Angewandte
Chemie
DOI: 10.1002/anie.200604031
Oligosaccharides
Direct and Stereoselective Synthesis of b-Linked 2,6-
Deoxyoligosaccharides**
Hiroshi Tanaka,* Atsushi Yoshizawa, and Takashi Takahashi*
2,6-Di- and 2,3,6-trideoxysaccharides are key components of
many biologically active natural products[1] and are difficult
and challenging synthetic targets.[2] The absence of electron-
withdrawing substituents on the saccharide units readily
promotes the anomerization of b-glycosides to more than
two anomeric isomers under acidic glycosylation conditions.
Furthermore, the non-availability of neighboring-group par-
ticipation from substituents at C2 and the enhanced con-
formational flexibility derived from the reduced number of
substituents make it difficult to achieve glycosidation in a
stereoselective manner.
Indirect methods involving the use of glycosyl donors and
acceptors to which stereodirecting and electron-withdrawing
substituents, such as halides and sulfides, are attached at the
C2 position, have been developed to overcome these prob-
lems.[3] The substituents at C2 promote stereoselective
glycosidation through an anchimetric effect and prevent the
generated glycosidic linkages from anomerization under the
acidic glycosidation conditions.On the other hand, several
methods are available for direct b-selective glycosylations, in
which a-glycosyl halides[4] and glycosyl phosphites[5] are used
as glycosyl donors.However, the synthesis of b-linked 2,6-di-
or 2,3,6-trideoxyoligosaccharides by direct and stereoselec-
tive glycosidation continues to be difficult to accomplish.[6]
Herein, we describe a direct b-selective glycosidation based
on the oxidative activation of glycosyl imidates and report its
application to the synthesis of b-linked 2-deoxyoligosacchar-
ides.
Table 1: b-Selective glycosidation of the 2,6-dideoxyglycosyl imidates 1
by oxidative activation with I2.
Entry
Donor
Product
Additive
Yield [%]
b/a[a]
1
1a
1a
1a
1b
3a
3a
3a
3b
Et3SiH
–
Et3SiH
Et3SiH
94
91
8
>95:5
91:9
>95:5
81:19
2[b]
3[c]
4
85
[a] Ratio estimated from 1H NMR spectral data. [b] The reaction was
conducted at ꢀ608C for 12 h. [c] Glycosidation initiated with 0.1 equiv of
I2 and 0.1 equiv of Et3SiH. Bn=benzyl, Bz=benzoyl, MS=molecular
sieves.
iodide, which served to accelerate the oxidation of the
imidates with I2.A catalytic amount of TMSI (TMS = trime-
thylsilyl) and HI generated from Et3SiH (0.1 equiv) and I2
(0.1 equiv) did not lead to the glycosidation of imidate 1a
(Table 1, entry 3).These results indicate that the oxidative
activation conditions would be effective for the b-selective
glycosidation of 2-deoxyglycosyl imidates without causing any
anomerization of the generated b-glycosides.Protection of
the hydroxy group at C4 with an electron-withdrawing
benzylsulfonate group was effective for improving the
b selectivity.[12]
To demonstrate the feasibility of the method, b-linked
deoxyglycosides composed of various 2,6-dideoxy- and 2,3,6-
trideoxyglycosides were synthesized (Table 2).The glycosy-
lation of the C6 primary alcohol of glucoside 7 as well as the
C4 hydroxyl group of olivoside 8 and amicetoside 9 with 1a
under the established conditions provided the corresponding
b-glycosides 11, 12, and 13 in excellent yields and with
excellent b selectivity (Table 2, entries 1–3).It should be
noted that the a-linked 2,3,6-trideoxyglycoside did not
decompose under the reaction conditions employed.The
glycosylation of 7 and 8 with the dibenzyl-protected donor 1b
resulted in reduced b selectivity (Table 2, entries 2 and 4).We
next examined the glycosidation of digitoxoside 4 and olioside
5 (Table 2, entries 6–8).The glycosylation of 2 with the 3,4-di-
O-benzoyl-protected digitoxosyl imidate 4 provided b-glyco-
side 16 in 90% yield and with excellent selectivity (b/a
> 95:5).Neighboring group participation by the axially
oriented benzoyl group at C3 assisted in the b-selective
glycosidation.[13] However, the axially oriented C4 hydroxy
group on the glycosyl donor makes b-selective glycosidation
Our approach to the direct b-selective glycosidation of 2-
deoxylglycosides was based on the oxidative activation of
glycosyl imidates with I2.[7] As illustrated in Table 1, the
treatment of 1.2 equivalents of the 4-O-benzylsulfonylolivosyl
imidates[8–10] 1a with acceptor 2 in the presence of I2
(1.5 equiv) and triethylsilane (0.1 equiv)[11] at ꢀ948C for
1.5 h provided the b-linked 2-deoxyglycoside 3a in 94% yield
and with excellent b selectivity (b/a > 95:5, Table 1, entry 1).
The triethylsilane was oxidized in situ with I2 to triethylsilyl
[*] Dr. H. Tanaka, A. Yoshizawa, Prof. Dr. T. Takahashi
Department of Applied Chemistry
Graduate School of Science and Engineering
Tokyo Institute of Technology
2-12-1 Ookayama, Meguro, Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2884
E-mail: thiroshi@apc.titech.ac.jp
[**] This work was supported by a Grant-in-Aid for Young Scientists (B)
(no. 18750079) fromthe Ministry of Education, Culture, Sports,
Science, and Technology.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2007, 46, 2505 –2507
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2505