α-Selective Glycosylation with β-Glycosyl Sulfonium Ions Prepared via Intramolecular Alkylation

Article abstract of DOI:10.1021/acs.joc.9b00022

Stereoselective glycosylation remains the main challenge in the chemical synthesis of oligosaccharides. Herein we report a simple method to convert thioglycosides into β-sulfonium ions via an intramolecular alkylation reaction, leading to highly α-selective glycosylations for a variety of glycosyl acceptors. The influence of the thioglycoside substituent and the protecting group pattern on the glycosyl donor was investigated and showed a clear correlation with the observed stereoselectivity.

Full text of DOI:10.1021/acs.joc.9b00022

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Note
#-Selective glycosylation with #-glycosyl sulfonium
ions prepared via intramolecular alkylation
Sam J Moons, Rens A. Mensink, Jeroen P. J. Bruekers, Maurits
L. A. Vercammen, Laura M Jansen, and Thomas J. Boltje
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00022 • Publication Date (Web): 27 Feb 2019
Downloaded from http://pubs.acs.org on March 1, 2019
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
-Selective glycosylation with β-glycosyl sulfonium ions prepared via intramolecular
alkylation
Sam J. Moons‡, Rens A. Mensink‡, Jeroen P.J. Bruekers, Maurits L.A. Vercammen, Laura M.
Jansen and Thomas J. Boltje*
1
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Radboud University, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ,
Nijmegen, The Netherlands, e-mail: t.boltje@science.ru.nl, ‡These authors contributed equally
Ph, DMP, TMP
O
O
Tf2O,
DTBMP
RO
SAr
O
O
RO
SAr
DCM
-40°C - 0°C
OH
Bn, CBn, 2,4-DCBn etc.
OTf
OTf

-selective
O
O
S
glycosylation
RO
Ar
ABSTRACT: Stereoselective glycosylation remains the main challenge in the chemical synthesis of
oligosaccharides. Herein we report a simple method to convert thioglycosides into β-sulfonium
ions via an intramolecular alkylation reaction leading to highly -selective glycosylations for a
variety of glycosyl acceptors. The influence of the thioglycoside substituent and the protecting
group pattern on the glycosyl donor was investigated and showed a clear correlation with the
observed stereoselectivity.
The main challenge of chemical oligosaccharide synthesis is the stereoselective synthesis of
glycosidic bonds.1, 2 In general, 1,2-trans glycosides can be synthesized by exploiting neighboring
group participation of a C-2-acyl group. The introduction of 1,2-cis glycosidic linkages is much
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more challenging and requires glycosyl donors having a non-assisting functionality at C-2. In
general, these glycosylations are less selective and require optimization to achieve acceptable
anomeric ratios. The development of methodology for stereoselective 1,2-cis glycosylation using a
generally applicable principle is therefore highly desirable as it allows for the use of standardized
monosaccharide building blocks. In this respect, the formation of glycosyl sulfonium ions holds
considerable potential.4-7 In particular, the use of C-2 auxiliaries to attain highly selective 1,2-cis
glycosylations via neighboring group participation allows for careful tuning of donor reactivity
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and stereoselectivity. First reported by Boons et al., C-2 chiral auxiliaries such as the (S)-
(
phenylthiomethyl)benzyl ether can be employed for the stereoselective introduction of 1,2-cis
9
glycosides such as -glucosides and -galactosides. Neighboring group participation by the
chiral auxiliary leads to a quasi-stable anomeric sulfonium ion (Figure 1) which, due to steric and
electronic factors, is formed as a trans-decalin ring system. Subsequent S 2-like displacement of
N
the sulfonium ion then leads to the stereoselective formation of -glycosides.10, 11 Although this
methodology is highly stereoselective in many cases, the stereoselectivity depends on the
protecting groups on the glycosyl donor and the structure of the auxiliary.10, 12-20 Since the
intermediate β-sulfonium ion is in rapid equilibrium with the oxocarbenium ion, its formation
alone is not a guarantee for -selective glycosylation since it may not be a reactive intermediate in
the glycosylation mechanism. 8, 13, 15, 21, 22In addition, the preparation of glycosyl donors equipped
with a C-2 auxiliary is still labor intensive.
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Boons et al. 2005
Turnbull et al. 2009
OTf
O
O
O
RO
Ph
ArS
R2
RO
RO
S
RO
S
Ar
O
O
CCl3
NH
O
O
R1
Ph
This work
SAr
O
O
R4
R5
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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0
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0
= R
Ar =
R3
Bn: R , R = H
OH
R6
Ph: R , R , R = H
2
3
4
5
6
CBn: R = Cl, R = H
PMP: R , R = H, R = OMe
4 6 5
DMP: R , R = OMe, R = H
4 6 5
TMP: R , R , R = OMe
4 5 6
2
3
CNBn: R = CN R = H
2
3
2,4-DCBn: R , R = Cl
2
3
Figure 1. Retrosynthetic routes towards cyclic β-sulfonium ions.
Herein we report a simple method to prepare anomeric β-sulfonium ions from the corresponding
β-thioglycosides via an intramolecular alkylation reaction. Thioglycoside precursors equipped
with a C-2 2-hydroxyethyl group were prepared using a straightforward three-step procedure
starting from commercially available glycal precursors. Triflation of the 2-hydroxyethyl group led
to intramolecular β-sulfonium ion formation and subsequent glycosylation. The influence of the
thiophenyl substituent and the nature of the protecting groups on the stereochemical outcome of
the reaction were investigated. The results reveal a systematic trend of increasing -selectivity
with an increase in electron density on the sulfonium ion and decrease in electron density on the
oxocarbenium ion. Hence, the most -selective couplings were achieved with a 2,4,6-trimethoxy
thiophenyl group and 2,4-dichloro benzyl protecting groups. The preactivation of the glycosyl
donor allowed for the use of thioglycoside acceptors opening the possibility for iterative
thioglycoside couplings.
Glycosyl donors equipped with a 2-hydroxyethyl group at C-2 were prepared from benzyl
protected glucal and galactal. Oxidation of these glycals with oxone in acetone led to the
formation of the -1,2-anhydro sugars which were reacted directly with thiophenol derivatives
and ZnCl to yield the corresponding β-thioglycosides as the main product in moderate to good
2
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yields (Table 1).23 To investigate the effect of the thiophenyl group on the stereoselectivity,
thiophenol, 4-methoxy-thiophenol (PMP), 2,6-dimethoxy thiophenol (DMP) and 2,4,6-trimethoxy
thiophenol (TMP) were used yielding the corresponding thiogluco- and galactosides (Table 1,
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0
1
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2
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1
2
3
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9
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1
2
3
4
5
6
7
8
9
0
entry 1-8). Next, the C-2 2-hydroxyethyl group was installed using THP-protected bromoethanol
and NaH followed by THP removal catalyzed by p-TsOH.
Table 1: Three step synthesis of glycosyl donors 7b-18b
O
Step A
) Acetone, oxone
NaHCO3
O
Step B
1) NaH, Br(CH ) OTHP
O
O
RO
SAr
RO
SAr
RO
1
2 2
OH
2) p-TsOH, MeOH
7
a-18a
2) ArSH, ZnCl2, DCM
OH
b-18b
7
Yield a Yield b
Typ
e
Entry Compound
R
Ar
Ph
7
a-18a 7b-18b
1
7
Glc
Glc
Glc
Glc
Gal
Gal
Gal
Gal
Glc
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
CBn
37%
81%
70%
81%
83%
20%
69%
66%
41%
82%
72%
85%
74%
2
3
4
5
6
7
8
9
8
9
PMP 47%
DMP 39%
TMP 76%
10
11
12
13
14
15
16
17
18
Ph
64%
PMP 26%
DMP 55%
TMP 59%
TMP 61%
1
0
Glc 2,4-DCBn TMP 50%
Gal CBn TMP 60%
Gal 2,4-DCBn TMP 50%
1
1
12
a
b
Isolated yields of the β-thioglycoside products. isolated yield over two steps.
Next, we investigated the possibility to perform glycosylations with 7b-14b by intramolecular
alkylation of the thioglycoside to form intermediate β-sulfonium ions. To this end, 7b-14b were
o
reacted with Tf O and 2,6-di-tertbutyl-4-methyl-pyridine (DTBMP) in DCM at -40 C and the
2
o
o
reactions were allowed to warm to 0 C. Subsequent addition of glycosyl acceptor 21 (-78 C to rt)
led to the formation of disaccharides 22-29 in moderate to good yields (Table 2, entries 1-8). A
clear trend of increasing -stereoselectivity was observed with increasing electron donating
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character of the aryl group in both the gluco and galacto series. The galacto series was more -
selective than the gluco series, consistent with earlier findings.22
Table 2: Glycosylation results of 7b-20b.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
OH
O
BzO
O
O
Tf2O,
DTBMP
OTf
BzO
O
O
RO
SAr
BzO
RO
21
OMe
O
O
OR1
SAr
RO
S
Ar
DCM
40°C - 0°C
-78°C - rt
-
OH
7b-20b
22-35
Entry Type Dono Ar
R
/βa Yield Product
1
Glc 7b
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
2.5/1 71%
2.5/1 62%
3.5/1 83%
22
23
24
25
26
27
28
29
30
31
2
3
4
5
6
7
8
9
Glc 8b PMP
Glc 9b DMP
Glc 10b TMP
Gal 11b Ph
Gal 12b PMP
Gal 13b DMP
Gal 14b TMP
Glc 15b TMP
Glc 19b TMP CNBn
Glc 16b TMP 2,4-DCBn
Gal 17b TMP CBn
Gal 20b TMP CNBn
Gal 18b TMP 2,4-DCBn 13/1
4/1
3/1
3/1
6/1
7/1
5/1
76%
55%
36%
37%
59%
75%
CBn
1
0
7.5/1 65%
11
9/1
81%
32
33
34
35
1
1
2
3
9/1
33%
12.5/1 87%
68%
1
4
a

/β ratios were determined using NMR spectroscopy of the crude reaction mixture after
extraction.25, 26
However, the stereoselectivity of the TMP donor 10b was considerably lower (/β = 4/1) than
1
4
expected based on an earlier report (-only). To investigate if the reaction indeed proceeds via a
β-sulfonium ion we performed low temperature NMR studies. Glycosyl donor 10b was reacted
o
o
with Tf O and DTBMP in CD Cl at -78 C (Figure 2). Upon warming to -20 C, a highly pure β-
2
2
2
sulfonium ion was formed via intramolecular alkylation (Figure 2 C,D). This result does therefore
not explain the discrepancy in stereoselectivity. Since our activation method is different we
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reproduced the reported experiment (SI). In our hands, this reaction gave the same /β = 4/1 ratio
as obtained with our new coupling protocol (Table 2, entry 4).
0
1
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1
Figure 2: Low temperature NMR spectra of the sulfonium ion derived from 10b. A) H NMR
o
1
o
1
spectrum of 10b at -78 C in CD Cl . B) H NMR of 10b at -78 C after the addition of Tf O C) H
2
2
2
o
1
o
NMR at -20 C D) H NMR at -20 C after 30 min. Complete conversion to sulfonium ion 10c is
observed.
