Synthesis of trisaccharide repeating unit of fucosylated chondroitin sulfate

Article abstract of DOI:10.1039/c9ob00057g

We described the chemical synthesis of a sulfated trisaccharide repeating unit of fucosylated chondroitin sulfate (FCS), which has significant anticoagulant activity. Well-functionalized monosaccharides were readily prepared, and highly efficient glycosyl

Full text of DOI:10.1039/c9ob00057g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
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DOI: 10.1039/C9OB00057G
Organic &Biomolecular Chemistry
COMMNICATION
Synthesis of Trisaccharide Repeating Unit of Fucosylated
Chondroitin Sulfate
Haiqing Hea,b, Dong Chena,b , Xiaomei Lia,b , , Chengji Lia,b Jin-Hua Zhao*, Hong-Bo Qin*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The chemical synthesis of
a sulfated trisaccharide
D-GalNAc
D-GlcA
repeating unit of fucosylated chondroitin sulfate (FCS), which
has significant anticoagulant activity, is described. Well-
functionalized monosaccharides were readily prepared and
highly efficient glycosylations using a common activator
(NIS/TfOH) were also presented. The synthetic trisaccharide 4
could be used to extend the oligosaccharide sequence.
OSO3Na
OSO3Na
COONa
O
O
O
O
O
O
OH
NHAc
O
OR
L-Fuc
OR
OR
R = SO3Na or H
Fucosylated
chondroitin
sulfate
(FCS),
a
unique
glycosaminoglycan (GAG) derivated from sea cucumber, is
composed of a chondroitin sulfate (CS)-like backbone and
sulfated fucose as side chain, which linked to O-3 of the
Fig. 1 Repeating unit of FCS
result.17 This paper also demonstrated that reduction in
1-5
glucuronic acid (GlcA) (Figure 1).
FCS exhibit various chain size may dramatically reduce its adverse effect of FXII
pharmacological effects such as anti-inflammatory, 7anti- activation. These results have boosted the discovery of
6,
tumor,6
anti-hyperglycemia
actions.,8,
promoting selective inhibitor of intrinsic coagulation pathway.
However, depolymerization of natural FCS is time-consuming
9
angiogenesis2, and regulating immune and cell growth. 10 Most
importantly, FCS has attracted broad attention for its high and less effective to obtain enough amount of pure
anticoagulant and antithrombotic activities because of its compounds for further research. It is necessary to develop an
1, 11-14
selective inhibition of the intrinsic tenase.
These effective synthetic route to investigate the structure and
biological effects are attributed to the sulfated α-fucose and activity relationship between the size and molecular weight.
they decrease significantly after selective removal of the Several groups have published interesting results in this aspect.
sulfated Fuc residues. 15
In 2013 Tamura group reported
a
synthesis of the
It is thought that well-defined oligosaccharides could trisaccharide β-D-GalNAc(4,6-diS)(1 → 4)[α-L-Fuc(2,4-diS)(1 →
facilitate the development of more efficacious anticoagulants. 3)]-β-D-GlcA as a repeating unit of FCS.18 Galactosyl imidate
In 2015, we reported a series of pure oligosaccharides with was coupled with glucosyl acceptor in the presence of BF3·Et2O
precise structure prepared via the deacetylation–deaminative to afford the 1,2-trans disaccharide only in 40% yield due to
cleavage of FCS.16 In this paper, nonasaccharide was non-neighbouring group participation. Furthermore, the
determined as the minimum structural unit that retained the installation of Fuc branch was not effective considering the
anticoagulation potency with negligible bleeding risk. Recently, way to synthesize donor. Nifantiev’s group also published
Chen group declared that a depolymerized heptasaccharide some synthetic works about the β-D-glucuronic acid residue
was the minimum fragment to obtain similar benefit/risk
bearing at O-3 α-L-fucosyl or α-L-fucosyl-(1 → 3)-α-L-fucosyl
19
substituents related to structural fragments of FCS, and the
20
Fuc(1→6)GalNAc derivatives without sulfated. Additionally,
a. State Key Laboratory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, Chinese Academy of Sciences, and Yunnan Key
Laboratory of Natural Medicinal Chemistry, Kunming 650201, P. R. China.
