Highly β-selective and direct formation of 2-O-glycosylated glucosides by ring restriction into twist-boat

Article abstract of DOI:10.1021/ol070720b

Three disaccharide donors, ethyl 2-O-(2,3,4-tris-O-tert-butyldimethylsilyl- β-D-xylopyranosyl)-3,4,6-tris-O-tert-butyldimethylsilyl-1-thio-β-D- glucopyranoside, ethyl 2-O-(2,3,4-tris-O-tert-butyldimethylsilyl-α-L- rhamnopyranosyl)-3,4,6-tris-O-tert-butyld

Full text of DOI:10.1021/ol070720b

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2755-2758
Highly
â-Selective and Direct Formation
of 2-O-Glycosylated Glucosides by Ring
Restriction into Twist-Boat
Yasunori Okada, Osamu Nagata, Miyoko Taira, and Hidetoshi Yamada*
School of Science and Technology, Kwansei Gakuin UniVersity, 2-1 Gakuen,
Sanda 669-1337, Japan
hidetosh@kwansei.ac.jp
Received March 24, 2007 (Revised Manuscript Received June 12, 2007)
ABSTRACT
Three disaccharide donors, ethyl 2-O-(2,3,4-tris-O-tert-butyldimethylsilyl-
ethyl 2-O-(2,3,4-tris-O-tert-butyldimethylsilyl- -rhamnopyranosyl)-3,4,6-tris-O-tert-butyldimethylsilyl-1-thio-
(2,3,4,6-tetrakis-O-tert-butyldimethylsilyl- -glucopyranosyl)-3,4,6-tris-O-tert-butyldimethylsilyl-1-thio- -glucopyranoside, produced a highly
-selective glycosidation up to
â
-
D
-xylopyranosyl)-3,4,6-tris-O-tert-butyldimethylsilyl-1-thio-
â-D-glucopyranoside,
r-L
â-D-glucopyranoside, and ethyl 2-O-
â
-D
â-D
â
r/â ) 2/98 using MeOTf as the activator and 2,6-lutidine as an additive. The ring conformations of the glucose
part in these disaccharide donors were all restricted to 3S1, and the conformation would lead to the stereoselectivity.
The 2-O-glycosylated â-O-glucosidic structure (Figure 1, A)
is ubiquitously found as a component in natural glycosides
of aliphatic alcohols,1 coumarins,2 flavonoids,3 terpenoids,4
and steroids.5 These glycosides often show biological activi-
ties and sometimes are sweet.6 Previous stereoselective
synthetic approaches to the 2-O-glycosylated â-O-glucosides
have necessitated a linear route [Figure 1, (1)];7 that is, the
â-selective introduction of the first glucosyl moiety to an
alcohol of the aglycon by way of support of the 2-O-acyl
(1) Recently reported glycosides of aliphatic alcohol containing A: (a)
Jassbi, A. R.; Zamanizadehnajari, S.; Kessier, D.; Baldwin, I. T. Z.
Naturforsch., B: Chem. Sci. 2006, 61, 1138-1142. (b) Setzer, W. N.;
Vogler, B.; Schmidt, J. M.; Petty, J. L.; Haver, W. A. Planta Med. 2005,
71, 686-688. (c) MacMillan, J. B.; Linigton, R. G.; Andersen, R. J.;
Molinski, T. F. Angew. Chem., Int. Ed. 2004, 43, 5946-5951. (d) Rencurosi,
A.; Michell, E. P.; Cioci, G.; Perez, S.; Pereda-Maranda, R.; Imberty, A.
Angew. Chem., Int. Ed. 2004, 43, 5918-5922.
(2) Recently reported glycosides of coumarins containing A: (a) Xiao,
W.; Li, S.; Shen, Y.; Li, X.; Sun, H. Heterocycles 2005, 65, 1189-1196.
(b) Mohamed, M. A.; Marzouk, M. S. A.; Moharram, F. A.; El-Sayed, M.
M.; Baiuomy, A. R. Phytochemistry 2005, 66, 2780-2786.
