C-2 auxiliaries for stereoselective glycosylation based on common additive functional groups

Article abstract of DOI:10.1039/c9ob02700a

The stereoselective introduction of the glycosidic bond is one of the main challenges in chemical oligosaccharide synthesis. Stereoselective glycosylation can be achieved using neighbouring group participation of a C-2 auxiliary or using additives, for example. Both methods aim to generate a defined reactive intermediate that reacts in a stereoselective manner with alcohol nucleophiles. This inspired us to develop new C-2 auxiliaries based on commonly used additive functionalities such as ethers, phosphine oxides and tertiary amides. Good 1,2-trans-selectivity was observed for the phosphine oxide and amide-based auxiliaries expanding the toolbox with new auxiliaries for stereoselective glycosylation reactions.

Full text of DOI:10.1039/c9ob02700a

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C-2 auxiliaries for stereoselective glycosylation
based on common additive functional groups†
Cite this: DOI: 10.1039/c9ob02700a
Frank F. J. de Kleijne, Sam J. Moons,
Paul B. White and Thomas J. Boltje
*
The stereoselective introduction of the glycosidic bond is one of the main challenges in chemical oligo-
saccharide synthesis. Stereoselective glycosylation can be achieved using neighbouring group partici-
pation of a C-2 auxiliary or using additives, for example. Both methods aim to generate a defined reactive
intermediate that reacts in a stereoselective manner with alcohol nucleophiles. This inspired us to develop
new C-2 auxiliaries based on commonly used additive functionalities such as ethers, phosphine oxides
and tertiary amides. Good 1,2-trans-selectivity was observed for the phosphine oxide and amide-based
auxiliaries expanding the toolbox with new auxiliaries for stereoselective glycosylation reactions.
Received 19th December 2019,
Accepted 16th January 2020
DOI: 10.1039/c9ob02700a
rsc.li/obc
acceptors. The ether-based auxiliaries showed very modest
stereoselectivity whilst the phosphine oxide and amide based
Introduction
Carbohydrates play an essential role in biological systems. auxiliaries lead to the stereoselective formation of 1,2-trans
A major challenge in relating carbohydrate structure to func- glycosides.
tion is the limited availability of structurally well-defined oligo-
saccharides and glycoconjugates. Such well-defined oligosac-
charides can be obtained by chemical synthesis. The major
Results and discussion
challenge in oligosaccharide synthesis is the stereoselective
introduction of the glycosidic bonds.1,2 Stereoselective glycosy-
Six auxiliaries based on ethers, phosphine oxide and amides
lation can be achieved using neighbouring group participation
(NGP) of a C-2 auxiliary or using additives, for example. Both
methods aim to generate a defined reactive intermediate that
reacts in a stereoselective manner with alcohol nucleophiles
(Fig. 1A). For example, NGP of C-2 auxiliaries such as esters,
picolyl ethers,3 aryl nitriles4 and ethers5 mainly leads to 1,2-
trans-glycosides, whilst other C-2 auxiliaries based on esters,
thioethers6–11 and selenoethers12 mainly lead to 1,2-cis-glyco-
sides. Alternatively, the use of additives for stereoselective gly-
were designed and installed on the C-2 position of glucose and
galactose leading to a set of 12 glycosyl donors (3–14, Table 1).
All glycosyl donors were prepared starting from benzyl pro-
tected D-glucal and D-galactal.11 Oxidation of the glycal led to
the corresponding α-1,2-anhydro sugar24 which was reacted
with sodium thiophenolate to yield corresponding
β-thioglycosides 1 and 2 in moderate yields (55–65%).25 The
C-2 auxiliary was introduced using sodium hydride and sub-
sequent addition of the appropriate bromide or tosylate
(15–20) resulted in moderate to good yields of coupled pro-
ducts 3–14 (54–86%, Table 1).
Donors 3–14 were glycosylated with glycosyl acceptor (21)
under premix condition using the commonly employed
N-iodosuccinimide (NIS) triflic acid (TfOH) promotor system.26
The glycosylation reactions were carried out in CH2Cl2 at
−15 °C and the stereoselectivity was determined using NMR
analysis of the crude reaction mixtures after work-up. The
corresponding purified disaccharides (22–33) were obtained in
moderate to excellent yields with α/β-selectivities ranging from
non-selective to high β-selectivity (Table 2). Donors containing
ether-based auxiliaries (3–6) were unselective and no clear
change in selectivity over the different donors was observed
(entries 1–4 and 7–10). Chiral auxiliaries have shown to induce
more stereoselectivity in glycosylation reactions.8,27 Therefore,
better stereoselectivities were expected for chiral THF-based
cosylations requires a non-assisting functionality at C-2.13
A
Lewis base additive, such as nitriles,14 ethers,15,16 sulfides,17
phosphine oxides,18–20 iodide based reagents21,22 and (form)
amides,19,20,23 is added to stabilize the glycosyl cation and
introduce facial selectivity in the subsequent nucleophilic dis-
placement by the glycosyl acceptor. Inspired by both these
approaches we set out to develop new C-2 auxiliaries based on
recently reported additives. To this end, new C-2 auxiliaries
based on linear and cyclic ethers, phosphine oxides, and
amide functionalities were prepared (Fig. 1B). Their glycosyla-
tion properties were established with a number of glycosyl
Institute for molecules and materials, Nijmegen, 6525AJ, Netherlands.
E-mail: t.boltje@science.ru.nl
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02700a
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Fig. 1 (A) The two main strategies for stereoselecitve glycosylation. The oxocarbenium ion is trapped either by a C-2 auxiliary or additive to control
the structure of the reactive intermediate. (B) Newly developed C-2 auxiliaries based on common additive functional groups.
Table 2 Glycosylation results of glycosyl donors 3–14 with glycosyl
acceptor 21
Table 1 Synthesis of glycosyl donors equipped with ether, phosphine
oxide and N,N-dimethylamide auxiliaries (3–14)
Entry
Donor
Type
α/βa
Yieldb [%]
Product
1
2
3
4
5
6
7
8
3
5
7
9
11
13
4
6
8
Glc
Glc
Glc
Glc
Glc
Glc
Gal
Gal
Gal
Gal
Gal
Gal
50/50
50/50
37/63
37/63
0/100
11/89
60/40
60/40
45/55
55/45
20/80
17/83
96
54
85
55
57
67
95
77
81
73
43
68
22
24
26
28
30
32
23
25
27
29
31
33
9
Entry
Product
Type
Yield [%]
10
11
12
10
12
14
1
2
3
4
5
6
7
8
3
4
5
6
7
8
9
10
11
12
13
14
Glc
Gal
Glc
Gal
Glc
Gal
Glc
Gal
Glc
Gal
Glc
Gal
59
73
86
69
54
83
72
66
58
65
45
41
a α/β ratios were determined by NMR spectroscopy29,30 of the crude
reaction mixture. b Isolated yields.
9
auxiliaries (7–10). Nevertheless, donors 7–10 did not show any
stereoselectivity (entries 3–4 and 9–10). In contrast, the N,N-di-
methylamide auxiliary proved the be β-selective for glucose
and moderately β-selective (α/β = 20/80) for galactose (entries 5
and 11, respectively). This β-selectivity was surprising com-
pared to findings by Mong and coworkers, where DMF as addi-
tive induced α-selectivity.23 Similarly, phosphine oxide auxili-
10
11
12
Reagents and conditions: 1-Bromo-2-methoxyethane (15), (2-bromo-
ethoxy)benzene
(bromomethyl)diphenylphosphine
(16),
2-bromo-N,N-dimethylacetamide
oxide (18) or (R)-
(17),
or
(S)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate (19–20)
(4 eq.), NaH (2–4 eq.), DMF, 0 °C to rt, 16 h.
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Table 4 Glycosylation results for glycosyl donors 11 and 12 using a
broader range of glycosyl acceptors
aries 13–14 induced high β-selectivity (entries 6 and 12), in
contrast to the α-selectivity observed when an additive combi-
nation of triphenylphosphine oxide/TMSI was used.19
Generally, the galacto-series were more α-selective compared to
the gluco-series counterparts consistent with earlier observed
trends.6,11,28
The high β-selectivity observed for glycosyl donor 11, led us
to further investigate the amide containing auxiliaries. The
amide functionality is more amendable for easy alteration in
substitution pattern and holds better prospects for removal
compared to the phosphine oxide auxiliaries which also
demonstrated good selectivity. Hence, we set out to further
optimize the amide auxiliaries starting with exploring the
influence of the amide substitution pattern on the stereo-
selectivity. To this end, we prepared diethyl- (34–35), diphenyl- Entry
Donor type
R1OH
α/βa
Yieldb [%]
Product
(36–37) and cyclic amide derivatives (38–39) according to the
1
2
3
4
5
6
7
8
Glc
Glc
Glc
Glc
Glc
Gal
Gal
Gal
Gal
Gal
21
46
47
48
49
21
46
47
48
49
0/100
0/100c
10/90
33/67
50/50
0/100
25/75c
20/80
50/50
40/60
57
39
61
30
34
43
40
56
22
28
30
50
51
52
53
31
54
55
56
57
protocol described in Table 1. These syntheses resulted in mod-
erate to good yields (32–77%) of glycosyl donors 34–39.
Glycosylations of 34–39 also showed excellent β-selectivity for
the gluco-type donors (Table 3, entries 1–4). For the galacto-type
donors, β-selectivity was moderate and increased with the intro-
duction of bulky substituents on the amide (Table 3, entries
5–7). The piperidine derived amide auxiliary gave selectivity
comparable to the dimethyl auxiliary (Table 3, entries 8).
In addition to the amide substituents we investigated the
glycosyl acceptor scope using a broader range of glycosyl accep-
tors for both gluco- and galacto-type glycosyl donors contain-
ing the dimethylamide auxiliary. Glycosylation with primary
alcohols (21, 46 and 47) resulted moderate to good yield (39%
9
10
a α/β ratios were determined by NMR spectroscopy29,30 of the crude
reaction mixture. b Isolated yields. c α/β ratios were determined by NMR
spectroscopy after removal of the acceptor residues by silica gel flash
column chromatography (30 to 80% EtOAc in n-heptane).
to 61%) with excellent β-selectivity for gluco-type donors cosylations resulted in low to moderate yield (22 to 56%) and
(Table 4, entries 1–3). However, secondary and tertiary alcohols moderate to non-selective for the β-anomer (α/β = 20/80 to 50/
gave poorer to no selectivity (α/β = 33/67 and 50/50 respectively) 50). Again, glycosylation with secondary and tertiary alcohols
and resulted in moderate yields (Table 4, entries 4 and 5). gave poorer selectivity compared to primary alcohols (Table 4,
Glycosylations with galacto-type donors were less β-selective entries 6–10).
compared to their gluco-type counterparts (Table 4). These gly-
To identify reaction intermediates for gluco-type donors 11
and 13, variable temperature (VT) NMR experiments were per-
formed. Glycosyl donor 11 was reacted with Ph2SO and Tf2O in
presence of TTBP at −80 °C in CD2Cl2 (Fig. 2). In a control
experiment using glycosyl donor 11 and this promotor system
(Tf2O, Ph2SO) no significant changes in yields or selectivity
were observed indicating that the promotor system does not
influence the glycosylation outcome. Directly after the addition
of Tf2O the α-iminium intermediate (11α) was formed
(Fig. 2b–f). In addition, a small amount of β-iminium ion
(11β) was observed (α/β = 5/1). The ratio of intermediate 11α
and 11β did not change even upon heating to room tempera-
ture and remained stable at this temperature (Fig. 2d).
Table 3 Glycosylation results using a series of amide-based auxiliaries
Entry
Donor
Type
α/βa
Yieldb [%]
Product
Additionally, we performed VT NMR experiments under the
same conditions for glycosyl donor 13 starting at −20 °C
(Fig. 3a and c). After addition of Tf2O, the expected α- (13α)
and β-phosphonium ions (13β) were observed in a α/β-ratio of
5/2 (Fig. 3). Both reaction intermediates were stable at 10 °C
and decomposed slowly at room temperature. Again, the ratio
of 13α and 13β did not change upon heating. Based on these
VT NMR results, the α-intermediates predominate for both the
amide and phosphine oxide auxiliaries and may be reactive
1
2
3
4
5
6
7
8
11
34
36
38
12
35
37
39
Glc
Glc
Glc
Glc
Gal
Gal
Gal
Gal
0/100
0/100
0/100
3/97
20/80
17/83
11/89
20/80
57
42
86
40
43
44
71
42
30
40
42
44
31
41
43
45
a α/β ratios were determined by NMR spectroscopy29,30 of the crude
reaction mixture. b Isolated yields.
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Fig. 2 VT-NMR spectra of the iminium ion derived from 11 (a) 1H NMR spectrum of 11 at −80 °C in CD2Cl2. (b) 1H NMR of 11 at −78 °C after the
addition of Tf2O. (c) 1H NMR of 11 at −20 °C. (d) 1H NMR at 25 °C. (e) Long range COSY at −20 °C. (f) 1H/13C HMBC at −20 °C.
intermediates with strong nucleophiles. However, the erosion intermediates resulting from NGP of the C-2 auxiliaries.
of stereoselectivity when glycosylating with secondary and ter- Potentially, chiral auxiliaries based on these functional groups
tiary alcohols suggests that other reactive intermediates such can be developed to obtain even better stereoselectivity.
as the oxocarbenium ion may be responsible for disaccharide
formation in these cases.
Finally, we explored the removal of amide auxiliaries. Using
Experimental section
General conditions
disaccharide 50 as a model substrate, the tertiary amide was
hydrolysed to yield the carboxylic acid.31,32 After a simple workup
the carboxylic acid was converted to the acyl azide, heated to 1H and 13C NMR spectra were recorded on a Bruker 400 or
form the isocyanate and reacted with t-BuOH at 100 °C to yield 500 MHz spectrometer. Chemical shifts are reported in parts
the Boc-protected amine. After a short workup the Boc group was per million (ppm) relative to tetramethylsilane (TMS) or
removed and the amine was subsequently treated with 1.0 M residual solvents as the internal standard. NMR data is pre-
NaOH in which it was eliminated to yield the unprotected 2-OH sented as follows: chemical shift, multiplicity (s = singlet, d =
(58) in 50% overall yield from 50 (Scheme 1).33
doublet, t = triplet, dd = doublet of doublets, m = multiplet
In conclusion, we prepared a series glycosyl donor contain- and/or multiple resonances), coupling constant (J) in hertz
ing new C-2 auxiliaries based on commonly used additives for (Hz), integration. All NMR signals were assigned on the basis
stereoselective glycosylation. The ether based auxiliaries gave of 1H NMR, 13C NMR, 31P NMR, COSY, HSQC, and TOCSY
rather unselective glycosylation reactions whilst tertiary experiments. NMR data is presented for the major anomer.
amides and our phosphine oxide based auxiliaries showed Mass spectra were recorded on an JEOL AccuTOF CS
good to absolute β-selectivity with reactive glycosyl acceptors. JMS-T100CS mass spectrometer. Automatic flash column
VT-NMR experiments confirmed the formation of reaction chromatography was performed using Biotage Isolera Spektra
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Fig. 3 VT-NMR spectra of the phosphonium ion derived from 13 (a) 31P NMR spectrum of 13 at −20 °C in CD2Cl2. (b) 31P NMR of 13 at −20 °C after
the addition of Tf2O. (c) 1H NMR spectrum of 13 at −20 °C in CD2Cl2. (d) 1H NMR of 13 at −20 °C after the addition of Tf2O. (e) 1H NMR of 13 at
10 °C. (f) 1H/31P HMBC at −20 °C.
General procedure A
5.0 grams (0.035 mol, 1.0 eq.) D-glucal or D-galactal was dis-
solved in dry DMF (170 mL). 7.0 grams (0.18 mol, 5.0 eq.) NaH
(60% dispersion in paraffin oil) was added on ice. The reaction
was stirred for 15 minutes and 21 mL (0.18 mol, 5.0 eq.)
benzyl bromide was added. The reaction was stirred at room
Scheme 1 Removal of the auxiliary. Reagents and conditions (i) H2O
temperature until TLC indicated full consumption of starting
(2.2 eq.), t-BuOK (5.9 eq.), THF, rt; (ii) DIPEA (1.2 eq.), DPPA (1.1 eq.),
material (16 hours). The reaction was quenched with methanol
DMF, 0 °C – rt; (iii) t-BuOH, DMF, 100 °C; (iv) NaOH, THF, EtOH, 60 °C.
and the solution was concentrated in vacuo. The resulting oil
was taken up in ethyl acetate and washed with water (3 ×
100 mL) and brine (1 × 100 mL). The organic layer was dried
over MgSO4 (anhydrous), filtrated and evaporated in vacuo to
result the crude product. The benzylated products were
obtained by purification of the crude product through silica
gel flash column chromatography.
One, using SNAP cartridges (Biotage, 30–100 μm, 60 Å), 4–50 g.
TLC analysis was conducted on silica gel F254 (Merck KGaA)
with detection by UV absorption (254 nm) where applicable; by
spraying with 10% sulfuric acid in methanol followed by char-
ring at ≈300 °C or by spraying with KMnO4 stain consisting of
(0.06 M KMnO4, 0.5 M K2CO3 and 0.02 M NaOH in water) after
gently heating of the plate. DCM, THF, and toluene were
General procedure B
freshly distilled. Molecular sieves (4 Å) were flame-activated To a cooled (0 °C) solution of 4.0 grams (9.6 mmol, 1.0 eq.)
under a vacuum prior to use. All inert reactions were carried benzylated glycal in DCM (40 mL) were added acetone (4 mL)
out under an argon atmosphere using flame-dried flasks.
and saturated aqueous NaHCO3 (68 mL). The mixture was
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stirred vigorously, and a solution of oxone (19.2 mmol, 2 eq.) a second vial under inert atmosphere was stirred 1.0 mL of
in H2O (24 mL) was added dropwise over 15 min. The mixture DCM-d2 for 1.5 h over molecular sieves (4 Å). The donor solu-
was stirred vigorously at 0 °C for 30 min and then at rt until tion was transferred to an NMR tube and was analysed at low
TLC indicated consumption of the starting material. The temperature by NMR. To the DCM-d2 was added Tf2O (1.1 eq.)
organic phase was separated, and the aqueous phase was and the solution was added at −78 °C to the tube. The tube
extracted with DCM (2 × 40 mL). The combined organic phases was quickly shaken and transferred to the NMR. The reaction
were dried over Na2SO4 and concentrated in vacuo. The crude was first analysed by NMR at low temperature and was
mixture was dissolved in dry THF (80 mL). The solution was measured at increasing temperatures.
cooled to −78 °C. MS (4 Å) and 2.2 grams (15 mmol, 1.6 eq.)
3,4,6-Tri-O-benzyl-D-glucal. Using general procedure A start-
sodium thiophenolate (90%) were added under an inert atmo- ing from D-glucal (5.14 g, 35.2 mmol), the crude product was
sphere. 1.0 mL (0.096 mmol, 0.1 eq.) ZnCl2 (1.0 M in Et2O) was purified by silica gel flash column chromatography (0% to
added and the mixture was stirred for 3 days allowing it to 30% EtOAc in n-heptane), affording 3,4,6-tri-O-benzyl-D-glucal
warm up to room temperature. An aqueous solution of 1.0 M (14.1 g, 98%) as white solid. TLC: Rf = 0.61 (EtOAc/heptane, 30/
NaOH (80 mL) was added to quench the reaction. The mixture 70 v/v); 1H NMR (500 MHz, CDCl3): δH 7.50–7.13 (m, 15H), 6.42
was filtrated and the organic layer was separated from the (dd, J = 6.1, 1.4 Hz, 1H, H-1), 4.87 (dd, J = 6.2, 2.7 Hz, 1H, H-2),
aqueous layer. The organic layer was washed with brine 4.83 (d, J = 11.3 Hz, 1H), 4.66–4.62 (m, 2H), 4.61–4.54 (m, 3H),
(80 mL), dried over Na2SO4 (anhydrous), filtrated and evapor- 4.21 (ddd, J = 6.1, 2.7, 1.4 Hz, 1H, H-3), 4.06 (ddd, J = 8.3, 5.1,
ated in vacuo. The crude product was purified with silica gel 2.8 Hz, 1H, H-5), 3.86 (dd, J = 8.7, 6.2 Hz, 1H, H-4), 3.83–3.74
flash column chromatography to obtain the pure product. If (m, 2H, H-6). 13C NMR (126 MHz, CDCl3): δC 144.9 (CH, C-1),
the product was strongly coloured, the product was dissolved 138.5, 138.3, 138.2 (all quaternary), 128.6, 128.5, 128.5, 128.1,
in DCM, norrit was added, filtrated over Celite and evaporated 127.9, 127.9, 127.8 (all aromatic), 100.1 (CH, C-2), 77.0 (CH,
in vacuo to yield the product.
