Novel molecular clamp method for anomeric stereocontrol of glycosylation

Article abstract of DOI:10.1055/s-1999-2997

Stereocontrolled glycosylation is described by using a molecular clamp, which binds a glycosyl donor to an acceptor and controls their spatial arrangement. An α(1→4) glycosidic linkage was formed in a good yield with high selectivity by the use of a phthaloyl bridge bound to both 6-positions of a glycosyl donor and an acceptor. β-Selective glycosylation was effected by the use of a silyl bridge attached to the same 6-positions of the same glycosyl donor and acceptor. Application of this method to the synthesis of a maltotetraose derivative is also described.

Full text of DOI:10.1055/s-1999-2997

LETTER
1911
Novel Molecular Clamp Method for Anomeric Stereocontrol of Glycosylation
Masahiro Wakao, Koichi Fukase,* Shoichi Kusumoto
Department of Chemistry, Graduate School of Science, Osaka University, Machikaneyama 1-1, Toyonaka, Osaka 560-0043, Japan
E-mail: koichi@chem.sci.osaka-u.ac.jp
Received 14 September 1999
of this method to the synthesis of maltotetraose is also de-
Abstract: Stereocontrolled glycosylation is described by using a
scribed by segment condensation of maltose moieties.
molecular clamp, which binds a glycosyl donor to an acceptor and
controls their spatial arrangement. An a(1Æ4) glycosidic linkage
was formed in a good yield with high selectivity by the use of a ph-
thaloyl bridge bound to both 6-positions of a glycosyl donor and an
acceptor. b-Selective glycosylation was effected by the use of a silyl
bridge attached to the same 6-positions of the same glycosyl donor
and acceptor. Application of this method to the synthesis of a mal-
totetraose derivative is also described.
O
O
O
O
O
OH
O
O
OH
BnO
BnO
1
O
SPh
BnO
BnO
SPh
Et3N in CH2Cl2
90%
BnO
2
BnO
O
HO
TrocO
Key words: intramolecular glycosylation, stereocontrol, molecular
clamp, glycosides, carbohydrate
O
O
O
BnO
BnO
Zn-Cu
3
OMe
O
BnO
O
SPh
HO
BnO
BnO
O
in AcOH
94%
DCC, DMAP
in CH2Cl2
80%
BnO
7
BnO
Stereoselective glycosylation has been a major issue for
efficient synthesis of oligosaccharides and glycoconju-
gates. Recently, various studies for anomeric stereocon-
trol of glycosylation have been reported by using
intramolecular reaction of a glycosyl donor and a glycosyl
acceptor linked together with an appropriate bridge.1-9
OMe
HO
O
BzO
(t-Bu)2Si(OTf)2
pyridine, DMAP
OH
O
BnO
BnO
OMe
4
BnO
BnO
SPh
in CH3CN
47%
BnO
1
tBu
tBu
So far described methods for intramolecular glycosylation
are divided into two categories. One is so-called "intramo-
lecular aglycon delivery". In this method, the glycosyl ac-
ceptor is delivered to the donor via a linker attached on the
donor moiety.1,2 In several cases, the glycosyl acceptors
were attached to the leaving groups of the donors.2 In the
other category, a stable bridge is used as a "molecular
clamp" which controls the spatial arrangement of a donor
and an acceptor to kinetically accelerate the glycosylation
and allows a stereo- and regioselective reaction.3-9 We re-
ported many years ago the first application of the latter
method to the synthesis of the glucosaminyl-muramic
acid residue which was not formed by direct glycosylation
using the oxazoline method without a molecular clamp.3
Recently, stereoselective glycosylation reaction using this
method was reported by several groups, especially by the
intensive work of Ziegler et al.4-9 More extensive studies
should be addressed in order to find more convenient and
practical route, since diverse sets of bridged positions and
linker moieties can be used for intramolecular glycosyla-
tion.
