Convergent strategy for the synthesis of S-linked oligoxylans

Article abstract of DOI:10.1016/j.carres.2017.03.016

Arabinoxylans (AX) are a major class of hemicellulose and an important polysaccharide component of lignocellulosic biomass. To utilize the glycan polymer effectively, it is desirable to learn more about the enzymatic hydrolysis of AXs. Well-defined glycan

Full text of DOI:10.1016/j.carres.2017.03.016

Accepted Manuscript
Convergent strategy for the synthesis of S-linked oligoxylans
Beatrice Bonora, Irene Boos, Mads H. Clausen
PII:
S0008-6215(17)30109-X
10.1016/j.carres.2017.03.016
CAR 7345
DOI:
Reference:
To appear in: Carbohydrate Research
Received Date: 10 February 2017
Revised Date: 20 March 2017
Accepted Date: 20 March 2017
Please cite this article as: B. Bonora, I. Boos, M.H. Clausen, Convergent strategy for the synthesis of
S-linked oligoxylans, Carbohydrate Research (2017), doi: 10.1016/j.carres.2017.03.016.
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Beatrice Bonora, Irene Boos, Mads H. Clausen

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Convergent strategy for the synthesis of S-linked oligoxylans
Beatrice Bonora, Irene Boos, Mads H. Clausen
Center for Nanomedicine and Theranostics, Department of Chemistry,
Technical University of Denmark, Kemitorvet, Building 207, Lyngby, Denmark
Arabinoxylans (AX) are a major class of hemicellulose and an important polysaccharide component of lignocellulosic
biomass. To utilize the glycan polymer effectively, it is desirable to learn more about the enzymatic hydrolysis of AXs. Well-
defined glycans can help to elucidate these processes. Here, we report the efficient synthesis of a mixed O- and S-linked
tetraxylan. This thio-oligosaccharide has been developed as a putative inhibitor of arabinoxylan degrading enzymes used for
the saccharification of biomass. Two common approaches for the synthesis of thio-oligosaccharides, either involving 1-
thioglycoside donors or thioacceptors, are presented and compared regarding byproduct formation and yields. Both methods
have shown to be useful for the synthesis of thiolinkages in oligoxylans assembly. However, the success of the reaction is
highly dependent on the “match” between donors and acceptors.
1
. Introduction
Using a thiol as the acceptor facilitates the utilization of most
of the known O-glycosylation methods and allows for the
variation of the donor to find the right “match” for the thiol
acceptor. However, only glycosylation methods using
promoters that are not thiophilic can be employed, which
The search for an environmentally and economically
sustainable process for biofuel production has focused on
biomass feedstock. Thereby, it is important that the source
material does not compete with feed and food production such
as waste biomass and biomass grown on degraded and
disqualifies some of the O-glycosylation methods (e.g.
[16]
thioglycosides). In the past, mostly anhydrosugars
and
[
1,2]
abandoned agricultural lands.
the major components of feedstocks that are currently being
Arabinoxylan (AX) is one of
[17]
glycals
were used as donors and more recently
[12,13]
trichloroacetimidates.
nd
[3,4]
investigated as a source of 2 generation biofuels.
composed of β-(1→4)- -xylopyranose, partially substituted
by α- -arabinofuranose residues on the second and third
position of the xylan residues. Many enzymes are required for
efficient AX degradation, and among them, we find
AXs are
The challenges of the second method are the stereospecific
introduction of the anomeric sulfur group and its activation
into the corresponding thiolate, in addition to the nature of the
electrophile. Because they can be selectively cleaved to form
the thiol in the presence of ester protecting groups, almost
only thiourea salts and thioacetates have been used as
D
L
endoxylanases, α-
process, β- -xylosidases. To optimize the production of 2
L-arabinofuranosidases and to complete the
[
5]
nd
D
[18,17,19–26]
intermediates in the synthesis of anomeric thiols.
generation biofuel a better understanding of the carbohydrate-
protein interactions that govern biomass degradation, is
needed. A versatile approach for mapping the active site of
glycosyl-hydrolases is to utilize enzyme resistant substrates
which are competitive inhibitors, like thiooligosaccharides
where the oxygen of one or more glycosidic bonds are
replaced by a sulfur atom.
There are two general approaches for the synthesis of
thiooligosaccharides.
In this work, we present the effective synthesis of the
tetraxylan 1, which bears a glycosidic thiolinkage on the first
glycosidic bond from the non-reducing end by using both
mentioned synthetic strategies. Moreover, a comparison
between the two mentioned methods for preparing
thiolinkages with
a special focus on the challenges
[6–9]
encountered and main byproducts is also presented.
[
10,11]
The first approach is
a
glycosylation with a saccharide thiol as the glycosyl
[12,13]
acceptor.
The second method is an “inverse”
glycosylation, using an anomeric thio function, which is
introduced first to yield the anomeric thiol or thiolate and then
reacted with a saccharide electrophile, to form the inter-S-
[8]
glycosidic linkage through an S 2 displacement reaction.
N
Both approaches are commonly used, but the latter approach,
where the anomeric configuration of the product is more
easily controlled has received the most attention. The
stereochemistry at the anomeric center is controlled during the
formation of the anomeric thiol function and not during the
coupling reaction. Furthermore, replacement of oxygen with
sulfur to create S-thioglycosides presents other synthetic
challenges than the mere formation of the thio-linkage itself
due to the difference in chemical properties of the two
elements. Firstly, sulfur atoms are incompatible with catalytic
[14]
hydrogenolysis , which complicates the use of benzyl ethers
as protective groups, and secondly, thiols easily form
[15]
disulfides, both as glycosyl donors and acceptors.

