Stereoselective Thioconjugation by Photoinduced Thiol-ene Coupling Reactions of Hexo- and Pentopyranosyl d- and l-Glycals at Low-Temperature—Reactivity and Stereoselectivity Study

Article abstract of DOI:10.1002/chem.201903095

A comprehensive optimization and mechanistic study on the photoinduced hydrothiolation of different d- and l- hexo- and pentoglycals with various thiols was performed, at the temperature range of RT to ?120 °C. Addition of thiols onto 2-substituted hexoglycals proceeded with complete 1,2-cis-α-stereoselectivity in all cases. Hydrothiolation of 2-substituted pentoglycals resulted in mixtures of 1,2-cis-α- and -β-thioglycosides of varying ratio depending on the configuration of the reactants. Hydrothiolation of unsubstituted glycals at ?80 °C proceeded with excellent yields and, except for galactal, provided the axially C2-S-linked isomers with high selectivity. Cooling was always beneficial to the efficacy, increased the yields and in most cases significantly raised the stereoselectivity. The suggested mechanism explains the different conformational preferences of the intermediate carbon-centered radicals, which is a crucial factor in the stereoselectivity of the reactions.

Full text of DOI:10.1002/chem.201903095

A Journal of
Accepted Article
Title: Stereoselective thioconjugation by photoinduced thiol-ene
coupling reactions of hexo- and pentopyranosyl D- and L-glycals
at low temperature – Reactivity and stereoselectivity study
Authors: Viktor Kelemen, Miklós Bege, Dániel Eszenyi, Nóra
Debreczeni, Attila Bényei, Tobias Stürzer, Pál Herczegh, and
Anikó Borbás
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To be cited as: Chem. Eur. J. 10.1002/chem.201903095
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Stereoselective thioconjugation by photoinduced thiol-ene
coupling reactions of hexo- and pentopyranosyl D- and L-glycals
at low temperature – Reactivity and stereoselectivity study
Viktor Kelemen,a,b Miklós Bege,a,c Dániel Eszenyi, Nóra Debreczeni, Attila Bényei, Tobias Stürzer,
a
a,d
e
f
a
a,
Pál Herczegh and Anikó Borbás, *
a
Department of Pharmaceutical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
b
Doctoral School of Pharmaceutical Sciences, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
c
MTA-DE Molecular Recognition and Interaction Research Group, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
Doctoral School of Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
Department of Physical Chemistry, University of Debrecen, Egyetem tér 1, H-4032 Debrecen, Hungary
d
e
f
Bruker AXS GmbH, Östliche Rheinbrückenstraße 49, 76187 Karlsruhe, Germany
Dedication ((optional))
Abstract: A comprehensive optimization and mechanistic study on
the photoinduced hydrothiolation of different D- and L- hexo- and
pentoglycals with various thiols was performed, at the temperature
and sugar thiols to 2-substituted hexoglycals occurs with
complete stereoselectivity, providing an easy access to 1,2-cis-
linked thiodisaccharides
and thioglycoconjugates.[26-30]
o
range of rt to −120 C. Addition of thiols onto 2-substituted hexoglycals
Recently, we have demonstated that the reaction temperature
profoundly influences the efficacy of the reactions by controlling
the equilibrium of the reversible propagation step of the radical
chain process.[28,29] Our study revealed that cooling promotes
while heating inhibits the thiol-ene couplings of 2-substituted
glycals, and the unfavourable steric and electronic effects
resulting in low conversions at room temperature could be
overcome by conducting the reactions at −80 °C.
To further investigate the applicability of the low-temperature
photoinitiated thiol-ene coupling in the stereoselective
thioconjugation, we continued to study the reactions of 2-
substituted hexoglycals (1-3), supplemented with the
disaccharide glycal 4. Applied thiol partners comprise alkyl thiols
proceeded with complete 1,2-cis--stereoselectivity in all cases.
Hydrothiolation of 2-substituted pentoglycals resulted in mixtures of
1,2-cis-- and --thioglycosides of varying ratio depending on the
configuration of the reactants. Hydrothiolation of unsubstituted glycals
o
at −80 C proceeded with excellent yields and, except for galactal,
provided the axially C2-S-linked isomers with high selectivity. Cooling
was always beneficial to the efficacy, increased the yields and in most
cases significantly raised the stereoselectivity. The suggested
mechanism explains the different conformational preferences of the
intermediate carbon-centered radicals, which is a crucial factor in the
stereoselectivity of the reactions.
(
1
12, 13, 15 and 16), thioacid 14, mercaptoacids (17 and 19) and
-thiosugars (18, 20-22) including disaccharide thiol 18 (Figure 1).
Introduction
Moreover, our study was extended to two additional glycal types
of both D- and L-configurations, the 2-acetoxy pentoglycals (5-7),
and the unsubstituted hexoglycals (8-11) (Figure 1). Only two
reports of thiol-ene reactions of these glycal types have been
published in the literature hitherto which are also limited to room-
temperature reactions of a few D-isomers. [23, 26]. Importantly,
while the thiol-ene coupling of 2-substituted hexoglycals proceeds
with exclusive 1,2-cis--stereoselectivity, the 2-substituted
pentoglycals were found to react with only moderate
diastereoselectivities [26]. Moreover, in the case of unsubstituted
hexoglycals, although regioselective hydrothiolation has been
observed to occur at the C2-position, the diastereoselectivity and
the efficacy of the reaction were strongly varying depending upon
the C-3 and C-4 configurations of the glycals. [23].
Herein, we report a systematic study on three types of glycals,
shown in Figure 1, by varying not only the experimental
parameters of the thiol-ene couplings such as reaction
temperature and ratio of reactants but examining sterical and
electronic factors on both the reacting glycal and thiol. The careful
analysis of the results of this comprehensive optimization study
made it possible to give a viable mechanistic explanation for the
highly different levels of stereoselectivity observed on the different
types of glycals.
Oligosaccharides, glycoconjugates and their mimetics are
investigated in molecular recognition studies, [1-3] drug discovery
[
4] and vaccine development. [5] Thioglycosides in which the
glycosidic oxygen is replaced by a sulfur atom are metabolically
stable analogues of the natural O-glycosides, justifying their
synthesis and application as glycomimetics. [6]
While many strategies exist for the synthesis of 1,2-trans-
thio-linked glycomimetics, [7-9] the formation of 1,2-cis-
thioglycosides with high stereocontrol is known to be a major
challenge. [10-13] The -glycosides are abundantly found in
nature, and many 1,2-cis--linked sugars, including -D-glucose,
D-galactose and D-glucosamine play crucial roles in various
biological processes. [14] Therefore, there is a high demand for
the stereoselective synthesis of thio-analogues of these
biorelevant sugars.
In this context, the radical mediated thiol-ene coupling
emerged as a powerful method for glycoconjugation [15-17] which,
if unsaturated sugars are applied as the alkene partners, opens
the way for the stereoselective synthesis of a broad range of thio-
linked glycomimetics.[18-30] We demonstrated that the UV-light-
initiated addition of various thiols including amino acid, peptide,
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Results and Discussion
Table 1. Hydrothiolation of 2-acetoxy-D-glucal 1 with various thiols at different
temperatures
Temperature Yield
Entry
Thiol
Product
(
thiol equiv.) (%)[a]
1
2
3
4
5
rt (5)
35
54
46
65
18
rt (3 x 5)
1
2
o
0 C (3)
(
3-15 equiv)
o
0
C (5)
o
-
40 C (3)
rt (5)
6
7
8
9
32
51
56
68
50
rt (3 x 5)
1
3
o
0 C (3)
(
3-15 equiv)
o
0
C (5)
10
o
-
40 C (3)
o
[b]
11
12
13
14
rt/-40 C
0
9
9
[
c]
14
rt
[b]
(6-24 equiv)
-20 o
C
-20 oC [c]
19
Figure 1. Investigated glycals and thiols
15
rt
0 C
55
81
15 (3 equiv)
o
16
Hydrothiolation of 2-substituted hexoglycals
We have found earlier that while 2-acetoxy-D-glucal 1 readily
reacted with thiol-containing peptides and sugars at room
temperature, only moderate conversions have been observed
with simple thiols such as t-butyl or benzyl mercaptans, and high
amount of unreacted 1 was recovered from the reaction
mixtures.[26, 27] Therefore, first, we studied the temperature-
dependence of the reactions between 1 and thiols 12-16 under
the previously established conditions using 3 x 15 minutes of
irradiation at λmax 365 nm in the presence of 3 x 0.1 equiv. of the
photoinitiator 2,2-dimethoxy-2-phenylacetophenone (DPAP).
Using 5 equiv. of alkyl thiols 12 and 13 at room temperature,
glycal 1 reacted with low conversions (Table 1, entries 1 and 6).
Increasing the thiol excess to 3 x 5 equiv. a significant progress
of the reactions was observed and the corresponding -
thioglycosides 23 and 24 were formed in 51-54% yields (Table 1,
1
18
7
rt
40
70
16 (2 equiv)
17 (2 equiv)
80 oC
-
19
rt
80 oC
55
67
20
-
21
rt
5
o
22
0 C
10
14
29
58
18
-20 o
C
C
C
2
2
3
4
(1.5 equiv)
o
-
-
40
80
25
o
o
entries 2 and 7). Performing the reactions at 0 C with 5 equiv thiol
[
a]
excess an even higher promoting effect was observed in both
cases (entries 4 and 9) to afford 23 and 24 with 65% and 68%
yields, respectively. However, further cooling of the reaction
mixture proved to be detrimental to the efficacy of the addition
reactions (Entries 5 and 10).
Isolated yield; by-product formation was not observed, the low/moderate
[
b]
yields are the results of the low/moderate conversion of the alkenes; 6 equiv.
of thiol was used; [ 3 x 8 equiv. of thiol was used.
c]
Interestingly, thioacetic acid 14 showed a significantly lower
reactivity than alkyl thiols, and the isolated yield of the -1-thio-
acetate product 25 did not reach 20% at any temperature despite
using very high thiol excess (Entries 11-14).
Spacer-armed -thioglycosides such as 26, 27 and 28 can be
considered as valuable building blocks in the construction of
neoglycoconjugates, glycopeptides and glycodendrimers.
Therefore, their synthesis was studied by using functionalized
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thiols 15, 16 and 17. In all three cases the conversion of the
starting glycal and also the isolated yield of the product could be
significantly increased by cooling. Importantly, the optimal
18
1
1
5
6
-40 o
C
C
35%
75%
o
(1.5 equiv)
reaction temperatures were remarkably different, 0 C for thiol 15
-80 o
+
2
o
while -80 C for thiols 16 and 17, producing the corresponding -
thioglycosides 26, 27 and 28 in 81%, 70% and 67% yields,
respectively (Entries 15-20). Applying disaccharide 18 as the thiol
partner, a very low conversion of 1 was observed at room
temperature to give trisaccharide 29 only with 5% yield. It was
surprising, because we have found earlier that 1-thioglycoses, e.g.
1
5
rt
46%
83%
45%
1
18
7
o
(
1.5 equiv)
+
0 C
3
-80
o
C
19
20 and 22, added to 1 efficiently at room temperature providing
the corresponding thiodisaccharides in high yields. [26]
Fortunately, the efficacy of the thiol-ene coupling between
disaccharide thiol 18 and glycal 1 increased gradually in line with
the decrease of the reaction temperature and the yield of 29
reached 58% at -80 oC (Entries 21-25). Noteworthy, in these
reactions we had to use DMF as a co-solvent due to the low
solubility of thiol 18 in toluene.
-20 o
[b]
[b]
[d]
[c]
36%
2
21
0
14
C
C
C
C
-40 o
50%
56%
63%
(6-24
equiv)
+ 3
o
2
2
2
3
-40
-80 o
1
8
2
2
4
5
(1.3 equiv)
-40 o
-80 o
C
C
65%
33%
+ 3
Table 2. The effect of the C4 configuration and type of the C2-substituent of
glycals on the thiol-ene reaction
[
a]
Isolated yield; by-product formation was not observed, the low/moderate
[
b]
yields are the results of the low/moderate conversion of the alkenes;
equiv. of thiol was used; [ 3 x 6 equiv. of thiol was used; 3 x 8 equiv. of
6
c]
[d]
thiol was used.
To further explore the mechanism and scope of the reaction the
D-galactose-derived glycal 2 and 2-acetamido-D-glucal 3 were
systematically reacted (Table 2). As already observed in our
previous experiments, efficient thiol-ene couplings of 2 and 3
required lower temperatures than those of the D-gluco analogue
1. [28, 29] Similar trends were observed when thiols 12 or 14 were
Thiol +
Alkene
Temperature Yield
Entry
Product
[
a]
(thiol equiv.)
1
2
3
4
rt
0 C
-40
-80
28%
26%
56%
22%
12
o
(
5 equiv)
o
C
C
+
2
o
o
coupled to 2, being −40 to −80 C the optimal temperature range
of these reactions.(Table 2). While reaction between thiol 12 and
o
rt [b]
glycal 2 occurred with low efficacy at rt and even at 0 C, a
5
6
7
8
9
0
1
6-18
equiv)
+
4
o
[b]
o
significantly increased conversion was observed at -40 C giving
0 C
15%
22%
26%
23%
(
-40 o
C
[b]
the corresponding -1-thio-galactoside 30 in a 56% yield.
However, conducting the reaction at -80 oC again led to a
decrease in the conversion. Using thioacetic acid 14 as the thiol
partner, the cooling exerted its beneficial promoting effect again.
Unfortunately, the best yields of 31, achieved at the −40 to −80 C
temperature range, did not exceed 26% (Entries 5-9). The
o
[c]
[b]
-40
C
C
2
80 o
-
o
10
11
12
15
(3 equiv)
+ 2
rt
52%
69%
41%
o
0 C
o
-40
C
reactivity of 2-acetoxy-galactal 2 towards thiols 15, 16 and 18
(
Entries 10-16) proved to be similar to the ones of 2-acetoxy-D-
o
glucal 1. The optimal reaction temperature was -80 C with thiols
16 and 18, giving the corresponding -thio-linked products 33 and
34 in high yields. At the same time, the most efficient reaction with
1
6
1
1
3
4
rt, (3)
58%
(
2-3 equiv)
+
-80 oC, (2) 86%
2
o
thiol 15 was found to occur at 0 C providing 32 with 69% yield.
These results highlight that the type of the thiol is also a crucial
factor in the thiol-ene coupling. Reactions of 2-acetamido-D-glucal
3
with thiols 15 and 14 showed a similar temperature dependence
as the analoguous reactions of 2-acetoxy-glycals 1 and 2.
Noteworthy, 2-acetamido-D-glucal 3 reacted with thioacetic acid
1
4 with much higher efficacy than either 1 or 2, and the yield of
the -1-thio-acetate 36 reached 63% at -80 oC. One possible
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reason behind this is that the 2-acetamido group is capable to
stabilise the carbon centered radical intermediate (vide infra)
formed from the acylated thiyl radical better than the 2-acetoxy
group. Interestingly, in the thiol-ene coupling between glycal 3 and
disaccharide thiol 18 the best yield of trisaccharide 37 was found
couplings of nucleoside exomethylenes. [21] The yield in the
coupling reaction of disaccharide glycal 4 with disaccharide thiol
18 was significantly lower than the ones observed in the reactions
of monosaccharide thiols and glycals, which can partly be
attributed to the low solubility of the disaccharides.
o
o
at -40 C and further cooling to -80 C led to a drop of the yield
from 65% to 33%.
Summarizing this detailed synthetic work makes it possible to get
deep insight into the mechanism of the reaction as follows. The
thiol-ene reaction is known to occur through a reversible thiyl
addition (propagation) step followed by an irreversible hydrogen
abstraction (chain transfer) step by the carbon centered radical
intermediate (e.g. 1-R and 2-R) formed in the first step (Scheme
2). [31-33] The efficiency of the thiol-ene reactions highly depends
on the stability of the carbon-centered radical intermediate, which
directly influences both the chain-transfer activation barrier and
the reversibility of the propagation step as revealed by recent
computational and kinetic studies. [33] The stability of the radical
intermediate depends on the difference of the activation energy
barriers in the forward and reverse steps, which difference is
determined by the relative energy levels of the starting
compounds (the glycal and the thiyl radical) and the intermediate
carbon centered radical. If the activation energy barrier of the
reverse propagation step is sufficiently higher than that of the
forward one, the equilibrium of the reversible propagation step lies
toward the intermediate carbon centered radical and efficient
reaction can occur at room temperature. However, if the energy
barrier of the reverse reaction is only slightly higher than that of
the forward one, the carbon centered radical readily fragments at
room temperature in an intramolecular reaction, without forming
the final product in an intermolecular way. In the case of the above
studied reactions, only few of the intermediates formed were
sufficiently stable at room temperature to allow hydrothiolation in
an acceptable efficacy. Similarly to our recent results, [28] we
have found that freezing the intermediate radical is an adequate
strategy to promote the reaction by preventing its degradation and
thereby allowing it to react with a thiol in the hydrogen abstraction
step. Although the cooling was beneficial in all reactions, the
optimal reaction temperature was found to be varying depending
on the configuration and substituents of the glycals, and also on
the nature of the thiols. The configuration effect can easily be
understood by the example of glucose and galactose (Scheme 2).