C-5) 75.9 (CH, C-3), 74.6 (CH, C-4), 73.9 (CH2), 73.7 (CH2), 70.6
(CH2), 68.7 (CH2, C-6). HRMS (ESI-TOF) (m/z): [M + Na]+ calcu-
lated for C27H28O4: 439.18853, found [M + Na]+: 439.18934.
General procedure C
An anomeric thioether with free 2-OH (1 or 2, 1.0 eq.) was dis-
3,4,6-Tri-O-benzyl-D-galactal. Using general procedure A
solved in dry DMF (0.1 M) under an inert atmosphere at 0 °C. starting from D-galactal (5.02 g, 35.0 mmol), the crude product
60% NaH dispersion in paraffin oil was added (2.0 eq. for the was purified by silica gel flash column chromatography (0% to
preparation of 11–14 and 34–39, 4.0 eq. for 3–10). After stirring 30% EtOAc in n-heptane), affording 3,4,6-tri-O-benzyl-D-galac-
for 15 minutes, ice was removed and the corresponding tal (13.6 g, 96%) as white solid. TLC: Rf = 0.57 (EtOAc/heptane,
1
bromide or tosylate (4.0 eq.) was added. The reaction was 30/70 v/v); H NMR (500 MHz, CDCl3): δH 7.36–7.23 (m, 15H),
stirred for overnight after which the reaction was quenched 6.36 (dd, J = 6.2, 1.5 Hz, 1H, H-1), 4.90–4.83 (m, 2H, H-2),
with methanol and the solvent was evaporated in vacuo. The 4.68–4.59 (m, 3H), 4.50 (d, J = 11.9 Hz, 1H), 4.42 (d, J = 11.9
donors were obtained by purification through silica gel flash Hz, 1H), 4.19 (tdd, J = 5.2, 2.6, 1.2 Hz, 2H, H-3, H-5), 3.95 (ddd,
column chromatography.
J = 4.0, 2.5, 1.3 Hz, 1H, H-4), 3.78 (dd, J = 10.2, 7.2 Hz, 1H,
H-6), 3.65 (dd, J = 10.1, 5.1 Hz, 1H, H-6). 13C NMR (126 MHz,
CDCl3): δC 144.3 (CH, C-1), 138.7, 138.5, 138.2 (all quaternary),
General procedure D
The corresponding glycosyl donor (1.0 eq.) and the corres- 128.6, 128.5, 128.3, 128.0, 127.8, 127.7, 127.6 (all aromatic),
ponding glycosyl acceptor (2.0 eq.) were dissolved in dry DCM 100.1 (CH, C-2), 75.8 (CH, C-5), 73.6 (CH2), 73.5 (CH2), 71.4
(0.02 M and 0.04 M respectively). MS (4 Å) were added and the (CH, C-4), 71.0 (CH, C-3), 70.9 (CH2), 68.6 (CH2, C-6). HRMS
mixture was cooled to −15 °C. NIS (1.1 eq.) was added followed (ESI-TOF) (m/z): [M + Na]+ calculated for C27H28O4: 439.18853,
by the addition of a catalytic amount TfOH (0.1 eq.). The reac- found [M + Na]+: 439.18909.
tion was stirred for 2 h allowing it to slowly reach room temp-
3,4,6-Tri-O-benzyl-1-thio-β-D-glucopyranoside
(1).
Using
erature. The reaction was quenched with TEA and taken up in general procedure B starting from 1 (4.0 gram, 9.6 mmol), the
EtOAc (20 mL). The solution was filtrated, washed with crude product was purified by silica gel flash column chrom-
aqueous thiosulfate solution (10%, 20 mL) and washed with atography (0% to 15% EtOAc in n-heptane), affording 1 (2.9 g,
brine (20 mL). The organic layer was dried over MgSO4 (anhy- 55%) as yellow/white solid. TLC: Rf = 0.51 (EtOAc/heptane, 30/
drous), filtrated and the solvent was evaporated in vacuo to 70 v/v); 1H NMR (500 MHz, CDCl3) δH 7.63–7.54 (m, 2H),
yield the crude product. The crude product was dissolved in 7.38–7.14 (m, 18H), 4.90 (d, J = 11.2 Hz, 1H), 4.86–4.81 (m,
CDCl3 and analysed by quantitative HSQC to determine the 2H), 4.64–4.53 (m, 3H), 4.50 (d, J = 9.7 Hz, 1H, H-1), 3.79 (dd, J
selectivity. After analysis the crude product was purified by = 11.0, 1.9 Hz, 1H, H-6), 3.74 (dd, J = 11.0, 4.4 Hz, 1H, H-6),
flash column chromatography to obtain the product.
3.63–3.57 (m, 2H, H-3, H-4), 3.56–3.46 (m, 2H, H-2, H-5), 2.39
(d, J = 2.1 Hz, 1H). 13C NMR (126 MHz, CDCl3) δC 138.6, 138.4,
138.2 (all quaternary), 133.1 (aromatic), 131.9 (quaternary),
VT-NMR studies procedure
Glycosyl donor (15 mg, 1.0 eq.), Ph2SO (1.2 eq.) and TTBP (2.5 129.1, 128.7, 128.6, 128.5, 128.2, 128.1, 128.1, 128.0, 127.8,
eq.) were dissolved in DCM-d2 (1 mL) under inert atmosphere. 127.7 (all aromatic), 88.2 (CH, C-1), 86.1 (CH, C-3), 79.6 (CH,
MS (4 Å) were added and the solution was stirred for 1.5 h. In C-5), 77.5 (CH, C-4), 75.5 (CH2), 75.2 (CH2), 73.6 (CH2), 72.7
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(CH, C-2), 69.2 (CH2 C-6). HRMS (ESI-TOF) (m/z): [M + Na]+ cal- 68.9 (CH2), 59.0 (CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+
culated for C33H34O5S: 565.20246, found [M + Na]+: 565.20159. Na]+:
calculated for C36H40O6S: 623.24433, found [M
3,4,6-Tri-O-benzyl-1-thio-β-D-galactopyranoside (2). Using 623.24509.
general procedure B starting from 2 (4.0 gram, 9.6 mmol), the Phenyl 3,4,6-tri-O-benzyl-2-O-(2-phenoxyethoxy)-1-thio-β-D-
+
crude product was purified by silica gel flash column chrom- glucopyranoside (5). Using general procedure C starting from 1
atography (0% to 5% Et2O in toluene), affording 2 (3.4 g, 65%) (80 mg, 0.15 mmol) and (2-bromoethoxy)benzene (16), the
as yellow/white solid. TLC: Rf = 0.31 (Et2O/toluene, 10/90 v/v); crude product was purified by silica gel flash column chrom-
1H NMR (500 MHz, CDCl3): δH 7.62–7.50 (m, 2H), 7.42–7.14 atography (0% to 10% EtOAc in n-heptane), affording 5
(m, 18H), 4.89 (d, J = 11.4 Hz, 1H), 4.76–4.65 (m, 2H), 4.57 (d, (84 mg, 86%) as white solid. TLC: Rf = 0.55 (EtOAc/heptane,
J = 11.5 Hz, 1H), 4.53 (d, J = 9.6 Hz, 1H, H-1), 4.51–4.42 (m, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH 7.57–7.53 (m, 2H),
2H), 4.06–3.93 (m, 2H, H-2, H-4), 3.67–3.75 (m, 3H, H-5, H-6), 6.92 (tt, J = 7.5, 1.1 Hz, 1H), 6.87–6.83 (m, 2H), 5.02 (d, J = 10.7
3.47 (dd, J = 9.2, 2.7 Hz, 1H, H-3), 2.43 (d, J = 2.1 Hz, 1H, OH) Hz, 1H), 4.84 (dd, J = 10.8, 3.9 Hz, 2H), 4.62 (d, J = 9.8 Hz, 1H,
ppm; 13C NMR (126 MHz, CDCl3): δC 138.8, 138.1, 138.0, 132.7 H-1), 4.60–4.57 (m, 2H), 4.52 (d, J = 12.0 Hz, 1H), 4.22–4.14 (m,
(all quaternary), 132.3, 129.0, 128.7, 128.6, 128.3, 128.1, 128.0, 2H), 4.13–4.06 (m, 2H), 3.77 (dd, J = 10.9, 2.0 Hz, 1H, H-6),
128.0, 127.9, 127.8, 127.7, 127.6 (all aromatic), 88.7 (CH, C-1), 3.73–3.66 (m, 2H, H-3, H-6), 3.61 (t, J = 9.4 Hz, 1H, H-4), 3.49
83.4 (CH, C-3), 77.8 (CH, C-5), 74.6, 73.7 (both CH2), 73.4 (CH, (ddd, J = 9.6, 4.8, 1.9 Hz, 1H, H-5), 3.39 (dd, J = 9.8, 8.6 Hz, 1H,
C-4), 72.6 (CH2), 69.2 (CH, C-2), 68.8 (CH2, C-6) ppm; HRMS H-2) ppm. 13C NMR (126 MHz, CDCl3): δC 158.9, 138.6, 138.4,
(ESI-TOF) (m/z): [M + Na]+ calculated for C33H34O5S: 565.20246, 138.2, 134.0 (all quaternary), 132.0, 129.5, 129.0, 128.6, 128.6,
found [M + Na]+: 565.20265.
128.5, 128.2, 128.1, 127.9, 127.9, 127.8, 127.7, 127.6, 120.9,
Phenyl 3,4,6-tri-O-benzyl-2-O-(2-methoxyethoxy)-1-thio-β-D- 114.7 (all aromatic), 87.6 (CH, C-1), 86.6 (CH, C-3), 81.8 (CH,
glucopyranoside (3). Using general procedure C starting from 1 C-2), 79.2 (CH, C-5), 77.8 (CH, C-4), 76.0 (CH2), 75.2 (CH2),
(101 mg, 0.186 mmol) and 1-bromo-2-methoxyethane (15), the 73.6 (CH2), 71.8 (CH2), 69.2 (CH2, C-6), 67.4 (CH2) ppm. HRMS
crude product was purified by silica gel flash column chrom- (ESI-TOF) (m/z): [M + Na]+ calculated for C41H42O6S: 685.25998,
atography (0% to 10% EtOAc in n-heptane), affording 3 found [M + Na]+: 685.25843.
(65 mg, 59%) as white oil. TLC: Rf = 0.54 (EtOAc/heptane, 30/
Phenyl 3,4,6-tri-O-benzyl-2-O-(2-phenoxyethoxy)-1-thio-β-D-
70 v/v); 1H NMR (500 MHz, CDCl3) δH 7.58–7.55 (m, 2H), galactopyranoside (6). Using general procedure C starting from
7.38–7.17 (m, 18H), 4.98 (d, J = 10.7 Hz, 1H), 4.82 (d, J = 10.9 2 (80 mg, 0.15 mmol) and (2-bromoethoxy)benzene (16), the
Hz, 2H), 4.63 (d, J = 9.8 Hz, 1H, H-1), 4.60–4.55 (m, 2H), 4.52 crude product was purified by silica gel flash column chrom-
(d, J = 12.0 Hz, 1H), 4.01 (ddd, J = 10.3, 5.6, 3.4 Hz, 1H, H-6), atography (0% to 10% EtOAc in n-heptane), affording 6
3.87 (ddd, J = 10.1, 6.4, 3.5 Hz, 1H, H-6), 3.76 (dd, J = 10.8, 2.0 (84 mg, 69%) as white solid. TLC: Rf = 0.56 (EtOAc/heptane,
Hz, 1H), 3.72–3.65 (m, 2H, H-3), 3.62–3.51 (m, 3H, H-5), 3.47 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH 7.55–7.50 (m, 2H),
(ddd, J = 9.7, 4.8, 2.0 Hz, 1H, H-4), 3.36 (s, 3H), 3.34 (t, J = 9.0 7.38–7.34 (m, 2H), 7.33–7.25 (m, 13H), 7.25–7.20 (m, 2H),
Hz, 1H, H-2) ppm. 13C NMR (126 MHz, CDCl3) δC 138.7, 138.4, 7.19–7.14 (m, 3H), 6.92 (tt, J = 7.3, 1.1 Hz, 1H), 6.88–6.83 (m,
138.2, 134.0 (all quaternary), 132.0, 129.0, 128.6, 128.6, 128.5, 2H), 4.94 (d, J = 11.5 Hz, 1H), 4.81–4.70 (m, 2H), 4.60 (d, J = 9.6
128.1, 128.1, 127.9, 127.8, 127.8, 127.7, 127.5 (all aromatic), Hz, 1H, H-1), 4.58 (d, J = 11.5 Hz, 1H), 4.48–4.38 (m, 2H),
87.5 (CH, C-1), 86.7 (CH, C-3), 81.9 (CH, C-2), 79.2 (CH, C-4), 4.16–4.05 (m, 4H), 3.94 (dd, J = 2.9, 0.8 Hz, 1H, H-4), 3.81 (t, J =
77.8 (CH, C-5), 75.9 (CH2), 75.2 (CH2), 73.5 (CH2), 72.5 (CH2), 9.4 Hz, 1H, H-2), 3.67–3.58 (m, 3H, H-5, H-6), 3.56 (dd, J = 9.3,
72.2 (CH2), 69.2 (CH2), 59.1 (CH3) ppm; HRMS (ESI-TOF) (m/z): 2.7 Hz, 1H, H-3) ppm; 13C NMR (126 MHz, CDCl3): δC 159.0,
[M + Na]+ calculated for C36H40O6S: 623.24433, found [M + 138.9, 138.5, 138.0, 134.3 (all quaternary), 131.6, 129.5, 128.9,
Na]+: 623.24404.
128.6, 128.6, 128.3, 128.0, 128.0, 127.9, 127.9, 127.8, 127.6,
Phenyl 3,4,6-tri-O-benzyl-2-O-(2-methoxyethoxy)-1-thio-β-D- 127.2, 120.8, 114.7 (all aromatic), 87.9 (CH, C-1), 83.9 (CH,
galactopyranoside (4). Using general procedure C starting from C-3), 78.4 (CH, C-2), 77.5 (CH, C-5), 74.6 (CH2), 73.9 (CH, C-4),
2 (100 mg, 0.184 mmol) and 1-bromo-2-methoxyethane (15), 73.7, 73.1, 71.9 (all CH2), 68.9 (CH2, C-6), 67.5 (CH2) ppm;
the crude product was purified by silica gel flash column HRMS (ESI-TOF) (m/z): [M + Na]+ calculated for C41H42O6S:
chromatography (0% to 15% EtOAc in n-heptane), affording 4 685.25998, found [M + Na]+: 685.25861.
(81 mg, 73%) as white solid. TLC: Rf = 0.40 (EtOAc/heptane,
Phenyl 3,4,6-tri-O-benzyl-2-O-(((R)-tetrahydrofuran-2-yl)methoxy)-
30/70 v/v); 1H NMR (500 MHz, CDCl3): δH 7.56–7.50 (m, 2H), 1-thio-β-D-glucopyranoside (7). Using general procedure C
7.41–7.22 (m, 16H), 7.21–7.13 (m, 3H), 4.93 (d, J = 11.6 Hz, starting from 1 (99 mg, 0.18 mmol) and (R)-(tetrahydrofuran-2-
1H), 4.81–4.69 (m, 2H), 4.60 (d, J = 9.6 Hz, 1H, H-1), 4.57 (d, J = yl)methyl 4-methylbenzenesulfonate (19), the crude product
11.6 Hz, 1H), 4.48–4.36 (m, 2H), 3.94–3.85 (m, 3H, H-5, H-6), was purified by silica gel flash column chromatography (0% to
3.75 (t, J = 9.4 Hz, 1H, H-2), 3.67–3.48 (m, 6H, H-3, H-4, H-6), 5% Et2O in toluene), affording (7) (63 mg, 54%) as colourless
3.35 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3): δC 138.9, 138.6, oil. TLC: Rf
=
0.30 (Et2O/toluene, 10/90 v/v); 1H NMR
138.0, 134.4 (all quaternary), 131.6, 128.9, 128.5, 128.5, 128.3, (500 MHz, CDCl3): δH 7.49–7.41 (m, 2H), 7.28–7.07 (m, 18H),
128.0, 128.0, 127.9, 127.8, 127.8, 127.6, 127.1 (all aromatic), 4.93 (d, J = 10.7 Hz, 1H), 4.72 (dd, J = 10.8, 2.4 Hz, 2H), 4.51 (d,
87.8 (CH, C-1), 84.0 (CH, C-3), 78.5 (CH, C-2), 77.4 (CH, C-4), J = 9.8 Hz, 1H, H-1), 4.49–4.45 (m, 2H), 4.41 (d, J = 11.9 Hz,
74.6 (CH, C-5), 73.9, 73.7, 73.0, 72.6 (all CH2), 72.3 (CH2, C-6), 1H), 4.06–3.98 (m, 1H), 3.74 (dt, J = 8.4, 6.6 Hz, 1H), 3.68–3.63
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(m, 4H, H-6), 3.61–3.55 (m, 2H, H-3, H-6), 3.49 (t, J = 9.4 Hz, starting from 2 (100 mg, 0.18 mmol) and (S)-(tetrahydrofuran-
1H, H-4), 3.37 (ddd, J = 9.8, 4.9, 1.9 Hz, 1H, H-5), 3.23 (dd, J = 2-yl)methyl 4-methylbenzenesulfonate (20), the crude product
9.8, 8.7 Hz, 1H, H-2), 1.86 (dtd, J = 12.4, 7.1, 5.9 Hz, 1H), was purified by silica gel flash column chromatography (0% to
1.79–1.72 (m, 2H), 1.53–1.46 (m, 1H) ppm. 13C NMR (126 MHz, 5% Et2O in toluene), affording 10 (76 mg, 66%) as colourless
CDCl3): δC 138.7, 138.4, 138.2, 134.1 (all quaternary), 132.0, oil. TLC: Rf
=
0.27 (Et2O/toluene, 10/90 v/v); 1H NMR
129.0, 128.5, 128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7, (500 MHz, CDCl3): δH 7.49–7.44 (m, 2H), 7.32–7.16 (m, 16H),
127.6, 127.5 (all aromatic), 87.6 (CH, C-1), 86.7 (CH, C-3), 81.7 7.10 (p, J = 3.6 Hz, 3H), 4.86 (d, J = 11.6 Hz, 1H), 4.69 (d, J =
(CH, C-2), 79.2 (CH, C-5), 78.0 (CH, C-4), 77.8 (CH), 76.2, 75.8, 11.7 Hz, 1H), 4.65 (d, J = 11.7 Hz, 1H), 4.51 (t, J = 10.4 Hz, 2H,
75.2, 73.5 (all CH2), 69.2 (CH2, C-6), 68.3, 28.3, 25.6 (all CH2) H-1), 4.38 (d, J = 11.7 Hz, 1H), 4.33 (d, J = 11.7 Hz, 1H), 3.98
ppm. HRMS (ESI-TOF) (m/z): [M
C38H42O6S: 649.25998, found [M + Na]+: 649.25857.
