Conformationally Switchable Glycosyl Donors

Article abstract of DOI:10.1021/acs.joc.9b00830

Glycosyl donors functionalized with 2,2′-bipyridine moieties on the 3-OH and 6-OH or the 2-OH and 4-OH undergo a conformational change when forming 1:1 complexes with Zn²⁺ ions. The pyranoside ring of the zinc complexes adopted axial-rich skew boat conformations. The reactivities of the two glycosyl donors were investigated by performing a series of glycosylations in the presence or absence of Zn²⁺ ions. These glycosylations suggested a decrease in reactivity when binding Zn²⁺. The conformational effect of binding Zn²⁺ was therefore studied using a third glycosyl donor, unable to undergo conformational changes when binding Zn²⁺. From competition experiments, it was observed that the binding-induced conformational change increased the reactivity slightly compared to the glycosyl donor unable to undergo a conformational change.

Full text of DOI:10.1021/acs.joc.9b00830

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Article
Conformationally Switchable Glycosyl Donors
Thomas Holmstrøm, and Christian Marcus Pedersen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00830 • Publication Date (Web): 04 Oct 2019
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The Journal of Organic Chemistry
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Conformationally Switchable Glycosyl Donors
Thomas Holmstrøm and Christian Marcus Pedersen*
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Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen, Denmark
Supporting Information Placeholder
Conformational switch
Reactivity?
Zn
Zn
O
O
O
ROH
Activator
O
Metal ion
O
SPh
BnO
BnO
SPh
OBn
O
O
O
OR
O
OBn
Ring flip
Glycosylation
OBn OBn
ABSTRACT: Glycosyl donors functionalized with 2,2’-bipyridine moieties on the 3-OH and 6-OH or the 2-OH and 4-OH
undergoes a conformational change forming 1:1 complexes with Zn2+ ions. The pyranoside ring of the zinc complexes adopted
axial-rich skew boat conformations. The reactivities of the two glycosyl donors were investigated by performing a series of
glycosylations in the presence or absence of Zn2+ ions. These glycosylations suggested a decrease in reactivity when binding
Zn2+. The conformational effect of binding Zn2+ was therefore studied using a third glycosyl donor, unable to undergo
conformational changes when binding Zn2+. From competition experiments, it was observed that the binding-induced
conformational change increased the reactivity slightly compared to the glycosyl donor unable to undergo a conformational
change.
these systems are based on chelation of metal ions in order
INTRODUCTION
to induce a conformational change e.g. by crown ether
moieties.13 Zn2+ ions have a strong chelation with 2,2’-
bipyridine groups and this has been used for molecular
machines, sensors and ion exchangers.14 We therefore
proposed that a glycosyl donor protected with two 2,2’-
bipyridine groups, would possess the same features as a
conformational switch.
In recent years, it has been recognized that the reactivity
of glycosyl donors is dependent on the conformation of the
pyranoside ring.1,2 Glycosyl donors in an axial-rich
conformation show a higher reactivity compared to their
equatorial-rich counterparts. This is often explained by that
the axial polar groups appears less electron withdrawing
compared to equatorial groups and hence destabilize the
formation of positive charge on the anomeric position to a
lower degree. These effects are possibly due to charge-
dipole interactions.3 The influence of protective groups on
the reactivity of glycosyl donors was first described by
Paulsen, and conceptualized by Fraser-Reid with the
introduction of the armed-disarmed concept.4 Fraser-Reid
also realized that conformational restriction reduced the
reactivity and termed this torsional disarming.5 Later, Bols
demonstrated that stereoelectronics plays a role.6 Based on
2
OTf
2
OTf
BnO
OBn
O
N
N
SPh
Zn2+
O
N
N
O
N
O
Zn2+
O
N
O
N
SPh
N
OBn
OBn
1 Zn
•
2 Zn
•
the above observations, super armed glycosyl donors were
Figure 1. Proposed structure of Zn2+ complex 1•Zn and 2•Zn.
2,7
introduced.
Equatorial hydroxyl groups are protected
with bulky silyl protective groups, inducing a ring-flip,
which increases the reactivity by 3 orders of magnitude.8
Similar increase in reactivity is also achievable by other
means e.g. 3,6-O-tethering9,10 and molecular levers.11 In this
work, a molecular conformational switch, which can induce
a ring-flip, is presented. Conformational switches are
molecules that can reversibly change between two or more
conformational states under external influence.12 Many of
Chelation would induce
a pseudo-locking of the
pyranoside in an axial-rich conformation. Carbohydrates
complexing metal ions can exist in axial-rich
conformations.15 However, the anomeric reactivity of such
systems has to our knowledge never been investigated.
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Glucopyranosides are ideal model compounds, as all the
Page 2 of 12
1
secondary alcohols
2
3
Scheme 1. Synthesis of Glycosyl Donor 1 and 2.
4
5
6
7
8
9
1) BnBr, NaH
DMF, 24h
2) p-TsOH (cat.)
MeOH, 2h, 65°C
N
OTBS
OH
O
O
N
3
N
, NaH
O
HO
BnO
HO
SPh
SPh
O
TBSO
BnO
SPh
OH
OBn
4 (
DMF
24h, rt
N
O
OBn
5
(65%)
92%)
1
(77%)
1) PhSH, BF3•OEt2
CH2Cl2
TBSCl, Imidazole
DMF, 20h, rt
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2) NaOMe
Amberlite IR120
MeOH
OAc
O
OH
O
AcO
AcO
HO
HO
OAc
SPh
OAc
10
OH
(90%)
8
TMSCl
OBn
O
Pyridine, 24h, rt
OTMS
PhCHO
FeCl3•6H2O 10 mol%,
Et3SiH
O
SPh
OBn
O
N
BnO
N
O
3
, NaH
O
TMSO
TMSO
HO
BnO
SPh
OTMS
SPh
N
N
DMF
24h, rt
N
N
OH
CH2Cl2/MeCN (4:1)
24h, rt
Cl
3
2
(79%)
7
6
(99%)
(50%)
resides trans to each other and the change from the all
equatorial to an axial rich conformation will therefore give
the maximal increase in reactivity. Two bipyridine
functionalized glycosyl donors 1 and 2 were therefore
synthesized (Figure 1). The donors would either form
complexes on the top or the bottom face of the pyranoside
ring.
strong binding and 1:1 stoichiometry. Interestingly, a
species was formed during the titration and then consumed
again around 0.3-0.5 equiv. of added guest. Coupling
constants suggested a 4C1 conformation and diffusion
ordered spectroscopy revealed that this species was larger
than the 1:1 complex and hence suggested a 12∙Zn complex
(2:1 stoichiometry). Formation of a 2:1 complex was not
1
observed in the H-NMR titration of 2 with zinc(II) triflate.
A UV-Vis titration of both glycosyl donors revealed a
square-binding isotherm indicative of the complex being
too stable (Kf > 108 M-1) for a binding constant to be
determined by a direct titration (Figure S12, S13).
RESULTS AND DISCUSSION
The synthesis of the two glycosyl donors 1 and 2 is shown
in Scheme 1. The 3,6-regioisomer 1 was achieved by a
regioselective silylation of thioglycoside 8 to afford the 3,6-
2
OTf
di-O-TBS protected thioglycoside
5 followed by a
N
N
benzylation and a desilylation to give the 2,4-di-O-benzyl
N
Zn2+
protected thioglycoside 4.10 Alkylating thioglycoside 4 with
N
N
O
N
N
Zn(OTf)2
2,2’-bipyridine derivative
3
afforded the 3,6-di-O-
O
O
O
BnO
SPh
bipyridine functionalized glycosyl donor 1.16 The 2,4-
regioisomer 2 was prepared by a regioselective 3,6-di-O-
benzylation of thioglycoside 7, followed by an alkylation
with 3.17 NMR spectroscopy revealed that the two glycosyl
donors existed in a 4C1 conformation.
N
O
O
MeCN-d3
OBn
SPh
OBn
OBn
1
1 Zn
•
H5
H3
H1
H6
H6 H4
H2
2.0
1.0
0.7
The metal binding ability of 1 and 2 were investigated
using 1H-NMR spectroscopy. Each glycosyl donor was
0.5
0.3
0.2
0.1
0.0
1
dissolved in acetonitrile-d3 and an H-NMR spectrum was
recorded to confirm the 4C1 conformation before 1.0 equiv.
of zinc(II) triflate was added. The 1H-NMR spectrum
underwent significant changes (Figure S1, S6) and in both
cases, all the signals arising from 1 or 2 had changed into
new signals. Using COSY and HSQC, 1∙Zn and 2∙Zn could be
fully assigned and the conformation of the zinc complexes
equiv.
5.7 5.5 5.3 5.1 4.9 4.7 4.5 4.3 4.1 3.9 3.7 3.5 3.3 3.1 2.9 2.7 2.5
ppm
1
determined based on the J-couplings observed in the H-
Figure 2. Titration of glycosyl donor 1 with zinc(II) triflate.
NMR spectra (Table S1, S2). Both had adopted an axial-rich
skew boat conformation, confirming that an intramolecular
zinc(II) complex had formed between the two bipyridine
Having established an understanding of the non-covalent
interactions between the two glycosyl donors and Zn2+ ions,
their glycosylation properties were studied. Initial
screening of glycosylation conditions revealed that
1
moieties (Figure 2). An H-NMR titration of 1 with zinc(II)
triflate revealed that exactly 1.0 equiv. of Zn2+ ions was
enough to saturate the binding sites, indicating a very
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Brønsted acid dependent promotor systems were quenched thereby give rise to high β-selectivity. The decrease of β-
1
2
3
4
5
6
7
8
by the pyridines and therefore not suitable for activation. It
has previously been shown that thioglycosides with
pyridine protective groups can be activated using DMTST.18-
selectivity of glycosyl donor 1∙Zn can be explained by the
2,2’-bipyridine groups being occupied by the complexing of
Zn2+ and therefore not able to mediate the delivery of the
acceptor. During the activation of the thioglycoside, a
stochiometric amount of protic acid is generated. Therefore,
two glycosylations were performed in the presence of an
acid scavenger (Table 1, Entry 3-4). A small decrease of -
selectivity was observed using glycosyl donor 1∙Zn in the
presence of 2,6-di-tert-butyl-4-methylpyridine (Table 1,
Entry 4). This could be explained by the generated protic
acid protonating the bipyridines, displacing Zn2+, thereby
allowing the bipyridine groups to deliver the acceptor from
the top face of the pyranoside ring when no acid scavenger
is present. The observed -selectivity can also be due the
influence of acetonitrile, which is known to increase
equatorial selectivity in glycosylations.22
21
A solvent mixture of acetonitrile and dichloromethane
(2:1) was chosen as the binding studies had shown, that the
metal complex, as well as the glycosyl donor, were soluble
in this mixture. Additionally, it was found that an aqueous
work up was sufficient for the displacement of Zn2+ ions
with a quantitative recovery of the glycosyl donors. Using
9
glycosyl donor
1 it was possible to perform the
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glycosylations both in the presence and the absence of
zinc(II) triflate. The outcome of the glycosylations are
presented in Table 1. Comparing the glycosylations of the
complexes with the glycosyl donors alone, there is no
remarkable difference between the two (Table 1, Entry 1-
2). In some cases, the zinc complex demanded longer
reaction times. Interestingly, glycosyl donor 1 showed a
difference in α/β-selectivity in the presence of Zn2+ ions
when using acceptor 12 and 13 (Table 1, Entry 5-8).
