Glycosyl trifluoroacetimidates. Part 1: Preparation and application as new glycosyl donors

Article abstract of DOI:10.1016/S0040-4039(01)00157-5

Glycosyl (N-phenyl)trifluoroacetimidates, readily prepared from 1-hydroxyl sugars by treatment with (N-phenyl)trifluoroacetimidoyl chloride in the presence of K₂CO₃, were demonstrated to be effective glycosyl donors.

Full text of DOI:10.1016/S0040-4039(01)00157-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2405–2407
Glycosyl trifluoroacetimidates. Part 1: Preparation and
application as new glycosyl donors
Biao Yu* and Houchao Tao
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
Received 6 December 2000; revised 16 January 2001; accepted 25 January 2001
Abstract—Glycosyl (N-phenyl)trifluoroacetimidates, readily prepared from 1-hydroxyl sugars by treatment with (N-
phenyl)trifluoroacetimidoyl chloride in the presence of K2CO3, were demonstrated to be effective glycosyl donors. © 2001 Elsevier
Science Ltd. All rights reserved.
Stimulated by the recognition of the significance of
oligosaccharides in many biological and pharmaceutical
processes, intensive efforts have been given to the devel-
opment of glycosylation methods over the last two
decades.1,2 Among the many methods now available,
the leaving groups of the glycosyl donors, have been
recognised as one of the most important parameters
responsible for the viability of glycosylation reactions;
indeed glycosylation reactions are now inevitably cate-
gorised by the leaving groups of the glycosyl donors.1,2
Glycosyl trichloroacetimidates, introduced by Schmidt
and co-workers in 1980,3 are one of the most widely
used glycosyl donors.2 The initial use of glycosyl imi-
dates as donors was reported by Sinay¨ in 1976.4 How-
ever, due to the enormous structural diversity of
glycosidic linkages, no single glycosylation method is
generally applicable including glycosylation with
trichloroacetimidate donors. For example, a disaccha-
ride trichloroacetimidate failed to be attached to the
hydroxyl group of a disaccharide macrolactone in the
synthesis of Tricolorin A,5 while an ethyl thioglycoside
counterpart succeeded.6 There are still difficulties in
constructing many glycosidic linkages, therefore, the
introduction of new and effective glycosylation meth-
ods is still necessary. Based on Schmidt’s successful
glycosyl trichloroacetimidate donors, we prepared gly-
cosyl trifluoroacetimidates and tried their application as
glycosyl donors. Some preliminary results are reported
herewith.
N-Substituted trifluoroacetimidoyl halides are readily
accessible from the reaction of trifluoroacetic acid with
primary amines in a PPh3–Et3N–CCl4 system.7 The
halogen attached to the imidoyl carbon can easily be
replaced by various nucleophiles, such as carbanions,
amines, and alcohols.8 Acetyl, benzoyl, and benzyl pro-
Scheme 1.
Keywords: glycosyl trifluoroacetimidate; glycosylation; glycosyl donor.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00157-5

2406
B. Yu, H. Tao / Tetrahedron Letters 42 (2001) 2405–2407
Scheme 2.
Table 1. Glycosylation with glycosyl trifluoroacetimidates 2a–c as donors
Entry
Acceptor
Donor
Product
Yield (%)a
a:bb
1
2
3
4
5
6
7
8
3a
2a
2b
2c
2a
2b
2c
2b
2c
2a
2b
2c
4a
4b
4c
4d
4e
4f
4g
4h
4i
95
94
90
86
94
96
98
95
99
99
94
a only
b only
a mainly
a only
b only
1.3: 1
b only
1: 1
a only
b only
1.5: 1
3b
3c
3d
9
10
11
4j
4k
a Isolated yields.
b Determined by 1H NMR analysis.
tected glycosyl trifluoroacetimidates (2a–c)9 were there-
fore readily synthesised in excellent yields (>90%) by
treatment of the corresponding 1-hydroxyl sugars (1a–
c) with N-phenyl trifluoroacetimidoyl chloride in the
presence of K2CO3 (2.0 equiv.) in CH2Cl2 at room
temperature for 3 h (Scheme 1). The a anomers were
produced predominantly due to the anomeric effect of
the corresponding 1-O-potassium sugars. It is notewor-
thy that these glycosyl trifluoroacetimidates (2a–c) were
stable to storage at 4°C for weeks.
ride saponin, dioscin10 (Scheme 3). Glycosylation of
diosgenin with 2,3,4,6-tetra-O-benzoyl- -glucopyra-
D
nosyl trifluoroacetimidate 2b under the promotion of a
catalytic amount of TMSOTf (0.05 equiv.) gave the
corresponding glycoside 5 in 92% yield. Removal of the
benzoyl groups followed by selective protection of the
6-OH and 3-OH with pivaloyl groups provided diol 6 in
60% yield. Glycosylation of diol 6 with 2,3,4-tri-O-ace-
tyl- -rhamnopyranosyl trifluoroacetimidate 2a under
L
similar glycosylation conditions afforded the trisaccha-
ride 7 in 64% yield, equal to a per glycosylation yield of
80%. Removal of the acyl protecting groups using
aqueous NaOH completed the synthesis of the target
saponin, dioscin.
The glycosyl trifluoroacetimidates (2a–c) were demon-
strated to be effective donors in the presence of
,
TMSOTf (0.05 equiv.) and 4 A MS in CH2Cl2 (rt, 3 h)
(Scheme 2), the typical reaction conditions for glycosy-
lation with trichloroacetimidate donors.2 As shown in
Table 1, all the glycosylation reactions, including the
tertiary alcohol, 1-adamantanol 3d, gave the corre-
sponding coupling products (4a–k) in very high yields.
Not surprisingly, donors with neighbouring participat-
ing groups (2a,b) gave only the corresponding 1,2-trans
products, whilst donors without a neighbouring group
2c gave mixtures of the a and b anomers.
In summary, glycosyl trifluoroacetimidates are readily
prepared and were used as glycosyl donors. Their acces-
sibility, stability, and activity were shown to be com-
parable with those of the corresponding glycosyl
trichloroacetimidate donors. Nevertheless, the easy
installation of various N-substituted groups might
provide an additional element for tuning the reactivities
of the glycosyl trifluoroacetimidate donors. This is our
purpose for developing glycosyl trifluoroacetimidate
donors, and these attempts will be published in due
course.
The present glycosyl trifluoroacetimidate donors were
also successfully applied to a synthesis of a trisaccha-

