Silylene/oxazolidinone double-locked sialic acid building blocks for efficient sialylation reactions in dichloromethane

Article abstract of DOI:10.1002/ejoc.200900543

We describe efficient sialylation reactions in CH₂ Cl ₂with the use of silylene/oxazolidinone double-locked sialic acid building blocks. The building blocks were synthesized from 4,5-oxazolidinone- protected phenylthiosialoside. In s

Full text of DOI:10.1002/ejoc.200900543

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900543
Silylene/Oxazolidinone Double-Locked Sialic Acid Building Blocks for
Efficient Sialylation Reactions in Dichloromethane
Shinya Hanashima,*[a,b] Ken-ichi Sato,[b] Yukishige Ito,[c] and Yoshiki Yamaguchi[a]
Keywords: Glycosylation / Silicon / Sialic acids / Oxygen heterocycles
We describe efficient sialylation reactions in CH2Cl2 with the
use of silylene/oxazolidinone double-locked sialic acid build-
ing blocks. The building blocks were synthesized from 4,5-
oxazolidinone-protected phenylthiosialoside. In sialylation
reactions towards primary and relatively reactive secondary
hydroxy groups on the galactosides, the double-locked
building blocks provided desired coupling products in good
yields with excellent α-selectivities. In the sialylation reaction
with the C3-OH of the galactoside, the double-locked build-
ing blocks expressed significantly better α-selectivity in com-
parison with the results obtained by using the oxazolidinone-
locked building block.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
of the flexibility of the anomeric configuration.[3] In con-
trast, sialic acid building blocks containing a C3 thiophenyl
or thiocarbonyl group have expressed excellent α-selectivi-
ties and reaction yields.[4,5] However, such artificial partici-
pating groups demand an additional removal step involving
radical reductions.
Direct α-selective sialylation methods using C5 N-substi-
tuted sialic acid building blocks such as N,N-diacetyl, N-
trifluoroacetyl, phthalimide, and several kinds of carb-
amates have been developed.[6] Such substitutions of the C5
protections augment the reactivity of the sialic acid building
blocks in comparison to that of the C5 acetamide,[6d] and
they are expected to provide a higher reaction yield. The
combined use of nitrile solvents with this strategy has often
assisted stereoselective sialylation reactions.
Recently, potent C4,5-oxazolidinone-protected sialic acid
building blocks have been reported by the group of
Tanaka–Takahashi.[7] Specifically, building blocks involving
the primary alcohol functions at C6 of galactose and at C9
of sialic acid exhibit good reactivity as well as excellent α-
selectivity without the nitrile effect. In contrast, such excel-
lent α-selectivity was dramatically diminished in reactions
involving the C3-OH group of galactosides.[7b] In such
cases, the employment of a nitrile solvent re-established the
good α-selectivities.[7d] Additionally, the oxazolidinone-
locked building blocks have been remarkably employed for
the efficient synthesis of α(2–8/9) oligosialic acids and a
huge ganglioside GP1c.[7a,8]
In other reports about glycosylation reactions involving
α-galactosylations as well as arabinofuranosylations, bulky
silicon-protecting groups on the glycosyl donor conferred
stereoselectivity due to its bulkiness and ring constraining
effects.[9] We expected that these effects would be applicable
to sialylation reactions, and thus we designed novel sialic
Chemical sialylation is an important method used to syn-
thesize homogeneous sialylated glycans because of the terti-
ary anomeric center and the 3-deoxy nature of the sialic
acid building blocks.[1] To improve the reaction yield and
α-selectivity, three different strategies have been adopted,
namely, the use of nitrile solvent, pre-introduction of artifi-
cial participating groups, and the tuning of the C5 N-pro-
tecting groups.
