Stereoselective glycosylation of 3-deoxy-d-manno-2-octulosonic acid with batch and microfluidic methods

Article abstract of DOI:10.1055/s-0030-1260313

A practical and efficient stereoselective synthesis of 3-deoxy-d-manno-2- octulosonic acid (Kdo) glycoside was achieved using N-trifluoroacetoimidate as the glycosyl donor with both batch and microfluidic methods. The method used a conformationally constr

Full text of DOI:10.1055/s-0030-1260313

LETTER
2359
Stereoselective Glycosylation of 3-Deoxy-D-manno-2-octulosonic Acid with
Batch and Microfluidic Methods
Stereoselective
G
ly
t
c
osyla
s
tion of 3-D
u
eoxy-
D
-m
a
s
nno-2-oc
t
h
ulosonic Ac
i
i
d
Shimoyama, Yukari Fujimoto,* Koichi Fukase
Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka 560-0043, Japan
Fax +81(6)68505419; E-mail: yukarif@chem.sci.osaka-u.ac.jp
Received 9 June 2011
synthesis of complex LPS partial structures with many
acyl groups and phosphates.
Abstract: A practical and efficient stereoselective synthesis of 3-
deoxy-D-manno-2-octulosonic acid (Kdo) glycoside was achieved
using N-trifluoroacetoimidate as the glycosyl donor with both batch
and microfluidic methods. The method used a conformationally
constrained glycosyl donor, which has a bulky isopropylidene
group at the 4,5-O-position. The strained conformation directed the
coordination of the acetonitrile solvent, which led to the enhance-
ment of reactivity and a-selectivity in the glycosylation.
Even in our previous method, we occasionally observed
the cleavage or migration of acid-labile protecting groups
during the glycosylation because strong Lewis acids were
required for the activation of the Kdo fluorides.4,5 There-
fore, the synthetic strategy was restricted, and longer reac-
tion schemes were often required for synthesizing LPS
partial structures composed of lipid A and Kdo. Recently,
we developed a Kdo glycosylation with an N-phenyltri-
fluoroacetimidate donor and applied it to the synthesis of
H. pylori Kdo-lipid A.21 The N-phenyltrifluoroacetimi-
dates can be activated by a catalytic amount of Lewis ac-
ids under mild conditions and have proven very useful for
various oligosaccharide and glycoconjugate syntheses.22–
26 We found that the combination of trimethylsilyltrifluo-
romethanesulfonate (TMSOTf) as the catalyst and cyclo-
pentyl methyl ether (CPME) as the solvent was efficient
for glycosylations with Kdo N-phenyltrifluoroacetimidate
1a. In addition, we observed that microfluidic conditions
reduced the formation of the undesired glycal.21 However,
the optimized reaction conditions varied depending on the
substrates. Therefore, in the present study, we investigat-
ed more efficient methods and found that Kdo glycosyla-
tion with 1a proceeded smoothly with trifluoro-
methanesulfonic acid (TfOH) in acetonitrile, and a-selec-
tivity was controlled by the donor–acceptor ratio in batch
conditions as well as in microfluidic mixing. The present
methods were applied to the synthesis of disaccharides
and trisaccharides with Kdo moieties, which are deriva-
tives of the LPS partial structures.
Key words: glycosylation, carbohydrates, stereoselective synthe-
sis, carbocation, natural products
3-Deoxy-D-manno-2-octulosonic acid (Kdo) is an acidic
2-ketooctose that is ubiquitously present in Gram-nega-
tive bacteria, particularly in the lipopolysaccharide (LPS)
of the outer membrane and also in the capsular polysac-
charide of the bacterial cell surface. Kdo serves as a linker
between the lipophilic terminal component called lipid A
and the polysaccharide part of LPS and is considered to
affect the interaction of lipid A with toll-like receptor 4
(TLR4), which specifically recognizes LPS and activates
the innate immune system. For further detailed investiga-
tions on the biological role of Kdo, the chemical syntheses
of Kdo-containing glycans are essential. In the glycosyla-
tion of Kdo, the following issues should always be consid-
ered: 1) The neighboring group effect is not available
because of the 2-keto-3-deoxy structure. 2) The presence
of the 3-deoxy structure and a C1 carboxyl group easily
lead to the b-hydrogen elimination to afford a glycal as the
major byproduct.
