Iterative glycosylation of 2-deoxy-2-aminothioglycosides and its application to the combinatorial synthesis of linear oligoglucosamines

Article abstract of DOI:10.1002/anie.200353552

Highly efficient coupling is observed with thioglycosides, which act both as glycosyl donors and acceptors. The iteration of the glycoside-coupling reaction under the same conditions allows the rapid assembly of a library of linear oligoglucosamines (see scheme; Phth = phthaloyl).

Full text of DOI:10.1002/anie.200353552

Angewandte
Chemie
Glycosylation
Iterative Glycosylation of 2-Deoxy-2-
aminothioglycosides and Its Application to the
Combinatorial Synthesis of Linear
Oligoglucosamines**
Shigeru Yamago,* Takeshi Yamada,
Tomokazu Maruyama, and Jun-ichi Yoshida
The development of new methods for oligosaccharide syn-
thesis is a major focus in synthetic carbohydrate chemistry
owing to the multifaceted role of complex oligosaccharides
and glycoconjugates in biology.[1,2] As oligosaccharides consist
À
of several anomeric C O bond linked monosaccharides, the
synthesis would necessarily require iterative glycosylation.
Although many methods have been developed to enhance the
efficiency of the iterative process,[3] the most straightforward
method is the use of one set of glycosylation conditions with a
single anomeric substituent for both glycosyl donors and
acceptors. However, this type of reaction has been limited to
the glycal assembly method.[4] Recently, new examples have
appeared from Gin and co-workers,[5] and from our own
laboratory.[6]
In a previous paper, we reported that b-bromoglycosides
generated from selenoglycosides could serve as glycosyl
cation equivalents and couple with selenoglycosides that
bear hydroxy groups to give new selenoglycosides, which
could then be used in the next glycosylation reaction under
the same reaction conditions. Although this method is
suitable for the iteration, it suffers from the low reactivity
of the b-bromoglycoside as a result of the strong covalent
character of the carbon–bromine bond. To overcome this, we
decided to use reactive glycosyl cation intermediates or their
equivalents. After the pioneering work by Crich and co-
workers, covalently bonded glycosyl cation equivalents, such
as glycosyl triflate intermediates, were recognized as discrete
intermediates with considerable stability.[7] Therefore, we
envisaged modulating the reactivity of glycosyl cations and
their equivalents by changing the counteranion species X,
from the covalently bonded 2 to the ionically bonded 2’
(Scheme 1). We were especially interested in the formation of
the b-glycoside bond of glucosamine derivatives, which is a
common structural unit in many biologically active oligosac-
charides.[8,9] We report herein a new iterative glycosylation
strategy that makes use of thioglycosides of the N-phthaloyl
[*] Prof. S. Yamago
Division of Molecular Material Science
Graduate School of Science, Osaka CityUniversity
Osaka 558–8585 (Japan)
Fax: (+81)6-6605-2565
E-mail: yamago@sci.osaka-cu.ac.jp
T. Yamada, T. Maruyama, Prof. J.-i. Yoshida
Department of Synthetic Chemistry and Biological Chemistry
Graduate School of Engineering, Kyoto University
Kyoto 615-8510 (Japan)
[**] This work was partlysupported bya Grant-in-Aid for the Scientific
Research from Japan Societyfor the Promotion of Science.
Angew. Chem. Int. Ed. 2004, 43, 2145 –2148
DOI: 10.1002/anie.200353552
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2145