Phenyl 3,4,6-tri-O-benzyl-2-O-(((R)-tetrahydrofuran-2-yl)methoxy)- 1H), 3.57–3.50 (m, 3H, H-4), 3.48 (dd, J = 9.2, 2.9 Hz, 1H),
1-thio-β-D-galactopyranoside (8). Using general procedure C 1.85–1.69 (m, 3H), 1.57 (ddt, J = 11.3, 8.0, 7.0 Hz, 1H) ppm; 13
+
Na]+ calculated for (qd, J = 6.7, 4.3 Hz, 1H), 3.86 (d, J = 2.8 Hz, 1H, H-5), 3.82–3.73
(m, 2H), 3.70–3.63 (m, 2H, H-2, H-3), 3.59 (dd, J = 9.8, 4.4 Hz,
C
starting from 2 (97 mg, 0.18 mmol) and (R)-(tetrahydrofuran-2- NMR (126 MHz, CDCl3): δC 138.9, 138.6, 138.0, 134.4 (all qua-
yl)methyl 4-methylbenzenesulfonate (19), the crude product ternary), 131.6, 128.8, 128.5, 128.5, 128.2, 128.0, 128.0, 127.0,
was purified by silica gel flash column chromatography (0% to 127.8, 127.7, 127.6, 127.1 (all aromatic), 87.8 (CH, C-1), 84.1
5% Et2O in toluene), affording (8) (95 mg, 83%) as white solid. (CH, C-4), 78.3 (CH, C-2), 78.1 (CH), 77.5 (CH, C-3), 76.0, 74.6
TLC: Rf = 0.18 (Et2O/toluene, 10/90 v/v); 1H NMR (500 MHz, (both CH2), 73.9 (CH, C-5), 73.7, 73.0, 69.0 (all CH2), 68.3
CDCl3): δH 7.56–7.50 (m, 2H), 7.41–7.36 (m, 2H), 7.35–7.23 (m, (CH2, C-6), 28.0, 25.7 (both CH2) ppm; HRMS (ESI-TOF) (m/z):
13H), 7.20–7.15 (m, 3H), 4.93 (d, J = 11.5 Hz, 1H), 4.81 (d, J = [M + Na]+ calculated for C38H42O6S: 649.25998, found [M +
11.6 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.61–4.54 (m, 2H, H-1), Na]+: 649.26015.
4.47–4.37 (m, 2H), 4.11 (qd, J = 7.0, 4.4 Hz, 1H, H-5), 3.93 (d, J
Phenyl 3,4,6-tri-O-benzyl-2-O-(methyl-N,N-dimethylacetamide)-
= 2.8 Hz, 1H), 3.86–3.70 (m, 4H, H-2, H-6), 3.67–3.53 (m, 5H, 1-thio-β-D-glucopyranoside (11). Using general procedure C
H-3, H-4), 1.97–1.87 (m, 1H), 1.87–1.79 (m, 2H), 1.61–1.57 (m, starting from 1 (101 mg, 0.19 mmol) and N,N-dimethyl-
1H) ppm; 13C NMR (126 MHz, CDCl3) δC 138.0, 138.6, 138.0, acetamide (17), the crude product was purified by silica gel
134.4 (all quaternary), 131.6, 128.9, 128.5, 128.5, 128.3, 128.0, flash column chromatography (0% to 10% Et2O in DCM),
128.0, 127.9, 127.7, 127.7, 127.6, 127.1 (all aromatic), 87.9 (CH, affording 11 (68 mg, 58%) as white solid. TLC: Rf = 0.30 (Et2O/
1
C-1), 84.2 (CH, C-4), 78.2 (CH, C-2), 78.0 (CH, C-5), 77.4 (CH, DCM, 10/90 v/v); H NMR (500 MHz, CDCl3): δH 7.60–7.52 (m,
C-3), 76.3, 74.5 (both CH2), 73.7 (CH), 73.0, 67.0 (both CH2), 2H), 7.39–7.18 (m, 18H), 4.93 (d, J = 10.6 Hz, 1H), 4.88–4.80
68.3 (CH2, C-6), 29.8, 28.2, 25.6 (all CH2) ppm; HRMS (m, 2H), 4.68 (d, J = 9.8 Hz, 1H, H-1), 4.59 (dd, J = 12.1, 5.3 Hz,
(ESI-TOF) (m/z): [M + Na]+ calculated for C38H42O6S: 649.25998, 3H), 4.53 (d, J = 11.9 Hz, 1H), 4.29 (d, J = 12.5 Hz, 1H), 3.76
found [M + Na]+: 649.25849.
(ddd, J = 10.2, 6.8, 1.4 Hz, 2H, H-3, H-6), 3.70 (ddd, J = 11.0,
Phenyl 3,4,6-tri-O-benzyl-2-O-(((S)-tetrahydrofuran-2-yl)methoxy)- 4.6, 1.3 Hz, 1H, H-6), 3.65–3.58 (m, 1H, H-4), 3.52–3.46 (m, 1H,
1-thio-β-D-glucopyranoside (9). Using general procedure C H-5), 3.39 (ddt, J = 9.9, 8.7, 1.1 Hz, 1H, H-2), 2.93 (d, J = 8.9 Hz,
starting from 1 (85 mg, 0.16 mmol) and (S)-(tetrahydrofuran-2- 6H). 13C NMR (126 MHz, CDCl3): δC 168.3, 138.5, 138.4, 138.1,
yl)methyl 4-methylbenzenesulfonate (20), the crude product 133.6 (all quaternary), 132.1, 129.0, 128.6, 128.5, 128.5, 128.3,
was purified by silica gel flash column chromatography (0% to 128.0, 127.9, 127.8, 127.7, 127.7, 127.7 (all aromatic), 86.9 (CH,
5% Et2O in toluene), affording 9 (71 mg, 72%) as colourless C-1), 86.5 (CH, C-3), 81.5 (CH, C-2), 79.1 (CH, C-5), 77.8 (CH,
oil. TLC: Rf
=
0.37 (Et2O/toluene, 10/90 v/v); 1H NMR C-4), 75.9, 75.2, 73.5, 72.0 (all CH2), 69.1 (CH2, C-6), 36.5, 35.5
(500 MHz, CHCl3): δH 7.60–7.51 (m, 2H), 7.39–7.14 (m, 18H), (both CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ calculated
4.96 (d, J = 10.7 Hz, 1H), 4.82 (dd, J = 10.8, 7.9 Hz, 2H), 4.62 (d, for C37H41NO6S: 650.25523, found [M + Na]+: 650.25491.
J = 9.8 Hz, 1H, H-1), 4.60–4.54 (m, 2H), 4.52 (d, J = 12.0 Hz,
Phenyl 3,4,6-tri-O-benzyl-2-O-(methyl-N,N-dimethylacetamide)-
1H), 4.06 (qd, J = 6.8, 4.0 Hz, 1H), 3.93–3.84 (m, 2H), 3.75 1-thio-β-D-galactopyranoside (12). Using general procedure C
(ddd, J = 12.7, 8.3, 1.9 Hz, 2H, H-6), 3.72–3.63 (m, 3H, H-3, starting from 2 (155 mg, 0.27 mmol) and N,N-dimethyl-
H-6), 3.59 (t, J = 9.4 Hz, 1H, H-5), 3.48 (ddd, J = 9.6, 4.8, 2.0 Hz, acetamide (17), the crude product was purified by silica gel
1H), 3.33 (dd, J = 9.7, 8.6 Hz, 1H, H-2), 1.96–1.75 (m, 3H), 1.66 flash column chromatography (0% to 10% Et2O in DCM),
(ddt, J = 11.9, 8.7, 7.3 Hz, 1H) ppm; 13C NMR (126 MHz, affording 12 (185 mg, 65%) as white solid. TLC: Rf = 0.59
CDCl3): δC 138.7, 138.4, 138.2, 134.0 (all quaternary), 132.0, (Et2O/DCM, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH
128.9, 128.5, 128.4, 128.0, 127.9, 127.7, 127.6, 127.5 (all aro- 7.57–7.51 (m, 2H), 7.39–7.23 (m, 15H), 7.17 (dd, J = 5.0, 1.9 Hz,
matic), 87.5 (CH, C-1), 86.7 (CH, C-3), 81.6 (CH, C-2), 79.1 (CH, 3H), 4.91 (d, J = 11.5 Hz, 1H), 4.76–4.68 (m, 3H, H-1), 4.57 (d,
C-5), 78.0 (CH), 77.8 (CH, C-4), 77.9, 75.8, 75.1, 73.5 (all CH2), J = 11.5 Hz, 1H), 4.46 (d, J = 12.3 Hz, 2H), 4.40 (d, J = 11.7 Hz,
69.2 (CH2, C-6), 68.4, 28.0, 25.8 (all CH2) ppm; HRMS 1H), 4.31 (d, J = 12.8 Hz, 1H), 3.96 (d, J = 2.6 Hz, 1H, H-4), 3.79
(ESI-TOF) (m/z): [M + Na]+ calculated for C38H42O6S: 649.25998, (t, J = 9.3 Hz, 1H, H-2), 3.70 (dd, J = 9.1, 2.7 Hz, 1H, H-3),
found [M + Na]+: 649.25998.
3.66–3.60 (m, 3H, H-5, H-6), 2.87 (s, 3H), 2.83 (s, 3H) ppm; 13
C
Phenyl 3,4,6-tri-O-benzyl-2-O-(((S)-tetrahydrofuran-2-yl)methoxy)- NMR (126 MHz, CDCl3): δC 168.5, 138.7, 138.3, 137.8, 133.8 (all
1-thio-β-D-galactopyranoside (10). Using general procedure C quaternary), 131.5, 128.8, 128.4, 128.4, 128.2, 127.9, 127.8,
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127.8, 127.7, 127.6, 127.5, 127.2 (all aromatic), 86.9 (CH, C-1), 0.050 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
83.8 (CH, C-3), 78.1 (CH, C-2), 77.2 (CH, C-5), 74.5, 73.5 (both (21), the crude product was purified by silica gel flash column
CH2), 73.5 (CH, C-4), 72.7, 71.9 (both CH2), 68.7 (CH2, C-6), chromatography (0% to 20% EtOAc in n-heptane), affording 22
36.2, 35.3 (both CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ as an anomeric mixture (α/β = 1/1, 48 mg, 96%). TLC: Rf = 0.31
calculated for C37H41NO6S: 650.25523, found [M + Na]+: (EtOAc/heptane, 30/70 v/v); 1H NMR (500 MHz, CHCl3): δH
650.25553.
8.03–7.96 (m, 2H), 7.96–7.88 (m, 2H), 7.89–7.81 (m, 2H),
Phenyl
3,4,6-tri-O-benzyl-2-O-(methyl-diphenylphosphine 7.55–7.46 (m, 2H), 7.47–7.20 (m, 26H), 7.15 (dd, J = 7.4, 2.2 Hz,
oxide)-1-thio-β-D-glucopyranoside (13). Using general pro- 2H), 6.15 (t, J = 9.8 Hz, 1H, H-3′), 5.47 (dd, J = 10.3, 9.5 Hz, 1H,
cedure C starting from 1 (90 mg, 0.17 mmol) and (bromo- H-4′), 5.26 (dd, J = 10.1, 3.6 Hz, 1H, H-2′), 5.22 (d, J = 3.6 Hz,
methyl)diphenylphosphine oxide (18), the crude product was 1H, H-1′), 5.01 (d, J = 10.8 Hz, 1H), 4.81 (d, J = 10.8 Hz, 1H),
purified by silica gel flash column chromatography (60% to 4.76 (d, J = 10.9 Hz, 1H), 4.54–4.48 (m, 2H), 4.44 (d, J = 12.2
100% EtOAc in n-heptane), affording 13 (56 mg, 45%) as white Hz, 1H), 4.39 (d, J = 7.8 Hz, 1H, H-1), 4.33 (ddd, J = 9.7, 7.0, 2.2
sticky compound. TLC: Rf = 0.57 (EtOAc/heptane, 80/20 v/v); 1H Hz, 1H, H-5′), 4.13 (ddd, J = 10.6, 5.5, 3.7 Hz, 1H, H-6), 4.07
NMR (500 MHz, CDCl3): δH 7.86 (dddd, J = 11.6, 8.3, 3.0, 1.3 (dd, J = 11.0, 2.2 Hz, 1H), 3.78 (qd, J = 6.9, 4.2 Hz, 2H, H-6,
Hz, 4H), 7.54–7.11 (m, 27H), 4.82 (dd, J = 12.2, 6.3 Hz, 1H), H-6′), 3.69–3.57 (m, 3H, H-3, H-6, H-6′), 3.58–3.50 (m, 3H,
4.73 (d, J = 10.8 Hz, 1H), 4.61–4.46 (m, 6H, H-1), 4.36 (d, J = H-5), 3.46 (s, 3H), 3.39 (ddd, J = 9.7, 4.6, 2.2 Hz, 1H, H-4), 3.33
10.7 Hz, 1H), 3.75 (dd, J = 10.9, 2.0 Hz, 1H, H-6), 3.68 (dd, J = (s, 3H), 3.27 (dd, J = 9.0, 7.8 Hz, 1H, H-2) ppm. 13C NMR
10.9, 4.8 Hz, 1H, H-6), 3.61–3.54 (m, 2H, H-3, H-4), 3.45 (ddd, J (126 MHz, CDCl3): δC 166.0, 165.9, 165.5, 139.0 (all quatern-
= 9.3, 4.7, 2.0 Hz, 1H, H-5), 3.41–3.33 (m, 1H, H-2) ppm; 13C ary), 139.0, 138.3, 138.3, 133.5, 133.5, 133.2, 130.0, 130.0(all
NMR (126 MHz, CDCl3): δC 138.3, 138.2, 138.0, 133.5 (all qua- aromatic), 129.8, 129.3, 129.1 (all quaternary), 128.6, 128.5,
ternary), 132.3, 132.3, 132.2, 132.2, 132.1, 132.0, 131.9 (all aro- 128.5, 128.5, 128.4, 128.2, 128.1, 127.9, 127.7, 127.7 (all aro-
matic), 131.8 (quaternary), 131.7, 131.7 (both aromatic), 131.3, matic), 104.0 (CH, C-1), 97.0 (CH, C-1′), 84.5 (CH, C-3), 83.4
131.0, 130.5 (all quaternary), 129.1, 128.7, 128.6, 128.5, 128.5, (CH, C-2), 77.7 (CH2), 75.7 (CH2), 75.1 (CH2), 75.0 (CH, C-4),
128.4, 128.06, 127.9, 127.8, 127.7, 127.7, 127.7, 127.7 (all aro- 73.6 (CH2), 72.3 (CH, C-5), 72.3 (CH, C-2′), 72.0 (CH, C-6), 70.7
matic), 87.0 (CH, C-1), 86.4 (CH, C-3), 83.1, 83.0 (both CH, (CH, C-3′), 69.9 (CH, C-4′), 69.1 (CH, C-5′), 68.9 (CH, C-6′), 59.0
C-2), 79.0 (CH, C-5), 77.9 (CH, C-4), 75.4, 75.1, 73.5, 71.3, 70.6 (CH3), 55.7 (CH3) ppm. HRMS (ESI-TOF) (m/z): [M + Na]+ calcu-
(all CH2), 69.0 (CH2, C-6) ppm; 31P NMR (202 MHz, CDCl3): δP lated for C58H60O15: 1019.38299. Found [M + Na]+: 1019.38148.
27.3 ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated for
Methyl 3,4,6-tribenzyl-2-O-(2-methoxyethoxy)-α/β-D-galacto-
pyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyranoside (23).
C46H45O6PS: 757.27527, found [M + H]+: 757.27581.
Phenyl
3,4,6-tri-O-benzyl-2-O-(methyl-diphenylphosphine Using general procedure D starting from 4 (40 mg,
oxide)-1-thio-β-D-galactopyranoside (14). Using general pro- 0.067 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
cedure C starting from 2 (100 mg, 0.18 mmol) and (bromo- (21), the crude product was purified by silica gel flash column
methyl)diphenylphosphine oxide (18), the crude product was chromatography (0% to 15% Et2O in toluene), affording 23 as
purified by silica gel flash column chromatography (60% to an anomeric mixture (α/β = 3/2, 63 mg, 95%). TLC: Rf = 0.27
1
100% EtOAc in n-heptane), affording 14 (63 mg, 45%) as col- (Et2O/toluene, 30/70 v/v); H NMR (500 MHz, CDCl3): δH 7.98
ourless sticky compound. TLC: Rf = 0.49 (EtOAc/heptane, 80/20 (dq, J = 7.0, 2.1, 1.7 Hz, 2H), 7.93–7.89 (m, 2H), 7.86–7.82 (m,
1
v/v); H NMR (500 MHz, CDCl3): δH 7.83 (dddd, J = 11.5, 9.5, 2H), 7.54–7.45 (m, 3H), 7.44–7.21 (m, 29H), 6.12 (t, J = 9.8 Hz,
8.2, 1.4 Hz, 4H), 7.54–7.43 (m, 2H), 7.42–7.12 (m, 26H), 4.84 1H, H-3′), 5.53 (dd, J = 10.3, 9.5 Hz, 1H, H-4′), 5.25 (dd, J =
(d, J = 11.4 Hz, 1H), 4.66 (dd, J = 12.3, 6.1 Hz, 1H), 4.58 (dd, J = 10.2, 3.7 Hz, 1H, H-2′), 5.14 (d, J = 3.7 Hz, 1H, H-1′), 4.99 (d, J =
12.3, 9.5 Hz, 1H), 4.53 (d, J = 9.7 Hz, 1H, H-1), 4.51–4.43 (m, 3.5 Hz, 1H, H-1), 4.92 (d, J = 11.5 Hz, 1H), 4.80 (d, J = 11.9 Hz,
3H), 4.39 (dd, J = 11.5, 5.3 Hz, 2H), 3.89 (d, J = 2.8 Hz, 1H, 1H), 4.70 (d, J = 11.9 Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.39 (d,
H-4), 3.77 (t, J = 9.4 Hz, 1H, H-2), 3.64–3.53 (m, 3H, H-5, H-6), J = 11.9 Hz, 1H), 4.34–4.28 (m, 2H, H-5′), 4.01 (t, J = 6.5 Hz, 1H,
3.49 (dd, J = 9.1, 2.8 Hz, 1H, H-3) ppm; 13C NMR (126 MHz, H-5), 3.96 (dd, J = 10.0, 3.5 Hz, 1H, H-2), 3.93–3.86 (m, 3H,
CDCl3): δC 138.7, 138.0, 137.9, 133.8 (all quaternary), 132.2, H-3, H-4, H-6′), 3.85–3.79 (m, 2H), 3.69 (dd, J = 11.2, 2.1 Hz,
132.2, 132.1, 132.1, 132.1, 132.0, 131.8, 131.7 (all aromatic), 1H, H-6′), 3.55–3.50 (m, 2H), 3.49–3.43 (m, 3H, H-6), 3.37 (s,
131.7 (quaternary), 131.6 (aromatic), 131.0, 130.9 (both qua- 3H), 3.32 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3): δC 165.9,
ternary), 129.0, 128.6, 128.6, 128.6, 128.5, 128.4, 128.3, 128.0, 165.5, 139.1, 138.3, 133.5 (all quaternary), 133.2, 130.1, 130.0,
127.9, 127.8, 127.6, 127.6, 127.4 (all aromatic), 87.3 (CH, C-1), 129.8, 129.5 (all aromatic), 129.3, 129.2, 128.5 (all quaternary),
84.3 (CH, C-3), 79.7, 79.6 (both CH, C-2), 77.3 (CH, C-5), 74.6, 128.5, 128.5, 128.5, 128.4, 128.4, 128.4, 128.3, 128.3, 128.0,
73.7 (both CH2), 73.3 (CH, C-4), 72.5, 71.3, 70.6 (all CH2), 127.9, 127.8, 127.7, 127.6, 127.5, 124.5, 123.6, 119.2, 119.0 (all
68.8 ppm (CH2, C-6); 31P NMR (202 MHz, CDCl3): δP aromatic), 98.0 (CH, C-1), 96.9 (CH, C-1′), 78.5 (CH, C-3), 77.8
27.59 ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated for (CH, C-2), 75.3 (CH, C-4), 74.9, 73.4, 73.0, 72.3 (all CH2), 72.3
C46H45O6PS: 757.27527, found [M + H]+: 757.27564.
Methyl 3,4,6-tribenzyl-2-O-(2-methoxyethoxy)-α/β-D-glucopyr- 68.9 (CH, C-6), 68.7 (CH, C-5′), 66.8 (C-6′), 59.1, 55.6 (both
anosyl-(1
6)-2,3,4-O-tribenzoyl-α-D-glucopyranoside (22). CH3) ppm. HRMS (ESI-TOF) (m/z): [M + Na]+ calculated for
Using general procedure starting from
(30 mg, C58H60O15: 1019.38299. Found [M + Na]+: 1019.37696.
(C-2′), 70.9 (C-3′), 70.7 (CH2), 69.7 (CH, C-4′), 69.4 (CH, C-5),
→
D
3
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Methyl 3,4,6-tribenzyl-2-O-(2-phenoxyethoxy)-α/β-D-glucopyr- C-6′), 69.8 (CH, C-4′), 69.5 (CH, C-5), 68.8 (CH2), 68.6 (CH,
anosyl-(1 6)-2,3,4-O-tribenzoyl-α-D-glucopyranoside (24). C-5′), 67.5 (CH2), 66.8 (CH2, C-6′), 55.6 (CH3) ppm; HRMS
Using general procedure starting from (40 mg, (ESI-TOF) (m/z): [M
Na]+ calculated for C63H62O15:
0.060 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose 1081.39864, found [M + Na]+: 1081.39683.
