Efficient and concise synthesis of βMan1-4GlcN linkage of pentasaccharide core by using 6-nitro-2-benzothiazolyl α-mannoside

Article abstract of DOI:10.1246/cl.2005.702

Efficient and concise synthesis of βMan1-4GlcN of pentasaccharide core is established; direct β-mannosylations of 4-OH group of 2-deoxy-2-phthaloyl and 2-azide-2-deoxy glucose derivatives by using 6-nitro-2-benzothiazolyl α-mannoside proceeded smoothly to

Full text of DOI:10.1246/cl.2005.702

702
Chemistry Letters Vol.34, No.5 (2005)
Efficient and Concise Synthesis of ꢀMan1–4GlcN Linkage of Pentasaccharide Core
by Using 6-Nitro-2-benzothiazolyl ꢁ-Mannoside
Hiroki Mandaiy;yy;yyy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute (TCI), 6-15-5 Toshima, Kita-ku, Tokyo 114-0003
yyThe Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
yyyFaculty of Phamaceutical Sciences, Tokyo University of Science, 2641 Yamazaki, Noda 278-8510
(Received January 14, 2005; CL-050066)
Efficient and concise synthesis of ꢀMan1–4GlcN of penta-
yl ꢁ-mannoside 2 in 77% yield as a major product (Scheme 1).
Although 6-nitro-2-benzothiazolyl ꢀ-mannoside was detected
by thin layer chromatography, it was too labile to isolate in pure
form. The anomeric configuration of 2 was determined to be ꢁ-
mannoside by measurement of NMR spectrum that showed
1JCH ¼ 177 Hz between H-1 and C-1.9
saccharide core is established; direct ꢀ-mannosylations of 4-
OH group of 2-deoxy-2-phthaloyl and 2-azide-2-deoxy glucose
derivatives by using 6-nitro-2-benzothiazolyl ꢁ-mannoside pro-
ceeded smoothly to afford the desired ꢀ-mannosides in high
yields.
KHMDS (1.1 equiv.)
2-Chloro-6-nitrobenzo-
thiazole (1.1 equiv.)
N-linked glycans are known to play numerous important bi-
ologically roles in cellular interactions.1 They are generally div-
ided into three classes; namely, high-mannose, complex, and hy-
brid types depend on structures of oligosaccharide chains.1 All
types of N-linked glycans have the common pentasaccharide
core including ꢀMan(1!4)GlcNAc linkage (Figure 1). Al-
though many methods to synthesize common pentasaccharide
core have been reported,2 there are only a few efficient and ver-
satile methods for construction of ꢀMan(1!4)GlcNAc linkage
because of its synthetic difficulties. Crich’s direct coupling
method was thought to be the best in forming ꢀMan(1!4)-
GlcNAc linkage when 2-azide-2-deoxy glucose3 or 2-deoxy-2-
sulfonamide chitobiose4 derivative having reactive 4-OH group
was used. While, ꢀ-mannosylation of less reactive 4-OH of 2-
deoxy-2-phthaloyl glucose derivatives afforded the desired prod-
ucts in moderate yields.5,6 Thus formed disaccharide was used in
further elongation of ꢀ-saccharide linkage because its reducing
end was effectively activated by neighboring effect of 2-PhthN
group.6
OBn
OBn
O
AllylO
AllylO
O
BnO
BnO
OH
AllylO
AllylO
N
S
THF, rt, 1 h
77 %
O
NO2
1
2
Scheme 1. Synthesis of mannosyl donor 2.