Communications
104 ppm in the 13C NMR in CD2Cl2 at À 758C. Although the
intramolecular participation of the Phth-group has been
proposed,[8] no such intermediate was observed by NMR
spectroscopic analysis. The glycosyl triflate intermediate was
stable at this temperature, but decomposed rapidly above À
508C.
The glycosyl triflate intermediate prepared by treatment
of 5a with benzenesulfenyl triflate (PhSOTf), which was
prepared in situ from benzenesulfenyl chloride and silver
triflate,[7b] afforded the same disaccharide in 62% yield. A
different counteranion of the silver salt in the formation of the
“glycosyl cation” intermediate resulted in a pronounced
effect on disaccharide synthesis. Thus, while the use of silver
Scheme 1. Strategy for iterative glycosylation.
(Phth)-protected glucosamine (GlcN) derivative 5 as both the
glycosyl donor and acceptor.
We initially examined the effect of the counteranion X on
iterative glycosylation, with thioglycosides 5 as the donors and
acceptors (Table 1). Representative results are as follows. The
thioglycoside 5a was treated with 1-benzenesulfinyl piper-
idine (BSP) and triflic anhydride,[10] and the resulting
“glycosyl triflate” intermediate was treated with 5b at À
608C for 15 min to give the desired disaccharide 6 in 82%
yield (Table 1, entry 1). The involvement of the a-glycosyl
triflate intermediate was suggested by the signal for the
bis[(trifluoromethyl)sulfonyl]amide
(triflimide,
NTf2)
afforded the same disaccharide in 82% yield,[11] other silver
salts, such as AgOTs, AgBF4, AgPF6, or AgSbF6 resulted in
low coupling efficiency (> 10% yield).
We next examined the generality in terms of glycosyl
acceptors. Although the hydroxy group at C4 of glucosamine
is known to be relatively unreactive, the glycosylation of 5a
with 7 afforded the desired disaccharide 8 in good yield
(Table 1, entry 2). The glycosyl acceptors are not limited to
glucosamine derivatives; galactose 9 and glucose 12 deriva-
tives, which bear hydroxy groups, coupled with the glycosyl
triflate intermediate with high efficiency (Table 1, entries 3–
5). The current method enables the construction of b-GlcN-
1,6-Gal, b-GlcN-1,3-Gal, and b-GlcN-1,4-Glc structures in 10,
11, and 13, respectively, which are found in many important
biologically active compounds such as proteoglycans, glyco-
lipids, and blood group substances.
3
anomeric proton at d = 6.19 ppm with JH-H = 3.0 Hz in the
1H NMR and the signal for the anomeric carbon atom at d =
Table 1: Glycosylation of thioglycosides.
The current method enables the use of hitherto impossible
glycosyl donor/acceptor combinations by selective activation
of glycosyl donors prior to the addition of acceptors. For
example, the activation of 12e is estimated to take place
approximately 1500 times faster than the activation of 5a
when these two glycosides are activated concurrently,[2e] and
thus 5a cannot serve as glycosyl donor in the presence of 12e
under conventional chemoselective glycosylation methods.[3h]
The present strategy, however, enables the use of 5a as donor
and 12e as acceptor to give 13 with high coupling efficiency
(Table 1, entry 5). Furthermore, while glycosides 12 f and 12g
are estimated to have a similar reactivity based on the armed/
disarmed glycosylation method,[3b] the coupling of 12 f and
12g was successful and gave the desired disaccharide 14h
(Table 1, entry 6). The coupling of 15j and 15k, both of which
have similar reactivity, also took place selectively to give 14i
(Table 1, entry 7). In all cases, we could not detect side
products derived from the activation of the glycosyl acceptors.
The most striking feature of the current method is the
existence of the unreduced phenylsulfanyl group, which can
be directly used for the next glycosylation reaction under the
same reaction conditions. This feature was demonstrated in
the combinatorial synthesis of oligoglucosamine (Scheme 2).
Thus, the disaccharides 6 or 8, activated with BSP and Tf2O
followed by coupling with either 5b or 7, afforded the
isomeric triglucosamines 16,17, 18, and 19 in good yields.
Repetition of the same reaction sequence with the triglucos-
amines as the glycosyl donors gave the isomeric tetraglucos-
amines 20–27. The tetra-b-GlcN-1,4-GlcN structure in 27,
[a]
EntryDonor
Acceptor
Method
Product
Yield [%]
1
5a
5b
A
B
C
A
A
A
A
A
D
6
82
62
82
84
76
46
62
61c
66
2
3
4
5
5a
5a
5a
5a
12 f
15j
7
9c
9d
12e
12g
15k
8
10
11
13
14h
14i
6[b]
7
[a] A: BSP/Tf2O; B: PhSCl/AgOTf; C: PhSCl/AgN(Tf)2; D: PhSCl/
AgSbCl6. The reaction was carried out in CH2Cl2. [b] The reaction was
carried out in toluene/CH2Cl2 mixture. [c] Products formed as a 39:61
mixture of a and b isomers.
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Chemie
oligosaccharides can be assembled
under a single set of conditions,
the current method would be suit-
able for the automated synthesis
of oligosaccharides. Furthermore,
the fundamental principle descri-