To further improve the -selectivity, we turned our attention to the protecting groups. It is
known that more electron withdrawing protecting groups improve the -selectivity of
glycosylation proceeding via β-sulfonium ions.11, 16 To investigate the role in our system, benzyl
27
ethers with increasingly electron withdrawing substituents were installed. Benzyl ethers were
used to minimize alternate reaction pathways such as neighboring group participation that may
arise when using ester protecting groups. To this end, glycal precursors were prepared equipped
with benzyl (Bn), p-chlorobenzyl (CBn) and 2,4-dichlorobenzyl (2,4-DCBn) ethers (SI).
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Subsequent oxidation and reaction with 2,4,6-trimethoxy thiophenol afforded TMP thioglycosides
15a-18a (Table 1, entries 9-12). Finally, installation of the 2-hydroxyethyl group as before yielded
glycosyl donors 15b-18b. In addition, the CBn protected donors 15b and 17b were converted to the
p-cyanobenzyl (CNBn) derivatives (19b and 20b) using a recently reported procedure.28
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Next, we evaluated the glycosylation properties of 15b-20b (Table 2, entry 9-14) using the
aforementioned glycosylation protocol. As expected, a clear trend was observed with increasingly
electron withdrawing benzyl ethers with the 2,4-DCBn giving the most -selective results. The
optimal combination for -selective glycosylation is therefore the electron rich 2,4,6-
trimethylthiophenyl group and the electron withdrawing 2,4-DCBn group to protect the C-3, 4
and 6 positions. Using this optimal combination for both glucose (16b) and galactose (18b) the
glycosyl acceptor scope was investigated. To this end, two additional glycosyl acceptors 36 and 37
were evaluated (Table 3).
Table 3: Glycosyl acceptor scope of glycosyl donors 16b and 18b.
O
O
Tf2O,
DTBMP
OTf
Acceptor
-78°C - rt
O
O
2,4-DCBnO
STMP
2,4-DCBnO
O
O
OR
2,4-DCBnO
S
TMP
DCM
40°C - 0°C
-
OH
STMP
a
Entry Type Donor
Acceptor
/β Yield Product
OBn
1
Glc
Gal
Glc
Gal
16b
18b
16b
18b
3.3/1 53%
21/1 48%
13/1 52%
15/1 49%
38
39
40
41
O
HO
BnO
2
3
4
BnO
OMe
36
OH
O
O
Ph
O
NapO
37 SPh
a

/β ratios were determined using NMR spectroscopy of the crude reaction mixture after
extraction.25, 26
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
From the results it is clear that the -stereoselecitivity is maintained across different glycosyl
acceptors. It is noteworthy that thioglycoside acceptors could be used (37) to perform
chemoselective coupling of thioglycoside donors 16b and 18b. Hence, the developed method is
amendable to iterative thioglycoside couplings.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
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2
3
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8
9
0
Finally, the importance of the β-sulfonium ion as a reactive intermediate was investigated using a
number of control experiments (Table 4). The effect of electron withdrawing protecting groups on
the stereoselectivity can be explained by widening of the energy gap between the oxocarbenium
and sulfonium ion. The inductive effect of the protecting groups is more remote from the
sulfonium ion than the oxocarbenium ion and hence affect the latter intermediate to a greater
extend. We prepared glycosyl donors containing a C-2 non-participating group (Bn or Pr) and
benzyl or 2,4-DCBn groups at the remaining sites. Using these donors a pre-activation method
o
was not possible at the typically used glycosylation temperature (0 C) and hence we resorted to
premix conditions (NIS, TfOH). From the results it is clear that in both the C-2 OBn and OPr
protected donors, the -selectivity increased with increased electron withdrawing protecting
groups (Table 4, entries 1-4).
Table 4: Control experiments to evaluate the contribution of the β-sulfonium ion
intermediate in the reaction mechanism.
RO
RO
RO
RO
RO
RO
O
O
O
BzO
BzO
STMP Method A or B
O
OR1
R O OR2
1
BzO
OMe
R2OH = 21
a
Entry Donor
R
Bn
2,4-DCBn
Bn
2,4-DCBn
Bn
R (method) /β
Yield
68%
57%
65%
51%
71%
49%
83%
Product
1
1
42
43
44
45
46
47
48
Bn (A)
Bn (A)
1.4/1
4/1
50
51
2
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7
Propyl (A) 1.2/1
Propyl (A) 3/1
(CH ) OH (B) 2/1
52
53
54
55
56
2 3
2,4-DCBn (CH ) OH (B) 2.5/1
2
3
Bn
Ac (A)
>1/20
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49
2,4-DCBn
Ac (A)
>1/20
60%
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Method A: 21, NIS, TfOH, DCM, 0°C; Method B: 1. Tf O, DTBMP, DCM, -40°C - 0°C. 2. 21, -40°C -
2
rt. a /β ratios were determined using NMR spectroscopy of the crude reaction mixture after
extraction.25, 26
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This suggests that the background reaction taking place in the sulfonium ion reactions also
becomes more -selective. It is clear that the sulfonium ion intermediate is important for -
selectivity since these reactions are considerably more selective (/β = 9/1 vs 4/1). This is
highlighted by the fact that increasing the ring size by the use of a C-2 3-hydroxypropyl group led
to a complete loss of stereoselectivity regardless of the protecting group used (Table 4, entry 5-6).
To demonstrate that late stage switching to β-selective couplings is possible and are not affected
by the protecting group pattern, compound 10a was acetylated and coupled using NIS/TfOH
(
Table 4, entry 7-8). Using this synthetic route, late stage introduction of the C-2 functionality
allows the synthesis of a highly - (10b) and β-selective (49) glycosyl donor in a one-step
procedure starting from a general building block (10a). Finally, deprotection of the auxiliary of 32
was achieved using a previously reported procedure involving methylation of the thioether
followed by elimination under basic conditions to afford the corresponding C-2 OH compound
(
58).14
In conclusion, a novel and versatile methodology for the formation of -glycosidic linkages was
developed. Thioglycosides were activated to form β-sulfonium ions via an intramolecular
alkylation reaction. The reactivity and selectivity of the β-sulfonium ions was modulated by the
systematic variation of the thioglycoside substituent and the electronic nature of the protecting
groups. An electron rich thioglycoside with electron withdrawing protecting groups proved to be
the optimal combination. Consistent -selectivity was observed for a number of glycosyl
acceptors. In addition, chemoselective coupling of glycosyl donor thioglyocosides to thioglycoside
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acceptors is possible. Mechanistic studies indicate the electron withdrawing protecting groups
also improve the -selectivity of C-2 benzyl protected donors in addition to the sulfonium ion.
Late-stage modulation of donor selectivity is possible by introduction of the 2-hydroxy ethyl
substituent for -selectivity or the installation of a C-2 acetyl group for β-selective couplings.
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EXPERIMENTAL SECTION
1
13
General Procedures: H and C NMR spectra were recorded on a Bruker 400 MHz or 500 MHz
spectrometer. Chemical shifts are reported in parts per million (ppm) relative to tetramethylsilane
(TMS), or residual solvents as the internal standard. NMR data is presented as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, dd = doublet of doublets, m = multiplet
and/or multiple resonances), coupling constant in hertz (Hz), integration. All NMR signals were
1
13
assigned on the basis of H NMR, C NMR, COSY, HSQC and TOCSY experiments. NMR data is
presented for the major anomer. Mass spectra were recorded on an JEOL AccuTOF CS JMS-
T100CS mass spectrometer. Optical rotations were measured at 589 nm using a Perkin Elmer
Polarimeter Model 241 MC. Automatic flash column chromatography was performed using
Biotage Isolera Spektra One, using SNAP cartridges (Biotage, 30-100 µm, 60 Å), 10-50 g. TLC-
analysis was conducted on Silica gel F254 (Merck KGaA) with detection by UV-absorption (254nm)
where applicable, and by spraying with 10% sulphuric acid in methanol followed by charring at
o
≈
300 C. DCM THF and toluene were freshly distilled. Molecular sieves (4Å) were flame activated
,
under vacuum prior to use. All inert reactions were carried out under argon atmosphere using
flame-dried flasks.
General procedure A: D-glucal or D-galactal was dissolved in dry DMF (0.2 M) under inert
°
atmosphere and cooled to 0 C. NaH (8 eq; 60% dispersion in mineral oil) was added and the
reaction mixture was stirred for 30 min, after which the corresponding benzylating agent (5 eq)
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was added. The reaction was stirred for 16 h at ambient temperature after which it was quenched
with MeOH. The mixture was concentrated under reduced pressure and taken up in DCM (100
mL) and water (100 mL). The aqueous layer was extracted with DCM (2 × 100 mL). The combined
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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0
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0
organic layers were washed with brine (100 mL), dried (MgSO ), filtered and concentrated under
4
reduced pressure to yield the crude product.
o
General procedure B: To a cooled (0 C) solution of a benzylated glycal (2.4 mmol) in DCM (10
mL) were added acetone (1 mL) and sat. aq. NaHCO (17 mL). The mixture was stirred vigorously,
3
and a solution of oxone (4.8 mmol) in H O (6 mL) was added dropwise over 15 min. The mixture
2
°
was stirred vigorously at 0 C for 30 min and then at rt until TLC indicated consumption of the
starting material. The organic phase was separated and the aqueous phase was extracted with
DCM (2 × 10 mL). The combined organic phases were dried (Na SO ) and concentrated in vacuo.
2
4
The crude mixture was dissolved in dry DCM (23 mL). MS (4Å) and the corresponding thiol (3.6
°
mmol) were added under inert atmosphere. The mixture was cooled to -78 C and stirred for 15
min. ZnCl (1M in Et O) (0.24 mmol) was added and the mixture was stirred overnight while
2
2
slowly warmed up to rt. The reaction was quenched with TEA and purified with silica gel flash
column chromatography to obtain the pure product.
General procedure C: An anomeric thioether with a free 2-OH (7a - 19a) was dissolved in dry
o
DMF (0.1 M) and cooled to 0 C. NaH (4 eq; 60% dispersion in mineral oil) was added and the
°
mixture was stirred at 0 C for 15 min, after which the appropriate auxiliary (Br(CH ) OTHP or
2
2
Br(CH ) OTHP) was added (4 eq). The reaction was stirred for 16 h at ambient temperature, after
2
3
which it was quenched with MeOH. The reaction mixture was concentrated under reduced
pressure and were taken up in MeOH (25 mL). p-TsOH was added until a pH of 2 was reached.
The reaction was stirred for 4 h and subsequently concentrated under reduced pressure. The
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residue was dissolved in EtOAc (20 mL) and washed with water (3 × 20 mL). The organic layer
was dried (MgSO ), filtered and concentrated under reduced pressure to yield the crude product.
4
General procedure D: Thioglucosides 10a or 16a were dissolved in dry DMF (0.1 M) and cooled
0
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2
3
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5
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7
8
9
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9
0
o
°
to 0 C. NaH (4 eq; 60% dispersion in mineral oil) was added and the mixture was stirred at 0 C for
15 min, after which benzyl- or propyl bromide was added (4 eq). The reaction was stirred for 16 h
at ambient temperature, after which it was quenched with MeOH. The reaction mixture was
concentrated under reduced pressure and the residue was taken up in EtOAc (20 mL). The
organic layer was washed with water (3 × 20 mL), brine (20 mL), dried (MgSO ), filtered and
4
concentrated under reduced pressure yielding the crude product.