→
D
5
+
(21), the crude product was purified by silica gel flash column
Methyl 3,4,6-tribenzyl-2-O-(((R)-tetrahydrofuran-2-yl)methoxy)-
chromatography (0% to 20% EtOAc in n-heptane), affording 24 α/β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano-
as an anomeric mixture (α/β = 1/1, 35 mg, 54%). TLC: Rf = 0.32 side (26). Using general procedure D starting from 7 (40 mg,
(EtOAc/heptane, 30/70 v/v); 1H NMR (500 MHz, CHCl3): δH 0.064 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
8.02–7.95 (m, 2H), 7.92 (dt, J = 8.4, 1.7 Hz, 2H), 7.84 (ddd, J = (21), the crude product was purified by silica gel flash column
8.5, 3.3, 1.4 Hz, 2H), 7.54–7.19 (m, 24H), 7.15 (ddt, J = 6.1, 4.2, chromatography (0% to 15% Et2O in toluene), affording 26 as
2.0 Hz, 2H), 6.95–6.89 (m, 1H), 6.86–6.79 (m, 1H), 6.61–6.56 an anomeric mixture (α/β = 1/2, 56 mg, 85%). TLC: Rf = 0.26
(m, 1H), 6.15 (td, J = 9.8, 2.1 Hz, 1H, H-3′), 5.55–5.47 (m, 1H, (EtOAc/heptane, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH
H-4′), 5.30–5.24 (m, 1H, H-2′), 5.22 (d, J = 3.7 Hz, 1H, H-1′), 8.00–7.95 (m, 2H), 7.94–7.89 (m, 2H), 7.87–7.83 (m, 2H),
5.03 (d, J = 10.8 Hz, 1H), 4.98 (d, J = 10.9 Hz, 1H), 4.81 (dd, J = 7.55–7.47 (m, 2H), 7.45–7.20 (m, 20H), 7.17–7.13 (m, 2H), 6.15
10.8, 6.8 Hz, 1H), 4.76 (dd, J = 10.8, 4.9 Hz, 1H), 4.57–4.43 (m, (dd, J = 10.1, 9.4 Hz, 1H, H-3′), 5.47 (dd, J = 10.3, 9.4 Hz, 1H,
3H), 4.42–4.36 (m, 1H, H-1), 4.32 (dtd, J = 12.1, 6.9, 6.1, 4.0 Hz, H-4′), 5.25 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), 5.21 (d, J = 3.6 Hz,
2H, H-5′), 4.19–3.99 (m, 4H, H-6, H-6′), 3.78 (dt, J = 11.3, 6.0 1H, H-1′), 5.06 (d, J = 10.8 Hz, 1H), 4.81 (d, J = 10.8 Hz, 1H),
Hz, 1H, H-6′), 3.70–3.52 (m, 4H, H-5, H-6, H-3), 3.45 (s, 3H), 4.76 (d, J = 10.8 Hz, 1H), 4.52 (d, J = 5.0 Hz, 1H), 4.49 (d, J = 3.7
3.41 (dt, J = 6.8, 2.1 Hz, 1H, H-4), 3.38–3.30 (m, 1H, H-2) ppm; Hz, 1H), 4.43 (d, J = 12.2 Hz, 1H), 4.37 (d, J = 7.8 Hz, 1H, H-1),
13C NMR (126 MHz, CDCl3): δC 165.9, 165.5, 158.9, 138.8 (all 4.33 (ddd, J = 9.9, 7.0, 2.2 Hz, 1H, H-5′), 4.14–4.05 (m, 2H),
quaternary), 138.3 (aromatic), 138.2 (quaternary), 135.5, 133.6, 3.96 (dd, J = 9.7, 4.3 Hz, 1H), 3.83 (dt, J = 8.4, 6.7 Hz, 1H),
133.5, 133.2, 130.1, 130.0, 129.8, 129.5 (all aromatic), 129.4, 3.79–3.72 (m, 2H, H-6′), 3.69–3.58 (m, 4H, H-3, H-6), 3.53 (t, J =
129.4, 129.2, 129.2, 129.1 (all quaternary), 129.0, 128.6, 128.6, 9.3 Hz, 1H, H-4), 3.46 (s, 3H), 3.39 (ddd, J = 9.7, 4.6, 2.2 Hz,
128.5, 128.5, 128.4, 128.3, 128.3, 128.2, 128.1, 127.9, 127.8, 1H, H-5), 3.29 (dd, J = 9.0, 7.8 Hz, 1H, H-2), 2.01–1.93 (m, 1H),
127.7, 127.7, 127.7, 125.8, 120.8, 117.1, 115.7, 114.6 (all aro- 1.86 (dt, J = 9.5, 6.6 Hz, 2H), 1.62–1.57 (m, 1H) ppm; 13C NMR
matic), 103.8 (CH, C-1), 97.1 (CH, C-1′), 84.4 (CH, C-3), 83.2 (126 MHz, CDCl3): δC 166.0, 165.9, 139.0, 138.3 (all quatern-
(CH, C-2), 82.9 (CH2), 77.7 (CH, C-5), 75.7 (CH2), 75.1 (CH, ary), 133.5, 133.2, 130.1, 130.0, 129.8 (all aromatic), 129.5,
C-4), 75.1 (CH2), 73.6 (CH2), 72.2 (CH, C-2′), 71.1 (CH2), 70.8 129.3, 129.1 (all quaternary), 128.6, 128.5, 128.5, 128.4, 128.2,
(CH, C-3′), 69.7 (CH, C-4′), 69.0 (CH, C-5′), 68.9 (CH2, C-6), 67.7 128.1, 127.8, 127.7, 127.7 (all aromatic), 103.9 (CH, C-1), 97.0
(CH2, C-6′), 55.7 (CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ (CH, C-1′), 84.6 (CH, C-3), 83.3 (CH, C-2), 78.1 (CH), 77.7 (CH,
calculated for C63H62O15: 1081.39864, found [M + Na]+: C-4), 75.8, 75.7, 75.1 (all CH2), 75.0 (CH, C-5), 73.5 (CH2), 72.3
1081.39610.
(CH, C-2′), 70.8 (CH, C-3′), 69.9 (CH, C-4′), 69.0 (CH, C-5′), 68.9
Methyl 3,4,6-tribenzyl-2-O-(2-phenoxyethoxy)-α/β-D-galacto- (CH2, C-6), 68.8 (CH2, C-6′), 68.2 (CH2), 55.7 (CH3), 28.4, 25.8
pyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyranoside (25). (both CH2) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ calculated
Using general procedure
0.067 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
D starting from 8
(40 mg, for C60H62O15: 1045.39864. Found [M + Na]+: 1045.39527.
Methyl 3,4,6-tribenzyl-2-O-(((R)-tetrahydrofuran-2-yl)methoxy)-
(21), the crude product was purified by silica gel flash column α/β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyra-
chromatography (0% to 15% Et2O in toluene), affording 25 as noside (27). Using general procedure D starting from 8 (40 mg,
an anomeric mixture (α/β = 3/2, 49 mg, 77%). TLC: Rf = 0.34 0.064 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
(Et2O/toluene, 10/90 v/v); 1H NMR (500 MHz, CDCl3): δH (21), the crude product was purified by silica gel flash column
8.00–7.96 (m, 2H), 7.92–7.88 (m, 2H), 7.86–7.82 (m, 2H), chromatography (0% to 15% Et2O in toluene), affording 27 as
7.55–7.17 (m, 27H), 6.93–6.82 (m, 2H), 6.11 (t, J = 9.8 Hz, 1H, an anomeric mixture (α/β = 1/1, 53 mg, 81%). TLC: Rf = 0.27
H-3′), 5.51 (t, J = 9.9 Hz, 1H, H-4′), 5.23 (dd, J = 10.2, 3.7 Hz, (Et2O/toluene, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH
1H, H-2′), 5.11 (d, J = 3.6 Hz, 1H, H-1′), 4.99 (d, J = 3.6 Hz, 1H, 8.00–7.96 (m, 2H), 7.89 (ddd, J = 27.7, 8.4, 1.4 Hz, 3H),
H-1), 4.92 (d, J = 11.5 Hz, 1H), 4.79 (d, J = 11.8 Hz, 1H), 4.70 (d, 7.55–7.19 (m, 25H), 6.12 (t, J = 9.9 Hz, 1H, H-3′), 5.56 (t, J = 9.9
J = 11.9 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.9 Hz, Hz, 1H, H-4′), 5.25 (dd, J = 10.2, 3.7 Hz, 1H, H-2′), 5.14 (d, J =
1H), 4.34–4.25 (m, 2H, H-5′), 4.13–3.96 (m, 6H, H-2, H-5, H-6), 3.7 Hz, 1H, H-1′), 4.99 (d, J = 3.4 Hz, 1H, H-1), 4.92 (d, J = 11.5
3.95–3.83 (m, 3H, H-3, H-4, H-6′), 3.66 (dt, J = 11.3, 2.7 Hz, 1H, Hz, 1H), 4.82 (d, J = 11.9 Hz, 1H), 4.70 (d, J = 12.0 Hz, 1H), 4.55
H-6′), 3.51–3.41 (m, 2H), 3.34 (s, 3H) ppm; 13C NMR (126 MHz, (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.9 Hz, 1H), 4.32–4.24 (m, 2H,
CDCl3): δC 165.9, 165.5, 159.0, 139.0, 138.9 (all quaternary), H-5′), 4.09–4.02 (m, 1H), 3.99–3.93 (m, 2H, H-2, H-5), 3.92–3.85
138.3 (aromatic), 138.2 (quaternary), 133.5, 133.2, 130.1, 130.0, (m, 3H, H-3, H-4), 3.84–3.81 (m, 1H, H-6′), 3.76–3.68 (m, 2H,
129.8, 129.5 (all aromatic), 129.5, 129.3, 129.2 (all quaternary), H-6), 3.64 (dd, J = 11.2, 2.0 Hz, 1H, H-6′), 3.58 (dd, J = 10.1, 5.1
128.5, 128.5, 128.5, 128.5, 128.4, 128.3, 127.8, 127.8, 127.7, Hz, 1H, H-6), 3.43 (d, J = 6.7 Hz, 2H), 3.37 (s, 3H), 1.98–1.77
127.6, 127.5, 120.9, 117.2 (all aromatic), 97.9 (CH, C-1), 96.9 (m, 3H), 1.72 (ddt, J = 11.3, 8.1, 6.5 Hz, 1H); 13C NMR
(CH, C-1′), 78.4 (CH, C-3), 78.0 (CH, C-2), 75.3 (CH, C-4), 74.9, (126 MHz, CDCl3): δC 165.8, 165.3, 139.0, 138.8, 138.1 (all qua-
73.4, 73.0 (all CH2), 72.3 (CH, C-2′), 70.8 (CH, C-3′), 70.2 (CH2, ternary), 133.3, 133.0, 129.9, 129.8, 129.7 (all aromatic), 129.4,
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129.2, 129.1 (all quaternary), 128.4, 128.4, 128.3, 128.3, 128.2, (dd, J = 6.6, 2.7 Hz, 2H), 3.37 (s, 3H), 1.96–1.75 (m, 3H), 1.63
128.2, 128.2, 127.6, 127.6, 127.5, 127.5, 127.4, 124.4, 123.5 (all (m, 2H) ppm; 13C NMR (126 MHz, CDCl3): δC 165.9, 165.4,
aromatic), 97.9 (CH, C-1), 96.8 (CH, C-1′), 78.3 (CH, C-3), 77.7 139.1, 138.9, 138.6 (all quaternary), 133.4, 133.2, 130.1, 130.0,
(CH), 77.5 (CH, C-2), 75.1 (CH, C-4), 74.7, 73.5, 73.2, 72.9 (all 129.8 (all aromatic), 129.5, 129.3, 129.2 (all quaternary), 128.5,
CH2), 72.2 (CH, C-2′), 70.7 (CH, C-3′), 69.4 (CH, C-4′), 69.3 (CH, 128.5, 128.5, 128.4, 128.4, 128.4, 128.3, 127.8, 127.7, 127.6,
C-5), 68.8 (CH2), 68.6 (CH, C-5′), 68.3 (CH2, C-6), 66.6 (CH2, 127.6, 127.5 (all aromatic), 97.9 (CH, C-1), 96.9 (CH, C-1′), 78.6
C-6), 55.4 (CH3), 29.7, 28.2, 25.7 (all CH2) ppm; HRMS (CH), 78.4 (CH, C-3), 77.9 (CH, C-2), 75.3 (CH, C-4), 74.9, 74.1,
(ESI-TOF) (m/z): [M
+
Na]+ calculated for C60H62O15: 73.4, 73.1 (all CH2), 72.3 (CH, C-2′), 70.9 (CH, C-3′), 69.7 (CH,
C-4′), 69.4 (CH, C-5), 68.9 (CH2, C-6), 68.7 (CH, C-5′), 68.3
1045.39864. Found [M + Na]+: 1045.39502.
Methyl 3,4,6-tribenzyl-2-O-(((S)-tetrahydrofuran-2-yl)methoxy)- (CH2), 66.8 (CH2, C-6′), 55.6 (CH3), 28.4, 25.7 (both CH2) ppm;
α/β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano- HRMS (ESI-TOF) (m/z): [M + Na]+ calculated for C60H62O15:
side (28). Using general procedure D starting from 9 (40 mg, 1045.39864, found [M + Na]+: 1045.39704.
0.064 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-dimethylacetamide)-
(21), the crude product was purified by silica gel flash column β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano-
chromatography (0% to 15% Et2O in toluene), affording 28 as side (30). Using general procedure D starting from 11 (40 mg,
an anomeric mixture (α/β = 0.7/1, 35 mg, 55%). TLC: Rf = 0.20 0.064 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
(EtOAc/heptane, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH (21), the crude product was purified by silica gel flash column
8.00–7.96 (m, 2H), 7.94–7.91 (m, 2H), 7.87–7.83 (m, 2H), chromatography (30% to 60% EtOAc in n-heptane), affording
7.53–7.47 (m, 2H), 7.44–7.20 (m, 20H), 7.14 (dd, J = 7.4, 2.1 Hz, 30 as pure β-anomer (38 mg, 57%). TLC: Rf = 0.18 (EtOAc/
1
2H), 6.16 (t, J = 9.8 Hz, 1H, H-3′), 5.45 (t, J = 9.9 Hz, 1H, H-5′), heptane, 50/50 v/v); H NMR (500 MHz, CDCl3): δH 8.00–7.96
5.26 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), 5.21 (d, J = 3.6 Hz, 1H, (m, 2H), 7.91 (dd, J = 8.3, 1.4 Hz, 2H), 7.86–7.83 (m, 2H),
H-1′), 5.01 (d, J = 10.9 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.76 7.54–7.47 (m, 2H), 7.44–7.21 (m, 22H), 7.18–7.12 (m, 2H), 6.15
(d, J = 10.9 Hz, 1H), 4.54–4.48 (m, 2H), 4.45–4.38 (m, 2H, H-1), (t, J = 9.8 Hz, 1H, H-3′), 5.47 (dd, J = 10.3, 9.5 Hz, 1H, H-4′),
4.34 (ddd, J = 10.0, 7.3, 2.2 Hz, 1H, H-5′), 4.05 (ddt, J = 14.5, 5.25 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), 5.21 (d, J = 3.6 Hz, 1H,
9.6, 4.3 Hz, 3H, H-6′), 3.84 (dt, J = 8.3, 6.6 Hz, 1H, H-6), H-1′), 5.00 (d, J = 11.0 Hz, 1H), 4.80 (dd, J = 10.9, 5.7 Hz, 2H),
3.81–3.69 (m, 2H, H-6, H-6′), 3.67–3.52 (m, 5H, H-3, H-4), 3.47 4.70 (d, J = 13.0 Hz, 1H), 4.55–4.49 (m, 2H), 4.48–4.42 (m, 2H,
(s, 3H), 3.39 (ddd, J = 9.7, 4.3, 2.3 Hz, 1H, H-5), 3.26 (dd, J = H-1), 4.34 (ddd, J = 9.9, 7.0, 2.3 Hz, 1H, H-5′), 4.26 (d, J = 13.0
8.9, 7.7 Hz, 1H, H-2), 1.96–1.78 (m, 3H), 1.64–1.58 (m, 1H) Hz, 1H), 4.06 (dd, J = 11.0, 2.3 Hz, 1H, H-6′), 3.77 (dd, J = 11.1,
ppm; 13C NMR (126 MHz, CDCl3): δC 166.0, 165.9, 165.6, 139.0, 7.0 Hz, 1H, H-6′), 3.69 (t, J = 9.0 Hz, 1H, H-3), 3.64–3.61 (m,
138.3, 138.3 (all quaternary), 133.5, 133.5, 133.2, 130.1, 130.1, 2H, H-6), 3.56 (t, J = 9.4 Hz, 1H, H-4), 3.46 (s, 3H), 3.40 (ddd, J
130.0, 129.8 (all aromatic), 129.4, 129.3, 129.1 (all quaternary), = 9.8, 4.2, 2.5 Hz, 1H, H-5), 3.33 (dd, J = 9.0, 7.8 Hz, 1H, H-2),
128.5, 128.5, 128.5, 128.4, 128.4, 128.1, 128.1, 127.8, 127.7 (all 2.94 (d, J = 10.3 Hz, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC
aromatic), 104.1 (CH, C-1), 96.9 (CH, C-1′), 84.6 (CH, C-3), 83.4 168.8, 166.0, 165.9, 165.5, 138.8, 138.2 (all quaternary), 133.5,
(CH, C-2), 78.1 (CH), 77.7 (CH, C-4), 75.8, 75.6, 75.1 (all CH2), 133.5, 133.2, 130.1, 130.0, 129.8 (all aromatic), 129.4, 129.2,
75.0 (CH, C-5), 73.6 (CH2), 72.3 (CH, C-2′), 70.7 (CH, C-3′), 70.1 129.1 (all quaternary), 128.5, 128.5, 128.5, 128.4, 128.4, 128.2,
(CH, C-4′), 69.1 (CH, C-5′), 68.9 (CH2, C-6′), 68.3 (CH2, C-6), 128.1, 127.8, 127.8, 127.7, 127.6 (all aromatic), 103.4 (CH, C-1),
55.7 (CH3), 28.2, 25.9 (both CH2) ppm; HRMS (ESI-TOF) (m/z): 97.0 (CH, C-1′), 84.2 (CH, C-3), 83.3 (CH, C-2), 77.6 (CH, C-4),
[M + Na]+ calculated for C60H62O15: 1045.39864, found [M + 75.7, 75.1 (both CH2), 75.0 (CH, C-5), 73.5 (CH2), 72.2 (CH,
Na]+: 1045.39864.
Methyl 3,4,6-tribenzyl-2-O-(((S)-tetrahydrofuran-2-yl)methoxy)- C-5′), 68.8 (CH2, C-6), 68.7 (CH2, C-6′), 55.7, 36.4, 35.5 (all CH3)
α/β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyra- ppm; HRMS (ESI-TOF) (m/z): [M
H]+ calculated for
noside (29). Using general procedure D starting from 10 C59H61NO15: 1024.41194, found [M + H]+: 1024.41336.