(3) Recently reported glycosides of flavonoids containing A: (a) Prieto,
J. M.; Sicilano, T.; Braca, A. Fitoterapia 2006, 77, 203-207. (b) Saleem,
M.; Kim. H. J.; Han, C. K.; Jin, C.; Lee, Y. S. Phytochemistry 2006, 67,
1390-1394. (c) Xie, W.; Li, P.; Jia, Z. Pharmazie 2005, 60, 233-236. (d)
Toki, K.; Saito, N.; Morita, Y.; Hoshino, A.; Iida, S.; Shigihara, A.; Honda,
T. Heterocycles 2004, 63, 1449-1453.
Figure 1. Conceptual structure of the 2-O-glycosylated â-O-
glucoside (A) and its previous synthetic routes. L ) leaving group.
10.1021/ol070720b CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/28/2007

group, cleavage of the acyl-protecting group of the resulting
monoglucoside, and introduction of the second sugar. On
the other hand, the direct introduction of the 2-O-glycosylated
glucosyl donors can change the synthetic route to a conver-
gent one. However, this method has often provided a mixture
of anomeric isomers [Figure 1, (2)]8 because there is no
positive factor enhancing the â-selectivity such as neighbor-
ing group participation. Therefore, the development of a
method for the highly â-selective and direct introduction of
a 2-O-glycosylated glucosyl moiety would facilitate the
synthesis of the 2-O-glycosylated â-O-glucosides.
We recently reported that the restricted twist-boat con-
formation of a glucosyl donor could provide a highly
â-selective glucosidation without the need for traditional
control methods such as through the participation of neigh-
boring groups, solvent effects, or properties of the leaving
groups that produce SN2-like displacements [Figure 2, (3)].9
by 1, and the 2-O-triisopropylsilyl (TIPS) group hinders the
approach of a glucosyl acceptor from the R-face to afford
the corresponding â-O-glucoside. Such ring restrictions have
also resulted from the introduction of bulky trialkylsilyl
groups into the 3-O and 4-O positions.10 In light of these
combined observations, it occurred to us that the silyl group
on the 2-O position could potentially be replaced by sugars
[Figure 2, (4)]. We herein report that disaccharide donors,
that is, ethyl 2-O-(2,3,4-tris-O-tert-butyldimethylsilyl-â-D-
xylopyranosyl)-3,4,6-tris-O-tert-butyldimethylsilyl-1-thio-â-
D-glucopyranoside (2), ethyl 2-O-(2,3,4-tris-O-tert-butyldi-
methylsilyl-R-L-rhamnopyranosyl)-3,4,6-tris-O-tert-butyldi-
methylsilyl-1-thio-â-D-glucopyranoside (3), and ethyl 2-O-
(2,3,4,6-tetrakis-O-tert-butyldimethylsilyl-â-D-glucopyrano-
syl)-3,4,6-tris-O-tert-butyldimethylsilyl-1-thio-â-D-glucopy-
ranoside (4), displayed a preference for highly â-selective
glycosidation. This is a new method for the highly â-selective
and direct formation of 2-O-glycosylated glucosides that is
based upon conferment of a twist boat conformation in the
sugar acceptor undergoing glycosylation.
The disaccharides 2-4 were stereoselectively synthesized
by the respective glycosylation of a thioglucoside 511 with
trichloroacetimidates 6-8, followed by deprotection and
introduction of TBS groups (Scheme 1). Thus, BF3‚Et2O-
catalyzed xylosylation of 5 with 612 in CH2Cl2 afforded
disaccharide 9 â-selectively. The acetyl groups in 9 were
first removed to provide the hexaol 10, to which the TBS
groups were introduced by heating the mixture of 10,
(5) Recently reported glycosides of steroids containing A: (a) Hayes,
P. Y.; Hasylla Jahidin, A.; Lehmann, R.; Penman, K.; Kitching, W.; De
Voss, J. J. Tetrahedron Lett. 2006, 47, 6965-6969. (b) Ono, M.; Nishimura,
K.; Suzuki, K.; Fukushima, T.; Igoshi, K.; Yoshimitsu, H.; Ikeda, T.; Nohara,
T. Chem. Pharm. Bull. 2006, 54, 230-233. (c) Zhou, X.; He, X.; Wang,
G.; Gao, H.; Zhou, G.; Ye, W.; Yao, X. J. Nat. Prod. 2006, 69, 1158-
1163. (d) Fujiwara, Y.; Takaki, A.; Uehara, Y.; Ikeda, T.; Okawa, M.;
Yamaguchi, K.; Ono, M.; Yoshimitsu, H.; Nohara, T. Tetrahedron 2004,
60, 4915-4920.