General glycosylation procedure E: the corresponding glycosyl donor (1 eq) and DTBMP (4 eq)
o
were dissolved in dry DCM (0.05 M). MS (4Å) were added and the mixture was stirred at -40 C for
°
1
5 min. Tf O (1.5 eq) was added and the mixture was allowed to slowly warm up to 0 C and stirred
2
°
at 0 C for 30 min. When TLC analysis indicated complete consumption of the triflated
o
intermediate, the mixture was cooled down to -78 C and the appropriate acceptor (1.5 eq) was
added. The reaction was left to warm up to rt in 16 hours and was subsequently taken up in EtOAc
(
(
20 mL) and filtered. The filtrate was washed with aq. Na S O (20 mL, 10%), brine (20 mL), dried
2
2
3
MgSO ), filtered and concentrated under reduced pressure to yield the crude product.
4
General glycosylation procedure F: The corresponding glycosyl donor (1 eq) and acceptor (2
°
eq) were dissolved in dry DCM (0.05 M). MS (4Å) were added and the mixture was cooled to -5 C.
NIS (1.1 eq) and TfOH (0.2 eq) were added and the reaction was stirred for 2h. The reaction was
quenched with Et N and taken up in EtOAc (20 mL) and filtered. The filtrate was washed with aq
3
Na S O sol (20 mL, 10%), brine (20 mL), dried (MgSO ), filtered and concentrated under reduced
2
2
3
4
pressure to yield the crude product.
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,4,6-Tri-O-benzyl-D-glucal (1): Via general procedure A starting from D-glucal (5.13 g, 35.1
mmol) using benzyl bromide. The crude product was purified by silica gel flash column
chromatography (0% to 30% EtOAc in n-heptane) affording 1 (13.3 g, 91%). TLC (EtOAc/n-
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
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7
8
9
0
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2
3
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5
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9
0
heptane, 30/70 v/v): R = 0.55. H NMR: (500 MHz, CDCl ) δ 7.37 – 7.21 (m, 15H), 6.42 (dd, J = 6.1,
f
3
1
.3 Hz, 1H, H-1), 4.87 (dd, J = 6.2, 2.7 Hz, 1H, H-2), 4.83 (d, J = 11.3 Hz, 1H), 4.66 – 4.61 (m, 2H), 4.61
4.53 (m, 3H), 4.21 (ddd, J = 6.2, 2.7, 1.3 Hz, 1H, H-3), 4.06 (ddd, J = 8.3, 5.1, 2.9 Hz, 1H, H-5), 3.86
–
13
1
(
dd, J = 8.7, 6.2 Hz, 1H, H-4), 3.83 – 3.72 (m, 2H, H-6); C{ H} NMR: (126 MHz, CDCl ) δ 144.7 (C-
3
1), 138.3, 138.2, 138.0, 128.5, 128.4, 128.3, 127.9, 127.8, 127.7, 127.6, 99.9 (C-2), 76.7 (C-5), 75.7 (C-3),
4.4 (C-4), 73.8, 73.51, 70.45, 68.5 (C-6).
7
3
,4,6-Tri-O-(4-chlorobenzyl)-D-glucal (2): Via general procedure A starting from D-glucal (2.0
g, 13.7 mmol) using 4-chlorobenzyl chloride (11.0 g, 68 mmol). The crude product was purified by
silica gel flash column chromatography (0% to 20% EtOAc in n-heptane) yielding 2 (6.23 g, 88%).
1
TLC (EtOAc/n-heptane 40/60 v/v): R = 0.76. H NMR (500 MHz, CDCl ) δ 7.33 – 7.19 (m, 11H),
f
3
7
.16 – 7.10 (m, 2H), 6.41 (dd, J = 6.1, 1.4 Hz, 1H, H-1), 4.85 (dd, J = 6.2, 2.6 Hz, 1H, H-2), 4.75 (d, J =
1.6 Hz, 1H), 4.58 (d, J = 11.8 Hz, 2H), 4.54 (d, J = 12.2 Hz, 1H), 4.50 – 4.45 (m, 2H), 4.18 (ddd, J = 6.3,
.6, 1.4 Hz, 1H, H-3), 4.01 (ddd, J = 8.8, 4.8, 2.7 Hz, 1H, H-5), 3.81 (dd, J = 8.9, 6.3 Hz, 1H, H-4), 3.77
1
2
13
1
(dd, J = 10.7, 4.8 Hz, 1H, H-6a), 3.72 (dd, J = 10.8, 2.7 Hz, 1H, H-6b). C{ H} NMR (126 MHz, CDCl )
3
δ 144.9 (C-1), 136.8, 136.6, 136.4, 133.54, 133.49, 133.46, 129.04, 129.01, 128.96, 128.60, 128.57, 99.7 (C-
2
), 76.7 (C-5), 76.0 (C-3), 74.5 (C-4), 72.9, 72.7, 69.6, 68.5 (C-6); HRMS (ESI-TOF) (m/z): [M+Na]+
Calcd for C H Cl O Na, 541.0716; found, 541.0707.
27
25
3
4
3
,4,6-Tri-O-(2,4-dichlorobenzyl)-D-glucal (3): Via general procedure A starting from D-glucal
(1.7 g, 11.6 mmol) using 2,4-dichloro-1-(chloromethyl)benzene. The crude product was purified by
silica gel flash column chromatography (0% to 20% EtOAc in n-heptane) yielding 3 (6.39 g, 90%).
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1
TLC (EtOAc/n-heptane 40/60 v/v): R = 0.76. H NMR (500 MHz, CDCl ) δ 7.49 – 7.26 (m, 9H),
f
3
7
.25 – 7.15 (m, 3H), 6.45 (dd, J = 6.1, 1.4 Hz, 1H, H-1), 4.92 (dd, J = 6.2, 2.5 Hz, 1H, H-2), 4.89 (d, J =
2.7 Hz, 1H), 4.73 (d, J = 12.8 Hz, 1H), 4.71 – 4.66 (m, 1H), 4.63 (d, J = 13.4 Hz, 1H), 4.56 (dd, J = 13.1,
3.7 Hz, 2H), 4.28 (ddd, J = 6.4, 2.6, 1.4 Hz, 1H, H-3), 4.07 (ddd, J = 9.1, 4.5, 2.6 Hz, 1H, H-5), 3.95 –
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
1
3
.87 (m, 2H, H-4, H-6a), 3.82 (dd, J = 10.7, 2.7 Hz, 1H, H-6b). C{ H} NMR (126 MHz, CDCl ) δ
3
1
1
45.0 (C-1), 134.53, 134.50, 134.3, 133.94, 133.87, 133.8, 133.36, 133.33, 133.2, 130.0, 129.9, 129.8, 129.7,
29.6, 129.2, 129.07, 129.05, 129.01, 127.2, 127.10, 127.07, 127.03, 99.6 (C-2), 76.7 (C-3), 76.6 (C-5), 74.6
+
(C-4), 71.0, 70.2, 69.9, 69.3, 69.0 (C-6), 67.0. HRMS (ESI-TOF) (ESI-TOF) (m/z): [M+Na] Calcd
for C H Cl O Na, 642.9547; found, 642.9545.
27
22
6
4
3
,4,6-tri-O-benzyl-β-D-galactal (4): Via general procedure A starting from D-galactal (5.00 g,
3
4.2 mmol) using benzyl bromide. Silica gel flash column chromatography (0% - 30% EtOAc in n-
1
heptane) afforded 4 (12.39 g, 29.8 mmol, 87%). TLC: (EtOAc/n-heptane,50/50 v/v): R = 0.74; H
f
NMR (500 MHz, CDCl ) δ 7.37 – 7.22 (m, 15H), 6.36 (dd, J = 6.2, 1.4 Hz, (H-1)), 4.85 (ddd, J = 8.5,
3
6
4
6
.6, 4.1 Hz, 1H, H-2), 4.67 – 4.58 (m, 3H), 4.50 (d, J = 11.9 Hz, 1H), 4.42 (d, J = 11.9 Hz, 1H), 4.21 –
.15 (m, H-3, H-5), 3.96 – 3.92 (m, H-4), 3.78 (dd, J = 10.1, 7.2 Hz, H-6a), 3.65 (dd, J = 10.2, 5.1 Hz, H-
13
1
b). C{ H} NMR (126 MHz, CDCl ) δ 144.2 (C-1), 138.5, 138.4, 138.0, 128.4, 128.3, 128.2, 127.9, 127.7,
3
127.6, 127.5, 100.0 (C-2), 75.7 (C-5), 73.44, 73.35, 71.3 (H-4), 70.9, 70.8 (C-3), 68.5 (H-6). HRMS
+
(
ESI-TOF) (m/z): [M+Na] Calcd for C H O Na, 439.1885; found, 439.1877.
27
28
4
3
,4,6-tri-O-(4-chlorobenzyl)-β-D-galactal (5): Via general procedure A starting from D-galactal
(
72 mg, 0.492 mmol) and 4-chlorobenzyl bromide. Silica gel flash column chromatography (0% -
3
0% EtOAc in n-heptane) afforded 5 (0.12 g, 0.231 mmol, 47%). TLC: (EtOAc/n-heptane, 30/70
1
v/v): R = 0.37; H NMR (500 MHz, CDCl ) δ 7.25 (m, 12H), 6.36 (dd, J = 6.3, 1.4 Hz, H-1), 4.84 (ddd,
f
3
J = 6.3, 3.0, 1.2 Hz, H-2), 4.79 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 12.0 Hz, 1H),
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.53 (d, J = 12.1 Hz, 1H), 4.49 (d, J = 12.1 Hz, 1H), 4.39 (d, J = 12.1 Hz, 1H), 4.17 (m, H-3, H-5), 3.91 (m,
13
1
H-4), 3.74 (dd, J = 10.1, 7.2 Hz, H-6a), 3.63 (dd, J = 10.1, 5.1 Hz, H-6b). C{ H} NMR (126 MHz,
CDCl ) δ 144.3 (C-1), 136.8, 136.7, 136.4, 133.54, 133.52, 133.4, 132.6, 129.2, 129.1, 128.7, 128.58, 128.56,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
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0
128.50, 99.6 (C-2), 75.5 (C-5), 72.6, 72.5, 71.6 (C-4), 70.8 (C-3), 70.2, 68.2 (C-6); HRMS (ESI-TOF)
+
(
m/z): [M+Na] Calcd for C H Cl O Na, 541.0716; found, 541.0709.
