An extremely mild and stereocontrolled construction of 1,2-cis-α-glycosidic linkages via benzyl-protected glycopyranosyl diethyl phosphites

Article abstract of DOI:10.1039/a902845e

A highly stereocontrolled 1,2-cis-α-glycosidation reaction under conditions mild enough for acid-labile alcohols has been developed using benzyl-protected glycopyranosyl diethyl phosphites as glycosyl donors in the presence of 2,6-di-tert-butylpyridinium

Full text of DOI:10.1039/a902845e

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An extremely mild and stereocontrolled construction of 1,2-cis-a-glycosidic
linkages via benzyl-protected glycopyranosyl diethyl phosphites
Hiroko Tanaka, Hiroki Sakamoto, Ai Sano, Seiichi Nakamura, Makoto Nakajima and Shunichi Hashimoto*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
E-mail: hsmt@pharm.hokudai.ac.jp
Received (in Cambridge, UK) 9th April 1999, Accepted 14th May 1999
OP(OEt)2
OR1
O
OBn
O
A highly stereocontrolled 1,2-cis-a-glycosidation reaction
BnO
under conditions mild enough for acid-labile alcohols has
been developed using benzyl-protected glycopyranosyl
diethyl phosphites as glycosyl donors in the presence of
2,6-di-tert-butylpyridinium iodide and tetrabutylammon-
ium iodide.
R2O
R3O
Me
O
OR
BnO
OR
R3O
BnO
RO
OP(OEt)2
OP(OEt)2
R1 = R2 = R3 = Bn
6
7
8
R = Bn
R = p-ClC6H4CH2
1
2
3
4
5
R1 = R2 = R3 = p-ClC6H4CH2
R1 = Tr, R2 = R3 = Bn
R1 = TBDPS, R2 = R3 = Bn
R1, R2 = PhCH, R3 = Bn
Due to the rapidly recognised biological significance of the
saccharide residues of carbohydrate-containing biomolecules,
the rational design and development of stereocontrolled glyco-
sidation reactions1 are of growing importance not only in
carbohydrate chemistry but also in medicinal chemistry.2 One
of the current topics in this area is the emergence of glycosyl
phosphites as a new family of glycosyl donors,3–6 the
effectiveness of which has been demonstrated well by high-
yield and a-selective sialylation3a,4a,b using sialyl phosphite as
a donor and TMSOTf as a promoter. As yet another advantage
of glycosyl phosphites, we recently reported that glycosidations
of benzyl-protected glycopyranosyl diethyl phosphites with a
variety of acceptor alcohols could be effected with the aid of
BF3·OEt2 as a promoter at 278 °C to exhibit the highest
1,2-trans-b-selectivity known to date for glycosidations without
neighboring group participation.7 During the course of mecha-
nistic investigations of the reaction, we found that the
glucopyranosyl phosphite 1† could not be directly activated by
BF3·OEt2 at 278 °C. This result, together with the finding that
the trimethylsilyl ether 10 derived from O-6-unprotected
glycoside 9 did not serve as a glycosyl donor (Scheme 1),
O
O
OH
X
O
O
OH
O
Y
BnO
O
O
O
O
BnO
O
OMe
O
9 X = OH, Y = OBn
10 X = OTMS, Y = OBn
11 X = OBn, Y = OH
13
12
O
O
OMe
Me
O
HO
OH
O
O
H
15
H
OH
16
14
HO
O
H
H
O
OBn
O
OBn
O
Acceptor (1.1 equiv.)
BF3•OEt2 (1.0 equiv.)
H
H
CO2CH2CH=CH2
NHCO2Bn
18
BnO
BnO
BnO
BnO
HO
OR
H
H
4 Å molecular sieves
CH2Cl2, –78 °C
BnO
BnO
OP(OEt)2
HO
H
1 (α:β = 90:10)
17
Acceptor
Scheme 1
9
10
97%, α:β = 1:99
no reaction
Since it is well-documented that glycosylations of less
nucleophilic alcohols favor 1,2-cis-a-glycosides, we first
examined glycosidation of 1 with 9 with a high reactivity in
order to make an assessment as accurately as possible. After
considerable experimentation, it was found that coupling of 1
(a+b = 90+10 or 75+25, 1.1 equiv.) with 9 (1.0 equiv.) in
CH2Cl2 in the presence of DTBPI (1.2 equiv.) and pulverised 4
Å molecular sieves proceeded at room temperature for 48 h to
afford the corresponding 1,2-cis-disaccharide in 85% yield with
an a+b ratio of 92+8 (Table 1, entry 1). Since TLC and 1H NMR
analyses showed that in situ conversion of 1 into the a-
glucopyranosyl iodide14 proceeded to completion within 30 min
irrespective of the anomeric composition of the donor, the
glycosidation of the iodide via in situ anomerisation was
presumed to be the rate-determining step. As expected, the
addition of Bu4NI (1.2 equiv.) to the above mixture facilitated
the anomerisation process and shortened the reaction time to 24
h, providing the disaccharide in 84% yield with the same a-
selectivity as above (entry 2).‡§
suggested that glycosidation should be effected with the aid of
the BF3–acceptor alcohol complex8 which functioned as a
proton donor to activate the phosphite group to give oxo-
carbenium ion and diethyl phosphite. Although TfOH is known
to activate the phosphite 1 to give mainly 1,2-trans-b-
glucosides,4c there has been no reported attempt to use
promoters with much lower Brønsted acidity. At this stage, we
envisaged that if the phosphite group could be activated using
promoters such as pyridinium iodides, the glycosidation process
via glycopyranosyl iodide coupled with Lemieux’s in situ
anomerisation method9 might lead to the construction of
1,2-cis-a-glycosidic linkages under extremely mild reaction
conditions.10–12 Herein, we report a new aspect of glycosida-
tions with benzyl-protected glycopyranosyl diethyl phosphites,
wherein the combined use of 2,6-di-tert-butylpyridinium iodide
(DTBPI)13 as a promoter and tetrabutylammonium iodide as an
additive proves to be the superior choice for allowing
exceptionally high levels of 1,2-cis-a-selectivity, as well as
glycosylations of even highly sensitive aglycones.
In order to clarify the scope and limitations of the present
method, we then explored the glycosidation of glycosyl
phosphites 1–8† with a range of acceptor alcohols. The
Chem. Commun., 1999, 1259–1260
1259