Glycosylations with 2 and 2∙Zn resulted in poor yields
and dark blue reaction mixtures (Table 1, Entry 9-10). TLC
analysis showed formation of highly polar byproducts upon
treatment with DMTST, even in the absence of an acceptor.
2-O-Picolylated glycosyl donors have been found to form
stable pyridinium ions upon anomeric activation.23 In order
to investigate this, 2 was fully converted with DMTST and
subsequent analyzed using NMR spectroscopy. This
revealed two doublets at 6.9 ppm and 6.3 ppm with
different coupling constants indicating that an anomeric
mixture of intermediate 14 had formed. The structure of
intermediate 14 was supported by cross-peaks observed in
the HMBC spectrum, showing a coupling between H1 of the
α- and β-anomers and two ipso-carbons on the 2,2’-
bipyridine group (Figure 3). The intermediate 14 was found
to be very stable and hence did not react with methanol,
explaining the low yields obtained in glycosylations with 2
(Table 1, Entry 6 and 7). A high β-selectivity was
nevertheless observed, which suggest that the α-pyridinium
salt is more reactive and shields the α-face or that the
acceptor competes with the pyridines to react on the
activated anomeric position, which seems a more likely
explanation as the pyridinium salt were found to be very
stable towards nucleophilic substitution.
Table 1. Glycosylations Using Glycosyl Donor 1 and 2.
DMTST (2 equiv.)
OR2
O
OR2
O
Acceptor
R1O
R2O
R1O
R2O
SPh
OR
MeCN/CH2Cl2 (2:1)
OR1
OR1
19-22
-30C rt
R1 = Bn, R2 = bipy
R1 = bipy, R2 = Bn
1
2
Acceptors:
HO
OH
O
O
BnO
BnO
HO
BnO
OMe
11
12
13
Entry
Donor
Acceptor
Metal
Time
Product
(%)
α:βb
-
1
2
3a
4a
5
1
1
1
1
1
1
1
1
2
11
11
11
11
12
12
13
13
13
3 h
5 h
3 h
5 h
4 h
3 h
3 h
3 h
3 h
19 (73)
19 (66)
19 (70)
19 (59)
20 (59)
20 (40)
21 (58)
21 (28)
22
1:2.0
1:1.8
1:2.6
1:1.3
1:3.0
1:1.5
β only
1:1.8
-
Zn2+
-
Zn2+
-
6
Zn2+
7
-
8
Zn2+
-
9
(traces)
22 (10)
β only
10
2
13
Zn2+
5 h
a
Performed in the presence of 2,6-di-tert-butyl-4-
methylpyridine (2.1 equiv.) as acid scavenger. b Determined by
integration of anomeric protons in 1H-NMR.
Performing the glycosylation in the absence of a metal
gave complete β-selectivity or a preference for the β-
anomer, while the glycosylation performed in the presence
of a metal resulted in lower selectivity. This is in accordance
with the work on remote directing groups done by
Demchenko et al.18-20 The pyridine attached to the 6-OH or
the 3-OH of a glucopyranoside can direct the acceptor and
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PhCH(OMe)2
Cu(OTf)2
OH
HMBC
O
Ph
O
H
N
1
2
3
4
5
6
7
8
N
O
O
HO
O
SPh
SPh
N
HMBC
HO
HO
MeCN
2h, sonication
O
OH
OH
15
(65%)
O
OTf
8
N
OTf
H
1) BnBr, NaH
2) 10-CSA
O
14
14


N
N
OH
O
N
N
O
HO
BnO
O
3
, NaH
SPh
O
BnO
SPh


OBn
OBn
DMF
24h
145
150
155
160
165
18
17
(50% 2 steps)
(43%)
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Zn(OTf)2
MeCN-d3
In solution
BnO
2 OTf
PhS
OBn
O
O
N
O
8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2
ppm
N
Zn2+
N
N
N
N
N
Figure 3. HMBC spectrum of intermediate 14.
O
N
O
BnO
O
(66' isomer)
182•Zn
SPh
OBn
Overall, the glycosylations listed in Table 1 indicated that
the binding of Zn2+ ions decreased the reactivity of the
glycosyl donors. In order to further elucidate the effects of
conformation in the glycosylation reactions, a glycosyl
donor that could complex Zn2+ ions without changing
conformation was desired for comparison with glycosyl
+ 4 4' isomer

With glycosyl donor 18 in hand, it was possible to
compare its reactivity to glycosyl donor 1. Both complex
Zn2+ ions, but only glycosyl donor
1 undergoes a
donor 1. It was proposed that
a glycosyl donor
conformational change upon complexation. A competition
experiment between the two was therefore used to
investigate the influence of conformation on reactivity. Due
to overlapping 1H-NMR spectra, 13C-NMR was used to
quantify the relative reactivity of the glycosyl donors.25 An
equimolar amount of the two glycosyl donors were
functionalized with 2,2’-bipyridine groups on the 4-OH and
6-OH would bind Zn2+ ions without undergoing a significant
conformational change. The synthesis was straight forward
starting with a regioselective 4,6-O-benzylidene protection
of thioglycoside 8 followed by benzylation of the remaining
2-OH and 3-OH.24 Acidic debenzylidenation followed by
alkylation with bipyridine derivative 3 to afford the 4,6-
bipyridine functionalized glycosyl donor 18 (Scheme 2).
Complexation studies showed that this glycosyl donor could
form two different complexes with almost identical
diffusion coefficients upon addition of 0.5 equivalents of
zinc(II) triflate indicative of the formation of two different
2:1 complexes. The stoichiometry of the complexes did not
change upon addition of an excess amount of zinc(II)
triflate. Analysis of the 1H-NMR spectrum of the two
complexes revealed that both pyranosides adopted 4C1
conformations (Table S3). Due to the high symmetry of the
complexes, two structure where the zinc complex is
comprised of the 6-O-bipyridine group of two different
glycosyl donors (6→6' isomer) or comprised of the 4-O-
bipyridine group of two different glycosyl donors (4→4’
isomer) were suggested (Scheme 2).
dissolved in chloroform-d and
a
13C-NMR spectrum
recorded in order to determine the ratio between the two
glycosyl donors (se SI for details). After removal of
chloroform-d, the glycosyl donors were subjected to the
glycosylation conditions using 0.5 equivalents of DMTST
compared to the total amount of glycosyl donor in the
presence of 2-methoxyethanol as acceptor. The glycosyl
donors were allowed to react for 2 hours before quenching
and aqueous work up. By comparing the integrals of the
signals arising from the unreacted starting material in the
crude 13C-NMR, it was possible to determine, which was the
most reactive glycosyl donor. Table 2 shows the measured
integrals of C4 of the two glycosyl donors before and after
the reaction in the presence and absence of Zn2+ ions.
Table 2. Competition Experiment Between Glycosyl
Donor 1 and 18.
Scheme 2. Synthesis of Glycosyl Donor 18 and suggested
structure of 182•Zn.
Obipy
O
Obipy
O
O
O
BnO
BnO
SPh
O
bipyO
bipyO
O
HO
OBn
(1 equiv.)
OBn
(5 equiv.)
1
DMTST (1 equiv.)
Obipy
O
Obipy
O
MeCN/CH2Cl2 2:1
(Zn(OTf)2)
bipyO
¨BnO
bipyO
¨BnO
SPh
O
OBn
(1 equiv.)
OBn
18
Entry
13C-NMR
spectrum
Metal
Integral
(1)
Integral
(18)
Reactivity
ratioa
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1
2
3
4
Before
After
-
1.0
1.0
1.0
1.0
0.94
0.92
0.89
1.31
Sodium hydride was used as a 60 % dispersion in mineral
1
oil. H-NMR and 13C{1H}-NMR spectra were recorded on a
1
2
3
4
5
6
7
1:1
-
Bruker 500 MHz Ultra Shield Plus spectrograph equipped
Before
After
Zn2+
Zn2+
1
with a cryoprobe. H-NMR spectra were recorded at 500
1:1.5
MHz and 13C-NMR spectra were recorded at 126 MHz.
Chemical shifts were referenced to the residual signals of
the deuterated solvents (CDCl3: 1H: 7.26 ppm, 13C: 77.16
ppm), (DMSO-d6: 1H: 2.50 ppm, 13C: 39.52 ppm) and
(Acetonitrile-d3: 1H: 1.94 ppm, 13C: 1.32 ppm). Coupling
constants are given in Hertz (Hz). High-resolution mass
spectrometry (HRMS) was performed on a Bruker SolariX
XR 7T ESI/MALDI-FT-ICR-MS instrument using matrix-
assisted laser desorption ionization (MALDI) with dithranol
as the matrix. All melting points are uncorrected.
a Reactivity ratio = (donor 1)/(donor 18), ratio refers to the
ratio of unreacted donors after glycosylation.
8
9
The competition experiment would suggest that glycosyl
donor 1 and 18 had the same reactivity in the absence of
Zn2+ ions (a reactivity ratio of 1:1, Table 2, Entry 1-2).
However, in the presence of Zn2+ ions, glycosyl donor 1 was
consumed faster, indicating a higher reactivity compared to
glycosyl donor 18 (reactivity ratio: 1:1.5, Table 2, Entry 3-
4). The increased reactivity of glycosyl donor 1 in the
presence of Zn2+ ions presumably arise from the pyranoside
ring taking a more reactive, axial rich conformation. The
change in reactivity could also be explained by the fact that
glycosyl donor 18 forms 2:1 with Zn2+ ions, thus appearing
in an effectively lower concentration.