Mannosylation between mannosyl donor 2 (1.2 equiv.) and
p-methoxyphenyl 3,6-di-O-benzyl-2-deoxy-2-phthalimido-ꢀ-
D-glucopyranoside 310 (1.0 equiv.) was carried out under previ-
ously reported conditions7 and the desired ꢀ-mannoside 4ꢀ6 was
obtained in 52% yield along with 25% yield of the ꢁ-one
(Table 1, Entry 1). This low ꢀ-selectivity was thought that less
reactive 4-OH group of glycosyl acceptor 3 generated the
undesired oxionium ion intermediate which lead to formation
of ꢁ-mannoside.7
In order to improve the yield of the desired ꢀ-mannoside,
optimization of several reaction conditions; that is, the molar ra-
tios between mannosyl donor 2 and glycosyl accepter 3, concen-
tration of the reaction mixture, and an experimental procedure
were further examined in detail. After the reaction conditions
were optimized, the scope of this mannosylation reaction was
studied. Direct ꢀ-mannosylation of several glycosyl acceptors
such as 4-OH of 2-deoxy-2-phthaloyl glucose derivatives 3, 5,6
and 711 or 4-OH of 2-azide-2-deoxy glucose derivative 612 were
carried out under the optimized reaction conditions (Table 1,
Entries 2–6).13
OH
O
O
β-mannoside
HO
HO
OH
O
OH
O
O
AcNH
H
N Asn
HO
HO
O
O
O
O
HO
AcNH
OH
HO
HO
O
OH
O
All ꢀ-mannosylation reactions proceeded smoothly to af-
ford the desired ꢀ-mannoside in higher yields compared with
those shown in previously reported direct mannosylation meth-
od.3,6 On the other hand, the mannosylation of glycosyl acceptor
5 having a fluorine atom on its reducing end gave disaccharide 86
in 71% yield (Entry 3). The reason for this decrease in yield was
explained by considering that the fluorine atom attached to di-
saccharide 8 was liberated by the interaction with HB(C6F5)4
catalyst during this mannosylation reaction.
Figure 1. Common pentasaccharide core of N-linked glycans.
It was recently disclosed that 6-nitro-2-benzothiazolyl ꢁ-
glucoside and ꢁ-mannoside, novel glycosyl donors, were reac-
tive enough to construct ꢀ-saccharide linkages via SN2-type
process.7 In this paper, we would like to report a general and ef-
fective method for ꢀ-mannosylation of 4-OH group of 2-deoxy-
2-phthaloyl and 2-azide-2-deoxy glucose derivatives to prepare
the part of pentasaccharide core.
This problem was overcome by shortening of the reaction
time to 0.2 h (Entry 4), however, ꢀ-stereoselevtivity was lower
than the other glycosyl acceptors since the fluorine atom at
anomeric position reduced the nucleophilicity of hydroxy group
at C-4 position. The glycosyl acceptor 6 gave the best result in
The present study started from the preparation of 6-nitro-2-
benzothiazolyl 3,6-di-O-allyl-2,4-di-O-benzyl-ꢁ-D-mannopyra-
noside 2 from the precursor 18 according to our previously re-
ported procedure.7 The condensation reaction proceeded
smoothly at room temperature to afford 6-Nitro-2-benzothiazol-
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.5 (2005)
703
Table 1. ꢀ-Mannosylation with several glycosyl acceptors
References and Notes
1
2
R. A. Dwek, Chem. Rev., 96, 683 (1996).
Acceptor (1.0 equiv.)
HB(C6F5)4 (20 mol %)
OBn
O
AllylO
OBn
O
AllylO
BnO
G. Arsequell and G. Valencia, Tetrahedron: Asymmetry, 10,
3045 (1999); J. J. Gridley and H. M. I. Osborn, J. Chem. Soc.,
Perkin Trans. 1, 2000, 1471; B. Ernst, G. W. Hart, and P.
AllylO
N
S
BnO
AllylO
O
OR
NO2
MS 5A (3 g/mmol)
CH2Cl2, −78 °C, 1 h
Donor 2 (1.8 equiv.)
Entry Acceptor
Mannoside
Sinay, ‘‘Carbohydrate in Chemistry and Biology, Part 1,’’
¨
WILEY-VCH, Weinheim etc. (2000), p 320; A. A.-H.
Abdel-Rahman, S. Jonke, E. S. H. El Ashry, and R. R.
Schmidt, Angew. Chem., Int. Ed. Engl., 41, 2972 (2002);
C.-H. Wong, ‘‘Carbohydrate-Based Drug Discovery,’’
WILEY-VCH, Weinheim etc. (2003), p 253.
V. Dudkin and D. Crich, Tetrahedron Lett., 44, 1787 (2003).
V. Dudkin, J. S. Miller, and S. J. Danishefsky, Tetrahedron
Lett., 44, 1791 (2003).
D. A. Crich and V. Dudkin, J. Am. Chem. Soc., 123, 6819
(2001).
I. Matsuo, Y. Nakahara, Y. Ito, T. Nukada, Y. Nakahara, and
T. Ogawa, Bioorg. Med. Chem., 3, 1455 (1995); Z.-W. Guo,
Y. Nakahara, and T. Ogawa, Tetrahedron Lett., 38, 4799
(1997).
T. Mukaiyama, T. Hashihayata, and H. Mandai, Chem. Lett.,
32, 340 (2003); T. Hashihayata, H. Mandai, T. Mukaiyama,
and H. Mandai, Chem. Lett., 32, 442 (2003); T. Hashihayata
and T. Mukaiyama, Heterocycles, 61, 51 (2003); T.
