The synthesis of 2-deoxy-α-d-glycosides from d-glycals catalyzed by TMSI and PPh3

Article abstract of DOI:10.1016/j.carres.2012.06.004

2-Deoxyglycosides were synthesized in high α-selectivity by the direct addition of alcohols to d-glucal and d-galactal catalyzed by TMSI and PPh₃. The acid labile isopropylidene group is tolerated under this condition.

Full text of DOI:10.1016/j.carres.2012.06.004

Carbohydrate Research 358 (2012) 19–22
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Carbohydrate Research
journal homepage: www.elsevier.com/locate/carres
The synthesis of 2-deoxy-
and PPh3
a-D-glycosides from D-glycals catalyzed by TMSI
⇑
⇑
Xi-Kai Cui, Ming Zhong, Xiang-Bao Meng , Zhong-Jun Li
The State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Deoxyglycosides were synthesized in high
a-selectivity by the direct addition of alcohols to D-glucal
Received 4 March 2012
Received in revised form 5 May 2012
Accepted 4 June 2012
and
D-galactal catalyzed by TMSI and PPh3. The acid labile isopropylidene group is tolerated under this
condition.
Ó 2012 Elsevier Ltd. All rights reserved.
Available online 16 June 2012
Keywords:
2-Deoxyglycoside
Glycal
TMSI
a-Selective glycosylation
1. Introduction
temperature.14 TMSI was also a good reagent for preparing glycosyl
iodide, which was used as a good glycosyl donor.15 As glycals are
liable to acidic conditions and led to 2,3-unsaturated glycosides,16
to the best of our knowledge, there is no report on the TMSI-cata-
2-Deoxy-sugars are an important class of carbohydrates that
are present in natural products.1–3 Many biologically active com-
pounds, especially antitumor antibiotics such as anthracyclines,
aureolic acids, orthosamycins, angucyclins, and enediynes, contain
one or more 2-deoxyglycoside in their scaffolds.4 In order to study
the roles of 2-deoxyglycosides, a variety of approaches for the syn-
thesis of 2-deoxyglycosides have been developed,1,5 such as they
can be prepared by use of thioglycoside donors, activated oxygen
derivatives, glycosyl halides, and glycals.6 Of these developed
methods, acid-catalyzed addition to glycals is the most direct
method. For example, triphenylphosphine hydrobromide (TPHB),
the most widely used catalytic system, promotes the addition of
alcohols to glycals and the products were obtained in good to
lyzed direct addition of alcohols to D-glucal and D-galactal to form
2-deoxyglycosides. Herein we used TMSI and PPh3 as mild catalyst
to activate the glycals in the presence of a variety of hydroxylic
nucleophiles and the corresponding 2-deoxyglycosides were pre-
pared in high
a-selectivity. Moreover, the acid labile protecting
group was tolerated under this condition.
2. Results and discussion
2.1. Promoter selection
excellent yields and high
a
-selectivity.7 In addition, many other
To find an alternative to the most widely used catalyst TPHB, we
replaced HBr with other Lewis acids or Brönsted acids to find out
which one could catalyze the reaction of glycals with alcohols to
acid-catalyzed systems such as BCl3 or BBr3,8 CeCl3ꢀ7H2O/NaI4,
GaCl3,9 ceric ammonium nitrate,10 and Rhenium(V) [ReOCl3(S-
Me2)(OPPh3)]11 have been developed. Recently, Lin’s group found
that AlCl3 could also promote the addition under microwave irra-
diation.12 However, several limitations of these catalysts including
high toxicity and high cost hamper their wider use. There is still a
need to find a low toxicity and low cost catalyst. It is well known
that TMSI can catalyze the tetrahydropyranylation of unbulky alco-
hols.13 Furthermore, Cha et al. found that TMSI–PPh3 was a conve-
nient and highly effective catalyst for the tetrahydropyranylation
of aliphatic and aromatic alcohols with dihydropyran at ambient
form
Ferrier rearrangement. 3,4,6-tri-O-benzyl-
from 3,4,6-tri-O-acetyl-
-galactal via a classic method,17 first re-
a
-2-deoxyglycosides, and effectively prevent the undesirable
D
-galactal (1a), prepared
D
acted with methanol in anhydrous dichloromethane at 40 °C in the
presence of PPh3. Several Lewis or Bronsted acids such as BF3ꢀOEt2,
TMSOTf, TMSI, FeCl3, and TfOH were added as catalyst (Table 1).
Among them, BF3ꢀOEt2 and TMSI activated the reaction and the
products were obtained in high yields and excellent
a-selectivity
without any Ferrier rearrangement. Similarly, TMSI catalyzed addi-
tion to 3,4,6-tri-O-benzyl- -glucal (1b) produced the corresponding
D
methyl 2-deoxy glycoside (2b) in both high yield and
However, methanol addition to 3,4,6-tri-O-benzyl-
a
-selectivity.
⇑
Corresponding authors.
E-mail address: xbmeng@bjmu.edu.cn (X.-B. Meng).
D
-glucal (1b)
0008-6215/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carres.2012.06.004