While glucal 1 is at a higher energy level relative to galactal 2, due
to the steric congestion between the equatorial C2 and C3
substituents in the 4
formed carbon centered radical intermediates existing in a 4
Scheme 1. Hydrothiolation reactions of 2-acetoxy-maltal 4
5
H half chair conformation of 1, out of the
C
1
chair conformation, the gluco configured 1-R featuring an all-
equatorial substitution pattern has a lower energy than the galacto
congener 2-R. It means that the galactosyl C2 radical
intermediate is less stable, more prone to decompose into the
starting compounds than the gluco one, consequently, the cooling
is more crucial in the galacto case to achive efficient thiol-ene
couplings.
Next, the thiol-ene coupling of the maltose-derived 2-acetoxy
glycal 4 was systematically studied as a block synthesis route to
thiomimetics of higher oligosaccharides and glycoconjugates
(
Scheme 1). In general, the reactivity of 4 proved to be slightly
lower than the ones of the monosaccharide congeners. [26-29]
Reacting 4 with thiols 19, 20 and 18 the best yields of the
corresponding thioglycosides 38, 39 and 42 were achieved at the
o
o
temperature range of -20 C to -40 C, while with 1-thiomannoses
1 and 22 the most efficient reactions occurred at -80 oC.
2
Comparing the reactions using the -D-gluco- and - and -D-
mannopyranosyl thiols 20, 21 and 22 reveals that the efficacy of
the addition is strongly dependent on the configuration of the thiol.
Noteworthy, this phenomenon has been observed in the thiol-ene
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Chemistry - A European Journal
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possible interconversion of the pyramidal carbon-centered radical
was not taken into account.
Scheme 2. Reversible thiyl addition (propagation) step and irreversible
hydrogen abstraction (chain transfer) step in the thiol-ene couplings of 2-
substituted glycals
Our results also proved that the nature of the thiols exerts great
influence on the efficiency of the addition too. For example, in the
case of thiols 12, 13 and 15 the excessive cooling proved to be
detrimental to the efficacy of the reaction.[34] We assume that the
excessive cooling could either over-stabilise these alkyl thiyl
radicals, shifting the equilibrium of the reversible propagation step
toward the starting glycals, or stop the reaction via preventing the
hydrogen abstraction step by the intermediate carbon centered
radicals.
Scheme 3. Productive and unproductive attacks of thiyl radicals onto 2-acetoxy
hexopyranosyl glycal 1. The only productive pathway leading to complete 1,2-
cis- diastereoselectivity is highlighted in green. The conformational changes of
the formed C2-radicals follow the pseudorotational itinerary of the pyranosyl ring
interconversion map. [38]
While the addition of thiyl radicals to linear olefins generally
exhibits poor stereoselectivity, in the case of substituted or
conformationally locked cyclic alkenes the addition occurs
preferentially in a trans-diaxial manner as the result of a kinetically
favored axial attack of the thiyl radical onto the cyclic alkene in its
half-chair conformation together with a stereoselective hydrogen
abstraction from the thiol into an axial position. [35, 36] However,
complete diastereoselectivity was rarely observed, because the
nature of the thiol, the configuration of the alkene, the molar ratio
of the reactants and also the temperature play a role in the
stereoselectivity observed. [18, 21, 23, 36]
Hydrothiolation of 2-substituted pentoglycals
The picture on the mechanism could be further clarified when
hydrothiolation reactions of 2-acetoxy pentoglycals 5-7 were
studied (Scheme 4). Surprisingly, no reaction was observed
between the D-xylose-derived glycal 5 and 1-thioglucose 20 at
o
o
either rt or 0 C. Conducting the reaction at -40 C, a moderate
conversion of 5 occurred producing a ~2:1 mixture of two 1,2-cis-
linked thiodisaccharides, the -D-lyxopyranosyl 43 and the -D-
xylopyranosyl 44 with 21% overall yield. Cooling the reaction to -
We assume that in the case of 2-substituted hexoglycals, the
rapidly reversible nature of the thiyl addition step [33] and the
8
0 oC, the isolated yield reached 50% and almost complete
diastereoselectivity was observed in favour of the -thiolyxoside
3. Reacting 5 with -1-thiomannose 22 at -80 oC complete
exquisite stability of the 4
1
C conformation of D-hexopyranoses
4
together ensure the exclusive 1,2-cis--stereoselectivity of the
reaction. As it is illustrated in the example of 1 (Scheme 3) the
starting hexoglycals exist in a rapid interconversion equilibrium
conversion and almost full stereoselectivity were observed and
the 1,2-cis-linked -D-lyxo configured thiodisaccharide 45 was
isolated with 95% yield. The structure of this compound was
supported by X-ray measurements (Figure 2). Interestingly,
4
5
between H
5 4
and H half chair conformations. [37] Although thiyl
radicals can attack both faces of both conformers, the only
o
running this reaction at 0 C an opposite diastereoselectivity was
productive attack occurs on the bottom face of the 4H
5
1
observed providing the -D-xylopyranosyl thioglycoside 46 as the
major product along with the -D-lyxo minor product 45 in a 2.5:1
ratio and with 40% overall yield. Upon thiol-ene coupling of the D-
conformational form leading to the formation of the stable 4
C
conformer of the C2-centered radical intermediate. This chair
conformation has exquisite stability due the equatorial position of
the bulky C6 group. (This productive route is highlighted in green.)
o
arabinose-derived glycal 6 with 1-thioglucose 20 at rt and 0 C,
very low conversions of the glycal were observed again and no
Upon other possible attacks of thiyl radicals the pyranosyl ring
o
product could be isolated. Conducting the reaction at -80 C gave
1
would only flip to high-energy skew boat and C
4
conformations
the -D-ribosyl thiodisaccharide 47 as the major product in 46%
yield along with 21% yield of the -D-arabinose-containing minor
stereoisomer 48. A further cooling to -100 oC led to a slight
decrease in both the yield and stereoselectivity of the addition
which rapidly decompose. In other words: thiyl additions that
produce high-energy C2-centered radical intermediates are
unproductive as the equilibrium of these rapidly reversible steps
[
33] completely shifts toward the starting materials. Our results
producing 47 and 48 in a 1.4:1 ratio. Hydrothiolation of 6 with -
demonstrate that radical hydrothiolation of all 2-substituted D-
hexoglycals proceeds via the route above. Analogously, the thiol-
o
1
-thiomannose 22 at 0 C gave a 1.4 to 1 mixture of the
corresponding α-D-ribosyl and -D-arabinosyl thiodisaccharides
ene couplings of L-hexo congeners proceed exclusively through
o
4
9 and 50 in 54% yield. By cooling the reaction to -80 C, the
1
the C
4
conformational form of the radical intermediates. [28] As
overall yield reached 91%, however, the stereoselectivity did not
increase. Hydrothiolation of the L-arabinose-derived glycal 7 with
the kinetically preferred axial H-abstraction can only occur on the
radical bearing an equatorially positioned acetoxy group, the
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-thioglucose 20 at -80 oC gave the -L-ribopyranosyl
Reaction between 7 and -1-thiomannose 22 at 0 C proceeded
o
1
thiodisaccharide 51 almost with complete stereoselectivity in 98%
isolated yield. The reaction proceeded with similar efficacy at 0 C, the corresponding thiodisaccharides 54 and 53 in a 6.3:1 ratio in
however slightly lower stereoselectivity was observed.
with complete conversion and high diastereoselectivity, affording
o
favour of the -L-arabinosyl isomer. Surprisingly, at -80 oC a
similarly high conversion but a much lower diastereoselectivity
(
54 to 53 ~ 2 to 1) was observed.
Figure 2. ORTEP view of thiodisaccharide 45, hydrogen atoms are omitted for
clarity
The low or no conversions of 2-acetoxy pentopyranosyl glycals
upon hydrothiolation at rt or 0 oC demonstrate that the C2-
centered pentopyranosyl radicals generally have lower stability
than the hexopyranosyl congeners (except for the L-arabino case),
therefore again, cooling is crucial for the efficient reactions.
Fortunately, good to high conversions could be achieved by
running the thiol-ene couplings at -80 oC. However, the
diastereoselectivity showed high dependence on the
configuration of the reactants and the temperature. Although in
most cases the cooling has increased the stereoselectivity of the
additions, the opposite effect was also observed (e.g. in reactions
of 6 + 22 and 7 + 22).
Scheme 5. Plausible mechanistic pathway of free-radical addition of thiols to 2-
acetoxy pentopyranosyl glycals, shown on the example of D-arabinose-derived
glycal 6. The productive routes resulting exclusively in 1,2-cis thioglycosides are
highlighted in green.
Scheme 4. Hydrothiolation reactions of 2-acetoxy pentoglycals
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Chemistry - A European Journal
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The lack of complete diastereoselectivity in the pentose series
can be explained with the higher conformational flexibility of the
pentopyranoses. [39] While in the case of hexopyranoses, one of
the chair conformations of the intermediate radical has exquisite
o
C decreased by cooling and transformed to a very slight galacto
o
selectivity at -80 C (Table 3, entries 4-7).
stability due the bulky C6 group, in the case of pentopyranoses, Table 3. Hydrothiolation reactions of D- and L-hexoglycals
1
4
4 1
the C and C forms of the radical intermediate have comparable
stabilities; therefore, the reaction can proceed through both chair
conformations (Scheme 5). Hence, productive attacks can occur
on the bottom face of the 4
upper face on the 5
centered radical intermediates existing in 1C
H
conformational form and on the
conformational form leading to carbon
and 4
chair
5
H
4
4
C
1
conformations, respectively. We assume that the cooling could
tune (generally increase) the stereoselectivity by either shifting
Alkene
+ thiol
Yield
[a]
Ratio
A:B
Entry
Product
Temp.
the interconversion equilibrium between 4H
and 5H
5
4
conformations of the starting glycal toward one of the half chair
conformers, or by inhibiting the thiyl addition process requiring the
higher activation energy.
1
2
3
8 + 20
(1.2
equiv)
rt
-80 o
-120 C 75%
80% 1.3:1[b]
76% 8.5:1
Hydrothiolation of unsubstituted glycals
C
o
6:1
Finally, to push the scope of the reaction further we extended our
study to D- and L-glycals without a C2 substituent (Table 3). The
room temperature hydrothiolation of peracetylated D-glycals have
been studied by Dondoni and Marra. [23] They described that
regioselective addition occurred in all cases producing 1-deoxy-
2-S-disaccharides through the corresponding glycosyl radical
intermediates. However, the efficiency and diastereoselectivity of
the reaction were highly varied depending on the C-3 and C-4
configurations of the glycals. For example, while hydrothiolation
of D-glucal 8 using 6 equiv. of thiol 20 proceeded efficiently but
with very low stereoselectivity, from D-allal 10, under the same
conditions, the altritol derivative 59 was found to be formed with
full stereoselectivity, however, only in low (38%) isolated yield.
o
4
5
6
7
0 C
67% 2.3:1
1.5:1
95% 1:1.2
9
(
+ 20
1.2
equiv)
o
-40
C
9
5%
-80 o
C
o
-120 C 95% 1:1.2
[
23] To study the effect of cooling on the efficiency and
diastereoselectivity of the additions, the D-glucose-, -galactose-, -
allose- and L-rhamnose-derived glycals 8, 9, 10 and 11 were
reacted with thiol 20 at different temperatures. Performing the
1
2
(1.2
equiv)
0 +
0
8
9
rt
38%
92%
1:0[b]
1:0
-80 o
C
o
reactions at -80 C, almost complete conversions were observed
in all cases and, with the exception of the galacto case, the
additions occurred with high to complete diastereoselectivity in
favour of the axially C2-S-linked products (Table 3). Addition of
20 to 8 and 11 at rt proceeded with low diastereoseletivity,
11 +
affording a 1.3:1 mixture of the D-manno (55) and D-gluco (56) as
well as a 2.5:1 mixture of the 6-deoxy-L-manno (L-rhamno) (60)
and 6-deoxy-L-gluco (61) products (Table 3, entries 1 and 10).
20
1.2-
1
1
0
1
rt
66% 2.5:1[c]
[d]
(
-80 o
C
81% 5.5:1
2.0
equiv)
o
Conducting the same reactions at -80 C using only slight thiol
excess efficient additions occurred yielding the corresponding
axially linked C-2-thiodisaccharides 55 and 60 with high
stereoselectivity (entries 2 and 11). The configuration of the major
[a]
Combined isolated yield; [b]. data are taken from Ref. [23], 6 equiv, of thiol
product 60 formed from 11 was proven by X-ray crystallography
was used; [c] 2.0 equiv of thiol was used. [d] 1.2 equiv of thiol was used
o
(
Figure 3). In the case of glycal 8, further cooling to -120 C did
The stereochemical outcome of the above additions can be
explained by the different conformational preferences of the
intermediate C-1 radicals. While the C-2-centered hexopyranosyl
radicals preferentially adopt chair conformation independently of
the configuration, the conformation of glycosyl radicals is
determined by the configuration of the C-2 substituent. [40, 41] It
has been demonstrated by Giese and co-workers on the basis of
electron paramagnetic resonance (ESR) spectroscopy study that
the most preferred conformation of glycopyranosyl radicals is the
one in which the C2-alkoxy/acyloxy substituent adopts a quasi
not improve the diastereoselectivity of the reaction. Importantly,
though the reaction mixture was frozen at -120 C, the reaction
o
took place. Hydrothiolation of D-allal 10 occurred with complete
o
diastereoselectivity at both rt and -80 C providing exclusively the
2
-S-axial D-altro-configured product 59, and by cooling the yield
of 59 reached 92% (entries 8 and 9). However, addition of 1-
thioglucose 20 to the D-galactal triacetate afforded
9
a
diastereomeric mixture of 57 and 58 at any of temperatures
studied. Interestingly, the moderate talo-selectivity observed at 0
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Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
axial position, because this conformer is stabilized by the so-
called quasi-homo-anomeric effect. [42-44] Accordingly, while C-
4
1
mannosyl radicals exist in C
1
chair conformation, C-1 glucosyl
radicals preferably flip to the most stable twisted B2,5 conformation
1
-
[
which is practically identical with the S
5
skew-boat conformer
half chair
conformation.[40-44] Consequently, products 55, 57 and 59 with
an axially linked SR group can be formed through the 4C
conformational form of the corresponding glycosyl radical via an
upper-face attack by the thiyl radical to the 4
conformational
38] -
and galactosyl radicals adopt the 4H
5
1
H
5
form of D-glycals, and, analogously, compound 60 was formed
upon bottom-face attack by the thiyl radical on L-glycal 11 in its
5
4
H conformation (Schemes 6, line A). Moreover, attacks from
opposite direction by thiyl radicals to the glycals in their same half-
chair conformations also proved to be productive in the case of 8,
Scheme 7. Stable glycopyranosyl radical intermediates formed upon upper-
and bottom-face attacks by the thiyl radicals to the H (D-series) or H (L-series)
5 4
conformational form of glycals 8-11. The conformational changes follow the
pseudorotational itinerary of the pyranosyl ring interconversion map. [38]
4
5
9
6
and 11, producing the equatorially S-linked products 56, 58 and
1 through the corresponding glucosyl and galactosyl radicals in
their stable skew-boat and half-chair conformations (Schemes 6,
line B). Upon attacks of thiyl radicals at either side to the other
half-chair conformation of the starting glycals the pyranosyl ring
would only flip to high-energy skew boat and chair conformations
bearing axial C6-group which decompose rapidly.
By cooling, the ratio of products formed through the lower-energy
radical intermediates can be raised. Hence, upon hydrothiolation
of 8 and 11 at low temperature the diastereoselectivity in favour
of the manno-configured products increased significantly. In the
case of galactal 9, the decreased ratio of the talo-configured
Conclusions
A systematic study on the photoinduced radical mediated
hydrothiolation of 2-substituted hexoglycals, 2-substituted
pentoglycals and unsubstituted hexoglycals were performed,
producing 39 thioglycosides up to tetrasaccharide (30 new). We
studied the effect of the temperature and the configuration of
thiols and glycals on the efficacy and stereochemical outcome of
the reactions. In the case of 2-substituted hexoglycals the
reactions proceeded with complete 1,2-cis--stereoselectivity in
all cases, however, the efficacy of the addition was varying
depending on the temperature and on the structure of the
reactants. The progression of the reactions could significantly be
promoted by cooling, and, except for alkyl thiols, good to high
product at low temperature can be attributed to the 1,3-diaxial
4
repulsion between the C2 and C4 substituents in the
C
1
conformation which destabilize the talopyranosyl radical
4
intermediate compared to the H
5
galacto one. In the case of D-
allal 11, the axial C3-substituent hinders the attack of thiyl radicas
from the bottom face ensuring the complete stereoselectivity of
addition occurring on the upper face.
o
conversions were achieved at -40 / -80 C. In the case of alkyl
thiols, applying high thiol excess and running the reactions at rt or
0 oC proved to be the adequate strategy to elicit efficient additions.
