Highly alpha-selective sialyl phosphate donors for efficient preparation of natural sialosides

Article abstract of DOI:10.1002/chem.200903035

A new sialylation reagent that employs an N-acetyl-5-N,4-O-carbonyl protection with dibutyl phosphate as the leaving group has been reported. N-Acetyl neuraminic acid (Neu5Ac) is most frequently found at the terminal end of glycoconjugates on the cell surface. The ring-opening product was obtained as the major product in the hydrolytic step. The one-pot synthetic operation was performed in the presence of NIS/trifluoromethanesulfonic acid (TfOH) promoter system. The sialyl phosphate donor also can be used in an orthogonal one-pot glycosylation, providing an alternative choice for the rapid synthesis of sialosides, allowing the coupling of building blocks independent of their relative reactivities, such as SSEA-4. Sialyl phosphate donors are very efficient at creating complex natural sialosides and are being used for rapid preparation of important sialoside microarrays.

Full text of DOI:10.1002/chem.200903035

DOI: 10.1002/chem.200903035
Highly Alpha-Selective Sialyl Phosphate Donors for Efficient Preparation of
Natural Sialosides
Che-Hsiung Hsu,[a, b, c, d] Kuo-Ching Chu,[a] Yih-Shyan Lin,[a] Jeng-Liang Han,[a]
Yu-Shiang Peng,[a] Chien-Tai Ren,[a] Chung-Yi Wu,*[a, c] and Chi-Huey Wong*[a, b, c]
N-Acetyl neuraminic acid (Neu5Ac) is most frequently
found at the terminal end of glycoconjugates on the cell sur-
face. This terminally exposed position allows Neu5Ac-con-
taining conjugates to be exploited as receptors for viruses
and bacteria, in addition to governing a wide variety of bio-
logical processes, such as tumor metastasis, cell differentia-
tion, and cell–cell interactions.[1] In naturally occurring sialo-
sides, Neu5Ac is found linked to galactosides through the a-
tions of the leaving group with positional modification.[12]
However, high yielding a-selective sialylation is still prob-
lematic owing to the presence of the C-1 electron-withdraw-
ing carboxyl group at the tertiary anomeric center and the
lack of a participating group at C-3 to direct the stereo-
chemical outcome of glycosylation.
The development of new strategies for the convergent
synthesis of saccharides is a major focus in carbohydrate
chemistry. Approaches such as armed–disarmed;[13] one-
pot;[14] reactivity-based, programmable one-pot;[6b,15] solid-
phase;[16] orthogonal;[17] and pre-activation[18] methods have
been developed to improve efficiency, with the ultimate goal
of developing an automated method for oligosaccharide syn-
thesis.[14–16] The basic concept of these strategies involves the
selective activation of one donor in the presence of an ac-
ceptor with the same or different leaving groups, so the
newly formed product can be directly elongated without fur-
ther aglycon leaving group adjustment. However, these ap-
proaches are not applicable to all glycosides. For example,
sialic acid thioglycosides have limitations in our programma-
ble reactivity-based, one-pot strategy due to their poor and
narrow range of anomeric reactivity values (RRVs).[12a,19] To
resolve the problem, sialylated disaccharides have been used
as building blocks.[20] However, application of this strategy is
limited by the lack of an efficient and a-selective sialic acid
donor that possesses a leaving group orthogonal to the thio-
glycoside.[20] Herein, we report a new sialylation reagent 1
that employs an N-acetyl-5-N,4-O-carbonyl protection with
dibutyl phosphate as the leaving group. Furthermore, the
new donor was applied to develop efficient strategies to use
to create natural sialosides.
