Facile TMSOTf-catalyzed preparation of 2-deoxy α-O-aryl-D-glycosides from glycosyl acetates

Article abstract of DOI:10.1007/s10719-012-9429-7

2-Deoxy a-O-aryl glycosides were conveniently obtained by reaction of 2-deoxy-glycosyl acetates with phenols in the presence of TMSOTf as the promoter. The current method provides the O-aryl glycosides with good to excellent yields, and sole alpha selecti

Full text of DOI:10.1007/s10719-012-9429-7

Glycoconj J (2012) 29:453–456
DOI 10.1007/s10719-012-9429-7
Facile TMSOTf-catalyzed preparation of 2-deoxy
α-O-aryl-D-glycosides from glycosyl acetates
Guofang Yang & Qingbing Wang & Xiaosheng Luo &
Jianbo Zhang & Jie Tang
Received: 13 April 2012 /Revised: 9 June 2012 /Accepted: 5 July 2012 /Published online: 5 August 2012
#
Springer Science+Business Media, LLC 2012
Abstract 2-Deoxy α-O-aryl glycosides were conveniently
obtained by reaction of 2-deoxy-glycosyl acetates with phe-
nols in the presence of TMSOTf as the promoter. The
current method provides the O-aryl glycosides with good
to excellent yields, and sole alpha selectivity.
synthesis of these natural products owing to the absence of
stereoelectronic influences of substitutions at C-2 carbon [12].
To circumvent these problems for 2-deoxy glycoside synthesis,
glycosyl donors with 2-substituents such as halides [13–15]
and aryl selenyl and sulfenyl derivatives [16–18] of 1, 2-
anhydropyranoses [19] acting as a neighboring group are wide-
ly applied in this kind of glycosylation, followed by reductive
removal of the 2-substituents (Scheme 1). The drawback of this
approach is that the introduction and removal of the participat-
ing functionality often requires toxic reagents; moreover, extra
steps often lead to time-consuming synthetic procedures.
Several methods are available for direct β-selective gly-
cosylation in which α-glycosyl halides, glycosyl phosphites,
glycosyl acetates, and trichloroacetimidates are employed as
glycosyl donors in combination with a mild promoter
[20–25]. In contrast, only a few procedures for preparation
of α-glycosides have been reported in moderate yields by
acid-catalyzed activation of glycals, silyl ethers [26–31]. For
example, Flack et al. have successfully employed triphenyl-
phosphinehydrogenbromide (TPHB) to promote direct ad-
dition of various alcohols and carboxylic acids to glycals
[32]. The approach directly introduces hydrogen at C-2, and
α-glycosides often predominate due to the kinetic anomeric
effect [33].
.
.
Keywords Stereoselective 2-deoxy sugars Aryl
.
.
glycoside Glycosyl acetates TMSOTf
Aromatic deoxygenated glycosides are common structural uni-
tes in many natural products possessing important biological
properties, which include antibiotics such as Landomycin,
antitumor agents such as Chromomycin and Olivomycin and
so on [1–3]. However, the efficient construction of O-aryl
glycosides can be difficult to achieve due to the electron-
withdrawing properties of aromatic rings [4] and the facile
rearrangement of the resulting O-aryl glycosides to their
corresponding C-aryl glycosides [5–9]. Additionally, stereo-
selective synthesis of 2-deoxy-glycosidic linkage [10,11] has
been found to be one of the most challenging tasks in the
Clearly, the application of direct methods for the
efficient and stereoselective construction of 2-deoxy O-
aryl glycosides is highly desirable [34–37]. In order to
develop more convenient synthetic route, we therefore
set out to use the 2-deoxy glycosyl acetates as a con-
venient glycosyl donor. In this note, we report the direct
glycosylation of phenols with 2-deoxy glycosyl acetates
[22] with exclusive α-selectivity.
Electronic supplementary material The online version of this article
(doi:10.1007/s10719-012-9429-7) contains supplementary material,
which is available to authorized users.
:
:
:
:
G. Yang Q. Wang X. Luo J. Zhang (*) J. Tang
Department of Chemistry, East China Normal University,
Shanghai 200062, China
e-mail: jbzhang@chem.ecnu.edu.cn
Q. Wang
State Key Laboratory of Bioorganic and Natural Products
Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Science,
354 Fenglin Road,
We initially employed Lewis acid in the presence of 1.0
equiv 2-deoxy-tetra-O-acetyl- α-D-glucopyranoside 1 and 1.0
equiv phenol 2a in CH2Cl2. As we anticipated, treatment of 2-
.
Shanghai 200032, China
deoxy glucosyl acetate with BF3 Et2O in dichloromethane