Hydrothiolation
of
2-substituted
pentoglycals
led
to
diastereosiomeric mixtures of 1,2-cis-- and 1,2-cis--
thioglycosides. Noteworthy, the additions occurred with exclusive
1,2-cis selectivity, no 1,2-trans-linked product was observed in
any case. Upon additions of different thiosugars to pentoglycals
the stereoselectivity and the efficacy of the additions highly
depended upon the configuration of both reactants. Although
good to excellent yields and in some cases almost complete
o
stereoselectivity were achieved at -80 C, the stereochemistry of
the products was hardly predictable. Hydrothiolation of
unsubstituted glycals proceeded with significantly higher efficacy
at -80 C than at rt, and the stereoselectivity could generally also
Figure 3. ORTEP view of 60, hydrogen atoms are omitted for clarity
o
be highly increased in favour of the axially C2-S-linked products.
The only exception was the D-galactal, hydrothiolation of which
gave the 2-thio-D-galacto and 2-thio-D-talo diastereoisomers in
similar amounts independently of the reaction temperature.
In agreement of all synthetic and kinetic observations we assume
that the stereoselectivity of the reactions are controlled by the
stability of the carbon-centered radical intermediates of different
conformations. The exclusive 1,2-cis--stereoselectivity of
hydrothiolation of 2-substituted hexoglycals can be explained by
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Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
the exquisite stability of the radical intermediate in the 4C
CCDC deposition numbers: 1937994 for 43; 1937995 for 60.
1
conformation. In the case of 2-substituted pentoglycals and
unsubstituted hexoglycals the higher conformational flexibility of
the intermediate radicals allows the formation of two
diastereoisomers, in these cases the low-reaction temperature
proved to be a controlling effect shifting the product ratio towards
the stereoisomer which formed through to more stable radical.
The chemical shifts of the compounds are signed according to
Figure 4.
Experimental Section
Figure 4: Denotion of the compounds for the NMR assignation.
General Information
General method for photoinitiated free radical thioladdition
2
,3,4,6-Tetra-O-acetyl-1,5-anhydro-D-arabino-hex-1-enitol (1)
46], 2,3,4,6-tetra-O-acetyl-1,5-anhydro-D-lyxo-hex-1-enitol (2)
46], 2-acetamido-3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxy-D-
[
[
The corresponding alkene, thiol and DPAP (DPAP, 0.1
equiv/alkene) were dissolved in the given solvent. The reaction
mixture was cooled to the given temperature and was irradiated
with UV light for 15 min. After irradiation another 0.1 equiv of
DPAP was added and the irradiation continued for another 15 min.
The addition of 0.1 equiv. of DPAP and the irradiation was
repeated one more time. In some cases, the reaction mixtures
were frozen by cooling (–80 to –120°C). In such cases the frozen
mixture was thawn before adding the next portion of DPAP. The
reactions also took place in frozen mixtures. The solvent was
evaporated in vacuo and the crude product was purified by
column chromatography or by flash column chromatography.
arabino-hex-1-enitol (3) [47], 2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-
O-acetyl-α-D-glucopyranosyl)-1,5-anhydro-D-arabino-hex-1-
enitol (2-acetoxy-maltal peracetate, 4) [48], 2,3,4-tri-O-acetyl-1,5-
anhydro-D-threo-pent-1-enitol (2-acetoxy-3,4-di-O-acetyl-D-xylal,
[49]), 2,3,4-tri-O-acetyl-1,5-anhydro-D-erythro-pent-1-enitol (2-
acetoxy-3,4-di-O-acetyl-D-arabinal) (6) [50], 2,3,4-tri-O-acetyl-
,5-anhydro-L-erythro-pent-1-enitol (2-acetoxy-3,4-di-O-acetyl-L-
arabinal, 7) [50], 3,4,6-tri-O-acetyl-1,5-anhydro-D-lyxo-hex-1-
enitol, (3,4,6-tri-O-acetyl-D-galactal, 9) [51], 3,4,6-tri-O-acetyl-1,5-
anhydro-D-ribo-hex-1-enitol (3,4,6-tri-O-acetyl-D-allal, 10) [52],
,4,6-tri-O-acetyl-1,5-anhydro-L-arabino-hex-1-enitol (3,4-di-O-
acetyl-L-rhamnal, 11) [53], mono-S-acetyl-ethanedithiol (15) [54],
,3,4,6-tetra-O-acetyl--D-glucopyranosyl-(14)-2,3,6-tri-O-
acetyl-1-thio--D-glucopyranose (18) [55], 2,3,4,6-tetra-O-acetyl-
-thio-β-D-glucopyranose (20) [56], 2,3,4,6-tetra-O-acetyl-1-thio-
5
1
3
Propyl 2,3,4,6-tetra-O-acetyl-1-thio-α-D-glucopyranoside
2
25]
(
23)[
1
β-D-mannopyranose (21) [55] and 2,3,4,6-tetra-O-acetyl-1-thio-α-
D-mannopyranose (22) [57] were prepared according to the
literature procedures. 3,4,6-Tri-O-acetyl-D-glucal (8) was
purchased fromCarbosynth. n-propyl-mercaptane (12), i-propyl-
mercaptane (13), thioacetic acid (14), mono-S-acetyl-
ethanedithiol (15), 2-mercaptoethanol (16), thioglycolic acid (17),
A: Compound 1 (0.5 mmol, 165 mg) in toluene (3.0 mL) was
reacted with thiol 12 (2.5 mmol, 225 μL, 5.0 equiv.) at rt. according
to the general method. The crude product was purified by flash
cromatography (n-hexane/acetone 75:25) to give compound 23
(72 mg, 35%) as white crystals. B: Compound 1 (0.5 mmol, 165
mg), thiol 12 (2.5 mmol, 225 μL, 5.0 equiv.) and DPAP (0.05
mmol, 14 mg, 0.1 equiv.) were dissolved in toluene (3.0 mL). The
reaction mixture was irradiated with UV-light at rt for 15 min. The
addition of 5.0 equiv. of thiol 12, 0.1 equiv. of DPAP and the
irradiation was repeated two more times. The solvent was
evaporeted in vacuo and the crude product was purified to give
compound 23 with 54% yield. C: The reaction was repeated at 0
N-acetyl-L-cysteine
(19)
and initiator
2,2-dimethoxy-2-
phenylacetophenone (DPAP) were purchased from Sigma Aldrich
Chemical Co. Optical rotations were measured at room
temperature with a Perkin-Elmer 241 automatic polarimeter. TLC
was performed on Kieselgel 60 F254 (Merck) with detection by UV-
light (254 nm) and immersing into sulfuric acidic ammonium-
molibdenate solution or 5% ethanolic sulfuric acid followed by
heating. Flash column chromatography was performed on Silica
gel 60 (Merck 0.040-0.063 mm), column chromatography was
performed on Silica gel 60 (Merck 0.063-0.200 mm). Organic
o
o
C with 3.0 and 5.0 equiv. of 12 at 0 C, with 46% and 65% yield,
respectively. D: The reaction was repeated at -40 oC with 3.0
equiv. of thiol 12 according to the general method to give 23 with
o
1
8% yield. R
f
= 0.47 (n-hexane/acetone 7:3); m.p. 106-108 C,
[
25]
o
20
[25]
lit. m.p. 105-106 C; [α]
D 3
=+185.7 (c = 0.28 in CHCl ), lit.
2 4 4
solutions were dried over Na SO or MgSO , and concentrated in
2
0
1
1
13
[α]D = +185; H NMR (400 MHz, CDCl ) δ (ppm) 5.66 (d, J = 5.8
vacuum. One- and two-dimensional H, C, COSY and HSQC
3
1
Hz, 1H, H-1), 5.37 (t, J = 9.8 Hz, 1H, H-3), 5.12 – 4.95 (m, 2H, H-
2, H-4), 4.44 (ddd, J = 10.2, 4.8, 2.3 Hz, 1H, H-5), 4.30 (dd, J =
12.2, 4.8 Hz, 1H, H-6a), 4.08 (dd, J = 12.3, 2.2 Hz, 1H, H-6b),
spectra spectra were recorded with Bruker DRX-360 ( H: 360
1
3
13
MHz; C:90 MHz), Bruker DRX-400 (1H: 400 MHz; C:100 MHz)
and Avance II 500 ( H: 500.13 MHz; 13C:125.76 MHz)
spectrometers at 25 ºC. Chemical shifts are referenced to Me Si
: 77.1,
OD: 49.3 for C). MALDI-TOF MS analyses
1
2
.67 – 2.36 (m, 2H, SCH
AcCH ), 2.04 (s, 3H, AcCH
Hz, 2H, SCH CH
C NMR (100 MHz, CDCl
4xC, AcCO), 82.1 (1xC, C-1), 70.8, 70.6, 68.6, 67.6 (4C, skeletal
carbons), 62.0 (1C, C-6), 32.3 (1C, SCH ), 22.8 (1C,
), 20.8, 20.7, 20.7, 20.6 (4C, AcCH ), 13.4 (1C,
S [M+Na]+
2
), 2.09 (s, 3H, AcCH
), 2.02 (s, 3H, AcCH ), 1.63 (q, J = 7.3
CH CH ).
) δ (ppm) 170.6, 169.9, 169.9, 169.6
3
), 2.07 (s, 3H,
4
1
3
3
3
(
0.00 ppm for H) and to the residual solvent signals (CDCl
3
13
2
2
), 0.98 (td, J = 7.4, 2.0 Hz, 3H, SCH
2
2
3
6 3
DMSO-d : 39.5, CD
1
3
3
of the compounds were carried out in the positive reflectron mode
using a BIFLEX III mass spectrometer (Bruker, Germany)
equipped with delayed-ion extraction. 2,5-Dihydroxybenzoic acid
(
2
SCH
CH CH
2
CH
2
CH
3
3
(
3
DHB) was used as matrix and F CCOONa as cationising agent
2
2
CH
3
); ESI-MS: m/z calcd for C17H26NaO
9
in DMF. ESI-TOF HRMS spectra were recorded by a microTOF-
Q type QqTOFMS mass spectrometer (Bruker) in the positive ion
mode using MeOH as the solvent.
The photoinduced reactions were carried out in a borosilicate
vessel by irradiation with a Hg-lamp giving maximum emission at
429.1195, found 429.1190
(
1-Methylethyl) 2,3,4,6-tetra-O-acetyl-1-thio-α-D-
glucopyranoside (24)
365 nm.
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Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
A: Compound 1 (3.0 mmol, 990 mg) was reacted with thiol 13 (9.0
(2-Acetylthio)ethyl
glucopyranoside (26)
2,3,4,6-tetra-O-acetyl-1-thio-α-D-
o
mmol, 845 μL, 3.0 equiv.) in toluene (5.0 mL) at 0 C according to
the general method. The crude product was purified by flash
cromatography (n-hexane/acetone 75:25) to give 24 (682 mg,
A: Compound 1 (660 mg, 2.0 mmol) and thiol 15 (6.0 mmol, 816
μL, 3.0 equiv.) were reacted in toluene (8.0 mL) at rt according to
the general method. The crude product was purified by flash
56%) as yellow powder. B: The reaction was repeated with 5.0
equiv. of 13 at rt to give 24 with 32% yield. C: The reaction was
o
repeated with 5.0 equiv. of 13 at 0 C to give 24 with 68% yield.
chromatography (n-hexane/acetone 8:2) to give 26 (512 mg,
o
D: The reaction was repeated with 3.0 equiv. of 13 at -40 C to
o
5
5%) as colourless syrup. B: The reaction was repeated at 0 C in
give 24 with 50% yield. E: Compound 1 (0.5 mmol, 165 mg), thiol
f
the same scale with 81% yield. R = 0.12 (n-hexane/acetone 8:2).
13 (2.5 mmol, 230 μL, 5.0 equiv.) and DPAP (0.05 mmol, 14 mg,
20
1
[
α]
D
= +164.9 (c= 0.41 in CHCl
3 3
), H NMR (400 MHz, CDCl ) δ
0.1 equiv.) were dissolved in toluene (3.0 mL). The reaction
(
ppm) 5.73 (d, J = 5.8 Hz, 1H, H-1), 5.34 (t, J = 9.8 Hz, 1H, H-3),
mixture was irradiated with UV-light at rt for 15 min. The addition
of 5.0 equiv. of thiol 13, 0.1 equiv. of DPAP and the irradiation
was repeated two more times. The solvent was evaporeted in
5
1
1
.08 – 5.00 (m, 2H, H-2, H-4), 4.43 (ddd, J = 10.1, 4.9, 2.0 Hz,
H, H-5), 4.29 (dd, J = 12.3, 5.0 Hz, 1H, H-6a), 4.09 (dd, J = 12.3,
.9 Hz, 1H, h-6b), 3.21 – 3.02 (m, 2H, SCH
), 2.35 (s, 3H, AcCH ), 2.08 (s, 3H, AcCH
AcCH ), 2.04 (s, 3H, AcCH
MHz, CDCl ) δ (ppm) 194.9 (1C, SAcCO), 170.5, 169.9, 169.8,
69.6 (4C, 4xAcCO), 82.5 (1C, C-1), 70.6, 70.4, 68.5, 67.9 (4C,
skeletal carbons), 62.0 (1C, C-6), 30.6 (1C, SAcCH ), 30.4, 29.2,
0.7, 20.7, 20.6, 20.6 (4C, 4xAcCH ), MALDI-TOF-MS: m/z calcd
[M+Na] 489.086, found 489.578.
2
), 2.85 – 2.66 (m, 2H,
vacuo and the crude product was purified to give compound 24
SCH
2
3
3
), 2.07 (s, 3H,
), 2.02 (s, 3H, AcCH ). C NMR (100
3 3
o
with 51% yield. R
f
= 0.55 (n-hexane/acetone 7:3); m.p. 71-73 C;
13
3
1
[
α]
D
20= +164.2 (c = 0.12 in CHCl
3 3
); H NMR (360 MHz, CDCl ) δ
3
(
ppm)5.75 (d, J = 5.9 Hz, 1H, H-1), 5.34 (t, J = 9.8 Hz, 1H, H-3),
1
5
1
2
2
2
1
.11 – 4.93 (m, 2H, H-2, H-4), 4.46 (ddd, J = 10.2, 4.7, 2.3 Hz,
H, H-5), 4.30 (dd, J = 12.3, 4.7 Hz, 1H, H-6a), 4.07 (dd, J = 12.4,
3
2
3
.3 Hz, 1H, H-6b), 3.00 (hept, J = 6.8 Hz, 1H, SCH(CH
.06, 2.04, 2.02 (4xs, 12H, 4xAcCH ), 1.30 (t, J = 6.8 Hz, 6H,
). C NMR (90 MHz, CDCl ) δ (ppm) 170.6, 169.9,
69.6 (4xC, AcCO), 81.1 (1C, C-1), 70.7, 70.6, 68.7, 67.6 (4C,
), 23.8,
); ESI-MS:
S [M+Na] 429.1195, found 429.1189
3
)
2
), 2.08,
+
for C18H16NaO10S
2
3
13
xSCHCH
3
3
(
2-Hydroxy)ethyl
2,3,4,6-tetra-O-acetyl-1-thio-α-D-
glucopyranoside (27)
skeletal carbons), 62.0 (1C, C-6), 35.0 (1C, SCH(CH
3.5 (2C, 2xi-PrCH ), 20.8, 20.7, 20.6 (4C, 4xAcCH
m/z calcd for C17
3 2
)
2
3
3
+
A: Compound 1 (165 mg, 0.5 mmol) and thiol 16 (71 μL, 1.0 mmol,
H
26NaO
9
o
2
.0 equiv.) were reacted in toluene (3.0 mL) at -80 C according
to the general method. The crude product was purified by flash
column chromatography (n-hexane/acetone 7:3) to give 27 (142
mg, 70%) as colourless syrup. B: The reaction was repeated at rt
2
,3,4,6-Tetra-O-acetyl-1-S-acetyl-1-thio-α-D-glucopyranose
[58]
(
25)
f
to give 27 with 40% yield. R = 0.17 (n-hexane/acetone 7:3);
A: Compound 1 (330 mg, 1.0 mmol) was reacted with thiol 14
429 μL, 6.0 mmol, 6.0 equiv.) in toluene (3.0 mL) at -20 o
according to the general method. The crude product was purified
20
1
[
α]
D
= +89.3 (c=0.43 in CHCl
3 3
); H NMR (400 MHz, CDCl ) δ
(
C
(
ppm) 5.71 (d, J = 5.8 Hz, 1H, H-1), 5.35 (t, J = 9.8 Hz, 1H, H-3),
5
1
1
2
2
.07 – 4.99 (m, 2H, H-2, H-4), 4.47 (ddd, J = 10.1, 4.9, 1.9 Hz,
H, H-5), 4.26 (dd, J = 12.3, 5.2 Hz, 1H, H-6a), 4.12 (dd, J = 12.3,
.9 Hz, 1H, H-6b), 3.77 (d, J = 6.5 Hz, 2H), 2.86 – 2.77 (m, 1H),
by flash column chromatography (n-hexane/acetone 8:2) to give
25 (37 mg, 9%) as yellow powder. B: Compound 1 (660 mg, 2.0
mmol), thiol 14 (16.0 mmol, 1.146 mL, 8.0 equiv) and DPAP (0.1
.77 – 2.68 (m, 1H), 2.10 (s, 3H, AcCH
.05 (s, 3H, AcCH ), 2.03 (s, 3H, AcCH
) δ (ppm) 170.8, 170.1, 169.8 84C, 4xAcCO), 82.7 (1C, C-
), 70.7, 70.3, 68.6, 67.9 (4C, skeletal carbon), 62.1, 61.6 (2C, C-
3
), 2.08 (s, 3H, AcCH
3
),
mmol, 25 mg, 0.1 equiv.) were dissolved in toluene (3.0 mL). The
13
3
3
). C NMR (100 MHz,
o
reaction mixture was cooled to -20 C and was irradiated with UV-
CDCl
3
light for 15 min. The addition of 8.0 equiv. of thiol 14, 0.1 equiv. of
DPAP and the irradiation was repeated two more times. The
solvent was evaporeted in vacuo and the crude product was
purified by flash column chromatography (n-hexane/acetone 8:2)
to give compound 25 with 19% yield. C: Compound 1 (660 mg,
1
6
4
4
, CH
xAcCH
31.0988, found 431.0982
2
OH), 34.0 (1C, SCH
2
), 20.8, 20.8, 20.7, 20.7 (4C,
[M+Na]+
3
); ESI-MS: m/z calcd for
16
C H24NaO10S
2
.0 mmol), thiol 14 (16.0 mmol, 1.146 mL, 8.0 equiv) and DPAP
2
-(2,3,4,6-Tetra-O-acetyl-1-thio-α-D-glucopyranosyl) acetic
(
0.1 mmol, 25 mg, 0.1 equiv.) were dissolved in toluene (3.0 mL).
acid (28)
The reaction mixture was irradiated with UV-light at rt for 15 min.