We have developed a glycosylation using Kdo fluorides
as glycosyl donors for the synthesis of Escherichia coli
Re-LPS, Helicobacter pylori Kdo-lipid A, and their deriv-
atives.1–7 High a-selectivity was obtained using 4,5-O-
isopropylidene- or tert-butyldimethylsilyl (TBS)-protect-
ed Kdo fluorides as donors. With these Kdo donors, the
undesirable b-side attack by a glycosyl acceptor is pre-
vented by the presence of the bulky isopropylidene or
TBS group. Other glycosylations have also been reported;
with Kdo chloride, bromide,8–16 phosphite,17 and 3-phe-
nylselenyl-Kdo18 via substitution of 6-O-triflate of glu-
cosamine with a Kdo residue19 and that of 3-iodo
intermediates with acyclic saccharide precursors.20 How-
ever, many of these methods are difficult to apply for the
First, we examined various acid catalysts for the glycosy-
lation of 1a with a glycosyl acceptor 2 in dichloromethane
(Table 1). Among the acids tested, TfOH was the most ef-
ficient for obtaining the highest yield. In addition, we
evaluated the selectivity at lower temperatures. At –78 °C,
the a-selectivity decreased to a/b = 43:57 (yield 34%)
with TMSOTf in CH2Cl2, which is comparable to the con-
ditions in Table 1, entry 1 (at 0 °C, the yield and selectiv-
ity were 61%, a/b = 73:27, respectively).
Then, the solvent effects on the glycosylation were inves-
tigated using donor 1a and acceptor 2 (Table 2, entries 1–
11). The a-selectivity in MeOt-Bu and CPME was higher
than that in dichloromethane, but the yield was lower
(Table 2, entries 3 and 4). In acetone or EtOAc, the stereo-
selectivity were scarcely observed (Table 2, entries 5 and
6). On the other hand, nonpolar solvents such as toluene,
SYNLETT 2011, No. 16, pp 2359–2362
x
x
.x
x
.2
0
1
1
Advanced online publication: 13.09.2011
DOI: 10.1055/s-0030-1260313; Art ID: U04811ST
© Georg Thieme Verlag Stuttgart · New York

2360
A. Shimoyama et al.
LETTER
Table 1 Effect of Activators on the Glycosylation of Kdo N-Phe-
nyltrifluoroacetimidate 1a
Table 2 Solvent Effects on the Glycosylation Using Kdo N-Phenyl-
trifluoroacetimidate 1a
OBn
OBn
OBn
OBn
O
O
OBn
OBn
OBn
O
OBn
O
O
O
TfOH
O
O
O
HO
BnO
BnO
HO
BnO
BnO
O
CO2Bn
CO2Bn
O
(1.0 equiv)
O
O
activator
O
CO2Bn
CO2Bn
NPh
+
+
O
O
4 Å MS
CH2Cl2
0 °C
4 Å MS
O
NPh
CF3
TrocHN
TrocHN OAllyl
OAllyl
O
solvent
0 °C
O
O
BnO
BnO
BnO
BnO
2
2
CF3
15 min
15 min
(1.0 equiv)
1a
(0.15 M)
3.0 equiv
TrocHN
TrocHN
OAllyl
OAllyl
1a
(0.15 M)
3.0 equiv
3a
3a
Entry
Activators (equiv)
TMSOTf (0.2)
TBSOTf (0.5)
TfOH (1.0)
Yield of 3a (%),a a/b
61, 73:27
Entry Solvents
Yield of 3a (%),
a/b (calcd from 2)
1
2
3
4
1
CH2Cl2
75, 72:28
13, n.d.
65, 78:22
2a 1,4-dioxane
75, 72:28
3
4
5
6
7
8
CPME
MeOt-Bu
acetone
EtOAc
toluene
DCE
54, 86:14
57, 95:5
BF3·OEt2 (0.2)
trace
a The yield was calculated from compound 2.
59, 50:50
73, 55:45
72, 91:9
1,2-dichloroethane, and benzene gave higher selectivity
than ether-type solvents (Table 2, entries 7–9). Subse-
quently, acetonitrile was found to give the best yield
(86%) with satisfactory selectivity (Table 2, entry 11).
The kinetic axial-oriented solvent effect of nitriles has
been well-known and used for various oligosaccharide
syntheses.24–29 In the present case, no such effect was ob-
served, indicating that steric hindrance due to the isopro-
pyridene group in 1a, with a boat-like conformation,
prevents the coordination of acetonitrile from the a-face.