B. Yu, H. Tao / Tetrahedron Letters 42 (2001) 2405–2407
2407
,
Scheme 3. Reagents and conditions: (a) TMSOTf (0.05 equiv.), 4 A MS, CH2Cl2, rt, 3 h, 92%; (b) NaOMe, HOMe, rt; (c) PivCl,
pyridine, 0°C, 60%; (d) conditions similar to (a), 64%; (e) NaOH, MeOH/H2O/THF (1:1:1), 90%.
Acknowledgements
9. Analytical data for 2a–c. 2a (a): [h]2D5=−39.5 (c 0.87,
CHCl3); 1H NMR (CDCl3, 300 MHz): 7.31 (t, 2H, J=7.6
Hz), 7.12 (t, 1H, J=7.4 Hz), 6.83 (d, 2H, J=7.7 Hz),
6.16 (br., 1H, H-1), 5.47 (br, 1H, H-2), 5.36 (dd, 1H,
J=10.2, 3.5 Hz, H-3), 5.17 (t, 1H, J=10.0 Hz, H-4), 4.03
(m, 1H, H-5), 2.17, 2.09, 2.02 (s each, 3H each, Ac), 1.28
(d, 3H, J=6.2 Hz, H-6). EIMS (m/z, %): 273 (100), 213
(26), 189 (3.5), 171 (18), 153 (90), 111 (32). Anal. calcd
for C20H22F3NO8: C, 52.06; H, 4.81; N, 3.04. Found: C,
52.33; H, 5.04; N, 3.18. 2b (a): [h]2D5=60.3 (c 0.98,
CHCl3); 1H NMR (CDCl3, 300 MHz): 8.10–7.00 (m,
25H), 6.82 (br, 1H, H-1), 6.25 (t, 1H, J=9.9 Hz), 5.82 (t,
1H, J=9.9 Hz), 5.62 (dd, 1H, J=9.9, 3.4 Hz), 4.67 (m,
2H), 4.52 (dd, 1H, J=12.0, 4.5 Hz). EIMS (m/z, %): 579
(30), 457 (1), 335 (3), 231 (13), 105 (100). Anal. calcd for
C42H32F3NO10: C, 65.71; H, 4.20; N, 1.82. Found: C,
65.40; H, 4.25; N, 1.83. 2c (a): [h]2D5=58.5 (c 0.87,
CHCl3); 1H NMR (CDCl3, 300 MHz): 7.19–7.04 (m,
23H), 6.74 (d, 2H, J=7.7 Hz), 6.54 (br., 1H, H-1),
5.00–4.43 (m, 8H), 4.05 (t, 1H, J=9.4 Hz), 3.99 (m, 1H),
3.82–3.69 (m, 4H). Anal. calcd for C42H40F3NO6: C,
70.87; H, 5.67; N, 1.97. Found: C, 70.96; H, 5.69; N,
1.86.
We thank the Ministry of Science and Technology of
China and the National Natural Science Foundation of
China (29925203) for financial support.
References
1. (a) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000,
2137; (b) Boons, G.-J. Contemp. Org. Syn. 1996, 173; (c)
Toshima, K.; Tatsuta, K. Chem. Rev. 1993, 93, 1503.
2. (a) Schmidt, R. R.; Kinzy, W. Adv. Carbohydr. Chem.
Biochem. 1994, 50, 21; (b) Schmidt, R. R. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 212.
3. Schmidt, R. R.; Michel, J. Angew. Chem., Int. Ed. Engl.
1980, 19, 731.
4. (a) Pougny, J.-R.; Sinay¨, P. Tetrahedron Lett. 1976, 4073;
(b) Pougny, J.-R.; Jacquinet, J.-C.; Nassr, M.; Duchet,
D.; Milat, M.-L.; Sinay¨, P. J. Am. Chem. Soc. 1977, 99,
6762.
5. Larson, D. P.; Heathcock, C. H. J. Org. Chem. 1997, 62,
8406.
10. Dioscin has been isolated from many plant species and
has been synthesized recently, see: (a) Deng, S.; Yu, B.;
Hui, Y.; Yu, H.; Han, X. Carbohydr. Res. 1999, 317, 53;
(b) Deng, S.; Yu, B.; Hui, Y. Tetrahedron Lett. 1998, 39,
6511.
6. Lu, S.-F.; O’yang, Q.; Guo, Z.-W.; Yu, B.; Hui, Y.-Z. J.
Org. Chem. 1997, 62, 8400.
7. Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32.
8. Uneyama, K. J. Fluorine Chem. 1999, 97, 11.
.
.