Cyclic di-t-butylsilylenediyl ether group as a convenient protective group for the glycoconjugate synthesis

Article abstract of DOI:10.1016/S0040-4039(01)00044-2

Treatment of methyl β-D-glucopyranoside, methyl α-D-glucopyranoside, 2-azido-2-deoxy-β-D-galactopyranosyl fluoride, and 1,6-anhydro-β-lactose with di-t-butyldichlorosilane gave the corresponding 4,6-cyclic di-t-butylsilylenediyl ether (4,6-CDBS) derivatives in high yields. It was suggested that the 4,6-CDBS group is quite stable under general conditions for further chemical manipulations such as the acetylation, benzylation and glycosylation reactions employed widely in the carbohydrate chemistry. This protective group was readily removed by treatment with tetrabutylammonium fluoride or triethylamine-3HF complex under mild conditions.

Full text of DOI:10.1016/S0040-4039(01)00044-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1953–1956
Cyclic di-t-butylsilylenediyl ether group as a convenient
protective group for the glycoconjugate synthesis
Daijyu Kumagai, Masaki Miyazaki and Shin-Ichiro Nishimura*
Laboratory for Bio-Macromolecular Chemistry, Division of Biological Sciences, Graduate School of Science,
Hokkaido University, Sapporo 060-0810, Japan
Received 21 November 2000; revised 4 January 2001; accepted 5 January 2001
Abstract—Treatment of methyl b-
D
-glucopyranoside, methyl a-
D
-glucopyranoside, 2-azido-2-deoxy-b-D-galactopyranosyl fluoride,
and 1,6-anhydro-b-lactose with di-t-butyldichlorosilane gave the corresponding 4,6-cyclic di-t-butylsilylenediyl ether (4,6-CDBS)
derivatives in high yields. It was suggested that the 4,6-CDBS group is quite stable under general conditions for further chemical
manipulations such as the acetylation, benzylation and glycosylation reactions employed widely in the carbohydrate chemistry.
This protective group was readily removed by treatment with tetrabutylammonium fluoride or triethylamine–3HF complex under
mild conditions. © 2001 Elsevier Science Ltd. All rights reserved.
Regioselective manipulations of hydroxyl groups in car-
bohydrate chemistry are crucial steps to achieve a
highly selective and efficient synthesis of oligosaccha-
rides and glycoconjugates.1 The use of some cyclic
acetals and ketals such as benzylidene, isopropylidene,
p-substituted benzylidene and cyclohexylidene groups
Scheme 1. (i) (t-Bu)2SiCl2, HOBt/Pyr., 95°C; (ii) Ac2O/Pyr.; (iii) BnBr, NaH/DMF.
Keywords: di-t-butyldichlorosilane; 4,6-cyclic di-t-butylsilylenediyl ether derivatives; 4,6-CDBS group; T antigenic glycopeptide.
* Corresponding author. Tel.: +81-11-706-3807; fax: +81-11-706-3435; e-mail: shin@glyco.sci.hokudai.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00044-2

1954
D. Kumagai et al. / Tetrahedron Letters 42 (2001) 1953–1956
at C-4 and C-6 positions have greatly accelerated fur-
ther chemical manipulations of the remaining sec-
ondary hydroxyl groups at C-2 and C-3 positions.2–4
The isopropylidene group has also been used for the
temporary protection of the 1,2-cis-diol groups existing
catalysts commonly employed as promoters for the
glycoside formation reactions have often caused consid-
erable destruction of these protective groups.
In the present study, our interest is focused on the
availability of a cyclic silyl ether protective group,
di-t-butylsilylenediyl group,6 as a convenient and ver-
satile protective group for oligosaccharide synthesis.
Although this protective group has often been utilized
for the syntheses of the anthracyclines7,8 and nucleotide
in
D-galactopyranose, D-mannopyranose and L-fucopy-
ranose derivatives.5 However, it has been well known
that reagents such as trimethylsilyltrifluoromethane sul-
fonate (TMSOTf), borane trifluoride etherate, tri-
fluoromethanesulfonic acid and other strong acid-
Scheme 2. (i) TMSOTf/CH2Cl2, −20°C, 3 h; (ii) Cp2ZrCl2, AgClO4/CH2Cl2, 25°C, 2 h; (iii) N-benzyloxycarbonyl
ester, Cp2ZrCl2, AgClO4/CH2Cl2, 25°C, 2 h.
L-serine benzyl