(6) Kinghorn, A. D.; Kim, N.-C. DiscoVering new natural sweeteners,
Optimising Sweet Taste in Foods; Woodhead and CRC: Cambridge and
Boca Raton, 2006; pp 292-306.
(7) Stepwise constructions of glycosides containing A: (a) Hou, S.; Zou,
C.; Zhou, L.; Lei, P.; Yu, D. Chem. Lett. 2005, 34, 1220-1221. (b) Sun,
J.; Han, X.; Yu, B. Synlett 2005, 437-440. (c) Brito-Arias, M.; Pereda-
Miranda, R.; Heathcock, C. H. J. Org. Chem. 2004, 69, 4567-4570. (d)
Du, Y.; Wei, G.; Linhardt, R. J. J. Org. Chem. 2004, 69, 2206-2209. (e)
Suhr, R.; Pfefferkorn, P.; Weingarten, S.; Thiem. J. Org. Biomol. Chem.
2003, 1, 4373-4379. (f) Nicolaou, K. C.; Michell, H. J.; Jain, N. F.;
Winssinger, N.; Hughes, R.; Bando, T. Angew. Chem., Int. Ed. 1999, 38,
240-244.
(8) Recently reported direct introduction of di- and greater saccharides:
(a) Kim, Y.-J.; Wang, P.; Navarro-Villalobos, M.; Rohde, B. D.; Derryberry,
J.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 11906-11915. (b) Hou, S.;
Xu, P.; Zhou, L.; Yu, D.; Lei, P. Bioorg. Med. Chem. Lett. 2006, 16, 2454-
2458. (c) Peng, W.; Li, Y.; Zhu, C.; Han, X.; Yu, B. Carbohydr. Res. 2005,
340, 1682-1688. (d) Zou, C.; Hou, S.; Shi, Y.; Lei, P.; Liang, X. Carbohydr.
Res. 2003, 338, 721-727. (e) Cheng, M. S.; Wang, Q. L.; Tian, Q.; Song,
H. Y.; Liu, Y. X.; Li, Q.; Xu, X.; Miao, H. D.; Yao, X. S.; Yang, Z. J.
Org. Chem. 2003, 68, 3658-3662. (f) Ikeda, T.; Miyashita, H.; Kajimoto,
T.; Nohara, T. Tetrahedron Lett. 2001, 42, 2353-2356. (g) Ikeda, T.;
Kajimoto, T.; Kinjo, J.; Nakayama, K.; Nohara, T. Tetrahedron Lett. 1998,
39, 3513-3516.
Figure 2. Reported â-glucosidation based on the restricted twist-
boat conformation (3), the concept of this paper (4), and disaccha-
ride donors that displayed the â-selective direct glycosidations. PG
) protecting group.
The introduction of bulky trialkylsilyl protecting groups
restricts the conformation of the pyranose ring as illustrated
(4) Recently reported glycosides of terpenoids containing A: (a) Dou,
D.; Li, W.; Guo, N.; Fu, R.; Pei, Y.; Koike, K.; Nikaido, T. Chem. Pharm.
Bull. 2006, 54, 751-753. (b) Cheng, G.; Zhang, Y.; Zhang, X.; Tang, H.;
Cao, W.; Gao, D.; Wang, X. Bioorg. Med. Chem. Lett. 2006, 16, 4575-
4580. (c) Min, B.; Oh, S.; Ahn, K.; Kim. J.; Lee. J.; Kim, D.; Kim, E.;
Lee, H. Planta Med. 2004, 70, 1210-1215. (d) Haddad, M.; Miyamoto,
T.; Lacaille-Dubois, M. HelV. Chim. Acta 2004, 87, 1228-1238. (e)
Suksamrarn, S.; Wongkrajang, K.; Kirtikara, K.; Suksamrarn, A. Planta
Med. 2003, 69, 877-879.
