tables, TMSOTf or TfOH (0.20−0.40 equiv) was added, and the
resulting mixture was stirred under argon for the time and
temperature specified in tables. Afterward, the solids were filtered
off through a pad of Celite and rinsed successively with CH2Cl2. The
combined filtrate (∼25 mL) was washed with water (2 × 10 mL).
The organic phase was separated, dried with magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (ethyl acetate−hexane gradient
elution) to yield a corresponding disaccharide derivative in a yield and
with a stereoselectivity specified in Tables 1−3 and below.
Analytical data for 1e: Rf = 0.70 (EtOAc/hexanes, 3/7 v/v); [α]23
D
+103.3 (c = 1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 8.03 (m,
4H, aromatic), 7.81 (d, 2H, aromatic), 7.71−7.37 (m, 7H, aromatic),
7.38−7.07 (m, 7H, aromatic), 5.93 (br d, 1H, H-4), 5.48 (dd, 1H, J3,4
= 3.2 Hz, H-3), 4.85 (d, 1H, 2J = 10.6 Hz, CHPh), 4.75 (d, 1H, J1,2
=
9.7 Hz, H-1), 4.67−4.57 (m, 2H, 2J = 11.0, J5,6a = 6.3 Hz, H-5,
CHPh), 4.35 (dd, 1H, J6a,6b = 11.4 Hz, H-6a), 4.23 (dd, 1H, H-6b),
3.95 (dd, 1H, J2,3 = 9.6 Hz, H-2), 2.96−2.72 (m, 2H, SCH2CH3), 1.37
(t, 3H, SCH2CH3) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ
166.0, 165.4, 165.3, 137.2, 133.5, 133.2, 133.1, 129.9 (×2), 129.7
(×2), 129.6 (×2), 129.4, 129.3, 129.2, 128.5, 128.4 (×2), 128.3, 128.2
(×5), 127.8, 85.7, 77.2, 76.2, 75.6, 74.5 (×2), 68.7, 62.2, 25.4, 15.2
ppm; HR-FAB MS [C36H34O8S + Na]+ calcd for 649.1867, found
649.1878.
Ethyl 4,6-Di-O-benzoyl-2,3-di-O-benzyl-1-thio-β-D-galacto-
pyranoside (1f). A solution of ethyl 2,3-di-O-benzyl-1-thio-β-D-
galactopyranoside (23,63 1.06 g, 2.62 mmol) in pyridine (20 mL) was
cooled to 0 °C. Benzoyl chloride (0.91 mL, 7.86 mmol, 3.0 equiv) was
added dropwise, followed by the addition of DMAP (64.0 mg, 0.52
mmol, 0.2 equiv). The external cooling was removed, and the
resulting mixture was stirred under argon for 16 h at rt. Afterward, the
reaction was quenched with MeOH (∼8 mL), the volatiles were
removed under reduced pressure, and the residue was coevaporated
with toluene. The resulting residue was dissolved in CH2Cl2 (∼20
mL) and washed with 1 N aq. HCl (10 mL), sat. aq. NaHCO3 (10
mL), and water (2 × 10 mL). The organic phase was separated, dried
with MgSO4, and concentrated under reduced pressure. The residue
was purified by column chromatography on silica gel (ethyl acetate−
hexane 10% gradient elution) to afford the title compound as a white
amorphous solid (1.43 g, 2.33 mmol, 90%). Analytical data for 1f: Rf
Methyl 6-O-(2,3,4,6-Tetra-O-benzoyl-β-D-galactopyranosyl)-
2,3,4-tri-O-benzyl-α-D-glucopyranoside (4a). 4a was obtained as
described previously,50 and its analytical data were consistent with
those reported previously.66
Methyl 6-O-(2,3,4,6-Tetra-O-benzyl-α/β-D-galactopyranosyl)-
2,3,4-tri-O-benzyl-α-D-glucopyranoside (4b). 4b was obtained as a
colorless amorphous solid from galactosyl bromide donor 2b and
acceptor 3 by the general glycosylation method (35 mg, 0.035 mmol,
87% yield, α/β = 1:1.2). The analytical data for 4b were consistent
with those reported previously.67
= 0.75 (EtOAc/hexanes, 3/7, v/v); [α]23 +10.8 (c = 1.0, CHCl3);
D
1H NMR (CDCl3 at 300 MHz): δ 8.20−8.08 (m, 2H, aromatic), 8.03
(dd, 2H, aromatic), 7.58 (m, 2H, aromatic), 7.53−7.16 (m, 14H,
2
aromatic), 5.90 (dd, 1H, H-4), 4.86 (d, 1H, J = 11.3 Hz, CHPh),
4.79 (dd, 2H, 2J = 10.1 Hz, CH2Ph), 4.62−4.52 (m, 3H, J6a,6b = 10.6
Hz, H-1, 6a, CHPh), 4.36 (dd, 1H, H-6b), 4.02 (m, 1H, J5,6a = 7.2,
J5,6b = 6.3 Hz, H-5), 3.73 (m, 2H, J2,3 = 9.1, J3,4 = 2.8 Hz, H-2, 3),
2.94−2.63 (m, 2H, SCH2CH3), 1.34 (t, 3H, SCH2CH3) ppm;
13C{1H} NMR (CDCl3 at 75 MHz): δ 166.1, 165.7, 137.9, 137.5,
Methyl 6-O-(6-O-Benzoyl-2,3,4-tri-O-benzyl-α/β-D-galactopyra-
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (4c). 4c was obtained
as a colorless foam from galactosyl bromide donor 2c and acceptor 3
by the general glycosylation method (34 mg, 0.034 mmol, 75% yield,
α/β = 1:2.7). Analytical data for 4c: Rf = 0.50 (EtOAc/hexane, 3/7,
133.3, 133.2, 130.0 (×3), 129.7 (×3), 129.5 (×2), 128.5, 128.4 (×2),
128.3 (×5), 128.0 (×2), 127.8, 127.7, 85.4, 80.9, 77.6, 75.9, 74.6,
71.9, 67.3, 62.8, 25.0, 15.1 ppm; HR-FAB MS [C36H36O7S + Na]+
calcd for 635.2074, found 635.2068.