The addition of 8.0 equiv. of thiol 14, 0.1 equiv. of DPAP and the
irradiation was repeated two more times. The solvent was
evaporeted in vacuo and the crude product was purified to give
compound 25 with 9% yield. D: The reaction was repeated at
A: Compound 1 (330 mg, 1.0 mmol) in a mixture of toluene (0.6
mL) and MeOH (1.2 mL) was reacted with thiol 17 (140 μL, 2.0
mmol, 2.0 equiv.) at -80 C according to the general method. The
o
o
crude product was purified by flash cromatography (CHCl
2
/MeOH
room temperature and at -40 C using 6.0 equiv of thiol according
to the general method, but no product could be isolated. R = 0.17
f
95:5) to give compound 28 (280 mg, 67%) as white foam. B: The
o
[58]
o
reaction was repeated at rt to give 28 with 55% yield. R
f
= 0.46
(
n-hexane/acetone 8:2); m.p. 129-132 C, lit. m.p. 123-125 C
20
1
2
0
[58]
20
1
(CH
2
Cl
2
/MeOH 9:1); [α]
) δ (ppm) 10.31 (br. s, 1H, COOH), 5.78 (d, J =
.8 Hz, 1H, H-1), 5.37 (t, J = 9.8 Hz, 1H, H-3), 5.18 – 5.00 (m, 2H,
D 3
= +175.6 (c=0.25 in CHCl ), H NMR
[
α]
D
= +123.6 (c = 0.11 in CHCl
3 D
), lit. [α] = +143.5; H NMR
(
400 MHz, CDCl
3
(
400 MHz, CDCl ) δ (ppm) 6.22 (d, J = 5.2 Hz, 1H, H-1), 5.24 (dd,
3
5
J = 10.1, 5.1 Hz, 1H, H-2), 5.18 (t, J = 9.5 Hz, 1H), 5.10 (t, J = 9.5
Hz, 1H) (H-3 and H-4), 4.28 (dd, J = 12.5, 4.1 Hz, 1H, H-6a), 4.05
H-2, H-4), 4.42 (d, J = 10.4 Hz, 1H, H-5), 4.28 (dd, J = 12.5, 4.3
Hz, 1H, H-6a), 4.07 (d, J = 10.0 Hz, 1H, H-6b), 3.44 (d, J = 15.6
Hz, 1H, SCH
AcCH
AcCH
(
1
dd, J = 12.5, 2.2 Hz, 1H, H-6b), 3.96 (ddd, J = 9.9, 4.0, 2.3 Hz,
H, H-5), 2.43 (s, 3H, AcCH ), 2.08 (s, 3H, AcCH ), 2.03 (s, 3H,
AcCH ), 2.02 (s, 3H, AcCH ), 2.02 (s, 3H, AcCH
MHz, CDCl ) δ (ppm) 170.7, 170.1, 169.5, 169.4 (4C, 4xAcCO),
0.5 (1C, C-1), 71.6, 71.3, 69.2, 68.0 (4C, skeletal carbons), 61.7
1C, C-6), 31.6 (1C, SAcCH ), 20.8, 20.7, 20.7 (4C, 4xOAcCH );
22NaO10S [M+Na]+ 429.0831, found
ESI-MS: m/z calcd for C16
29.0826
2
a), 3.26 (d, J = 15.7 Hz, 1H, SCH
), 2.08 (s, 3H, AcCH ), 2.05 (s, 3H, AcCH
). C NMR (100 MHz, CDCl ) δ (ppm) 174.5 (1C, COOH),
2
b), 2.10 (s, 3H,
3
3
). 1 C NMR (100
3
3
3
3
) 2.02 (s, 3H,
3
3
3
13
3
3
3
1
6
70.9, 170.0, 169.9, 169.7 (4C, 4xAcCO), 82.1 (1C, C-1), 70.4,
8.3, 68.0 (3C, skeletal carbons), 61.7 (1C, C-6), 31.5 (1C,
COOH), 20.7, 20.6, 20.5 (3C, 3xAcCH ); MALDI-TOF-MS:
22NaO11S [M+Na] : 445.078 found: 445.077;
8
(
3
3
CH
m/z calcd for C16
2
3
H
+
H
4
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
2
,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-
(CH
2
Cl
2
/acetone 110:2) to give 31 (46 mg, 23%) as yellow syrup.
o
acetyl-1-thio-β-D-glucopyranosyl-(1→1)-2,3,4,6-tetra-O-
acetyl-α-D-glucopyranoside (29)
B: The reaction was repeated at -40 C in the same scale with 22%
yield C: The reaction was repeated at 0 C in the same scale with
o
15% yield. D: Compound 2 (3.0 mmol, 990 mg), thiol 14 (18.0
mmol, 1.29 mL, 6.0 equiv.) and DPAP (0.3 mmol, 75 mg, 0.1
equiv.) were dissolved in toluene (5.0 mL). The reaction mixture
was cooled to -40 C and was irradiated with UV-light at rt for 15
min. The addition of 6.0 equiv. of thiol 14, 0.1 equiv. of DPAP and
the irradiation was repeated two more times. The solvent was
evaporeted in vacuo and the crude product was purified to give
31 (250 mg, 26%) as yellow syrup. E: The reaction was repeated
at room temperature using 6.0 equiv. of thiol according to the
A: Compound 1 (66 mg, 0.2 mmol) and thiol 18 (196 mg, 0.3
mmol, 1.5 equiv.) were reacted in a mixture of toluene (1.0 mL)
o
o
and DMF (0.5 mL) at 0 C according to the general method. The
crude product was purified by flash cromatography
(
2 2
CH Cl /acetone 94:6) to give compound 29 (20 mg, 10%) as
o
white foam. B: The reaction was repeated at -20 C in the same
scale with 14% yield. C: The reaction was repeated at -40 C in
o
the same scale with 29% yield. D: The reaction was repeated at -
general method, but no product could be isolated. R
f
= 0.29
o
8
0
C in the same scale with 58% yield. E: The reaction was
= 0.24
o
[59]
(
CH
C [α]
2
Cl
D
2
20
/acetone = 98:2); m.p. 119-121 C (Et
2
O), lit. m.p. 119
repeated at rt in the same scale with 5% yield. R
f
o
[59]
20
1
= +120.9 (c= 0.21 in CHCl
) δ (ppm) 6.27 (d, J = 5.5 Hz, 1H, H-1), 5.48 (dd,
J = 11.0, 5.5 Hz, 1H, H-2), 5.44 (dd, J = 3.3, 1.2 Hz, 1H, H-4),
.04 (dd, J = 11.0, 3.3 Hz, 1H, H-3), 4.18 (td, J = 6.5, 1.1 Hz, 1H,
H-5), 4.11 – 4.03 (m, 2H, H-6ab), 2.42 (s, 3H, SAcCH ), 2.15 (s,
), 2.00 (s,
) δ (ppm) 191.8 (1C,
3 D
), lit. [α] = +48; H NMR
20
1
(
(
CH
2
Cl
2
/acetone 9:1); [α]
D 3
= +104.4 (c=0.32 in CHCl ), H NMR
(
400 MHz, CDCl
3
500 MHz, CDCl
3
) δ (ppm) 5.93 (d, J = 5.7 Hz, 1H, H-1’’), 5.41 (d,
J = 4.0 Hz, 1H, H-1), 5.38 – 5.30 (m, 1H), 5.32 – 5.24 (m, 1H),
.23 (t, J = 9.0 Hz, 1H), 5.13 (t, J = 9.8 Hz, 1H), 5.06 (t, J = 9.9
Hz, 2H), 4.99 (dd, J = 10.3, 5.7 Hz, 1H), 4.91 (t, J = 9.6 Hz, 1H),
.86 (dd, J = 10.5, 4.0 Hz, 1H), 4.60 (d, J = 10.1 Hz, 1H), 4.57
5
5
3
3
3
H, AcCH
H, AcCH
3
), 2.03 (s, 3H, AcCH
3
), 2.02 (s, 3H, AcCH
3
4
13
3
). C NMR (100 MHz, CDCl
3
(
(
dd, J = 12.4, 2.5 Hz, 1H), 4.42 (dd, J = 12.7, 2.8 Hz, 1H), 4.33
dt, J = 10.3, 2.6 Hz, 1H), 4.29 – 4.24 (m, 2H), 4.10 (dt, J = 12.3,
SAcCO), 170.4, 170.2, 170.0, 169.7 (4C, 4xOAcCO), 81.2 (1C,
C-1), 70.4, 69.0, 67.3, 66.5 (4C, skeletal carbons), 61.2 (1C, C-6),
3.0 Hz, 3H), 4.05 (dd, J = 12.5, 2.4 Hz, 2H), 4.01 – 3.94 (m, 3H),
3
1.6 (1C, SAcCH
3
), 20.7, 20.7, 20.7 (4C, 4xAcCH
3
); MALDI-TOF-
3
.70 (ddd, J = 9.8, 4.1, 2.5 Hz, 1H), 2.15 (s, 3H), 2.11 (d, J = 1.3
+
MS: m/z calcd for C16
H22NaO10S [M+Na] 429.083, found 429.199
1
3
3
Hz, 8H), 2.04 – 1.98 (m, 33H, 11xAcCH ). C NMR (126 MHz,
CDCl
69.6, 169.6, 169.5 (11C, 11xAcCH
C-1’, C-1’’), 76.3, 72.3, 72.0, 70.5, 70.4, 70.2, 69.5, 68.8, 68.7,
3
) δ (ppm) 170.7, 170.7, 170.5, 170.3, 170.0, 170.0, 169.7,
(
2-Acetylthio)ethyl
2,3,4,6-tetra-O-acetyl-1-thio-α-D-
1
3
), 95.8, 82.0, 81.8 (3C, C-1,
galactopyranoside (32)
6
6
1
1
8.1, 68.0 (12C, skeletal carbons), 62.6, 61.6, 61.3 (3C, C-6, C-
A: Compound 2 (660 mg, 2.0 mmol) and thiol 15 (816 μL, 6.0
mmol, 3.0 equiv.) were reacted in toluene (5.0 mL) at room
temperature according to the general method. The crude product
’, C-6’’), 21.0, 21.0, 20.9, 20.9, 20.8, 20.8, 20.7 (11C,
+
3
1xAcCH ); ESI-MS: m/z calcd for C40H54NaO26S [M+Na]
005.252, found 1005.250.
was purified by flash column chromatography (CH
2 2
Cl /acetone
9
5/5) to give 32 (473 mg, 52%) as yellow oil. B: Compound 2 (110
Propyl
30)
2,3,4,6-tetra-O-acetyl-1-thio-α-D-galactopyranoside
mg, 0.3 mmol) and thiol 15 (136 μL, 0.9 mmol, 3.0 equiv.) were
(
reacted in toluene (3.0 mL) at 0 oC according to the general
o
method with 69% yield. C: The reaction was repeated at -40 C in
A: Compound 2 (165 mg, 0.5 mmol) and thiol 12 (225 μL, 2.5
mmol, 5.0 equiv.) were reacted in toluene (2.0 mL) at rt according
to the general method. The crude product was purified by flash
cromatography (n-hexane/acetone 85:15) to give compound 30
the same scale with 41% yield. R
f
= 0.67 (CH
2
Cl
), H NMR (400 MHz, CDCl
ppm) 5.80 (d, J = 5.5 Hz, 1H, H-1), 5.46 – 5.43 (m, 1H), 5.27 (dd,
J = 10.8, 5.6 Hz, 1H, H-2), 5.19 (dd, J = 10.8, 3.2 Hz, 1H, H-3),
.58 (t, J = 6.4 Hz, 1H), 4.12 (d, J = 6.4 Hz, 2H), 3.20-3.02 (m, 2H,
SCH ), 2.84 – 2.76 (m, 1H, SCH a), 2.75 – 2.65 (m, 1H, SCH b),
.35 (s, 3H, AcCH ), 2.15 (s, 3H, AcCH ), 2.08 (s, 3H, AcCH ),
.04 (s, 3H, AcCH ), 1.99 (s, 3H, AcCH ). C NMR (100 MHz,
) δ (ppm) 194.9, 170.3, 170.1, 170.0, 169.8 (5C, 5xAcCO),
2.8 (1C, C-1), 68.0, 67.9, 67.8, 66.8 (4C, skeletal carbons), 61.9
1C, C-6), 30.6 (1C, SAcCH ), 30.1, 29.2 (2C, 2xSCH ), 20.8, 20.6,
). MALDI-TOF-MS: m/z calcd for
2
/acetone 95:5),
20
1
[
α]
D
= +164.0 (c=0.52 in CHCl
3
3
) δ
(
(
0
57 mg, 28%) as white powder. B: The reaction was repeated at
4
o
C in the same scale with 26% yield. C: The reaction was
2
2
2
o
repeated at -40 C in the same scale with 56% yield. D: The
reaction was repeated at -80 C in the same scale with 22% yield.
R
=
2
2
3
3
3
o
13
3
3
o
20
f
= 0.30 (CH = +167.8 (c
2
Cl
2
1
/acetone 9:1); m.p. 77-80 C; [α]
D
CDCl
3
0.27 in CHCl ); H NMR (400 MHz, CDCl ) δ (ppm) 5.72 (d, J =
3
3
8
5.2 Hz, 1H, H-1), 5.45 (dd, J = 3.0, 1.0 Hz, 1H, H-3), 5.25 (d, J =
5.2 Hz, 1H, H-2), 5.23 (d, J = 3.1 Hz, 1H, H-4), 4.60 (t, J = 6.7 Hz,
1H, H-5), 4.12 (s, 1H, H-6a), 4.10 (d, J = 0.6 Hz, 1H, H-6b), 2.57
(
3
2
2
C
0.6 (4C, 4xOAcCH
3
H26NaO10S [M+Na] 489.087, found 489.080
18 2
+
(
ddd, J = 12.8, 7.7, 6.7 Hz, 1H, SCH
2
a), 2.52 – 2.43 (m, 1H,
), 2.08 (s, 3H, AcCH ), 2.05 (s, 3H,
3
), 1.63 (ddd, J = 14.8, 7.4, 2.6 Hz, 2H,
SCH
2
b), 2.15 (s, 3H, AcCH
), 2.00 (s, 3H, AcCH
CH CH ), 0.99 (t, J = 7.3 Hz, 3H, CH
MHz, CDCl ) δ (ppm) 170.4, 170.3, 169.9 (4C, 4xAcCO), 82.4
1C, C-1), 68.2, 68.1, 66.5 (3C, skeletal carbons), 61.9 (1C, C-6),
3
3
(
2-Hydroxyethyl)
2,3,4,6-tetra-O-acetyl-1-thio-α-D-
AcCH
CH
3
galactopyranoside (33)
13
2
2
3
2 2 3
CH CH ). C NMR (100
3
A: Compound 2 (1.32 g, 4.0 mmol) and thiol 16 (844 μL, 12.0
mmol, 3.0 equiv.) were reacted in toluene (5.0 mL) at rt according
to the general method. The crude product was purified by flash
column chromatography (n-hexane/EtOAc 7:3) to give 33 (938
(
3
4
C
2.1 (1C, SCH
2
), 22.9 (1C, CH
CH CH
2
CH
2 3
CH ), 20.9, 20.8, 20.7 (4C,
xAcCH ), 13.6 (1C, CH
3
2
2
3
); MALDI-TOF-MS: m/z calcd for
+
17
H26NaO
9
S [M+Na] 429.120, found 429.144
mg, 58%) as white foam. B: The reaction was repeated with 2.0
o
equiv. of thiol at -80 C with 86% yield. R
f
= 0.42 (n-hexane/EtOAc
2
,3,4,6-tetra-O-acetyl-1-S-acetyl-1-thio-α-D-galactopyranose
20
1
1
:1), [α]
δ (ppm) 5.77 (d, J = 5.2 Hz, 1H, H-1), 5.45 (s, 1H), 5.26 (dd, J =
0.7, 5.4 Hz, 1H, H-2), 5.19 (dd, J = 10.8, 2.3 Hz, 1H, H-3), 4.63
D 3 3
= +180.2 (c=0.47 in CHCl ); H NMR (400 MHz, CDCl )
[59]
(
31)
1
A: Compound 2 (165 mg, 0.5 mmol) and thiol 14 (280 μL, 3.0
(t, J = 5.9 Hz, 1H), 4.13 (d, J = 6.1 Hz, 2H), 3.88 (t, J = 5.6 Hz,
1H), 3.74 (dd, J = 17.0, 5.4 Hz, 3H), 2.88 (t, J = 5.9 Hz, 2H), 2.85
– 2.79 (m, 1H), 2.76 – 2.66 (m, 2H, SCH ), 2.16 (s, 3H, AcCH ),
mmol, 6.0 equiv) were reacted in a mixture of toluene (1.0 mL)
o
and methanol (1.0 mL) at -80 C according to the general method.