27
25
3
4
3
,4,6-tri-O-(2,4-dichlorobenzyl)-β-D-galactal (6): Via general procedure A starting from D-
galactal (2.0 g, 13.7 mmol) and 2,4-dichlorobenzylchloride. Silica gel flash column
chromatography (0% - 30% EtOAc in n-heptane) afforded 6 (3.88 g, 6.29 mmol, 46%). TLC:
1
(EtOAc/n-heptane, 30/70 v/v): R = 0.60; H NMR (500 MHz, CDCl ) δ 7.46 – 7.15 (m, 9H), 6.41
f
3
(
dd, J = 6.2, 1.3 Hz, H-1), 4.93 – 4.87 (m, 1H, H-2), 4.72 (d, J = 6.6 Hz, 1H), 4.69 (d, J = 6.6 Hz, 1H),
.66 – 4.58 (m, 2H), 4.51 (d, J = 13.0 Hz, 1H), 4.32 – 4.26 (m, H-3, H-5), 4.08 – 4.04 (m, H-4), 3.87 –
4
1
3
1
3
.76 (m, H-6a, H-6b). C{ H} NMR (126 MHz, CDCl ) δ 144.4 (C-1), 134.70, 134.65, 134.2, 134.0, 133.8,
3
133.6, 133.1, 133.0, 130.07, 130.01, 129.6, 129.2, 129.0, 128.9, 127.11, 127.07, 99.5 (C-2), 75.3 (C-5), 72.4
+
(
H-4), 71.6 (C-3), 70.0, 69.9, 68.6 (C-6), 67.8; HRMS (ESI-TOF) (m/z): [M+Na] Calcd for
C H Cl O Na, 642.9547; found, 642.9545.
27
22
6
4
3
,4,6-tri-O-benzyl-2-O-(2-(2,4,6-trimethoxybenzenethio)ethyl-α-D-
glycopyranosyl)trichloroacetimidate (10d): Glucosyl donor 10b (1 eq) and DTBMP (4 eq) were
dissolved in dry DCM (2 mL). MS (4Å) were added under inert atmosphere and the mixture was
°
stirred at -40 C for 15 min. Tf O (1.5 eq) was added and the mixture was allowed to slowly warm up
2
°
°
to 0 C and stirred at 0 C for 30 min. When TLC analysis indicated complete consumption of the
triflated intermediate, the mixture was quenched with H O, taken up in EtOAc (20 mL) and
2
filtered. The filtrate was washed with aq. Na S O (20 mL, 10%), brine (20 mL), dried (MgSO ),
2
2
3
4
filtered and concentrated under reduced pressure. The crude product was purified using silica gel
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flash column chromatography (20% - 60% EtOAc in n-heptane) yielded the lactol (98 mg, 0.16
mmol, 63%). The lactol (1 eq) was dissolved in dry DCM (0.015M). Trichloroacetonitrile (10 eq)
°
and DBU (4 eq) were added, and the mixture was stirred at 0 C. After 7h, TLC showed the
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formation of a major product. The reaction was concentrated in vacuo and purified using silica gel
flash column chromatography (Pet ether:EtOAc (20%, with 1% TEA) to afford 10d (51 mg, 84%).
Spectral data was consistent with literature values of the reported compound by Singh et al.14
Using 10d, a glycosylation reaction under idential conditions was performed as reported by Singh
et al. In our hands, this experiment gave 4/1, /β ratio. This is consistent with the results obtained
with 10b but different from the report of Singh et al.
Phenyl 3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (7a): Via general procedure B starting
from 1 (0.81 g, 1.52 mmol) and thiophenol. Silica gel flash column chromatography (0% → 30% -
EtOAc in n-heptane) afforded 7a (0.30 g, 0.56 mmol, 37%). TLC: (EtOAc/n-heptane, 30/70 v/v): Rf
1
= 0.4; H NMR (500 MHz, CDCl ) δ 7.60 – 7.52 (m, 2H), 7.37 – 7.16 (m, 18H), 4.91 (d, J = 11.2 Hz,
3
1
H), 4.86 – 4.80 (m, 2H), 4.61 (d, J = 12.1 Hz, 1H), 4.57 (d, J = 10.9 Hz, 1H), 4.54 (d, J = 12.0 Hz, 1H),
4
6
.50 (d, J = 9.6 Hz, 1H, (H-1)), 3.79 (dd, J = 10.9, 2.0 Hz, 1H, (H-6)), 3.73 (dd, J = 11.0, 4.5 Hz, 1H, (H-
13
1
)), 3.64 – 3.46 (m, 4H, (H-2, H-3, H-4, H-5)), 2.45 (s, 1H). C{ H} NMR (126 MHz, CDCl ) δ 138.4,
3
138.2, 138.0, 132.8, 131.7, 128.9, 128.5, 128.4, 128.3, 128.0, 127.92, 127.89, 127.7, 127.6, 127.5, 88.0(C-1),
8
5.9(C-3), 79.4(C-5), 77.3(C-4), 75.3, 75.0, 73.4, 72.5 (C-2), 68.9(C-6). HRMS (ESI-TOF) (m/z):
+
[
M+Na] Calcd for C H O SNa, 565.2025; found, 565.2022
3
3
34
5
4-Methoxyphenyl 3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (8a):
Via general
procedure B starting from 1 (0.185 g, 0.446 mmol) and 4-methoxythiophenol. Silica gel flash
column chromatography (0% → 30% - EtOAc in n-heptane) afforded 8a (0.12 g, 0.21 mmol, 47%).
1
TLC: (EtOAc/n-heptane, 40/60 v/v): R = 0.7; H NMR (500 MHz, CDCl ) δ 7.50 (d, J = 8.8 Hz, 1H),
f
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.38 – 7.15 (m, 14H), 6.76 (d, J = 8.8 Hz, 1H), 4.93 – 4.78 (m, 3H), 4.64 – 4.51 (m, 3H), 4.36 (d, J = 9.6
Hz, 1H, (H-1)), 3.80 – 3.72 (m, 5H, (H-6, H-6, OMe)), 3.61 – 3.53 (m, 2H, (H-3, H-4)), 3.50 (ddd, J =
13
1
7.4, 4.3, 2.1 Hz, 1H, (H-5)), 3.40 (dd, J = 9.6, 8.4 Hz, 1H, (H-2)), 2.41 (s, 1H). C{ H} NMR (126 MHz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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2
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8
9
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CDCl ) δ 160.2, 138.5, 138.4, 138.1, 136.0, 128.5, 128.43, 128.35, 128.01, 127.98, 127.8, 127.64, 127.56, 121.1,
3
1
14.5, 88.0(C-1), 85.9(C-3), 79.4(C-5), 77.4(C-4), 75.3, 75.1, 73.5, 72.3(C-2), 69.0(C-6), 55.3. HRMS
+
(
ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa, 595.2130; found, 595.2134
3
4
36
6
2
,6-Dimethoxyphenyl 3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (9a): Via general
procedure B starting from 1 (0.779 g, 1.87 mmol) and 2,6-dimethoxythiophenol. Silica gel flash
column chromatography (0% → 30% - EtOAc in n-heptane) afforded 9a (0.44 g, 0.731 mmol, 39%).
1
TLC: (EtOAc/n-heptane, 40/60 v/v): R = 0.6; H NMR (500 MHz, CDCl ) δ 7.45 – 7.08 (m, 16H),
f
3
6
.56 (d, J = 8.4 Hz, 2H), 5.04 (d, J = 11.1 Hz, 1H), 4.79 (dd, J = 11.0, 1.7 Hz, 2H), 4.57 – 4.50 (m, 2H),
.46 (d, J = 11.7 Hz, 1H), 4.29 (d, J = 9.6 Hz, 1H, H-1), 3.83 (m, 7H), 3.79 (d, J = 2.7 Hz, 2H, (H-6, H-
4
6)), 3.61 (t, J = 8.7 Hz, 1H, (H-3)), 3.53 (dd, J = 9.7, 8.7 Hz, 1H, (H-4)), 3.46 (dt, J = 9.7, 2.7 Hz, 1H,
13
1
(
H-5)), 3.32 (ddd, J = 9.5, 8.6, 1.9 Hz, 1H, (H-2)). C{ H} NMR (126 MHz, CDCl ) δ 162.2, 138.8,
3
1
38.4, 138.3, 131.6, 128.27, 128.26, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 127.4, 105.0, 104.6, 88.4 (C-1),
8
5.6 (C-3), 80.0 (C-5), 76.9 (C-4), 75.2, 75.0, 73.6, 73.5 (C-2), 69.1 (C-6), 56.4. HRMS (ESI-TOF)
+
(m/z): [M+Na] Calcd for C H O SNa, 625.2236; found, 625.2223
3
5
38
7
2,4,6-Trimethoxyphenyl 3,4,6-tri-O-benzyl-1-thio-β-D-glucopyranoside (10a): Via general
procedure B starting from 1 (0.303 g, 0.729 mmol) and 2,4,6-trimethoxythiophenol. The crude
product was purified by silica gel flash column chromatography (10% → 40% EtOAc in n-heptane)
1
yielding 10a (0.35 g, 0.554 mmol, 76%). TLC (EtOAc/n-heptane 40/60 v/v): R = 0.41. H NMR (500
f
MHz, CDCl ) δ 7.40 – 7.13 (m, 15H), 6.11 (s, 2H), 5.04 (d, J = 11.0 Hz, 1H), 4.79 (dd, J = 11.0, 2.6 Hz,
3
2
H), 4.54 (dd, J = 11.2, 7.6 Hz, 2H), 4.45 (d, J = 11.6 Hz, 1H), 4.20 (d, J = 9.4 Hz, 1H, H-1), 3.84 – 3.77
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(
m, 11H, H-2, H-6), 3.61 (t, J = 8.8 Hz, 1H, H-3), 3.54 (t, J = 9.3 Hz, 1H, H-4), 3.46 (ddd, J = 9.7, 3.2,
13
1
2
.0 Hz, 1H, H-5), 3.28 (ddt, J = 9.5, 8.7, 2.5 Hz, 1H, H-2). C{ H} NMR (126 MHz, CDCl ) δ 163.2,
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1
63.0, 139.0, 138.6, 138.4, 128.3, 128.2, 128.0, 127.9, 127.7, 127.6, 127.49, 127.45, 96.2, 91.5, 88.5 (C-1),
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85.6 (C-3), 80.0 (C-5), 76.9 (C-4), 75.2, 75.1, 73.7, 73.2 (C-2), 73.1, 69.2 (C-6), 56.4, 55.4. HRMS (ESI-
+
TOF) (m/z): [M+Na] Calcd for C H O SNa, 655.2342; found, 655.2339.