Next, the stoichiometry of the donor, acceptor, and TfOH
were examined in acetonitrile (Table 2, entries 11–14).
Reducing the amount of TfOH decreased the selectivity
(Table 2, entry 12). Interestingly, only a-glycoside was
obtained when 1.5 equivalents of glycosyl acceptor 2 was
used with Kdo donor 1a (Table 2, entry 14), with 62%
yield.
66, >95:5
63, 100:0
complex mixture
86, 85:15
88, 68:32
68, 71:29
62, 100:0
9a benzene
10 DMF
11 MeCN [1a (3.0 equiv), 2 (1.0 equiv)]
12b MeCN [1a (3.0 equiv), 2 (1.0 equiv)]
13b MeCN [1a (1.5 equiv), 2 (1.0 equiv)]
14c MeCN [1a (1.0 equiv), 2 (1.5 equiv)]
a The reaction was performed at 25 °C.
b TfOH (0.1 equiv).
c TfOH (1.0 equiv). The yield was calculated from donor 1a.
The present Kdo glycosylation reaction was then applied
to the synthesis of trisaccharide 6a. Because acceptor 5
possessed the acid-labile p-methoxybenzyl group (MPM),
and many synthetic steps were required for synthesizing
5, a catalytic amount of TfOH and a large excess of Kdo
donor 1a were used for the glycosylation. Thus, trisaccha-
ride 6a was obtained in good yield with moderate selectiv-
ity (Table 3, entry 1).
give the desired disaccharide 3b in a good yield with mod-
erate selectivity (Table 3, entry 3). The glycosylation of
disaccharide acceptor 5 with 1b gave the desired trisac-
charide 6b in a good yield (Table 3, entry 4). Furthermore,
Kdo donor 1b exhibited higher selectivity than Kdo donor
1a (Table 3, entries 1 and 4).
As described earlier, the stoichiometry of the donor, ac-
ceptor, and TfOH considerably influenced stereoselectiv-
ity. Because reducing the amount of TfOH decreased a-
selectivity and using an excess of the acceptor had the op-
posite effect, rapid activation of the donor and fast addi-
tion of the acceptor to the intermediate oxocarbenium ion
seemed to be important for obtaining high a-selectivity.
Although the reason why these kinetic processes are crit-
ical for improving stereoselectivity is still uncertain, en-
hancing the mixing efficiency was expected to provide
further improvements. Therefore, we applied this reaction
to a microfluidic reaction system (Table 4), which enables
efficient mixing and rapid heat transfer.30 In fact, we have
In addition, the Kdo–Kdo disaccharide 7a was obtained
by the glycosylation of Kdo acceptor 4 with 1a in a good
yield with moderate selectivity (Table 3, entry 2).
We also investigated the glycosylation with Kdo N-phe-
nyltrifluoroacetimidate 1b having bulky TBS groups at
the 4- and 5-positions. In our previous study on the syn-
thesis of Re-LPS, the TBS-protected Kdo fluoride showed
lower reactivity than the 4,5-O-isopropylidene-protected
Kdo fluoride.6 On the other hand, the glycosylation with
1b in CPME in the presence of Lewis acids did not pro-
ceed at all. However, the present conditions efficiently
promoted the glycosylation of the acceptor 2 with 1b to
Synlett 2011, No. 16, 2359–2362 © Thieme Stuttgart · New York

LETTER
Stereoselective Glycosylation of 3-Deoxy-D-manno-2-octulosonic Acid
2361
Table 3 Glycosylation Reactions of Kdo N-Phenyltrifluoroacetimidates 1a,b
3a R = R1
6a R = R2
7a R = R3
OBn
OBn
O
O
O
HO
O
CO2Bn
OR
BnO
BnO
OBn
OBn
O
TrocHN
OAllyl
O
OBn
O
BnO
2
CO2Bn
NPh
CF3
TBSO
3b R = R1
6b R = R2
or
O
O
CO2Bn
OR
TBSO
OBn
BnO
HO
TfOH
(0.1 equiv)
1a
or
O
+
CO2Bn
HO
4 Å MS
MeCN
0 °C
OBn
BnO
OBn
O
OAllyl
BnO
TBSO
HO
O
4
or
O
15 min
BnO
BnO
O
R1 =
R2 =
R3 =
BnO
CO2Bn
OAllyl
CO2Bn
NPh
TBSO
TrocHN
OAllyl
O
HO
BnO
MPMO
O
O
O
BnO
ZO
AllocHN
O
O
CF3
BnO
ZO
AllocHN
TrocHN
OAllyl
1b
MPMO
5
TrocHN
OAllyl
Entry
Donor (equiv)
1a (5.0)
Acceptor (equiv)
5 (1.0)
Yield (%),a/b (calcd from acceptor)
6a (quant.), 75:25
7a (92), 79:21
1
2
3
4
1a (3.0)
4 (1.0)
1b (3.0)
2 (1.0)
3b (91), 80:20
1b (5.0)
5 (1.0)
6b (95), 84:16
achieved practical and stereoselective glycosylations such entries 2–4). The higher concentrations of the acceptor led
as a-sialylation,25,26 b-mannosylation,31 and N-glycosyla- to higher selectivity. These results suggested that a reac-
tion of asparagines32 by using the microfluidic system.