D. Kumagai et al. / Tetrahedron Letters 42 (2001) 1953–1956
1955
Scheme 3. (i) (n-Bu)4NF/THF, 0°C, 24 h; (ii) AcSH/Pyr., 16 h; (iii) a. Et3N–3HF/THF, 0–25°C, 4 h, b. 0.1N NaOH aq./MeOH,
0°C, 20 min, c. Pd-C/MeOH, H2, 1.5 h.
derivatives,9 there has been no example for this group
being used for oligosaccharide synthesis. Since silyl
ether groups show satisfactory stability under strong
acidic conditions and they can be removed selectively
by treating with fluoride ions under mild conditions,
use of the cyclic dialkylsilylene ether groups10 might
become a potential and versatile procedure for the
diol-protections of sugar residues.
ride 13 were obtained in 52 and 29% yields, respec-
tively.13 On the other hand, the reaction of 2 (2.0
equiv.) with 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-
b- -glucopyranosyl fluoride 14 (1.0 equiv.) under
D
Suzuki’s conditions14 gave 2-O-substituted disaccharide
15 and 3-O-substituted 16 in 50 and 35%, respectively.
This result suggests that the steric hindrance between
the 4,6-CDBS protection of the acceptor 2 and the
2-phthalimido group of the donor 14 seems to interrupt
the glycoside bond formation at C-3 position of com-
pound 2. Moreover, a disaccharide–amino acid inter-
mediate 18 was also synthesized by means of compound
10 as a key starting material. Here, compound 10 was
first employed as an acceptor for the coupling with an
imidate 11. This orthogonal-type glycosidation also
proceeded smoothly and gave disaccharide 17 in 85%
yield. Subsequently compound 17 was allowed to react
First, silylation of methyl b- -galactopyranoside 1 in
D
pyridine was performed at 95°C with 1.5 equiv. of
di-t-butyldichlorosilane in the presence of 0.5 equiv. of
1-hydroxybenzotriazole (HOBt). The reaction pro-
ceeded selectively at 1,3-diol groups of C-4 and C-6
positions and gave a cyclic di-t-butylsilylenediyl ether
(CDBS) derivative 2 in 87% yield. Compound 2 was
subsequently converted into the 2,3-di-O-acetylated
derivative 3 and 2,3-di-O-benzylated derivative 4. Simi-
with N-benzyloxycarbonyl
L-serine benzyl ester to
larly, methyl a-
D
-glucopyranoside 5, 1,6-anhydro-b-lac-
afford the sugar–amino acid derivative 18 in 73% yield.
As demonstrated in these examples, CDBS protection
of carbohydrates seems to be widely applicable for the
preparation of the common glycosyl donors as well as
glycosyl acceptors.
tose and 2-azido-2-deoxy-b-
7
D
-galactopyranosyl
fluoride 911 were employed for the same procedure and
converted to the corresponding CDBS derivatives 6
(70%), 8 (69%) and 10 (76%). In all cases, the formation
of the five-membered CDBS derivatives of 1,2-diols was
not observed by TLC monitoring during the reaction
and all products could be isolated by using general
silica gel chromatography (Scheme 1).
Deprotection of the CDBS derivatives could be accom-
plished satisfactorily with fluoride ions under mild con-
ditions (Scheme 3). Treatment of CDBS derivative 4
with 1.0 equiv. of tetra-n-butylammonium fluoride in
tetrahydrofuran for 24 h at 0°C afforded the depro-
tected diol 19 in 92% yield. Intermediate 18 can also be
converted into compound 21, which is known to be a
key component of the T antigenic glycopeptides.15 After
the transformation of the 2-azido group to the N-acetyl
group, protected derivative 20 was treated with triethy-
lamine–3HF complex (2.0 equiv.) in tetrahydrofuran at
Stability of the CDBS derivatives in the glycosylation
reactions was demonstrated by using compounds 2 and
10 as shown in Scheme 2. When the diol 2 was
employed as an acceptor for the glycosylation reaction
with the known 2,3,4,6-tetra-O-acetyl-a-D-galactopyra-
nosyl imidate 1112 (1.5 equiv.) in the presence of
TMSOTf as a promoter, disaccharide 12 and trisaccha-