Ethyl 3,4-Di-O-benzoyl-2,6-di-O-benzyl-1-thio-β-D-galacto-
pyranoside (1g). A solution of ethyl 2,6-di-O-benzyl-1-thio-β-D-
galactopyranoside (24,65 3.10 g, 7.66 mmol) in pyridine (50 mL) was
cooled to 0 °C. Benzoyl chloride (2.67 mL, 22.9 mmol, 3.0 equiv) was
added dropwise, followed by the addition of DMAP (187 mg, 1.53
mmol, 0.2 equiv). The external cooling was removed, and the
resulting mixture was stirred under argon for 16 h at rt. Afterward, the
reaction was quenched with MeOH (∼10 mL), the volatiles were
1
v/v); Selected H NMR data for α-4c (CDCl3 at 300 MHz): δ 4.94
(d, H-1′), 4.49 (d, H-1), 4.05 (dd, H-2′), 3.89 (dd, H-3), 3.22 (dd,
1
H-2) ppm; Selected H NMR data for β-4c (CDCl3 at 300 MHz): δ
4.58 (d, J1,2 = 3.5 Hz, H-1), 4.33 (d, H-1′), 3.98 (dd, H-3) 3.90 (dd,
H-2′), 3.52 (dd, H-3′), 3.48 (dd, H-2) ppm; 13C{1H} NMR (CDCl3
at 75 MHz): δ 166.0 (×2), 138.8, 138.6, 138.5, 138.3, 138.2, 138.1
(×2), 133.1, 133.0, 129.9, 129.7, 129.5 (×2), 128.4, 128.3 (×2), 128.2
(×2), 128.1, 127.9 (×2), 127.8, 127.7, 127.6 (×2), 127.5, 127.4,
104.1, 97.8, 97.5, 97.4, 82.2, 81.9, 80.0, 79.7, 79.1, 78.2, 78.0, 77.2,
E
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
75.6, 75.1, 74.9, 74.8, 74.5, 74.4, 73.3 (×2), 73.2, 73.1, 72.7, 72.0,
70.0, 69.8, 68.6, 66.2, 64.0, 63.1, 55.1, 54.9 ppm; HR-FAB MS
[C62H64O12 + Na]+ calcd for 1023.4290, found 1023.4312.
Methyl 6-O-(4-O-Benzoyl-2,3,6-tri-O-benzyl-α/β-D-galactopyra-
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (4d). 4d was ob-
tained from thioglycoside donor 2d and acceptor 3 by the general
glycosylation method (35 mg, 0.035 mmol, 87% yield, α/β = 6.0:1).
The analytical data for 4d were consistent with those reported
previously.56
70.2, 69.8, 68.3, 67.6, 66.1, 55.1 ppm; HR-FAB MS [C62H62O13
Na]+ calcd for 1037.4083, found 1037.4096.
+
Methyl 2-O-(4,6-Di-O-benzoyl-2,3-di-O-benzyl-α-D-galactopyra-
nosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (10). 10 was ob-
tained from galactosyl bromide donor 2f and acceptor 5 by the
general glycosylation method (35 mg, 0.034 mmol, 91% yield).
Analytical data for 10: Rf = 0.50 (EtOAc/hexane, 3/7, v/v); [α]23
D
+81.9 (c = 1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 8.09−7.89
(m, 4H, aromatic), 7.60−7.52 (m, 1H, aromatic), 7.47−7.03 (m,
30H, aromatic), 5.33 (d, 1H, H-4′), 4.96 (d, 1H, J1′,2’ = 3.7 Hz, H-1′),
4.92 (d, 1H, J1,2 = 3.0 Hz, H-1), 4.74 (m, 6H, 2J = 11.1, 2J = 12.4 Hz,
6 × CHPh), 4.60−4.43 (m, 4H, 4 × CHPh), 4.39 (dd, 1H, J5′,6a’ = 3.5,
J5′,6b’ = 8.1 Hz, H-5′), 4.22−4.02 (m, 2H, J3,4 = 9.2 Hz, H-3, 6a′),
4.00−3.88 (m, 3H, J3′,4’ = 2.9 Hz, H-2, 3′, 6b′), 3.88−3.73 (m, 3H, H-
2′, 5, 6a), 3.69 (m, 1H, H-6b), 3.60 (dd, 1H, H-4), 3.47 (s, 3H,
OCH3) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ 165.8, 165.6,
138.7, 138.5, 138.0, 137.9, 137.8, 133.1, 132.9, 129.8 (×5), 129.7,
129.6, 128.4 (×9), 128.3 (×3), 128.2 (×2), 128.0 (×2), 127.9 (×2),
127.8 (×2), 127.7 (×2), 127.6, 127.5, 127.2 (×2), 96.3, 94.9, 80.7,
78.4, 77.2, 76.0, 75.6, 74.9, 74.6, 74.1, 73.6, 73.3, 71.8, 70.1, 68.5
(×2), 66.9, 63.3, 55.0, 53.4 ppm; HR-FAB MS [C62H62O13 + Na]+
calcd for 1037.4083, found 1037.4096.
Methyl 6-O-(3,4,6-Tri-O-benzoyl-2-O-benzyl-α-D-galactopyrano-
syl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (4e). 4e was obtained
from galactosyl bromide donor 2e and acceptor 3 by the general
glycosylation method (38 mg, 0.037 mmol, 97% yield). Analytical
data for 4e: Rf = 0.30 (EtOAc/hexane, 3/10, v/v); [α]23D +117.8 (c =
1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 7.94 (m, 4H,
aromatic), 7.80 (d, 2H, aromatic), 7.66−7.05 (m, 29H, aromatic),
5.88 (d, 1H, H-4′), 5.72 (dd, 1H, J3′,4’ = 3.2 Hz, H-3′), 5.16 (d, 1H,
2
2
J1′,2’ = 3.3 Hz, H-1′), 4.94 (2 d, 2H, J = 10.9, J = 11.2 Hz, 2 ×
CHPh), 4.81 (d, 1H, 2J = 10.9 Hz, CHPh), 4.71 (d, 1H, 2J = 12.2 Hz,
CHPh), 4.65−4.54 (m, 5H, J1,2 = 3.4 Hz, H-1, 4 × CHPh), 4.53−4.36
(m, 2H, J5′,6a’ = 4.1, J6a’,6b’ = 10.2 Hz, H-5′, 6a′), 4.29 (dd, 1H, H-6b′),
4.11 (dd, 1H, J2′,3′ = 10.4 Hz, H-2′), 3.98 (dd, 1H, J3,4 = 9.2 Hz, H-3),
3.89−3.71 (m, 3H, J5,6a = 6.8, J6a,6b = 12.4 Hz, H-5, 6a, 6b), 3.55−3.28
(m, 5H, J2,3 = 3.4 Hz, H-2, 4, OCH3) ppm; 13C{1H} NMR (CDCl3 at
75 MHz): δ 165.9, 165.4 (×2), 138.7, 138.3, 138.0, 137.7, 133.3,
133.1, 133.0, 129.7 (×2), 129.6 (×5), 129.3, 128.4 (×9), 128.3 (×5),
128.1 (×2), 127.9 (×3), 127.8 (×3), 127.7 (×3), 127.6, 127.5, 97.7,
97.2, 82.0, 79.8, 77.8, 75.6, 75.0, 73.2, 73.0, 72.3, 70.1, 70.0, 69.5,
66.8, 66.1, 62.7, 55.1 ppm; HR-FAB MS [C62H60O14 + Na]+ calcd for
1051.3875, found 1051.3890.
Methyl 3-O-(4,6-Di-O-benzoyl-2,3-di-O-benzyl-α-D-galactopyra-
nosyl)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (11). 11 was ob-
tained from galactosyl bromide donor 2f and acceptor 6 by the
general glycosylation method (28 mg, 0.028 mmol, 73% yield).
Analytical data for 11: Rf = 0.40 (EtOAc/hexane, 3/7, v/v); [α]23
D
+85.7 (c = 1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 8.13−8.00
(m, 2H, aromatic), 8.00−7.88 (m, 2H, aromatic), 7.55 (m, 2H,
aromatic), 7.41 (m, 5H, aromatic), 7.35−7.10 (m, 18H, aromatic),
Methyl 6-O-(4,6-Di-O-benzoyl-2,3-di-O-benzyl-α-D-galactopyra-
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (4f). 4f was obtained
from galactosyl bromide donor 2f and acceptor 3 by the general
glycosylation method (36 mg, 0.035 mmol, 93% yield, α/β = 33:1).