(40 mg, 0.064 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glyco- Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-dimethylacetamide)
C-2′), 71.5 (CH2), 70.7 (CH, C-3′), 69.9 (CH, C-4′), 69.0 (CH,
+
pyranose (21), the crude product was purified by silica gel -α/β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyr-
flash column chromatography (0% to 15% Et2O in toluene), anoside (31). Using general procedure D starting from 12
affording 29 as an anomeric mixture (α/β = 1/1, 41 mg, 73%). (40 mg, 0.064 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glyco-
TLC: Rf = 0.30 (Et2O/toluene, 30/70 v/v); 1H NMR (500 MHz, pyranose (21), the crude product was purified by silica gel
CDCl3): δH 8.01–7.96 (m, 2H), 7.93–7.89 (m, 2H), 7.87–7.83 (m, flash column chromatography (30% to 60% EtOAc in
2H), 7.55–7.20 (m, 24H), 6.12 (t, J = 9.9 Hz, 1H, H-3′), 5.54 (t, n-heptane), affording 31 as an anomeric mixture (α/β = 1/4,
1
J = 9.9 Hz, 1H, H-4′), 5.24 (dd, J = 10.2, 3.7 Hz, 1H, H-2′), 5.14 28.1 mg, 43%). TLC: Rf = 0.65 (EtOAc/heptane, 80/20 v/v); H
(d, J = 3.7 Hz, 1H, H-1′), 5.03 (d, J = 3.5 Hz, 1H, H-1), 4.92 (d, NMR (500 MHz, CDCl3): δH 7.99–7.95 (m, 2H), 7.91–7.87 (m,
J = 11.5 Hz, 1H), 4.81 (d, J = 11.9 Hz, 1H), 4.70 (d, J = 11.9 Hz, 2H), 7.86–7.82 (m, 2H), 7.55–7.45 (m, 2H), 7.44–7.22 (m, 20H),
1H), 4.55 (d, J = 11.5 Hz, 1H), 4.38 (d, J = 11.9 Hz, 1H), 7.22–7.18 (m, 2H), 6.13 (dd, J = 10.1, 9.5 Hz, 1H, H-3′), 5.38
4.34–4.26 (m, 2H, H-5′), 4.05 (qd, J = 6.8, 5.1 Hz, 1H, H-3), (dd, J = 10.4, 9.4 Hz, 1H, H-4′), 5.22 (dd, J = 10.1, 3.6 Hz, 1H,
4.02–3.96 (m, 2H, H-2, H-5), 3.91–3.86 (m, 2H, H-4, H-6′), 3.81 H-2′), 5.18 (d, J = 3.6 Hz, 1H, H-1′), 4.88 (d, J = 11.6 Hz, 1H),
(dt, J = 8.4, 6.6 Hz, 1H, H-6), 3.73–3.61 (m, 4H, H-6, H-6′), 3.44 4.78 (d, J = 11.8 Hz, 1H), 4.72 (d, J = 11.8 Hz, 1H), 4.64 (d, J =
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12.7 Hz, 1H), 4.56 (d, J = 11.6 Hz, 1H), 4.42 (d, J = 7.5 Hz, 1H, 9H), 7.55–7.04 (m, 29H), 6.03 (t, J = 9.8 Hz, 1H), 5.24–5.17 (m,
H-1), 4.38–4.26 (m, 4H, H-5′), 4.01 (dd, J = 10.9, 2.2 Hz, 1H, 1H), 5.12 (dd, J = 10.2, 3.6 Hz, 1H), 4.95–4.87 (m, 2H), 4.76 (d, J
H-6′), 3.84 (d, J = 2.9 Hz, 1H, H-4), 3.73 (dd, J = 10.9, 7.9 Hz, = 11.6 Hz, 1H), 4.43 (d, J = 11.6 Hz, 1H), 4.41–4.33 (m, 3H),
1H, H-6′), 3.66 (dd, J = 9.6, 7.6 Hz, 1H, H-2), 3.55 (dd, J = 9.6, 4.27–4.21 (m, 3H), 4.17 (d, J = 11.8 Hz, 1H), 3.92 (dd, J = 10.3,
2.9 Hz, 1H, H-3), 3.53–3.45 (m, 3H, H-5, H-6), 3.44 (s, 3H), 2.92 2.1 Hz, 1H), 3.68 (d, J = 2.9 Hz, 1H), 3.61 (dd, J = 9.6, 7.6 Hz,
(d, J = 9.4 Hz, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC 169.0, 1H), 3.50 (dd, J = 10.3, 9.0 Hz, 1H), 3.38–3.30 (m, 3H),
166.0, 165.9, 165.6, 138.7, 138.7, 138.0 (all quaternary), 133.5, 3.30–3.26 (m, 1H), 3.17 (s, 3H) ppm; 13C NMR (126 MHz,
133.2, 130.1, 130.0, 129.8 (all aromatic), 129.4, 129.2, 129.1 (all CDCl3) δC 165.8, 165.8, 165.7, 138.5, 138.4, 137.9 (all quatern-
quaternary), 128.6, 128.5, 128.5, 128.4, 128.4, 128.3, 128.0, ary), 133.5, 133.4, 133.2, 132.7, 132.7, 132.2, 132.2 (all aro-
127.9, 127.8, 127.7, 127.6 (all aromatic), 103.7 (CH, C-1), 96.8 matic), 131.9 (quaternary), 131.9, 131.8, 131.7, 131.6 (all aro-
(CH, C-1′), 81.7 (CH, C-3), 80.6 (CH, C-2), 74.7, 73.6 (both matic), 131.1, 131.1 (both quaternary), 130.0, 130.0, 129.7 (all
CH2), 73.6 (CH, C-4), 73.5 (CH, C-5), 73.2 (CH2), 72.3 (CH, aromatic), 129.4, 129.2 (both quaternary), 129.0 (aromatic),
C-2′), 72.0 (CH2), 70.7 (CH, C-3′), 70.1 (CH, C-4′), 69.0 (CH, 128.9 (quaternary), 128.9, 128.6, 128.6, 128.5, 128.5, 128.4,
C-5′), 68.9 (CH2, C-6′), 68.7 (CH2, C-6), 55.7, 36.5, 35.5 (all CH3) 128.4, 128.4, 128.3, 127.9, 127.9, 127.7, 127.6, 127.5 (all aro-
ppm; HRMS (ESI-TOF) (m/z): [M
+
H]+ calculated for matic), 103.7 (CH, C-1), 96.6 (CH, C-1′), 82.1 (CH, C-2), 81.4
(CH, C-3), 74.7, 73.6 (both CH2), 73.5 (CH, C-5), 73.4 (CH, C-4),
C49H61NO15: 1024.41194, found [M + H]+: 1024.41045.
Methyl 3,4,6-tribenzyl-2-O-(methyldiphenylphosphine-oxide)- 73.0 (CH2), 72.1 (CH, C-2′), 70.7 (CH, C-3′), 70.5 (CH2), 70.3
α/β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano- (CH, C-4′), 70.0 (CH2), 69.4 (CH2, C-6′), 68.7 (CH, C-5′), 68.6
side (32). Using general procedure D starting from 13 (40 mg, (CH, C-5′), 55.6 (CH3) ppm; 31P NMR (202 MHz, CDCl3): δP
0.053 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose 27.73 ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated for
(21), the crude product was purified by silica gel flash column C68H65O15P: 1153.41393, found [M + H]+: 1153.41352.
chromatography (30% to 80% EtOAc in n-heptane), affording
Phenyl 3,4,6-tri-O-benzyl-2-O-(methyl-N,N-diethylacetamide)-
32 as an anomeric mixture (α/β = 1/8, 41 mg, 67%). TLC: Rf = 1-thio-β-D-glucopyranoside (34). Using general procedure C
0.64 (EtOAc/heptane, 80/20 v/v); 1H NMR (500 MHz, CDCl3): δH starting from 1 (106 mg, 0.20 mmol) and 2-chloro-N,N-diethyl-
8.00–7.95 (m, 2H), 7.92–7.79 (m, 8H), 7.56 (td, J = 7.4, 1.4 Hz, acetamide, the crude product was purified by silica gel flash
1H), 7.54–7.45 (m, 4H), 7.44–7.31 (m, 8H), 7.31–7.18 (m, 13H), column chromatography (0% to 10% Et2O in DCM), affording
7.15–7.09 (m, 2H), 7.09–7.05 (m, 2H), 6.13 (t, J = 9.8 Hz, 1H, 34 (84 mg, 66%) as sticky yellowish compound. TLC: Rf = 0.68
H-3′), 5.31 (dd, J = 10.1, 9.3 Hz, 1H, H-4′), 5.19 (dd, J = 10.2, 3.6 (Et2O/DCM, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH
Hz, 1H, H-2′), 5.04 (dd, J = 12.6, 6.3 Hz, 1H), 4.98 (d, J = 3.5 Hz, 7.59–7.51 (m, 2H), 7.40–7.19 (m, 18H), 4.99 (d, J = 10.4 Hz,
1H, H-1′), 4.71 (d, J = 10.8 Hz, 1H), 4.51–4.41 (m, 4H), 1H), 4.84 (t, J = 10.7 Hz, 2H), 4.67 (d, J = 9.8 Hz, 1H, H-1),
4.40–4.30 (m, 4H, H-1, H-5′), 4.01 (dd, J = 10.4, 2.2 Hz, 1H, 4.65–4.57 (m, 3H), 4.52 (d, J = 12.0 Hz, 1H), 4.25 (d, J = 12.1
H-6′), 3.63 (dd, J = 10.5, 8.7 Hz, 1H), 3.57 (d, J = 3.2 Hz, 2H, Hz, 1H), 3.80–3.74 (m, 2H, H-3, H-6), 3.71 (dd, J = 10.9, 4.7 Hz,
H-6), 3.53 (d, J = 9.4 Hz, 1H, H-4), 3.48 (t, J = 8.9 Hz, 1H, H-3), 1H, H-6), 3.61 (t, J = 9.4 Hz, 1H, H-4), 3.50 (ddd, J = 9.9, 4.7, 1.9
3.33 (ddt, J = 7.8, 5.7, 2.5 Hz, 2H, H-2, H-5), 3.28 (s, 3H) ppm; Hz, 1H, H-5), 3.44–3.32 (m, 3H, H-2), 3.26 (hept, J = 7.5 Hz,
13C NMR (126 MHz, CDCl3): δC 165.9, 165.8, 165.8, 138.5, 2H), 1.12 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC 167.3,
138.1, 138.1 (all quaternary), 133.6, 133.5, 133.2, 132.3, 132.3, 138.4, 138.1, 133.5 (all quaternary), 132.0, 129.0, 128.5, 128.5,
132.2, 132.2, 131.9, 131.8, 131.8, 131.7 (all aromatic), 131.0, 128.4, 128.4, 128.0, 127.9, 127.8, 127.7, 127.6, 127.6 (all aro-
130.9 (both quaternary), 130.1, 130.0, 129.8 (all aromatic), matic), 86.8 (CH, C-1), 86.4 (CH, C-3), 81.6 (CH, C-2), 79.1 (CH,
129.4, 129.2, 128.9 (all quaternary), 128.7, 128.6, 128.6, 128.6, C-5), 77.7 (CH, C-4), 75.9, 75.1, 73.4, 72.1 (all CH2), 69.1 (CH2,
128.5, 128.5, 128.4, 128.4, 128.4, 128.0, 127.9, 127.8, 127.8, C-6), 41.3, 40.2 (both CH2), 14.4, 13.0 (both CH3) ppm; HRMS
127.7, 127.6 (all aromatic), 103.5 (CH, C-1), 96.7 (CH, C-1′), (ESI-TOF) (m/z): [M
84.8 (CH, C-2), 84.0 (CH, C-3), 77.5 (CH, C-4), 75.3, 75.0 (both 656.30458, found [M + H]+: 656.30491.
+
H]+ calculated for C39H45NO6S:
CH2), 74.9 (CH, C-5), 73.6 (CH2), 72.1 (CH, C-2′), 70.5 (CH,
Phenyl 3,4,6-tri-O-benzyl-2-O-(methyl-N,N-diethylacetamide)-
C-3′), 70.3 (CH, C-4′), 69.8 (CH2), 69.5 (CH2, C-6′), 68.8 (CH, 1-thio-β-D-galactopyranoside (35). Using general procedure C
C-5′), 68.5 (CH2, C-6), 55.7 (CH3) ppm; 31P NMR (202 MHz, starting from 2 (105 mg, 0.19 mmol) and 2-chloro-N,N-diethyl-
CDCl3): δP 27.35 ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calcu- acetamide, the crude product was purified by silica gel flash
lated for C68H65O15P: 1153.41393, found [M + H]+: 1153.41312.
column chromatography (0% to 10% Et2O in DCM), affording
Methyl 3,4,6-tribenzyl-2-O-(methyldiphenylphosphine-oxide) 35 (86 mg, 68%) as sticky white compound. TLC: Rf = 0.76
-α/β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyr- (Et2O/DCM, 30/70 v/v); 1H NMR (500 MHz, CDCl3): δH
anoside (33). Using general procedure D starting from 14 7.58–7.49 (m, 2H), 7.42–7.07 (m, 18H), 4.93 (d, J = 11.5 Hz,
(48 mg, 0.063 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glyco- 1H), 4.77 (d, J = 11.5 Hz, 1H), 4.73 (d, J = 11.5 Hz, 1H), 4.66 (d,
pyranose (33), the crude product was purified by silica gel J = 9.6 Hz, 1H, H-1), 4.57 (d, J = 11.6 Hz, 1H), 4.50 (d, J = 12.3
flash column chromatography (30% to 80% EtOAc in Hz, 1H), 4.46 (d, J = 11.7 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.29
n-heptane), affording 33 as an anomeric mixture (α/β = 1/8, (d, J = 12.4 Hz, 1H), 3.95 (d, J = 2.8 Hz, 1H, H-4), 3.78 (t, J = 9.3
50 mg, 68%). TLC: Rf = 0.48 (EtOAc/heptane, 80/20 v/v); 1H Hz, 1H, H-2), 3.69–3.59 (m, 4H, H-3, H-5, H-6), 3.35 (q, J = 7.1
NMR (500 MHz, CDCl3): δH 7.91–7.88 (m, 2H), 7.82–7.70 (m, Hz, 2H), 3.21 (qd, J = 7.2, 2.9 Hz, 2H), 1.08 (dt, J = 28.1, 7.0 Hz,
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6H) ppm; 13C NMR (126 MHz, CDCl3): δC 167.6, 138.9, 138.4, 4.59 (dd, J = 12.0, 1.8 Hz, 3H), 4.52 (d, J = 11.9 Hz, 1H), 4.30 (d,
138.0, 134.0 (all quaternary), 131.6, 128.9, 128.6, 128.5, 128.3, J = 12.0 Hz, 1H), 3.79–3.74 (m, 2H, H-3, H-6), 3.70 (dd, J = 10.9,
128.0, 128.0, 127.9, 127.9, 127.8, 127.6, 127.3 (all aromatic), 4.7 Hz, 1H, H-6), 3.60 (t, J = 9.5 Hz, 1H, H-4), 3.57–3.47 (m, 3H,
87.2 (CH, C-1), 83.8 (CH, C-3), 78.3 (CH, C-2), 77.4 (CH, C-5), H-5), 3.41–3.30 (m, 3H, H-2), 1.62 (q, J = 6.2 Hz, 2H), 1.57–1.50
74.6 (CH2), 73.8 (CH, C-4), 73.7, 73.0, 72.2 (all CH2), 68.9 (CH2, (m, 3H), 1.50–1.43 (m, 1H) ppm; 13C NMR (126 MHz, CDCl3):
C-6), 41.2, 40.1 (both CH2), 14.4, 13.1 (both CH3) ppm; HRMS δC 166.5, 138.4, 138.2, 133.6 (all quaternary), 132.1, 129.1,
(ESI-TOF) (m/z): [M
656.30458, found [M + H]+: 656.30448.
Phenyl 3,4,6-tri-O-benzyl-2-O-(methyl-N,N-diphenylaceta- C-2), 79.1 (CH, C-5), 77.8 (CH, C-4), 76.0, 75.2, 73.5, 72.3 (all
mide)-1-thio-β-D-glucopyranoside (36). Using general pro- CH2), 69.1 (CH2, C-6), 46.2, 43.0, 26.6, 25.7, 24.7 (all CH2)
cedure C starting from 1 (106 mg, 0.20 mmol) and 2-chloro-N, ppm; HRMS (ESI-TOF) (m/z): [M
H]+ calculated for
N-diphenylacetamide, the crude product was purified by silica C40H45NO6S: 668.30458, found [M + H]+: 668.30591.
gel flash column chromatography (0% to 30% EtOAc in Phenyl 3,4,6-tri-O-benzyl-2-O-((piperidin-1-yl)ethan-1-one)-1-
+
H]+ calculated for C39H45NO6S: 128.6, 128.6, 128.5, 128.4, 128.0, 128.0, 127.9, 127.5, 127.7,
127.7 (all aromatic), 87.0 (CH, C-1), 86.5 (CH, C-3), 81.5 (CH,
+
n-heptane), affording 36 (83 mg, 56%) as sticky yellow com- thio-β-D-galactopyranoside (39). Using general procedure C
pound. TLC: Rf = 0.29 (EtOAc/heptane, 30/70 v/v); 1H NMR starting from 2 (120 mg, 0.22 mmol) and 2-chloro-1-(piperi-
(500 MHz, CDCl3): δH 7.43–7.38 (m, 2H), 7.36–7.06 (m, 28H), din-1-yl)ethan-1-one, the crude product was purified by silica
4.99 (d, J = 10.7 Hz, 1H), 4.86 (d, J = 10.7 Hz, 1H), 4.81 (d, J = gel flash column chromatography (0% to 10% Et2O in DCM),
10.8 Hz, 1H), 4.64 (d, J = 9.7 Hz, 1H, H-1), 4.59–4.55 (m, 2H), affording 39 (77 mg, 52%) as white solid. TLC: Rf = 0.78 (Et2O/
1
4.52–4.44 (m, 2H), 4.10 (d, J = 14.6 Hz, 1H), 3.80–3.73 (m, 2H, DCM, 30/70 v/v); H NMR (500 MHz, CDCl3): δH 7.59–7.49 (m,
H-3, H-6), 3.70 (dd, J = 10.8, 4.3 Hz, 1H, H-6), 3.55 (t, J = 9.5 2H), 7.42–7.22 (m, 15H), 7.22–7.13 (m, 3H), 4.92 (d, J = 11.5
Hz, 1H, H-4), 3.47 (ddd, J = 9.8, 4.3, 2.0 Hz, 1H, H-5), 3.21 (t, J Hz, 1H), 4.73 (s, 2H), 4.66 (d, J = 9.6 Hz, 1H, H-1), 4.57 (d, J =
= 9.2 Hz, 1H, H-2) ppm; 13C NMR (126 MHz, CDCl3): δC 168.2, 11.6 Hz, 1H), 4.46 (dd, J = 12.0, 2.4 Hz, 2H), 4.41 (d, J = 11.7
138.7, 138.4, 138.1, 132.7 (all quaternary), 132.6, 128.9, 128.5, Hz, 1H), 4.33 (d, J = 12.2 Hz, 1H), 3.96 (d, J = 2.8 Hz, 1H, H-4),
128.4, 128.1, 128.0, 127.9, 127.8, 127.6, 127.6, 127.6 (all aro- 3.77 (t, J = 9.4 Hz, 1H, H-2), 3.68–3.58 (m, 4H, H-3, H-5, H-6),
matic), 86.3 (CH, C-3), 86.3 (CH, C-1), 81.3 (CH, C-2), 79.0 (CH, 3.51 (tq, J = 13.2, 7.6, 5.9 Hz, 2H), 3.37–3.23 (m, 2H), 1.72–1.33
C-5), 77.5 (CH, C-4), 75.8, 75.1, 73.4, 72.1 (all CH2), 69.0 (CH2, (m, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC 166.8, 138.9,
C-6) ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated for 138.4, 138.0, 134.0 (all quaternary), 131.7, 128.9, 128.6, 128.5,
C47H45NO6S: 752.30458, found [M + H]+: 752.30680.