2
3
The crude product was purified by flash silica gel chromatography
3 3 3
2.09 (s, 3H, AcCH ), 2.07 (s, 3H, AcCH ), 2.00 (s, 3H, AcCH ).
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
1
3
C NMR (100 MHz, CDCl
3
) δ (ppm) 170.4, 170.1, 169.8 (4C,
(CH
2
Cl
2
/acetone 96/4) to give 36 (146 mg, 36%) as yellow
o
4
xAcCO), 82.8 (1C, C-1), 67.9, 67.8, 67.7, 66.7 (4C, skeletal
powder. B: The reaction was repeated at -40 C in the same scale
to give 36 with 50% yield. C: The reaction was repeated at -40 C
in the same scale using 3 x 8 equiv. of thiol 14 to give 36 with 56%
yield. D: The reaction was repeated at -80 C in the same scale
o
carbons), 61.8, 61.4, 60.2, 33.3 (1C, SCH ), 20.6, 20.5, 20.4 (4C,
2
+
4
xAcCH
3
). MALDI-TOF-MS: m/z calcd for C16
H24NaO10S [M+Na]
o
431.099, found 431.094
using 3 x 8 equiv. of thiol 14 to give 36 with 63% yield. R
f
= 0.28
o
20
(
CH
2
Cl
2
/acetone 9:1); m.p. 140-143 C; [α]
D
= +101.6 (c=0.25 in
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-
1
CHCl
3
); H NMR (400 MHz, CDCl
3
) δ (ppm) 6.07 (d, J = 5.1 Hz,
acetyl-1-thio-β-D-glucopyranosyl-(1→1)-2,3,4,6-tetra-O-
acetyl-α-D-galactopyranoside (34)
1
–
H, NHAc), 5.76 (d, J = 8.8 Hz, 1H H-1), 5.15 – 5.03 (m, 1H), 4.90
4.78 (m, 1H), 4.60 (ddd, J = 11.2, 8.7, 5.2 Hz, 1H), 4.19 (dd, J
=
3
12.5, 4.1 Hz, 1H, H-6a), 3.99 (dd, J = 12.5, 2.4 Hz, 1H, H-6b),
.87 (ddd, J = 10.1, 4.1, 2.4 Hz, 1H, H-5), 2.40 (s, 3H, SAcCH ),
), 1.97 (s, 3H,
). 13C NMR (100 MHz, CDCl
) δ
), 171.4, 170.6, 169.9, 169.1 (4xC,
), 82.3 (1C, C-1), 71.9, 71.8, 67.7 (3C, skeletal carbons),
), 23.0 (1C,
). ESI-MS: m/z calcd
S [M+Na] 428.0991, found 428.0985
A: Compound 2 (83 mg, 0.25 mmol) and thiol 18 (225 mg, 0.375
3
mmol, 1.5 equiv.) were reacted in a mixture of toluene (2.0 mL)
o
3 3
2.01 (s, 3H, OAcCH ), 1.97 (s, 3H, OAcCH
OAcCH
and N-N-dimethylformamide (1.0 mL) at -40 C according to the
3
), 1.86 (s, 3H, NHCAcH
3
3
general method. The crude product was purified by flash column
(
ppm) 190.7 (1C, SCOCH
3
chromatography (n-hexane/acetone 7:3) to give 34 (86 mg, 35%)
o
COCH
3
as white powder. B: The reaction was repeated at -80 C to give
61.7 (1C, C-6), 51.6 (1C, C-2), 31.6 (1C, SCOCH
3
3
f
4 with 75% yield. R = 0.15 (n-hexane/acetone 7:3), m.p.: 78-81
o
20
1
NHCOCH ), 20.6, 20.6, 20.5 (3C, OCOCH
for C16H23NNaO
9
3
3
C , [α]
δ (ppm) 5.99 – 5.93 (m, 1H, H-1), 5.45 (d, J = 1.6 Hz, 1H, H-1’’),
D 3 3
= +116.1 (c = 0.33 in CHCl ), H NMR (400 MHz, CDCl )
+
5
5
.42 (d, J = 3.9 Hz, 1H), 5.39 – 5.30 (m, 2H), 5.27 – 5.18 (m, 2H),
.14 (dd, J = 11.0, 3.2 Hz, 1H), 5.06 (t, J = 9.9 Hz, 1H), 4.92 (d, J
2
-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-1-thio-α-D-
glucopyranosyl-(11)-2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-
acetyl-α-D-glucopyranosyl)-β-D-glucopyranoside (37)
=
1
=
9.7 Hz, 1H), 4.89 – 4.82 (m, 1H), 4.62 (d, J = 10.0 Hz, 1H, H-
’), 4.55 (d, J = 2.3 Hz, 1H), 4.51 (d, J = 6.6 Hz, 1H), 4.26 (ddd, J
16.8, 10.4, 6.7 Hz, 3H), 4.16 (d, J = 3.6 Hz, 1H), 4.14 – 4.10 (m,
H), 4.09 – 3.91 (m, 5H), 3.75 – 3.69 (m, 1H), 2.15 (d, J = 4.1 Hz,
3
6
A: Compound 3 (110 mg, 0.3 mmol) and thiol 18 (254 mg, 0.38
mmol, 1.3 equiv.) were reacted in a mixture of toluene (2.0 mL)
and DMF (1.0 mL) at -80 C according to the general method. The
crude product was purified by flash column chromatography
1
3
H), 2.11 (s, 3H), 2.07 – 1.98 (m, 30H). C NMR (100 MHz,
) δ (ppm) 170.6, 170.4, 170.3, 170.3, 170.1, 170.0, 169.9,
69.5 (11C, 11xAcCO), 95.6 (1C, C-1’’), 82.1, 81.7 (2C, C-1, C-
’), 76.6, 76.3, 72.2, 71.9, 70.1, 69.3, 68.6, 68.0, 67.8, 67.3, 67.2
o
CDCl
1
1
3
(CH
2 2
Cl /MeOH 95/5) to give 37 (98 mg, 33%) as colorless syrup.
o
(
2
12C, skeletal carbons), 62.6, 61.5, 60.3 (3C, C-6, C-6’, C-6’’),
0.9, 20.8, 20.7, 20.7 (11C, 11xAcCH ). MALDI-TOF-MS: m/z
54NaO26S [M+Na] 1005.252, found 1005.318.
B: The reaction was repeated at -40 C in the same scale to give
2
0
3
37 with 65% yield. R
f
= 0.23 (CH
), H NMR (400 MHz, CDCl
8.2 Hz, 1H, NH), 5.74 (d, J = 5.3 Hz, 1H, H-1’’), 5.36 (d, J = 3.9
Hz, 1H, H-1), 5.29 (t, J = 10.0 Hz, 1H), 5.19 (t, J = 7.4 Hz, 1H),
2
Cl
2
/MeOH 95:5), [α]
D
= +90.4
+
1
calcd for C40
H
(c=0.23 in CHCl
3
3
) δ (ppm) 5.78 (d, J
=
(
2-Acetylthio)ethyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-1-
5
1
.14 (t, J = 8.1 Hz, 1H), 5.00 (t, J = 9.9 Hz, 1H, ), 4.97 – 4.91 (m,
H), 4.89 (t, J = 8.4 Hz, 1H), 4.80 (dd, J = 10.5, 4.0 Hz, 1H), 4.59
thio-α-D-glucopyranoside (35)
(
=
d, J = 10.0 Hz, 1H), 4.52 (dd, J = 12.1, 1.5 Hz, 1H), 4.42 (ddd, J
11.5, 8.2, 5.4 Hz, 1H), 4.33 (dd, J = 12.6, 2.4 Hz, 1H), 4.21 (dd,
J = 12.8, 3.8 Hz, 1H), 4.17 (d, J = 10.2 Hz, 1H), 4.06 (dd, J = 12.2,
A: Compound 3 (660 mg, 2.0 mmol), and thiol 15 (408 μL, 3.0
mmol, 1.5 equiv) were reacted in toluene (10 mL) at rt according
to the general method. The solvent was evaporated under
reduced pressure and the crude product was purified by flash
4
3
.0 Hz, 2H), 4.01(dd, J= 5.7, 1.7 Hz, 1H), 3.97 (d, J = 5.6 Hz, 1H),
.95 – 3.87 (m, 2H), 3.67 (d, J = 9.6 Hz, 1H), 2.10 (s, 3H, AcCH ),
), 2.05 (s, 3H, AcCH ), 1.97 (dd, J = 9.6, 5.2
), 1.88 (s, 3H, AcCH
) δ (ppm) 171.7, 170.6, 170.5, 170.3, 170.1, 169.9, 169.4,
169.1 (11C, 11xAcCO), 95.7 (1C, C-1’’), 83.0, 81.7 (2C, C-1, C-
’), 76.6, 76.1, 72.1, 71.8, 71.1, 70.0, 69.3, 69.3, 68.5, 67.9, 67.4
11C, skeletal carbons), 62.4, 61.4, 61.2 (3C, C-6, C-6’, C-6’’),
2.5 (1C, C-2) , 23.0, 20.9, 20.7, 20.7, 20.6 (11C, 11xAcCH ),
55NNaO25S [M+Na] 1004.2682, found
3
2 2
chromatography (CH Cl /acetone 9:1) to give 35 (432 mg, 46%)
o
2.06 (s, 3H, AcCH
Hz, 21H, 7x AcCH
CDCl
3
3
as white foam. B: The reaction was repeated at 0 C in the same
13
o
3
3
). C NMR (100 MHz,
scale with 83% yield. C: The reaction was repeated at -80 C in
3
the same scale with 45% yield. R
f
= 0.25 (CH
2
Cl
), H NMR (400 MHz, CDCl
ppm) 5.79 (d, J = 8.7 Hz, 1H, NH), 5.50 (d, J = 5.4 Hz, 1H, H-1),
.15 – 4.99 (m, 2H, H-2, H-4), 4.51 (ddd, J = 10.7, 8.7, 5.4 Hz, 1H,
2
/acetone 9:1),
2
0
1
[
α]
D
= + 108.5 (c= 0.16 in CHCl
3
3
) δ
1
(
5
(
5
3
H-5), 4.36 (ddd, J = 9.6, 4.8, 2.2 Hz, 1H), 4.26 (dd, J = 12.3, 4.9
Hz, 1H, H-6a), 4.09 (dd, J = 12.3, 2.3 Hz, 1H, H-6b), 3.16 (ddd, J
+
ESI-MS: m/z calcd for C40
004.2680
H
1
=
13.6, 8.6, 6.3 Hz, 1H), 3.06 (ddd, J = 13.6, 8.7, 6.3 Hz, 1H), 2.81
qdd, J = 13.5, 8.6, 6.3 Hz, 2H, CH ), 2.34 (s, 3H, COCH ), 2.08
s, 3H, COCH ), 2.04 (s, 3H, COCH ), 2.03 (s, 3H, COCH
s, 3H, COCH
70.7, 170.0, 169.3, (5C, 5xCOCH
C-5, C-4, C-3), 62.1 (C-6), 52.5 (C-2), 31.7 (SCH
SCOCH ), 29.5 (SCH ), 23.3, 20.8, 20.7 (5C, 5xCOCH ). MALDI-
M+Na : 488.102 found ,
(
(
(
1
(
(
2
3
N-Acetyl-S-[4-O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-
2,3,6-tri-O-acetyl-1-thio-α-D-glucopyranosyl]-L-cysteine (38)
3
3
3
), 1.96
1
3
3
). C NMR (100 MHz, CDCl
3
) δ (ppm) 195.0, 171.6,
3
) 85.1 (C-1), 71.3, 68.7, 68.2
), 30.7,
2
A: Compound 4 (309 mg, 0.5 mmol), and thiol 19 (160 mg, 1.0
mmol, 2.0 equiv.) and DPAP (15 mg, 0.05 mmol, 0.1 equiv.) were
dissolved in a mixture of toluene (2.0 mL) and MeOH (1.0 mL).
3
2
3
+
9 2
TOF-MS: m/z calcd for C18H27NO S
found 488.100
o
The reaction mixture was cooled to -20 C and was irradiated with
UV light (365 nm) for 15 minutes. The addition of DPAP and
irradiation were repeated four times more. The solvent was
evaporated under reduced pressure. The crude product was
2
-Acetamido-2-deoxy-3,4,6-tri-O-acetyl-1-S-acetyl-1-thio-α-D-
glucopyranose (36)
purified by flash cromatography (CH
2 2
Cl /MeOH 95:5) to give 38
(
292 mg, 75%) as colourless crystals. B: The reaction was
A: Compound 3 (329 mg, 1.0 mmol) and thiol 14 (429 μL, 6.0
mmol, 6.0 equiv.) were reacted at -20 C in a mixture of toluene
o
o
repeated at -40 C in the same scale to give 38 with 79% yield. C:
The reaction was repeated at -80 C in the same scale to give 38
with 56% yield. R
o
(
2.0 mL) and MeOH (1.0 mL) according to the general method.
o
f
= 0.34 (CH
= +116.7 (c = 0.27 in CHCl
2
Cl
3
2
/MeOH 9:1); m.p. 141-144 C;
The crude product was purified by flash column chromatography
2
0
1
[
α]
D
); H NMR (400 MHz, DMSO) δ
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
3 3 3
3H, AcCH ), 1.98 (s, 3H, AcCH ) δ
). 13C NMR (100 MHz, CDCl
(
ppm) 7.85 (d, J = 7.8 Hz, 1H, NH), 5.54 (d, J = 5.3 Hz, 1H, H-1’),
5
=
.25 (d, J = 2.7 Hz, 1H, H-1), 5.20 (t, J = 10.2 Hz, 2H), 5.00 (t, J
9.8 Hz, 1H), 4.93 – 4.89 (m, 1H, H-2’), 4.87 (dd, J= 10.7, 3.1 Hz,
(ppm) 170.7, 170.7, 170.5, 170.4, 170.2, 170.1, 169.8, 169.7,
169.6, 169.4 (11C, 11xAcCO), 95.6 (1C, C-1’’), 82.2, 82.0 (2C, C-
1, C-1’), 77.0, 72.3, 72.1, 71.8, 71.2, 70.8, 70.1, 69.2, 68.9, 68.4,
67.8, 65.0 (12C, skeletal carbons), 62.6, 62.1, 61.2 (3C, C-6, C-
6’, C-6’’), 20.9, 20.8, 20.8, 20.7, 20.7, 20.7, 20.6, 20.6 (11C,
1
–
1
2
H), 4.41 (d, J = 11.2 Hz, 1H), 4.27 (d, J = 7.1 Hz, 2H, H-α), 4.22
4.13 (m, 2H), 3.98 (dd, J = 18.9, 10.2 Hz, 3H), 3.03 – 2.93 (m,
H, H-β), 2.87 (dd, J = 12.7, 7.9 Hz, 1H, H-β), 2.08 (s, 3H, AcCH
.02 (s, 3H, AcCH
3
),
), 1.96 (s, 3H,
). C NMR (100 MHz, DMSO) δ (ppm)
3
), 2.01 – 1.97 (m, 12H, 4x AcCH
3
11xAcCH
3
); MALDI-TOF-MS: m/z calcd for
40
C H54NaO26S
1
3
+
AcCH
3
), 1.87 (s, 3H, AcCH
3
[M+Na] 1005.252, found 1005.303.
1
8
6
70.3, 170.1, 170.0, 169.6, 169.6, 169.5, 169.2, 169.0 (8C,
xAcCO), 95.7 (1C, C-1’), 82.1 (1C, C-1), 73.7, 71.6, 70.1, 69.5,
8.9, 68.2, 68.1, 67.7 (8C, skeletal carbons), 62.7, 61.4 (2C, C-6,
2
,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-
acetyl-1-hio-α-D-glucopyranosyl-(1→1)-2,3,4,6-tetra-O-
acetyl-α-D-mannopyranoside (41)
C-6’), 53.8 (1C, C-α), 33.1 (1C, C-β), 22.8 (1C, NAcCH
0.5, 20.4, 20.3 (7C, 7xOAcCH ); MALDI-TOF-MS: m/z calcd for
43NnaO20S [M+Na] 804.200, found 804.139.