7.10−6.90 (m, 6H, aromatic), 5.58 (br d, 2H, J1′,2’ = 3.4 Hz, H-1′, 4′),
2
5.00 (d, 1H, J = 11.7 Hz, CHPh), 4.84 (m, 2H, J5′,6a’ = 7.6, J5′,6b’
=
2
2
6.8, J = 10.9 Hz, H-5′, CHPh), 4.78−4.67 (m, 2H, J1,2 = 3.4, J =
11.6 Hz, H-1, CHPh), 4.65−4.38 (m, 7H, 7 × CHPh), 4.33 (dd, 1H,
J3,4 = 9.0 Hz, H-3), 4.22 (dd, 1H, J6a’,6b’ = 12.0 Hz, H-6a′), 4.13 (dd,
Analytical data for α-4f: Rf = 0.55 (EtOAc/hexane, 3/7, v/v); [α]23
D
+80.4 (c = 1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 8.10−7.91
(m, 4H, aromatic), 7.64−7.49 (m, 2H, aromatic), 7.47−7.10 (m,
29H, aromatic), 5.80 (br d, 1H, H-4′), 5.03 (d, 1H, J1′,2’ = 3.4 Hz, H-
1H, J3′,4’ = 3.0 Hz, H-3′), 4.00 (dd, 1H, H-6b′), 3.90 (dd, 1H, J2′,3′
=
10.2 Hz, H-2′), 3.83 (dd, 1H, J4,5 = 9.2 Hz, H-4), 3.78−3.54 (m, 4H,
H-2, 5, 6a, 6b), 3.31 (s, 3H, OCH3) ppm; 13C{1H} NMR (CDCl3 at
75 MHz): δ 166.2, 165.7, 138.3, 137.9, 137.7 (×2), 137.6, 133.0,
132.7, 130.0 (×3), 129.8 (×2), 129.7, 128.4 (×9), 128.3 (×5), 128.2
(×2), 128.1 (×3), 128.0 (×3), 127.8, 127.6, 127.5, 127.4, 127.2, 126.7
(×3), 97.8, 97.3, 78.8, 78.7, 76.5, 74.8, 74.0, 73.9, 73.4, 72.7, 71.7,
2
2
1′), 4.95 (d, 1H, J = 10.9 Hz, CHPh), 4.86−4.74 (m, 4H, J = 12.3
2
Hz, 4 × CHPh), 4.69 (d, 1H, J = 12.0 Hz, CHPh), 4.67−4.61 (dd,
2H, 2J = 11.9 Hz, CH2Ph), 4.59 (d, 1H, CHPh), 4.52 (dd, 2H, J1,2
=
2
3.4, J = 12.0 Hz, H-1, CHPh), 4.41−4.28 (m, 3H, H-5′, 6a′, 6b′),
4.03 (dd, 1H, J3′,4’ = 2.9 Hz, H-3′), 3.98−3.87 (m, 2H, J2′,3′ = 10.0 Hz,
69.7, 68.8, 68.2, 66.6, 63.8, 55.0 ppm; HR-FAB MS [C62H62O13
+
Na]+ calcd for 1037.4083, found 1037.4096.
J
3,4 = 9.2 Hz, H-2′, 3), 3.83−3.69 (m, 3H, H-5, 6a, 6b), 3.38 (dd 1H,
H-4), 3.32−3.19 (m, 4H, J2,3 = 9.5 Hz, H-2, OCH3) ppm; 13C{1H}
NMR (CDCl3 at 75 MHz): δ 165.9, 165.7, 138.7, 138.4, 138.3, 138.1,
137.9, 133.1 (×2), 129.9 (×2), 129.7, 129.6, 129.5 (×2), 128.4 (×7),
128.3 (×5), 128.2 (×4), 127.9 (×3), 127.8 (×3), 127.7 (×2), 127.6
(×3), 127.5, 127.4, 97.5 (×2), 82.0, 79.9, 78.0, 75.6, 75.1, 75.0, 74.8,
73.1, 72.9, 71.6, 70.0, 68.6, 67.1, 66.1, 63.2, 54.9 ppm; HR-FAB MS
[C62H62O13 + Na]+ calcd for 1037.4083, found 1037.4094.
Methyl 4-O-(4,6-Di-O-benzoyl-2,3-di-O-benzyl-α-D-galactopyra-
nosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (12). 12 was ob-
tained from galactosyl bromide donor 2f and acceptor 7 by the
general glycosylation method (19 mg, 0.019 mmol, 49% yield).
Analytical data for 12: Rf = 0.45 (EtOAc/hexane, 3/7, v/v); [α]23
D
1
+34.6 (c = 1.0, CHCl3); H NMR (CDCl3 at 300 MHz): δ 7.99 (m,
4H, aromatic), 7.57 (m, 2H, aromatic), 7.49−7.05 (m, 29H,
aromatic), 5.70 (br d, 2H, J1′,2’ = 3.2 Hz, H-1′, 4′), 5.00−4.64 (m,
5H, 2J = 11.8 Hz, 5 × CHPh), 4.61−4.47 (m, 4H, J1,2 = 3.2 Hz, H-1, 3
Methyl 6-O-(3,4-Di-O-benzoyl-2,6-di-O-benzyl-α-D-galactopyra-
nosyl)-2,3,4-tri-O-benzyl-α-D-glucopyranoside (4g). 4g was ob-
tained from galactosyl bromide donor 2g and acceptor 3 by the
general glycosylation method (37 mg, 0.036 mmol, 96% yield).
2
2
× CHPh), 4.43 (2 d, 2H, J = 9.1, J = 11.6 Hz, 2 × CHPh), 4.37−
4.27 (m, 1H, H-6a′), 4.22−3.97 (m, 3H, J5′,6a’ = 5.3 Hz, H-3, 5′, 6a′),
3.96−3.79 (m, 4H, J2′,3′ = 10.2 Hz, H-2′, 3′, 4, 5), 3.64 (dd, 2H, J6a,6b
= 10.0 Hz, H-6a, 6b), 3.52 (dd, 1H, J2,3 = 9.4 Hz, H-2), 3.39 (s, 3H,
OCH3) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ 165.9, 165.7,
139.0, 137.9 (×2), 137.8, 133.1 (×2), 129.8 (×2), 129.6 (×5), 129.0,
128.4 (×9), 128.3, 128.1 (×5), 127.9 (×3), 127.8, 127.7, 127.6 (×2),
127.5, 127.4, 127.0, 126.7, 126.5, 125.2, 97.6, 97.5, 81.7, 79.9, 76.1,
74.2, 73.7, 73.6, 73.3, 73.1, 71.9, 69.3 (×2), 69.2, 68.3, 67.4, 63.1, 55.1
ppm; HR-FAB MS [C62H62O13 + Na]+ calcd for 1037.4083, found
1037.4096.