1956
D. Kumagai et al. / Tetrahedron Letters 42 (2001) 1953–1956
11. Tsuda, T.; Nishimura, S.-I. Chem. Commun. 1996, 2776–
2777.
12. Schmidt, R. R.; Michel., J.; Rooms, M. Liebigs Ann.
0°C for 4 h, saponified and finally hydrogenolized to
afford the target compound (21) in 94% overall yield.
Chem. 1984, 1343–1357.
In summary, the ease of formation, stability to Lewis
acids and mild conditions for the deprotection of the
CDBS group suggest that this protecting group will be
useful in the selective transformation and assembly of a
variety of functional carbohydrates.
13. When the excess amount of glycosyl acceptor (2.0 equiv.)
was employed for this reaction, only 3-O-substituted
disaccharide 12 was obtained as a major product and
2-O-substituted disaccharide could not be isolated.
14. Matsumoto, T.; Maeda, H.; Suzuki, K.; Tsuchihashi, G.
Tetrahedron Lett. 1988, 29, 3567–3570.
15. Selected spectral data for compound 17: lH (CDCl3) 5.38
(dd, 1H, J 3.3 Hz, H-4%), 5.31 (dd, 1H, J 7.8 and 10.0 Hz,
H-2%), 5.02 (dd, 1H, J 3.3 and 10.4 Hz, H-3%), 5.00 (dd,
1H, J 7.6 and 52.5 Hz, H-1), 4.80 (d, 1H, J 7.8 Hz, H-1%),
4.61 (t, 1H, J 3.0 Hz, H-4), 4.31–4.22 (m, 2H, H-6%a and
H-6%b), 4.15–4.04 (m, 2H, H-6a and H-6b), 3.90 (m, 1H,
H-5), 3.86 (m, 1H, H-2), 3.42 (m, 1H, H-5%), 3.35 (dd, 1H,
J 2.9 and 10.4 Hz, H-3), 2.15–2.00 (all s, 12H, 4×Ac),
1.04 (s, 9H, t-Bu), and 1.01 (s, 9H, t-Bu). Compound 18:
lH (CDCl3) 7.38–7.32 (m, 10H, aromatic protons), 5.75
(d, 1H, J 8.8 Hz, Ser-NH-), 5.38 (d, 1H, J 2.9 Hz, H-4%),
5.30 (dd, 1H, J 7.4 and 10.3 Hz, H-2%), 5.22–5.12 (m, 4H,
2×PhCH2), 5.01 (dd, 1H, J 2.9 and 10.3 Hz, H-3%), 4.79
(d, 1H, J 3.1 Hz, H-1), 4.72 (d, 1H, J 7.3 Hz, H-1%), 4.65
(t, 1H, J<1.0 Hz, H-4), 4.57 (m, 1H, Ser-a), 4.11–4.06 (m,
4H, H-6a, H-6b, H-6%a, and H-6%b), 4.06–3.96 (dd, 1H, J
3.4 and 10.8 Hz, Ser-b), 3.92 (t, 1H, J 6.6 Hz, H-5), 3.77
(dd, 1H, J 1.4 and 10.3 Hz, H-3), 3.63 (dd, 1H, J 3.7 and
10.3 Hz, H-2), 3.54 (br s, 1H, H-5%), 2.14–1.99 (all s, 12H,
4×Ac), 1.04 (s, 9H, t-Bu), and 1.01 (s, 9H, t-Bu). Com-
pound 21: lH (D2O) 4.78 (d, 1H, J 3.8 Hz, H-1), 4.33 (d,
1H, J 7.8 Hz, H-1%), 4.24 (ddd, 1H, J 3.7 and 11.0 Hz,
H-2), 4.10 (br d, 1H, H-4), 3.99–3.88 (dd, 2H, J 3.4 and
10.8 Hz, Ser-b), 3.90 (dd, 1H, J 3.1 and 11.1 Hz, H-3),
3.78 (m, 1H, Ser-a), 3.77 (br d, 1H, H-4%), 3.69–3.61 (m,
2H, H-6a and H-6b), 3.66–3.60 (m, 2H, H-6%a and H-6%b),
3.62 (m, 1H, H-5), 3.52 (t, 1H, J 2.8 Hz, H-5%), 3.48 (dd,
1H, J 3.3 and 10.0 Hz, H-3%), 3.38 (ddd, 1H, J 7.8 and 9.9
Hz, H-2%), and 1.9 (s, 3H, NAc).
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.