Phenyl 3,4,6-tri-O-benzyl-2-O-(methyl-N,N-diphenylaceta- matic), 87.2 (CH, C-1), 84.0 (CH, C-3), 78.1 (CH, C-2), 77.3 (CH,
128.3, 128.1, 127.9, 127.9, 127.9, 127.8, 127.6, 127.3 (all aro-
mide)-1-thio-β-D-galactopyranoside (37). Using general pro- C-5), 74.6, 73.7 (both CH2), 73.6 (CH, C-4), 72.9, 72.4 (both
cedure C starting from 2 (102 mg, 0.19 mmol) and 2-chloro-N, CH2), 68.9 (CH2, C-6), 46.1, 42.9, 26.5, 25.6, 24.7 (all CH2)
N-diphenylacetamide, the crude product was purified by silica ppm; HRMS (ESI-TOF) (m/z): [M
gel flash column chromatography (0% to 30% EtOAc in C40H45NO6S: 668.30458, found [M + H]+: 668.30369.
n-heptane), affording 37 (45 mg, 32%) as sticky white com- Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-diethylacetamide)-
+
H]+ calculated for
pound. TLC: Rf = 0.29 (EtOAc/heptane, 40/60 v/v); 1H NMR β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano-
(500 MHz, CDCl3): δH 7.45–7.04 (m, 30H), 4.90 (d, J = 11.6 Hz, side (40). Using general procedure D starting from 34 (40 mg,
1H), 4.79 (d, J = 11.5 Hz, 1H), 4.75 (d, J = 11.5 Hz, 1H), 4.64 (d, 0.061 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
J = 9.4 Hz, 1H, H-1), 4.54 (d, J = 11.6 Hz, 1H), 4.48–4.37 (m, (21), the crude product was purified by silica gel flash column
3H), 4.11 (d, J = 14.7 Hz, 1H), 3.92 (d, J = 2.8 Hz, 1H, H-4), 3.69 chromatography (30% to 60% EtOAc in n-heptane), affording
(dd, J = 6.3, 2.8 Hz, 1H, H-3), 3.65–3.57 (m, 4H, H-2, H-5, H-6) 40 as pure β-anomer (27 mg, 43%). TLC: Rf = 0.53 (EtOAc/
1
ppm; 13C NMR (126 MHz, CDCl3): δC 168.6, 138.9, 138.7, 138.0, heptane, 60/40 v/v); H NMR (500 MHz, CDCl3): δH 8.00–7.96
133.4 (all quaternary), 132.0, 128.8, 128.5, 128.5, 128.3, 128.0, (m, 2H), 7.93–7.89 (m, 2H), 7.87–7.82 (m, 2H), 7.54–7.47 (m,
127.9, 127.7, 127.7, 127.5, 127.2 (all aromatic), 86.8 (CH, C-1), 2H), 7.45–7.21 (m, 30H), 7.15 (dd, J = 7.4, 2.0 Hz, 2H), 6.15 (t, J
83.7 (CH, C-3), 78.4 (CH, C-5), 77.2 (CH, C-2), 74.6 (CH2), 74.0 = 9.8 Hz, 1H, H-3′), 5.45 (t, J = 9.8 Hz, 1H, H-4′), 5.25 (dd, J =
(CH, C-4), 73.7, 73.1, 72.2 (all CH2), 68.7 (CH2, C-6) ppm; 10.2, 3.6 Hz, 1H, H-2′), 5.20 (d, J = 3.6 Hz, 1H, H-1′), 5.03 (d, J =
HRMS (ESI-TOF) (m/z): [M + H]+ calculated for C47H45NO6S: 10.8 Hz, 1H), 4.82 (d, J = 10.9 Hz, 1H), 4.78 (d, J = 10.8 Hz, 1H),
752.30458, found [M + H]+: 752.30458.
4.72 (d, J = 12.8 Hz, 1H), 4.53 (d, J = 4.0 Hz, 1H), 4.51 (d, J = 2.6
Phenyl 3,4,6-tri-O-benzyl-2-O-((piperidin-1-yl)ethan-1-one)-1- Hz, 1H), 4.44 (d, J = 6.9 Hz, 2H, H-1), 4.34 (ddd, J = 9.8, 7.2, 2.3
thio-β-D-glucopyranoside (38). Using general procedure C start- Hz, 1H, H-5′), 4.23 (d, J = 12.8 Hz, 1H), 4.04 (dd, J = 11.1, 2.3
ing from 1 (101 mg, 0.19 mmol) and 2-chloro-1-(piperidin-1-yl) Hz, 1H, H-6′), 3.78 (dd, J = 11.1, 7.1 Hz, 1H, H-6′), 3.69 (t, J =
ethan-1-one, the crude product was purified by silica gel flash 9.0 Hz, 1H, H-3), 3.64–3.62 (m, 2H, H-6), 3.55 (t, J = 9.3 Hz, 1H,
column chromatography (0% to 10% Et2O in DCM), affording H-4), 3.45 (s, 3H), 3.43–3.35 (m, 3H, H-5), 3.34–3.20 (m, 3H,
38 (95 mg, 77%) as white solid. TLC: Rf = 0.68 (Et2O/DCM, 20/ H-2), 1.15 (dt, J = 16.9, 7.1 Hz, 6H) ppm; 13C NMR (126 MHz,
80 v/v); 1H NMR (500 MHz, CDCl3): δH 7.57–7.53 (m, 2H), CDCl3): δC 167.9, 166.0, 165.9, 165.5, 138.8, 138.3 (all quatern-
7.39–7.18 (m, 18H), 4.95 (d, J = 10.5 Hz, 1H), 4.85 (d, J = 4.5 ary), 133.5, 133.5, 133.2, 130.1, 130.0, 129.8 (all aromatic),
Hz, 1H), 4.83 (d, J = 4.0 Hz, 1H), 4.67 (d, J = 9.8 Hz, 1H, H-1), 129.4, 129.2, 129.1 (all quaternary), 128.6, 128.5, 128.5, 128.4,
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128.4, 128.1, 127.9, 127.8, 127.7, 127.7 (all aromatic), 103.6 H-5′), 4.11 (d, J = 14.8 Hz, 1H), 4.01 (dd, J = 11.2, 2.5 Hz, 1H,
(CH, C-1), 97.0 (CH, C-1′), 84.2 (CH, C-3), 83.6 (CH, C-2), 77.6 H-6′), 3.81 (d, J = 5.8 Hz, 1H), 3.73 (dd, J = 11.2, 5.5 Hz, 1H,
(CH, C-4), 75.7, 75.1 (both CH2), 75.0 (CH, C-5), 73.5 (CH2), H-6′), 3.70–3.63 (m, 2H, H-3, H-6), 3.60 (dd, J = 10.9, 4.8 Hz,
72.2 (CH, C-2′), 71.6 (CH2), 70.7 (CH, C-3′), 69.9 (CH, C-4′), 69.1 1H, H-6), 3.50–3.44 (m, 1H, H-4), 3.43 (s, 3H), 3.37 (ddd, J =
(CH, C-5′), 68.9 (C-6, C-6′), 55.7 (CH3), 41.3, 40.2 (both CH2), 9.9, 4.8, 2.0 Hz, 1H, H-5), 3.14 (dd, J = 9.1, 7.8 Hz, 1H, H-2)
14.5, 13.1 (both CH3) ppm; HRMS (ESI-TOF) (m/z): [M + H]+ ppm; 13C NMR (126 MHz, CDCl3): δC 168.6, 165.9, 165.8, 165.2,
calculated for C61H65NO15: 1052.44324, found [M + H]+: 138.9, 138.2, 138.1 (all quaternary), 133.4, 133.3, 133.0, 132.6,
1052.44311.
132.6, 131.5, 131.5 (all aromatic), 130.5 (quaternary), 130.0,
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-diethylacetamide)-α/ 129.9 (both aromatic), 129.6 (quaternary), 129.6 (aromatic),
β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyra- 129.4, 129.1, 129.1 (both quaternary), 128.8, 128.4, 128.4,
noside (41). Using general procedure D starting from 35 128.3, 128.3, 128.2, 128.1, 128.0, 127.7, 127.6, 127.5, 127.5 (all
(40 mg, 0.061 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glyco- aromatic), 103.1 (CH, C-1), 97.0 (CH, C-1′), 84.2 (CH, C-3), 83.0
pyranose (21), the crude product was purified by silica gel (CH, C-2), 77.4 (CH, C-4), 75.6, 74.9 (both CH2), 74.9 (CH, C-5),
flash column chromatography (30% to 60% EtOAc in 73.3 (CH2), 72.0 (CH, C-2′), 72.0 (CH2), 70.8 (CH, C-3′), 69.3
n-heptane), affording 41 as an anomeric mixture (α/β = 1/5, (CH, C-4′), 68.8 (CH2, C-6), 68.7 (CH, C-5), 68.2 (CH2, C-6′),
28 mg, 44%). TLC: Rf = 0.63 (EtOAc/heptane, 60/40 v/v); 1H 55.6 (CH3) ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated for
NMR (500 MHz, CDCl3): δH 8.00–7.95 (m, 2H), 7.89 (dd, J = 8.3, C69H65NO15: 1148.44324, found [M + H]+: 1148.44728.
1.4 Hz, 2H), 7.86–7.81 (m, 2H), 7.53–7.45 (m, 2H), 7.45–7.35
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-diphenylacetamide)-
(m, 5H), 7.34–7.23 (m, 19H), 7.23–7.18 (m, 2H), 6.13 (t, J = 9.8 α/β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyr-
Hz, 1H, H-3′), 5.38 (dd, J = 10.3, 9.5 Hz, 1H, H-4′), 5.23 (dd, J = anoside (43). Using general procedure D starting from 37
10.2, 3.6 Hz, 1H, H-2′), 5.17 (d, J = 3.7 Hz, 1H, H-1′), 4.89 (d, J = (20 mg, 0.027 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glyco-
11.6 Hz, 1H), 4.81 (d, J = 11.8 Hz, 1H), 4.72 (d, J = 11.8 Hz, 1H), pyranose (21), the crude product was purified by silica gel
4.66 (d, J = 12.6 Hz, 1H), 4.56 (d, J = 11.6 Hz, 1H), 4.42 (d, J = flash column chromatography (30% to 60% EtOAc in
7.6 Hz, 1H, H-1), 4.39–4.32 (m, 2H, H-5′), 4.30 (d, J = 11.8 Hz, n-heptane), affording 43 as an anomeric mixture (α/β = 1/8,
1H), 4.26 (d, J = 12.7 Hz, 1H), 4.00 (dd, J = 11.0, 2.2 Hz, 1H, 22 mg, 71%). TLC: Rf = 0.76 (EtOAc/heptane, 60/40 v/v); 1H
H-6′), 3.84 (d, J = 2.9 Hz, 1H, H-4), 3.75 (dd, J = 11.0, 8.0 Hz, NMR (500 MHz, CDCl3): δH 8.02–7.97 (m, 2H), 7.86 (ddd, J =
1H, H-6′), 3.65 (dd, J = 9.6, 7.5 Hz, 1H, H-2), 3.55 (dd, J = 9.6, 16.8, 8.3, 1.4 Hz, 4H), 7.54–7.49 (m, 1H), 7.48–7.44 (m, 1H),
3.0 Hz, 1H, H-3), 3.52–3.44 (m, 3H, H-5, H-6), 3.43 (s, 3H), 7.42–7.20 (m, 32H), 6.11 (t, J = 9.8 Hz, 1H, H-3′), 5.42 (t, J = 9.9
3.39–3.33 (m, 2H), 3.24 (ddq, J = 28.6, 14.0, 7.1, 6.7 Hz, 2H), Hz, 1H, H-4′), 5.22 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), 5.17 (d, J =
1.12 (t, J = 7.1 Hz, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC 3.6 Hz, 1H, H-1′), 4.88 (d, J = 11.6 Hz, 1H), 4.83 (d, J = 11.7 Hz,
168.1, 166.0, 165.9, 165.6, 138.8, 138.8, 138.0 (all quaternary), 1H), 4.73 (d, J = 11.7 Hz, 1H), 4.56–4.48 (m, 2H), 4.40–4.31 (m,
133.5, 133.2, 130.1, 130.0, 129.8 (all aromatic), 129.4, 129.2, 3H, H-1), 4.25 (ddd, J = 9.5, 6.7, 2.3 Hz, 1H, H-5′), 4.17 (d, J =
129.1 (all quaternary), 128.6, 128.5, 128.4, 128.4, 128.4, 128.3, 14.8 Hz, 1H), 3.94 (dd, J = 11.2, 2.4 Hz, 1H, H-6′), 3.81 (d, J =
128.0, 127.9, 127.9, 127.6, 127.6 (all aromatic), 103.8 (CH, C-1), 2.9 Hz, 1H, H-4), 3.72 (dd, J = 11.2, 6.7 Hz, 1H, H-6′), 3.56 (dd,
96.8 (CH, C-1′), 81.7 (CH, C-3), 80.7 (CH, C-2), 74.7 (CH2), 73.7 J = 9.6, 3.0 Hz, 1H, H-3), 3.53–3.44 (m, 4H, H-2, H-5, H-6), 3.39
(CH, C-4), 73.6 (CH2), 73.5 (CH, C-5), 73.3 (CH2), 72.3 (CH, (s, 3H) ppm; 13C NMR (126 MHz, CDCl3): δC 169.1, 166.0,
C-2′), 72.0 (CH2), 70.7 (CH, C-3′), 70.1 (CH, C-4′), 69.1 (CH, 166.0, 165.5, 139.0, 138.9, 138.0 (all quaternary), 133.5, 133.4,
C-5′), 68.9 (CH2, C-6′), 68.7 (CH, C-6), 55.7 (CH3), 41.2, 40.1 133.1 (all aromatic), 130.1, 130.0, 129.7 (all quaternary), 129.5,
(both CH2), 14.5, 13.1 (both CH3) ppm; HRMS (ESI-TOF) (m/z): 129.3, 129.2, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.9,
[M + H]+ calculated for C61H65NO15: 1052.44324, found [M + 127.8, 127.6, 127.6 (all aromatic), 103.7 (CH, C-1), 96.9 (CH,
H]+: 1052.44158.
C-1′), 81.9 (CH, C-3), 80.6 (CH, C-2), 74.7 (CH2), 74.1 (CH, C-4),
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-diphenylacetamide) 73.6, 73.5 (both CH2), 73.4 (CH, C-5), 72.3 (CH, C-2′), 72.1 (CH,
-β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano- C-2′), 70.9 (CH2), 69.7 (CH, C-4′), 69.0 (CH, C-5′), 68.7 (CH2,
side (42). Using general procedure D starting from 36 (40 mg, C-6), 68.6 (CH2, C-6′), 55.7 (CH3) ppm; HRMS (ESI-TOF) (m/z):
0.053 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose [M + H]+ calculated for C69H65NO15: 1148.44324, found
(21), the crude product was purified by silica gel flash column [M + H]+: 1148.44155.
chromatography (30% to 60% EtOAc in n-heptane), affording
Methyl
3,4,6-tribenzyl-2-O-((piperidin-1-yl)ethan-1-one)-α/
42 as pure β-anomer (53 mg, 86%). TLC: Rf = 0.31 (EtOAc/ β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyrano-
1
heptane, 40/60 v/v); H NMR (500 MHz, CDCl3): δH 8.03–7.98 side (44). Using general procedure D starting from 38 (40 mg,
(m, 2H), 7.89 (dd, J = 8.3, 1.4 Hz, 2H), 7.87–7.78 (m, 5H), 0.060 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose
7.62–7.57 (m, 1H), 7.54–7.46 (m, 5H), 7.42–7.19 (m, 27H), (21), the crude product was purified by silica gel flash column
7.18–7.14 (m, 2H), 6.14 (t, J = 9.9 Hz, 1H, H-3′), 5.52 (t, J = 9.9 chromatography (30% to 60% EtOAc in n-heptane), affording
Hz, 1H, H-4′), 5.26 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), 5.21 (d, J = 44 as an anomeric mixture (α/β = 1/30, 26 mg, 40%). TLC: Rf =
3.6 Hz, 1H, H-1′), 5.03 (d, J = 10.9 Hz, 1H), 4.80 (dd, J = 10.9, 0.56 (EtOAc/heptane, 40/60 v/v); 1H NMR (500 MHz, CDCl3): δH
2.9 Hz, 2H), 4.59 (d, J = 14.8 Hz, 1H), 4.56–4.46 (m, 3H), 4.36 8.00–7.95 (m, 2H), 7.93–7.90 (m, 2H), 7.84 (dd, J = 8.4, 1.4 Hz,
(d, J = 7.8 Hz, 1H, H-1), 4.24 (ddd, J = 10.3, 5.4, 2.4 Hz, 1H, 2H), 7.54–7.47 (m, 2H), 7.44–7.20 (m, 20H), 7.18–7.13 (m, 2H),
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6.15 (t, J = 9.8 Hz, 1H, H-3′), 5.46 (dd, J = 10.3, 9.5 Hz, 1H, 50 as pure β-anomer (30 mg, 39%). TLC: Rf = 0.54 (EtOAc/
1
H-4′), 5.26 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), 5.21 (d, J = 3.6 Hz, heptane, 60/40 v/v); H NMR (500 MHz, CDCl3): δH 7.29 (tdt, J
1H, H-1′), 5.00 (d, J = 10.8 Hz, 1H), 4.80 (dd, J = 12.2, 10.9 Hz, = 18.9, 8.6, 3.4 Hz, 28H), 7.17–7.14 (m, 2H), 4.97 (dd, J = 11.0,
2H), 4.72 (d, J = 12.5 Hz, 1H), 4.53–4.50 (m, 2H), 4.46–4.41 (m, 2.6 Hz, 2H), 4.85–4.75 (m, 5H), 4.66 (d, J = 12.2 Hz, 1H),
2H, H-1), 4.34 (ddd, J = 9.8, 7.0, 2.3 Hz, 1H, H-5′), 4.24 (d, J = 4.62–4.51 (m, 6H, H-1′), 4.40 (d, J = 7.8 Hz, 1H, H-1), 4.24 (d, J
12.6 Hz, 1H), 4.06 (dd, J = 11.0, 2.3 Hz, 1H, H-6′), 3.77 (dd, J = = 13.3 Hz, 1H), 4.11 (dd, J = 10.9, 2.1 Hz, 1H, H-6′), 3.99 (t, J =
11.0, 7.1 Hz, 1H, H-6′), 3.68 (t, J = 9.0 Hz, 1H, H-3), 3.62 (t, J = 9.2 Hz, 1H, H-4′), 3.84 (ddd, J = 10.2, 5.5, 2.0 Hz, 1H, H-5′),
3.1 Hz, 2H), 3.59–3.51 (m, 3H, H-4, H-6), 3.46 (s, 3H), 3.40 3.73–3.61 (m, 4H, H-3, H-6, H-6′), 3.56 (t, J = 9.4 Hz, 1H, H-4),
(ddd, J = 9.9, 4.3, 2.5 Hz, 1H, H-5), 3.31 (dd, J = 9.0, 7.8 Hz, 1H, 3.48 (dd, J = 9.6, 3.6 Hz, 1H, H-2′), 3.45–3.33 (m, 6H, H-2, H-5,
H-2), 1.75–1.57 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC H-3′), 2.79 (s, 3H), 2.75 (s, 3H) ppm; 13C NMR (126 MHz,
167.1, 166.0, 165.9, 165.5, 138.8, 138.3 (all quaternary), 133.5, CDCl3): δC 168.5, 138.9, 138.9, 138.4, 138.3, 138.2, 138.2 (all
133.5, 133.2, 130.1, 130.0, 129.8 (all aromatic), 129.4, 129.2, quaternary), 128.6, 128.5, 128.5, 128.5, 128.5, 128.5, 128.5,
129.1 (all quaternary), 128.6, 128.5, 128.5, 128.5, 128.4, 128.3, 128.4, 128.2, 128.2, 128.1, 128.1, 127.9, 127.9, 127.8, 127.7,
128.1, 127.9, 127.8, 127.7, 127.7 (all aromatic), 103.5 (CH, C-1), 127.7, 127.6 (all aromatic), 103.4 (CH, C-1), 98.0 (CH, C-1′),
97.0 (CH, C-1′), 84.2 (CH, C-3), 83.3 (CH, C-2), 77.4 (CH, C-4), 84.3 (CH, C-3), 83.0 (CH, C-5), 82.0 (CH, C-4′), 79.9 (CH, C-2′),
75.7, 75.1 (both CH2), 75.0 (CH, C-5), 73.5 (CH2), 72.2 (CH, 78.4 (CH, C-3′), 77.8 (CH, C-4), 75.9, 75.6 (both CH2), 75.1 (CH,
C-2′), 71.8 (CH2), 70.7 (CH, C-3′), 69.9 (CH, C-4′), 69.0 (CH, C-5), 75.0, 75.0, 73.5, 73.34, 71.3 (all CH2), 70.0 (CH, C-5′), 69.1
C-5′), 68.8 (CH2, C-6), 68.8 (CH2, C-6′), 55.7 (CH3), 46.1, 42.9, (CH2, C-6), 68.9 (CH2, C-6′), 55.4, 36.1, 35.3 (all CH3) ppm;
26.6, 25.7, 24.7 (all CH2) ppm; HRMS (ESI-TOF) (m/z): [M + H]+ HRMS (ESI-TOF) (m/z): [M + Na]+ calculated for C59H67NO12:
calculated for C62H65NO15: 1064.44324, found [M + H]+: 1004.45609, found [M + Na]+: 1004.45386.