Analytical data for 4g: Rf = 0.60 (EtOAc/hexane, 3/7, v/v); [α]23
D
+132.5 (c = 1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 7.88 (d,
2H, aromatic), 7.80 (d, 2H, aromatic), 7.59 (dd, 1H, aromatic),
7.54−7.10 (m, 30H, aromatic), 5.83 (d, 1H, H-4′), 5.70 (dd, 1H, J3′,4’
= 2.9 Hz, H-3′), 5.19 (d, 1H, J1′,2’ = 3.4 Hz, H-1′), 4.96 (dd, 2H, 2J =
11.0 Hz, CH2Ph), 4.83 (d, 1H, 2J = 11.0 Hz, CHPh), 4.71 (2 d, 2H, 2J
= 11.2, 2J = 12.3 Hz, 2 × CHPh), 4.59 (m, 4H, H-1, 3 × CHPh,), 4.46
2
(d, 1H, J = 11.9 Hz, CHPh), 4.40−4.31 (m, 2H, H-5′, CHPh),
4.13−4.02 (dd, 1H, J2′,3′ = 10.4 Hz, H-2′), 3.99 (dd, 1H, J3,4 = 9.3 Hz,
H-3), 3.92−3.75 (m, 3H, H-5, 6a, 6b), 3.63 (dd, 1H, H-4), 3.58−3.30
(m, 6H, J2,3 = 9.3 Hz, H-2, 6a’, 6b’, OCH3) ppm; 13C{1H} NMR
(CDCl3 at 75 MHz): δ 165.4 (×2), 138.7, 138.3, 138.1, 137.8, 137.6,
133.1, 132.8, 129.7 (×3), 129.6 (×3), 128.4 (×7), 128.3 (×3), 128.2
(×3), 128.1, 128.0, 127.9 (×4), 127.8 (×4), 127.7, 127.6 (×2), 127.5
(×4), 97.9, 97.4, 82.0, 79.8, 77.7, 75.6, 75.0, 73.3, 73.2, 72.1, 70.4,
6-O-(4,6-Di-O-benzoyl-2,3-di-O-benzyl-α/β-D-galactopyranosyl)-
1,2:3,4-di-O-isopropylidene-α-D-galactopyranose (13). 13 was
obtained from galactosyl bromide donor 2f and acceptor 8 by the
general glycosylation method (21 mg, 0.026 mmol, 68% yield, α/β =
11.0:1). The analytical data for 13 were consistent with those
reported previously.58
F
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Methyl 2,3,4-Tri-O-benzoyl-6-O-(4,6-di-O-benzoyl-2,3-di-O-ben-
zyl-α-D-galactopyranosyl)-α-D-glucopyranoside (14). 14 was ob-
tained from galactosyl bromide donor 2f and acceptor 9 by the
general glycosylation method (35 mg, 0.033 mmol, 87% yield).
aromatic), 7.17−6.94 (m, 9H, aromatic), 5.84 (br. d, 2H, J1′,2’ = 3.6
2
Hz, H-1′, 4′), 5.70 (dd, 1H, J32′,4’ = 2.4 Hz, H-3′), 5.05 (d, 1H, J =
11.9 Hz, CHPh), 4.84 (d, 1H, J = 11.9 Hz, CH2Ph), 4.74−4.38 (m,
7H, J1,2 = 3.6 Hz, H-1, 6 × CHPh), 4.32−4.22 (m, 2H, 2J = 12.6 Hz,
H-5′, CHPh), 4.14−4.07 (m, 3H, H-3, 4, CHPh), 4.01 (dd, 1H, J2′,3′
= 10.6 Hz, H-2′), 3.97−3.85 (m, 2H, J5,6b = 9.2 Hz, H-5, 6a), 3.70
(dd, 1H, H-6b), 3.60 (dd, 1H, J2,3 = 9.3 Hz, H-2), 3.45−3.29 (m, 5H,
H-6a′, 6b′, OCH3) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ
165.5, 165.3, 139.2, 138.4, 138.2, 138.0, 137.9, 137.8, 137.7, 137.5,
137.3, 137.2, 133.0, 132.8, 129.7, 129.6, 128.7, 128.5, 128.3 (×2),
128.2, 128.1 (×2), 128.0 (×2), 127.8 (×3), 127.7, 127.6, 127.5, 127.4,
127.3, 127.2, 127.1, 126.9, 126.6, 126.5, 97.7, 97.6, 97.3, 81.8, 80.1,
78.9, 78.7, 76.1, 74.2, 73.4, 73.2, 73.0, 72.8, 70.5, 70.3, 70.1, 69.6,
69.4, 69.0, 68.3, 68.1, 67.8, 67.1, 55.1 ppm; HR-FAB MS [C62H62O13
+ Na]+ calcd for 1037.4083, found 1037.4095.
Analytical data for 14: Rf = 0.40 (EtOAc/hexane, 3/7, v/v); [α]23
D
1
+100.31 (c = 1.0, CHCl3); H NMR (CDCl3 at 300 MHz): δ 8.14−
7.77 (m, 10H, aromatic), 7.66−7.14 (m, 25H, aromatic), 6.05 (dd,
1H, J3,4 = 9.8 Hz, H-3), 5.85 (d, 1H, H-4′), 5.24 (dd, 1H, H-4), 5.13
(d, 1H, J1,2 = 3.7 Hz, H-1), 4.94 (dd, 1H, J2,3 = 9.9 Hz, H-2), 4.89−
4.80 (m, 3H, J1′,2’ = 3.5 Hz, H-1′, 2 × CHPh), 4.67 (d, 2H, 2J = 11.2
Hz, 2 × CHPh), 4.47−4.36 (m, 2H, J5,’6b’ = 8.5 Hz, H-5′, 6a′), 4.30−
4.20 (m, 2H, H-5, 6b′), 4.12 (dd, 1H, J3′,4’ = 2.8 Hz, H-3′), 3.99−3.84
(m, 2H, J2′,3′ = 10.0, J6a,6b = 10.6 Hz, H-2′, 6a), 3.58 (d, 1H, H-6b),
3.28 (s, 3H, OCH3) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ
165.9, 165.7, 165.6, 165.5, 165.3, 138.2, 137.8, 133.4, 133.2 (×2),
133.0, 129.9 (×4), 129.8, 129.7 (×4), 129.6, 129.5 (×2), 129.1, 129.0,
128.7, 128.5 (×2), 128.4 (×3), 128.3 (×2), 128.2 (×6), 128.1 (×3),
127.8 (×3), 127.7, 127.5, 97.4, 96.4, 75.3, 74.6, 73.4, 71.9, 71.6, 70.4,
69.3, 68.7, 68.1, 67.3, 66.0, 63.3, 55.2 ppm; HR-FAB MS [C62H56O16
+ Na]+ calcd for 1079.3461, found 1079.3471.
6-O-(3,4-Di-O-benzoyl-2,6-di-O-benzyl-α-D-galactopyranosyl)-
1,2:3,4-di-O-isopropylidene-α-D-glucopyranose (18). 18 was ob-
tained from galactosyl bromide donor 2g and acceptor 8 by the
general glycosylation method (23 mg, 0.028 mmol, 75% yield).