3
6
40
8
Phenyl 3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-glucopyranoside (7b): Via
general procedure C starting from 7a (0.137 g, 0.253mmol). Silica gel flash column
chromatography (0% → 30% - EtOAc in n-heptane) afforded 7b (0.12 g, 0.205 mmol, 81%). TLC:
1
(EtOAc/n-heptane, 30/70 v/v): R = 0.4; H NMR (500 MHz, CDCl ) δ 7.61 – 7.54 (m, 2H), 7.38 –
f
3
7
.15 (m, 17H), 4.91 (d, J = 10.9 Hz, 1H), 4.85 (d, J = 10.9 Hz, 1H), 4.80 (d, J = 10.8 Hz, 1H), 4.64 – 4.56
m, 2H), 4.57 (d, J = 9.8 Hz, 1H (H-1)), 4.54 (d, J = 12.0 Hz, 1H), 3.89 (ddd, J = 10.7, 5.8, 3.0 Hz, 1H),
.83 (ddd, J = 10.7, 6.0, 3.0 Hz, 1H), 3.78 (dd, J = 10.9, 2.0 Hz, 1H, (H-6)), 3.72 (dd, J = 10.9, 4.5 Hz,
1H, (H-6)), 3.70 – 3.61 (m, 4H, (H-3, H-4)), 3.50 (ddt, J = 6.6, 4.6, 1.9 Hz, 1H, (H-5)), 3.40 – 3.33 (m,
(
3
13
1
1
1
H, (H-2)), 2.72 (s, 1H). C{ H} NMR (126 MHz, CDCl ) δ 138.2, 137.9, 137.8, 133.2, 131.9, 128.9, 128.5,
3
28.4, 128.3, 127.9, 127.9, 127.8, 127.64, 127.59, 127.57, 87.5 (C-1), 86.6 (C-3), 80.6 (C-2), 79.1 (C-5),
7
7.9 (C-4), 77.3, 77.0, 76.8, 75.9, 75.0, 74.7, 73.4, 68.8 (C-6), 62.3. HRMS (ESI-TOF) (m/z):
+
[M+Na] Calcd for C H O SNa, 609.2287; found, 609.2275
3
5
38
6
4-Methoxyphenyl
3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-glucopyranoside
(
8b): Via general procedure C starting from 8a (0.172 g, 0.301 mmol.) Silica gel flash column
chromatography (0% → 30% - EtOAc in n-heptane) afforded 8b (0.13 g, 0.211 mmol, 70%). TLC:
1
(
EtOAc/n-heptane, 40/60 v/v): R = 0.4; H NMR (500 MHz, CDCl δ 7.46 (d, J = 8.9 Hz, 2H), 7.30
f
3)
– 7.16 (m, 13H), 7.12 (dd, J = 7.5, 2.1 Hz, 2H), 6.67 (d, J = 8.8 Hz, 2H), 4.83 (d, J = 10.9 Hz, 1H), 4.76
(
d, J = 10.9 Hz, 1H), 4.72 (d, J = 10.9 Hz, 1H), 4.57 – 4.42 (m, 4H), 4.36 (d, J = 9.7 Hz, 1H), 3.83 (ddd,
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J = 10.7, 5.4, 3.1 Hz, 1H), 3.76 (ddd, J = 10.7, 6.1, 3.1 Hz, 1H), 3.72 – 3.51 (m, 11H, (H-3, H-4, H-6, H-
6)), 3.38 (ddd, J = 9.5, 4.3, 1.9 Hz, 1H, (H-5)), 3.22 (dd, J = 9.7, 8.6 Hz, 1H, (H-2)), 2.72 (s, 1H);
13
1
C{ H} NMR (126 MHz, CDCl ) δ 159.8, 138.2, 137.90, 137.85, 135.2, 128.5, 128.4, 128.3, 127.86, 127.84,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
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5
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0
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0
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127.6, 127.5, 122.7, 114.4, 87.8 (C-1), 86.6 (C-3), 80.5 (C-2), 79.0 (C-5), 78.0 (C-4), 75.8, 75.0, 74.7,
+
7
3.4, 73.3, 68.9 (C-6), 62.3, 55.3; HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa,
3
6
40
7
639.2392; found, 639.2382
2
,6-Dimethoxyphenyl 3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-glucopyranoside
(
9b): Via general procedure C starting from 9a (0.184 g, 0.306 mmol). Silica gel flash column
chromatography (0% → 30% - EtOAc in n-heptane) afforded 9b (0.16 g, 0.248 mmol, 81%). TLC:
1
(
(
EtOAc/n-heptane, 40/60 v/v): R = 0.30; H NMR (500 MHz, CDCl ) δ 7.37 – 7.21 (m, 14H), 7.17
f
3
dd, J = 7.3, 2.2 Hz, 2H), 6.56 (d, J = 8.3 Hz, 2H), 4.87 (s, 2H), 4.79 (d, J = 10.8 Hz, 1H), 4.55 (d, J =
1
0.9 Hz, 1H), 4.53 (d, J = 10.0 Hz, 1H (H-1)), 4.49 (d, J = 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 4.05
(ddd, J = 10.9, 5.7, 2.5 Hz, 1H), 3.95 (ddd, J = 10.8, 6.7, 2.4 Hz, 1H), 3.84 (m, 7H), 3.75 – 3.67 (m, 2H,
(
H-6)), 3.66 – 3.59 (m, 2H, (H-3, H-6)), 3.59 – 3.48 (m, 2H, (H-4)), 3.43 – 3.32 (m, 2H, (H-2, H-5));
13
1
C{ H} NMR (126 MHz, CDCl ) δ 161.0, 138.4, 138.2, 137.9, 130.4, 128.5, 128.4, 128.3, 127.93, 127.88,
3
1
27.82, 127.80, 127.5, 108.6, 104.3, 87.9 (C-1), 87.2 (C-3), 81.7 (C-2), 79.6 (C-5), 78.2 (C-4), 75.8, 75.0,
+
74.9, 73.6, 69.4 (C-6), 61.9, 56.3; HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa,
3
7
42
8
669.2498; found, 669.2495.
2
,4,6-trimethoxyphenyl
3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-
glucopyranoside (10b): via general procedure C starting from 10a (330 mg, 0.55 mmol). Silica gel
flash column chromatography (30% to 60% EtOAc in n-heptane) afforded 10b as a white solid
1
(0.294 g, 0.434 mmol, 83%). TLC (EtOAc/n-heptane 40/60 v/v): R = 0.21. H NMR (500 MHz,
f
CDCl ) δ 7.46 – 7.11 (m, 18H), 6.12 (s, 2H), 4.87 (s, 2H), 4.78 (d, J = 10.8 Hz, 1H), 4.55 (d, J = 10.9 Hz,
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H), 4.48 (s, 2H), 4.38 (d, J = 9.9 Hz, 1H, H-1), 4.05 (ddd, J = 10.8, 5.6, 2.5 Hz, 1H), 3.94 (ddd, J =
0.8, 6.8, 2.5 Hz, 1H), 3.82 (s, 7H), 3.79 (s, 3H), 3.74 – 3.67 (m, 2H, H-6a), 3.64 – 3.58 (m, 3H, H-3,
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H-6b), 3.49 (t, J = 9.4 Hz, 1H, H-4), 3.39 – 3.31 (m, 2H, H-2, H-5). C{ H} NMR (126 MHz, CDCl ) δ
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
162.3, 162.1, 138.4, 138.3, 137.9, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.80, 127.79, 127.5, 100.0, 91.2,
8
8.7 (C-1), 87.2 (C-3), 81.6 (C-2), 79.6 (C-5), 78.2 (C-4), 75.8, 75.0, 74.9, 73.6, 69.6 (C-6), 61.9, 56.2,
+
5
5.3; HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa, 699.2604; found, 699.2583.
3
8
44
9
Phenyl 3,4,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (11a): Via general procedure B
starting from 4 (0.682g, 1.64 mmol) and thiophenol. Silica gel flash column chromatography (0% -
30% - Et O in toluene) afforded 11a (0.57 g, 1.05 mmol, 64%). TLC: (EtOAc/n-heptane, 30/70 v/v):
2
1
R = 0.38; H NMR (500 MHz, CDCl ) δ 7.56 – 7.53 (m, 2H), 7.52 – 7.48 (m, 2H), 7.39 – 7.17 (m,
f
3
1
6H), 5.70 (d, J = 5.5 Hz), 4.89 (d, J = 11.4 Hz, 2H), 4.75 (dd, J = 13.9, 11.7 Hz, 2H), 4.70 – 4.63 (m,
H), 4.59 - 4.56 (d, J = 7.0 Hz, 2H), 4.55 – 4.41 (m, 2H, H-1), 4.01 (t, J = 9.4 Hz, H-2), 3.98 (d, J = 2.7
Hz, H-4), 3.67 – 3.64 (m, 3H, H-6, H-5), 3.58 (dd, J = 9.4, 6.0 Hz, 1H, H-6), 3.47 (dd, J = 9.2, 2.8 Hz,
2
13
1
H-3). C{ H} NMR (126 MHz, CDCl ) δ 138.7, 138.4, 138.0, 137.9, 137.9, 137.8, 134.0, 132.6, 132.2, 132.0,
3
1
1
28.9, 128.8, 128.63, 128.58, 128.55, 128.45, 128.42, 128.3, 128.2, 128.02, 128.01, 127.93, 127.87, 127.84,
27.81, 127.79, 127.77, 127.74, 127.69, 127.57, 127.5, 127.3, 127.0, 88.5 (C-1), 83.2 (C-3), 77.6 (C-5), 74.8,
74.4, 73.6, 73.5, 73.2 (C-4), 72.4, 72.4, 69.1 (C-2), 68.7 (C-6); HRMS (ESI-TOF) (m/z): [M+Na]+
Calcd for C H O SNa, 565.2024; found, 565.2014.
3
3
34
5
4
-methoxyphenyl 3,4,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (12a): Via general
procedure B starting from 4 (530 mg, 1.28 mmol) and 4-methoxythiophenol. Silica gel flash
column chromatography (0% to 30% Et O in toluene) afforded 12a (0.19 g, 0.331 mmol, 26%).
2
1
TLC: (Et O/toluene, 20/80 v/v): R = 0.65; H NMR (500 MHz, CDCl ) δ 7.49 (d, J = 8.7 Hz, 2H),
2
f
3
7
.38 – 7.18 (m, 15H), 6.75 (d, J = 8.8 Hz, 2H), 4.87 (d, J = 11.5 Hz, 1H), 4.69 (dd, J = 11.9 Hz, 2H), 4.55
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(
(
3
d, J = 11.5 Hz, 1H), 4.46 (q, J = 11.7 Hz, 2H), 4.40 (d, J = 9.5 Hz, H-1), 3.95 (d, J = 2.6 Hz, H-4), 3.91
td, J = 9.4, 1.5 Hz, H-2), 3.74 (s, 3H), 3.69 – 3.58 (m, H-6a, H-6b, H-5), 3.45 (dd, J = 9.3, 2.7 Hz, H-
13
1
), 2.45 (d, J = 1.8 Hz, 1H); C{ H} NMR (126 MHz, CDCl ) δ 159.8, 138.7, 138.1, 137.9, 135.3, 128.54,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
128.45, 128.1, 127.92, 127.85, 127.83, 127.7, 127.6, 127.4, 122.2, 114.4, 88.9 (C-1), 83.2 (C-3), 77.6 (C-5),
+
7
4.3, 73.6, 73.3 (C-4), 72.4, 69.0 (C-2), 68.7 (C-6); HRMS (ESI-TOF) (m/z): [M+Na] Calcd for
C H O SNa, 595.2130; found, 595.2110.