The use of a nitrile solvent in the sialylation reaction has
been adopted for formation of α-sialosides as the major iso-
mer. The nitrile solvent preferentially associates to the β-
face of the oxonium ion intermediate upon activation of
the anomeric leaving groups.[2] Even though the traditional
strategies are very simple, the stereoselective effect is moder-
ate because of the weak association properties of the nitrile
group.
To obtain a stereoselective neighboring group participa-
tion effect, various artificial auxiliaries have been devel-
oped. Such auxiliary groups were loaded on either the C1
carboxyl moiety or at the C3 position. The use of a readily
removal C1 ester-type participating group in the sialylation
reactions afforded moderate levels of α-selectivity, because
[a] Structural Glycobiology Team, Systems Glycobiology Research
Group, RIKEN Advanced Science Institute,
Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
Fax: +81-48-467-9620
E-mail: shanashima@riken.jp
[b] Material and Life Chemistry, Faculty of Engineering, Kana-
gawa University,
Rokkakubashi 3-27-1, Yokohama 221-8686, Japan
[c] Synthetic Cellular Chemistry, RIKEN Advanced Science Insti-
tute,
Hirosawa 2-1, Wako-shi, Saitama 351-0198, Japan
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900543.
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S. Hanashima, K. Sato, Y. Ito, Y. Yamaguchi
SHORT COMMUNICATION
Scheme 1. Synthesis of double-locked sialic acid building blocks 1 and 2 and oxazolidinone building block 3.
acid building blocks 1 and 2 (Scheme 1). To achieve im-
proved stereoselectivities in the sialylation reactions by tun-
ing the highly reactive oxazolidinone building blocks, bulky
di-tert-butylsiloxanylidene (DTBS) groups were introduced
at the C5,7-positions. The central pyranose ring of building
blocks 1 and 2 were doubly constrained with oxazolidinone
and DTBS groups. The double-locking might augment the
stereoselectivity because the α- and β-faces of the oxonium
intermediate could be highly distinguishable. For the pur-
pose, C8,9-DTBS protected building block 1 and C8,9-tet-
raisopropyldisiloxanylidene (TIPDS) protected building
block 2 were prepared to disclose additional steric effects
of the C8,9-protecting groups. All sialylation reactions were
performed in CH2Cl2 to examine whether the unique build-
ing block structures are able to control stereoselectivity
without the use of a nitrile solvent.
no C5,7-DTBS lock, was also synthesized from intermedi-
ate 5 by acetylation in 91% yield.
After obtaining building blocks 1, 2, and 3, sialylation
reactions to the C6-OH group of galactose acceptors 6, 7,
and 8 were investigated (Table 1). In all entries, phenylthios-
ialosides 1–3 were activated with N-iodosuccinimide (NIS)
and TfOH in CH2Cl2 at –40 °C in the presence of 4 Å mo-
lecular sieves. Initially, C6-OH galactoside 6 was employed
and coupled with building blocks 1–3. With the use of
double-locked 1, desired disaccharide 9 was obtained in
92% with excellent α-selectivity (α/β = 22:1; Table 1, En-
try 1). Double-locked building block 2 provided disaccha-
ride 10 in 80% yield with complete α-selectivity (Table 1,
Entry 2). The use of single-locked 3 similarly provided di-
saccharide 11 in 83% yield with excellent α-selectivity (α/β
= 15:1; Table 1, Entry 3). For primary acceptors, such excel-
lent α-selectivity of oxazolidinone-protected sialic acid
building blocks was identical with previous reports.[7] Actu-
ally, simple-to-prepare building block 1 expressed potent α-
selectivities with galactose acceptors 7 and 8 to give corre-
sponding disaccharides 12 and 13 in good yields (Table 1,
Entries 4 and 5). Additionally, no further differences be-
tween building block 1 and 2 were found in terms of the
stereoselectivity of the sialylation reactions.