bed herein should be applicable to
a wide variety of oligosaccharide
structures. Such possibilities are
now under active investigation.
Experimental Section
Typical procedure (6): Tf2O (230.3 mg,
0.82 mmol) was added to a solution of
5a (316.5 mg, 0.60 mmol), BSP
(138.1 mg, 0.66 mmol), 2,6-di-tert-
butyl-4-methylpyridine
(246.8 mg,
1.20 mmol), and molecular sieves
(4 Š; ꢀ 600 mg) in CH2Cl2 (6.0 mL)
at À 608C. After 30 min, a solution of
5b (548.7 mg, 0.90 mmol) in CH2Cl2
(3.0 mL) was added. After 15 min,
the reaction was quenched by the
addition of Et3N (ca. 0.60 mL), and
the resulting mixture was warmed to
room temperature, filtered, and
washed with
a saturated aqueous
NaHCO3 solution. After separation
of the organic layer, the aqueous
phase was extracted with ethyl acetate,
and the combined organic extract was
washed with saturated aqueous NaCl
solution, dried over MgSO4, filtered,
and concentrated under reduced pres-
sure to give a crude oil. Purification by
flash chromatography (silica gel:
70.0 g; eluent: EtOAc/hexane (55%))
afforded 6 (557.3 mg, 90%) as a white
amorphous powder. IR (KBr): n˜ =
1779, 1717 (s), 1387, 1273, 1244, 1109,
1071, 1028, 720 cmÀ1
;
1H NMR
Scheme 2. Reaction conditions: a) Donor (1.0 equiv), BSP (1.1 equiv), Tf2O (1.4 equiv), CH2Cl2,
À608C; then 5b (1.5 equiv), À608C. b) Donor (1.0 equiv), BSP (1.1 equiv), Tf2O (1.4 equiv), CH2Cl2,
À608C; then 7 (1.5 equiv), À608C. BSP=1-benzenesulfinyl piperidine; Tf=trifluoromethanesulfonyl.
(500 MHz, CDCl3): d = 1.87 (s, 3H),
2.03 (s, 3H), 2.05 (s, 3H), 3.76 (dd, J =
11.3, 7.3 Hz, 1H), 3.78–3.82 (m, 1H),
4.01 (dd, J = 11.0, 2.0 Hz, 1H), 4.05–
4.12 (m, 2H), 4.25 (dd, J = 12.3, 4.8 Hz,
which is a fundamental sugar skeleton of Nod factors,[12] could
be easily prepared under a single set of conditions.
1H), 4.35 (dd, J = 10.5, 8.5 Hz, 1H), 4.42 (t, J = 10.3 Hz, 1H), 5.13 (t,
J = 9.5 Hz, 1H), 5.29 (t, J = 9.5 Hz, 1H), 5.50 (d, J = 8.5 Hz, 1H), 5.70
(d, J = 10.5H, 1H), 5.74 (dd, J = 10.5, 9.0 Hz, 1H), 6.15 (t, J = 9.8 Hz,
The reactive phenylsulfanyl groups in these tetraglucos-
amines can be used for further elongation of oligosaccharides
or for the synthesis of a simple reducing-end glycoside by the
glycosylation with alcohol. For example, activation of 20
followed by treatment with methanol afforded the corre-
sponding O-glycoside, which was transformed into free
glycoside 28b by standard deprotection procedures
(Scheme 3).
In summary, we have developed a new iterative glyco-
sylation to carry out b-glycosidic bond formation of glucos-
amine derivatives with the corresponding thioglycosides as
both donors and acceptors. Because thioglycosides are stable
and readily available, the current method offers practical
advantages for the rapid assembly of oligosaccharides. As
Scheme 3. Reaction conditions: a) BSP (1.2 equiv), Tf2O (1.5 equiv),
CH2Cl2, À608C; then methanol (2.0 equiv), 15 min; b) N2H4
(420 equiv), CD3OD, 608C, 11 h, c) Ac2O (430 equiv), py(450 equiv),
DMAP (2 equiv), room temperature, 1 h, 69% (three steps),
d) NaOMe (56 equiv)/MeOH/H2O, room temperature, 2 h, 65%.
DMAP=dimethylaminopyridine.
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Communications
1H), 7.20 (t, J = 10.5 Hz, 2H), 7.26–7.35 (m, 7H), 7.35–7.41 (m, 1H),
[10] D. Crich, M. Smith, J.Am.Chem.Soc. 2001, 123, 9015.
[11] The 1H and 13C NMR spectroscopic analyses suggested the
formation of a 72:28 mixture of two b-glycosyl triflimide
intermediates, in which the signal for the anomeric proton
7.45–7.50 (m, 1H), 7.58–7.86 ppm (m, 12H); 13C NMR (125 MHz,
CDCl3): d = 20.4 (CH3), 20.6 (CH3), 20.7 (CH3), 53.5 (CH), 54.4 (CH),
61.9 (CH2), 68.8 (CH2), 69.0 (CH2), 69.8 (CH), 70.8 (CH), 71.8 (CH),
71.8 (CH), 77.3 (CH), 82.6 (CH), 98.3 (CH), 123.6 (CH), 128.2 (CH),
128.2 (CH), 128.4 (CH), 128.4 (C), 128.6 (C), 129.0 (CH), 129.7 (CH),
129.7 (CH), 131.1 (C), 131.1 (C), 131.5 (C), 132.8 (CH), 133.2 (CH),
appeared at d = 6.53 (d,3JH-H = 9.5 Hz) and 6.39 ppm (d,3JH-H
=
10.0 Hz) and the signal for the anomeric carbon atom at d = 85.9
and 86.4 ppm at À 758C, respectively. Because the two peaks
tended to coalesce upon warming, we tentatively assigned them
as the rotamer of the carbon–nitrogen bond. The intermediates
decomposed above À 208C, before complete peak coalescence.
[12] K. C. Nicolaou, N. J. Bockovich, D. R. Carcanague, C. W.
=
133.4 (CH), 134.0 (CH), 134.1 (CH), 134.2 (CH), 165.1 (C O), 165.5
=
=
=
=
=
(C O), 166.7 (C O), 167.8 (C O), 169.5 (C O), 170.1 (C O),
=
170.7 ppm (C O); HRMS (FAB): m/z: calcd for C48H46O17NS
[M+H+]: 940.2486; found: 940.2493.
Hummel, L. F. Even, J.Am.Chem.Soc.
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Wang, C. Li, Q. W. Wang, Y. Z. Hui, J.Chem.Soc.Perkin Trans.1
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Received: December 17, 2003 [Z53552]
Keywords: carbohydrates · combinatorial chemistry ·
.
glycosylation · oligosaccharides · thioglycosides
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