The length of the target structure is four units as this is the
Scheme 1: a) i. Trimethyl chloro-orthoacetate, p-TsOH, CH
3
CN,
ACCEPTED MANUSCRIPT
[27]
4
0 ˚C, 10 min, ii. TFA, CH CN, 22 ˚C, 1 h, b) BzCl, DMAP, Et N,
minimal length recognized by endo-β-1,4-xylanases , but
also a suitable length for studying β-xylosidases, therefore, a
possible interesting candidate for the investigation and the
characterization of AX degrading enzymes.
3
3
CH Cl , c) thiourea, NaHCO , TBAI, THF.
2
2
3
The thioacetate donor 9 was obtained from the corresponding
bromide 14 by reaction with KSAc in DMF (Scheme 2;
[16,30]
α:β = 1:4).
Compound 9 was selectively deprotected with
NaSMe, and the resulting crude intermediate 15 was treated
with NaH in THF and mixed with the triflate 16, which was
freshly prepared from compound 10 and Tf O/pyridine
2
[31]
(
Scheme 3.1).
The glycosylation yielded S-disaccharide 6
in 52% yield.
Scheme 2: KSAc, DMF, 22 ˚C, 1 h.
However, the coupling reaction gives a degree of uncertainty
about the effective amount of donor and acceptor used in the
reaction because their crude mixtures are employed. To
investigate alternatives, we decided to vary the approach
[32]
slightly according to Driguez and co-workers. The method
still uses the thioacetate 9 as a glycosidic donor and involves
the employment of cysteamine for the removal of the acetate
in situ and dithioerytritol (DTE) as reducing agent and
Figure 1: A proposed retrosynthetic strategy for the synthesis of
tetraxylan 1.
[33,34]
scavenger (Scheme 3.2).
The coupling reaction between
2
. Results and Discussion
9 and the activated acceptor 16 was performed at room
temperature for 16 h and yielded merely the β-1,4 linked S-
disaccharide 6 in 78%. We assume that the 9α anomer
epimerizes during the coupling reaction, since we do not
detect the corresponding α-1,4 linked S-disaccharide.
The synthesis of target 1 is based on a 2 + 2 block strategy
between the S-disaccharide donor 3 and the O-disaccharide
acceptor 4 (Figure 1). The acceptor 4 can be obtained by the
employment of thioglycoside 5, which can be used as a donor
but also converted in the desired acceptor in a few steps. S-
disaccharide 6 is envisioned to be obtained through a
glycosylation reaction between a trifluoroacetimidate donor 7
and thioacceptor 8, but also by employing acceptor 9 and
thiodonor 10 (Figure 2). We decided to initially investigate
the first method involving a thiodonor as the nucleophile to
produce the thiolinkage.
Scheme 3: One pot syntheses of S-disaccharide 6; 1 a) Tf O,
2
pyridine, CH Cl , 22 ˚C, 30 min, b) NaSMe, CH Cl /MeOH (1:1), c)
2
2
2
2
NaH, THF, then 16, DMF, 0 ˚C , 1 h, 2 d) cysteamine, DTE, DMF,
2 ˚C, 16 h.
2
The most typical side reactions in these type of coupling are
the elimination of the triflate and the anomerization of the
Figure 2: Different approaches for the synthesis of S-linked
disaccharide 6.
[35]
thiol.
We observed mainly the elimination of triflic acid
from compound 16 as a byproduct. However, we also
identified the presence of the disulphide originating from
dimerization of the thiol donor 9.
Acceptor 10 was prepared from allyl β-
1, which was first functionalized at C4-OH with a
chloroacetyl protecting group followed by benzoylation of the
L-arabinopyranoside
1
[28,29]
remaining positions (Scheme 1).
subsequently deprotected to afford 10.
Compound 13 was
Scheme 4: a) i. Tf O, pyridine, CH Cl , 30 min, ii. KSAc, DMF,
2
2
2
2
2 ˚C, 2 h, b) NaSMe, CH Cl /MeOH (1:1).
2 2
Next, we investigated the coupling of thiol acceptor 8 and the
imidate 7. To this end, 10 was treated with Tf O and pyridine,
2
36]
[
followed by reaction with KSAc in DMF
and selective