Analytical data for 18: Rf = 0.45 (EtOAc/hexane, 3/7, v/v); [α]23
D
1
+58.6 (c = 1.0, CHCl3); H NMR (CDCl3 at 300 MHz): δ 7.90 (d,
2H, aromatic), 7.82 (d, 2H, aromatic), 7.64−7.56 (m, 1H, aromatic),
7.53−7.39 (m, 3H, aromatic), 7.36−7.11 (m, 12H, aromatic), 5.88 (d,
1H, H-4′), 5.74 (dd, 1H, J3′,4’ = 2.8 Hz, H-3′), 5.54 (d, 1H, J1,2 = 5.0
Methyl 2-O-(3,4-Di-O-benzoyl-2,6-di-O-benzyl-α-D-galactopyra-
nosyl)-3,4,6-tri-O-benzyl-α-D-glucopyranoside (15). 15 was ob-
tained from galactosyl bromide donor 2g and acceptor 5 by the
general glycosylation method (36 mg, 0.035 mmol, 93% yield).
Analytical data for 15: Rf = 0.45 (EtOAc/hexane, 3/7, v/v); [α]23
Hz, H-1), 5.18 (d, 1H, J1′,2’ = 3.5 Hz, H-1′), 4.70−4.57 (m, 3H, J3,4
=
D
2
1
8.0 Hz, H-3, 5′, CHPh), 4.54−4.37 (m, 4H, J = 12.0 Hz, H-4, 3 ×
CHPh), 4.32 (dd, 1H, J2,3 = 2.3 Hz, H-2), 4.14−4.05 (m, 2H, J2′,3′
+209.2 (c = 1.0, CHCl3); H NMR (CDCl3 at 300 MHz): δ 7.93−
=
7.79 (m, 4H, aromatic), 7.64−7.06 (m, 31H, aromatic), 5.85 (dd, 1H,
J3′,4’ = 3.3 Hz, H-3′), 5.62 (br d, 1H, H-4′), 5.13 (d, 1H, J1′,2’ = 3.5 Hz,
10.5, J5,6a = 6.0, J5,6b = 8.0 Hz, H-2′, 5), 3.92 (dd, 1H, J6a,6b = 10.0 Hz,
H-6a), 3.87−3.75 (m, 1H, H-6b), 3.62−3.48 (m, 2H, H-6a’, 6b′),
1.61, 1.46, 1.37, 1.24 (4 s, 12H, 4 × CH3) ppm; 13C{1H} NMR
(CDCl3 at 75 MHz): δ 165.4 (×2), 137.8, 137.6, 133.1, 132.8, 129.8,
129.7 (×3), 129.6 (×2), 128.4 (×2), 128.2 (×6), 128.1, 127.6 (×4),
127.5, 109.0, 108.7, 97.7, 96.2, 77.2, 73.4, 73.3, 72.1, 70.6 (×2), 70.5,
70.2, 69.8, 68.1, 67.6, 66.7, 65.9, 26.0, 24.9, 24.5 ppm; HR-FAB MS
[C46H50O13 + Na]+ calcd for 833.3144, found 833.3152.
Methyl 2,3,4-Tri-O-benzoyl-6-O-(3,4-di-O-benzoyl-2,6-di-O-ben-
zyl-α-D-galactopyranosyl)-α-D-glucopyranoside (19). 19 was ob-
tained from galactosyl bromide donor 2g and acceptor 9 by the
general glycosylation method (39 mg, 0.037 mmol, 97% yield).
2
H-1′), 5.04−4.82 (m, 4H, J1,2 = 3.4, J = 11.1 Hz, H-1, 3 × CHPh),
2
2
4.73 (d, 1H, J = 12.4 Hz, CHPh), 4.63 (d, 2H, J = 12.2 Hz, 2 ×
2
CHPh), 4.53 (m, 3H, J5′,6a’ = 6.8, J5′,6b’ = 5.3, J = 12.0 Hz, H-5′,
CH2Ph), 4.21−4.06 (m, 4H, J2′,3′ = 10.5 Hz, H-2′, 3, CH2Ph), 3.93
(dd, 1H, J2,3 = 9.9 Hz, H-2), 3.86−3.56 (m, 4H, H-4, 5, 6a, 6b), 3.46
(s, 3H, OCH3), 3.38 (dd, 1H, J6a’,6b’ = 10.4 Hz, H-6a′), 3.17 (dd, 1H,
H-6b′) ppm; 13C{1H} NMR (CDCl3 at 75 MHz): δ 165.4, 165.3,
138.2, 138.0 (×2), 137.8, 133.1, 132.8, 129.8, 129.7, 129.6 (×2),
128.5 (×3), 128.4 (×8), 128.3 (×2), 128.2 (×4), 128.0, 127.9 (×5),
127.8 (×2), 127.7 (×4), 127.3 (×3), 127.2, 96.4, 94.8, 80.6, 78.2,
75.0, 74.7, 73.5, 73.0, 72.7, 72.5, 70.4, 70.2, 69.8, 68.4, 68.3, 67.0, 55.0
ppm; HR-FAB MS [C62H62O13 + Na]+ calcd for 1037.4190, found
1037.4095.
Analytical data for 19: Rf = 0.35 (EtOAc/hexane, 3/7, v/v); [α]23
D
1
+154.7 (c = 1.0, CHCl3); H NMR (CDCl3 at 300 MHz): δ 8.11−
7.75 (m, 10H, aromatic), 7.67−7.09 (m, 25H, aromatic), 6.18 (dd,
1H, J3,4 = 8.7 Hz, H-3), 5.87 (br d, 1H, H-4′), 5.77 (dd, 1H, J3′,4’ = 3.0
Hz, H-3′), 5.52 (dd, 1H, H-4), 5.27 (dd, 2H, J1,2 = 3.4, J2,3 = 10.8 Hz,
Methyl 3-O-(3,4-Di-O-benzoyl-2,6-di-O-benzyl-α-D-galactopyra-
nosyl)-2,4,6-tri-O-benzyl-α-D-glucopyranoside (16). 16 was ob-
tained from galactosyl bromide donor 2g and acceptor 6 by the
general glycosylation method (27 mg, 0.027 mmol, 70% yield).
H-1, 2), 4.98 (d, 1H, J1′,2′ = 3.4 Hz, H-1′), 4.76−4.28 (m, 6H, J5,6a
=
=
7.3, J5,6b = 9.1, 2J = 12.4 Hz, H-5, 5′, 4 × CHPh), 4.11 (dd, 1H, J2′,3′
Analytical data for 16: Rf = 0.50 (EtOAc/hexane, 3/7, v/v); [α]23
D
10.4 Hz, H-2′), 3.96 (dd, 1H, J6a,6b = 10.9 Hz, H-6a), 3.65 (d, 1H, H-
6b), 3.57−3.39 (m, 5H, H-6a′, 6b′, OCH3) ppm; 13C{1H} NMR
(CDCl3 at 75 MHz): δ 165.7 (×2), 165.4, 165.3 (×2), 137.8, 137.6,
133.4, 133.3, 133.1, 133.0, 132.8, 129.9 (×5), 129.8, 129.7 (×2),
129.6 (×5), 129.1, 129.0, 128.8, 128.3 (×4), 128.2 (×8), 128.1 (×2),
127.9, 127.7, 127.5 (×2), 127.4, 97.4, 96.7, 73.5, 73.2, 72.8, 72.1, 70.4,
70.2, 69.8, 69.6, 68.5, 68.0, 67.6, 66.7, 55.6 ppm; HR-FAB MS
[C62H56O16 + Na]+ calcd for 1079.3461, found 1079.3471.