3
), 20.6,
2
3
+
31
C H
Compound 4 (309 mg, 0.5 mmol) and thiol 22 (273 mg, 0.75
mmol, 1.5 mmol) were reacted in toluene (2.0 mL) at -80 C
according to the general method. The crude product was purified
by flash cromatography (hexane/acetone 7/3) to give 41 (481 mg,
o
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-
acetyl-1-thio-α-D-glucopyranosyl-(1→1)-2,3,4,6-tetra-O-
acetyl-β-D-glucopyranoside (39)
20
98%) as white foam. R
f D
= 0.25 (n-hexane/acetone 6:4), [α] =
1
+
187,1 (c=0.21 in CHCl ), H NMR (400 MHz, CDCl ) δ (ppm)
3
3
A: Compound 4 (309 mg, 0.5 mmol) was dissolved in toluene (2.0
mL) and thiol 20 (273 mg, 0.75 mmol, 1.5 equiv.) and DPAP (15
mg, 0.05 mmol, 0.1 equiv.) were added. The reaction mixture was
5.70 (d, J = 5.6 Hz, 1H, H-1’’), 5.46 – 5.24 (m, 7H), 5.07 (t, J = 9.8
Hz, 1H), 4.99 (dd, J = 9.3, 5.7 Hz, 1H, H-2’’), 4.88 (dd, J = 10.4,
3.8 Hz, 1H), 4.47 (d, J = 11.9 Hz, 1H), 4.35 (d, J = 9.5 Hz, 1H),
4.30 – 4.19 (m, 4H), 4.01 (ddd, J = 28.9, 21.1, 9.8 Hz, 4H), 2.18
o
cooled to 0 C and was irradiated with UV light (365 nm) for 15
minutes. The addition of DPAP and irradiation were repeated four
times more. The solvent was evaporated under reduced pressure.
The crude product was purified by flash cromatography
(s, 4H), 2.12 (s, 3H, AcCH
3
), 2.10 (s, 9H, 3x AcCH
), 2.07 (s, 3H, AcCH ), 2.05 (s, 3H, AcCH
), 2.03 (s, 3H, AcCH ), 2.01 (s, 3H, AcCH
) δ (ppm) 170.7, 170.6, 170.5, 169.8, 169.7, 169.6
3
), 2.09 (s, 3H,
AcCH
AcCH
3
3
3
), 2.04 (s, 3H,
). 1 C NMR (100
3
3
3
3
(
hexane/acetone 7/3) to give 39 (252 mg, 51%) as white foam. B:
MHz, CDCl
3
o
The reaction was repeated at -20 C to give 39 with 72% yield. C:
The reaction was repeated at -40 C to give 39 with 71% yield. D:
The reaction was repeated at -80 C, to give 39 with 60% yield. R
(11C, 11xAcCO), 95.9 (1C, C-1’’), 79.7, 79.0 (2C, C-1, C-1’), 73.2,
72.3, 71.2, 70.3, 70.1, 70.0, 69.4, 69.3, 68.6, 68.0, 66.2 (11C,
skeletal carbons), 62.7, 62.4, 61.6 (3C, C-6, C-6’, C-6’’), 20.9,
o
o
f
2
0
=
0.24 (n-hexane/acetone 6:4); [α]
D
= +116.7 (c = 0.27 in CHCl
3
);
20.7, 20.7 (11C, 11xAcCH
3
), MALDI-TOF-MS: m/z calcd for
1
+
H NMR (500 MHz, CDCl
3
) δ (ppm) 5.81 (d, J = 5.6 Hz, 1H, H-1’’),
C H54NaO26S [M+Na] 1005.252, found 1005.187.
40
5
2
3
1
1
2
.40 (d, J = 4.0 Hz, 1H, H-1), 5.35 (ddd, J = 11.3, 10.2, 9.0 Hz,
H), 5.18 (t, J = 9.3 Hz, 1H), 5.08 (ddd, J = 17.4, 10.0, 8.6 Hz,
H), 4.89 – 4.82 (m, 2H), 4.58 (d, J = 10.1 Hz, 1H), 4.47 (dd, J =
2.4, 2.6 Hz, 1H), 4.33 (dt, J = 9.7, 2.6 Hz, 1H), 4.26 (ddd, J =
8.7, 12.4, 2.9 Hz, 2H), 4.19 (t, J = 3.1 Hz, 2H), 4.06 – 3.99 (m,
H), 3.93 (dt, J = 10.3, 2.8 Hz, 1H), 3.74 (ddd, J = 10.0, 3.9, 2.6
2
,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl-(14)-2,3,6-tri-O-
acetyl-1-thio-α-D-glucopyranosyl-(11)-2,3,6-tri-O-acetyl-4-
O-(2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl)-β-D-
glucopyranoside (42)
Hz, 1H), 2.15, 2.11, 2.09, 2.06, 2.03, 2.02, 2.02, 2.00, 2.00 (9xs,
A: Compound 4 (309 mg, 0.5 mmol) and thiol 18 (489 mg, 0.75
13
3
1
1
7
3 3
3H, 11xAcCH ). C NMR (126 MHz, CDCl ) δ (ppm) 170.7,
mmol, 1.5 equiv.) were reacted in a mixture of toluene (2.0 mL)
70.7, 170.6, 170.5, 170.2, 169.9, 169.8, 169.6, 169.5, 169.4,
69.1 (11C, AcCO), 95.7 (1C, C-1), 82.8, 81.8 (2xC, C-1’, C-1’’),
6.4, 73.9, 72.4, 72.3, 71.1, 70.1, 69.4, 69.1, 68.5, 68.0, 67.8
o
and N,N-dimethylformamide (1.0 mL) at -20 C. The crude
product was purified by flash chromatography (CH
2 2
Cl /acetone
9
/1) to give 42 (158 mg, 25%) as colourless syrup. B: The reaction
(
2
C
12C, skeletal carbons), 62.3, 61.9, 61.3 (3C, C-6, C-6’, C-6’’),
1.0, 20.8, 20.7 (11C, 11xAcCH ). MALDI-TOF-MS: m/z calcd for
54NaO26S [M+Na] 1005.252, found 1005.220.
o
was repeated at -40 C in the same scale to give 42 with 35%
yield. C: The reaction was repeated at -80 C in the same scale
to give 42 with 20% yield. D: The reaction was repeated at 0 C
3
o
+
40
H
o
in the same scale with 3 equiv of thiol 18 to give 42 with 29% yield.
2
,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl-(1→4)-2,3,6-tri-O-
20
f D
R = 0.34 (n-hexane/acetone 6:4), [α] = +144.1 (c=0.19 in
acetyl-1-hio-α-D-glucopyranosyl-(1→1)-2,3,4,6-tetra-O-
acetyl-β-D-mannopyranoside (40)
1
CHCl
1
2
3
), H NMR (400 MHz, CDCl
H), 5.48 – 5.28 (m, 6H), 5.24 (t, J = 9.0 Hz, 1H), 5.12 – 5.03 (m,
H), 4.96 – 4.80 (m, 4H), 4.64 – 4.58 (m, 2H), 4.49 (d, J = 10.6
3
) δ (ppm) 5.80 (d, J = 5.6 Hz,
A: Compound 4 (163 mg, 0.25 mmol) and thiol 21 (124 mg, 0.375
Hz, 1H), 4.33 – 4.21 (m, 5H), 4.17 – 4.12 (m, 1H), 4.10 – 3.92 (m,
mmol, 1.5 equiv.) were reacted in a mixture of toluene (2.0 mL)
and N-N-dimethylformamide (0.5 mL) at -40 C according to the
7H), 3.73 (d, J = 9.5 Hz, 1H), 2.17 (s, 9H), 2.11 (s, 7H), 2.07 (s,
3H), 2.06 – 1.99 (m, 30H). C NMR (100 MHz, CDCl ) δ (ppm)
3
o
13
general method. The crude product was purified by flash
170.8, 170.7, 170.5, 170.3, 170.0, 169.6, 169.5 (14C, 14xAcCO),
95.7 (2C, C-1’’, C-1’’’), 82.1 (2C, C-1, C-1’), 76.8, 76.3, 72.4, 72.2,
71.0, 70.1, 69.4, 69.2, 68.6, 68.5, 68.0, 68.0 (16C, skeletal
carbons), 62.6, 62.3, 61.5, 61.3 (4C, C-6, C-6’, C-6’’, C-6’’), 21.0,
cromatography (hexane/acetone 7/3) to give 40 (66 mg, 27%) as
o
white powder. B: The reaction was repeated at -80 C to give 40
o
with 58% yield. R
f
= 0.26 (n-hexane/acetone 6:4); m.p. 96-99 C,
2
0
1
[
α]
D
= +95.0 (c = 0.32 in CHCl
3
); H NMR (400 MHz, CDCl
3
) δ
21.0, 20.9, 20.8, 20.7, 20.6 (14C, 14xAcCH
3
). MALDI-TOF-MS:
+
(
ppm) 5.76 (d, J = 5.5 Hz, 1H), 5.55 (d, J = 3.2 Hz, 1H), 5.44 –
m/z calcd for C52H70NaO34S [M+Na] 1293.337, found 1293.327.
5
5
.40 (m, 2H), 5.36 (t, J = 10.0 Hz, 1H), 5.25 (t, J = 10.1 Hz, 1H),
.10 (d, J = 9.8 Hz, 1H), 5.05 (dd, J = 10.5, 3.7 Hz, 1H), 4.95 (dd,
2
,3,4-Tri-O-acetyl-β-D-lyxopyranosyl-(11)-2,3,4,6-tetra-O-
J = 10.0, 5.5 Hz, 1H), 4.85 (dd, J = 10.4, 3.8 Hz, 2H), 4.48 (t, J =
acetyl-1-thio-β-D-glucopyranoside (43) and 2,3,4-Tri-O-
acetyl-α-D-xylopyranosyl-(11)-2,3,4,6-tetra-O-acetyl-1-thio-
β-D-glucopyranoside (44)
1
1
3
3
2.7 Hz, 2H), 4.30-4.16 (m, 5H), 4.09 – 3.99 (m, 2H), 3.92 (d, J =
0.1 Hz, 1H), 3.78 – 3.69 (m, 1H), 2.24 (s, 3H, AcCH ), 2.15 (s,
H, AcCH ), 2.13 (s, 3H, AcCH ), 2.10 (s, 3H, AcCH ), 2.07 (s,
H, AcCH ), 2.06 (s, 3H, AcCH ), 2.03 (s, 9H, 3xAcCH ), 2.01 (s,
3
3
3
3
3
3
3
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
A: Compound 5 (100 mg, 0.387 mmol) and thiol 20 (169 mg,
(126 MHz, CDCl
6xCOCH
67.4, 66.2 (7C, skeleton carbons), 62.1, 60.5 (2C, C-5, C-6’), 21.0,
20.9, 20.8, 20.8, 20.7 (6C, 6xCOCH ). MALDI-TOF-MS: m/z calcd
for C25H34NaO16S [M+Na] 645.147, found 645.147
3
) δ (ppm) 170.7, 170.0, 169.9, 169.7, 169.7 (6C,
3
), 83.6, 83.2 (2C, C-1, C-1’), 70.6, 69.8, 69.4, 68.8, 68.7,
0
.465 mmol, 1.2 equiv.) were reacted in toluene (2.7 mL) at -80
o
C according to the general method. The crude product was
purified by flash chromatography (n-hexane/acetone 7:3) to give
3
+
43 (116 mg, 48%) as white crystals and 44 (6 mg, 2%) as
o
colourless syrup. B: The reaction was repeated at 0 C. The
conversion was less than 5%, only disulfide byproduct could be
isolated. C: The reaction was repeated at -40 C to give a mixture
of 43 and 44 with a 2.3:1 ratio with 21% overall yield.
Data of 46: NMR data are given from the 1:2.5 mixture of 45 and
6.
o
4
1H NMR (400 MHz, CDCl
5
1
) δ (ppm) 5.71 (d, J = 5.3 Hz, 1H, H-1),
.37 (s, 1H, H-1’), 5.35 (dd, J = 3.1, 1.5 Hz, 1H), 5.34 – 5.31 (m,
H), 5.29 (s, 1H), 5.28 – 5.25 (m, 2H), 5.04 – 4.98 (m, 2H), 4.33
3
o
Data of 43: R
f
= 0.24 (n-hexane/acetone 7:3); m.p. 74-77 C,
2
0
, 1
[
α]
D
3 3
= -97,7 (c=0.27 in CHCl ) H NMR (500 MHz, CDCl ) δ
ppm) 5.46 (t, J = 3.5 Hz, 1H, H-2), 5.34 (d, J = 3.5 Hz, 1H, H-1),
.23 (t, J = 9.4 Hz, 1H, H-3’), 5.17 (dd, J = 7.0, 3.3 Hz, 1H, H-3),
.09 (t, J = 9.7 Hz, 1H, H-4’), 5.04 – 4.99 (m, 2H, H-4, H-2’), 4.76
(
5
5
(
(
(
dt, J = 13.5, 3.4 Hz, 1H), 4.29 – 4.26 (m, 1H), 4.24 (s, 1H), 4.23
–
1
3
3
4.18 (m, 1H), 4.08 (dd, J = 14.2, 10.3 Hz, 2H), 4.02 – 3.94 (m,
H), 3.89 (dd, J = 11.5, 5.7 Hz, 1H), 2.17 (s, 3H, COCH ), 2.11 (s,
H, COCH ), 2.10 (s, 3H, COCH ), 2.07 (s, 3H, COCH ), 2.06 (s,
H, COCH ), 2.05 (s, 3H, COCH
) δ (ppm) 169.9, 169.9, 169.8, 169.6, 169.6 (7C,
), 80.2, 79.0 (2C, C-1, C-1’), 70.8, 70.1, 69.8, 69.4, 69.3,
8.6, 66.1 (7C, skeletal carbons), 62.2, 60.1 (2C, C-5, C-6’), 20.7,
0.7, 20.6, 20.6 (7C, 7xCOCH ).
3
d, J = 10.2 Hz, 1H, H-1’), 4.29 – 4.24 (m, 2H, H-6’
dd, J = 12.4, 2.1 Hz, 1H, H-6’ ), 3.72 (ddd, J = 10.0, 4.9, 2.2 Hz,
H, H-5’), 3.52 (dd, J = 12.4, 5.6 Hz, 1H, H-5 ), 2.11 (s, 3H,
COCH ), 2.10 (s, 6H, 2×COCH ), 2.06 (s, 3H, COCH ), 2.06 (s,
H, COCH ), 2.03 (s, 3H, COCH
126 MHz, CDCl ) δ (ppm) 170.6, 170.1, 169.8, 169.7, 169.5,
69.4 and 169.3 (6C, 6xCOCH ), 81.4 (C-1), 79.8 (C-1’), 75.9 (C-
a a
, H-5 ), 4.12
3
3
3
13
b
3 3
), 2.01 (s, 3H, COCH ). C NMR
3
1
b
(
100 MHz, CDCl
3
3
3
3
7
6
2
xCOCH
3
13
3
3
3 3
), 2.01 (s, 3H, COCH ); C NMR
(
3
3
1
5
6
3
’), 73.8 (C-3’), 70.2 (C-2’), 68.7 (C-3), 68.2 (C-4’), 68.0 (C-2),
7.5 (C-4), 62.8 (C-5) , 62.0 (C-6’), 20.8, 20.7, 20.6, 20.6 and 20.6
2,3,4-Tri-O-acetyl-1-thio-α-D-ribopyranosyl-(11)-2,3,4,6-
*
tetra-O-acetyl-β-D-glucopyranoside (47) and 2,3,4-tri-O-
acetyl-1-thio-β-D-arabinopyranosyl-(11)-2,3,4,6-tetra-O-
acetyl-β-D-glucopyranoside (48)
(
6C, 6xCOCH
3
). *Note: Peak can only be seen on HSQC
+
spectrum. MALDI-TOF-MS: m/z calcd for C25
H
34NaO16S [M+Na]
645.147, found 645.146
A: Compound 6 (258 mg, 1.0 mmol) and thiol 20 (437 mg 1.2
mmol, 1.2 equiv.) in toluene (4.0 mL) were reacted at -80 o
C
o
Data of 44: R
[
f
= 0.25 (n-hexane/acetone 7:3). m.p. 176-179 C,
according to the general method. The crude product was purified
by flash column chromatography (gradient elution n-
hexane/acetone 75/25→6/4) to give compounds 47 (284 mg,
2
0
1
D 3 3
α] = +70.5 (c = 0.20 in CHCl ), H NMR (400 MHz, CDCl ) δ
ppm) 5.81 (d, J = 5.5 Hz, 1H, H-1), 5.30 (t, J = 9.6 Hz, 1H), 5.17
t, J = 9.3 Hz, 1H), 5.12 – 5.00 (m, 2H), 4.94 (tt, J = 8.8, 4.5 Hz,
H), 4.54 (d, J = 10.1 Hz, 1H, H-1’), 4.15 (qd, J = 12.4, 3.7 Hz,
H), 3.99 (dd, J = 11.6, 10.4 Hz, 1H), 3.80 (dd, J = 11.6, 5.7 Hz,
(
(
4
6%) and 48 (128 mg, 21%) both as white syrup. B: The reaction
2
2
1
2
o
was repeated at -100 C to give 47 and 48 with 60% overall yield.
The 47:48 ratio was 1.4:1. C: The reaction was repeated at room
temperature using 1.5 equiv. of thiol, but no product could be
isolated.