[
37]
deprotection to thiol 8 with NaSMe
(Scheme 4). The
ACCEPTED MANUSCRIPT
coupling reaction to the desired S-disaccharide 6 was
performed at −35 C in CH Cl with TMSOTf as a promoter
°
2
2
(
Scheme 5).
Scheme 7: a) 2,3-butanedione, CH(OMe) , CSA, MeOH, 22 ˚C, b)
3
Tf O, pyridine, CH Cl , 22 ˚C, c) 9, 21, cysteamine, DTE, DMF,
2
2
2
2
2 ˚C.
We believed it would be of interest to investigate not only the
possible influence of different protecting groups but also the
possibility of extending the reaction to other substrates.
Therefore, acceptor 20 and triflate 21 were obtained from the
allyl protected L-arabinose 11 (Scheme 7). The acid-catalyzed
reaction of 11 with 2,3-butanedione in methanol allowed
protection of the trans-diequatorial hydroxyl groups on the 2-
and 3-positions with a cyclic butane diacetal to afford
compound 20 in 59% yield. The yield of the reaction between
triflate 21 and thioacetate 9 affording 22 was not as high as it
was for the analogue thiol acceptor 16. We can hypothesize
that due to the diacetal, the transition state of the more
strained 21 is disfavored compared to 16. Also side reactions
such as the elimination of the triflate group in 21 as well as
the corresponding disulphide dimer of 9 were observed.
Scheme 5: a) TMSOTf, CH Cl , -35 ˚C, b) Cs CO , DMF, 22 ˚C, c)
2
2
2
3
AgOTf, 2,4,6-collidine, CH Cl , -20 °C.
2
2
We envisioned the successful use of N-phenyl
trifluoroacetimidate 7, due to its lower propensity to undergo
side reactions and rearrangements to acetamide during
[38]
glycosylations
compared
to
trichloroacetimidates.
Unfortunately, no S-linked disaccharide 6 was detected in the
reaction mixture. One of the major problems was the
dimerization of the acceptor into the corresponding
disulphide, which was found to be stable to several reducing
agents. We investigated the possibility of reducing
disulphides to thiol acceptors both before the glycosylation
and in situ using NaCNBH , P(OCH ) , DTT, P(n-Bu) , or
3
3 3
3
PPh . However, conversion to the thiol 8 was only obtained
3
employing PPh3, and when this was added to the
glycosylation reaction, the yield of disaccharide 6 was still
unsatisfactory (< 25%). Another byproduct isolated in the
reaction mixture was the glycal and hydrolyzed donor. This
result was found to be consistent with previous reports from
other groups. Changing the ratio of acceptor to donor, the
concentration, the solvent as well as the promoter did not lead
to the formation of 6. We concluded that the N-phenyl
trifluoroacetimidate 7 was not applicable under these
conditions.
Scheme 8: a) i. Tf O, pyridine, CH Cl , ii. KSAc, DMF, 22 ˚C, b)
NaOMe, MeOH.
2
2
2
The thioacceptor 24 was obtained from 20 in three steps
Scheme 8). The epimerization of 20 to thioacetate 23 was
(
[39]
performed with Tf O and pyridine, followed by KSAc in
2
[36]
DMF. The acetate 23 was converted to the corresponding