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Table 1 1,2-cis-Glycosidation reaction with glycopyranosyl diethyl phos-
This research was supported in part by a Grant-in-Aid
(No.08557119) from the Ministry of Education, Science, Sports
and Culture of Japan.
phitesa
O
DTBPI, Bu4NI
O
O
+
ROH
4 Å molecular
sieves, CH2Cl2
BnO
BnO
BnO
OP(OEt)2
I
OR
Notes and references
d
† Glycopyranosyl diethyl phosphites 1–8 were readily prepared from the
corresponding glycopyranoses according to the reported procedure (ref. 7),
the anomeric ratios of which were determined by 109 MHz 31P NMR using
85% H3PO4 as an external standard.
Entry
Donorb
Acceptor
t/h
Yieldc (%)
a+b
1e
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
3
4
5
6
6
6
7
7
8
8
9
9
48
24
48
24
48
48
48
36
24
48
48
48
48
24
48
3
85
84
59
91
81
88
89
92
88
88
91
80
85
94
87
82
95
87
95
92+8
92+8
‡ Typical experimental procedure: A solution of 1 (72.6 mg, 0.11 mmol) in
CH2Cl2 (1 ml) was added to a mixture of 9 (46.4 mg, 0.1 mmol), DTBPI
(38.3 mg, 0.12 mmol), Bu4NI (44.3 mg, 0.12 mmol) and pulverised 4 Å
molecular sieves (50 mg). The whole mixture was stirred at room
temperature for 24 h. Standard workup followed by column chromatog-
raphy (silica gel, 6+1 hexane–AcOEt) furnished the corresponding
disaccharide (82.9 mg, 84%) as a 92:8 mixture of a- and b-anomers.
§ The combined use of 2,6-di-tert-butylpyridinium bromide and Bu4NBr
under otherwise identical conditions (reaction time; 48 h) provided the
disaccharide with the a+b ratio of 87+13 in 80% yield.
11
12
13
15
16
17
9
9
9
9
9
14
18
9
12
9
95+5
94+6
92+8
91+9f
90+10
92+8
95+5g
96+4g
96+4g
90+10g
95+5g
93+7g
93+7
10
11
12
13
14
15
16
17
18
19
1 For recent reviews see: K. Toshima and K. Tatsuta, Chem. Rev., 1993,
93, 1503; G.-J. Boons, Tetrahedron, 1996, 52, 1095; Modern Methods
in Carbohydrate Synthesis, ed. S. H. Khan and R. A. O’Neil, Harwood,
Amsterdam, 1996.
2 Synthetic Oligosaccharides, ACS Symp. Ser. No. 560, ed. P. Kovác,
ACS, Washington, D.C., 1993; Carbohydrates in Drug Design, ed. Z. J.
Witczak and K. A. Nieforth, Marcel Dekker, New York, 1997.
3 (a) T. J. Martin and R. R. Schmidt, Tetrahedron Lett., 1992, 33, 6123;
(b) T. Müller, R. Schneider and R. R. Schmidt, Tetrahedron Lett., 1994,
35, 4763.
4 (a) H. Kondo, Y. Ichikawa and C.-H. Wong, J. Am. Chem. Soc., 1992,
114, 8748; (b) M. M. Sim, H. Kondo and C.-H. Wong, J. Am. Chem.
Soc., 1993, 115, 2260; (c) H. Kondo, S. Aoki, Y. Ichikawa, R. L.
Halcomb, H. Ritzen and C.-H. Wong, J. Org. Chem., 1994, 59, 864.
5 Y. Watanabe, C. Nakamoto, T. Yamamoto and S. Ozaki, Tetrahedron,
1994, 50, 6523.
88:12
89+11g
95+5
4
4
4
12
93+7g
a Donor+acceptor+DTBPI+Bu4NI molar ratio = 1.1+1.0+1.2+1.2. b The
anomeric ratio of the phosphites: 1, 90+10; 2, 61+39; 3, 50+50; 4, 83+17; 5,
66:34; 6, 52+48; 7, 49+51; 8, 57+43. c Isolated total yield based on the
acceptor alcohol used. d Determined by HPLC (column, Zorbax® Sil, 4.6 3
250 mm; eluent, 9–30% EtOAc in hexane or 14–22% THF in hexane; flow
rate, 1.5 ml min21). e In the absence of Bu4NI. f Determined by 125 MHz
13C NMR. g Determined by 500 MHz 1H NMR.
examples highlighted in Table 1 deserve some comment. In all
cases except for the exceedingly sterically hindered, unreactive
O-4-unprotected glycoside 11 (entry 3), the present glycosida-