3
4
36
6
2
,6-dimethoxyphenyl 3,4,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (13a): Via general
procedure B starting from 4 (0.838g, 2.01 mmol and 2,6-dimethoxythiophenol. Silica gel flash
column chromatography (0% - 30% Et O in toluene) afforded 13a (0.667 g, 1.11 mmol, 55%). TLC:
2
1
(
(
Et O/toluene, 20/80 v/v): R = 0.52; H NMR (500 MHz, CDCl ) δ 7.40 – 7.19 (m, 15H), 7.16 – 7.11
2
f
3
m, 2H), 6.59 (d, J = 8.4 Hz, 1H), 4.89 (d, J = 11.7 Hz, 1H), 4.83 (d, J = 12.2 Hz, 1H), 4.71 (d, J = 12.0
Hz, 1H), 4.49 (d, J = 11.7 Hz, 1H), 4.42 (dd, J = 11.7 Hz, 2H), 4.26 (d, J = 9.4 Hz, H-1), 3.90 – 3.69 (m,
13
1
3H, H-2, H-4), 3.65 – 3.50 (m, H-5, H-6a, H-6b), 3.45 (dd, J = 9.4, 2.8 Hz, H-3). C{ H} NMR (126
MHz, CDCl ) δ 162.0, 139.1, 138.7, 138.0, 131.3, 128.4, 128.3, 128.0, 127.9, 127.7, 127.53, 127.47, 127.3,
3
1
27.1, 104.7, 89.8 (C-1), 82.7 (C-3), 77.6 (C-5), 74.14 (C-4), 74.12, 73.5, 72.7, 70.5 (C-2), 68.5 (C-6),
+
5
6.5. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa, 625.2235; found, 625.2228.
3
5
38
7
2
,4,6-trimethoxyphenyl 3,4,6-tri-O-benzyl-1-thio-β-D-galactopyranoside (14a): Via general
procedure B starting from 4 (0.681g, 1.64 mmol and 2,4,6-trimethoxythiophenol. Silica gel flash
column chromatography (0% - 30% Et O in toluene) afforded 14a (0.61 g, 0.965 mmol, 59%). TLC:
2
1
(
EtOAc/n-heptane, 50/50 v/v): R = 0.44; H NMR (400 MHz, CDCl ) δ 7.40 - 7.10 (m, 15H), 6.16 (s,
f
3
2
H), 4.89 (d, J = 11.8 Hz, 1H), 4.84 (d, J = 12.2 Hz, 1H), 4.71 (d, J = 12.2 Hz, 1H), 4.44 (dt, J = 11.5 Hz,
3H), 4.17 (d, J = 9.3 Hz, H-1), 3.87 (d, J = 2.6 Hz, H-4), 3.82 (s, 3H), 3.81 (s, 6H), 3.76 - 3.51 (m, H-2),
13
1
3
.46 (dd, J = 9.5, 2.8 Hz, H-3, H-5, H-6a, H-6b). C{ H} NMR (126 MHz, CDCl ) δ 163.0, 162.8,
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
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1
62.3, 139.2, 138.7, 138.0, 128.39, 128.35, 128.0, 127.9, 127.7, 127.6, 127.5, 127.2, 127.0, 97.7, 91.6, 90.6,
8
9.9 (C-1), 82.7 (C-3), 77.5 (C-5), 74.2 (C-4), 74.1, 73.5, 72.8, 70.2 (C-2), 68.5 (C-6), 56.4, 56.0, 55.43,
+
5
5.41. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa 655.2341; found, 655.2327.
36 40
8
,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Phenyl 3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-galactopyranoside (11b): Via
general procedure C starting from 11a (0.541g, 0.998 mmol.) Silica gel flash column
chromatography (0% - 30% Et O in toluene) afforded 11b (0.117 g, 0.200 mmol, 20%). TLC:
2
1
(
(
Et O/toluene, 50/50 v/v): R = 0.61; H NMR (500 MHz, CDCl ) δ 7.55 – 7.51 (m, 5H), 7.36 – 7.13
2
f
3
m, 15H), 4.89 (d, J = 11.4 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 11.6 Hz, 1H), 4.57 (d, J = 11.5
Hz, 1H), 4.54 (d, J = 9.6 Hz, H-1), 4.45 (q, J = 11.7 Hz, 2H), 4.00 (d, J = 2.4 Hz, H-4), 3.86 – 3.80 (m,
13
1
2
H, H-2), 3.68 – 3.58 (m, 2H, H-5, H-6a, H-6b), 3.55 (dd, J = 9.3, 2.7 Hz, H-3). C{ H} NMR (126
MHz, CDCl ) δ 131.4, 129.1, 128.9, 128.6, 128.5, 128.2, 128.1, 128.0, 127.86, 127.84, 127.79, 127.6, 127.2,
3
1
25.3, 88.0 (C-1), 84.0 (C-3), 77.3 (C-5), 77.2 (C-2), 75.0, 74.5, 73.6, 72.9 (C-4), 72.2, 68.6 (C-6), 62.3,
+
60.4. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H O SNa, 609.2286; found, 609.2274.
3
5
38
6
4-methoxyphenyl
3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-galactopyranoside
(
12b): Via general procedure C from 12a (0.197 g, 0.344 mmol.) Silica gel flash column
chromatography (0% - 40% EtOAc in n-heptane) afforded 12b (0.142 g, 0.230 mmol 67%). TLC:
1
(
Et O/toluene, 50/50 v/v): R = 0.61; H NMR (500 MHz, CDCl ) δ 7.53 – 7.47 (m, 2H), 7.36 – 7.23
2
f
3
(m, 15H), 6.73 (d, J = 8.8 Hz, 2H), 4.87 (d, J = 11.5 Hz, 1H), 4.73 (d, J = 11.6 Hz, 1H), 4.62 (d, J = 11.6
Hz, 1H), 4.55 (d, J = 11.5 Hz, 1H), 4.49 – 4.40 (m, 2H, H-1), 3.98 (d, J = 2.4 Hz, H-4), 3.86 (t, J = 4.4
Hz, 2H), 3.74 (s, 3H, H-2), 3.65 (dd, J = 10.4, 5.6 Hz, 2H, H-6a, H-6b), 3.59 – 3.51 (m, H-3, H-5), 3.07
13
1
(
t, J = 6.2 Hz, 1H). C{ H} NMR (126 MHz, CDCl ) δ 159.6, 138.6, 137.8, 137.4, 134.6, 128.6, 128.4,
3
128.2, 128.0, 127.9, 127.84, 127.80, 127.73, 127.5, 123.4, 114.4, 88.6 (C-1), 84.0 (C-3), 77.22 (C-5), 77.17
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C-2), 75.0, 74.4, 73.6, 72.8 (C-4), 72.1, 68.6 (C-6), 62.3, 55.3. HRMS (ESI-TOF) (m/z): [M+Na]+
(
Calcd for C H O SNa, 639.2392; found, 639.2376.
3
6
40
7
2
,6-dimethoxyphenyl
3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
galactopyranoside (13b): Via general procedure C from 13a (0.657 g, 1.09 mmol). Silica gel flash
column chromatography (0% - 50% EtOAc in n-heptane) afforded 13b (0.465 g, 0.720 mmol,
1
6
6%). TLC: (EtOAc/n-heptane, 30/70 v/v): R = 0.35; H NMR (500 MHz, CDCl ) δ 7.35 (d, J = 4.6
f
3
Hz, 2H), 7.33 – 7.18 (m, 15H), 6.54 (d, J = 8.4 Hz, 1H), 4.88 (d, J = 11.6 Hz, 1H), 4.71 (d, J = 11.6 Hz,
H), 4.64 (d, J = 11.6 Hz, 1H), 4.56 (d, J = 11.5 Hz, 1H), 4.44 (d, J = 9.8 Hz, H-1), 4.37 (dd, J = 11.6 Hz,
2H), 4.06 (ddd, J = 11.1, 5.6, 2.3 Hz, 1H), 3.94 (ddd, J = 11.2, 6.3, 2.0 Hz, 1H), 3.91 (d, J = 2.2 Hz, H-4),
1
3
.82 (s, 3H), 3.79 – 3.73 (m, 1H, H-2), 3.71 – 3.64 (m, 1H), 3.62 – 3.53 (m, H-6a, H-6b), 3.49 (dd, J =
13
1
9
.2, 2.8 Hz, H-3), 3.44 (t, J = 6.3 Hz, H-5), 1.67 (s, 1H). C{ H} NMR (126 MHz, CDCl ) δ 161.0, 138.7,
3
1
37.98, 137.96, 130.2, 128.5, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6, 127.5, 109.3, 104.3, 88.9 (C-1), 84.7
(C-3), 78.3 (C-2), 77.5 (C-5), 75.1, 74.4, 73.5, 73.4 (C-4), 72.3, 69.1 (C-6), 61.8, 56.2. HRMS (ESI-
+
TOF) (m/z): [M+Na] Calcd for C H O SNa, 669.2498; found, 669.2484.
3
7
42
8
2
,4,6-trimethoxyphenyl
3,4,6-tri-O-benzyl-2-O-(2-hydroxyethyl)-1-thio-β-D-
galactopyranoside (14b): Via general procedure C starting from 14a (0.371 g, 0.586 mmol) Silica
gel flash column chromatography (0% - 20% EtOAc in toluene) afforded 14b (0.162 g, 0.240 mmol,
1
41%). TLC: (EtOAc/n-heptane, 30/70 v/v): R = 0.30; H NMR (400 MHz, CDCl ) δ 7.39 – 7.17 (m,
f
3
1
5H), 6.11 (s, 2H), 4.88 (d, J = 11.6 Hz, 1H), 4.68 (dd, J = 28.1, 11.6 Hz, 2H), 4.55 (d, J = 11.7 Hz, 1H),
.37 (q, J = 11.6 Hz, 2H), 4.30 (d, J = 9.8 Hz, H-1), 4.06 (ddd, J = 11.3, 5.3, 2.6 Hz, 1H), 3.99 – 3.87 (m,
H, H-4), 3.80 (m, 10H), 3.72 (t, J = 9.5 Hz, 1H, H-2), 3.63 – 3.51 (m, H-6a, H-6b), 3.48 (dd, J = 9.2,
4
1
13
1
2.8 Hz, H-3), 3.42 (t, J = 6.3 Hz, H-5). C{ H} NMR (126 MHz, CDCl ) δ 162.20, 162.15, 138.7, 138.03,
3
1
38.02, 128.5, 128.4, 128.2, 127.97, 127.95, 127.8, 127.7, 127.6, 127.5, 100.8, 91.2, 89.8 (C-1), 84.7 (C-3),
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2
2
2
2
2
2
2
2
3
3
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7
8.1 (C-2), 77.4 (C-5), 75.1, 74.4, 73.6, 73.4 (C-4), 72.3, 69.2 (C-6), 61.8, 56.2, 55.4. HRMS (ESI-TOF)
+
(
m/z): [M+Na] Calcd for C H O SNa, 699.2603; found, 699.2593.
3
8
44
9
2
,4,6-trimethoxyphenyl 3,4,6-Tri-O-(4-chlorobenzyl)-1-thio-β-D-glucopyranoside (15a): via
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
general procedure B starting from 2 (1.0 g, 1.9 mmol). The crude product was purified by silica gel
flash column chromatography (0% to 30% EtOAc in n-heptane) to afford 15a as white solid (0.84
1
g, 1.2 mmol, 61%). TLC (EtOAc/n-heptane 40/60 v/v): R = 0.52. H NMR (500 MHz, CDCl ) δ 7.28
f
3
–
4
7.19 (m, 8H), 7.12 (d, J = 8.4 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.11 (s, 2H), 4.99 (d, J = 11.4 Hz, 1H),
.75 – 4.62 (m, 2H), 4.50 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 11.3 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 4.18 (d,
J = 9.4 Hz, 1H, H-1), 3.85 (d, J = 2.0 Hz, 1H), 3.81 (s, 9H), 3.77 – 3.73 (m, 2H, H-6a, H-6b), 3.56 (t, J =
.7 Hz, 1H, H-3), 3.47 (t, J = 9.2 Hz, 1H, H-4), 3.42 (dt, J = 9.7, 2.5 Hz, 1H, H-5), 3.26 (td, J = 9.1, 2.0
8
13
1
Hz, 1H, H-2). C{ H} NMR (126 MHz, CDCl ) δ 163.1, 163.0, 137.3, 136.9, 136.7, 133.34, 133.26, 133.24,
3
1
29.2, 129.0, 128.9, 128.42, 128.39, 91.5, 88.4 (C-1), 85.4 (C-3), 79.9 (C-5), 76.7 (C-4), 74.2, 74.1, 73.2
+
(C-2), 72.9, 69.0 (C-6), 56.3, 55.4; HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H Cl O SNa,
3
6
37
3
8
757.1172; found, 757.1148.