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
U
of glycoproteins and glycolipids.[2] The biological signifi-
cance of sialoside receptors has driven research for their ef-
ficient synthesis. This has included significant efforts direct-
ed toward the development of sialic acid donors for efficient
a-sialylation,[3] including the use of anomeric leaving groups,
such as halides,[4] phosphites,[5] sulfides,[6] xanthates,[7] and
phenyltrifluoroacetimidates,[8] the introduction of an auxili-
ary group at C-1[9] and C-3,[10] the modification of the N-
acetyl functional group at C-5,[11] or the optimized combina-
[a] C.-H. Hsu, Dr. K.-C. Chu, Y.-S. Lin, Dr. J.-L. Han, Y.-S. Peng,
Dr. C.-T. Ren, Prof. C.-Y. Wu, Prof. C.-H. Wong
The Genomics Research Center, Academia Sinica (Taiwan)
128 Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
Fax : (+886)2-2785-3852
E-mail: cyiwu@gate.sinica.edu.tw
chwong@gate.sinica.edu.tw
[b] C.-H. Hsu, Prof. C.-H. Wong
Department of Chemistry, The Scripps Research Institute
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Many researchers have focused on the modification of the
N-acetyl functional group of sialic acid for highly efficient
a-sialylation. However, there is no general donor for differ-
ent acceptors. The choice of C-5 modification to be used is
highly dependent on protecting groups and the nature of
glycosyl acceptors. There is an excellent review on C-5
modification by De Meo.[11] Crich and co-workers have
shown that the N-acetyl-5-N,4-O-carbonyl thiosialoside can
[c] C.-H. Hsu, Prof. C.-Y. Wu, Prof. C.-H. Wong
Chemical Biology and Molecular Biophysics
Taiwan International Graduate Program, Academia Sinica
128 Academia Road, Section 2, Nankang, Taipei 115 (Taiwan)
[d] C.-H. Hsu
Institute of Bioinformatics and Structural Biology
National Tsing-Hua University, Hsin-Chu (Taiwan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903035.
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COMMUNICATION
provide high a-selectivity and excellent yield in sialylation
reactions, and importantly, that the oxazolidinone group can
be readily cleaved under mild conditions leaving the acet-
amide intact.[12f] Building on this method for its applicability
to one-pot procedures, we designed a donor that combines
the N-acetyl-5-N,4-O-carbonyl protection and phosphite de-
rivatives as the leaving group. Unfortunately, attempts to
transform the N-acetyl-5-N,4-O-carbonyl-protected thiosia-
loside donor to the corresponding phosphite donor were not
successful. The ring-opening product was obtained as the
major product in the hydrolytic step. Thus, we turned to the
phosphate approach.
Less attention has been given to phosphate methods be-
cause of reported low yields and poor a-selectivity in glyco-
sylation reactions.[5a,d] To our surprise, dibutyl sialyl phos-
phate 1 can be synthesized by the treatment of N-acetyl-5-
N,4-O-carbonyl-protected thiosialoside and commercially
available dibutyl phosphate in the presence of N-iodosucci-
nimide (NIS), catalytic triflic acid, and 4 ꢁ molecular sieve
at 08C in CH2Cl2. Under these conditions, the a- and b-
phosphate sialoside isomers were obtained as a 3/1 mixture
in 96% yield (Scheme 1).
be fully activated by TMSOTf at higher temperature
(ꢀ508C) in only 5 min. Both anomeric donors afforded the
products in similar yields, albeit in slightly different a/b
ratios. The difference in reactivity between 1a and 1b is
smaller when compared with the galactosyl phosphate
donor.[21]
Encouraged by these preliminary results, we investigated
the glycosyl donor properties of 1a in producing naturally
occurring sialoside linkages (Table 2). Regioselective sialyla-
tion of galactopyranoside 4,6-diols 4 (Table 2, entry 2) under
TMSOTf activation in CH2Cl2 at ꢀ788C, gave sialylated
(2!6)disaccharides 5 with complete a selectivity and high
yields. Moreover, sialylation of one equivalent of diol 6
(Table 2, entry 3) with 1a, gave Neu5Aca
G
lylated disaccharide product 7 as a single a isomer in 71%
yield, along with a disialylated trisaccharide in 13% yield,
and 2,3-glycal in 9% yield. For another sialylation of 8, an
anomer of 6, disaccharide 9 was synthesized in 70% yield
(Table 2, entry 4). Compound 7 possesses the framework of
sialyl-TN-antigen (Neu5Aca
and can be easily modified to O-linked sialylated antigens,
such as sialyl-TF antigen (Galb (NeuAca(2!
(1!3)
6)GalNAca
A
N
A
R
ACHTUNGTRENNUNG
The configurations of the glycosyl phosphates have pro-
found effects on reactivity and stereoselectivity.[21] For exam-
ple, pure a- and b-anomeric isomers 1a and 1b were reacted
with acceptor 2 (Table 1), in the presence of trimethylsilyl
trifluoromethanesulfonate (TMSOTf) (1 equiv) in CH2Cl2,
a-phosphate 1a was completely activated at ꢀ788C within
5 min, while the b-phosphate 1b was only partially activated
over a short time. On the other hand, phosphate 1b could
A
C-8 (Table 2, entry 5) and C-9 (entry 6) acceptors was also
investigated. Good a selectivity is still retained because
single a-anomeric products 11 and 13 were obtained in 67
and 82% yield, respectively. The a configuration was as-
signed by the J(C-1,H-3ax) coupling constants (Table 2).[23]
This method is a general protocol for the efficient and a-se-
lective synthesis of major naturally occurring aCAHUTGTNRENN(GU 2,6)-, aACHTUNGTRENNUNG(2,3)-,
aN
aACHTUNGTRENNUNG
with special note that the sialyl
disaccharides can be directly
applied to subsequent glycosy-
lation without aglycon adjust-
ment.