thiol 24 under Zémplen conditions in 91% yield.
Glycosylation of thioacceptor 24 with trichloroacetimidate 19
afforded 22 in a good yield of 64% (Scheme 9).
Cao et al. reported the successful synthesis of an S-linked
heparan sulfate trisaccharide employing halides as donors,
[40]
where acetimidate donors failed. Inspired by these results,
glycosylation between bromide 18 and thioacceptor 8 was
performed using two different promoter systems (Scheme 5).
Scheme 9: a) TMSOTf, CH Cl , -40 ˚C, b) i. Pd(PPh ) , AcOH,
2
2
3 4
Disappointingly, neither reaction afforded disaccharide 6.
6
0 ˚C, ii. CCl CN, DBU, CH Cl .
O
3 2 2
BzO
BzO
O
HS
BzO
O
CCl3
NH
+
6
BzO
BzO
The anomeric position of the reducing end of the S-
disaccharides 6 and 22 was deprotected with Pd(0). Allyl
deprotection of 22 at 40 ˚C did not proceed to completion.
Therefore, the reaction was performed at 60 ˚C for 15 min
affording the hemiacetal in 86%. The deallylated structures
O
57%
1
9
8
Scheme 6: TMSOTf, CH Cl , -35 ˚C
.
2
2
We hypothesized that the reactivity between the chosen
donors 7 or 18 and acceptor 8 was poorly matched. Therefore,
we were prompted to try a different donor with higher
reactivity like trichloracetimidates, as the group of Pinto et al.
showed the applicability of these in the synthesis of S-linked
were
then
converted
in
the
corresponding
trichloroacetimidates 25 and 3 under standard conditions
[41,42]
(
Scheme 9 and 10).
[12]
glycans.
Using trichloracetimidate 19 to glycosylate
acceptor 8 afforded 6 in 57% yield (Scheme 6). The choice of
the trichloroacetimidate donor seems to be critical for this
reaction, as it appears to favor the glycosylation to 6 over the
dimerization of the thiol 8.
Scheme 10: i. Pd(PPh ) , AcOH, 40 ˚C, ii. CCl CN, K CO , CH Cl .
3
4
3
2
3
2
2
The synthesis of the O-disaccharide acceptor 4 starts with
benzoylation of diol 26, which was prepared following

[
43–46]
literature procedures (Scheme 11).
The anomeric
References
ACCEPTED MANUSCRIPT
thioacetal of 5 was hydrolyzed and benzoylation afforded
compound 27 in 70% yield . The 4-position was deprotected
with DDQ to provide acceptor 28 in 74% yield.
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Acknowledgments
We acknowledge financial support from the Danish Council
for Independent Research “A biology-driven approach for
understanding
enzymatic
degradation
of
complex
polysaccharide systems” (Grant Case no.: 107279), the
Carlsberg Foundation, the Danish Strategic Research Council
(
(
(
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PLANET project) and the Novo Nordisk Foundation
Biotechnology-based Synthesis and Production Research).

ACCEPTED MANUSCRIPT
Convergent strategy for the synthesis of S-linked oligoxylans
Highlights:
•
•
•
The synthesis of a mixed O- and S-linked tetraxylan
Investigation of two approaches for S-disaccharide synthesis
Determination of side-product during S-glycosylation for both strategies