+114.4 (c = 1.0, CHCl3); 1H NMR (CDCl3 at 300 MHz): δ 7.84 (dd,
4H, aromatic), 7.64−6.90 (m, 31H, aromatic), 5.92 (dd, 1H, J3′,4’
=
3.2 Hz, H-3′), 5.74 (dd, 2H, J1′,2’ = 3.3 Hz, H-1′, 4′), 5.03−4.85 (m,
2H, J5′,6a’ = 6.1, J5′,6b’ = 6.7, 2J = 11.8 Hz, H-5′, CHPh), 4.78 (d, 1H, 2J
= 11.3 Hz, CHPh), 4.68−4.42 (m, 3H, J1,2 = 3.7 Hz, H-1, CH2Ph),
2
4.52−4.40 (m, 4H, 4 × CHPh), 4.38−4.17 (m, 3H, J3,4 = 9.1, J =
12.0 Hz, H-3, CH2Ph), 4.12 (dd, 1H, J2′,3′ = 10.7 Hz, H-2′), 3.88−
3.57 (m, 5H, H-2, 4, 5, 6a, 6b), 3.50 (dd, 1H, J6a’,6b’ = 10.1 Hz, H-6a′),
3.34 (d, 1H, H-6b′), 3.31 (s, 3H, OCH3) ppm; 13C{1H} NMR
(CDCl3 at 75 MHz): δ 165.5, 165.4, 138.4, 138.0, 137.8, 137.7, 137.2,
133.0, 132.8, 129.9, 129.8, 129.7 (×2), 129.6 (×2), 128.7 (×2), 128.6
(×2), 128.3 (×5), 128.2 (×4), 128.1 (×4), 128.0 (×4), 127.8 (×2),
127.7 (×2), 127.6, 127.5, 127.2, 127.1, 126.6, 97.7, 97.5, 78.9, 78.6,
77.2, 76.1, 73.5 (×2), 73.4, 73.2, 72.8, 70.5, 70.3, 69.6, 68.3, 67.1, 55.0
ppm; HR-FAB MS [C62H62O13 + Na]+ calcd for 1037.4083, found
1037.4094.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01279.
Characterization data for all new compounds (PDF)
Methyl 4-O-(3,4-Di-O-benzoyl-2,6-di-O-benzyl-α-D-galactopyra-
nosyl)-2,3,6-tri-O-benzyl-α-D-glucopyranoside (17). 17 was ob-
tained from galactosyl bromide donor 2g and acceptor 7 by the
general glycosylation method (25 mg, 0.025 mmol, 65% yield).
AUTHOR INFORMATION
■
Corresponding Author
Analytical data for 17: Rf = 0.45 (EtOAc/hexanes, 3/7, v/v); [α]23
Alexei V. Demchenko − Department of Chemistry and
Biochemistry, University of MissouriSt. Louis, St. Louis,
Missouri 63121, United States; orcid.org/0000-0003-3515-
212X; Email: demchenkoa@umsl.edu
D
1
+114.0 (c = 1.0, CHCl3); H NMR (CDCl3 at 300 MHz): δ 7.90−
7.83 (m, 2H, aromatic), 7.80−7.72 (m, 2H, aromatic), 7.63−7.56 (m,
1H, aromatic), 7.51−7.38 (m, 3H, aromatic), 7.35−7.23 (m, 18H,
G
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(16) Yu, F.; Li, J.; DeMent, P. M.; Tu, Y.-J.; Schlegel, H. B.; Nguyen,
H. M. Phenanthroline-Catalyzed Stereoretentive Glycosylations.
Angew. Chem., Int. Ed. 2019, 58, 6957−6961.
Authors
Melanie Shadrick − Department of Chemistry and Biochemistry,
University of MissouriSt. Louis, St. Louis, Missouri 63121,
United States
Yashapal Singh − Department of Chemistry and Biochemistry,
University of MissouriSt. Louis, St. Louis, Missouri 63121,
United States
(17) Ishikawa, T.; Fletcher, H. G. The synthesis and solvolysis of
some D-glucopyranosyl bromides having a benzyl group at C-2. J. Org.
Chem. 1969, 34, 563−571.
(18) Frechet, J. M.; Schuerch, C. Solid-phase synthesis of
oligosaccharides. II. Steric control by C-6 substituents in glucoside
syntheses. J. Am. Chem. Soc. 1972, 94, 604−609.
(19) Kronzer, F. J.; Schuerch, C. The methanolysis of some
derivatives of 2,3,4-tri-O-benzyl-J-D-glucopyranosyl bromide in the
presence and absence of silver salts. Carbohydr. Res. 1973, 27, 379−
390.
(20) Lemieux, R. U.; Hendriks, K. B.; Stick, R. V.; James, K. Halide
ion catalyzed glycosylation reactions. Syntheses of -linked disacchar-
ides. J. Am. Chem. Soc. 1975, 97, 4056−4062 and references therein.
(21) Lemieux, R. U.; Driguez, H. The chemical synthesis of 2-O-(-L-
fucopyranosyl)-3-O-(–D-galactopyranosyl)-D-galactose. The terminal
structure of blood-group B antigenic determinant. J. Am. Chem. Soc.
1975, 97, 4069−4075.
(22) Lemieux, R.; Driguez, H. Chemical synthesis of 2-acetamido-2-
deoxy-4-O-(alpha-L-fucopyranosyl)-3-O-(beta-D-galactopyranosyl)-
D-glucose. Lewis a blood-group antigenic determinant. J. Am. Chem.
Soc. 1975, 97, 4063−4069.
(23) West, A. C.; Schuerch, C. The reverse anomeric effect and the
synthesis of -glycosides. J. Am. Chem. Soc. 1973, 95, 1333−1335.
(24) Kronzer, F. J.; Schuerch, C. The use of 2,3,4,6-tetra-O-benzyl-o-
D-glycopyranosyl iodides in –glycoside synthesis. Carbohydr. Res.
1974, 34, 71−78 and references therein.
(25) Higashi, K.; Nakayama, K.; Uoto, K.; Shioya, E.; Kusama, T. A
novel glycoside anomerization catalyzed by trimethylsilyl bromide and
zinc bromide in combination. Chem. Pharm. Bull. 1991, 39, 590−592.
(26) Higashi, K.; Nakayama, K.; Shioya, E.; Kusama, T. Direct
transformation of O-glycosides into other O-glycosides using
trimethylsilyl bromide and zinc bromide. Chem. Pharm. Bull. 1992,
40, 1042−1043.
(27) Nakayama, K.; Higashi, K.; Soga, T.; Uoto, K.; Kusama, T. Zinc
triflate-promoted glycosidation: synthesis of lipid A disaccharide
intermediates. Chem. Pharm. Bull. 1992, 40, 2909−2912.
(28) Kihlberg, J. O.; Leigh, D. A.; Bundle, D. R. The in situ
activation of thioglycosides with bromine: an improved glycosylation
method. J. Org. Chem. 1990, 55, 2860−2863.
(29) Kaeothip, S.; Yasomanee, J. P.; Demchenko, A. V.