E-mail: qinhongbo@mail.kib.ac.cn; .zhaojinhua@mail.kib.ac.cn;
a modular approach to a library of semi-synthetic FCS
polysaccharides had been presented by Bedini group via
chemical transformation of a microbial sourced unsulfated
chondroitin polysaccharide. 21, 22 Recently, significant progress
has been reported by Li group for the elegant synthesis of new
FCS utilizing their enzyme degradation of chondroitin sulfate
b. University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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polymers.23-25 Di-, tetra- and hexasaccharides have been used as a permanent protection group during the synthesis of
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prepared directly and used as backbone, thus improved the 1, and secondly, it could be selectively rDeOmI:o1v0e.1d03t9o/Ce9xOteB0n0d05th7Ge
synthesis efficacy dramatically.
main chain if necessary. The carboxylic acid group was blocked
with benzyl group due to its higher reactivity than that of
methyl ester when it was used as a donor. 26 PMB was used for
a temporary protection at C-3 hydroxy of GlcA in order to
couple with the Fuc branch. Finally, the Bz and Bn protecting
groups were used as permanent protection groups for other
free hydroxy groups and would be removed at late stage of
synthesis.
Herein, we report a synthesis of trisaccharide repeating unit
[α-L-Fuc(2,4-diS)(1 → 3)]-β-D-GlcA(1 → 3)-β-D-GalNAc(4,6-diS),
via a convenient and effective synthetic route, which may
provide a different approach to bioactive FCS oligomers.
OSO3Na
OSO3Na
COONa
O
HO
O
O
OMP
O
OH
NHAc
OAc
O
Ph
Ph
O
OSO3Na
O
b
AcO
AcO
a
O
O
O
HO
O
O
1
NaO3SO
OAc
HO
PMBO
STol
STol
OAc
OH
OR
15
14
13
R=H
c
12
R=Bz
Ph
OH
BnOOC
RO
PMBO
O
d
e
O
HO
PMBO
BnOOC
LevO
O
O
STol
STol
O
O
O
OMP
O
OBz
OBz
10
11
OBz
N3
R=H
f
O
7
R=Lev
OAlloc
OBn
OAlloc
4
Scheme
2 Synthesis of building block 7. Reagents and conditions: (a):1) p-
toluenethiol, BF3·Et2O, DCM,rt,10h; 2) Na,MeOH,rt,1h; 3) PhCH(OMe)2, MeCN, CSA,
45°C, overnight , 3 steps 91%; (b): 1) Et3N, TMSCl, DCM, rt, 6h; 2) Et3SiH, Anisic
aldehyde, TMSOTf, DCM, TBAF, overnight, 91%;(c): Bz2O, DMAP, Et3N, rt,overnight,
94%; (d): p-TsOH·H2O, MeOH, MeCN,50 °C,3h, 79%; (e): 1) TEMPO, BIAB, DCM, H2O,
rt, 40min; 2) K2CO3, BnBr, Acetone, 50 °C, 5h, 68%; (f ) LevOH, EDCI, DMAP, DCM, rt,
8h, 93%. PhCH(OMe)2 = benzaldehyde dimethyl acetal, CSA = camphorsulfonic acid,
Ph
O
BnOOC
LevO
PMBO
O
STol
O
O
OAlloc
+
O
O
OMP
OBn
OAlloc
TEMPO
=
2,2,6,6-tetramethyl-1-piperidinyloxy,
BAIB=2,2,6,6-tetramethyl-1-
OBz
N3
piperidinyloxy, Et3N
dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
dimethylaminopyridine
=
triethylamine, LevOH Levulinic acid, EDCI
=
=
N-(3-
4-
9
6
,
DMAP
=
Ph
O
BnOOC
LevO
PMBO
O
OH
OH
O
O
Based on the analysis, monosaccharide building blocks were
initially synthesized. The glucouronic acid building block 7 was
synthesized starting from commercially available β-D-Glucose
pentaacetate 15 in nine steps (Scheme 2). Treatment of 15
O
+
STol
OMP
HO
OH
OH
OBz
N3
8
7
24
with p-toluenethiol in the presence of BF3·Et2O provided the β-
OAc
27
OH
OH
HO
thioglycoside in almost quantitative yield.
