Di-tert-butylsilylene (DTBS) group-directed α-selective galactosylation unaffected by C-2 participating functionalities

Article abstract of DOI:10.1016/S0040-4039(03)01647-2

We have discovered an unusual α-galactosylation using phenylthioglycoside of 4,6-O-di-tert-butylsilylene (DTBS)-protected galactose derivatives as a glycosyl donor, which was not hampered by the neighboring participation of C-2 acyl functionality such as NTroc and OBz. The power of the DTBS effect has been exemplified by the coupling reaction with various glycosyl acceptors.

Full text of DOI:10.1016/S0040-4039(03)01647-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6725–6728
Di-tert-butylsilylene (DTBS) group-directed a-selective
galactosylation unaffected by C-2 participating functionalities
Akihiro Imamura,a,c Hiromune Ando,a,* Satomi Korogi,a Genzoh Tanabe,b Osamu Muraoka,b
Hideharu Ishidaa,c and Makoto Kisoa,c,
*
aDepartment of Applied Bioorganic Chemistry, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
bSchool of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashiosaka, Osaka 577-8502, Japan
cCREST, Japan Science and Technology Corporation (JST), 1-1 Yanagido, Gifu 501-1193, Japan
Received 15 May 2003; revised 23 June 2003; accepted 27 June 2003
Abstract—We have discovered an unusual a-galactosylation using phenylthioglycoside of 4,6-O-di-tert-butylsilylene (DTBS)-pro-
tected galactose derivatives as a glycosyl donor, which was not hampered by the neighboring participation of C-2 acyl
functionality such as NTroc and OBz. The power of the DTBS effect has been exemplified by the coupling reaction with various
glycosyl acceptors.
© 2003 Elsevier Ltd. All rights reserved.
In view of the increasing attention in the biological field
being paid to multi-functional carbohydrates,1 which for
example serve as an interface in cell–cell, pathogen–cell
and toxin–receptor recognition and also as modulator in
cell signaling, the procurement of homogeneous targeting
carbohydrates has been a matter of great importance for
investigation at the molecular level. In this context, the
chemical fabrication of fine oligosaccharides incorpo-
rated with peptide, protein or lipid scaffolds has sustained
the molecular biological study.
have reported alternative approaches to a-predominant
glycosylation utilizing a tethering method,3,5 a carb-
oxyphenylthio group as a leaving group,6 remote partici-
pating groups7 and conformational locking of the sugar
acceptor,8 in which, however, the participating function-
alities on C-2 will be ill-suited to the a-anomeric selectiv-
ity. In this paper we report a novel methodology of
a-selective galacto-type glycoside formation, in which C-2
acyl groups on the donor are permissible.9
The key feature of our approach is the 4,6-O-di-tert-
butylsilylene (DTBS) group10 on the galacto-type donors,
which is responsible for a-selective galactosylation com-
patible with the neighboring functionality on the C-2
position, e.g. NTroc and OBz.
The feasibility of oligosaccharide synthesis, in general,
mainly relies on the stereoselectivity in the glycoside
formation where the a- and b-glycoside outcome would
be produced simultaneously. In the situation of gluco- and
galacto-type glycoside formation incorporated within
oligosaccharide synthesis, b (1,2-trans)-selectivity can be
efficiently accomplished by the neighboring effect of
various acyl functionalities mounted on the C-2 hydroxyl
or amino group of the glycosyl donor, by nitrile solvent
effect2 under thermodynamically controlled condition, or
by tethering of the glycosyl donor to the glycosyl
acceptor.3 For a (1,2-cis)-selective glycosylation, on the
contrary, the glycosyl donors with non-neighboring func-
tionality on C-2 have been commonly exploited in order
to maximize the anomeric effect, often with the aid of
ethereal solvent effect.4 Recently, several research groups
The potential of DTBS group as a-galactosylation
enhancer was found by chance during a synthetic
study on b-series gangliosides, in which phenyl 2-deoxy-
4,6-O-di-tert-butylsilylene-3-O-(2,2,2-trichloroethoxy-
carbonyl) - 2 - (2,2,2 - trichloroethoxycarbonylamino) - 1-
thio-b-
-galactopyranoside 1,† used as a surrogate of
D
† This compound was synthesized from phenyl 2-deoxy-1-thio-2-
-galactopyranoside in
(2,2,2-trichloroethoxycarbonylamino)-b-
D
one-pot manner: 4,6-O-DTBS formation with tBu2Si(OTf)2 and
DMAP in pyridine at room temperature, and successive addition of
TrocCl to the reaction mixture gave objective compound in 65 %
yield. Other DTBS-protected glycosyl donors used in this study
were also prepared in a similar manner. For DTBS formation, see:
Corey, E. J.; Hopkins, P. B. Tetrahedron Lett. 1982, 25, 4871.