H), 3.72 (ddd, J = 10.0, 4.9, 2.4 Hz, 1H), 2.08 (s, 3H, AcCH
3
),
C NMR (100
) δ (ppm) 170.7, 170.3, 170.0, 169.8, 169.8, 169.4,
69.2 (7xC, AcCO), 82.8, 82.3 (2C, C-1, C-1’), 76.2, 74.0, 71.0,
0.9, 69.6, 69.1, 68.1(7C, skeletal carbons), 62.1 (1C, C-5), 60.0
). MALDI-TOF-MS: m/z calcd
S [M+Na] 645.147, found 645.128.
13
3 3
.05-2.02 (m, 15H, 5xAcCH ), 2.00 (s, 3H, AcCH )
MHz, CDCl
3
1
7
20= +52.45
) δ (ppm) 5.60 (d, J
5.1 Hz, 1H, H-1), 5.51 (t, J = 2.7 Hz, 1H, H-3), 5.20 – 5.14 (m,
f D
Data of 47: R = 0.39 (n-hexane/acetone 6:4), [α]
1
(
3 3
c=0.10 in CHCl ), H NMR (400 MHz, CDCl
(
1C, C-6’), 20.8, 20.7 (7C, 7x AcCH
3
=
+
for C37H42NaO
5
1
4
H, H-2’), 5.13 – 5.07 (m,, 3H, H-4’, H-3’, H-2), 4.99 (ddd, J = 9.6,
.8, 3.1 Hz, 1H, H-4), 4.50 (d, J = 9.7 Hz, 1H, H-1’), 4.22 (dd, J =
2
,3,4-Tri-O-acetyl-β-D-lyxopyranosyl-(1→1)-2,3,4,6-tetra-O-
12.4, 4.9 Hz, 1H, H-6’
4.08 (dd, J = 11.4, 9.8 Hz, 1H, H-5
Hz, 1H, H-5’), 3.63 (dd, J = 11.5, 4.7 Hz, 1H, H-5
COCH ), 2.09 (s, 3H, COCH ), 2.05 (s, 6H, 2xCOCH
H, COCH ), 2.03 (s, 3H, COCH
100 MHz, CDCl ) δ (ppm) 170.7 (COCH
), 169.6 (COCH ), 169.4 (COCH
a
), 4.14 (dd, J = 12.4, 2.4 Hz, 1H, H-6’
), 3.75 (ddd, J = 9.8, 4.8, 2.4
), 2.15 (s, 3H,
), 2.03 (s,
b
),
acetyl-1-thio-α-D-mannopyranoside (45) and 2,3,4-tri-O-
acetyl-α-D-xylopyranosyl-(1→1)-2,3,4,6-tetra-O-acetyl-1-thio-
α-D-mannopyranoside (46)
a
b
3
3
3
13
3
3
3
), 2.00 (s, 3H, COCH
), 170.3 (COCH
), 169.4 (COCH
3
). C NMR
(
(
(
3
3
3
), 169.9
), 169.0
A: Compound 5 (100 mg, 0.387 mmol) and thiol 22 (169 mg,
COCH
COCH
3
3
3
3
0.465 mmol, 1.2 equiv.) were reacted in toluene (2.7 mL), at
3
), 83.1 (C-1’), 80.3 (C-1), 76.2 (C-5’), 74.2, 71.1, 68.1,
−
80°C according to the general method. The crude product was
6
7.8, 67.5 (5C, C-4’, C-3’, C-3, C-2’, C-2), 65.8 (C-4), 62.1 (C-6
and C-6’), 58.2 (C-5)* 20.9, 20.8, 20.7, 20.6 and 20.6 (7C,
7xCOCH ). *Note: Signal can only be seen on HSQC spectrum.
purified by column chromatography to give 45 (214 mg, 89%) as
white crystals and an inseparable ~2:1 mixture of 45 and 46 (12
mg, 6%). B: The reaction was repeated at 0 C in the same scale
o
3
+
+
MALDI-TOF-MS: m/z calcd for C25H34NaO16S [M+Na] 645.15,
to give an inseparable mixture of 45 and 46 in a ratio of 1:2.5 with
found 645.16.
40% overall yield.
Data of 48: R
(c=0.46 in CHCl
5.3 Hz, 1H, H-1), 5.38 (dd, J = 10.4, 5.4 Hz, 1H, H-2), 5.34 (s
broad), 1H, H-4), 5.22 (t, J = 9.3 Hz, 1H, H-3’), 5.14 – 5.03 (m,
f D
= 0.47 (n-hexane/acetone 6:4), [α]
20= -161.2
3 3
), H NMR (400 MHz, CDCl ) δ (ppm) 5.86 (d, J
o
Data of 45: R
f
= 0.26 (n-hexane/acetone 7:3); m.p. 160-162 C,
1
2
0
1
[
α]
D
= -10.0 (c=0.40 in CHCl
3
), H NMR (500 MHz, CDCl
3
) δ
=
(
(
(
(
(
ppm) 5.46 (t, J = 3.4 Hz, 1H, H-2), 5.39 (s, 1H, H-1’), 5.35 – 5.31
m, 2H) and 5.29 (dd, J = 10.0, 3.1 Hz, 1H) (H-4, H-3’, H-2’), 5.19
d, J = 3.2 Hz, 1H, H-1), 5.16 (dd, J = 7.1, 3.3 Hz, 1H, H-3), 5.01
3
H, H-4’, H-3, H-2’), 4.69 (d, J = 10.3 Hz, 1H, H-1’), 4.28 (dd, J =
2.4, 5.2 Hz, 1H, H-6’ ), 4.16 (d, J = 12.8 Hz, 1H, H-5 ), 4.07 (dd,
), 3.75 (dd, J = 13.1, 2.3 Hz, 1H, H-5
.68 (ddd, J = 9.7, 5.0, 1.9 Hz, 1H, H-5’), 2.15 (s, 3H, COCH
.10 (s, 3H, COCH ), 2.08 (s, 3H, COCH ), 2.07 (s, 3H, COCH
), 2.01 (s, 3H, COCH
) δ (ppm)170.7, 170.2, 170.2, 169.9, 169.4, 169.3 (7C,
1
a
a
ddd, J = 7.0, 5.9, 3.7 Hz, 1H, H-4), 4.35 – 4.27 (m, 2H, H-6’
a
, H-
J = 12.3, 1.8 Hz, 1H, H-6’
b
b
3
3
),
),
),
5’), 4.23 (dd, J = 12.4, 3.6 Hz, 1H, H-5
a
), 4.06 (dd, J = 11.9, 1.9
3
2
Hz, 1H, H-6’
b
), 3.51 (dd, J = 12.4, 5.9 Hz, 1H, H-6’
b
), 2.17 (s, 3H,
), 2.09 (s, 3H,
), 2.00 (s, 3H, COCH ); C NMR
3
3
3
COCH
COCH
3
), 2.14 (s, 3H, COCH
), 2.06 (s, 3H, COCH
3
), 2.10 (s, 3H, COCH
3
3
1
3
13
2.02 (s, 6H, 2xCOCH
CDCl
3
3
). C NMR (100 MHz,
3
3
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201903095
FULL PAPER
7
6
xCOCH
3
), 80.5, 80.4 (2C, C-1’, C-1), 76.1 (C-5’), 73.9, 70.1,
1H, H-4’), 5.05 – 5.00 (m, 2H, H-4, H-2’), 4.68 (d, J = 10.2 Hz, 1H,
8.3, 68.3, 67.7, 67.4 (6C, C-4’, C-4, C-3’, C-3, C-2’, C-2), 62.0
),
34NaO16S [M+Na] 645.15,
H-1’), 4.27 (dd, J = 12.4, 5.3 Hz, 1H, H-6’
9.2 Hz, 2H, H-6’ , H-5 ), 3.72 – 3.67 (m, 1H, H-5’), 3.66 (dd, J =
11.5, 4.7 Hz, 1H, H-5 ), 2.13 (s, 3H, COCH ), 2.09 (s, 3H,
), 2.07 (s, 3H, COCH ), 2.07 (s, 3H, COCH ), 2.05 (s, 3H,
), 2.03 (s, 3H, COCH ), 2.01 (s, 3H, COCH
) δ (ppm) 170.8, 170.3, 169.9, 169.8, 169.6,
69.6, 169.4 (7C, 7xCOCH ), 82.1, 79.8 (2C, C-1, C-1’), 76.1,
4.0, 70.4, 68.4, 67.7, 67.6, 65.9 (7C, skeletal carbons), 62.2 (C-
’), 21.0, 20.8, 20.8, 20.7 (7C, 7xCOCH ). MALDI-TOF-MS: m/z
34NaO16S [M+Na] 645.147, found 645.144
a
), 4.10 – 4.05 (m, J =
(
C-6’), 61.4 (C-5), 20.9, 20.8, 20.8, 20.7, 20.6 (7C, 7xCOCH
3
b
a
+
MALDI-TOF-MS: m/z calcd for C25
H
b
3
found 645.17.
COCH
COCH
3
3
3
13
3
3
3
); C NMR
(
126 MHz, CDCl
3
2,3,4-Tri-O-acetyl-1-thio-α-D-ribopyranosyl-(11)-2,3,4,6-
1
7
6
3
tetra-O-acetyl-α-D-mannopyranoside (49) and 2,3,4-tri-O-
acetyl-1-thio-β-D-arabinopyranosyl-(11)-2,3,4,6-tetra-O-
acetyl-α-D-mannopyranoside (50)
3
+
calcd for C25
H
A: Compound 6 (100 mg, 0.387 mmol) and thiol 22 (170 mg,
2
,3,4,6-Tetra-O-acetyl-α-D-mannopyranosyl-(1→1)2,3,4-tri-O-
0
.464 mmol, 1.2 equiv.) were reacted in toluene (2.0 mL) at -80
o
acetyl-α-L-ribopyranoside (53) and 2,3,4,6-Tetra-O-acetyl-α-
D-mannopyranosyl-(1→1)-2,3,4-tri-O-acetyl-β-L-
arabinopyranoside (54)
C according to the general method. The crude product was
purified by flash column chromatography (n-hexane/acetone 7/3)
to give a 1:1.3 mixture of 49 and 50 (221 mg, 91%). A second
purification by flash column chromatography (gradient elution
CH
2
Cl
2
/acetone 100/1→100/2) gave 50 (82 mg, 34%) and a 2.4:1
A: Compound 7 (200 mg, 0.75 mmol) and thiol 22 (336 mg, 0.93
mmol, 1.2 equiv.) were reacted in toluene (1.0 mL) at -80 C. The
crude product was purified by flash column chromatography
o
mixture of 49:50 (67 mg, 28%), both as colorless syrup B: The
reaction was repeated at 0 C in the same scale to give 49 and 50
o
with 54% overall yield, the 49:50 ratio was 1:1.4
(gradient elution n-hexane/EtOAc 65/35→6/4) to give 53 (150 mg,
3
2%) and 54 (298 mg, 64%) both as a colourless syrup. B: The
o
reaction was repeated at 0 C to give 53 and 54 with 92% overall
yield, the 53:54 ratio was 1:6.3.
Data of 49 (NMR data are given from the 2.4:1 mixture of 49:50):
1
R
f
= 0.28 (n-hexane/acetone 7:3); H NMR (400 MHz, CDCl
3
) δ
(
ppm) 5.50 (s, 1H), 5.42 – 5.38 (m, 2H), 5.34 – 5.28 (m, 3H), 5.21
5.16 (m, 1H), 5.03 (dt, J = 7.7, 3.9 Hz, 1H), 4.33 – 4.21 (m, 3H),
.19 – 4.05 (m, 3H), 3.68 (dd, J = 11.5, 4.3 Hz, 1H), 2.18 (s, 6H,
Data of 53: R = 0.24 (n-hexane/EtOAc 1:1), [α]D20= -8,0 (c=0.15
–
4
2
f
1
in CHCl ), H NMR (400 MHz, CDCl ) δ (ppm) 5.50 (t, J = 3.1 Hz,
3
3
xAcCH
), 2.06 (s, 3H, AcCH
MHz, CDCl ) δ (ppm) 170.0, 169.9, 169.7, 169.7, 169.5 (7C,
xAcCO), 79.9, 79.1, (2C, C-1 & C-1’)70.6, 69.5, 69.4, 67.5, 67.4,
6.3, 65.9 (7C, skeletal carbons), 62.3 (1C, C-6’), 21.0, 20.9, 20.7,
0.7 (7C, 7xAcCH ).
= 0.28 (n-hexane/acetone 7:3); [α]
3
), 2.11 (s, 3H, AcCH
3
), 2.11 (s, 3H, AcCH
3
), 2.06 (s, 3H,
1H, H-3), 5.38 (d, J = 5.3, 1H, H-1), 5.36-.28 (m, Hz, 4H, H-1’, H-
1
3
AcCH
3
3
), 2.01 (s, 3H, AcCH ); C NMR (100
3
2’, H-3’, H-4’), 5.15 (dd, J = 5.0, 3.1 Hz, 1H, H-2), 5.01 (ddd, J =
8.8, 4.4, 3.1 Hz, 1H, H-4), 4.35 (m, 1H, H-5’), 4.27 (dd, J = 12.2,
5.3 Hz, 1H, H-6’a), 4.13 – 4.05 (m, 2H, H-6’b, H-5a), 3.69 (dd, J
3
7
6
2
=
11.6, 4.4 Hz, 1H, H-5b), 2.17 (s, 6H, 2xAcCH
3
), 2.11 (s, 3H,
), 2.05 (s, 3H,
). C NMR (100 MHz, CDCl ) δ (ppm)
3
AcCH
AcCH
3
3 3
), 2.09 (s, 3H, AcCH ), 2.07 (s, 3H, AcCH
Data of 50: R
f
D
20= -46.9 (c=
) δ (ppm) 5.80 (d, J =
.9 Hz, 1H, H-1), 5.38 – 5.35 (m, 1H, H-4’), 5.34 – 5.29 (m, 3H,
13
3
), 2.01 (s, 3H, AcCH
3
3
1
0
4
3 3
.29 in CHCl ); H NMR (400 MHz, CDCl
1
8
70.6, 169.9, 169.8, 169.7, 169.6, 169.6, 169.5 (7C, 7xAcCO),
3.8 (1C, C-1’), 83.3 (1C, C-1), 70.4, 69.5, 69.3, 66.2 (4C, C-5’,
H-1’, H-2, H-4), 5.28 – 5.24 (m, 1H, H-3’), 5.19 (dd, J = 10.2, 3.3
Hz, 1H, H-3), 4.32 – 4.21 (m, 2H, H-6’a and H-2’), 4.13 (d, J =
1
1
2
2
C2’, C-3’, C-4’), MALDI-TOF-MS: m/z calcd for C25H34NaO16S
+
[
M+Na] 645.147, found 645.142.
3.1 Hz, 1H, H-5a), 4.08 (d, J = 10.4 Hz, 1H, H-6’b), 3.76 (dd, J =
3.2, 2.6 Hz, 1H, H-5b), 2.17 (s, 3H, AcCH
.12 (s, 3H, AcCH ), 2.08 (s, 3H, AcCH ), 2.07 (s, 3H, AcCH
.04 (s, 3H, AcCH ), 2.01 (s, 3H, AcCH
) δ (ppm)170.5, 170.2, 170.0, 169.8, 169.7 (7C, 7xAcCO),
4.6, 82.7 (2C, C-1 and C-1’), 71.4 (1C, C-4’), 70.4 (1C, C-2’),
3
), 2.14 (s, 3H, AcCH
3
),
20= +186,5
D
3
) δ (ppm) 5.81 (d, J
Data of 54: R = 0.36 (n-hexane/EtOAc 1:1), [α]
f
3
3
3
),
1
(
c=0.70 in CHCl
3
), H NMR (400 MHz, CDCl
13
3
3
). C NMR (100 MHz,
=
5.3 Hz, 1H, H-1), 5.37 (d, J = 1.5 Hz, 1H), 5.36 – 5.33 (m, 2H),
CDCl
3
5
4
.33 (s, 1H), 5.29 – 5.25 (m, 1H), 5.16 (dd, J = 10.4, 3.4 Hz, 1H),
.30 – 4.19 (m, 3H), 4.16 – 4.08 (m, 2H), 3.77 (dd, J = 13.2, 2.6
8
6
5
7
6
9.3 (1C, C-3’), 67.5 (1C, C-3), 68.2, 68.1, 66.0 (3C, C-2, C-4, C-
Hz, 1H), 2.17 (s, 3H, AcCH
3
), 2.14 (s, 3H, AcCH
3
), 2.13 (s, 3H,
), 2.03 (s, 3H,
). C NMR (100 MHz, CDCl ) δ (ppm)
’)62.4, 62.2 (2C, C-5 and C-6), 20.9, 20.8, 20.7, 20.7, 20.7 (7C,
AcCH
AcCH
3
), 2.11 (s, 3H, AcCH
3
), 2.07 (s, 3H, AcCH
3
+
xAcCH
3
). MALDI-TOF-MS: m/z calcd for C25
H34NaO16S [M+Na]
13
3
), 2.01 (s, 3H, AcCH
3
3
45.146, found 645.149
1
8
70.8, 170.2, 170.0, 169.9, 169.9, 169.8, 169.7 (7C, 7xAcCO),
1.1, 79.2 (2C, C-1, C-1’), 71.0, 70.0, 69.4, 68.4, 67.8, 67.6, 66.2
2
,3,4-Tri-O-acetyl-α-L-ribopyranosyl-(11)-2,3,4,6-tetra-O-
(
2
C
7C, skeletal carbons), 62.4, 61.8 (2C, C-6, C-5’), 21.0, 20.8, 20.8,
0.7 (7C, 7xAcCH ), MALDI-TOF-MS: m/z calcd for
acetyl-1-thio-β-D-glucopyranoside (51) and 2,3,4-tri-O-acetyl-
β-L-arabinopyranosyl-(11)-2,3,4,6-tetra-O-acetyl-1-thio-β-
D-glucopyranoside (52)
3
+
25
H34NaO16S [M+Na] 645.146, found 645.149
3
,4,6-Tri-O-acetyl-1,5-anhydro-2-thio-2-S-(2,3,4,6-tetra-O-
A: Compound 7 (100 mg, 0.387 mmol) and thiol 20 (169 mg,
acetyl-β-D-glucopyranosyl)-D-mannitol (55) and 3,4,6-tri-O-
acetyl-1,5-anhydro-2-thio-2-S-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-D-glucitol (56)
0
.465 mmol, 1.20 equiv.) were reacted in toluene (2.7 mL) at -80
o
C according to the general method. The crude product was
purified by flash chromatography to give 51 (225 mg, 93%) and a
mixture of 51 and 52 (11 mg, 5%, 51:52 = 1:0.41) both as
A: Compound 8 (136 mg, 0.5 mmol) and thiol 20 (218 mg, 0.6
mmol, 1.2 equiv.) were reacted in toluene (5.0 mL), at −80°C
according to the general method. The crude product was purified
by column chromatography (n-hexane/acetone 7:3) to give
compound 55 (216 mg, 68%) and 56 (26 mg, 8%). B: The reaction
was carried out at −120 °C in the same scale using 1.2 equiv. of
thiol 20 to give 55 and 56 in 75% overall yield with a ratio of 55:56
o
colourless syrup. B: The reaction was repeated at 0 C to give 51
and 52 with 90% overall yield, the 51:52 ratio was ~6:1.
