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
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Chem. Commun., 1999, 1259–1260