1064.44448.
3,4,6-Tribenzyl-2-O-(methyl-N,N-diphenylacetamide)-α/β-D-
Methyl 3,4,6-tribenzyl-2-O-((piperidin-1-yl)ethan-1-one)-α/β-D- glucopyranosyl-(1 → 6)-1,2:3,4-di-O-isopropylidene-α-D-galacto-
galactopyranosyl-(1 → 6)-2,3,4-O-tribenzoyl-α-D-glucopyranoside pyranose (51). Using general procedure D starting from 11
(45). Using general procedure D starting from 39 (30 mg, (30 mg, 0.048 mmol) and 1,2:3,4-di-O-isopropylidene-α-D-galac-
0.045 mmol) and methyl 2,3,4 tri-O-benzoyl-α-D-glycopyranose topyranose (47), the crude product was purified by silica gel
(21), the crude product was purified by silica gel flash column flash column chromatography (30% to 80% EtOAc in
chromatography (30% to 60% EtOAc in n-heptane), affording n-heptane), affording 51 as an anomeric mixture (α/β = 1/9,
45 as an anomeric mixture (α/β = 1/4, 20 mg, 42%). TLC: Rf = 23 mg, 61%). TLC: Rf = 0.33 (EtOAc/heptane, 80/20 v/v); 1H
0.69 (EtOAc/heptane, 60/40 v/v); 1H NMR (500 MHz, CDCl3): δH NMR (500 MHz, CDCl3): δH 7.42–7.37 (m, 2H), 7.35–7.23 (m,
8.00–7.93 (m, 2H), 7.91–7.86 (m, 2H), 7.86–7.81 (m, 2H), 11H), 7.14 (dd, J = 7.5, 2.1 Hz, 2H), 5.48 (d, J = 5.0 Hz, 1H,
7.53–7.45 (m, 2H), 7.43–7.35 (m, 5H), 7.34–7.22 (m, 15H), H-1′), 5.09 (d, J = 10.9 Hz, 1H), 4.84 (d, J = 10.8 Hz, 1H), 4.81
7.22–7.17 (m, 2H), 6.13 (t, J = 9.8 Hz, 1H, H-3′), 5.38 (dd, J = (d, J = 2.6 Hz, 1H), 4.78 (d, J = 5.0 Hz, 1H), 4.61–4.56 (m, 2H,
10.3, 9.5 Hz, 1H, H-4′), 5.24 (dd, J = 10.2, 3.6 Hz, 1H, H-2′), H-3′), 4.50 (dd, J = 11.5, 4.7 Hz, 2H), 4.43 (d, J = 7.8 Hz, 1H,
5.18 (d, J = 3.7 Hz, 1H, H-1′), 4.88 (d, J = 11.6 Hz, 1H), 4.79 (d, J H-1), 4.29 (dd, J = 5.0, 2.4 Hz, 1H, H-2′), 4.23–4.21 (m, 1H),
= 11.8 Hz, 1H), 4.72 (d, J = 11.8 Hz, 1H), 4.65 (d, J = 12.4 Hz, 4.20 (d, J = 2.1 Hz, 1H, H-4′), 4.11 (dd, J = 10.7, 2.9 Hz, 1H,
1H), 4.55 (d, J = 11.6 Hz, 1H), 4.40 (d, J = 7.6 Hz, 1H, H-1), H-6′), 4.01 (dt, J = 8.0, 2.4 Hz, 1H, H-5′), 3.73–3.63 (m, 4H, H-3,
4.37–4.25 (m, 4H, H-6′), 4.01 (dd, J = 10.9, 2.2 Hz, 1H, H-6′), H-6, H-6′), 3.63–3.56 (m, 1H, H-4), 3.42 (ddd, J = 9.9, 4.4, 2.1
3.83 (d, J = 2.9 Hz, 1H, H-4), 3.73 (dd, J = 10.9, 7.9 Hz, 1H), Hz, 1H, H-5), 3.36 (dd, J = 9.0, 7.8 Hz, 1H, H-2), 2.96 (s, 3H),
3.64 (dd, J = 9.6, 7.6 Hz, 1H, H-2), 3.60–3.18 (m, 11H, H-3, H-5, 2.93 (s, 3H), 1.49 (s, 3H), 1.43 (s, 3H), 1.30 (d, J = 4.9 Hz, 6H)
H-6), 1.57–1.41 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC ppm; 13C NMR (126 MHz, CDCl3): δC 169.2, 138.9, 138.3, 138.3
167.2, 166.0, 165.9, 165.6, 138.7, 138.7, 138.0 (all quaternary), (all quaternary), 128.5, 128.5, 128.4, 128.1, 128.0, 127.8, 127.7,
133.5, 133.2, 130.1, 130.0, 129.8 (all aromatic), 129.4, 129.3, 127.6 (all aromatic), 109.5, 108.6 (both quaternary), 103.8 (CH,
129.1 (all quaternary), 128.5, 128.5, 128.5, 128.4, 128.3, 128.0, C-1), 96.4 (CH, C-1′), 84.1 (CH, C-3), 83.5 (CH, C-2), 77.6 (CH,
127.9, 127.8, 127.7, 127.6 (all aromatic), 103.7 (CH, C-1), 96.8 C-4), 75.6, 75.1 (both CH2), 74.8 (CH, C-5), 73.6 (CH2), 71.6
(CH, C-1′), 81.7 (CH, C-3), 80.5 (CH, C-2), 74.7, 73.6 (both (CH, C-4′), 71.3 (CH2), 70.9 (CH, C-3′), 70.5 (CH, C-2), 69.9
CH2), 73.6 (CH, C-5), 73.5 (CH, C-4), 73.2, 72.3 (both CH2), 72.2 (CH2, C-6′), 68.9 (CH2, C-6), 67.6, 36.5, 35.5, 26.2, 26.1, 25.1,
(CH, C-2′), 70.7 (CH, C-3′), 70.1 (CH, C-4′), 69.0 (CH, C-5′), 68.9 24.6 (all CH3) ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated
(CH2, C-6′), 68.7 (CH2, C-6), 55.7 (CH3), 46.1, 42.9, 26.6, 25.7, for C43H55NO12: 778.38025, found [M + H]+: 778.38084.
24.7 (all CH2) ppm; HRMS (ESI-TOF) (m/z): [M + H]+ calculated
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-dimethylacetamide)-
α/β-D-glucopyranosyl-(1 → 4)-2,3,6-O-benzyl-α-D-glucopyrano-
for C62H65NO15: 1064.44324, found [M + H]+: 1064.43913.
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-dimethylacetamide)- side (52). Using general procedure D starting from 12 (30 mg,
β-D-glucopyranosyl-(1 → 6)-2,3,4-O-tribenzyl-α-D-glucopyrano- 0.048 mmol) and methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside
side (50). Using general procedure D starting from 12 (50 mg, (48), the crude product was purified by silica gel flash column
0.080 mmol) and methyl 2,3,4 tri-O-benzyl-α-D-glycopyranose chromatography (30% to 80% EtOAc in n-heptane), affording
(46), the crude product was purified by silica gel flash column 52 as an anomeric mixture (α/β = 1/2, 10 mg, 30%). TLC: Rf =
chromatography (30% to 60% EtOAc in n-heptane), affording 0.46 (EtOAc/heptane, 80/20 v/v); 1H NMR (500 MHz, CDCl3): δH
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7.42–7.18 (m, 28H), 7.16 (dd, J = 7.5, 2.0 Hz, 2H), 5.03 (d, J = 1H), 4.37 (m, 4H, H-1), 4.30 (d, J = 13.1 Hz, 1H), 4.08 (dd, J =
11.4 Hz, 1H), 4.88 (d, J = 11.1 Hz, 1H), 4.84 (d, J = 11.2 Hz, 1H), 10.8, 2.1 Hz, 1H, H-6′), 3.96 (t, J = 9.2 Hz, 1H, H-3′), 3.88 (d, J =
4.79–4.74 (m, 3H), 4.63–4.60 (m, 2H), 4.59–4.50 (m, 4H, H-1′), 2.9 Hz, 1H, H-4), 3.83 (ddd, J = 10.2, 6.0, 2.1 Hz, 1H, H-5′), 3.70
4.45 (d, J = 7.9 Hz, 1H, H-1), 4.41 (d, J = 7.1 Hz, 1H), 4.36 (d, J = (dd, J = 9.6, 7.6 Hz, 1H, H-2), 3.62–3.46 (m, 6H, H-5, H-6, H-2′,
13.4 Hz, 1H), 4.29 (d, J = 13.1 Hz, 1H), 4.01 (t, J = 9.4 Hz, 1H, H-4′, H-6), 3.38–3.32 (m, 4H, H-3), 2.84–2.68 (m, 6H) ppm; 13C
H-5′), 3.98–3.94 (m, 1H, H-6′), 3.84 (t, J = 9.2 Hz, 1H, H-3′), NMR (126 MHz, CDCl3): δC 168.9, 139.0, 138.8, 138.7, 138.5,
3.73–3.68 (m, 2H, H-4′, H-6′), 3.66 (dd, J = 11.0, 1.9 Hz, 1H, 138.3, 138.0 (all quaternary), 131.1, 129.0, 128.6, 128.6, 128.5,
H-6), 3.60 (t, J = 9.3 Hz, 1H, H-4), 3.55–3.47 (m, 3H, H-2′, H-3′, 128.5, 128.5, 128.3, 128.3, 128.2, 128.2, 128.0, 128.0, 128.0,
H-6), 3.36 (s, 3H), 3.28–3.21 (m, 2H, H-2, H-5), 2.86 (s, 3H), 127.7, 127.7, 127.7, 127.6, 127.6 (all aromatic), 103.7 (CH,
2.78 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3): δC 176.1, 168.6, C-1′), 97.9 (CH, C-1), 82.1 (CH, C-3′), 82.0 (CH, C-5), 80.3 (CH,
139.7, 138.9, 138.6, 138.5, 138.4, 138.3 (all quaternary), 128.6, C-2), 80.0 (CH, C-2′), 78.6 (CH, C-3), 75.9, 75.0, 74.8 (all CH2),
128.5, 128.5, 128.5, 128.4, 128.4, 128.3, 128.3, 128.2, 128.2, 73.7 (CH, C-4), 73.4 (CH, C-4′), 73.4, 73.0, 71.7 (all CH2), 70.0
128.1, 128.1, 127.9, 127.9, 127.9, 127.8, 127.8, 127.7, 127.7, (CH, C-5′), 69.0 (CH2, C-6′) 68.7 (CH2, C-6), 55.4, 36.2, 35.3 (all
127.6, 127.6, 127.5, 127.5, 127.4, 127.4, 127.2, 127.2, 127.0 (all CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ calculated for
aromatic), 101.9 (CH, C-1), 98.5 (CH, C-1′), 84.6 (CH, C-3), 83.8 C59H67NO12: 1004.45609, found [M + Na]+: 1004.45410.
(CH, C-2), 80.4 (CH, C-3′), 79.2 (CH, C-2′), 78.2 (CH, C-4), 76.3
(CH, C-5′), 75.5, 75.4 (both CH2), 75.2 (CH, C-5), 74.9, 73.8, topyranosyl-(1
3,4,6-Tribenzyl-2-O-(methyl-N,N-diphenylacetamide)-α/β-D-galac-
6)-1,2:3,4-di-O-isopropylidene-α-D-galactopyra-
→
73.5, 73.4, 71.6 (all CH2), 70.2 (CH, C-4′), 68.9 (CH2, C-6), nose (55). Using general procedure D starting from 12 (40 mg,
68.6 (CH2, C-6′), 55.6, 36.3, 35.4 (all CH3) ppm; HRMS 0.063 mmol) and 1,2:3,4-di-O-isopropylidene-α-D-galactopyra-
(ESI-TOF) (m/z): [M
1004.45609, found [M + Na]+: 1004.45235.
+
Na]+ calculated for C59H67NO12: nose (47), the crude product was purified by silica gel flash
column chromatography (30% to 80% EtOAc in n-heptane),
1-Adamantanyl-2-O-(methyl-N,N-dimethylacetamide)-3,4,6-tri- affording 55 as an anomeric mixture (α/β = 1/4, 28 mg, 56%).
1
benzyl-α/β-D-glucopyranoside (53). Using general procedure D TLC: Rf = 0.40 (EtOAc/heptane, 80/20 v/v); H NMR (500 MHz,
starting from 11 (30 mg, 0.048 mmol) and adamantanol (49), CDCl3): δH 7.35–7.32 (m, 2H), 7.31–7.15 (m, 18H), 5.40 (d, J =
the crude product was purified by silica gel flash column 5.0 Hz, 1H, H-1′), 4.84 (dd, J = 16.0, 11.7 Hz, 2H), 4.70 (t, J =
chromatography (30% to 60% EtOAc in n-heptane), affording 12.5 Hz, 2H), 4.54 (d, J = 11.7 Hz, 1H), 4.49 (dd, J = 7.9, 2.4 Hz,
53 as an anomeric mixture (α/β = 1/1, 11 mg, 34%). TLC: Rf = 1H, H-3′), 4.38–4.30 (m, 2H, H-1), 4.20 (dd, J = 5.0, 2.4 Hz, 1H,
1
0.36 (Et2O/toluene, 50/50 v/v); H NMR (500 MHz, CDCl3): δH H-2′), 4.17 (d, J = 13.2 Hz, 1H), 4.10 (dd, J = 8.0, 1.9 Hz, 1H,
7.38–7.34 (m, 2H), 7.33–7.23 (m, 12H), 7.19 (dd, J = 7.7, 1.9 Hz, H-4′), 4.00 (dd, J = 10.7, 2.9 Hz, 1H, H-6′), 3.92 (dt, J = 8.0, 2.5
2H), 4.99 (d, J = 11.0 Hz, 1H), 4.83 (d, J = 10.9 Hz, 2H), 4.71 (d, Hz, 1H, H-5′), 3.78 (d, J = 2.9 Hz, 1H, H-4′), 3.62 (dd, J = 9.7, 7.6
J = 7.8 Hz, 1H, H-1), 4.64 (d, J = 13.2 Hz, 1H), 4.60–4.50 (m, Hz, 1H, H-2), 3.56–3.45 (m, 4H, H-3, H-6, H-6′), 3.45–3.40 (m,
3H), 4.28 (d, J = 13.2 Hz, 1H), 3.73–3.68 (m, 2H, H-3, H-6), 3.60 1H, H-5), 2.87 (s, 3H), 2.85 (s, 3H), 1.40 (s, 3H), 1.35 (s, 3H),
(dd, J = 10.7, 5.5 Hz, 1H, H-6), 3.50 (dd, J = 9.9, 8.6 Hz, 1H, 1.22 (s, 3H), 1.22 (s, 4H) ppm; 13C NMR (126 MHz, CDCl3): δC
H-4), 3.45 (ddd, J = 9.8, 5.5, 1.9 Hz, 1H, H-5), 3.30 (dd, J = 9.2, 169.4, 138.9, 138.8, 138.0 (all quaternary), 128.6, 128.6, 128.4,
7.8 Hz, 1H, H-2), 2.92 (s, 3H), 2.90 (s, 3H), 2.14 (p, J = 3.1 Hz, 128.3, 128.2, 128.1, 128.0, 127.9, 127.9, 127.7, 127.6 (all aro-
3H), 1.92–1.87 (m, 3H), 1.81 (dp, J = 11.2, 1.9 Hz, 3H), matic), 109.5, 108.6 (both quaternary), 104.0 (CH, C-1), 96.4
1.67–1.60 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC 168.9, (CH, C-1′), 81.3 (CH, C-3), 80.9 (CH, C-2), 74.0 (CH, C-4), 73.6,
139.0, 138.5, 138.3 (all quaternary), 128.5, 128.4, 128.4, 128.1, 73.5 (both CH2), 73.4 (CH, C-5), 71.7 (CH2), 71.7 (CH, C-4′),
128.1, 127.9, 127.7, 127.6 (all aromatic), 96.1 (CH, C-1), 84.7 70.9 (CH, C-3′), 70.5 (CH, C-2′), 69.8 (CH2, C-6′), 68.8 (CH2,
(CH, C-3), 83.6 (CH, C-2), 78.3 (CH, C-4), 75.7, 75.0 (both CH2), C-6), 67.6 (CH, C-5′), 36.5, 35.5, 26.2, 26.1, 25.2 (all CH3) ppm;
74.6 (CH, C-5), 73.5, 71.6 (both CH2), 69.6 (CH2, C-6), 42.9 HRMS (ESI-TOF) (m/z): [M + H]+ calculated for C43H55NO12:
(CH2), 36.4 (CH3 and CH2), 30.9 (CH) ppm; HRMS (ESI-TOF) 778.38025, found [M + H]+: 778.38075.
(m/z): [M + Na]+ calculated for C41H51NO7: 692.35632, found
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-dimethylacetamide)-
α/β-D-galactopyranosyl-(1 → 4)-2,3,6-O-benzyl-α-D-glucopyrano-
[M + Na]+: 692.35509.
Methyl 3,4,6-tribenzyl-2-O-(methyl-N,N-dimethylacetamide)- side (56). Using general procedure D starting from 12 (40 mg,
α/β-D-galactopyranosyl-(1 → 6)-2,3,4-O-tribenzyl-α-D-glucopyra- 0.063 mmol) and methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside
noside (54). Using general procedure D starting from 12 (48), the crude product was purified by silica gel flash column
(30 mg, 0.048 mmol) and methyl 2,3,4 tri-O-benzyl-α-D-glyco- chromatography (30% to 80% EtOAc in n-heptane), affording
pyranose (46), the crude product was purified by silica gel 56 as an anomeric mixture (α/β = 1/1, 14 mg, 22%). TLC: Rf =
flash column chromatography (30% to 60% EtOAc in 0.69 (EtOAc/heptane, 80/20 v/v); 1H NMR (500 MHz, CDCl3): δH
n-heptane), affording 54 as mixture of anomers (α/β = 1/3, 7.40–7.19 (m, 27H), 7.18–7.11 (m, 3H), 5.00 (d, J = 10.7 Hz,
20 mg, 40%). TLC: Rf = 0.54 (EtOAc/heptane, 60/40 v/v); 1H 1H), 4.91 (d, J = 11.4 Hz, 1H), 4.80 (d, J = 12.0 Hz, 1H),
NMR (500 MHz, CDCl3): δH 7.72 (dd, J = 5.7, 3.3 Hz, 2H), 7.53 4.75–4.70 (m, 2H), 4.67–4.58 (m, 2H), 4.57 (d, J = 3.7 Hz, 1H,
(dd, J = 5.7, 3.3 Hz, 2H), 7.41–7.17 (m, 35H), 4.95 (d, J = 11.2 H-1′), 4.54–4.51 (m, 2H), 4.50–4.46 (m, 1H), 4.43 (d, J = 7.7 Hz,
Hz, 1H), 4.89 (d, J = 11.5 Hz, 1H), 4.80–4.74 (m, 4H), 4.65 (d, J 1H, H-1), 4.36 (d, J = 6.7 Hz, 1H), 4.33 (d, J = 2.2 Hz, 1H), 4.23
= 12.2 Hz, 1H), 4.57–4.55 (m, 3H, H-1′), 4.42 (d, J = 11.8 Hz, (d, J = 11.9 Hz, 1H), 4.02–3.97 (m, 1H, H-6′), 3.95 (d, J = 9.4 Hz,
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1H, H-4′), 3.91–3.88 (m, 1H, H-4), 3.82 (t, J = 9.3 Hz, 1H, H-3′), room temperature and was stirred for 2 h. The solution was
3.75–3.70 (m, 2H, H-5′, H-6′), 3.61 (dd, J = 9.7, 7.6 Hz, 1H, H-2), cooled on ice and 1.4 μL (0.012 mmol, 0.5 eq.) of an acetic acid
3.52 (t, J = 8.7 Hz, 1H, H-6), 3.48 (dd, J = 9.6, 3.8 Hz, 1H, H-2′), in dry DMF solution (1/1 v/v) was added to quench the reac-
3.42–3.32 (m, 6H, H-3, H-6), 3.29 (dd, J = 8.6, 5.0 Hz, 1H, H-5), tion. At ambient temperature was added 21 μL (0.23 mmol, 9
2.83 (s, 3H), 2.77 (s, 3H) ppm; 13C NMR (126 MHz, CDCl3): δC eq.) of t-BuOH and the mixture was heated to 100 °C for 1 h.