O
Si
MeONa
O
BnO
BnO
O
SPh
HO
BnO
O
in MeOH
99%
BnO
8
BnO
OMe
Scheme 1
In order to investigate the effect of various linkers, a series
of different bridged saccharides were prepared. Typical
synthetic routes are shown in Scheme 1. Treatment of
phenyl 1-thio-b-D-glucopyranoside 1 with phthalic anhy-
dride afforded the phthaloylated derivative 2, which was
then condensed with 3 by the use of dicyclohexylcarbodi-
imide (DCC) and 4-(dimethylamino)pyridine (DMAP).
The 4-O-trichloroethoxycarbonyl (Troc) group of the re-
sulting 6,6’-phthaloyl-bridged saccharide was selectively
removed with Zn-Cu in AcOH to give compound 7. The
6,6’-succinyl-bridged saccharide 6 and the 6,6’-glutaryl-
bridged saccharide 5 were obtained in a similar manner.
The silyl-bridged saccharide 8 was prepared by the suc-
cessive reaction of (t-Bu)2Si(OTf)2 with 1 and 4 followed
by the removal of the benzoyl group.
In the present study, we focused on the synthesis of (1Æ4)
glycosidic linkage, since the 4-position of glucose is most
sterically hindered and thus sometimes difficult to be gly-
cosylated. We selected the 6-positions of a donor and an
acceptor for cross-linking, since 6-positions are most re-
active and thus can be readily functionalized. Either
a(1Æ4) or b(1Æ4) glucoside was selectively obtained by
using a phthaloyl or silyl bridge, respectively. Application
Glycosylation reactions of these bridged saccharides were
then examined by using 1.1 equiv of PhIO and 0.5 equiv
of trimethylsilyl trifluoromethanesulfonate (TMSOTf) as
activating reagents of thioglycosides10 under N2 atmo-
sphere in CH2Cl2.11 Under these reaction conditions, ste-
Synlett 1999, No. 12, 1911–1914 ISSN 0936-5214 © Thieme Stuttgart · New York

1912
M. Wakao et al.
LETTER
1) TBAF in THF
quant.
O
O
O
Ph
O
O
OH
O
2) phthalic anhydride
Et3N in CH2Cl2
quant.
BnO
16
O
BnO
O
DCC
Ph
O
SPh
O
BnO
O
DMAP
OTBDPS
BnO
BnO
O
1) PhIO, TMSClO4, MeOH
MS4A in CH2Cl2, -15 ˚C
76% (α:β = 3:1)
BnO
O
in CH2Cl2
87%
SPh
HO
HO
BnO
BnO
15
BnO
O
OTBDPS
O
BnO
O
2) 80% AcOH, 50 ˚C
88%
BnO
17
BnO
OMe
O
Ph
O
O
O
O
O
O
BnO
O
O
O
PhIO (1.1 eq)
TMSOTf (0.5 eq.)
BnO
O
O
Ph
O
O
BnO
O
BnO
HO
BnO
SPh
O
O
BnO
O
OTBDPS
O
O
BnO
OTBDPS
O
O
BnO
BnO
MS4A in CH2Cl2, -15 ˚C
85%
O
O
19
BnO
O
BnO
BnO
BnO
BnO
BnO
18
OMe
BnO
OMe
Scheme 2
reoselectivity was not observed without a molecular
clamp (data not shown).
O
X
X
O
O
O
A
O
O
O
HO
BnO
BnO
BnO
SPh
BnO
BnO
O
O
BnO
OMe
BnO
a-Selective glycosylations were achieved by the use of di-
ester bridges. With the glutaryl linker, the desired disac-
charide 9 was obtained with some a-selectivity but the
yield of the glycosylation was low because of preferential
hydrolysis of the thioglycoside moiety in the donor part
(Table 1, Entry 1). By decreasing the chain length of the
linker from glutaryl to succinyl, both the yield and a-se-
lectivity were improved (Table 1, Entry 2). We then ex-
amined the glycosylation of 7 possessing a more rigid
phthaloyl linker which is expected to suppress the free ro-
tations around the linker. Indeed, both the yield and selec-
tivity were dramatically improved by using a phthaloyl
linker (86%, a:b = 99:1, Entry 3).