2
,4,6-trimethoxyphenyl 3,4,6-tri-O-(2,4-dichlorobenzyl)-1-thio-β-D-glucopyranoside (16a):
via general procedure B starting from 3 (2.01 g, 3.22 mmol). The crude product was purified by
silica gel flash column chromatography (0% to 30% EtOAc in n-heptane) to afford 16a as white
1
solid (1.35 g, 1.61 mmol, 50%). TLC (EtOAc/n-heptane 40/60 v/v): R = 0.52. H NMR (500 MHz,
f
CDCl ) δ 7.41 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 2.0 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 7.25 – 7.23 (m, 2H),
3
7
.18 – 7.13 (m, 3H), 7.09 (dd, J = 8.3, 2.1 Hz, 1H), 6.12 (s, 2H), 5.08 (d, J = 12.8 Hz, 1H), 4.77 (m, 2H),
.58 (d, J = 12.8 Hz, 1H), 4.52 (d, J = 12.9 Hz, 1H), 4.46 (d, J = 12.8 Hz, 1H), 4.20 (d, J = 9.5 Hz, 1H, H-
1), 3.85 (d, J = 2.0 Hz, 1H), 3.81 (m, 11H, H-6a, H-6b), 3.62 (t, J = 8.7 Hz, 1H, H-3), 3.55 (dd, J = 9.7,
4
13
1
8
.7 Hz, 1H, H-4), 3.46 (dt, J = 9.7, 2.6 Hz, 1H, H-5), 3.27 (ddd, J = 9.5, 8.7, 2.0 Hz, 1H, H-2). C{ H}
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NMR (126 MHz, CDCl ) δ 163.2, 163.1, 135.2, 134.74, 134.73, 133.67, 133.63, 133.57, 133.4, 133.2, 133.0,
3
1
30.1, 130.0, 129.6, 128.93, 128.85, 127.0, 126.9, 96.1, 91.5, 88.4 (C-1), 85.7 (C-3), 79.4 (C-5) 76.7 (C-4),
+
7
3.2 (C-2), 71.2, 71.1, 70.0, 69.6 (C-6), 56.4, 55.4. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C H Cl O SNa, 859.0003; found, 858.9974.
3
6
34
6
8
2,4,6-trimethoxyphenyl 3,4,6-tri-O-(4-chlorobenzyl)-1-thio-β-D-galactopyranoside (17a):
Via general procedure B starting from 5 (0.97 g, 1.87 mmol) and 2,4,6-trimethoxythiophenol. Silica
gel flash column chromatography (0% - 20% - Et O in toluene) afforded 17a (0.85 g, 1.12 mmol,
2
1
6
0%). TLC: (Et O/toluene, 20/80 v/v): R = 0.39; H NMR (500 MHz, CDCl ) δ 7.36 – 6.98 (m,
2
f
3
12H), 6.17 (s, 2H), 4.82 (d, J = 11.9 Hz, 1H), 4.80 (d, J = 11.9 Hz, 1H), 4.69 – 4.63 (m, 1H), 4.44 (d, J =
1.9 Hz, 1H), 4.39 (d, J = 11.9 Hz, 1H), 4.34 (d, J = 11.9 Hz, 1H), 4.15 (d, J = 9.3 Hz, H-1), 3.86 – 3.78 (m,
1
9H, H-4), 3.73 – 3.65 (m, H-2), 3.61 – 3.49 (m, H-5, H-6a, H-6b), 3.43 (dd, J = 9.4, 2.8 Hz, H-3).
13
1
C{ H} NMR (126 MHz, CDCl ) δ 163.0, 162.9, 137.5, 137.2, 136.4, 133.6, 133.2, 132.7, 129.1, 128.8, 128.6,
3
128.5, 128.2, 128.1, 97.5, 91.5, 90.6, 89.8 (C-1), 82.6 (C-3), 77.2 (C-5), 74.4 (C-4), 73.2, 72.7, 72.1, 70.3
+
(
C-2), 68.3 (C-6), 56.4, 56.0, 55.4. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H Cl O SNa,
3
6
37
3
8
757.1172; found, 757.1148.
2
,4,6-trimethoxyphenyl
3,4,6-tri-O-(2,4-dichlorobenzyl)-1-thio-β-D-galactopyranoside
(
18a): Via general procedure B starting from 6 (1.05 g, 1.70 mmol and 2,4,6-trimethoxythiophenol.
Silica gel flash column chromatography (0% - 20% Et O in toluene) afforded 18a (0.71g, 0.851
2
1
mmol, 50%). TLC: (Et O/toluene, 20/80 v/v): R = 0.49; H NMR (500 MHz, CDCl ) δ 7.48 – 7.00
2
f
3
(
(
m, 9H), 6.19 (s, 2H), 4.92 (d, J = 13.3 Hz, 1H), 4.85 (d, J = 13.5 Hz, 1H), 4.75 (d, J = 13.4 Hz, 1H), 4.54
d, J = 12.7 Hz, 1H), 4.48 (d, J = 13.5 Hz, 1H), 4.44 (d, J = 12.7 Hz, 1H), 4.20 (d, J = 9.0 Hz, H-1), 3.96
(d, J = 2.5 Hz, H-4), 3.89 – 3.75 (m, 9H), 3.71 – 3.56 (m, H-2, H-5, H-6a, H-6b), 3.53 (dd, J = 9.2, 2.5
13
1
Hz, H-3). C{ H} NMR (126 MHz, CDCl ) δ 163.2, 162.9, 135.5, 135.0, 134.1, 134.0, 133.8, 133.6, 133.1,
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1
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2
2
2
2
2
2
2
2
3
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33.0, 132.0, 130.2, 129.8, 129.2, 129.0, 128.94, 128.85, 128.4, 128.2, 127.1, 126.8, 125.3, 97.1, 91.5, 89.5 (C-
), 82.9 (C-3), 76.8 (C-5), 74.8 (C-4), 70.6, 70.1 (C-2), 69.9, 69.7, 68.4 (C-6), 56.4, 55.4. HRMS (ESI-
+
TOF) (m/z): [M+Na] Calcd for C H Cl O SNa, 859.0003; found, 859.0024.
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8
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
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6
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8
9
0
2
,4,6-trimethoxyphenyl
3,4,6-tri-O-(4-chlorobenzyl)-2-O-(2-hydroxyethyl)-1-thio-β-D-
glucopyranoside (15b): via general procedure C starting from 15a (0.127 g ,0.172 mmol.) The
crude product was purified by silica gel flash column chromatography (20% to 60% EtOAc in n-
heptane) affording 15b as a white solid (0.11 g, 0.141 mmol, 82%). TLC (EtOAc/n-heptane 40/60
1
v/v): R = 0.24. H NMR (500 MHz, CDCl ) δ 7.31 – 7.19 (m, 9H), 7.18 – 7.13 (m, 2H), 7.05 (d, J = 8.4
f
3
Hz, 2H), 6.12 (s, 2H), 4.84 (d, J = 11.3 Hz, 1H), 4.75 (d, J = 11.3 Hz, 1H), 4.66 (d, J = 11.3 Hz, 1H), 4.49
d, J = 11.3 Hz, 1H), 4.45 (d, J = 11.9 Hz, 1H), 4.42 (d, J = 12.0 Hz, 1H), 4.39 (d, J = 9.9 Hz, 1H, H-1),
.01 (ddd, J = 10.7, 5.5, 2.5 Hz, 1H), 3.93 (ddd, J = 10.7, 6.8, 2.5 Hz, 1H), 3.82 (s, 6H), 3.80 (s, 3H),
.74 – 3.68 (m, 1H), 3.67 (dd, J = 11.4, 2.0 Hz, 1H, H-6a), 3.63 – 3.51 (m, 2H, H-3, H-6b), 3.45 (t, J =
(
4
3
13
1
9.4 Hz, 1H, H-4), 3.37 – 3.28 (m, 2H, H-2, H-5); C{ H} NMR (126 MHz, CDCl ) δ 162.4, 162.1, 136.8,
3
1
36.6, 136.3, 133.56, 133.54, 133.3, 129.1, 128.9, 128.6, 128.5, 128.4, 99.7, 91.2, 88.5 (C-1), 87.0 (C-4), 81.7
(
(
C-2), 79.4 (C-5), 78.1 (C-3), 74.8, 74.7, 74.0, 72.8, 69.4 (C-6), 61.8, 56.2, 55.3; HRMS (ESI-TOF)
+
m/z): [M+Na] Calcd for C H Cl O SNa, 801.1435; found, 801.1399.
3
8
41
3
9
2
,4,6-trimethoxyphenyl 3,4,6-tri-O-(2,4-dichlorobenzyl)-2-O-(2-hydroxyethyl)-1-thio-β-D-
glucopyranoside (16b): via general procedure C starting from 16a (0.593 g, 0.710 mmol.) The
crude product was purified by silica gel flash column chromatography (30% to 60% EtOAc in n-
heptane) affording 16b as a white solid (0.45 g, 0.511 mmol, 72%). TLC (EtOAc/n-heptane 40/60
1
v/v): R = 0.35. H NMR (500 MHz, CDCl ) δ 7.39 (d, J = 8.3 Hz, 1H), 7.33 (d, J = 2.1 Hz, 1H), 7.30 (d,
f
3
J = 8.3 Hz, 1H), 7.29 (d, J = 2.1 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.19 (dd, J = 8.3, 2.1 Hz, 1H), 7.18 –
7
.13 (m, 2H), 7.10 (dd, J = 8.3, 2.0 Hz, 1H), 6.12 (s, 2H), 4.92 (d, J = 13.1 Hz, 1H), 4.81 (d, J = 13.1 Hz,
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H), 4.71 (d, J = 12.7 Hz, 1H), 4.59 (d, J = 12.7 Hz, 1H), 4.54 (d, J = 13.0 Hz, 1H), 4.47 (d, J = 13.0 Hz,
H), 4.41 (d, J = 9.9 Hz, 1H, H-1), 4.01 – 3.87 (m, 2H), 3.83 (s, 6H), 3.80 (s, 3H), 3.79 – 3.67 (m, 5H,
H-6), 3.64 (t, J = 8.8 Hz, 1H, H-3), 3.55 (t, J = 9.4 Hz, 1H, H-4), 3.49 (s, 1H), 3.41 – 3.32 (m, 2H, H-2,
13
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
0
H-5); C{ H} NMR (126 MHz, CDCl ) δ 162.4, 162.1, 134.7, 134.6, 134.3, 133.9, 133.7, 133.4, 133.1, 132.7,
3
1
30.1, 129.7, 129.3, 129.0, 128.94, 128.92, 127.1, 127.00, 126.98, 99.7 , 91.2, 88.7 (C-1), 87.2 (C-3), 81.7 (C-
2
), 79.0 (C-5), 78.1 (C-4), 74.9, 71.7, 71.1, 70.0 (C-6), 61.9, 56.2, 55.4. HRMS (ESI-TOF) (m/z):
+
[
M+Na] Calcd for C H Cl O SNa, 903.0265; found, 903.0224.