Then it was
AcO
AcO
O
O
deacetylated under Zemplen conditions, and this was followed
by treatment of PhCH(OMe)2 and CSA in acetonitrile to give
4,6-O-benzylidence 14. The regioselective introduce of Bn was
realized with Bu2SnO, TBAB, PMBCl, but this proved
OAc
OH
OAc
NH2•HCl
15
21
Scheme 1. A retrosynthetic analysis of trisaccharide 1. Abbreviations: Ac = acetyl, Ph =
Phenyl, MP = 4-methoxyphenyl, Bn = benzyl, Bz = benzoyl, Lev = levulinyl, PMB = p-
methoxybenzyl, Alloc = Allyloxycarbonyl, Tol=4-tolyl.
troublesome during chromatographic separation. To avoid the
28
tin reagent, Hung’s one-pot protection strategy
was used
and reaction proceeded smoothly with excellent
regioselectivity. Removal of the 4,6-O-benzylidene group of 12
using p-TsOH·H2O gave diol 11 in 79% yield, which was
subjected to selective oxidation of the resulting primary
hydroxy group with TEMPO in the presence of BAIB as co-
We envisioned a convergent strategy (Scheme 1) to access
the trisaccharide
1
using
a
set of functionalized
monosaccharide building blocks 7, 8 and 9. These were readily
accessible from commercially available starting materials 15,
21 and 24, respectively. The protecting group strategy was
established for selective O-sulfation as well as stereoselectivity
of glycosylation. The sulfated 4- and 6-hydroxyls of D-
galactosamine were masked with a benzylidene acetal which
could selectively be removed with 80% AcOH. The Alloc
protecting groups of fucose intended to be O-sulfated and
could be more easily removed comparing with the Allyl. 23 The
benzoyl protecting C-2 hydroxy of GlcA allowed the
stereoselective introduction of 1,2-trans-glycosidic linkages by
neighbouring group participation. The levulinoyl group was
installed at C-4 of GlcA for two reasons: firstly, it could be
29
oxidant. The resulting carboxylic acid was then esterified in
the presence of K2CO3, BnBr to give desired 10 in 68% yield
over two steps in one-pot. 26, 30 The GlcA thioglycoside donor 7
was obtained by further protection of the remaining C-4
hydroxy group with LevOH and EDCI in the presence of a
catalytic amount of DMAP in a yield of 95%.
To synthesize the disaccharide efficiently, extensive
investigation was made using a number of acceptors with
different protecting groups of NH2, which presumably possess
31
different reactivity in glycosylation. The building blocks 16
17
,
32,
34, 35
33, 18
could easily be prepared according to the
2 | J. Name., 2012, 00, 1-3
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described synthetic protocols. The building block 8 was repeating unit of chondroitin sulphate (CS) according to Zhao’s
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31
DOI: 10.1039/C9OB00057G
synthesized from D-galactosamine hydrochloride 21 in five report . Two more steps were needed while transforming the
steps with 37% overall yield (Scheme 3). 21 was reacted with donor into trichloroacetimidate. To avoid it,
a direct
36
imidazole-1-sulfonyl azide,
a diazotransfer reagent, to give glycosylation condition of thioglycoside would be explored.
2-azido-2-deoxy-d-galactopyranose,37 followed by global Therefore, a series of acceptors had to be tested. As depicted
acetylation (Ac2O, Pyridine, DMAP). Compound 20 was isolated in the Table 1. First, N-acetyl acceptor 16 was reacted with
in 75% yield with two steps in one-pot. Then treatment of 20 glucuronate 7 by activating the thiotolyl group with the
40
with 4-methoxyphenol in the presence of TfOH gave 19 as a NIS/TfOH acid reagent (entry 1). Unfortunately, it failed to
1.1: 1 mixture of the corresponding α- and β-isomers. Finally, afford desired disaccharide.
removal of the three O-acetyl groups by NaOMe, followed by
31
protection of the 4,6- di-OH with PhCH(OMe)2, provided the
galactoazide acceptor 8 (β-anomer and α-anomer is not
shown).
Table 1 Glycosylation of GlcA and GlaN
Ph
O
O
O
Ph
O
HO
OMP
BnOOC
LevO
PMBO
R
BnOOC
LevO
PMBO
O
O
O
O
STol
Ph
O
OMP
OBz
OBz
R
O
O
6
R=N3
R=NHAc
R=NHTroc
R=NPhth
O
8
R=N3
OMP
HO
6-1
6-2
6-3
16
17
18
R=NHAc
R=NHTroc
R=NPhth
NHAc
16
entry
acceptor
promoter
NIS/TfOH
NIS/TfOH
NIS/TfOH
NIS/TfOH
NIS/TfOH
NIS/TfOH
Temp/ °C
yield
NR[a]
NR[a]
Trace [b]
45% [b,c]
75% [c]
Trace [b]
Ref. 31
Ph
O
1
2
3
4
5
6
16
17
18
8
-45 °C ~ -20 °C
-45 °C ~ -20 °C
-45 °C ~ -20 °C
-45 °C ~ -20 °C
-70 °C ~ -45 °C
-20 °C ~ rt
OAc
OH
O
OAc
O
OH
HO
Ref. 34,35
a
O
O
OMP
HO
OH
OR
b
AcO
NPhth
NH2•HCl
N3
20
19
R=Ac
R=MP
21
18
8
Ref. 32,33
c
8
[a]: no reaction, and the donor was completely hydrolyzed; [b]: the donor
was partially hydrolyzed and incomplete consumption of acceptor; [c]:
isolated yield .