BnO
BnO
BnO
OMe
A: PhIO (1.1 eq), TMSOTf (0.5 eq), MS4A in CH2Cl2, -15 ˚C
5, X = glutaryl
6, X = succinyl
7, X = phthaloyl
8, X = silyl
9, X = glutaryl
10, X = succinyl
11, X = phthaloyl
12, X = silyl
Table 1. Intramolecular Glycosylation
α : βa
Entry
Yield (%)
37
Time
X (linker)
Solvent
CH2Cl2
O
O
1
2
10 min
10 min
89 : 11
93 : 7
O
O
CH2Cl2
67
The solvent effect was then investigated on the glycosyla-
tion of 7. Glycoside 11 was obtained also with high a-se-
lectivity in Et2O, which generally promotes a-selective
glycosylation12a,b (Entry 4). The yield was, however, de-
creased owing to hydrolysis of the donor moiety. In
CH3CN, the b-glycoside was obtained preferentially via
the known a-nitrilium kinetic intermediates12 (Entry 5).
Without the molecular clamp, b(1Æ4)-glycoside was also
obtained preferentially (a:b = 12:88) under the same reac-
tion conditions.10 In this case, the solvent effect of CH3CN
dominated over the effect of the molecular clamp, though
the a-oriented effect of the phthaloyl bridge was observed
to some extent.
CH2Cl2
Et2O
10 min
15 h
86
46
83
99 : 1
99 : 1
28 : 72
3
4
O
O
CH3CN
5
30 min
CH2Cl2
Et2O
6
20 min
30 min
30 min
82
70
77
15 : 85
2 : 98
3 : 97
tBu
tBu
7
8
Si
CH3CN
a The ratio of α:β was determined by 1H-NMR.
then the proximal acceptor immediately attacked the in-
termediate from the b-face before the a-orientated Et2O
complex changed into the thermodynamically more stable
b-orientated one. This assumption is supported by the
very fast reaction rate of this particular glycosylation as
compared to the normal a-preferential reaction in ether
(e.g. Entry 4). b-Selective glycosylation was also effected
with a similarly high selectivity by the use of the known
solvent effect of CH3CN (Entry 8).
b-Selective glycosylation was effected by the use of the
silyl linker. The glycosylation of 8 proceeded smoothly to
give the b-glucoside 12 preferentially even in CH2Cl2, a
solvent in which stereoselective glycosylation is seldom
observed, in a good yield (82%, a:b = 15:85, Entry 6). In-
terestingly, Et2O promoted b-glycosylation in this case to
afford b-glucoside with a higher selectivity (Entry 7). This
peculiar result suggests that Et2O first kinetically attached
to the oxocarbenium ion intermediate from the a-face and
Synlett 1999, No. 12, 1911–1914 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Novel Molecular Clamp Method for Anomeric Stereocontrol of Glycosylation
1913
(5) b(1Æ4)-Linkage was selectively formed by intramolecular
glycosylation of two glucose units connected by a rigid m-
xylylene linker either at the 6-positions of a donor and an
acceptor or at the 6-position of a donor and the 3-position of
an acceptor: Huchel U.; Schmidt R. R. Tetrahedron Lett.
1998, 39, 7693-7694.
(6) Stereoselective rhamnosylation and its application to the
synthesis of a natural tetrasaccharide: Schüle, G.; Ziegler, T.
Liebigs Ann. 1996, 1599-1607.
The present "molecular clamp" method was next applied
to the synthesis of maltotetraose [ = a(1Æ4) linked tetra-
glucose] by a segment condensation of two maltose units
as shown in Scheme 2. The disaccharide thioglycoside
1513 was prepared from maltose as a common synthetic in-
termediate for both glycosyl donor and acceptor. After t-
butyldiphenylsilyl (TBDPS) group of 15 was removed
with tetrabutylammonium fluoride (TBAF), the resulting
6-OH free disaccharide was reacted with phthalic anhy-
dride to give the donor part 16.14 The acceptor part 1715
was obtained by glycosylation of 15 with MeOH followed
by debenzylidenation. Compounds 16 and 17 were cou-
pled with DCC and DMAP to afford the bridged tetrasac-
charide 18.16 Intramolecular glycosylation of compound
18 was carried out under N2 atmosphere in CH2Cl2 by us-
ing 1.1 equiv of PhIO and 0.5 equiv of TMSOTf to afford
the desired tetrasaccharide 1917 in a good yield with per-
fect a-selectivity.