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Phenyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-glucopyranoside
(9) To a cooled solution of 1,2,3,4,6-penta-O-acetyl- β -D-
glucopyranose 1 (10.00 g, 25.62 mmol) and thiophenol (4.0
mL, 4.3 g, 39 mmol, 1.5 equiv.) in CH2Cl2 was slowly added
BF3 ·OEt2 (5.0 mL, 5.7 g, 40 mmol, 1.5 equiv.). The reaction
mixture was stirred for 20 h at rt after which Et3N (5 mL)
was added. The resulting mixture was concentrated in
vacuo and subjected to flash column chromatography (SiO2,
1:5 to 1:1 EtOAc/PhMe) to afford 9 (10.16 g, 23.07 mmol,
90 %) as a white solid. HRMS (MALDI/FT-ICR): m/z:
[M+Na]+ Calc. for C20H24O9SNa+ 463.1033; Found 463.1034.
1H-NMR (CDCl3, 500 MHz) δ: 7.51-7.48 (m, 2H), 7.34-7.30
(m, 3H), 5.22 (t, J = 9.3 Hz, 1H, H3), 5.04 (t, J = 9.3 Hz, 1H,
H4), 4.98 (dd, J = 9.3, 10.0 Hz, 1H, H2), 4.71 (d, J = 10.0 Hz,
1H, H1), 4.22 (dd, J = 12.3, 5.1 Hz, 1H, H6), 4.18 (dd, J = 12.3,
2.6 Hz, 1H, H6), 3.73 (ddd, J = 10.0, 5.1, 2.6 Hz, 1H, H5), 2.09
(s, 1H), 2.08 (s, 1H), 2.02 (s, 1H), 1.99 (s, 1H) ppm. 13C{1H}-
NMR (CDCl3, 126 MHz) δ: 170.7, 170.3, 169.5, 169.4, 133.3,
131.8, 129.1, 128.6, 85.9, 76.0, 74.1, 70.1, 68.4, 62.3, 20.9,
20.9, 20.8. 20.7 ppm.
CONCLUSION
In conclusion, three new Zn2+ complexing glycosyl donors
have been synthesized and their metal binding ability
investigated by NMR spectroscopy. All glycosyl donors
exhibited strong complexation with the metal ions and 1
and 2 worked as conformational switches, which can be
turned on by metal ions and turned off by washing with
water. In glycosylation reactions the reactivity gained by a
conformational flip was lost upon chelating the metal ion. β-
Selectivity was observed in the absence of a metal ions,
suggesting that the bipyridine groups participate in
directing the acceptor to approach from the top face of the
pyranoside ring. Glycosyl donor 2, gave low yields in
glycosylations due to formation of
a
unreactive
intermediate 14. A competition between glycosyl donor 1
and a model glycosyl donor 18, a regioisomer that cannot
undergo a conformational flip upon complexing Zn2+,
showed that the reactivity of glycosyl donor 1 could be
altered by the addition of metal ions.
Phenyl 1-thio-β-D-glucopyranoside (8) To a suspension of
9 (9.60 g, 21.8 mmol) in MeOH was added sodium metal
(180 mg). The reaction mixture was stirred for 1 h at rt after
which it was neutralized with AmberliteTM IR120, filtered
and concentrated in vacuo to afford 8 (5.98 g, 100 %) as a
1
white solid. H-NMR (DMSO-d6, 500 MHz) δ: 7.47-7.44 (m,
EXPERIMENTAL SECTION
2H), 7.32-7.28 (m, 2H), 7.24-7.19 (m, 1H), 5.28 (s, 1H), 5.1
(s, 1H), 4.98 (s, 1H), 4.60 (d, J = 9.8 Hz, 1H, H1), 4.55 (s, 1H),
3.68 (d, J = 11.6 Hz, 1H, H6), 3.46-3.42 (m, 1H, H6), 3.23-3.16
(m, 2H, H5, H3), 3.11-3.02 (m, 2H, H2, H4) ppm. 13C{1H}-
NMR (DMSO-d6, 126 MHz) δ : 135.0, 129.5, 128.8, 126.3,
87.1, 81.0, 78.1, 72.4, 69.8, 61.0 ppm.
General information. Chemicals have been applied directly
without further purification prior to use. Dry solvents were
collected from an Innovative Technology PS-MD-05 solvent
drying system. Air and water sensitive reactions were
carried out under an inert atmosphere of nitrogen.
Purification by flash column chromatography was carried
out using silica gel (40-63 μ m) or aluminum oxide
(activated, neutral, Brockmann Activity I). Thin layer
chromatography (TLC) was carried out using aluminum
sheets coated with silica gel (60F) or plastic sheets coated
with aluminum oxide. TLC plates were visualized with UV-
light before being stained with a 10 % solution of H2SO4 in
ethanol. TLC plates were deactivated by pretreating the
plates with a solution of 5% Et3N in heptane. Concentration
on samples under reduced pressure was done at 40 °C.
Phenyl 3,6-di-O-TBS-1-thio-β-D-glucopyranoside (5)
Prepared from a literature procedure.10 To a cooled solution
of 8 (6.18 g, 22.7 mmol) and imidazole (5.41 g, 79.4 mmol,
3.5 equiv.) in dry DMF (50 mL) was added TBSCl (10.26 g,
68.01 mmol, 3 equiv.). The resulting mixture was allowed to
reach rt and stirred for 24 h after which MeOH (10 mL) was
added. The mixture was transferred to EtOAc and washed
with 1 M HCl, satd. bicarbonate and brine. The organic layer
was dried with MgSO4, concentrated in vacuo and subjected
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The Journal of Organic Chemistry
to flash column chromatography (SiO2, 1:9 to 3:7
Page 6 of 12
(t, J = 7.7 Hz, 1H), 7.29 (ddd, J = 7.4, 4.8, 1.2 Hz, 1H), 7.17 (d,
J = 7.6 Hz, 1H), 2.64 s, 3H, CH3) ppm. 13C{1H}-NMR (CDCl3,
126 MHz) δ: 158.1, 156.7, 155.8, 149.3, 137.2, 137.0, 123.6,
123.4, 121.3, 118.2, 24.8 (CH3) ppm.
1
2
3
4
5
6
7
8
EtOAc/heptane) to afford 5 (6.49 g, 13.0 mmol, 57 %) as a
clear oil. HRMS (MALDI/FT-ICR): m/z: [M+Na]+ Calc. for
C24H44O5SSi2Na+ 523.2340; Found 523.2336. 1H-NMR
(CDCl3, 500 MHz) δ: 7.55-7.53 (m, 2H), 7.31-7.28 (m, 3H),
4.53 (d, J = 9.7 Hz, 1H, H1), 3.89 (d, J = 4.8 Hz, 2H, H6), 3.53
(t, J = 8.5 Hz, 1H, H3), 3.47 (td, J = 8.9, 2.0 Hz, 1H, H4), 3.38
(dt, J = 9.4, 4.8 Hz, 1H, H5), 3.31 (ddd, J = 2.2, 8.4, 10.3 Hz, 1H,
H2), 2.67 (d, J = 2.0 Hz, 1H, 4-OH), 2.34 (d, J = 2.2 Hz, 1H, 2-
OH), 0.92-0.90 (m, 18H), 0.15-0.13 (m, 6H), 0.11-0.09 (m,
6H) ppm. 13C{1H}-NMR (CDCl3, 126 MHz) δ: 132.8, 132.4,
129.1, 128.0, 88.7, 79.6,79.2, 72.5, 72.4, 64.3, 26.1, 26.1,
18.5. 14.5, −4.2, −4.4, −5.22, −5.23 ppm.
6-((Trimethylsilyl)methyl)-2,2’-bipyridine (24) Prepared
from a literature procedure.[16] To a cooled (−78 °C) solution
of diisopropylamine (0.49 mL, 3.52 mmol, 1.2 equiv.) in dry
THF was slowly added n-BuLi (2.5 m in hexane, 1.3 mL, 3.23
mmol, 1.1 equiv.). The resulting solution was stirred for 15
min at 0 °C after which it was once again cooled to −78 °C. A
solution of 23 (500 mg, 2.94 mmol) in THF was slowly
added. The reaction mixture was stirred for 1 h at −78 °C
followed by addition of TMSCl (0.45 mL, 3.52 mmol, 1.2
equiv.). During 5 min, the reaction mixture was allowed to
reach rt at which point a satd. aqueous solution of NaHCO3
was added. The aqueous phase was extracted with Et2O and
the combined organic layers were washed two times with
brine, dried over Na2SO4 and concentrated in vacuo to yield
24 (712 mg, 2.94 mmol, 100 %) as a yellow liquid. HRMS
(ESI/FT-ICR): m/z: [M+H]+ Calc. for C14H19N2Si+ 243.1312;
Found 243.1312. 1H-NMR (CDCl3, 500 MHz) δ: 8.65 (ddd, J =
4.8, 1.8, 0.93 Hz, 1H), 8.41 (dt, J = 7.9, 1.1 Hz, 1H), 8.09 (dd,
J = 7.9, 1.0 Hz, 1H), 7.79 (ddd, J = 8.0, 7.5, 1.8 Hz, 1H), 7.63
(t, J = 7.7 Hz, 1H), 7.29-7.27 (m, 1H), 6.98 (dd, J = 7.7, 1.0 Hz,
1H), 2.41 (s, 2H, CH2), 0.07 (s, 9H, TMS) ppm. 13C{1H}-NMR
(CDCl3, 126 MHz) δ: 161.0, 157.0, 155.4, 149.2, 136.9, 136.9,
123.5, 122.5, 121.2, 116.6, 30.3, −1.4 ppm.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl 2,4-di-O-benzyl-1-thio- β -D-glucopyranoside (4)
Prepared from a literature procedure.10 To a cooled solution
of 5 (1.37 g, 2.74 mmol) and benzyl bromide (1.40 g, 8.21
mmol, 3 equiv.) in DMF (10 mL) was added NaH (328 mg,
8.21 mmol, 3 equiv.). The reaction mixture was stirred for
20 h while it was allowed to reach rt. The reaction was
quenched by addition of MeOH, diluted with Et2O, washed
with water and brine, and concentrated in vacuo. The
resulting clear oil was dissolved in MeOH (20 mL) and a
catalytic amount of p-toluenesulfonic acid was added. The
reaction mixture was refluxed for 3 h after which it was
added Et3N (1 mL), concentrated in vacuo and subjected to
flash column chromatography (SiO2, 1:9 to 3:7
EtOAc/heptane) to afford 4 (1.25 g, 2.54 mmol, 92 %) as a
white solid. HRMS (MALDI/FT-ICR): m/z: [M+Na]+ Calc. for
1
C26H28O5SNa+ 475.1550; Found 475.1547. H-NMR (CDCl3,
6-(Chloromethyl)-2,2’-bipyridine (3) Prepared from
a
500 MHz) δ: 7.52-7.50 (m, 2H), 7.42-7.29 (m, 13H), 4.98 (d,
J = 11.0 Hz, CH2-benzyl), 4.83 (d, J = 11.3 Hz, 1H, CH2-
benzyl), 4.72-4.69 (m, 2H, CH2-benzyl, H1), 3.89 (ddd, J =
11:9; 5:7; 2:5 Hz, 1H, H6), 3.79 (td, J = 8.8, 2.5 Hz, 1H, H3),
3.72 (ddd, J = 11.9, 7.0, 4.9 Hz, 1H, H6), 3.48 (t, J = 9.3 Hz, 1H,
H4), 3.40-3.33 (m, 2H, H5, H1), 2.44 (d, J = 2.7 Hz, 1H, 3-OH),
1.91 (t, J = 6.8 Hz, 1H, 6-OH) ppm. 13C{1H}-NMR (CDCl3, 126
MHz) δ: 138.2, 138.1, 133.6, 131.9, 129.2, 128.8, 128.7,
128.4, 128.3, 128.2, 128.2, 127.9, 87.3, 81.1, 79.2, 78.7, 77.3,
75.4, 74.9, 62.4 ppm.