Ph
O
Ph
O
O
O
O
O
OMP
HO
OMP
HO
NHTroc
N3
17
8
Subsequently, N-trichloroethoxycarbonyl (Troc) group was
employed instead of acetyl in the galactosyl building block41
(entry 2). Surprisingly, no desired product formed, while
substantial decomposition of the glycosyl donor was observed,
Scheme
3 Synthesis of disaccharide acceptors 8,16,17 and 18. Reagents and
conditions: (a): 1) K2CO3, imidazole-1-sulfony azide hydrochloride, CuSO4·5H2O, MeOH,
rt,4h; 2) Pyridine, Ac2O, rt, 10h, 2 steps 80% (α/β = 1/7) ; (b): 4-Methoxyphenol, TfOH,
DCM, rt, 16h, 96% (α/β = 1.1/1); (c): 1)Na, MeOH, rt, 1h; 2) PhCH(OMe)2, MeCN, p-
TsOH, 45°C, overnight , 2 steps, 50% for α, 45% for β (8);
presumably due to the poor solubility of acceptors in organic
41,42
solvents
and the low reactivity of donor. After that, the
coupling reaction of benzylidene-2-deoxy-2-phthalimido-β--D-
galactopyranoside 18 and the donor 7 was studied. However,
it only gave trace amount of disaccharide 35 (entry 3) while the
donor was partially hydrolyzed. The low yield might be
attributed to the steric effect of Phth group. Finally, we tried
to couple the 2-azido-2-deoxy-d-galactopyranose 8 with the
donor 7 using the same condition as above (entry 4). To our
delight, the β-linked disaccharide 6 was isolated in 45% yield
while the α-isomer was not detected (J1’,2’=8.2Hz). The
temperature was critical for the reaction. When it was below -
70°C, a remarkable increase in the yield to 75% (entry 5) was
observed. On the other hand, when the temperature rose to -
20°C, the yield decreased heavily because donor hydrolyzation
occurred as side reaction (entry 6). We thus concluded that an
azido-containing acceptor gave best result for its smaller size
and good solubility, when compared with its acetamido, Troc
and corresponding Phth acceptor.
a
STol
OR
OH
OH
b
STol
OAc
O
O
O
OBn
OR
OH
OH
OAc
OAc
23
24
22
R=H
R=Alloc
c
9
Scheme 4 Synthesis of building block 9. Reagents and conditions: (a): 1) Pyridine, Ac2O,
rt, 6h; 2) p-Toluenethiol, BF3·Et2O, DCM, rt, 10h, 2 steps 95%; (b): 1) Na, MeOH, rt, 1h;
2) Bu2SnO, TBAB, BnBr, toluene, reflux, overnight, 68%; (c): Allyl chloroformate, DMAP,
DCM, rt, 4h, 86%. Bu2SnO = dibutyltin oxide, TBAF = tetrabutylammonium fluoride
The synthesis of β-thiofucoside donor 9 is outlined in
Scheme 4. From L-fucose, the known β-thiofucoside 2338 was
synthesized with two steps in 95% yield. Deacetylation under
Zemplen conditions provided triol, which was regioselectively
protected as 3-O-benzylation 22 39 when treating with Bu2SnO,
BnBr, and TBAF in 75% yield with two steps in one-pot. Then
donor 9 was readily obtained with AllocCl and DMAP in 89%
yield.
With functionalized donors and acceptors in hand, we
initially investigated the synthesis of β (1 → 3) disaccharides.