Results and Discussion
Before investigating the sialylation reactions, the silylene/
oxazolidinone double-locked sialic acid building blocks 1
and 2, as well as oxazolidinone-type building block 3, were
synthesized (Scheme 1). Building block 1, whose pyranose
Our interest was then shifted toward the secondary C3-
ring was fixed with a DTBS group at the C5,7-positions OH group of the galactose acceptors (Table 2). In all en-
and a oxazolidinone at the C4,5-positions, was synthesized tries, the reaction conditions were similar to those reported
from known C4,5-oxazolidinone derivative 4.[7a,7c] The sin- in Table 1. When excellent α-selective results were obtained,
3
gle-step treatment of 5 with tBu2Si(OTf)2 in pyridine pro- the α-configuration was ascertained by JC1-H3ax coupling
duced building block 1 in 80% yield. Building block 2, constants by measuring the phase-sensitive gradient-en-
which has bulkier C8,9-TIPDS protections, was synthesized hanced HMBC spectra.[10] The other cases, each α/β-isomer
by a two-step procedure. Treatment of 4 with (iPr2SiCl)2O was determined by empirical rule.[11] Galactose C3-OH ac-
in pyridine produced 5 in 80% yield, and subsequent intro- ceptor 14 was initially adopted, and sialylations with
duction of the DTBS group onto the C5,7-positions pro- double-locked building blocks 1 and 2 and single-locked 3
duced desired 2 in 95% yield. Building block 3, which has were investigated. Building block 1 was used with galactose
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Sialylation with Silylene/Oxazolidinone Double-Locked Sialic Acids
Table 1. Sialylation reactions using double-locked sialic acid build- 85% yield (Table 2, Entry 2). In contrast, the use of single-
ing blocks 1 and 2 and oxazolidinone-type 3 toward the C6-OH
group of galactosides 6, 7, and 8.
locked building block 3 dramatically diminished the α-
stereoselectivity, and desired sialoside 19 was afforded in
79% yield with an α/β ratio of 1:2.5 (Table 2, Entry 3).
As next task, the C3-OH group of lactose 15, which
would be a practical acceptor toward several gangliosides
syntheses, was employed. The sialylation reaction between
building block 1 and acceptor 15 provided trisaccharide 20
in 83% yield with moderate α-selectivity (α/β = 1.6:1;
Table 2, Entry 4). In contrast, the use of building block 2
produced trisaccharide 21 in 80% yield in a highly α-selec-
tive manner (Table 2, Entry 5). As expected, the reaction
between single-locked building block 3 and lactoside 15
provided moderate β-selectivity (α/β = 1:1.4) and gave 22
in 61% yield (Table 2, Entry 6). Unfortunately, the high α-
selectivity vanished with the use of 2-OBz galactose ac-
ceptors 16a/b. Neither building block 1 nor 2 produced the
desired α-anomer of disaccharides 23 or 24 in CH2Cl2
(Table 2, Entries 7 and 8). With regard to the C3-OH group
of the C2-OBn-protected galactose acceptors, which is rela-
tively reactive, potent α-selectivities were expressed with the
use of silylene/oxazolidinone double-locked sialic acid
building blocks 1 and 2. In the comparison with single ox-
azolidinone-locked building block 3, both 1 and 2 showed
better α-selectivities. When lactose acceptor 15 was submit-
ted for sialylations, building blocks 2 exhibited excellent α-
selectivity.
In previous reports, C5,7-oxazolidinone-locked sialic
acid building blocks yielded the undesired β-anomer pre-
dominantly.[12] Thus, the excellent stereoselectivity of C4,5-
oxazolidinone and C5,7-silylene double-locked sialic acid
building blocks 1 and 2 were highly intriguing.
We propose the plausible reaction mechanism indicated
in Scheme 2. Before presenting the mechanism, the global
minimum structures of key building blocks 1 and 2 were
estimated by molecular modeling (MacroModel ver8.1).