(7) Synthesis of b-mannosides: Ziegler, T.; Lemanski, G. Angew.
Chem. Int. Ed. 1998, 37, 3129-3132.
(8) Synthesis of a-mannosides: Ziegler, T.; Lemanski, G. Eur. J.
Org. Chem. 1998, 163-170, and references therein.
(9) Stereo- and regiocontrol of glycosylation: (a) Valverde, S.;
Gómez, A. M.; López, J. C.; Herradón, B. Tetrahedron Lett.
1996, 37, 1105-1108. (b) Yamada, H.; Imamura, K.;
Takahashi, T. Tetrahedron Lett. 1997, 38, 391-394.
(10) Fukase, K.; Kinoshita, I.; Kanoh, T; Nakai, Y; Hasuoka, A;
Kusumoto, S. Tetrahedron 1996, 52, 3897-3904.
(11) A typical procedure for glycosylation by molecular clamp
method: To a suspension of 7 (22 mg, 21 mmol), PhIO (4.4 mg,
23 mmol), and Molecular Sieves 4A (MS4A) (50 mg) in 2 ml
of CH2Cl2 was added TMSOTf (2 ml, 10 mmol) at -15 °C under
N2 atmosphere. After the mixture was stirred at -15 °C for 15
min, ethyl acetate (AcOEt) and saturated aqueous NaHCO3
solution were added. After MS4A were removed by filtration,
the organic layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. The residue was purified by
preparative silica-gel thin layer chromatography (TLC)
(toluene : AcOEt = 5:1) to give 11: Yield 17 mg (86%, a :
b = 99:1). 11: 1H NMR (500 MHz, CDCl3), a-anomer:
d = 5.94 (d, 1H, J1’,2’= 4.12 Hz, H-1'), 4.54 (d, 1H, J1,2 = 3.43
Hz, H-1), 3.40 (s, 3H, OMe); b-anomer: d = 3.36 (s, 3H,
OMe); ESI-MS m/z 925.385 [(M+Na)+]. 9: 1H NMR (500
MHz, CDCl3), a-anomer: d = 5.84 (d, 1H, J1’,2’= 3.89 Hz, H-
1'), 4.62 (d, 1H, J1,2 = 3.43 Hz, H-1), 3.39 (s, 3H, OMe); b-
anomer: d = 3.38 (s, 3H, OMe); ESI-MS m/z 959.409
[(M+Na)+]. 10: 1H NMR (500 MHz, CDCl3), a-anomer:
d = 5.94 (d, 1H, J1’,2’= 4.12 Hz, H-1'), 4.60 (d, 1H, J1,2 = 3.43
Hz, H-1), 3.39 (s, 3H, OMe); b-anomer: d = 3.40 (s, 3H,
OMe); ESI-MS m/z 911.360 [(M+Na)+]. 12: b-anomer:
d = 4.87 (d, 1H, J1’,2’= 6.64 Hz, H-1'), 4.61 (d, 1H, J1,2 = 3.66
Hz, H-1), 3.42 (s, 3H, OMe); a-anomer: d = 3.38 (s, 3H,
OMe); ESI-MS m/z 969.455 [(M+Na)+].
In summary, the molecular clamp method allows facile
and stereocontrolled glycosylations. In previous studies of
the molecular clamp method, anomeric selectivity has
been controlled by the selection of both bridged positions
and linker moieties.3-9 We demonstrated here phthaloyl
and silyl bridges attached to the same 6-positions of the
donor and the acceptor afforded a- and b-anomers, re-
spectively, with high selectivity. Our results indicate ano-
meric selectivity can be also controlled by the length,
rigidity, and structural feature of linkers, even if the at-
tached positions to the donor and an acceptor are fixed.
This method is expected to be useful particularly for oli-
gosaccharide synthesis via segment condensation as de-
scribed above.
Acknowledgement
The present work was financially supported in part by "Research for
the Future" Program No. 97L00502 from the Japan Society for the
Promotion of Science.