However, the yield was unsatisfactory when thioglycoside was
used as a donor for the construction of the disaccharide
To assemble the target trisaccharide 4 (Scheme 5), a
temporary protection group 3-O-PMB of 6 was removed
smoothly by treating with DDQ to obtain disaccharide acceptor
5 in 85% yield. 30 The coupling reaction of 5 with 9 proceeded
under similar glycosylation condition to afford exclusively the
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α-linked trisaccharide 4 in 83% yield (J1’’,2’’=3.4Hz, see the an amino group with 1,3-propanedithiol 45, then acetylated
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supporting information). This 1,2-cis selectivity, as distinct with Ac2O in Pyridine, followed by remoDvaOlI:o1f0.1039/C9OB00057G
from typical glycosylation with the assistance of neighbouring
group participation, was attributed to reversible in situ
anomerization and the stabilizing anomeric effect.42-44
Next, a series of functional group transformations were
carried out (Scheme 5). The azido group in 4 was reduced into
Ph
Ph
O
O
BnOOC
LevO
O
BnOOC
LevO
O
O
O
a
c
O
OMP
O
O
7
+
8
9
+
O
RO
O
OBz
OMP
N3
OBz
O
N3
OAlloc
OBn
OAlloc
6
5
R=PMB
R=H
b
4
OSO3Na
OSO3Na
OH
COONa
O
OH
BnOOC
HO
O
LevO
f
O
O
O
OMP
NHAc
O
O
d
OMP
NHAc
O
OH
OBz
O
O
OSO3Na
OR
HO
NaO3SO
OBn
3
2
R=Alloc
R=H
OR
e
1
Scheme 5 Synthesis of trisaccharide 1. Reagents and conditions: (a): 1) NIS, TfOH, DCM, 1.5h, -70°C -45°C, 40min, 75%; (b): 1) DDQ, DCM, rt, 12h, 85%; (c): NIS,TfOH,-50°C,1h,
83%; (d): 1) 1,3-dimercaptopropane, pyridine, Et3N,H2O,1h;2) Ac2O, Et3N, DCM,3h; 3) 80% AcOH/H2O, reflux, 3h, 3 steps 70%; (e): Pd(PPh3)4, PPh3, Ammonium formate. THF, 3h,
86%; (f): 1) SO3·Me3N, DMF, 60°C, 30h; 2)LiOH, H2O2, NaOH, MeOH, THF, rt, 2d; 3) Pd/C, H2, H2O, MeOH,1d, 3 steps 69%. NIS = N-iodosuccinimide, TfOH =
trifluoromethanesulfonic, DDQ = 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone.
the 4,6-O-benzylidene group using 80% AcOH gave diol 3 in 1,2-cis glycosidic linkages was achieved with exclusive
70% yield with three steps in one-pot. Alloc esters were stereoselectivity using Alloc protecting groups. Furthermore,
deprotected to generate 2 with ammonium formate and a the trisaccharide 4 could be readily transformed into a new
46
catalytic amount of Pd(PPh3)4 in 85% yield.
Per-O- donor by oxidative removal of the 4-methoxyphenyl group
sulfonation of all hydroxyls with sulfur trioxide trimethylamine with ceric ammonium nitrate (CAN). 42,49-51 Meanwhile, it could
complex (SO3·Me3N) in DMF led to the corresponding sulfated also act as a new acceptor by selective removal of Lev in the
trisaccharide derivative, followed by saponification utilizing presence of hydrazine hydrate, pyridine and AcOH.49-52 In
sequential LiOOH-NaOH treatment to minimize β-elimination addition, the azide group could be easily transformed into
47, 48
at the C-4 position.
The remaining O-Bn group in the other groups in one-pot, such as TFA 31, Troc 53, Phth 54 , which
fucosyl residue was cleavaged via Pd/C-catalyzed can be used as neighbouring group to control the
hydrogenolysis to yield the target trisaccharide 1 in 69% yield stereochemistry of further glycosylation. These features make
over three steps in one-pot. NMR spectroscopy (DEPT, COSY, it possible to prepare hexasaccharide and nonasaccharide for
HSQC experiments) and mass spectrometry analysis confirmed further structure–activity relationship research.
the structure of 1.
Conclusions
In summary, we have synthesized
Conflicts of interest
a trisaccharide, the
repeating unit of FCS, through a convergent synthetic route in
20 collective steps from commercially available starting
materials in 1.5% overall yield. The use of one-pot reactions
effectively reduced the synthetic and purification steps. The
azide group is a crucial and ideal protecting group of the
acceptor. And the construction of the fucose-branch with a
There are no conflicts to declare.
Acknowledgements
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