The global minimum structure of 2 and the superimposed
structures within 5 kJmol–1 are shown in Scheme 2. From
the model, the tricyclic ring on the C4,5-and C5,7-positions
of building block 2 completely separate the Re and Si faces
of the corresponding oxonium ion, and the bulky TIPDS
group at the C8,9-positions covers the Si face. After NIS–
TfOH activation, TfOH approaches from the Re face to
give presumable intermediates 2a and 2aЈ as described by
Crich.[13] With regard to the reaction of reactive alcohols,
that is, primary alcohols, as well as C2-OBn-protected 14
and 15, the HO group would attack from the Si face
through an SN2-like pathway. In contrast, less reactive C2-
OBz-protected 16 would remain difficult to react with rela-
tively stable intermediate 2aЈ. Then, 2aЈ would decompose
to give highly reactive oxonium ion 2aЈЈ, which could react
with 16 from the Re face to settle into the β-anomer. Ad-
ditionally, the silylene/oxazolidinone double-lock on 1 and
2 would stabilize the conformation of the pyranose ring
acceptor 14 to give disaccharide 17 in 83% yield in a highly more than the single oxazolidinone-type building block 3.
α-selective manner (Table 2, Entry 1). A similar result was Such conformational constraining would stabilize plausible
obtained with the use of building block 2. After sialylation, intermediates 2a/2aЈ, which provide the stereoselective ef-
desired disaccharide 18 was stereoselectively produced in fects for building block 1 and 2.
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S. Hanashima, K. Sato, Y. Ito, Y. Yamaguchi
SHORT COMMUNICATION
Table 2. Sialylation reactions using double-locked sialic acid building blocks 1 and 2 and oxazolidinone-type 3 toward the 3-OH group
of galactosides 14, 15, and 16a/b.
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Sialylation with Silylene/Oxazolidinone Double-Locked Sialic Acids
ficient global minimum when the structure did not reach a gradient
to Ͻ0.05 kJÅ–1 mol–1 by C-search.
Supporting Information (see footnote on the first page of this arti-
cle): Synthetic procedures, spectroscopic data, and 1H and 13C
NMR spectra of compounds 1–3, 5, 9–13, and 17–24.
Acknowledgments
We thank Dr. Ishiwata (RIKEN) for MM and MD calculations.
This work was supported by the Science Frontier Project of Kana-
gawa University and the Japan Society for the Promotion of Sci-
ence by Grants-in-Aid for Scientific Research for Young Scientists
B (No. 20710171 to S. H.). We thank Dr. S. Akai (Kanagawa Uni-
versity) for helpful discussions. We thank A. Takahashi, K. Ueno,
and I. Hara for their technical assistance.
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Conclusions
We here described efficient sialylation reactions in
CH2Cl2 using silylene/oxazolidinone double-locked sialic
acid building blocks 1 and 2. Initially, building blocks 1
and 2 were prepared from known oxazolidinone 4. Then,
sialylation reactions using building blocks 1–3 were demon-
strated in CH2Cl2, with no nitrile-supported system. In
comparison to the sialylation results obtained using 3, the
results for building blocks 1 and 2, which have additional
C5,7-DTBS lock, provided significant α-selectivities. In the
sialylation reaction toward the C6-OH group of galactose
acceptors, double-locked 1 and 2 as well as simple oxazolid-
inone-locked 3 provided the desired α-anomer with excel-
lent α-selectivity. When double-locked building blocks, es-
pecially compound 2, were submitted for sialylation with
the C3-OH group of galactosides 14 or 15, desired coupling
products were obtained with excellent α-selectivity.
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Experimental Section
Experimental details can be found in the Supporting Information.
Molecular modeling was performed with MacroModel ver8.1
through conformational search program. Conformational profiles
were generated by 2000 step Monte Carlo (MCMM) searches with
MMFFs force fields in CHCl3 and then reminimized by multiple
minimization program with the force fields in order to give a suf-
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Received: May 16, 2009
Published Online: July 14, 2009
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