454
Glycoconj J (2012) 29:453–456
Scheme 1 Known synthetic
strategies towards 2-deoxy
O-glycosides
within 3.2 h afforded phenyl 2-deoxy-α-D-glucopyranoside
3a with 40 % yield, while no β-anomer was detected (Table 1,
entry 1). The conversion to the α-phenolic glycoside was
evidenced by 1H NMR data showing a dramatic upfield shift
of the anomeric proton (δ 5.68 ppm) when compared with the
anomeric acetate (δ 6.26 ppm), and the chemical shifts are
identical to the data reported [32].
With amount of boron trifluoride diethyl etherate ranged
from 0.3 to 2.0 equivalents, the yields were still low and the
reactions were incomplete (entries 1–3). Similarly, changing
the catalyst to tin tetrachloride, the reaction was incomplete
even after 3.0 h (entries 4–5), and the formation of by-
products was increased when 1.0 equiv of the promoter
was used (entry 6). We found that 0.1 or 0.2 equiv
TMSOTf (entries 7 and 8) was better to promote the glyco-
sylation of 2-deoxy glucosyl acetates 1 with phenol. With
0.3 equiv TMSOTf, the reaction proceeded well and the
product was obtained in acceptable yield (entry 9).
However, the yield of the glucoside 3a could be dropped
to 61 % when 0.4 equiv of TMSOTf was used (entry 10);
however, the use of H2SO4-SiO2 reagent [38–40] (entry 11
and 12), which is a solid acid catalyst as a novel promoter
for glycosylation, made the reactions sluggish.
During the transformation performed by 1.0 equiv of the
phenol and 0.3 equiv of the TMSOTf, trace amount of the
unreacted 2-deoxy glycosyl acetates was observed. In order
to improve the yield, then we investigated the other factors
on the reaction (Table 2). Apparently, the best result was
achieved when the reaction was processed with 1.5 equiv
phenol (entry 3). Treatment of both 2-deoxy glucose acetate
donor 1 and phenol 2a (1.5 equiv) with 0.3 equiv TMSOTf
at −15 °C, provided the desired O-aryl glycoside 3a.
However, it took 3 h for the reaction to go to completion.
Raising the temperature shortened the reaction time (Table 2,
entry7), however, the yield decreased to 80 % at 20 °C.
Additionally, we also found that the addition of 4 Å molecular
sieves powder was helpful to the progress of the reaction and
reduce the decomposition of our donor (entry 5–7).
With TMSOTf (0.3 equiv) as promoter and CH2Cl2 as
solvent at 0 °C, we then examined the generality of this α-
selective glycosylation of 2-deoxyglucosyl acetates 1 with a
Table 1 Optimization of promoters in the glycosylation
Promoter
BF3.Et2O
Time(h)
Entry
Equivalent
Yield(%)a
Table 2 Optimization of the direct glycosylation
3.2
3.0
1.0
3.0
3.0
1.0
3.0
1.8
1.2
1.0
4.0
3.0
1
0.3
0.5
2.0
0.2
0.3
1.0
0.1
0.2
0.3
0.4
0.3
1.0
40
43
2
3
35
SnCl4
4
38
Phenol (equiv)
Time (h)
Yield(%)a
5
40
Entry
Temp,
(°C)
Additive
6
10
TMSOTf
7
51
1.0
1.2
1.5
2.0
1.5
1.5
1.5
1.2
1.2
1.2
1.2
1.2
3.0
1.0
66
71
80
78
89
56
80
1
2
3
4
5
6
7
0
0
0
0
0
−15
20
none
none
none
none
4Å MS
4Å MS
4Å MS
8
60
9
66
10
11
12
61
NRb
H2SO4-SiO2
NR
a Isolated yield
b No product was detected
a Isolated yield