(9) Okada, Y.; Mukae, T.; Okajima, K.; Taira, M.; Fujita, M.; Yamada,
H. Org. Lett. 2007, in press.
(10) (a) Yamada, H.; Tanigakiuchi, K.; Nagao, K.; Okajima, K.; Mukae,
T. Tetrahedron Lett. 2004, 45, 5615-5618. (b) Yamada, H.; Nakatani, M.;
Ikeda, T.; Marumoto, Y. Tetrahedron Lett. 1999, 40, 5573-5576.
(11) Liu, M.-Z.; Fan, H.-N.; Guo, Z.-W.; Hui, Y.-Z. J. Carbohydr. Chem.
1996, 15, 1139-1145.
(12) Mori, M.; Ito, Y.; Ogawa, T. Carbohydr. Res. 1990, 195, 199-
204.
2756
Org. Lett., Vol. 9, No. 15, 2007

and Cs2CO3,15 afforded the disaccharide 13 with good
â-selectively in toluene. The acetyl and benzoyl groups in
13 were first removed to give 14, in which three benzyl
groups were cleaved by hydrogenolysis to provide the
corresponding heptaol. Seven TBS groups were then intro-
duced to give 4.
Scheme 1. Preparation of the Disaccharide Donors 2-4
The ring conformation of each of the glucose components
in 2-4 was in the 3S1 conformation; the xylose in 2 flipped
1
1
to C4, and the rhamnose part in 3 stayed in the C4 form
that is the general conformation of the sugar. The observed
ring-proton vicinal coupling constants in the 1H NMR spectra
were linked to ring torsion angles.16 The molecular models
assembled on the basis of these dihedral angles displayed
the aforementioned conformations.17 Significant long-range
4J couplings were detected in all these compounds and
supported the proposed ring conformations.10,18
The glycosidation reactions of 2, 3, and 4 with cholesterol
proceeded in a highly â-selective manner to give 15, 16,
and 17, respectively (Table 1). These disaccharide donors
Table 1. Glycosidations of the Disaccharide Donors 2-4 with
Cholesterol
TBSOTf, and 2,6-lutidine at 130 °C to give 2. The introduc-
tion of six TIPS groups to 10 was not complete, even using
TIPSOTf. The rhamnosylation of 5 with 713 (R/â ) 77/23)
provided R-rhamnoside 11. The acetyl and benzyl groups in
11 were successively removed by methanolysis and hydro-
genolysis. Despite the presence of an ethylthio group in the
molecule, the hydrogenolysis successfully proceeded. Finally,
six TBS groups were introduced to afford 3. The glucosy-
lation of 5 with a glucosyl trichloroacetimidate 8, which was
prepared from 1214 by treatment with trichloroacetonitrile
were activated by MeOTf (4 equiv) in CH2Cl2 in the presence
of molecular sieves (4 Å) and 2,6-lutidine (2 equiv). The
R/â ratio was determined on the basis of the integral ratio
of the anomeric protons in the 1H NMR spectra. The reaction
conditions were similar to our previous report using 1 except
for the use of 2,6-lutidine. In this case, migration of the TIPS
(13) Rathore, H.; From, A. H. L.; Ahmed, K.; Fullerton, D. S. J. Med.
Chem. 1986, 29, 1945-1952.
(14) Mach, M.; Schlueter, U.; Mathew, F.; Fraser-Reid, B.; Hazen, K.
C. Tetrahedron 2002, 58, 7345-7354.
(15) Egusa, K.; Kusumoto. S.; Fukase, K. Eur. J. Org. Chem. 2003,
3435-3445.
(16) Haasnoot, C. A. G.; de Leeuw, F. A. A. M.; Altona, C. Tetrahedron
1980, 36, 2783-2792.