Table 1. Comparison of reactivities between sialyl a-phosphate 1a and
sialyl b-phosphate 1b.
To extend the synthetic
method into the programmable
one-pot strategy, the RRVs of
the sialylated disaccharides 3, 5,
and 14, were measured (Sche-
me 2).[6b]
Disaccharide
3
showed the highest reactivity
among the three building
blocks. Compound 14, contain-
ing the extra C-4 O-benzyla-
tion, is 1.7-fold more reactive
than 5. In general, the sialyla-
Donor Acceptor Reaction time [min] T [8C] Yield[a] [%] a/b[b]
1a
1b
2
2
5
5
ꢀ788C 83
ꢀ508C 82
a only
10:1
[a] Isolated yield. [b] Determined by 1H NMR spectroscopic analysis of
the crude reaction mixture.
Scheme 1. Synthesis of N-acetyl-5-N,4-O-carbonyl-protected sialyl phosphate donor 1. Tol=p-tolyl.
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C.-Y. Wu, C.-H. Wong et al.
Table 2. Results of sialylation by using the N-acetyl-5-N,4-O-carbonyl-protected sialyl phosphate 1a.
Entry Acceptor Product
Yield [%] a/b ratio[c] dC1 [ppm] 3J(C-1,H-3eq) [Hz]
1
83
85
a only
a only
168.7
168.2
5.5
5.7
2
3
4
71
70
a only
a only
168.4
168.3
6.2
6.0
5
6
67[a]
a only
168.7
168.5
6.0
6.0
82[b]
a only
[a] Better yield was obtained when a mild base, such as NaHCO3, was chosen to quench the reaction. [b] Some product decomposed into other uncharac-
1
terized side products after silica gel chromatography, and thus reduced the yield. [c] Determined by H NMR spectroscopic analysis of the crude reaction
mixture.
tion of a thioglycoside results in a modest deactivation of
the anomeric reactivity of the acceptor, as exemplified by 3.
To demonstrate the synthetic application of sialylated dis-
accharides as building blocks, we conducted a representative
reactivity-based, one-pot synthesis of the a
N
lylated pentasaccharide 17. The RRVs of all three building
units, 3 (RRV=1462), 15 (RRV=57), and 16 (RRV=0),
presented an appropriate reactivity profile for one-pot syn-
thesis. The one-pot synthetic operation was performed in
the presence of NIS/trifluoromethanesulfonic acid (TfOH)
promoter system (Scheme 3). The second glycosylation be-
tween 15 and 16 required higher temperatures (ꢀ208C to
room temperature). Obtaining the high-yielding, one-pot
glycosylation product (48%) indicated that the sialylated
disaccharides with Neu5Ac as the terminal residue can be
used as building blocks for the programmable one-pot syn-
thesis of oligosaccharides.
We next turned our attention to using the sialyl phosphate
donor 1a in an orthogonal one-pot synthesis of sialosides.
Two trisaccharides 19 (NeuAca
(2!6)Galb
N
Scheme 2. Relative reactivity values (in parentheses) of sialylated disac-
charides. Bn=benzyl, Bz=benzoyl.
20 (NeuAca (1!4)GlcNAc), and tetrasaccharide
A
ACHTUNGTRENNUNG
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Alpha-Selective Sialyl Phosphate Donors
COMMUNICATION
21 with disialosylgalactosylglo-
boside
(NeuAca
G
(DSGG)
(2!3)Galb
(2!6)GalNAc) were
as one-pot targets
epitope[24]
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
(Scheme 4). Treatment of the
first acceptor 4 (1.0 equiv) with
1a (1.5 equiv) under the activa-
tion of TMSOTf gave disac-
charide 5. Next, the second cou-
pling proceeded, without added
TfOH, within 30 min with the
addition of NIS (1.2 equiv). The
trisaccharide 19 was produced
in excellent yield as only a
product (80% based on second
acceptor, crude result). Parallel
studies were done by the as-
sembly of a
G
charide 20 and tetrasaccharide
21 (Scheme 4).[25] The a config-
uration was assigned by the
3J(C-1,H-3ax) coupling constants
Scheme 3. Reactivity-based one-pot glycosylation of pentasaccharide 17. i) NIS, TfOH, 4 ꢁ molecular sieves,
CH2Cl2, ꢀ788C; ii) NIS, TfOH, ꢀ208C to RT. Phth=phthaloyl.