Glycosidation of thioglycosides in the presence of bromine:
mechanism, reactivity, and stereoselectivity. J. Org. Chem. 2012, 77,
291−299.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01279
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by awards from the NIGMS
(GM111835) and the NSF (CHE-1058112). We thank Dr.
Rensheng Luo (UMSt. Louis) for help with aquiring
spectral data using an NMR spectrometer that was purchased
thanks to the NSF (Award CHE-0959360).
DEDICATION
■
In loving memory of Kyle Dewayne Robert Hill and Lester
Gene Shadrick.
REFERENCES
■
(1) Michael, A. On the synthesis of helicin and phenolglucoside. Am.
Chem. J. 1879, 1, 305−312.
(2) Koenigs, W.; Knorr, E. Uber einige derivate des traubenzuckers
̈
und der galactose. Ber. Dtsch. Chem. Ges. 1901, 34, 957−981.
(3) Fischer, E.; Armstrong, E. F. Over isomers of the aceto-halogen
derivative of grape sugar and the synthesis of the glucosides. Ber.
Dtsch. Chem. Ges. 1901, 34, 2885−2900.
(4) Helferich, B.; Bohn, E.; Winkler, S. Unsaturated derivatives of
gentiobiose and cellobiose. Ber. Dtsch. Chem. Ges. B 1930, 63B, 989−
998.
(5) Hudson, C. Relations between rotatory power and structure in
the sugar group. XXV. The ring structures of various mono-
saccharides. J. Am. Chem. Soc. 1930, 52, 1680−1700.
(6) Isbell, H. The structures of the acetylmethylmannosides. J. Am.
Chem. Soc. 1930, 52, 5298−5298.
(7) Perlin, A. Formation of diastereomeric orthoacetates of D-
mannose: N.M.R. spectral evidence. Can. J. Chem. 1963, 41, 399−
406.
(30) Panza, M.; Civera, M.; Yasomanee, J. P.; Belvisi, L.;
Demchenko, A. V. Bromine-promoted glycosidation of conforma-
tionally superarmed thioglycosides. Chem. - Eur. J. 2019, 25, 11831−
11836.
(31) Imamura, A.; Ando, H.; Korogi, S.; Tanabe, G.; Muraoka, O.;
Ishida, H.; Kiso, M. Di-tert-butylsilylene (DTBS) group-directed α-
selective galactosylation unaffected by C-2 participating function-
alities. Tetrahedron Lett. 2003, 44, 6725−6728.
(32) Imamura, A.; Ando, H.; Ishida, H.; Kiso, M. Di-tert-
butylsilylene-Directed a-Selective Synthesis of 4-Methylumbelliferyl
T-Antigen. Org. Lett. 2005, 7, 4415−4418.
(8) Nigudkar, S. S.; Demchenko, A. V. Stereocontrolled 1,2-cis
glycosylation as the driving force of progress in synthetic carbohydrate
chemistry. Chem. Sci. 2015, 6, 2687−2704.
(9) Helferich, B.; Bredereck, H. Zuckersynthesen. VIII. Liebigs Ann.
Chem. 1928, 465, 166−184.
̈
́
(10) Zemplen, G.; Pacsu, E. Uber die Verseifung acetylierter Zucker
und verwandter Substanzen. Ber. Dtsch. Chem. Ges. B 1929, 62, 1613−
1614.
(11) Zemplen, G.; Gerecs, A. Action of mercury salts on
acetohalogenosugars. IV. Direct preparation of alkyl biosides of the
α-series. Ber. Dtsch. Chem. Ges. B 1930, 63B, 2720−2729.
(12) Helferich, B.; Zirner, J. Synthesis of tetra-O-acetyhexoses with a
free 2-hydroxyl group. Synthesis of disaccharides. Chem. Ber. 1962, 95,
2604−2611.
(33) Demchenko, A. V.; Rousson, E.; Boons, G. J. Stereoselective
1,2-cis-galactosylation assisted by remote neighboring group partic-
ipation and solvent effects. Tetrahedron Lett. 1999, 40, 6523−6526.
(34) Kalikanda, J.; Li, Z. Study of the stereoselectivity of 2-azido-2-
deoxygalactosyl donors: remote protecting group effects and temper-
ature dependency. J. Org. Chem. 2011, 76, 5207−5218.
(35) Komarova, B. S.; Tsvetkov, Y. E.; Nifantiev, N. E. Design of α-
Selective Glycopyranosyl Donors Relying on Remote Anchimeric
Assistance. Chem. Record 2016, 16, 488−506.
(13) Fischer, E.; von Mechel, L. Synthesis of phenyl glucosides. Ber.
Dtsch. Chem. Ges. 1916, 49, 2813−2820.
(14) Helferich, B.; Doppstadt, A.; Gottschlich, A. Synthesen von
Glykosiden im homogenen Medium. Naturwissenschaften 1953, 40,
441−442.
(15) Lemieux, R.; Morgan, A. The mechanism for the formation of
1, 2-cis-pyridine nucleosides from 1, 2-cis-acetohalogenosugars. A
novel rearrangement. J. Am. Chem. Soc. 1963, 85, 1889−1890.
(36) Zhang, Y.; Zhou, S.; Wang, X.; Zhang, H.; Guo, Z.; Gao, J. A
new method for α-specific glucosylation and its application to the
H
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
one-pot synthesis of a branched α-glucan. Org. Chem. Front. 2019, 6,
762−772.
effect by remote electron-withdrawing protecting groups at O-3 or O-
4 position of donors in glucosylations and galactosylations.
Tetrahedron 2015, 71, 5315−5320.
(57) Marianski, M.; Mucha, E.; Greis, K.; Moon, S.; Pardo, A.;
Kirschbaum, C.; Thomas, D.; Meijer, G.; von Helden, G.; Gilmore,
K.; Seeberger, P.; Pagel, K. Direct Evidence for Remote Participation
in Galactose Building Blocks during Glycosylations Revealed by
Cryogenic Vibrational Spectroscopy. Angew. Chem., Int. Ed. 2020, 59,
6166−6171.
(37) Liu, H.; Hansen, T.; Zhou, S. Y.; Wen, G. E.; Liu, X. X.; Zhang,
Q. J.; Codee, J. D. C.; Schmidt, R. R.; Sun, J. S. Dual-Participation
Protecting Group Solves the Anomeric Stereocontrol Problems in
Glycosylation Reactions. Org. Lett. 2019, 21, 8713−8717.
(38) Kim, J. H.; Yang, H.; Park, J.; Boons, G. J. A general strategy for
stereoselective glycosylations. J. Am. Chem. Soc. 2005, 127, 12090−
12097.
(58) Cheng, Y. P.; Chen, H. T.; Lin, C. C. A convenient and highly
stereoselective approach for -galactosylation performed by galactopyr-
anosyl dibenzyl phosphite with remote participating groups.
Tetrahedron Lett. 2002, 43, 7721−7723.
(59) Bandara, M. D.; Yasomanee, J. P.; Demchenko, A. V.:
Application of armed, disarmed, superarmed and superdisarmed
building blocks in stereocontrolled glycosylation and expeditious
oligosaccharide synthesis. In Selective Glycosylations: Synthetic Methods
and Catalysts; Bennett, C. S., Ed.; Wiley: 2017; pp 29−58.