Keywords: a-galactosylation; neighboring participation; di-tert-
butylsilylene group.
* Corresponding authors. Tel./fax: +81-58-293-2916; e-mail: hando@
cc.gifu-u.ac.jp; kiso@cc.gifu-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01647-2

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A. Imamura et al. / Tetrahedron Letters 44 (2003) 6725–6728
4,6-O-benzylidene type donor 2, exhibited excellent a-
selectivity in the iodonium-promoted coupling
reaction11 in CH2Cl2 at 0°C with trisaccharide acceptor
312 to afford tetrasaccharide 4 despite the presence of
the neighboring Troc group on the C-2 amino function-
ality. On the other hand, the corresponding 4,6-O-benz-
ylidenated donor 2 gave b-glycosyl product 5 exclu-
sively (Scheme 1). The stereochemistry of the new gly-
cosides in compounds 4 and 5 was confirmed to be a
1
and b from H NMR spectra, l 5.09 (d, J1,2=3.4 Hz,
H-1GalN) in 4 and l 5.05 (d, J1,2=8.6 Hz, H-1GalN) in 5,
respectively. This unexpected and unusual result has
prompted us to examine the power of the DTBS effect
on various coupling reactions (Fig. 1).
As shown in Table 1‡, both donors 1 and 2 gave
predominantly a and b glycosyl product in the coupling
reaction with relatively high reactive acceptor 11 in
high yield again, respectively (entries 1 and 2), by which
Figure 1. Donors and acceptors used in this study.
it turned out to be apparent that the aforesaid result of
the incorporation with acceptor 3 is not just a case for
a-selective glycosidation of donor 1. Furthermore,
donor 1 has also enjoyed the coupling reactions with
acceptor 12–1413,14 in a-selective and high-yielding
manner (entries 3–5). Gratifyingly, a-anomeric products
were preferentially afforded by the condensation of
3-O-Ac-GalNTroc (6), 3-O-Ac-GalNPhth (7) and 3-O-
Bn-GalNPhth (8) donor with acceptor 11 in good yields
as well (entries 6–8). In addition, it is of note that even
the C-2 acetamide group was accepted to furnish the
a-product exclusively (entry 9). These results strongly
suggest that the 4,6-O-DTBS group is a dominant
factor in these a-selective galactosylations.
Phenylthioglycoside of a galactose derivative having the
4,6-O-DTBS and benzoyl group on both C-2 and C-3
hydroxyl, 10, has also come up to our anticipation. In
entries 10 and 11, a-selective and high-yielding coupling
reaction of the donor 10 has been accomplished, unaf-
fected by the reactivity of the acceptor hydroxyls.
Scheme 1. First encounter with unusual a-galactosylation.
Reagents and conditions: (a) 1 or 2, NIS-TfOH/CH2Cl2, MS 4
,
A, 0°C.
In summary, we have established a 4,6-O-DTBS-
directed a-galactosylation methodology, in which the
neighboring participation of the NHTroc, NPhth,
NHAc and OBz groups was ineffectual to selectively
produce b-glycoside. Although, very recently, a similar
kind of a-galactosylation methodology using 4,6-O-
benzylidene-protected donor has been first reported by
Kong’s group,15 stereoselectivity in their method
appears to be influenced by the reactivity of acceptor to
some extent. In this regard, our DTBS-directed
approach can be tolerant toward any type of acceptors
as shown above.16 However, the mechanism of the a-
galactosylation is ambiguous at the moment. The X-ray
crystallographic analysis of compound 717 showed that
‡ A typical experimental procedure for a-galactosylation (actual
scale): To a solution of 4,6-O-DTBS-protected donor (192 mmol)
and acceptor (128 mmol) in dry CH2Cl2 (3.2 mL) was added
,
pre-activated 4 A molecular sieves (200 mg) under an Ar atmo-
sphere, then the mixture was stirred for 1 h. After addition of NIS
(384 mmol) and TfOH (38 mmol) at 0°C, the reaction mixture was
continuously stirred at 0°C until the donor was completely con-
sumed on TLC analysis (actual duration time ranges from 30 min to
5 h). The mixture was filtered through Celite®, washed with CHCl3,
and the combined filtrate and washings were washed with satd
Na2CO3 aq., satd Na2S2O3 aq. and brine, dried over Na2SO4 and
concentrated in vacuo. Silica gel (80 mesh; product of Fuji Silysia
Co.) column chromatography of resulting syrup gave glycosyl prod-
ucts.