175.9, 169.3, 168.9, 139.6, 139.1, 138.6, 138.6, 138.3, 137.6 (all The solution was cooled on ice and 92 μL of a 2 M HCl solu-
quaternary), 128.6, 128.6, 128.5, 128.5, 128.5, 128.4, 128.4, tion was added. The mixture was taken up in water (5 mL) and
128.4, 128.3, 128.3, 128.2, 128.2, 128.1, 128.1, 128.1, 128.1, extracted with toluene (3 × 10 mL). The combined toluene
128.0, 128.0, 128.0, 127.9, 127.9, 127.8, 127.8, 127.7, 127.6, layers were washed with 1 M NaOH (10 mL), water (10 mL),
127.6, 127.5, 127.5, 127.4, 127.4, 127.1, 127.1, 126.7 (all aro- brine (10 mL), dried over Na2SO4 (anhydrous), filtrated and
matic), 102.4 (CH, C-1), 98.5 (CH, C-1′), 82.5 (CH, C-3), 80.9 evaporated in vacuo. The residue was dissolved in ethanol
(CH, C-2), 80.5 (CH, C-3′), 79.3 (CH, C-2′), 76.7 (CH, C-4′), 75.5, (10 μL), THF (30 μL) and 1 M NaOH was added (30 μL). The
74.9, 73.8 (all CH2), 73.5 (CH, C-4), 73.4, 73.1 (both CH2), 73.1 mixture was heated to 60 °C and for 3 h, heating was removed
(CH, C-5′), 72.3, 72.0 (both CH2), 68.7 (CH2, C-6′), 68.2 (CH2, and the reaction was stirred for 14 h at ambient temperature.
C-6), 55.5, 36.6, 36.3 (all CH3) ppm; HRMS (ESI-TOF) (m/z): The reaction mixture was taken up in water (10 mL) and was
[M + H]+ calculated for C59H67NO12: 982.47415, found [M + extracted with toluene (3 × 10 mL). The combined toluene
H]+: 982.47593.
layers were washed with water (2 × 15 mL), washed with brine
1-Adamantanyl-2-O-(methyl-N,N-dimethylacetamide)-3,4,6-tri- (15 mL), dried over Na2SO4 (anhydrous), filtrated and evapor-
benzyl-α/β-D-galactopyranoside (57). Using general procedure D ated in vacuo to yield the crude product. The product was puri-
starting from 12 (40 mg, 0.063 mmol) and adamantanol (49), fied by silica gel flash column chromatography (30 to 60%
the crude product was purified by silica gel flash column EtOAc in n-heptane) to afford the product 58 (11.3 mg, 50%).
1
chromatography (30% to 60% EtOAc in n-heptane), affording TLC: Rf = 0.48 (EtOAc/heptane, 40/60 v/v); H NMR (500 MHz,
57 as an anomeric mixture (α/β = 2/3, 12 mg, 28%). TLC: Rf = CDCl3): δH 7.37–7.23 (m, 27H), 7.18–7.10 (m, 3H), 4.98 (d, J =
0.47 (EtOAc/heptane, 60/40 v/v); 1H NMR (500 MHz, CDCl3): δH 10.8 Hz, 1H), 4.90 (t, J = 11.7 Hz, 2H), 4.84–4.76 (m, 4H), 4.65
7.37–7.17 (m, 15H), 4.90 (d, J = 11.6 Hz, 1H), 4.77–4.70 (m, (d, J = 12.1 Hz, 1H), 4.63–4.60 (m, 2H, H-1′), 4.58 (d, J = 12.2
2H), 4.67 (d, J = 7.4 Hz, 1H), 4.61 (d, J = 10.2 Hz, 1H), 4.58 (d, Hz, 1H), 4.54–4.50 (m, 2H), 4.22 (d, J = 6.7 Hz, 1H, H-1), 4.14
J = 8.8 Hz, 1H), 4.44 (d, J = 11.7 Hz, 1H), 4.39 (d, J = 11.7 Hz, (dd, J = 11.1, 2.3 Hz, 1H, H-6′), 3.99 (t, J = 9.3 Hz, 1H, H-3),
1H), 4.34 (d, J = 7.0 Hz, 1H), 3.85 (d, J = 2.8 Hz, 1H), 3.64 (dd, 3.82 (ddd, J = 10.1, 5.1, 2.2 Hz, 1H, H-5), 3.72 (dd, J = 10.9, 2.0
J = 9.7, 7.5 Hz, 1H), 3.59 (t, J = 3.1 Hz, 1H), 3.56 (d, J = 7.1 Hz, Hz, 1H, H-6), 3.67 (ddd, J = 10.9, 4.9, 2.0 Hz, 2H, H-6, H-6′),
2H), 3.52–3.50 (m, 1H), 2.90 (s, 3H), 2.89–2.88 (s, 3H), 2.11 (s, 3.59–3.47 (m, 5H, H-2, H-3, H-4, H-2′, H-4′), 3.44 (dq, J = 7.1,
3H), 1.87 (d, J = 12.2 Hz, 3H), 1.78 (dd, J = 11.1, 2.6 Hz, 3H), 2.1 Hz, 1H, H-5), 3.37 (s, 3H) ppm; 13C NMR (126 MHz,
1.64–1.59 (m, 6H) ppm; 13C NMR (126 MHz, CDCl3): δC 169.1, CDCl3): δC 138.7, 138.6, 138.2, 138.2, 138.1, 138.1 (all quatern-
138.8, 138.8, 138.3, 138.2 (all quaternary), 128.5, 128.5, 128.44, ary), 129.4, 128.5, 128.4, 128.4, 128.3, 128.1, 128.0, 128.0,
128.3, 128.3, 128.0, 127.9, 127.8, 127.8, 127.8, 127.7, 127.6, 127.9, 127.8, 127.8, 127.7, 127.7, 127.7, 127.6, 127.6, 124.4,
127.6, 127.5, 127.5, 127.5 (all aromatic), 96.3 (CH, C-1), 82.4 121.3 (all aromatic), 103.5 (CH, C-1′), 98.1 (CH, C-1), 84.5 (CH,
(CH, C-3), 80.7 (CH, C-2), 74.6 (CH2), 73.8 (CH, C-4), 73.7 C-2), 82.0 (CH, C-3), 79.7 (CH, C-4), 78.0 (CH, C-4′), 77.5 (CH,
(CH2), 73.3 (CH2), 73.2 (CH, C-5), 72.1 (CH2), 69.4 (CH2, C-6), C-2′), 75.8 (CH2), 75.3 (CH, C-5), 75.1, 75.0, 75.0 (all CH2), 74.5
42.8 (CH2), 36.4 (CH3 and CH2), 30.8 (CH) ppm; HRMS (CH, C-3), 73.5, 73.4 (both CH2), 69.8 (CH, C-5′), 69.0 (CH2,
(ESI-TOF) (m/z): [M + H]+ calculated for C41H51NO7: 670.37438, C-6), 68.8 (CH2, C-6′), 55.3 (CH3) ppm; HRMS (ESI-TOF) (m/z):
found [M + H]+: 670.37506.
3,4,6-Tribenzyl-β-D-galactopyranosyl-(1 → 6)-2,3,4-O-triben- 919.40370.
zyl-α-D-glucopyranoside (58). 25 mg (0.025 mmol, 1.0 eq.) of 50 (R)-(Tetrahydrofuran-2-yl)methanol. In a three neck round
[M +
Na]+ calculated for C55H60O11: 919.40333, found
was dissolved in THF (250 μL) and 1.0 μL (0.056 mmol, 2.2 eq.) bottom flask equipped with cooler, thermometer and dropping
water was added. To the mixture was added 150 μL of a 1.0 M funnel was dissolved 0.95 gram (25 mmol, 1.6 eq.) LiAlH4 at
t-BuOK solution (0.15 mmol, 5.9 eq.). The reaction mixture 0 °C under an inert atmosphere in dry THF (24 mL). The
was stirred at room temperature for 18 h. The reaction was LiAlH4 solution was stirred for 15 minutes. 1.5 mL (15 mmol,
quenched with ice until two layers were formed. A solution of 1.0 eq.) (2R)-tetrahydro-2-furancarboxylic acid was dissolved in
2 M KHSO4 was added until the pH was 1. The solution was dry THF (15 mL). The carboxylic acid in THF solution was
taken up in water (5 mL). The mixture was extracted with Et2O added dropwise to the LiAlH4 solution. The solution was
(5 × 10 mL) and the combined organic layers were dried over allowed to reach a maximum temperature of 40 °C during
anhydrous MgSO4, filtrated and evaporated in vacuo to yield addition of carboxylic acid solution in THF. The mixture was
the carboxylic acid. The carboxylic acid was dissolved in dry stirred at room temperature for 16 hours. The reaction was
DMF (40 μL). 5.3 μL DIPEA (0.031 mmol, 1.2 eq.) was added quenched by slow addition of saturated ammonium chloride
and the mixture was stirred on ice. To the cold solution was (130 mL) at 0 °C. EtOAc (90 mL) was added to the mixture. The
added 11 μL (0.027 mmol, 1.1 eq.) of a DPPA in dry DMF solu- mixture was filtrated and the organic layer was separated from
tion (1.1/1 v/v) and the solution was allowed to warm up to the aqueous layer. The aqueous layer was washed with EtOAc
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(5 × 30 mL). The combined organic layers were dried over (4.6 mmol, 1.7 eq.) tosylchloride and 0.7 mL (8.7 mmol, 3.3
MgSO4, filtrated and evaporated in vacuo to afford the pure eq.) pyridine in DCM (10 mL) was added 271 mg (2.65 mmol,
product as colourless liquid (300 mg, 19%). TLC: Rf = 0.25 1.0 eq.) 56-(S) in DCM (10 mL). The reaction was stirred for
(EtOH/DCM, 1/20 v/v); 1H NMR (500 MHz, CDCl3): δH 4.01 (qd, 16 hours. Subsequently, water (20 mL) and DCM (20 mL) were
J = 6.8, 3.3 Hz, 1H), 3.90–3.84 (m, 1H), 3.83–3.75 (m, 1H), 3.66 added. The organic layer was separated from the aqueous layer
(dd, J = 11.7, 3.3 Hz, 1H), 3.50 (dd, J = 11.6, 6.2 Hz, 1H), 2.60 and the organic layer was washed with 10% HCl (40 mL) and
(s, 1H), 1.98–1.85 (m, 3H), 1.70–1.60 (m, 1H) ppm. 13C NMR brine (40 mL). The organic layer was dried over Na2SO4, fil-
(126 MHz, CDCl3): δC 79.5 (CH), 68.2, 64.9, 27.1, 26.0 (all CH2) trated and evaporated in vacuo. The remaining oil was purified
ppm.
using silica gel flash column chromatography (0% to 20%
(S)-(Tetrahydrofuran-2-yl)methanol. In a three neck round EtOAc in n-heptane) to afford the product 17-(S) (410 mg,
bottom flask equipped with cooler, thermometer and dropping 60%). TLC: Rf = 0.30 (EtOAc/heptane, 3 : 7 v/v); 1H NMR
funnel was dissolved 1.13 gram (30 mmol, 1.9 eq.) LiAlH4 at (500 MHz, CDCl3): δH 7.87–7.73 (m, 2H), 7.40–7.30 (m, 2H),
0 °C under an inert atmosphere in dry THF (10 mL). The 4.12–4.06 (m, 1H), 4.04–3.95 (m, 2H), 3.76 (ddt, J = 30.0, 8.3,
LiAlH4 solution was stirred for 15 minutes. 1.24 mL (13 mmol, 6.7 Hz, 2H), 2.45 (s, 3H), 2.04–1.94 (m, 1H), 1.87 (dtt, J = 8.0,
1.0 eq.) (2S)-tetrahydro-2-furancarboxylic acid was dissolved in 6.7, 3.2 Hz, 2H), 1.71–1.64 (m, 1H) ppm; 13C NMR (126 MHz,
dry THF (5 mL). The carboxylic acid in THF solution was CDCl3): δC 144.91, 133.13 (both quaternary), 129.94, 128.10
added dropwise to the LiAlH4 solution. The solution was (both aromatic), 76.05 (CH), 71.60, 68.75, 27.99, 25.71 (all
allowed to reach a maximum temperature of 40 °C during CH2), 21.78 (CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ cal-
addition of carboxylic acid in THF. The mixture was stirred at culated for C12H16O4S: 279.06670, found [M + Na]+: 279.06504.
room temperature for 16 hours. The reaction was quenched by
(Hydroxymethyl)diphenylphosphine oxide, method based
slow addition of saturated ammonium chloride (130 mL) at on literature.35 To a solution consisting of 6.2 mL 37%
0 °C. EtOAc (90 mL) was added to the mixture. The mixture aqueous formaldehyde (0.083 mmol, 25 eq.) and 6.5 mL con-
was filtrated and the organic layer was separated from the centrated hydrochloric acid was added 0.6 mL (0.003 mmol,
aqueous layer. The aqueous layer was washed with EtOAc (5 × 1.0 eq.) chlorodiphenylphosphine. The solution was heated to
30 mL). The combined organic layers were dried over MgSO4, 100 °C and was stirred for 16 hours. After 16 hours the reaction
filtrated and evaporated in vacuo to obtain the pure product as mixture was neutralised using NaHCO3. The neutralised solu-
yellow liquid (530 mg, 33%). TLC: Rf = 0.40 (EtOH/DCM, 1/20 tion was extracted with DCM (3 × 40 mL), dried over MgSO4,
1
v/v); H NMR (500 MHz, CDCl3): δH 4.01 (qd, J = 6.7, 3.3 Hz, filtrated and evaporated. The product was without further puri-
1H), 3.91–3.83 (m, 1H), 3.82–3.75 (m, 1H), 3.66 (dd, J = 11.6, fication as white solid (660 mg, 85%). TLC: Rf = 0.57 (MeOH/
3.3 Hz, 1H), 3.50 (dd, J = 11.6, 6.2 Hz, 1H), 2.69 (s, 1H), EtOAc, 10/90 v/v); 1H NMR (500 MHz, CDCl3): δH 7.82–7.72 (m,
2.04–1.84 (m, 3H), 1.73–1.58 (m, 1H) ppm; 13C NMR (126 MHz, 4H), 7.59–7.42 (m, 6H), 5.23 (s, 1H), 4.42 (dd, J = 11.0, 3.8 Hz,
CDCl3): δC 79.6 (CH), 68.3 (CH2), 64.9 (CH2), 27.2 (CH2), 26.1 2H) ppm; 13C NMR (126 MHz, CDCl3): δC 132.2, 131.41, 131.3
(CH2) ppm.
(all quaternary), 130.9, 130.1 (both quaternary), 128.8, 128.7
(R)-(Tetrahydrofuran-2-yl)methyl 4-methylbenzene-sulfonate (both aromatic), 61.67, 61.0 (both CH2) ppm; 31P NMR
(19), method based on literature.34 To a solution of 0.88 gram (202 MHz, CDCl3): δP 30.77 ppm; HRMS (ESI-TOF) (m/z): [M +
(4.6 mmol, 1.6 eq.) tosylchloride and 0.7 mL (8.8 mmol, 3.0 H]+ calculated for C13H13O2P: 233.07314, found [M + H]+:
eq.) pyridine in DCM (10 mL) was added 300 mg (2.94 mmol, 233.07190.
1.0 eq.) 56-(R) in DCM (10 mL). The reaction was stirred for
(Bromomethyl)diphenylphosphine oxide (18), method
16 hours. Subsequently, water (20 mL) and DCM (20 mL) were based on literature.36 A suspension of 500 mg (2.15 mmol, 2.5
added. The organic layer was separated from the aqueous layer eq.) 56 and molecular sieves (4 Å) in benzene (2 mL) was
and the organic layer was washed with 10% HCl (40 mL) and heated to reflux. While refluxing, 0.1 mL (1.1 mmol, 1.2 eq.)
brine (40 mL). The organic layer was dried over Na2SO4, fil- PBr3 was added dropwise and the solution started to boil
trated and evaporated in vacuo. The remaining oil was purified heavily. After stirring for 10 minutes an orange sticky precipi-
using silica gel flash column chromatography (0% to 20% tate was formed. The solution was refluxed for 5 h. The solu-
EtOAc in n-heptane) to yield the product 17-(R) (545 mg, 73%). tion (orange) was cooled to room temperature, chloroform
TLC: Rf = 0.30 (EtOAc/heptane, 3 : 7 v/v); 1H NMR (500 MHz, (5 mL) was added, the mixture was stirred for 15 minutes and
CDCl3): δH 7.83–7.77 (m, 2H), 7.37–7.33 (m, 2H), 4.11–4.06 (m, the precipitate was scratched of the flask surface, stirred for
1H), 4.04–3.96 (m, 2H), 3.81–3.70 (m, 2H), 2.45 (s, 3H), 1 h and filtrated. The organic layer was washed with water
2.02–1.93 (m, 1H), 1.87 (dddd, J = 10.0, 8.0, 6.1, 3.0 Hz, 2H), (15 mL), saturated aqueous NaHCO3 solution (15 mL) and
1.66 (ddt, J = 12.1, 8.2, 6.8 Hz, 1H) ppm. 13C NMR (126 MHz, water (15 mL). The organic layer was dried over Na2SO4 and fil-
CDCl3): δC 144.9, 133.1 (both quaternary carbon), 129.9, 128.1 trated. The solvent was evaporated and the remaining crude
(both aromatic carbon), 76.0 (CH), 71.6, 68.7, 28.0, 25.7 (all product was purified by silica gel flash column chromato-
CH2), 21.8 (CH3) ppm; HRMS (ESI-TOF) (m/z): [M + Na]+ calcu- graphy (60% to 100% EtOAc in n-heptane) to afford 91
1
lated for C12H16O4S: 279.06670, found [M + Na]+: 279.06612.
(375 mg, 59%). TLC: Rf = 0.57 (EtOAc/heptane, 90/10 v/v); H
(S)-(Tetrahydrofuran-2-yl)methyl 4-methylbenzene-sulfonate NMR (500 MHz, CDCl3): δH 7.85–7.76 (m, 4H), 7.64–7.56 (m,
(20), method based on literature.34 To a solution of 0.88 gram 2H), 7.56–7.48 (m, 4H), 3.81 (d, J = 5.8 Hz, 2H) ppm; 13C NMR
Org. Biomol. Chem.
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Paper
(126 MHz, CDCl3): δC 132.8, 131.6 (both aromatic), 130.6, 129.8
β-sulfonium ion mediated glycosylations, Org. Lett., 2010,
13(2), 284–287.
(both quaternary), 128.9 (aromatic), 23.9, 23.4 (both CH2)
ppm; 31P NMR (202 MHz, CDCl3): δP 27.05 ppm; HRMS 11 S. J. Moons, R. A. Mensink, J. P. J. Bruekers,
(ESI-TOF) (m/z): [M
+
H]+ calculated for C13H12BrOP:
M. L. A. Vercammen, L. M. Jansen and T. J. Boltje, alpha-
Selective Glycosylation with beta-Glycosyl Sulfonium Ions
Prepared via Intramolecular Alkylation, J. Org. Chem., 2019,
84(7), 4486–4500.
294.98874, found [M + H]+: 294.98977.
Conflicts of interest
12 D. J. Cox, G. P. Singh, A. J. A. Watson and A. J. Fairbanks,
Neighbouring Group Participation During Glycosylation:
Do 2-Substituted Ethyl Ethers Participate?, Eur. J. Org.
Chem., 2014, 2014(21), 4624–4642.
There are no conflicts to declare.
13 S. S. Nigudkar and A. V. Demchenko, Stereocontrolled 1,2-
cis glycosylation as the driving force of progress in synthetic
carbohydrate chemistry, Chem. Sci., 2015, 6(5), 2687–2704.
14 C. S. Chao, C. Y. Lin, S. Mulani, W. C. Hung and
K. K. Mong, Neighboring-group participation by C-2 ether
functions in glycosylations directed by nitrile solvents,
Chemistry, 2011, 17(43), 12193–12202.
Acknowledgements
We gratefully acknowledge the Nederlandse Organisatie voor
Wetenschappelijk Onderzoek (NWO) for the NWO Vidi grant
VI.VIDI.192.070 awarded to TJB.
15 W. Gilbert, Z. Youlin and H. Xuefei, Pre-activation based
stereoselective glycosylations: Stereochemical control by
additives and solvent, Sci. China: Chem., 2011, 54(1), 66–73.
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