38 38
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2
,4,6-trimethoxyphenyl
3,4,6-tri-O-(4-cyanobenzyl)-2-O-(2-hydroxyethyl)-1-thio-β-D-
t
t
glucopyranoside (19b): 15b (0.15 g, 0.2 mmol), BuXPhos-Pd-G3 (0.01 mmol, 5 mol%), BuXPhos
(
(
0.01 mmol, 5 mol%) and K [Fe(CN) ]·3H O (0.3 mmol) were added to a solution of 1,4-dioxane
4
6
2
1.3 mL) and 0.05 M KOAc in degassed water (1.3 mL) The mixture was vigorously at 100°C for 4h.
The reaction was cooled to rt and diluted with EtOAc (50 mL) and brine (50 mL). The aqueous
layer was further extracted with EtOAc (2 × 25 mL). The combined organic layers were dried
(
MgSO ), filtered and concentrated under reduced pressure. The residue was purified using silica
4
gel flash column chromatography (0-80% EtOAc in n-heptane to obtain the product 19b (0.16 g,
1
9
3%). TLC: (EtOAc/n-heptane, 60/40 v/v): R = 0.16. H NMR (500 MHz, CDCl ) δ 7.61 – 7.22 (m,
f
3
12H), 6.13 (s, 2H), 4.96 (d, J = 12.5 Hz, 1H), 4.79 (d, J = 12.5 Hz, 1H), 4.74 (d, J = 12.5 Hz, 1H), 4.62 (d,
J = 12.5 Hz, 1H), 4.53 (q, J = 12.8 Hz, 2H), 4.45 (d, J = 9.9 Hz, H-1), 3.96 (dd, J = 5.2, 2.7 Hz, 2H), 3.82
(
d, J = 6.5 Hz, 9H), 3.69 (m, 1H, H-6a, H-6b), 3.61 (t, J = 8.9 Hz, H-3), 3.51 (t, J = 9.4 Hz, H-4), 3.41 –
13
1
3
.33 (m, H-2, H-5). C{ H} NMR (126 MHz, CDCl ) δ 162.5, 162.1, 143.8, 143.4, 143.2, 132.3, 132.2,
3
132.1, 127.8, 127.5, 127.4, 118.7, 118.6, 118.5, 111.64, 111.61, 111.3, 99.4, 91.2, 88.3 (C-1), 87.2 (C-3), 81.9 (C-
2
), 79.3 (C-5), 78.3 (C-4), 74.9, 74.4, 73.7, 72.7, 69.7 (C-6), 61.9, 56.3, 55.4. δ HRMS (ESI-TOF)
+
(
m/z): [M+Na] Calcd for C H N O SNa, 774.2461; found, 774.2465.
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2
,4,6-trimethoxyphenyl
3,4,6-tri-O-(4-chlorobenzyl)-2-O-(2-hydroxyethyl)-1-thio-β-D-
galactopyranoside (17b): Via general procedure C starting from 17a (0.55g, 0.748 mmol). Silica
gel flash column chromatography (0% - 50% Et O in toluene) afforded 17b (0.51 g, 0.634 mmol,
2
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
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1
2
3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
85%). TLC: (Et O/toluene, 30/70 v/v): R = 0.21; H NMR (500 MHz, CDCl ) δ 7.35 – 7.09 (m, 12H),
2
f
3
6
.11 (s, 2H), 4.78 (d, J = 11.9 Hz, 1H), 4.63 (m, 2H), 4.48 (d, J = 11.9 Hz, 1H), 4.39 (d, J = 11.7 Hz, 1H),
.32 – 4.27 (m, 1H, H-1), 4.04 (ddd, J = 10.9, 5.6, 2.3 Hz, 1H), 3.96 – 3.89 (m, 1H), 3.81 – 3.72 (m, 10H,
4
13
1
H-4), 3.68 (t, J = 9.5 Hz, 1H), 3.60 – 3.51 (m, H-6a, H-6b), 3.49 – 3.39 (m, H-3, H-5). C{ H} NMR
(126 MHz, CDCl ) δ 162.3, 162.1, 137.0, 136.40, 136.39, 133.63, 133.58, 133.2, 129.2, 129.0, 128.8, 128.7,
3
1
28.5, 128.3, 100.5, 91.1, 89.8 (C-1), 84.6 (C-3), 78.2 (C-2), 77.2 (C-5), 75.1, 73.8 (C-4), 73.6, 72.7, 71.6,
+
6
9.0 (C-6), 61.8, 56.2, 55.4. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H Cl O SNa, 801.1434;
3
8
41
3
9
found, 801.1419.
2
,4,6-trimethoxyphenyl 3,4,6-tri-O-(2,4-dichlorobenzyl)-2-O-(2-hydroxyethyl)-1-thio-β-D-
galactopyranoside (18b): Via general procedure C starting from 18a (0.500 mg, 0.599 mmol).
Silica gel flash column chromatography (0% - 20% Et O in toluene) afforded 18b (0.39 g, 0.443
2
1
mmol, 74%). TLC: (Et O/toluene, 30/70 v/v): R = 0.37; H NMR (500 MHz, CDCl ) δ 7.48 – 7.10
2
f
3
(
m, 9), 6.13 (s, 2H), 4.91 (d, J = 13.2 Hz, 1H), 4.75 (m, 2H), 4.55 (d, J = 13.2 Hz, 1H), 4.51 (d, J = 12.6
Hz, 1H), 4.40 (d, J = 12.6 Hz, 1H), 4.33 (d, J = 9.8 Hz, H-1), 4.05 – 3.99 (m, 1H, H-4), 3.93 – 3.87 (m,
1
H), 3.86 – 3.75 (m, 10H), 3.76 – 3.64 (m, 1H, H-6a, H-2), 3.61 (dd, J = 9.3, 5.5 Hz, H-6b), 3.58 – 3.50
13
1
(
m, H-3, H-5). C{ H} NMR (126 MHz, CDCl ) δ 162.4, 162.2, 135.0, 134.2, 134.1, 134.0, 133.9, 133.4,
3
1
33.2, 132.4, 130.4, 129.76, 129.75, 129.2, 129.1, 129.0, 128.6, 128.2, 127.3, 127.01, 127.00, 125.3, 100.3, 91.1,
90.0 (C-1), 84.9 (C-3), 78.2 (C-2), 76.7 (C-5), 75.2, 74.60(C-4), 71.1, 70.0, 69.1, 68.9 (C-6), 61.8, 56.2,
+
5
5.4. HRMS (ESI-TOF) (m/z): [M+Na] Calcd for C H Cl O SNa, 903.0265; found, 903.0303.
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,4,6-trimethoxyphenyl
3,4,6-tri-O-(4-cyanobenzyl)-
2-O-(2-hydroxyethyl)-1-thio-β-D-
t
galactopyranoside (20b): 17b (0.178 mg, 0.222 mmol), BuXPhos-Pd-G3 (0.01 mmol, 5 mol%),
t
BuXPhos (0.01 mmol, 5 mol%) and K [Fe(CN) ]·3H O (0.3 mmol) were added to a solution of
4
6
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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4
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5
5
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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9
0
dioxane (1.3 mL) and 0.05 M KOAc in degassed water (1.3 mL) The mixture was vigorously at
00°C for 4h. The reaction was cooled to rt and diluted with EtOAc (50 mL) and brine (50 mL).
The aqueous layer was further extracted with EtOAc (2 × 25 mL). The combined organic layers
1
were dried (MgSO ), filtered and concentrated under reduced pressure. The residue was purified
4
using silica gel flash column chromatography (0 - 100% EtOAc in n-heptane to obtain the product
1
2
0b (0.16 g, 0.207 mmol, 93%). TLC: (EtOAc/n-heptane, 60/40 v/v): R = 0.08. H NMR (500 MHz,
f
CDCl ) δ 7.67 – 7.24 (m, 12H), 6.13 (s, 1H), 4.92 (d, J = 12.7 Hz, 1H), 4.79 (s, 2H), 4.57 (d, J = 12.7 Hz,
3
1
H), 4.50 (d, J = 12.7 Hz, 1H), 4.42 (d, J = 12.7 Hz, 1H), 4.35 (d, J = 9.8 Hz, H-1), 4.03 (ddd, J = 10.7,
5.5, 2.3 Hz, 1H), 3.97 – 3.90 (m, 1H, H-4), 3.82 (m, 10H), 3.75 – 3.58 (m, 1H, H-2, H-6a, H-6b), 3.55 –
13
1
3
.48 (m, H-3, H-5). C{ H} NMR (126 MHz, CDCl ) δ 162.4, 162.2, 143.8, 143.3, 143.2, 132.4, 132.2,
3
1
32.1, 127.8, 127.5, 127.4, 118.7, 118.60, 118.55, 111.7, 111.6, 111.3, 100.1, 91.2, 89.7 (C-1), 84.7 (C-3), 78.4 (C-
2), 76.9 (C-5), 75.3, 74.8 (C-4), 73.7, 72.5, 71.6, 69.3 (C-6), 61.8, 56.2, 55.4. HRMS (ESI-TOF) (m/z):
+
[M+Na] Calcd for C H N O SNa, 774.2461; found, 774.2448.
4
1
41
3
9
Methyl 3,4,6-tribenzyl-2-O-(2-benzenethioethyl)-α/β-D-glucopyranosyl-(1→6)- 2,3,4-O-
tribenzoyl-α-D-glucopyranoside (22): Via general procedure E and donor 7b (53 mg, 0.090
mmol Silica gel flash column chromatography (0% → 40% - EtOAc in n-heptane) afforded 22 as
1
an anomeric mixture (69 mg, 0.064 mmol, 71%). TLC: (EtOAc/n-heptane, 40/60 v/v): R = 0.5; H
f
NMR (500 MHz, CDCl ) δ 7.98 (d, J = 7.8 Hz, 2H), 7.93 (d, J = 7.8 Hz, 2H), 7.85 (d, J = 7.8 Hz, 2H),
3
7.55 – 7.44 (m, 2H), 7.44 – 7.17 (m, 24H), 7.17 – 7.05 (m, 3H), 6.14 (t, J = 9.9 Hz, 1H, (H-3')), 5.53 (t, J
=
9.9 Hz, 1H, (H-4')), 5.25 (dd, J = 10.3, 3.7 Hz, 1H, (H-2')), 5.18 (d, J = 3.7 Hz, 1H, (H-1')), 4.92 (d, J =
3
.5 Hz, 1H, (H-1)), 4.87 (d, J = 11.0 Hz, 1H), 4.80 (d, J = 11.1 Hz, 1H), 4.73 (d, J = 11.0 Hz, 1H), 4.55 (d, J
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