Scheme 4. Orthogonal one-pot synthesis of trisaccharides 19, 20, and tetrasaccharide 21.
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C.-Y. Wu, C.-H. Wong et al.
(see the Supporting Information). The power of this method
was further demonstrated by the synthesis of tumor-associat-
ed antigen stage-specific embryonic antigen-4 (SSEA-4)[26]
hexasaccharide, which belongs to the globo series of ganglio-
sides. The SSEA-4 derivative 24 was synthesized in an excel-
lent 78% yield by using the one-pot procedure outlined
above. After global deprotection, the SSEA-4 hexasacchar-
ide 25 was obtained in 30% yield (Scheme 5).
loside derivative 29 in 70% yield (Scheme 6). The a isomer
is the only product in these reactions (crude result), the
major side product being the unconsumed acceptor, which
can be recovered and reused. The advantage of this method
is that the product aACTHNUTRGNE(UNG 2,9)-tetrasialoside derivative can be di-
rectly subject to similar derivations to synthesize aACHTUNGTRENNUNG(2,9)-oc-
tasialoside.
In conclusion, we have demonstrated the application of
the sialylation reagent with the combination of C-4/C-5
modification and dibutyl phosphate leaving group for effi-
cient and a-selective synthesis of natural sialosides that are
typically difficult to make. Sialylation using a sialyl phos-
phate donor has several advantages. First, its heightened re-
activity makes it able to react with more hindered glycosyl
acceptors, such as acceptor 2, in high yield. Second, sialylth-
ioglycoside building units with defined stereochemistry and
reactivity (RRVs), which can be used in programmable one-
pot methodology, are synthesized in a facile manner by
using sialyl phosphate in the presence of thioglycosyl accept-
ors. Third, the sialyl phosphate donor also can be used in an
orthogonal one-pot glycosylation, providing an alternative
choice for the rapid synthesis of sialosides, allowing the cou-
pling of building blocks independent of their relative reac-
tivities, such as SSEA-4. Sialyl phosphate donors are very
Recently, Takahashi and co-workers reported the a-specif-
ic synthesis of a
G
E
side,[27] which have long been difficult to synthesize, by using
5N,4O-carbonyl protected thiosialosides. The sequence of
assembly was from the reducing to nonreducing end. Their
strategy provided the opportunity to stereoselectively elon-
gate the sugar chain one residue at a time after selective de-
protection at the C-8 or C-9 positions. Herein, we developed
an alternative strategy for the synthesis of a
losides via the 5-N,4-O-carbonyl-protected sialyl phosphate
donor. Because a
(2!9)-tetrasia-
A
silica gel chromatography, we synthesized disaccharides 26,
27, and 28 (see detailed procedures in the Supporting Infor-
mation). The disaccharides of 27 (1.1 equiv) and 28
(1.0 equiv) were coupled in CH2Cl2/CH3CN (3/2) co-solvent
under TMSOTf (1.2 equiv) activation to give aACTHNUGRTENUNG(2,9)-tetrasia-
Scheme 5. One-pot synthesis of SSEA-4 hexasaccharide 25. i) TMSOTf, MS 4 ꢁ, CH2Cl2, ꢀ788C, ii) NIS, overall 78%, iii) a) NaOMe, MeOH, b) Zn,
AcOH, THF; c) Ac2O, pyridine, DMAP, d) 0.1n NaOH, e) Pd(OH)2, H2, THF/MeOH/AcOH/H2O 10:8:1:0.7. Troc=2,2,2-trichloroethoxycarbonyl.
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Alpha-Selective Sialyl Phosphate Donors
COMMUNICATION
Scheme 6. Synthesis of a
N
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Acknowledgements
We thank Dr. Sarah R. Hanson and Dr. Schelwies Mathias for critically
reading the manuscript. This work was supported by Academia Sinica
and National Science Council, Taiwan (grant no. NSC-96-2321-B-001-
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Keywords: one-pot glycosylation
phosphate · sialylation · synthetic methods
· sialic acids · sialyl
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Received: November 3, 2009
Published online: January 11, 2010
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