literature procedure.16 A suspension of hexachloroethane
(1.39 g, 5.87 mmol, 2 equiv.), CsF (892 mg, 5.87 mmol, 2
equiv.) and 24 (710 mg, 2.94 mmol) in acetonitrle was
heated to reflux for 2 h after which it was cooled to rt and
added water. The mixture was extracted with EtOAc and the
organic layers were washed with brine, dried over Na2SO4,
concentrated in vacuo and subjected to flash column
chromatography (deactivated SiO2, 3:7 EtOAc/heptane) to
afford 3 (551 mg, 2.69 mmol, 92 %) as a pale yellow liquid.
HRMS (ESI/FT-ICR): m/z: [M+H]+ Calc. for C11H10ClN2
+
1
205.0527; Found 205.0527. H-NMR (CDCl3, 500 MHz) δ:
6-Methyl-2,2’-bipyridine (23) Prepared from a literature
procedure.16 To a cooled (0 °C) solution of 2,2’-bipyridine
(1.00 g, 6.40 mmol) in dry Et2O (20 mL) was slowly added a
solution of MeLi (1.6 m in Et2O, 6.40 mmol, 1 equiv.). The
resulting dark purple solution was refluxed for 3 h after
which it was cooled to rt and added water. The aqueous
phase was extracted with Et2O and the combined organic
phase was washed two times with brine, dried over Na2SO4
and concentrated in vacuo. The resulting crude product was
dissolved in acetone (50 mL) and KMnO4 was added until no
more MnO2 was formed. The reaction mixture was filtered
through celite. The filtrate was concentrated and subjected
to flash column chromatography (deactivated SiO2, 1:1
EtOAc/heptane) to afford 23 (570 mg, 3.35 mmol, 52 %) as
a yellow liquid. HRMS (ESI/FT-ICR): m/z: [M+H]+ Calc. for
8.68 (ddd, J = 4.8, 1.8, 0.94 Hz, 1H), 8.44 (dt, J = 8.0, 1.1 Hz,
1H), 8.34 (dd, J = 7.9, 1.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.51
(dd, J = 7.7, 1.1 Hz, 1H), 7.32 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H),
2.76 (s, 2H, CH2) ppm. 13C{1H}-NMR (CDCl3, 126 MHz) δ :
156.2, 155.9, 155.9, 149.4, 138.1, 137.1, 124.0, 122.8, 121.5,
120.4, 47.1 ppm.
Phenyl 2,3,4,6-tetra-O-TMS-1-thio- β-D-glucopyranoside
(7) To a solution of 8 (800 mg, 2.94 mmol) in dry pyridine (3
mL) was slowly added TMSCl (1.60 g, 14.7 mmol, 5 equiv.)
and the resulting white suspension was stirred at rt for 24
h after which it was diluted with EtOAc and washed with
water. The organic phase was dried over MgSO4 and
concentrated under reduced pressure to afford 7 (1.65 g,
2.94 mmol, 99 %) as a colorless oil. HRMS (MALDI/FT-ICR):
m/z: [M+Na]+ Calc. for C24H48O5SSi4Na+ 583.2192; Found
+
1
C11H11N2 171.0917; Found 171.0917. H-NMR (CDCl3, 500
MHz) δ: 8.68 (ddd, J = 4.8, 1.8, 0.94 Hz, 1H), 8.40 (dt, J = 8.0,
1.0 Hz, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.82-7.79 (m, 1H), 7.70
1
583.2184. H-NMR (CDCl3, 500 MHz) δ: 7.55-7.49 (m, 2H),
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The Journal of Organic Chemistry
7.33-7.18 (m, 3H), 4.64 (d, J = 8.7 Hz, 1H, H1), 3.81 (dd, J = 7.60 (m, 2H, Ar), 7.52-7.51 (m, 1H, Ar), 7.42-7.40 (m, 3H,
1
2
3
4
5
6
7
8
11.1, 2.3 Hz, 1H, H6), 3.63 (dd, J = 11.1, 6.3 Hz, 1H, H6), 3.54-
3.41 (m, 3H, H2, H3, H4), 3.34-3.26 (m, 1H, H5), 0.24 (s, 9H,
TMS), 0.17 (s, 9H, TMS), 0.16 (s, 9H, TMS), 0.10 (s, 9H, TMS)
ppm. 13C{1H}-NMR (CDCl3, 126 MHz) δ: 130.6, 128.8, 126.8,
89.4 (C1), 81.4 (C1), 80.0, 75.3, 71.8, 62.8 (C6), 1.9 (TMS),
1.5 (TMS), 1.1 (TMS), -0.2 (TMS) ppm.
Ar), 7.31-7.22 (m, 13H, Ar), 5.13 (d, J = 11.8 Hz, 1H, CH2-Ar),
5.08 (d, J = 11.8 Hz, 1H, CH2-Ar), 4.96-4.90 (m, 2H, CH2-Ar),
4.83-4.78 (m, 2H, CH2-Ar), 4.72 (d, J = 9.8 Hz, 1H, H1), 4.68
(d, J = 10.8 Hz, 1H, CH2-Ar), 3.93 (dd, J = 10.8, 1.6 Hz, 1H, H6),
3.88 (dd, J = 10.8, 4.8 Hz, 1H, H6), 3.83 (t, J = 8.9 Hz, 1H, H4),
3.76 (t, J = 9.4 Hz, 1H, H3), 3.60-3.57 (m, 2H, H2, H5) ppm.
13C{1H}-NMR (CDCl3, 126 MHz) δ: 158.3, 157.7, 156.4, 156.3,
155.7, 155.5, 149.3, 149.2, 138.1, 137.7, 137.1, 137.0, 136.9,
133.9, 132.1, 129.1, 128.58, 128.55, 128.5, 128.2, 128.01,
127.99, 127.6, 123.81, 123.78, 122.1, 121.40, 121.38, 121.4,
119.9, 119.8, 87.6 (C1), 87.2 (C4), 80.9, 79.1, 77.8 (C3), 75.6,
75.3, 74.6, 69.9 (C6) ppm (1 signal missing possibly due to
overlap). 1H-NMR (Acetonitrile-d3, 500 MHz) δ: 8.64 (tdd, J
= 4.9, 1.8, 0.9 Hz, 2H, Ar), 8.39 (dt, J = 7.9, 1.1 Hz, 1H, Ar),
8.35-8.27 (m, 3H, Ar), 7.87 (t, J = 7.8 Hz, 1H, Ar), 7.85-7.75
(m, 3H, Ar), 7.59-7.52 (m, 2H, Ar), 7.49 (ddd, J = 11.6, 7.7, 1.1
Hz, 2H, Ar), 7.41-7.33 (m, 4H, Ar), 7.31-7.17 (m, 11H, Ar),
5.04 (d, J = 11.9 Hz, 1H, CH2-Ar), 5.01 (d, J = 11.9 Hz, 1H, CH2-
Ar), 4.89-4.82 (m, 3H, H1, 2 x CH2-Ar), 4.81 (d, J = 10.6 Hz,
1H, CH2-Ar), 4.74 (d, J = 13.1 Hz, 1H, CH2-Ar), 4.68 (d, J = 13.1
Hz, 1H, CH2-Ar), 4.65 (d, J = 10.9 Hz, 1H, CH2-Ar), 3.89 (dd, J
= 11.1, 1.7 Hz, 1H, H6), 3.86-3.81 (m, 2H, H3, H6), 3.67 (dd,
J = 9.9, 8.3 Hz, 1H, H4), 3.65-3.62 (ddd, J = 9.8, 4.8, 1.7 Hz,
1H, H5), 3.53 (dd, J = 9.8, 8.8 Hz, 1H, H2) ppm. 13C{1H}-NMR
(MeCN-d3, 126 MHz) δ: 159.1, 158.9, 156.8, 156.3, 150.2,
138.8, 138.04, 137.98, 131.7, 130.1, 129.2, 129.1, 129.0,
128.8, 128.6, 128.2, 125.0, 123.2, 122.8, 121.6, 120.44,
120.37, 87.8, 87.4, 81.8, 79.5, 78.8, 77.3, 75.8, 75.6, 75.0,
70.7.