Org. Lett., Vol. 9, No. 15, 2007
2757

group was not observed unless 2,6-lutidine was used.
However, during the glycosidation of the TBS-protected 2
with cholesterol, migration of a TBS group occurred without
2,6-lutidine to provide the TBS-protected cholesterol as the
major product. An O-TBS bond is generally more sensitive
under acidic conditions than an O-TIPS bond.19 Additionally,
the relatively strong steric repulsion due to the adjacent TBS
groups facilitated the cleavage of one of the O-TBS bonds
with trifluoromethanesulfonic acid, which was generated
during the reaction. The cleavage provided TBSOTf which
would react with cholesterol. The addition of 2,6-lutidine
was therefore fundamental in these cases as an acid
scavenger.
coupling constants due to the adjacent hydrogens on the
pyranose ring were around 10 Hz. Compounds 16 and 17
were similarly treated as above to give 19 and 20, respec-
tively, structures of which were confirmed as well as 18.
The direct â-glycosidation of the disaccharides was useful
for glycosylation of steroidal and carbocyclic alcohol agly-
cons, but was difficult to achieve with carbohydrate accep-
tors. The reaction of 2 with a tertiary alcohol, 1-adamantanol,
provided the corresponding glycoside â-selectively (R/â )
2/98) in 65% yield. On the other hand, with methyl 2,3,6-
tri-O-benzyl-R-D-glucopyranoside and methyl 2,4,6-tri-O-
benzyl-R-D-glucopyranoside, only a trace of the correspond-
ing trisaccharide was detected in each case.
The structures of the cholesteryl disaccharides 15-17 were
clarified by further transformations (Figure 3), namely the
In conclusion, we have introduced 2-O-glycosyl-D-glucosyl
units â-selectively. The stereoselectivity was controlled by
the restricted twist-boat conformation of the glucose part in
the disaccharide donors. Despite the use of cholesterol or
1-adamantanol as the aglycon in this study, multistep
preparations of the aglycon parts have often occurred in the
syntheses of glycosides. For the aglycons, straightforward
constructions with repeated monoglycosidation tend to be
adopted in the completion steps for the target glycosides.
The results disclosed here demonstrate that the convergent
synthesis of the 2-O-glycosylated â-O-glucosides became
possible.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (16510170) from JSPS
and a Grant-in-Aid for Scientific Research on Priority Areas
(17035086) from MEXT.
Supporting Information Available: Experimental pro-
cedures and product characterization for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 3. Clarifications of the anomeric stereochemistry. R )
cholesteryl.
OL070720B
removal of the TBS groups to return the conformation of
the sugars back to their generally stable forms and by
acetylation of the resulting hydroxy groups. Thus, the 3/97
anomeric mixture of 15 was treated with TBAF to remove
all of the TBS groups, and then the resulting six hydroxy
groups were acetylated to give an anomeric mixture (R/â )
1/99) of the corresponding hexaacetate 18 in 87% yield. In
the 1H NMR of â-18, the coupling constant between the H-1
and H-2 of the glucose part was 7.6 Hz, and the other
(17) Spartan (‘04 Windows) constructed the molecular models of 2-4.
Each model was optimized by a simple MMFF calculation after constraint
of the dihedral angles (H-1-C-1-C-2-H-2, H-2-C-2-C-3-H-3, H-3-
C-3-C-4-H-4, and H-4-C-4-C-5-H-5) to the calculated dihedral angles
based on the observed coupling constants (3JH-H) in each 1H NMR spectrum.
(18) (a) Yamada, H.; Tanigakiuchi, K.; Nagao, K.; Okajima, K.; Mukae,
T. Tetrahedron Lett. 2004, 45, 9207-9209. (b) Yamada, H.; Okajima, K.;
Imagawa, H.; Nagata, Y.; Nishizawa, M. Tetrahedron Lett. 2004, 45, 4349-
4351. (c) Okajima, K.; Mukae, T.; Imagawa, H.; Kawamura, Y.; Nishizawa,
M.; Yamada, H. Tetrahedron 2005, 61, 3497-3506.
(19) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
2758
Org. Lett., Vol. 9, No. 15, 2007