(60) Zhang, F.; Zhang, W.; Zhang, Y.; Curran, D. P.; Liu, G.
Synthesis and Applications of a Light-Fluorous Glycosyl Donor. J.
Org. Chem. 2009, 74, 2594−2597.
(39) Kim, J. H.; Yang, H.; Khot, V.; Whitfield, D.; Boons, G. J.
Stereoselective glycosylations using (R)- or (S)-(ethoxycarbonyl)-
benzyl chiral auxiliaries at C-2 of glycopyranosyl donors. Eur. J. Org.
Chem. 2006, 2006, 5007−5028.
(40) Boltje, T. J.; Kim, J. H.; Park, J.; Boons, G. J. Chiral-auxiliary-
mediated 1,2-cis-glycosylations for the solid-supported synthesis of a
biologically important branched α-glucan. Nat. Chem. 2010, 2, 552−
557.
(41) Mensink, R. A.; Boltje, T. J. Advances in Stereoselective 1,2-cis
Glycosylation using C-2 Auxiliaries. Chem. - Eur. J. 2017, 23, 17637−
17653.
(42) Yasomanee, J. P.; Demchenko, A. V. The effect of remote
picolinyl and picoloyl substituents on the stereoselectivity of chemical
glycosylation. J. Am. Chem. Soc. 2012, 134, 20097−20102.
(43) Mensah, E. A.; Yu, F.; Nguyen, H. M. Nickel-catalyzed
stereoselective glycosylation with C(2)-N-substituted benzylidene D-
glucosamine and galactosamine trichloroacetimidates for the for-
mation of 1,2-cis-2-amino glycosides. Applications to the synthesis of
heparin disaccharides, GPI anchor pseudodisaccharides, and a-
GalNAc. J. Am. Chem. Soc. 2010, 132, 14288−14302.
(44) Sletten, E. T.; Tu, Y.-J.; Schlegel, H. B.; Nguyen, H. M. Are
Brønsted Acids the True Promoter of Metal-Triflate-Catalyzed
Glycosylations? A Mechanistic Probe into 1, 2-Cis-Aminoglycoside
Formation by Nickel Triflate. ACS Catal. 2019, 9, 2110−2123.
(45) Bradshaw, G.; Colgan, A.; Allen, N.; Pongener, I.; Boland, M.;
Ortin, Y.; McGarrigle, E. Stereoselective organocatalyzed glycosyla-
tions-thiouracil, thioureas and monothiophthalimide act as Brønsted
acid catalysts at low loadings. Chem. Sci. 2019, 10, 508−514.
(46) Park, J.; Kawatkar, S.; Kim, J. H.; Boons, G. J. Stereoselective
glycosylations of 2-azido-2-deoxy-glucosides using intermediate
sulfonium ions. Org. Lett. 2007, 9, 1959−1962.
(61) Dondoni, A.; Marra, A.; Scherrmann, M.-C.; Casnati, A.;
Sansone, F.; Ungaro, R. Synthesis and properties of O-glycosyl
calix[4]arenes (calixsugars). Chem. - Eur. J. 1997, 3, 1774−1782.
(62) Yan, S.; Ding, N.; Zhang, W.; Wang, P.; Li, Y.; Li, M. An
efficient and recyclable catalyst for the cleavage of tert-butyldiphe-
nylsilyl ethers. Carbohydr. Res. 2012, 354, 6−20.
(63) Garegg, P. J.; Kvarnstrom, I.; Niklasson, A.; Niklasson, G.;
Svensson, S. C. T. Partial substitution of thioglycosides by phase
transfer catalyzed benzoylation and benzylation. J. Carbohydr. Chem.
1993, 12, 933−953.
(64) Gao, P. C.; Zhu, S. Y.; Cao, H.; Yang, J. S. Total Synthesis of
Marine Glycosphingolipid Vesparioside B. J. Am. Chem. Soc. 2016,
138, 1684−1688.
(65) Agoston, K.; Kerekgyarto, J.; Hajko, J.; Batta, G.; Lefeber, D. J.;
Kamerling, J. P.; Vliegenthart, J. F. G. Synthesis of fragments of the
glycocalyx glycan of the parasite Schistosoma mansoni. Chem. - Eur. J.
2002, 8, 151−161.
(66) Codee, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.;
Overkleeft, H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; Van der
Marel, G. A. Chemoselective glycosylations using sulfonium triflate
activator systems. Tetrahedron 2004, 60, 1057−1064.
(67) Vibhute, A. M.; Dhaka, A.; Athiyarath, V.; Sureshan, K. M. A
versatile glycosylation strategy via Au (III) catalyzed activation of
thioglycoside donors. Chem. Sci. 2016, 7, 4259−4263.
(47) Lu, S. R.; Lai, Y. H.; Chen, J. H.; Liu, C. Y.; Mong, K. K.
Dimethylformamide: an unusual glycosylation modulator. Angew.
Chem., Int. Ed. 2011, 50, 7315−7320.
(48) Sun, L.; Wu, X.; Xiong, D. C.; Ye, X. S. Stereoselective Koenigs-
Knorr glycosylation catalyzed by urea. Angew. Chem., Int. Ed. 2016,
55, 8041−8044.
(49) Park, Y.; Harper, K. C.; Kuhl, N.; Kwan, E. E.; Liu, R. Y.;
Jacobsen, E. N. Macrocyclic bis-thioureas catalyze stereospecific
glycosylation reactions. Science 2017, 355, 162−166.
(50) Singh, Y.; Demchenko, A. V. Koenigs-Knorr Glycosylation
Reaction Catalyzed by Trimethylsilyl Trifluoromethanesulfonate.
Chem. - Eur. J. 2019, 25, 1461−1465.
(51) Singh, Y.; Demchenko, A. V. Defining the scope of the acid-
catalyzed glycosidation of glycosyl bromides. Chem. - Eur. J. 2020, 26,
1042−1051.
(52) Pistorio, S. G.; Yasomanee, J. P.; Demchenko, A. V. Hydrogen
bond-mediated aglycone delivery: focus on β-mannosylation. Org.
Lett. 2014, 16, 716−719.
(53) Yasomanee, J. P.; Demchenko, A. V. Hydrogen bond-mediated
aglycone delivery: the synthesis of linear and branched α-glucans.
Angew. Chem., Int. Ed. 2014, 53, 10453−10456.
(54) Ranade, S. C.; Kaeothip, S.; Demchenko, A. V. Glycosyl
alkoxythioimidates as complementary building blocks for chemical
glycosylation. Org. Lett. 2010, 12, 5628−5631.
(55) Lourenco̧ , E. C.; Ventura, M. R. The effect of electron
withdrawing protecting groups at positions 4 and 6 on 1,2-cis
galactosylation. Tetrahedron 2013, 69, 7090−7097.
(56) Baek, J. Y.; Kwon, H.-W.; Myung, S. J.; Park, J. J.; Kim, M. Y.;
Rathwell, D. C. K.; Jeon, H. B.; Seeberger, P. H.; Kim, K. S. Directing
I
https://dx.doi.org/10.1021/acs.joc.0c01279
J. Org. Chem. XXXX, XXX, XXX−XXX