Phenyl 3,6-di-O-benzyl-1-thio- β -D-glucopyranoside (6)
Prepared from a literature procedure.17 To a cooled (0 °C)
solution of 7 (400 mg, 0.71 mmol) and benzaldehyde (227
mg, 2.14 mmol, 3 equiv.) in CH2Cl2 (0.8 mL) was added a
solution of FeCl3·6H2O (9.6 mg, 0.04 mmol, 0.05 equiv.) in
dry acetonitrile and triethylsilane (92 mg, 0.78 mmol, 1.1
eq.). The reaction mixture was stirred for 3 h after which
additional FeCl3·6H2O (9.6 mg, 0.04 mmol, 0.05 equiv.) and
triethylsilane (413 mg, 3.56 mmol, 5 equiv.) was added. The
reaction was then stirred for 24 h at rt after which it was
quenched with a satd. Bicarbonate solution and diluted with
EtOAc. The organic phase was washed with water and brine,
dried over MgSO4, concentrated in vacuo and subjected to
flash column chromatography (SiO2, 1:5 to 1:1
EtOAc/heptane) to afford 6 (161 mg, 0.36 mmol, 50 %) as a
white solid. HRMS (MALDI/FT-ICR): m/z: [M+Na]+ Calc. for
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
C26H28O5SNa+ 475.1550; Found 475.1547. H-NMR (CDCl3,
500 MHz) δ: 7.56-7.54 (m, 2H), 7.38-7.26 (m, 13H), 4.95 (d,
J = 11.6 Hz, 1H, CH2-benzyl), 4.82 (d, J = 11.6 Hz, 1H, CH2-
benzyl), 4.61 (d, J = 11.9 Hz, 1H, CH2-benzyl), 4.57 (d, J = 11.9
Hz, 1H, CH2-benzyl), 4.53 (d, J = 9.4 Hz, 1H, H1), 3.83-3.73
(m, 2H, H6), 3.66-3.58 (m, 1H, H3), 3.57-3.49 (m, 1H, H5),
3.48 (t, J = 9.0 Hz, 1H, H2), 3.43 (t, J = 8.6 Hz, 1H, H4), 2.63
(s, 1H, OH), 2.45 (s, 1H, OH) ppm. 13C{1H}-NMR (CDCl3, 126
MHz) δ : 138.6, 138.1, 133.0, 131.9, 129.1, 128.8, 128.6,
128.3, 128.2, 128.1, 127.9, 127.8, 88.5 (C1), 85.3 (C4), 78.5
(C5), 75.1 (CH2-benzyl), 73.8 (CH2-benzyl), 72.4 (C2), 71.4
(C3), 70.5 (C6) ppm.
1•Zn Complex To a suspension of 1 (50.0 mg, 0.063
mmol) in acetonitrile (8.0 mL) was added zinc
trifluoromethanesulfonate (23.0 mg, 0.068 mmol, 1 equiv.).
The resulting solution was concentrated under reduced
pressure to afford 1•Zn (73.0 mg, 0.068 mmol) as a pale
yellow solid. Melting point: 95-107 °C, HRMS (MALDI/FT-
ICR): m/z: [M+H]+ Calc. for C50H45F6N4O11S3Zn+ 1151.1437;
Found 1151.1467. 1H-NMR (Acetonitrile-d3, 500 MHz) δ :
8.58-8.55 (m, 2H, Ar), 8.51-8.47 (m, 3H, Ar), 8.43 (t, J = 8.0
Hz, 1H, Ar), 8.34-8.24 (m, 3H, Ar), 7.93-7.89 (m, 2H, Ar)
7.81-7.74 (m, 3H, Ar), 7.70-7.66 (m, 2H, Ar), 7.62 (ddd, J =
7.6, 5.2, 1.0 Hz, 1H, Ar), 7.57 (ddd, J = 7.6, 5.1, 1.0 Hz, 1H, Ar),
7.47-7.45 (m, 2H, Ar), 7.38-7.27 (m, 7H, Ar), 7.16-7.15 (m,
3H, Ar), 6.97-6.95 (m, 2H, Ar), 5.62 (d, J = 15.3 Hz, 1H, CH2-
Ar), 5.22 (d, J = 10.6 Hz, 1H, H1), 5.17 (d, J = 15.3 Hz, 1H, CH2-
Ar), 5.03 (d, J = 15.9 Hz, 1H, CH2-Ar), 4.75 (d, J = 16.7 Hz, 1H,
CH2-Ar), 4.55 (d, J = 11.9 Hz, 1H, CH2-Ar), 4.50 (d, J = 11.9 Hz,
1H, CH2-Ar), 4.24-4.22 (m, 2H, H3, H5), 4.09 (d, J = 12.4 Hz,
1H, CH2-Ar), 4.03 (d, J = 12.4 Hz, 1H, CH2-Ar), 3.95 (dd, J =
14.2, 4.9 Hz, H6), 3.46 (d, J = 14.2 Hz, 1H, H6), 3.29 (s, 1H,
H4), 2.94 (dd, J = 10.6, 4.1 Hz, H2) ppm. 13C{1H}-NMR
(Acetonitrile-d3, 126 MHz) δ : 157.4, 156.5, 150.1, 149.5,
149.3, 148.9, 148.6, 145.0, 144.8, 143.7, 143.6, 138.6, 138.4,
134.5, 132.2, 130.2, 129.7, 129.2, 129.1, 129.0, 128.9, 128.7,
127.7, 126.3, 126.1, 124.4, 124.3, 123.6, 123.4, 123.2, 88.4,
82.8, 81.2, 77.5, 76.7, 73.9, 72.6, 71.7, 71.5, 71.4 ppm.
Phenyl
2,4-di-O-benzyl-3,6-di-O-([2,2’-bipyridin]-6-
ylmethoxy)-1-thio- β -D-glucopyranoside (1) To a cold
solution of 4 (100 mg, 0.22 mmol) in dry DMF (2 mL) was
added NaH (35 mg, 0.88 mmol, 4 equiv.) and the resulting
suspension was stirred at 0 °C for 1 h before a solution of 3
(99.5 mg, 0.49 mmol, 2.2 equiv.) in DMF was added slowly.
The reaction mixture was allowed to reach rt and stirred for
24 h after which it once again was cooled to 0 °C and an
excess of MeOH was added. The resulting solution was
extracted with Et2O and the organic phase was washed with
water several times before being washed with brine, dried
over Na2SO4 and concentrated in vacuo. The crude residue
was subjected to flash column chromatography (Al3O5, 1:3
to 1:1 EtOAc/heptane) to afford 1 (132 mg, 0.17 mmol, 77
%) as a white solid. Melting point: 95-96 °C, HRMS
(MALDI/FT-ICR): m/z: [M+H]+ Calc. for C48H45N4O5S+
298
789.3105; Found 789.3106. [α]D
= 0.558 (c = 0.0072,
1
CHCl3). H-NMR (CDCl3, 500 MHz) δ: 8.69-8.66 (m, 2H, Ar),
8.40 (dt, J = 8.0, 1.0 Hz,1H, Ar), 8.35 (dt, J = 8.0, 1.0 Hz,1H,
Ar), 8.32-8.30 (m, 1H, Ar), 8.28 (d, J = 7.8 Hz, 1H, Ar) 7.81-
7.74 (m, 3H, Ar), 7,71 (td, J = 7.9, 7.7, 1.0 Hz, 1H, Ar), 7.62-
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3.51 (dd, J = 9.6, 8.1 Hz, 1H, H6), 3.48 (broad apparent d, J =
Phenyl
ylmethoxy)-1-thio-
3,6-di-O-benzyl-2,4-di-O-([2,2’-bipyridin]-6-
β -D-glucopyranoside (2) To a cold
3.3 Hz, 1H, H4) ppm. 13C{1H}-NMR (Acetonitrile-d3, 126
MHz) δ : 157.0, 156.5, 149.7, 149.5, 149.1, 148.8, 148.5,
145.1, 143.9, 143.7, 139.2, 138.0, 134.7, 131.5, 131.2, 130.3,
130.2, 129.6, 129.5, 129.2, 129.04, 128.99, 128.89, 128.82,
128.78, 128.7, 126.6, 126.2, 124.4, 124.2, 123.5, 123.3, 86.5
(C2), 84.8 (C1), 77.6 (C3), 76.7 (C5), 75.6 (C4), 74.0, 72.9,
72.2, 70.7 (C6), 66.9 ppm.
1
2
3
4
5
6
7
8
solution of 6 (500 mg, 1.1 mmol) in dry DMF (5 mL) was
added NaH (177 mg, 4.42 mmol, 4 equiv.) and the resulting
suspension was stirred at 0 °C for 1 h before a solution of 3
(497 mg, 2.43 mmol, 2.2 equiv.) in DMF was added slowly.
The reaction mixture was allowed to reach rt and stirred for
24 h after which it once again was cooled to 0 °C and an
excess of MeOH was added. The resulting solution was
extracted with Et2O and the organic phase was washed with
water several times before being washed with brine, dried
over Na2SO4 and concentrated in vacuo. The crude residue
was subjected to flash column chromatography (Al3O5, 1:3
to 1:1 EtOAc/heptane) to afford 2 (690 mg, 0.87 mmol, 79
%) as a colorless oil that solidified upon storage. Melting
9
Phenyl 4,6-di-O-benzylidene-1-thio-β-D-glucopyranoside
(15) Prepared from a literature procedure.24 A solution of 8
(1.00 g, 3.67 mmol), benzaldehyde dimethyl acetal (671 mg,
4.41 mmol, 1.2 equiv.) and Cu(OTf)2 (66 mg, 0.2 mmol, 0.05
equiv.) in dry acetonitrile (40 mL) was subjected to
sonication at rt for 2h after which the reaction mixture was
concentrated in vacuo and purified by flash column
chromatography (SiO2, 1:1 EtOAc/heptane) to yield 15 (860
mg, 2.39 mmol, 62 %) as white crystals. HRMS (MALDI/FT-
ICR): m/z: [M+H]+ Calc. for C19H21O5S+ 361.1104; Found
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
point: 105-106 °C, HRMS (MALDI/FT-ICR): m/z: [M+H]+
298
Calc. for C48H45N4O5S+ 789.3105; Found 789.3106. [α]D
=
10.6 (c = 0.0053, CHCl3). 1H-NMR (CDCl3, 500 MHz) δ: 8.68-
8.66 (m, 2H), 8.41-8.37 (m, 2H), 8.32-8.29 (m, 2H), 7.82-
7.73 (m, 4H), 7.34-7.19 (m, 16H), 5.16-5.00 (m, 3H, CH2-Ar),
4.96 (d, J = 10.6 Hz, 1H, CH2-Ar), 4.90 (d, J = 10.6 Hz, 1H, CH2-
Ar), 4.83 (d, J = 12.1 Hz, 1H, CH2-Ar), 4.74 (d, J = 9.8 Hz, 1H,
H1), 4.61 (d, J = 11.9 Hz, 1H, CH2-Ar), 4.55 (d, J = 11.9 Hz, 1H,
CH2-Ar), 3.86 (dd, J = 10.8, 1.9 Hz, 1H, H6), 3.85-3.73 (m, 3H,
H3, H4, H6), 3.65-3.56 (m, 2H, H2, H5) ppm. 13C{1H}-NMR
(CDCl3, 126 MHz) δ: 157.8, 157.6, 156.4, 156.3, 155.6, 155.5,
149.3, 149.3, 138.4, 138.3, 137.6, 137.0, 133.9, 132.1, 129.1,
128.5, 128.5, 128.4, 128.4, 127.8, 127.8, 127.8, 127.7, 127.6,
123.8, 123.8, 122.3, 121.9, 121.4, 121.4, 119.9, 87.5 (C1),
86.6, 81.4 (C2), 79.4 (C5), 78.5, 76.5, 76.2, 76.0, 73.6, 69.3
(C6) ppm (1 signal missing possibly due to overlap). 1H-
NMR (Acetonitrile-d3, 500 MHz) δ: 8.70-8.60 (m, 2H, Ar),
8.35 (dd, J = 7.9, 5.7 Hz, 2H, Ar), 8.31 (dd, J = 7.8, 3.0 Hz, 2H,
Ar), 7.88-7.80 (m, 4H, Ar), 7.58-7.52 (m, 3H, Ar), 7.41-7.25
(m, 13H, Ar), 7.24-7.17 (m, 3H, Ar), 5.05-4.92 (m, 3H, 3 x
CH2-Ar), 4.91 (m, 2H, 2 x CH2-Ar), 4.87 (d, J = 9.8 Hz, 1H, H1),
4.80 (d, J = 11.9 Hz, 1H, CH2-Ar), 4.55 (d, J = 11.9 Hz, 1H, CH2-
Ar), 4.49 (d, J = 11.8 Hz, 1H, CH2-Ar), 3.85-3.77 (m, 2H, H3,
H6), 3.77-3.68 (m, 2H, H4, H6), 3.64 (ddd, J = 9.7, 4.8, 1.8 Hz,
1H, H5), 3.59 (dd, J = 9.8, 8.7 Hz, 1H, H2) ppm. 13C{1H}-NMR
(Acetonitrile-d3, 126 MHz) δ : 158.7, 156.8, 150.2, 139.7,
138.7, 138.7, 138.0, 135.3, 131.7, 130.1, 129.3, 129.2, 129.0,
128.7, 128.5, 128.2, 125.0, 124.9, 123.3, 123.2, 121.6, 120.5,
87.7, 87.1, 82.2, 79.5, 79.2, 76.9, 76.6, 76.2, 73.8, 70.1 ppm.