A. Imamura et al. / Tetrahedron Letters 44 (2003) 6725–6728
6727
Table 1. a-Selective coupling of GalN and Gal donors with various acceptorsa
Entry
Donor
Acceptor
Time
Product
Yield (a:b) (%)b
1
2
3
4
5
6
7
8
1
2
1
1
1
6
7
8
11
11
12
13
14
11
11
11
11
11
15
5 h
30 min
1 h
30 min
30 min
30 min
30 min
30 min
30 min
3 h
16
17
18
19
20
21
22
23
24
25
26
96:3
<7c:93
91:7
90:0
78:0
96:0
90:5d
94:0
50:0
71:0
74:0
9
10
11
9
10
10
30 min
a NIS (2.0 equiv. for donor) and TfOH (0.2 equiv. for donor).
b Isolated yield.
c Including inseparable impurity.
d Ratio was calculated from relative signal intensity in 1H NMR spectra.
the six-membered ring comprised of a 4,6-O-DTBS
acetal moiety and a C4ꢀC5ꢀC6 bond took near half-
chair conformation, which resulted in the tert-butyl
group being positioned closer to the anomeric carbon
(Fig. 2). Although it could be one indirect evidence of
the steric effect of the DTBS group in the a-selective
galactosylation, further study on the transient state of
the oxocarbenium intermediate should be carried out
for precise discussion regarding the reaction mecha-
nism. Now we are also undertaking the synthesis of
biologically relevant carbohydrates including O-glycans
and globo-series oligosaccharides as a practical exten-
sion of this DTBS-directed a-galactosylation.
Acknowledgements
This work was partly supported by the Ministry of
Education, Culture, Sports, Science, and Technology
(MEXT) of Japan (Grant-in-Aid for Scientific Research
to M. Kiso, No. 12306007 and Grant-in-Aid for JSPS
Fellows to H. Ando) and CREST of JST (Japan Sci-
ence and Technology Corporation.). We thank Ms.
Kiyoko Ito for technical assistance.
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6728
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75.20, 76.31, 76.55, 76.84, 76.93, 79.84, 80.14, 95.91,
154.11, 154.35. For compound 18b: H NMR (500 MHz,
1
DMSO-d6) l 0.95 and 1.02 (2s, 18H, 2 t-Bu), 1.22–2.00
(m, 14H, Adamantane unit), 3.62 (s, 1H, H-5GalN), 3.74
(broad t, 1H, H-2Adamantane), 3.94 (q, 1H, J1,2=J2,3
J
=
2,NH=8.0 Hz, H-2GalN), 4.04 (dd, 1H, Jgem=11.2 Hz,
H-6GalN), 4.22 (dd, 1H, Jgem=11.2 Hz, H-6%GalN), 4.61 (d,
1H, J1,2=8.0 Hz, H-1GalN), 4.64 (d, 1H, J3,4=3.4 Hz,
H-4GalN), 4.72 (dd, 1H, J2,3=8.0 Hz, J3,4=3.4 Hz, H-
3GalN), 4.77–5.04 (4d, 4H, 2 Cl3CCH2), 7.80 (d, 1H, NH);
13C NMR (100 MHz, DMSO-d6) l 20.40, 22.77, 26.56,
26.79, 27.19, 27.41, 29.00, 30.68, 30.83, 30.90, 32.97,
35.68, 35.94, 36.96, 50.98, 55.57, 66.68, 68.96, 69.48,
73.38, 73.67, 75.96, 77.65, 79.10, 79.89, 94.90, 96.16,