(12) (a) Hashimoto, S.; Hayashi, M.; Noyori, R. Tetrahedron Lett.
1984, 25, 1379-1382. (b) Ito, Y; Ogawa, T. Tetrahedron Lett.
1987, 28, 4701-4704. (c) Andersson, F.; Fügedi, P.; Garegg,
P. J.; Nashe, M. Tetrahedron Lett. 1986, 27, 3919-3922, and
references therein.
References and Notes
(1) (a) Barresi, F.; Hindsgaul, O. J. Am. Chem. Soc. 1991, 113,
9376-9377; Synlett 1992, 759-761; Can. J. Chem. 1994, 72,
1447-1465. (b) Stork, G.; Kim, G. J. Am. Chem. Soc. 1992,
114, 1087-1088. (c) Stork, G.; La Clair, J. J. J. Am. Chem. Soc.
1996, 118, 247-248. (d) Ito, Y.; Ogawa, T. Angew. Chem. Int
Ed. Engl. 1994, 33, 1765-1767; J. Am. Chem. Soc. 1997, 119,
5562-5566. (e) Bols, M. J. Chem. Soc., Chem. Commun. 1992,
913-914; J. Acta Chem. Scand. 1996, 50, 931-937.
(2) (a) Inaba, S.; Yamada, M.; Yoshino, T.; Ishido, Y. J. Am.
Chem. Soc. 1973, 95, 2062-2063. (b) Iimori, T.; Shibazaki, T.;
Ikegami, S. Tetrahedron Lett. 1996, 37, 2267-2270.
(c) Scheffler, G.; Schmidt, R. R. J. Org.Chem. 1999, 64, 1319-
1325. (d) Mukai, C.; Itoh, T.; Hanaoka, M. Tetrahedron Lett.
1997, 38, 4595-4598.
(13) The maltose unit 15 was prepared as follows. To a solution of
maltose octaacetate (85.3 g, 126 mmol) in (CH2Cl)2 (1.3 l)
were added phenylthio trimethylsilane (TMSSPh, 26.3 ml,
139 mmol) and ZnI2 (65.0 g 252 mmol) at room temperature.
After being stirred overnight, the mixture was filtered and the
filtrate was concentrated in vacuo. The residue was dissolved
in AcOEt and the solution was washed with brine, dried over
MgSO4, and concentrated in vacuo. The residue was purified
by flash silica-gel column chromatography (toluene :
AcOEt = 2:1) to give the phenyl thiomaltoside as an oily
product (75.8 g, 83%). To the solution of the resulting
thioglycoside (16.8 g, 23.1 mmol) in MeOH (1 l) was added
1M NaOMe in MeOH (10 ml) at room temperature. After
being stirred for 4 h, the reaction mixture was neutralized with
Dowex 50W-X8 (H+). The resin was removed by filtration and
the filtrate was concentrated in vacuo. To the solution of the
residue in DMF (200 ml) were added PhCH(OMe)2 (5.2 ml,
34.7 mmol) and TsOH∑H2O (1.0 g) at room temperature. The
reaction mixture was warmed to 60 °C under reduced pressure
(15 mmHg) and then stirred for 3 h. After the reaction mixture
(3) Kusumoto, S.; Imoto, M.; Ogiku, T. Shiba, T. Bull. Chem.
Soc. Jpn. 1986, 59, 1419-1423.
(4) a(1Æ4)-Linked disaccharides (D-Glcp-(1Æ4)D-Glcp, D-
Glcp-1(Æ4)D-GlcNp) were selectively obtained in good
yields by using a succinyl linker bridged to the 2-position of a
donor and the 3-position of an acceptor: Ziegler T.; Ritter, A.;
Hürttlen J. Tetrahedron Lett. 1997, 38, 3715-3718.