1
361.1105. H-NMR (CDCl3, 500 MHz) δ: 7.56-7.54 (m, 2H),
7.49-7.47 (m, 2H), 7.38-7.34 (m, 6H), 5.53 (s, 1H, PhCH),
4.64 (d, J = 9.7 Hz, 1H, H1), 4.39 (dd, J = 10.6, 4.5 Hz, 1H, H6),
3.87-3.83 (m, 1H, H4), 3.80-3.76 (m, 1H, H6), 3.55-3.50 (m,
2H, H3, H5), 3.49-3.45 (m, 1H, H2) 2.74 (bs, 2H, 2 x OH) ppm.
13C{1H}-NMR (CDCl3, 126 MHz) δ: 137.0, 133.2, 131.4, 129.5,
129.3, 128.7, 128.5, 126.4, 102.1, 88.8, 80.6, 74.7, 72.7, 70.7,
68.7 ppm.
Phenyl 2,3-di-O-benzyl-4,6-di-O-benzylidene-1-thio-β-D-
glucopyranoside (16) To a cooled solution of 15 (850 mg,
2.36 mmol) and NaH (377 mg, 9.43 mmol, 4 equiv.) in DMF
(5 mL) was added benzyl bromide (1.21 g, 7.08 mmol, 3
equiv.). The reaction mixture was stirred for 48 h after
which it was quenched with MeOH, diluted with Et2O,
washed with water and brine, dried over MgSO4,
concentrated in vacuo, and subjected to flash column
chromatography (SiO2, 1:20 to 1:4 EtOAc/PE) to afford 16
(810 mg, 1.50 mmol, 63 %) as a white solid. HRMS
(MALDI/FT-ICR): m/z: [M+Na]+ Calc. for C33H32O5SNa+
1
563.1863; Found 563.1859. H-NMR (CDCl3, 500 MHz) δ:
7.55-7.52 (m, 2H), 7.49-7.48 (m, 2H), 7.41-7.27 (m, 16H),
5.59 (s, 1H, PhCH), 4.94 (d, J = 11.2 Hz, 1H, CH2-benzyl), 4.87
(d, J = 10.2 Hz, 1H, CH2-benzyl)), 4.82 (d, J = 10.3 Hz, 1H, CH2-
benzyl)), 4.79-4.75 (m, 2H, CH2-benzyl, H1), 4.39 (dd, J =
10.5, 5.0 Hz, 1H, H6)), 3.91-3.77 (m, 2H, H6, H3), 3.71 (t, J =
9.4 Hz, 1H, H4), 3.56-3.38 (m, 2H, H2, H5) ppm. 13C{1H}-
NMR (CDCl3, 126 MHz) δ: 138.4, 138.2, 137.4, 133.2, 132.5,
129.2, 129.1, 128.6, 128.5, 128.4, 128.4, 128.3, 128.0, 128.0,
127.9, 126.1, 101.3, 88.4, 83.2, 81.6, 80.6, 76.1, 75.5, 70.4,
68.9 ppm.
2•Zn Complex To a solution of 2 (4.00 mg, 0.005 mmol) in
acetonitrile-d3
(0.5
mL)
was
added
zinc
trifluoromethanesulfonate (1.83 mg, 0.005 mmol, 1 equiv.)
to afford 2•Zn. 1H-NMR (Acetonitrile-d3, 500 MHz) δ: 8.52-
8.49 (m, 2H), 8.43-8.39 (m, 2H), 8.36-8.33 (m, 2H), 8.28-
8.23 (m, 2H), 7.93-7.88 (m, 2H), 7.69-7.66 (m, 1H), 7.62-
7.60 (m, 1H), 7.53-7.50 (m, 1H), 7.39-7.29 (m, 13H), 7.20-
7.15 (m, 1H), 7.09 (d, J = 6.5 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H),
5.33 (d, J = 16.8 Hz, 1H, CH2-Ar), 4.94-4.87 (m, 2H, 2 x CH2-
Ar), 4.62 (d, J = 16.0 Hz, 1H, CH2-Ar), 4.62 (d, J = 12.1 Hz, 1H,
CH2-Ar), 4.51 (d, J = 12.0 Hz, 1H, CH2-Ar), 4.38 (d, J = 8.2 Hz,
1H, H1), 4.35 (dd, J = 3.3, 1.3 Hz, 1H, H3), 4.27 (broad s, 2H,
2 x CH2-Ar), 4.16 (broad apparent t, J = 7.1 Hz, 1H, H5), 4.03
(dd, J = 8.3, 1.3 Hz, 1H, H2), 3.66 (dd, J = 9.5, 6.2 Hz, 1H, H6),
Phenyl 2,3-di-O-benzyl-1-thio- β-D-glucopyranoside (17)
A suspension of 16 (625 mg, 1.16 mmol) and a catalytic
amount of 10-CSA in MeOH was stirred at rt for 4 days,
concentrated in vacuo and purified by flash column
chromatography (SiO2, 1:1 EtOAc/heptane) to yield 17 (410
mg, 0.91 mmol, 78 %) as white crystals. HRMS (MALDI/FT-
ICR): m/z: [M+Na]+ Calc. for C26H28O5SNa+ 475.1550; Found
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The Journal of Organic Chemistry
1
475.1549. H-NMR (CDCl3, 500 MHz) δ: 7.53-7.50 (m, 2H),
7.43-7.27 (m, 13H), 4.99-4.93 (m, 2H, 2 x CH2-benzyl,), 4.82-
4.56 (m, 3H, 2 x CH2-benzyl, H1), 3.88 (ddd, J = 11.9, 6.6, 3.4
Hz, 1H, H6), 3.75 (ddd, J = 12.0, 6.8, 5.4 Hz, 1H, H6), 3.58 (td,
J = 9.2, 2.7 Hz, 1H, H4), 3.56-3.45 (m, 2H, H3, H2), 3.36 (ddd,
J = 9.1, 5.4, 3.4 Hz, 1H, H5), 2.25 (d, J = 2.7 Hz, 1H, 4-OH),
2.01 (t, J = 6.7 Hz, 1H, 6-OH) ppm. 13C{1H}-NMR (CDCl3, 126
MHz) δ : 138.4, 137.9, 133.7, 131.9, 129.2, 128.9, 128.6,
128.4, 128.3, 128.2, 128.1, 127.9, 87.9, 86.2, 81.1, 79.3,
75.60, 75.57, 70.6, 63.0 ppm.
182•Zn Complexes To a solution of 18 (4.00 mg, 0.005
mmol) in acetonitrile-d3 (0.5 mL) was added zinc
trifluoromethanesulfonate (0.92 mg, 0.0025 mmol, 0.1
1
2
3
4
5
6
7
8
1
equiv.) to afford 18’2•Zn and 182•Zn in a 1:1.5 ratio. H-
NMR (Acetonitrile-d3, 500 MHz) δ: 8.64-8.45 (m, 10H), 8.34
(td, J = 7.9; 1.6 Hz, 1H), 8.29 (qd, J = 7.7; 1.6 Hz, 2H), 8.22 (td,
J = 7.9; 1.7 Hz, 1H), 7.98 (dt, J = 5.2; 1.4 Hz, 1H), 7.88-7.84
(m, 5H), 7.77 (d, J = 8.0 Hz, 1H), 7.65 (ddd, J = 7.6; 5.2; 1.1
Hz, 1H), 7.62-7.59 (m, 2H), 7.57 (ddd, J = 5.2; 1.7; 0.9 Hz, 1H),
7.52-7.49 (m, 4H), 7.44-7.42 (m, 2H), 7.42-7.16 (m, 29H),
7.10 (dd, J = 8.4; 6.9 Hz, 2H), 6.81-6.77 (m, 2H), 5.41 (d, J =
16.3 Hz, 1H, CH2-Ar), 5.26-5.18 (m, 3H, 2 x CH2-Ar’, CH2-Ar),
5.13 (d, J = 16.3 Hz, 1H, CH2-Ar), 4.95-4.90 (m, 3H, 2 x CH2-
Ar’, CH2-Ar), 4.81 (d, J = 10.6 Hz, 1H, CH2-Ar), 4.76 (d, J = 10.5
Hz, 1H, CH2-Ar’), 4.71 (d, J = 9.9 Hz, 1H, H1) 4.66-4.59 (m,
5H, 2 x CH2-Ar’, H1’, 2 x CH2-Ar), 4.54 (d, J = 10.9 Hz, 1H),
4.27 (d, J = 11.2 Hz, 1H, CH2-Ar’), 4.18-4.10 (m, 3H, H3, H5,
H6), 3.93 (dd, J = 13.3; 8.0 Hz, 1H, H6’), 3.88 (dd, J = 15.2; 5.3
Hz, 1H, H6), 3.82 (d, J = 13.2 Hz, 1H, H6’), 3.71 (t, J = 10.3 Hz,
1H, H4), 3.62 (t, J = 9.3 Hz, 1H, H4’), 3.43-3.32 (m, 3H, H2’,
H3’, H2), 3.19-3.11 (m, 1H, H5’) ppm. 13C{1H}-NMR
(Acetonitrile-d3, 126 MHz) δ : 157.6, 157.0, 156.7, 156.4,
150.1, 149.53, 149.45, 149.34, 149.3, 149.1, 148.88, 148.87,
148.7, 144.9, 144.6, 144.5, 144.4, 143.9, 143.7, 143.6, 143.4,
139.1, 138.99, 138.97, 138.6, 134.4, 133.9, 132.7, 132.0,
130.2, 129.4, 129.3, 129.1, 128.97, 128.94, 128.92, 128.90,
128.87, 128.81, 128.74, 128.65, 128.6, 128.5, 127.0, 126.2,
125.91, 125.89 124.5, 124.3, 124.1, 124.0, 123.5, 123.42,
123.40, 123.3, 123.2, 120.9, 88.4 (C1), 88.3 (C1’), 86.8 (C4’),
85.8 (C3’), 82.1 (C2), 81.9 (C2’), 80.9 (C3), 78.8 (C4), 77.9
(C6), 76.0 (CH2-Ar’), 75.8 (CH2-Ar), 75.4 (H5), 74.6 (CH2-Ar),
73.8 (CH2-Ar’), 73.7 (H5’), 72.5 (C6’), 71.4 (CH2-Ar’), 70.1
(CH2-Ar), 63.9 (CH2-Ar) ppm (1 CH2-Ar’ signal and 7
aromatic signals missing possibly due to overlap.).