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1
98.93, 152.93, 154.34. For compound 25: H NMR (500
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18H, 2 t-Bu), 1.24–1.31 (m, 6H, CH3(CH2)3CH2), 1.44–
1.52 (m, 2H, CH2CH2CH2O), 1.98, 2.00 and 2.01 (3s, 9H,
3 Ac), 3.34–3.39 and 3.69–3.73 (2m, 2H, CH2CH2O), 3.58
(d, 1H, Jgem=11.0 Hz, H-6Glc), 3.62 (m, 1H, J4,5=9.1 Hz,
H-5Glc), 3.78 (dd, 1H, Jgem=11.0 Hz, H-6%Glc), 3.98 (s, 1H,
H-5Gal), 4.20 (d, 1H, Jgem=12.1 Hz, H-6Gal), 4.31 (d, 1H,
J
gem=12.1 Hz, H-6%Gal), 4.42 (d, 1H, J1,2=8.0 Hz, H-
1Glc), 4.84 (dd, 1H, J1,2=8.0 Hz, J2,3=9.6 Hz, H-2Glc),
4.87 (d, 1H, J3,4=2.2 Hz, H-4Gal), 5.01 (t, 1H, J3,4=J4,5
=
9.1 Hz, H-4Glc), 5.16 (near t, 1H, J2,3=9.6 Hz, J3,4=9.1
Hz, H-3Glc), 5.32 (d, 1H, J1,2=3.4 Hz, H-1Gal), 5.59 (dd,
1H, J2,3=10.5 Hz, J3,4=2.2 Hz, H-3Gal), 5.75 (dd, 1H,
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J
1,2=3.4 Hz, J2,3=10.5 Hz, H-2Gal), 7.26–8.05 (m, 10H, 2
Ph); 13C NMR (100 MHz, CDCl3) l 14.64, 21.27, 21.41,
23.26, 23.95, 26.21, 27.94, 28.18, 29.28, 30.08, 32.19,
67.21, 67.65, 67.91, 69.27, 69.74, 70.45, 71.68, 71.87,
72.12, 73.64, 73.78, 97.57, 101.29, 129.00, 129.12, 130.01,
130.38, 130.54, 130.68, 133.05, 133.68, 133.84, 166.75,
166.83, 169.78, 170.01, 170.92.
16. NMR data of selected compounds: for compound 18a:
1H NMR (500 MHz, CDCl3) l 1.02 and 1.08 (2s, 18H, 2
t-Bu), 1.53–1.99 (m, 14H, Adamantane unit), 3.80 (broad
t, 1H, H-2Adamantane), 3.83 (s, 1H, H-5GalN), 4.16 (dd, 1H,
17. Crystal data for 7: orthorhombic, space group P212121,
,
a=18.849(5), b=20.083(3), c=8.207(2) A, V=3106(1)
,
3
A , Z=4, v(Mo-Ka)=1.87 cm−1, F(000)=1240, Dc=
1.248 g/cm3, crystal dimensions: 0.32×0.30×0.38 mm. A
total of 4049 reflections (4022 unique) were collected
using the ꢀ–2q scan technique to a maximum 2q value of
55°, and 3197 reflections with I>0|(I) were used in the
structure determination. Final R and Rw values (full-
matrix least-squares refinement on F2) were 0.092 and
0.128, respectively. The data have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication number CCDC 209522.
J
gem=12.5 Hz, H-6GalN), 4.28 (dd, 1H, Jgem=12.5 Hz,
H-6%GalN), 4.57 (ddd, 1H, J1,2=3.4 Hz, J2,3=11.2 Hz,
H-2GalN), 4.70 and 4.78 (2d, 2H, Cl3CCH2), 4.75 (d, 1H,
J
3,4=2.7 Hz, H-4GalN), 4.76 and 4.85 (2 d, 2H, Cl3CCH2),
4.91 (dd, 1H, J2,3=11.2 Hz, J3,4=2.7 Hz, H-3GalN), 5.11
(d, 1H, J1,2=3.4 Hz, H-1GalN), 5.16 (d, 1H, NH); 13C
NMR (100 MHz, CDCl3) l 20.83, 23.47, 27.18, 27.26,
27.31, 27.42, 27.65, 30.83, 31.80, 32.01, 33.65, 36.30,
36.73, 37.38, 49.31, 67.09, 67.56, 70.08, 70.18, 74.63,