Glycoconj J (2012) 29:453–456
455
Fig. 1 Phenols in the coupling
reaction
Table 3 Substrate scope for TMSOTf-catalyzed glycosylationa
glycosides were not observed in the reaction. Compared to
glycosylation of 2-deoxyglucosyl acetate 1, the glycosylation of
2-deoxygalactosyl acetate 4 with acceptors (2a-h) proceeded
smoothly, providing the expected corresponding α-O-aryl gal-
actosides 5a-h in good yields under the catalysis of TMSOTf
(0.3 equiv) in CH2Cl2 at 0 °C. Notably, the efficiency of this
methodology is demonstrated by the coupling of 2-deoxy ga-
lactose acetate donor with the relatively hindered 2-
methylphenol (2f) to form α-O-aryl galactoside 5f in 81 % yield
(entry 14), though the reaction is a little slower compared to the
corresponding glucosides counterpart (compared to entry 10)2.
Entry
R1
R2
R
Product
Yield(%)b
1
H
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
H
H
3a
3b
3c
3d
3e
3f
89
85
88
85
90
82
79
95
81
75
85
84
72
81
80
88
2
H
p-CH3
p-OCH3
tyrosinec
p-NO2
o-CH3
3,5-di-F
phenyld
H
3
H
4
H
5
H
6
H
7
H
3g
3h
5a
5b
5c
5d
5e
5f
1
2 Selected spectral data for new compounds: Compound 3d: H NMR
8
H
(500 MHz, CDCl3) δ 1.98 (1 H, dd, J03.2, 12.2 Hz), 2.02 (3 H, s), 2.04
(3 H, s), 2.05 (3 H, s), 2.45 (1 H, td, J05.2, 13.0 Hz), 3.06 (2 H, dd, J05.5,
13.0 Hz), 3.73 (3 H, s), 3.96 (1 H, d, J012.5 Hz), 4.03 (1 H, d, J08.6 Hz),
4.20 (1 H, t, J06.5 Hz), 4.29 (1 H, dd, J04.0, 12.2 Hz), 4.36 (1 H, dd, J0
6.8, 10.5 Hz), 4.46 (1 H, dd, J07.2, 10.5 Hz), 4.63 (1 H, d, J07.5 Hz), 5.09
(1 H, t, J09.9 Hz), 5.25 (1 H, d, J08.0 Hz), 5.51 (1 H, ddd, J03.9, 5.5,
11.1 Hz), 5.62 (1 H, br s), 6.99 (4 H, s), 7.30–7.38 (8 H, m). 13C NMR
(125 MHz, CDCl3) δ 14.1, 20.6, 20.7, 20.9, 22.6, 29.3, 29.6, 31.9, 35.0,
37.3, 47.1, 52.3, 54.8, 61.9, 66.8, 68.5, 68.8, 69.0, 95.3, 116.4, 120.0,
124.9, 125.0, 127.0, 127.7, 129.6, 130.3, 141.3, 143.6, 143.7, 155.3, 155.5,
169.8, 170.2, 170.6, 171.8. ESI-HRMS: Calcd for C37H39NO12Na (M+Na)
712.2370,, found 712.2365. Compound 5d: 1H NMR (500 MHz, CDCl3)
δ 1.91 (3 H, s), 2.03 (3 H, s), 2.07 (1 H, dd, J04.6, 12.8 Hz), 2.16 (3 H, s),
2.23 (1 H, td, J03.2, 12.4 Hz), 3.06 (2 H, dd, J06.0, 14.0 Hz), 3.74 (3 H, s),
4.04 (2 H, d, J06.4 Hz), 4.18 (2 H, d, J06.4 Hz), 4.35 (1 H, dd, J07.5,
10.5 Hz), 4.45 (1 H, dd, J07.5, 10.5 Hz), 4.64 (1 H, d, J07.5 Hz), 5.22
(1 H, d, J08.2 Hz), 5.37 (1 H, s), 5.47 (1 H, ddd, J03.7, 4.4, 8.0 Hz), 5.67
(1 H, br s), 6.98 (4 H, s), 7.30–7.38 (8 H, m). 13C (125 MHz, CDCl3) δ
14.1, 20.5, 20.7, 20.8, 29.6, 30.2, 37.3, 47.1, 52.3, 54.8, 61.9, 65.9, 66.3,
66.8, 67.4, 95.9, 166.5, 120.0, 124.9, 125.0, 127.0, 127.7, 129.5, 130.3,
141.3, 143.7, 143.8, 155.5, 170.1, 170.2, 170.3, 171.8. ESI-HRMS: Calcd
for C37H39NO12Na (M+Na) 712.2370,, found 712.2365. Compound 3g:
1H NMR (500 MHz, CDCl3) δ 1.98–2.14 (10 H, m), 2.47 (1 H, dd, J05.0,
13.0 Hz), 4.01 (2 H, t, J06.0 Hz), 4.31 (1 H, dd, J06.0, 13.0 Hz), 5.08 (1 H,
t, J010.0 Hz), 5.44–5.48 (1 H, m), 5.62 (1 H, d, J03.0 Hz), 6.49–6.68(3 H,