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Phenyl
2,3-di-O-benzyl-4,6-di-O-([2,2’-bipyridin]-6-
ylmethoxy)-1-thio- β -D-glucopyranoside (18) To a cold
solution of 17 (100 mg, 0.22 mmol) in dry DMF (2 mL) was
added NaH (35 mg, 0.88 mmol, 4 equiv.) and the resulting
suspension was stirred at 0 °C for 1 h before a solution of 3
(99.5 mg, 0.49 mmol, 2.2 equiv.) in DMF was added slowly.
The reaction mixture was allowed to reach rt and stirred for
24 h after which it once again was cooled to 0 ºC and an
excess of MeOH was added. The resulting solution was
extracted with Et2O and the organic phase was washed with
water several times before being washed with brine, dried
over Na2SO4 and concentrated in vacuo. The crude residue
was subjected to flash column chromatography (Al3O5, 1:3
to 1:1 EtOAc/heptane) to afford 18 (132 mg, 0.17 mmol, 77
%) as a white soild. Melting point: 95-96 °C, HRMS
(MALDI/FT-ICR): m/z: [M+H]+ Calc. for C48H45N4O5S+
789.3105; Found 789.3106. [α]D
298
= −3.10 (c = 0.0078,
CHCl3). 1H-NMR (CDCl3, 500 MHz) δ: 8.69-8.66 (m, 2H, Ar),
8.40 (dt, J = 8.0, 1.0 Hz,1H, Ar), 8.35 (dt, J = 8.0, 1.0 Hz, 1H,
Ar), 8.32-8.30 (m, 1H, Ar), 8.28 (d, J = 7.8 Hz, 1H, Ar) 7.81-
7.74 (m, 3H, Ar), 7.71 (td, J = 7.9, 7.7, 1.0 Hz, 1H, Ar), 7.62-
7.60 (m, 2H, Ar), 7.52-7.51 (m, 1H, Ar), 7.42-7.40 (m, 3H,
Ar), 7.31-7.22 (m, 13H, Ar), 5.13 (d, J = 11.8 Hz, 1H, CH2-Ar),
5.08 (d, J = 11.8 Hz, 1H, CH2-Ar), 4.96-4.90 (m, 2H, CH2-Ar),
4.83-4.78 (m, 2H, CH2-Ar), 4.72 (d, J = 9.8 Hz, 1H, H1), 4.68
(d, J = 10.8 Hz, 1H, CH2-Ar), 3.93 (dd, J = 10.8, 1.6 Hz, 1H, H6),
3.88 (dd, J = 10.8, 4.8 Hz, 1H, H6), 3.83 (t, J = 8.9 Hz, 1H, H4),
3.76 (t, J = 9.4 Hz, 1H, H3), 3.60-3.57 (m, 2H, H2, H5) ppm.
13C{1H}-NMR (CDCl3, 126 MHz) δ: 158.3, 157.7, 156.4, 156.3,
155.7, 155.5, 149.3, 149.2, 138.1, 137.7, 137.6, 137.00,
136.9, 133.9, 132.1, 129.1, 128.58, 128.55, 128.5, 128.2,
128.01, 127.99, 127.6, 123.8, 123.8, 122.1, 121.4, 121.4,
121.4, 119.9, 119.8, 87.6 (H1), 87.2 (H4), 80.9, 79.1, 77.8
(H3), 75.6, 75.3, 74.6, 69.9 (H6) ppm (1 signal missing
possibly due to overlap). 1H-NMR (Acetonitrile-d3, 500
MHz) δ: 8.65-8.58 (m, 1H), 8.35 (dt, J = 8.0, 1.1 Hz, 1H), 8.30-
8.23 (m, 3H), 7.83-7.74 (m, 4H), 7.58-7.53 (m, 2H), 7.46 (dd,
J = 7.7, 1.0 Hz, 1H), 7.41-7.21 (m, 15H), 4.97 (d, J = 11.9 Hz,
1H, CH2-Ar), 4.89 (d, J = 11.0 Hz, 1H, CH2-Ar), 4.87-4.84 (m,
2H, H1, CH2-Ar), 4.82 (d, J = 12.0 Hz, 1H, CH2-Ar), 4.76 (d, J =
10.6 Hz, 1H, CH2-Ar), 4.71 (d, J = 13.1 Hz, 1H, CH2-Ar), 4.64
(d, J = 13.1 Hz, 1H, CH2-Ar), 3.91 (dd, J = 11.0, 2.0 Hz, 1H, H6),
3.86 (dd, J = 11.1, 4.7 Hz, 1H, H6), 3.78 (t, J = 8.9 Hz, 1H; H3),
3.74 (t, J = 8.9 Hz, 1H, H4), 3.67 (ddd, J = 9.4, 4.8, 2.0 Hz, 1H,
H5), 3.50 (dd, J = 9.8, 8.3 Hz, 1H, H2) ppm.
General procedure for glycosylations using DMTST A stock
solution of DMTST in CH2Cl2 was prepared by adding methyl
triflate (0.42 mL, 0.64 g, 3.9 mmol, 1 equiv.) to a solution of
dimethyl disulfide (0.36 mL, 0.38 g, 4.1 mmol, 1.1 equiv.) in
dry CH2Cl2 (5 mL). The reaction mixture was stirred at rt for
24 h after which the volume was adjusted to 10 mL to afford
a 3.9 mM stock solution.
Glycosylation without Zn2+ The glycosyl donor (100 mg,
1.26 mmol, 1 equiv.) and the acceptor (2 equiv.) was
coevaporated with toluene three times and dried together
with 3 Å molecular sieves on a Schlenk line for 1 h. Dry
acetonitrile (2 mL) and CH2Cl2 (1 mL) was added to the
reaction flask and the temperature of the reaction mixture
was lowered to −30 °C. DMTST (1 equiv.) was added as a
solution where after the temperature of the reaction
mixture was allowed to reach rt. After the specified amount
of time, the reaction mixture was diluted with Et2O and the
organic phase was washed one time with water and one
time with brine after which it was filtered, dried over
Na2SO4 and concentrated in vacuo. The residue was
subjected to column chromatography on neutral alumina.
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Page 10 of 12
Glycosylation with Zn2+ The glycosyl donor (100 mg, 1.26
mmol, 1 equiv.), the acceptor (2 equiv.) and zinc triflate (46
mg, 1.3 mmol, 1 equiv.) was coevaporated with toluene
three times and dried together with 3 Å molecular sieves on
a Schlenk line for 1 h. Dry acetonitrile (2 mL) and CH2Cl2 (1
mL) was added to the reaction flask and the reaction
mixture was stirred at rt for 1 h after which the temperature
was lowered to −30 °C. DMTST (1 equiv.) was added as a
solution where after the temperature of the reaction
mixture was allowed to reach rt. After the specified amount
of time, the reaction mixture was diluted with Et2O and the
organic phase was washed one time with water and one
time with brine after which it was filtered, dried over
Na2SO4 and concentrated in vacuo. The residue was
subjected to column chromatography on neutral alumina.
α-H5), 3.92 (dd, J = 10.6, 3.9 Hz, 1H, α-H6), 3.87 (dd, J = 10.7,
1
2
3
4
5
6
7
8
1.9 Hz, 1H, β-H6), 3.81-3.74 (m, 4H, α-H4, α-H6, β-H3, β-H6),
3.67-3.57 (m, 2H, α-H2, β-H4), 3.55 (ddd, J = 9.9, 5.6, 2.0 Hz,
1H, β-H5), 3.50 (dd, J = 9.2, 7.8 Hz, 1H, β-H2), 2.14 (broad s,
6H, 3 x α-CH, 3 x β-CH), 1.96 (broad apparent d, J = 11.8 Hz,
6H, 6 x α-CH2), 1.86 (broad apparent d, J = 13.3 Hz, 6H, 6 x
β-CH2), 1.63 (broad s, 6H, 3 x α-CH2, 3 x β-CH2) ppm. 13C{1H}-
NMR (CDCl3, 126 MHz) δ: 158.4, 158.2, 158.1, 156.37,
156.34, 156.3, 155.49, 155.49, 155.45, 155.4, 149.3, 149.2,
149.1, 138.6, 138.44, 138.39, 138.2, 137.49, 137.47, 136.92,
136.86, 128.48, 128.47, 128.41, 128.39, 128.37, 128.2,
127.9, 127.81, 127.80, 127.7, 123.70, 123.69, 123.68, 122.1,
122.0, 121.5, 121.4, 121.3, 121.3, 119.72, 119.69, 119.6,
96.4, 90.0, 85.53, 82.47, 82.2, 80.0, 78.28, 78.26, 76.7, 76.54,
75.48, 75.3, 75.1, 75.0, 74.7, 74.6, 74.53, 74.51, 72.8, 70.3,
69.8, 69.8, 42.9, 42.6, 36.4, 30.8, 30.8 ppm (13 aromatic
signals and 1 aliphatic signal missing possibly due to
overlap).