Hashihayata, H. Mandai, and T. Mukaiyama, Bull. Chem.
Soc. Jpn., 77, 169 (2004).
T. Ogawa, T. Kitajima, and T. Nukada, Carbohydr. Res.,
123, C5 (1983).
K. Bock and C. Pedersen, J. Chem. Soc., Perkin Trans. 2,
1974, 293.
a
Time/h Mannoside Yield/% (α/β)
OBn
O
1b HO
BnO
0.5
1
4
4
77 (33/67)
99 (18/82)
OMP
PhthN
2
3
3
4
OBn
O
3
4
1
8
8
71 (22/78)
91 (26/74)
HO
F
BnO
0.2
PhthN
5
6
5
OBn
O
HO
5
6
1
1
9
95 (13/87)
95 (20/80)
OTBS
BnO
N3
6
OBn
O
OBn
O
HO
10
7
O
BnO
BnO
N3
PhthN
PhthN
7
aThe ꢁ=ꢀ ratios were determined by isolations of both stereoisomers.
bThe reaction was carried out under previously reported conditions.
OBn
O
OBn
O
AllylO
AllylO
BnO
BnO
OBn
O
OBn
O
AllylO
AllylO
8
9
O
O
OMP
F
BnO
BnO
PhthN
PhthN
4
8
OBn
OBn
AllylO
AllylO
O
O
BnO
BnO
OBn
O
OBn
O
OBn
O
10 T. Nakano, Y. Ito, and T. Ogawa, Carbohydr. Res., 243, 43
(1993).
11 M. R. Pratt and C. R. Bartizan, J. Am. Chem. Soc., 125, 6149
(2003).
AllylO
AllylO
O
O
OTBS
O
BnO
BnO
N3
BnO
N3
PhthN
PhthN
10
9
12 C. Metadata and T. Ogawa, Carbohydr. Res., 234, 75
(1992).
the present method to afford the desired ꢀ-mannoside 9ꢀ in 83%
yield along with 12% of the ꢁ-one (Entry 5). Further, it was in-
teresting to note that the chitobiose acceptor 7 gave the desired
ꢀ-trisaccharide 10ꢀ6 in 76% yield along with 19% of the ꢁ-one.
The anomeric configurations of all mannosides were confirmed
13 A typical experimental procedure was as follows: To a stir-
red suspension MS 5A (150 mg) and glucosyl acceptor 7
(49.4 mg, 0.05 mmol) in CH2Cl2 (0.5 mL) was successively
added HB(C6F5)4 (0.05 M in toluene–Et2O (1:1), 0.20 mL,
0.01 mmol)14 at ꢁ78 ꢂC and, 5 min later, a solution of man-
nosyl donor 1 (55.9 mg, 0.09 mmol) in CH2Cl2 (1.25 mL)
added over 30 min. After the mixture was stirred for 1 h at
ꢁ78 ꢂC, the reaction was quenched by adding sat. aq.
NaHCO3. Then, the mixture was filtered through Celite
and the aqueous layer was extracted with CH2Cl2. The com-
bined organic layer was washed with brine and dried over
Na2SO4. After filtration and evapolation, the resulting
residue was purified by preparative TLC (silica gel, toluene:
EtOAc = 7:1) to afford ꢀ-mannoside 10ꢀ (53.6 mg, 76%)
and 10ꢁ (13.6 mg, 19%).
1
by JCH coupling constant measurement. Ogawa et al. utilized
trisaccharide 10ꢀ prepared from 4ꢀ or 8ꢀ in the total synthesis
of pentasaccharide core of N-linked glycans after removal of
protecting group of allyl ether.6
It is noted that an efficient and concise method for synthesis
of ꢀMan1–4GlcN, a part of the pentasaccharide core, was estab-
lished by using 6-nitro-2-benzothiazolyl ꢁ-mannosyl donor 2.
This method was quite useful in direct mannosylation and
provided several ꢀ-di- or trisaccharides in high yields.
Further studies for synthesis of pentasaccharide core of
N-linked glycans are now in progress.
14 HB(C6F5)4 was generated accoding to literal procedure:
H. Jona, H. Mandai, W. Chavasiri, K. Takeuchi, and T.
Mukaiyama, Bull. Chem. Soc. Jpn., 75, 291 (2002).
This study was supported in part by the Grant of the 21st
Century COE program from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
Published on the web (Advance View) April 16, 2005; DOI 10.1246/cl.2005.702