Synlett 1999, No. 12, 1911–1914 ISSN 0936-5214 © Thieme Stuttgart · New York

1914
M. Wakao et al.
LETTER
was cooled to room temperature, pyridine (100 ml), DMAP
(282 mg, 2.31 mmol), and TDBPSCl (12.7 ml, 46.2 mmol)
were added. After being stirred overnight, the mixture was
concentrated in vacuo. The residue was dissolved in AcOEt
and the solution was washed with 1 M HCl and brine, dried
over MgSO4, and concentrated in vacuo. After the residue
(crude product 23.7 g) was dissolved in DMF (300 ml), NaH
(5.56 g, 139 mmol) and BnBr (14.2 ml, 116 mmol) was added
at 0 °C. The mixture was stirred at room temperature
overnight. After usual work-up, purification by flash silica-gel
column chromatography (toluene : AcOEt = 30:1) gave 15
(20.2 g, 78%).
methyl glycosides (a-anomer:107 mg, 59%; b-anomer:36 mg,
36%). The solution of the the a-glycoside (107 mg, 102 mmol)
in 80% AcOH (5 ml) was stirred at 50 °C for 4 h and the
mixture was then concentrated in vacuo. The residue was
purified by flash silica-gel column chromatography (toluene :
AcOEt = 5:1) to give 17 as a syrup (85 mg, 88%).
(16) To a solution of compound 16 (159 mg, 155 mmol) and 17
(114 mg, 119 mmol) in CH2Cl2 (2 ml) were added DCC (49
mg, 239 mmol) and DMAP (1.5 mg, 12 mmol) at 0 °C. The
mixture was then stirred at room temperature overnight. The
insoluble materials were filtered off and the filtrate
concentrated in vacuo. The residue was purified by flash
silica-gel column chromatography (toluene : AcOEt = 10:1)
to give 18 as a syrup (204 mg, 87%).
(14) To a solution of 15 (532 mg, 474 mmol) in THF (2.5 ml) was
added 1 M TBAF in THF (2.5 ml, 2.5 mmol). The mixture was
stirred at room temperature for 2.5 h. After usual work-up, the
residue was purified by flash silica-gel column
(17) To a suspension of 18 (42 mg, 21 mmol), PhIO (6.9 mg, 32
mmol), and MS4A (50 mg) in 2 ml of CH2Cl2 was added
TMSOTf (0.39 ml, 2 mmol) at -15 °C under N2 atmosphere.
After the mixture was stirred at -15 °C for 30 min, AcOEt and
saturated aqueous NaHCO3 solution were added. After usual
work-up, purification by preparative silica-gel TLC (toluene :
AcOEt = 7:1) gave 19 as a syrup: Yield 33 mg (85%, a-
anomer only). 1H NMR (500 MHz, CDCl3) d = 5.72 (d, 1H,
J1’,2’= 3.89 Hz, H-1'), 5.57 (d, 1H, J1’’,2’’= 4.12 Hz, H-1''), 5.44
(d, 1H, J1’’’,2’’’= 3.66 Hz, H-1'''), 4.60 (d, 1H, J1,2 = 3.43 Hz, H-
1), 3.40 (s, 3H, OMe); ESI-MS m/z 1879.71 [(M+Na)+].
chromatography (toluene : AcOEt = 10:1) to give the 6-OH
free disaccharide as a syrup, quantitatively. To the solution of
the disaccharide (436 mg, 494 mmol) in CH2Cl2 were added
phthalic anhydride (113 mg, 763 mmol) and Et3N (138 ml, 988
mmol) at room temperature and the mixture was stirred at the
same temperature overnight. After usual work-up, purification
by flash silica-gel column chromatography (CHCl3:
acetone = 3:1) gave 16 as a syrup, quantitatively.
(15) To a suspension of 15 (200 mg, 178 mmol), MeOH (14.4 ml,
356 ml), PhIO (59 mg, 267 mmol), AgClO4 (4.6 mg, 67 mmol),
and MS4A (50 mg) in 2 ml of CH2Cl2 was added TMSCl (4.5
ml, 53 mmol) at -15 °C under N2 atmosphere. The mixture was
stirred at -15 °C for 1 h. After usual work-up, purification by
preparative silica-gel TLC (toluene : AcOEt = 30:1) gave the
Article Identifier:
1437-2096,E;1999,0,12,1911,1914,ftx,en;Y18699ST.pdf
Synlett 1999, No. 12, 1911–1914 ISSN 0936-5214 © Thieme Stuttgart · New York