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19
20
21
22
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Glycoside 19 The title compound 19 was achieved as a
pale yellow oil (73 %, 66 %(Zn2+)). HRMS (MALDI/FT-ICR):
+
m/z: [M+H]+ Calc. for C45H47N4O7 755.3439; Found
1
755.3427. [α]D298 = 12.7 (c = 0.0204, CHCl3). H-NMR (CDCl3,
Glycoside 21 The title compound 21 was achieved as a
pale yellow oil (58 %, 28 %(Zn2+)). HRMS (MALDI/FT-ICR):
500 MHz) δ: 8.68-8.66 (m, 4H), 8.40-8.37 (m, 4H), 8.31-8.25
(m, 4H), 7.81-7.70 (m, 8H), 7.52-7.43 (m, 4H), 7.38-7.37 (m,
4H), 7.30-7.21 (m, 20H), 5.21 (d, J = 12.1 Hz, 1H, CH2-Ar),
5.17 (d, J = 12.2 Hz, 1H, CH2-Ar), 5.08 (d, J = 12.4 Hz, 1H, CH2-
Ar), 5.05 (d, J = 12.2 Hz, 1H, CH2-Ar), 5.00 (d, J = 11.1 Hz, 2H,
2 x CH2-Ar), 4.96-4.94 (m, 2H, 2 x CH2-Ar), 4.92 (d, J = 3.6 Hz,
1H, α-H1), 4.85-4.73 (m, 8H, 8 x CH2-Ar), 5.65-4.62 (m, 2H,
2 x CH2-Ar), 4.50 (d, J = 7.8 Hz, 1H, β-H1), 4.13 (t, J = 9.3 Hz,
1H, α -H3), 4.08 (ddd, J = 3.8, 5.3, 10.9 Hz, 1H, β-H6), 3.95-
3.37 (m, 8H, β-CH2, β-H4, β-H6, α-CH2, α-H6), 3.73-3.69 (m,
2H, β-H3, α-H6), 3.64-3.60 (m, 6H, β-CH2, α-CH2, α-H2),
3.57-3.53 (m, 2H, β-H2, β-H5), 3.39 (s, 3H, β-CH3), 3.37 (s,
3H, α-CH3) ppm. 13C{1H}-NMR (CDCl3, 126 MHz) δ: 158.3,
158.2, 158.1, 158.0, 156.34, 156.31, 156.30, 156.26, 155.5,
149.27, 149.26, 149.18, 149.15, 137.58, 137.57, 137.53,
137.51, 136.94, 136.93, 136.89, 136.88, 128.51, 128.49,
128.47, 128.41, 128.2, 128.1, 128.1, 127.90, 127.88, 127.8,
127.7, 123.7, 123.7, 122.1, 122.0, 121.5, 121.4, 121.37,
121.35, 121.3, 119.8, 119.77, 119.74, 104.1 (β-C1), 97.3 (α-
C1), 85.1 (β-C4), 82.4 (α-C3), 82.0 (β-C2), 79.9 (α-C2), 77.9
(β-C3), 77.8, 76.7 (CH2-Ar), 75.3 (CH2-Ar), 75.2 (CH2-Ar),
74.9 (β-C5), 74.8 (CH2-Ar), 74.7 (CH2-Ar), 73.1 (CH2-Ar),
71.9 (β-CH2), 71.8 (α-CH2), 70.2, 69.9 (β-CH2), 69.6 (α-CH2),
69.2 (β- C6), 67.1 (a-C6), 59.1 (α-CH3), 59.1 (β-CH3) ppm (2
CH2-Ar signals missing possibly due to overlap).
+
m/z: [M+H]+ Calc. for C70H71N4O11 1143.5114; Found
298
1143.5094. [α]D
= 19.4 (c = 0.0132, CHCl3). 1H-NMR
(CDCl3, 500 MHz) δ: 8.60 (ddd, J = 7.6, 4.9, 1.8 Hz, 2H), 8.36-
8.26 (m, 2H), 8.21 (dd, J = 13.5, 7.8 Hz, 2H), 7.75-7.60 (m,
6H), 7.43 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.6 Hz, 1H), 7.29-
7.10 (m, 25H), 5.08 (d, J = 12.1 Hz, 1H, CH2-Ar), 4.99 (d, J =
11.9 Hz, 1H CH2-Ar), 4.93-4.86 (m, 3H, 3 x CH2-Ar), 4.76-
4.68 (m, 4H, 4 x CH2-Ar), 4.67 (d, J = 10.7 Hz, 1H CH2-Ar),
4.63-4.56 (m, 4H, H1’, 3 x CH2-Ar), 4.47 (d, J = 11.2 Hz, 1H,
CH2-Ar), 4.34 (d, J = 7.8 Hz, 1H, H1), 4.15 (dd, J = 11.0, 2.0
Hz, 1H, H6), 3.94 (t, J = 9.2 Hz, 1H), 3.82-3.77 (m, 3H, 2 x H6),
3.70-3.62 (m, 3H, H6), 3.51-3.44 (m, 4H, H2, H2’), 3.27 (s,
3H, CH3’) ppm. 13C{1H}-NMR (CDCl3, 126 MHz) δ: 158.3,
158.0, 156.29, 156.28, 155.51, 155.48, 149.3, 149.2, 139.0,
138.5, 138.4, 138.3, 138.1, 137.6, 137.5, 136.93, 136.86,
128.6, 128.50, 128.47, 128.45, 128.4, 128.3, 128.2, 128.1,
128.0, 127.93, 127.89, 127.8, 127.71, 127.65, 127.6, 123.74,
123.71, 122.0, 121.4, 121.3, 121.3, 119.8, 119.7, 104.0 (C1),
98.2 (C1’), 85.3, 82.1, 82.0, 79.9, 78.1, 77.9, 76.7, 75.8, 75.2,
75.0, 74.6, 73.5, 70.0, 69.9 (C6), 68.7 (C6), 55.4 (CH3’) ppm.
Glycoside 22 The title compound 22 was achieved as a
pale yellow oil (10 %(Zn2+)). Contains glycosyl acceptor 13
as an impurity. HRMS (MALDI/FT-ICR): m/z: [M+H]+ Calc.
+
for C70H71N4O11 1143.5114; Found 1143.5103. 1H-NMR
(CDCl3, 500 MHz) δ: 8.37 (tt, J = 8.9, 1.1 Hz, 1H), 8.64 (ddd, J
= 4.8, 1.8, 0.9 Hz, 2H), 8.37 (tt, J = 8.9, 1.1 Hz, 2H), 8.30 (dd,
J = 7.9, 1.1 Hz, 1H), 8.23 (dd, J = 7.8, 1.0 Hz, 1H), 7.86-7.79
(m, 1H), 7.77-7.70 (m, 2H), 7.63 (td, J = 7.7, 1.8 Hz, 1H), 7.56
(t, J = 7.8 Hz, 1H), 7.45 (dd, J = 7.7, 1.1 Hz, 2H), 7.36.7.16 (m,
25H), 5.22 (d, J = 12.7 Hz, 1H, CH3-Ar), 5.06 (d, J = 12.1 Hz,
1H, CH3-Ar), 5.01-4.71 (m, 10H, 5 x CH3-Ar), 4.68-4.53 (m,
3H, 2 x CH3-Ar, H1’), 4.45 (d, J = 7.8 Hz, 1H, H1), 4.21 (dd, J =
10.8, 2.0 Hz, 1H, H6), 3.84 (ddd, J = 10.2, 5.0, 2.0 Hz, 1H, H5),
3.81-3.67 (m, 5H, 3 x H6), 3.67-3.58 (m, 3H, H2), 3.55-3.46
(m, 2H, H2’), 3.33 (s, 3H, OCH3) ppm. 13C{1H}-NMR (CDCl3,
126 MHz) δ: 157.9, 157.5, 156.03, 155.99, 155.4, 155.3,
149.1, 149.0, 138.8, 138.3, 138.24, 138.1, 137.42, 137.35,
Glycoside 20 The title compound 20 was achieved as a
pale yellow oil (59 %, 40 %(Zn2+)). HRMS (MALDI/FT-ICR):
m/z: [M+H]+ Calc. for C52H55N4O6 831.4116; Found
+
1
831.4107. [α]D298 = 20.7 (c = 0.0144, CHCl3). H-NMR (CDCl3,
500 MHz) δ: 8.68-6.65 (m, 4H), 8.40-6.36 (m, 4H), 8.31-8.24
(m, 4H), 7.79-7.69 (m, 8H), 7.52-7.51 (m, 1H), 7.49-7.47 (m,
2H), 7.41-7.39 (m, 2H), 7.37-7.35 (m, 4H), 7.30-7.20 (m,
19H), 5.34 (d, J = 3.6 Hz, 1H, α-H1), 5.20 (d, J = 12.0 Hz, 1H,
α-CH2-Ar), 5.14 (d, J = 12.1 Hz, 1H, β-CH2-Ar), 5.07 (d, J =
12.0 Hz, 1H, α-CH2-Ar), 5.06-4.97 (m, 3H, 3 x CH2-Ar), 4.94
(d, J = 10.8 Hz, 1H, β-CH2-Ar), 4.65-4.61 (m, 8H, 7 x CH2-Ar,
β-H1), 4.65-4.61 (m, 2H, 2 x CH2-Ar), 4.16-4.19 (m, 2H, α-H3,
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The Journal of Organic Chemistry
[5] Fraser-Reid, B.; Wu, Z.; Andrews, C. W.; Skowronski, E.;
137.1, 137.0, 136.9, 128.33, 128.30, 128.27, 128.26, 128.08,
Bowen, J. P. Torsional effects in glycoside reactivity: saccharide
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1
2
3
4
128.05, 127.8, 127.7, 127.6, 127.5, 124.1, 123.7, 123.6,
121.8, 121.6, 121.2, 120.9, 119.7, 119.5, 103.7 (C1), 98.0
(C1), 84.5, 82.3, 82.0, 79.9, 78.5, 78.00, 75.9, 75.68, 75.65,
75.1, 74.9, 73.5, 73.3, 69.8, 69.1 (C6), 68.7 (C6), 55.2 (OMe’)
ppm.
5
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7
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
University of Copenhagen, Department of Chemistry.
Universitetsparken 5, 2100 Copenhagen. cmp@chem.ku.dk
ACKNOWLEDGMENT
The Villum Foundation is acknowledged for financial support.
We thank Christian G. Tortzen for help with the NMR
experiments.
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