Data of 51: R
(
f
= 0.16 (n-hexane/acetone 7:3); [α]
D
20= -48,65
3 3
c=0.37 in CHCl ); H NMR (500 MHz, CDCl ) δ (ppm) 5.50 (t, J =
1
2
1
.6 Hz, 1H, H-3), 5.48 (d, J = 4.8 Hz, 1H, H-1), 5.22 (t, J = 9.4 Hz,
H, H-3’), 5.16 (dd, J = 5.0, 2.9 Hz, 1H, H-2), 5.08 (t, J = 9.8 Hz,
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Chemistry - A European Journal
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2
0
) lit.[23] -72.0; 56 [α]
20=
=
6:1. 55 [α]
D
= −68.4 (c= 0.13 in CHCl
3
D
10.3, 2.8 Hz, 1H, H-4), 5.23 (t, J = 9.3 Hz, 1H, H-3’), 5.13 (t, J =
9.7 Hz, 1H, H-4’), 5.04 (t, J = 9.6 Hz, 1H, H-2’), 4.79 (d, J = 10.1
6.89 (c= 0.12 in CHCl
3
) lit.[ -18.8.
23]
−
Hz, 1H, H-1’), 4.23 (dd, J = 12.3, 2.3 Hz, 1H, H-6’
.3 Hz, 1H, H-6’b), 4.18 (s, 1H, H-6 ), 4.17 (s, 1H, H-6
J = 12.3, 2.4 Hz, 1H, H-1 ), 3.97 (d, J = 12.3 Hz, 1H, H-1 ), 3.91
a
), 4.20 (d, J =
4
a
b
), 4.10 (dd,
NMR data of 55 and 56 are identical to the ones described in
literature. [23]
a
b
(
1
dt, J = 9.9, 3.7 Hz, 1H, H-5), 3.79 – 3.73 (m, 1H, H-5’), 3.19 (s,
H, H-2), 2.14 (s, 3H, COCH ), 2.11 (s, 3H, COCH ), 2.07 (s, 3H,
), 2.02 (s, 3H, COCH ), 2.01 (s, 3H,
); C NMR (100 MHz, CDCl ) δ
3
3
3,4,6-Tri-O-acetyl-1,5-anhydro-2-thio-2-S-(2,3,4,6-tetra-O-
COCH
COCH
3
), 2.06 (s, 3H, COCH
), 2.00 (s, 3H, COCH
3
3
acetyl-β-D-glucopyranosyl)-D-talitol (57) and 3,4,6-tri-O-
acetyl-1,5-anhydro-2-thio-2-S-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-D-galactitol (58)
1
3
3
3
3
(
ppm) 170.9, 170.7, 170.2, 169.7, 169.4, 169.3, 169.1 (7C,
7
3
xCOCH ), 84.3 (C-1’), 76.0 (C-5’), 73.9 (C-3’), 73.0 (C-5), 70.5
(
C-3), 70.2 (C-2’), 68.2 (C-4’), 67.0 (C-1), 64.6 (C-4), 62.9 (C-6’),
A: Compound 9 (310 mg, 1.14 mmol) and thiol 20 (498 mg, 1.37
6
7
6
1.8 (C-6), 45.0 (C-2), 21.0, 20.8, 20.7, 20.6, 20.6 (7C,
mmol, 1.2 equiv.) were reacted in toluene (5.0 mL) at 0 o
C
[M+Na]+
3 26
). ESI-MS: m/z calcd for C H36NaO16S
xCOCH
59.162, found 659.159
according to the general method. The crude product was purified
by flash chromatography (CHCl /acetone 95/5) to give 57 and 58
3
with 67% overall yield (486 mg), with 2.3:1 57:58 ratio, as yellow
syrup. B: The reaction was repeated at -40 C to give 57 and 58
o
3,4-Di-O-acetyl-1,5-anhydro-6-deoxy-2-thio-2-S-(2,3,4,6-tetra-
O-acetyl-β-D-glucopyranosyl)-L-manno-hexitol (60) and 3,4-
di-O-acetyl-1,5-anhydro-6-deoxy-2-thio-2-S-(2,3,4,6-tetra-O-
acetyl-β-D-glucopyranosyl)-L-gluco-hexitol (61)
with 95% overall yield, (57:58 = 1.5:1). C: The reaction was
o
repeated at -80 C to give 57 and 58 with 95% overall yield, (57:58
o
=
1:1.2). D: The reaction was repeated at -120 C to give 57 and
5
8 with 95% overall yield,(57:58 = 1:1.2).
A: Compound 11 (107 mg, 0.5 mmol), thiol 20 (219 mg, 0.6 mmol,
1.2 equiv.) and DPAP (38 mg, 0.05 mmol, 0.1 equiv.) were
reacted in toluene (3.0 mL), at −80°C according to the general
method. The crude product was purified by flash chromatography
20= -48.28
2 2 D
Cl /acetone 95:5), [α]
) lit. -44.3 [58], H NMR (400 MHz, CDCl ) δ
3 3
Data of 57: R
f
= 0.15 (CH
c=0.29 in CHCl
ppm) 5.26 – 5.21 (m, 2H), 5.19 (d, J = 9.3 Hz, 1H), 5.07 (t, J =
1
(
(
(
(
n-hexane/acetone 75/25) to give compound 60 as white crystals
135 mg, 47%), 61 as white foam (36 mg, 12%), and an
7
4
5
3
1
.3 Hz, 1H), 5.03 (t, J = 7.2 Hz, 1H), 4.49 (d, J = 10.0 Hz, 1H),
.30 – 4.22 (m, 2H), 4.16 (dd, J = 12.3, 4.0 Hz, 1H), 4.12 (d, J =
.0 Hz, 1H), 4.08 (dd, J = 8.3, 3.8 Hz, 1H), 3.92 – 3.86 (m, 1H),
.83 (dd, J = 12.3, 2.7 Hz, 1H), 3.68 (ddd, J = 10.0, 4.7, 2.1 Hz,
H, H-5’), 3.37 (dd, J = 6.6, 4.1 Hz, 1H), 2.12 (s, 3H, AcCH
), 2.06 (s, 6H, 2x AcCH ), 2.02 (s, 3H, AcCH
). C NMR (100 MHz, CDCl ) δ (ppm) 170.6, 170.2,
inseparable 3:1 mixture of 60 and 61 (22%). B: The reaction was
repeated at rt with 2.0 equiv of 20 to give 60 and 61 with 66%
overall yield (60:61 = 2.5:1).
3
), 2.08
), 2.00
(
(
s, 3H, AcCH
s, 3H, AcCH
3
3
3
o
13
Data of 60: R = 0.11 (n-hexane/acetone 7:3), m.p. 176-178 C,
f
3
3
2
0
1
[
α]
D
= −0.90, (c= 0.11 in CHCl
ppm) 5.18 (t, J = 9.3 Hz, 1H, H-3’), 5.06 (t, J = 9.7 Hz, 1H, H-4’),
.04 (dd, J = 9.6, 4.4 Hz, 1H, H-3), 4.96 (t, J = 9.7 Hz, 1H) and
4.96 (t, J = 9.2 Hz, 1H) (H-4 and H-2’), 4.60 (d, J = 10.1 Hz, 1H,
H-1’), 4.20 (dd, J = 12.4, 5.1 Hz, 1H, H-6’ ), 4.15 – 4.10 (m, 2H, ,
H-6’ and H-1 ), 3.83 (dd, J = 12.3, 1.9 Hz, 1H, H-1 ), 3.68 – 3.60
(m, 2H, H-5’ and H-2), 3.42 (dq, J = 8.8, 6.2 Hz, 1H, H-5), 2.11 (s,
3 3
), H NMR (400 MHz, CDCl ) δ
169.9, 169.4, 169.3 (6C, 7xAcCO), 83.3 (1C, C-1’), 76.2, 74.6,
(
5
73.9, 69.6, 69.2, 68.1, 67.0 (7C, skeletal carbons), 62.0, 61.7 (2C,
C-1, C-6’), 42.0 (1C, C-2), 20.8, 20.8, 20.6, 20.6 (7C, 6xAcCH
MALDI-TOF-MS: m/z calcd for C26
found 659.159
3
).
+
H36NaO16S [M+Na] 659.162,
a
b
a
b
20= -27.5 (c=0.12
2 2 D
Cl /acetone 95:5), [α]
Data of 58:R
f
= 0.24 (CH
), H NMR (400 MHz, CDCl
H), 5.21 (t, J = 9.3 Hz, 1H), 5.06 (t, J = 9.7 Hz, 1H), 4.95 – 4.89
m, 1H), 4.89 – 4.86 (m, 1H), 4.69 (d, J = 10.2 Hz, 1H), 4.31 (d, J
4.8 Hz, 1H), 4.27 (t, J = 5.3 Hz, 1H), 4.24 (d, J = 5.2 Hz, 1H),
.14 (dd, J = 12.4, 2.3 Hz, 1H), 4.07 (dd, J = 6.4, 2.2 Hz, 2H), 3.80
t, J = 6.5 Hz, 1H), 3.73 (ddd, J = 9.9, 5.1, 2.3 Hz, 1H), 3.40 (t, J
11.8 Hz, 1H), 3.28 (dd, J = 11.5, 4.8 Hz, 1H), 2.17 (s, 3H,
1
3H, COCH
H, COCH
3
), 2.09 (s, 3H, COCH
), 2.03 (s, 3H, COCH
3
), 2.09 (s, 3H, COCH ), 2.06 (s,
3
), 2.01 (s, 3H, COCH ), 1.19 (d,
3
in CHCl
1
(
=
4
(
=
3
3
) δ (ppm) 5.36 (d, J = 2.7 Hz,
3
3
3
1
3
J = 6.2 Hz, 3H, 3xH-6); C NMR (100 MHz, CDCl
3
) δ (ppm) 170.6,
1
7
1
6
70.3, 170.2, 169.7, 169.5, 169.3 (6C, 6xCOCH ), 84.1 (C-1’),
6.0, 75.3, 73.8, 71.6, 70.3, 68.1 (7C, skeleton carbons), 70.4 (C-
), 62.0 (C-6’), 45.7 (C-2), 20.9, 20.8, 20.7, 20.7, 20.6, 20.6 (6C,
3
xCOCH
3
), 17.6 (C-6). MALDI-TOF-MS: m/z calcd for
+
24
C H
34NaO14S [M+Na] 601.157, found 601.064
AcCH
AcCH
AcCH
3
3
3
), 2.10 (s, 3H, AcCH
), 2.03 (s, 3H, AcCH
). C NMR (100 MHz, CDCl
3
), 2.05 (s, 3H, AcCH
), 2.02 (s, 3H, AcCH
3
), 2.04 (s, 3H,
), 2.00 (s, 3H,
3
3
Data of 61: R = 0.15 (n-hexane/acetone 7:3), [α]D20= −48.52 (c=
13
) δ (ppm) 170.7, 170.6, 170.3,
f
3
1
0.27 in CHCl
3
), H NMR (400 MHz, CDCl
3
) δ (ppm) 5.21 (t, J = 9.3
1
1
6
7
6
70.2, 169.4, 169.3 (7C, 7xAcCO), 84.8 (1C, C-1’), 70.6 (1C, C-
), 76.0, 75.1, 73.6, 72.5, 70.5, 68.3, 67.4 (7C, skeletal carbons),
2.1 (1C, C-6’), 42.4 (1C, C-2), 20.8, 20.8, 20.8, 20.7 (7C,
Hz, 1H, H-3’), 5.05 (t, J = 9.8 Hz, 1H, H-4’), 5.00 – 4.93 (m, 2H,
H-3, H-2’), 4.75 (t, J = 9.3 Hz, 1H, H-4), 4.60 (d, J = 10.0 Hz, 1H,
H-1’), 4.22 (dd, J = 12.3, 5.4 Hz, 1H, H-6’ ), 4.17 – 4.09 (m, 2H,
a
+
xAcCH
3
). ESI-MS: m/z calcd for
C
26
H
36NaO16
S
[M+Na]
H-6’
b
, H-1
a
), 3.72 (ddd, J = 10.0, 5.3, 2.4 Hz, 1H, H-5’), 3.48 –
), 3.11 (td, J = 11.4, 4.9 Hz, 1H, H-2), 2.10
59.162, found 659.159
3.40 (m, 2H, H-5, H-1
b
(
(
(
1
7
7
6
s, 3H, COCH
s, 3H, COCH
3
), 2.05 (s, 3H, COCH
), 2.03 (s, 3H, COCH
3
), 2.04 (s, 3H, COCH
), 2.00 (s, 3H, COCH
3
), 2.03
), 1.19
3
,4,6-Tri-O-acetyl-1,5-anhydro-2-thio-2-S-(2,3,4,6-tetra-O-
3
3
3
acetyl-β-D-glucopyranosyl)-D-altritol (59)
d, J = 6.1 Hz, 3H); 13C NMR (100 MHz, CDCl
) δ (ppm) 170.7,
70.4, 170.2, 170.0, 169.5, 169.2 (6C, 6xCOCH ), 81.6 (C-1’),
6.0, 75.1, 75.0, 73.9, 72.2, 70.1, 68.2 (7C, skeleton carbons),
3
3
Compound 10 (200 mg, 0.735 mmol), thiol 20 (321 mg, 0.882
mmol, 1.2 equiv.) and DPAP (19 mg, 0.073 mmol, 0.1 equiv.)
were reacted in toluene (5.5 mL), at −80°C according to the
general method. The crude product was purified by column
chromatography (n-hexane/acetone 7/3) to give compound 59
0.8 (C-1’), 62.2 (C-6’), 44.5 (C-2), 20.8, 20.8, 20.7, 20.7 (6C,
3
xCOCH ), 17.9 (C-6). MALDI-TOF-MS: m/z calcd for
+
24
C H
34NaO14S [M+Na] 601.157, found 601.064.
(
6
f
430 mg, 92%) as colourless syrup. R = 0.41 (n-hexane/acetone
:4); [α] = −14.5 (c= 0.29 in CHCl ) lit. -8.8; H NMR (400
D 3
20
[23]
1
MHz, CDCl
3
) δ (ppm) 5.54 (t, J = 3.1 Hz, 1H, H-3), 5.31 (dd, J = Acknowledgements
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
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FULL PAPER
This research was funded by: the National Research,
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Three types of acetylated glycals were
reacted with various thiols under UV-
irradiation at the temperature range of
rt to -120 oC. Cooling proved always
beneficial to the reaction efficacy,
Viktor Kelemen, Miklós Bege, Dániel
Eszenyi, Nóra Debreczeni, Attila Bényei,
Tobias Stürzer, Pál Herczegh and Anikó
Borbás*
o
being -80 C the optimal temperature in
Page No. – Page No.
Stereoselective thioconjugation by
photoinduced thiol-ene coupling
reactions of hexo- and
pentopyranosyl D- and L-glycals at
low temperature – Reactivity and
stereoselectivity study
most cases. The low-temperature thiol-
ene coupling of glycals was found to
provide an easy access to 1,2-cis--1-
thio-hexosides up to tetrasaccharides,
1,2-cis-- and -1-thio-pentosides and
axially C2-S-linked glycomimetics.
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Title
Text for Table of Contents
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