tions were found to offer a high-yielding entry to 1,2-cis-linked
glycosides and disaccharides, utilising conditions under which
highly acid-sensitive alcohols such as digitoxigenin 16 and
tigogenin 17 were safely glycosylated (entries 7 and 8). While
glycosidations of the d-gluco- and d-galactopyranosyl donors 1
and 6 displayed high levels of a-selectivity with various
alcohols of different reactivities (entries 1–8 and 13–15), that of
l-fucopyranosyl donor 7 was found to exhibit less satisfactory
selectivity (entries 16 and 17). However, the a-selectivity was
greatly improved by switching the protective group from a
benzyl group to a p-chlorobenzyl group (entries 18 and 19),15
although only a small enhancement was observed with the d-
glucopyranosyl donor (entry 9). According to a general
trend,10,16 protection of the O-6 hydroxy group as a bulky
triphenylmethyl or tert-butyldiphenylsilyl ether gave further
enhanced a-selectivities of up to 96+4 (entries 10 and 11). In
this regard, it is also of interest that the present protocol could
be advantageously extended to glycosidation with 4,6-O-
benzylidene-protected glucopyranosyl donor 5 (entry 12).11
In conclusion, the present method constitutes an exception-
ally mild and general procedure for the highly stereocontrolled
construction of 1,2-cis-a-glycosidic linkages. Thus, we have
now developed a stereoselective entry to either 1,2-cis-a-
glycosides or 1,2-trans-b-glycosides using glycosyl phosphites
as common glycosyl donors by proper choice of the reaction
conditions.
6 H. Schene and H. Waldmann, Eur. J. Org. Chem., 1998, 1227.
7 S. Hashimoto, K. Umeo, A. Sano, N. Watanabe, M. Nakajima and S.
Ikegami, Tetrahedron Lett., 1995, 36, 2251.
8 The pKa values of BF3–alcohol complexes are estimated to be +1.0 to
+7.3: K. S. Minsker, V. A. Babkin and G. E. Zaikov, Int. J. Polym.
Mater., 1995, 28, 77.
9 R. U. Lemieux, K. B. Hendriks, R. V. Stick and K. James, J. Am. Chem.
Soc., 1975, 97, 4056.
10 We previously developed 1,2-cis-a-glycosidation with benzyl-pro-
tected glycopyranosyl phosphorodiamidimidothioates in the presence of
2,6-lutidinium toluene-p-sulfonate and Bu4NI, however, this method
suffered from lengthy preparation of the glycosyl donors: S. Hashimoto,
T. Honda and S. Ikegami, Tetrahedron Lett., 1990, 31, 4769.
11 It has recently been reported by Waldmann’s group that LiI-mediated
glycosidation reactions with glycopyranosyl phosphates in a 1 m
solution of LiClO4 in CH2Cl2 gave 1,2-cis-glycosides via in situ
generated glycopyranosyl iodides in moderate yields and with apprecia-
ble a-selectivity: U. Schmid and H. Waldmann, Liebigs Ann./Recl.,
1997, 2573.
12 T. Uchiyama and O. Hindsgaul, Synlett, 1996, 499; J. Gervay and M. J.
Hadd, J. Org. Chem., 1997, 62, 6961.
13 Y. Okamoto and Y. Shimakawa, J. Org. Chem., 1970, 35, 3752.
14 B. Ernst and T. Winkler, Tetrahedron Lett., 1989, 30, 3081.
15 S. Koto, S. Inada, N. Morishima and S. Zen, Carbohydr. Res., 1980, 87,
294; N. L. Pohl and L. L. Kiessling, Tetrahedron Lett., 1997, 38,
6985.
16 S. Houdier and P. J. A. Vottero, Carbohydr. Res., 1992, 232, 349; G.-J.
Boons, S. Bowers and D. M. Coe, Tetrahedron Lett., 1997, 38, 3773; K.
Fukase, Y. Nakai, T. Kanoh and S. Kusumoto, Synlett, 1998, 84.
Communication 9/02845E
1260
Chem. Commun., 1999, 1259–1260