tive species with a relatively shorter lifetime was generat-
ed from the donor, and kinetically regulated fast addition
of the acceptor resulted in the higher a-selectivity.
For the present microfluidic Kdo glycosylation, an aceto-
nitrile solution of Kdo donor 1a and acceptor 2 was mixed
with TfOH solution in acetonitrile with various concentra- In conclusion, we developed a practical a-selective Kdo
tions using an IMM’s micromixer33 at a flow rate of 0.5 glycosylation with N-phenyltrifluoroacetimidate-func-
mL/min. The reaction mixture was allowed to flow for an tionalized glycosyl donors in acetonitrile under both batch
additional 42 s through a tubular reactor (F = 1.0 mm), and microfluidic conditions. The use of acetonitrile en-
and then quenched by adding it to an Et3N–CH2Cl2 solu- hances reactivity and supports high a-selectivity. The
tion. As a result, the microfluidic reaction gave noticeably present glycosylation method using N-phenyltrifluoroacet-
higher a-selectivity than the batch-type reaction (Table 4, imidate and TfOH in acetonitrile would be applicable to
Table 4 Microfluidic Methods for the Glycosylation of Kdo N-Phenyltrifluoroacetimidate 1aa
OBn
OBn
TfOH in MeCN
0.05 M
OBn
O
OBn
O
O
HO
BnO
BnO
O
O
O
CO2Bn
O
0.5 mL/min
CO2Bn
+
O
TrocHN OAllyl
IMM
micro
reactor
0 °C, 42 s
0.5 mL/min
O
NPh
CF3
O
2
BnO
BnO
f = 1.0 mm
l = 25 cm
in MeCN
1a
TrocHN
OAllyl
3a
Entry
Donor 1a (equiv)
Acceptor 2 (equiv)
12.5 mM (1.0)
25.0 mM (1.0)
25.0 mM (1.0)
50.0 mM (1.0)
Yield of 3a (%), a/b (calcd from 2)
1
2
3
4
37.5 mM (3.0)
37.5 mM (1.5)
75.0 mM (3.0)
75.0 mM (1.5)
67, 80:20
60, 95:5
83, 92:8
73, 95:5
a All of the concentrations in Table 4 are the final concentrations. The concentration of TfOH in the reaction mixture was 25.0 mM in all cases.
Synlett 2011, No. 16, 2359–2362 © Thieme Stuttgart · New York

2362
A. Shimoyama et al.
LETTER
(2) Imoto, M.; Kusunose, N.; Kusumoto, S.; Shiba, T.
the synthesis of Kdo glycosides as well as other glyco-
sides in nature.
Tetrahedron Lett. 1988, 29, 2227.
(3) Kusumoto, S.; Kusunose, N.; Imoto, M.; Shimamoto, T.;
Kamikawa, T.; Takada, H.; Kotani, S.; Rietschel, E. T.;
Shiba, T. Pure Appl. Chem. 1989, 61, 461.
(4) Fukase, K.; Kamikawa, T.; Iwai, Y.; Shiba, T.; Rietschel,
E. T.; Kusumoto, S. Bull. Chem. Soc. Jpn. 1991, 64, 3267.
(5) Fukase, K.; Kurosawa, M.; Kusumoto, S. J. Endotoxin Res.
1994, 1, 149.