m). 13C NMR (125 MHz, CDCl3) δ 20.5, 20.6, 20.8, 34.6, 61.9, 68.4, 68.8,
68.9, 95.6, 97.8, 98.0, 98.2, 100.1, 100.2, 100.3, 100.4, 157.7, 162.3,
162.4, 164.3, 164.4, 169.7, 170.1, 170.4. ESI-MS: Calcd for
C18H20F2O8Na (M+Na) 425.10, found 425.01. Anal. Calcd for
C18H20F2O8: C, 53.73; H, 5.01. Found: C, 53.93; H, 5.11. Compound
5g: 1H NMR (500 MHz, CDCl3) δ 1.95 (3 H, s), 2.03 (3 H, s), 2.11 (1 H,
dd, J05.0, 10.0 Hz), 2.15 (3 H, s), 2.24 (1 H, dd, J05.0, 10.0 Hz), 4.04–
4.12 (2 H, m), 4.19 (1 H, t, J05.0 Hz), 5.38 (1 H, s), 5.41–5.44 (1 H, m),
5.67 (1 H, d, J03.0 Hz), 6.47–6.64 (3 H, m). 13C NMR (125 MHz, CDCl3)
δ 20.4, 20.6, 20.8, 29.9, 62.0, 65.6, 67.2, 67.9, 96.4, 87.7, 97.9, 98.1, 100.2,
100.3, 100.4, 100.5, 158.0, 162.4, 162.5, 164.3, 164.5, 169.9, 170.1, 170.4.
ESI-MS: Calcd for C18H20F2O8Na (M+Na) 425.10, found 425.04. Anal.
Calcd for C18H20F2O8: C, 53.73; H, 5.01. Found: C, 53.93; H, 5.11.
9
OAc
OAc
OAc
OAc
OAc
OAc
OAc
OAc
10
11
12
13
14
15
16
H
p-CH3
p-OCH3
tyrosinec
p-NO2
o-CH3
3,5-di-F
phenyld
H
H
H
H
H
5g
5h
H
a Reaction condition: TMSOTf (0.3 equiv), glycosyl acetates (1.0 equiv)
and phenols (1.5 equiv) were stirred in CH2Cl2 at 0 °C
b Isolated yield
c N-Fmoc-(L)-tyrosine methyl ester
d 2-Naphthol
panel of phenols (2a-h in Fig. 1) as acceptors1. From Table 3,
we can conclude that not only the phenols with electron-
donating substituents (entries 2, 3 and 4), but also those with
electron-withdrawing (entry 5, 7 and 8) and hindered phenols
(entry 6) could give excellent results. All the reactions pro-
vided the corresponding 2-deoxy α-aryl-O-glycosides 3a-h as
the only detectable glycosylation products in good to excellent
yields (79–95 %). Additionally, the undesired C-aryl
1 Experimental procedure: The 2-deoxy glycosyl acetate 1 or 4
(30 mg, 0.09 mmol), 4 Å molecular sieves, and 2a-g (1.5 equiv) were
combined with 0.3 equvilent of TMSOTf in anhydrous dichlorome-
thane (3 ml) at 0 °C. After 0.5–3.0 h, the molecular sieves was filtered
off, followed the reaction mixture washed with iced saturated NaHCO3
and iced brine, dried over anhydrous Na2SO4, and concentrated in
vacuum. The residue was purified by silica gel column chromatogra-
phy to obtain products (petroleum ether/ethyl acetate 05/1, v/v).

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Glycoconj J (2012) 29:453–456
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In conclusion, we have developed an efficient method for
the stereoselective synthesis of 2-deoxy α-O-aryl glycosides
from glycosyl acetates under the catalysis of TMSOTf in
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Acknowledgement We thank the analytic center of East China Nor-
mal University for data measurement. We appreciate Mr Jie Fu for
helpful discussion. The project was supported by Shanghai Rising-Star
Program (06QA14018) and the Natural Science Foundation of Shang-
hai (11ZR1410400) and large instruments Open Foundation of East
China Normal University (2011–76 & 2012–9).
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