(6) Yoshizaki, H.; Fukuda, N.; Sato, K.; Oikawa, M.; Fukase,
K.; Suda, Y.; Kusumoto, S. Angew. Chem. Int. Ed. 2001, 40,
1475.
Representative Procedure of Batch Reaction for the Synthesis
of Disaccharide 3a
To a mixture of donor 1a (8.8 mg, 12.2 mmol), acceptor 2 (2.4 mg,
4.08 mmol) and MS 4 Å in anhyd MeCN (70 mL) was added a solu-
tion of TfOH (0.36 mL, 4.08 mmol) in MeCN (10 mL) at 0 °C under
Ar atmosphere, and the reaction mixture was stirred 15 min. After
addition of Et3N, the mixture was concentrated in vacuo. The resi-
due was purified by silica gel column chromatography (toluene–
EtOAc = 20:1 → 10:1 → 3;1) to give 3a as a colorless amorphous
solid (3.7 mg, 85% from acceptor).
(7) Fujimoto, Y.; Iwata, M.; Imakita, N.; Shimoyama, A.; Suda,
Y.; Kusumoto, S.; Fukase, K. Tetrahedron Lett. 2007, 48,
6577.
(8) Unger, F. M. Adv. Carbohydr. Chem. Biochem. 1981, 38,
323.
(9) Paulsen, H.; Stiem, M.; Unger, F. M. Tetrahedron Lett.
1986, 27, 1135.
(10) Paulsen, H.; Hayauchi, Y.; Unger, F. M. Liebigs Ann. Chem.
1984, 1270.
(11) Paulsen, H.; Schueller, M. Liebigs Ann. Chem. 1987, 249.
(12) Paulsen, H.; Stiem, M.; Unger, F. M. Liebigs Ann. Chem.
1987, 273.
(13) Kiso, M.; Fujita, M.; Tanahashi, M.; Fujishima, Y.; Ogawa,
Y.; Hasegawa, A.; Unger, F. M. Carbohydr. Res. 1988, 177,
51.
(14) D’Souza, F. W.; Kosma, P.; Brade, H. Carbohydr. Res.
1994, 262, 223.
1H NMR (500 MHz, CDCl3): d = 7.34–7.21 (m, 25 H, CH2C6H5),
5.93–5.80 (m, 1 H, OCH2CH=CH2), 5.25 (dd, J = 17.2, 1.5 Hz, 1 H,
OCH2CH=CH2), 5.18 (dd, J = 10.4, 1.5 Hz, 1 H, OCH2CH=CH2),
5.15 (d, Jgem = 12.2 Hz, 1 H, COOCH2C6H5), 5.04 (d, J = 10.0 Hz,
1 H, H-1), 4.95 (d, Jgem = 12.2 Hz, 1 H, COOCH2C6H5), 4.83–4.60
(m, 10 H, C6H5CH2, COOCH2CCl3), 4.38 (d, J = 7.8 Hz, 1 H, H-4¢),
4.33 (d, J = 12.3 Hz, 1 H, H-5¢), 4.15 (dd, J = 12.8, 5.3 Hz, 1 H,
OCH2CH=CH2), 4.03 (dd, J = 10.5, 1.6 Hz, 1 H, H-7¢), 3.98–3.89
(m, 3 H, OCH2CH=CH2, H-2, H-6a), 3.80 (d, J = 9.5 Hz, 1 H, H-3),
3.75 (dd, J = 10.5, 5.3 Hz, 1 H, H-8a¢), 3.69 (dd, J = 9.3, 2.0 Hz, 1
H, H-8b¢), 3.69 (t, J = 8.9 Hz, 1 H, H-4), 3.57 (t, J = 9.4 Hz, 1 H, H-
5), 3.52 (dd, J = 10.6, 6.1 Hz, 1 H, H-6b), 2.34 (dd, J = 14.7, 5.3 Hz,
1 H, H-3a¢), 2.09 (dd, J = 14.6, 6.1 Hz, 1 H, H-3b¢), 1.51 (s, 1 H,
CHCH3), 1.34 (s, 1 H, CHCH3). HRMS (ESI-QTOF, positive): m/z
calcd for C58H64Cl3NO14 [M + Na]+: 1126.3290; found: 1126.3285.
(15) Kosma, P.; Hofinger, A.; Muller-Loennies, S.; Brade, H.
Carbohydr. Res. 2010, 345, 704.
(16) Van der Klein, P. A. M.; Filemon, W.; Boons, G. J. P. H.;
Veeneman, G. H.; Van der Marel, G. A.; Van Boom, J. H.
Tetrahedron 1992, 48, 4649.
Representative Procedure of Microfluidic Reaction for the Syn-
thesis of 3a
Dry MeCN was injected in advance to the micromixer by using a sy-
ringe pump and saturated the microfluidic system. Subsequently, a
solution of donor 1a (54.0 mg, 75.0 mmol, 0.15 M) and the acceptor
2 (14.3 mg, 25.0 mmol, 0.05 M) dissolved in MeCN (500 mL) and a
solution of TfOH (2.2 mL, 25.0 mmol, 0.05 M) dissolved in MeCN
(500 mL) were injected to the IMM micromixer by each syringe
pump at the flow rate of 0.5 mL/min and mixed at 0 °C. After the
reaction mixture was allowed to flow at 0 °C for 42 s through a
stainless reactor tube (F = 1.0 mm, l = 25 cm), the mixture was add-
ed dropwise to Et3N–CH2Cl2 at 0 °C. The mixture was concentrated
in vacuo to give the crude product. The residue was purified by sil-
ica gel column chromatography (toluene–EtOAc = 20:1 → 10:1 →
3:1) to give 3a (51 mg, 72%) and the stereoselectivity was analyzed
by 1H NMR (a/b = 92:8).
(17) Reiner, M.; Schmidt, R. R. Tetrahedron: Asymmetry 2000,
11, 319.
(18) Ikeda, K.; Akamatsu, S.; Achiwa, K. Carbohydr. Res. 1989,
189, C1.
(19) Esswein, A.; Rembold, H.; Schmidt, R. R. Carbohydr. Res.
1990, 200, 287.
(20) Tanaka, H.; Takahashi, D.; Takahashi, T. Angew. Chem. Int.
Ed. 2006, 45, 770.
(21) Shimoyama, A.; Saeki, A.; Tanimura, N.; Tsutsui, H.;
Miyake, K.; Suda, Y.; Fujimoto, Y.; Fukase, K. Chem. Eur.
J. 2011, 17, in press.
(22) Yu, B.; Tao, H. Tetrahedron Lett. 2001, 42, 2405.
(23) Adinolfi, M.; Barone, G.; Iadonisi, A.; Schiattarella, M.
Tetrahedron Lett. 2002, 43, 5573.
(24) Yu, B.; Sun, J. Chem. Commun. 2010, 46, 4668.
(25) Goi, T.; Tanaka, K.; Fukase, K. J. Carbohydr. Chem. 2007,
26, 369.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(26) Tanaka, K.; Fujii, Y.; Tokimoto, H.; Mori, Y.; Tanaka, S.;
Bao, G. M.; Siwu, E. R.; Nakayabu, A.; Fukase, K. Chem.
Asian. J. 2009, 4, 574.
(27) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett.
1984, 25, 1379.
(28) Murase, T.; Ishida, H.; Kiso, M.; Hasegawa, A. Carbohydr.
Res. 1988, 184, C1.
(29) Ikami, T.; Ishida, H.; Kiso, M. Methods Enzymol. 2000, 311,
Acknowledgment
This work was supported in part by Grant-in-Aid for Scientific Re-
search (No. 22310136, 21106008, 23241074 and 20-870) from
JSPS/MEXT, grants from Osaka University Global COE program
(Frontier Biomedical Science Underlying Organelle Network Bio-
logy) and the Naito Foundation, and a funding program for Next
Generation World-Leading Researchers (NEXT Program; LR025)
from JSPS and CSTP.
547.
(30) Suga, S.; Yamada, D.; Yoshida, J. Chem. Lett. 2010, 404.
(31) Tanaka, K.; Mori, Y.; Fukase, K. J. Carbohydr. Chem. 2009,
28, 1.
(32) Tanaka, K.; Miyagawa, T.; Fukase, K. Synlett 2009, 1571.
(33) IMM’s micromixer: http://www.imm-mainz.de.
References and Notes
(1) Imoto, M.; Kusunose, N.; Matsuura, Y.; Kusumoto, S.;
Shiba, T. Tetrahedron Lett. 1987, 28, 6277.
Synlett 2011, No. 16, 2359–2362 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.