20
X.-K. Cui et al. / Carbohydrate Research 358 (2012) 19–22
Table 1
Table 3
Effect of promoters on the formation of methyl 2-deoxyglycosidesa
Synthesis of 2-deoxyglycosides from glycals and various alcoholsa
R1
R1
OBn
O
R1
R1
0.2 eq Acid
OBn
O
OBn
O
OBn
O
0.2 eq PPh3
R2
R2
R2
TMSI-PPh3
DCM
R2
+ MeOH
+ ROH
BnO
CH2Cl2
BnO
BnO
BnO
OMe
OR
1a: R1=OBn, R2=H
2~11a: R1=OBn, R2=H
2~11b: R1= H, R2=OBn
Galactal (1a): R1=OBn, R2=H
Glucal (1b): R1=H, R2= OBn
2a: R1=OBn, R2=H
2b: R1=H, R2=OBn
1b: R1=H, R2=OBn
Yieldb
%
a
/bc ratio
Entry Donor Acceptor
hours Yieldb
a
/b ratioc
Entry
Glycal
Promoter
Product
1
2
3
4
1a
1b
1a
1b
1a
1b
1a
1b
Methanol
2
2
4
4
2a: 85%
2b: 92%
3a: 84%
3b: 94%
4a: 84%
4b: 89%
5a: 57%
5b: 56%
>19:1
6:1
>19:1
15:1
>19:1
3:1
1
2
3
4
5
6
7
8
9
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
BF3ꢀOEt2
BF3ꢀOEt2
TMSI
TMSI
TfOH
2a
88
—
91
92
—
—
—
—
—
>19:1
Mixtured
2a
Benzyl alcohol
2-Propanol
t-Butanol
>19:1
6:1
2b
Mixturee
Mixturee
Mixturee
Mixturee
Mixturee
Mixturee
TfOH
>19:1
5:1
TMSOTf
TMSOTf
FeCl3
5
1a
1b
10
6a: 67%
6b: 75%
>19:1
>19:1
H3CO
OH
10
FeCl3
—
a
b
c
All reactions were carried out in anhydrous dichloromethane at 40 °C.
Isolated yield.
a
Mixture means 2,3-unsaturated glucoside and some other products.
Mixture means 2-deoxyglycoside remained, a trace amount of 2,3-unsaturated
OH
O
/b ratio is determined by 1H NMR.
6d
1a
1b
10
7a: 80%
7b: 86%
>19:1
>19:1
d
e
BnO
BnO
BnO
OCH3
OCH3
glycoside and several unidentified byproducts.
OBn
O
HO
BnO
7d
8d
9d
1a
1b
10
10
10
8a: 73%
8b: 74%
>19:1
>19:1
Table 2
BnO
Optimization of the loading of TMSI–PPh3 using 1a and methanola
OBn
O
OBn
BnO
OBn
O
OBn
O
OH
O
TMSI, PPh3
DCM
+ MeOH
O
BnO
1a
1b
9a: 84%
9b: 79%
>19:1
7:1
O
OMe
O
Entry
Equivalent
Time (h)
Yieldb (%)
a
/bc ratio
1
2
3
0.05
0.10
0.20
2.0
1.0
1.0
91
89
85
>19:1
>19:1
>19:1
O
O
O
O
1a
1b
10a: 75% >19:1
10b: 87% >19:1
a
b
c
All reactions were carried out in anhydrous dichloromethane at 40 °C.
Isolated yield.
a
O
HO
/b ratio is determined by 1H NMR.
OBn
O
10d
1a
1b
10
11a: 72% >19:1
11b: 70% >19:1
HO
BnO
catalyzed by BF3ꢀOEt2 was slow under the same condition. Based on
these results, TMSI was chosen as the activator to catalyze the addi-
tion reaction of the glycals and alcohols.
BnO
OCH3
a
b
c
All reactions were carried out in anhydrous dichloromethane at 40 °C.
2.2. Optimization of the amount of TMSI–PPh3
The yield is the isolated yield.
a
/b ratio is determined by 1H NMR.
d
20% PPh3 and TMSI were used.
We investigated the effect of catalyst loading (5%, 10%, 20% eq
TMSI–PPh3) on the reaction (Table 2). With the increase of the
amount of catalyst used, the reaction time decreased significantly
but the yield also decreased slightly. To achieve the highest yield
and selectivity, 5% TMSI was selected as the optimal amount of cat-
alyst, although it took 2 h for the reaction to go to completion.
carried out in the presence of 5% TMSI–PPh3 in anhydrous
dichloromethane. However, when steric bulky glycosyl acceptors
(Table 3, entries 6–10) were used, the reaction did not go to
completion in 4 h because of the hindrance. It is needed to increase
the amount of TMSI and PPh3 from 5% to 20% in order to drive the
reaction to completion. The desired disaccharide products 7–11
were isolated in 70–87% yield. Isopropylidene, the most commonly
used protecting group in carbohydrate chemistry, is easily re-
moved under acidic condition. It is notable that the isopropylidene
group was well tolerated even with 20% TMSI treatment. Therefore,
this TMSI–PPh3 catalytic system should be useful for formation of
2.3. The scope of glycosyl acceptors
Under the optimized conditions, a variety of hydroxylic nucleo-
philes were used as the acceptor to react with 1a and 1b (Table 3).
Simple alcohols including methanol, isopropanol, and benzyl alco-
hol produced good yield and high stereoselectivity, while the bulky
tert-butanol produced moderate yield. This protocol also effec-
tively promoted the phenol addition to glycal and yielded the cor-
responding products 6a and 6b (entry 5). The reactions were
various a-glycosides.

X.-K. Cui et al. / Carbohydrate Research 358 (2012) 19–22
21
The addition reactions to galactal displayed high
tivity, which is consistent with the anomeric effect. In contrast,
addition reactions to glucal generally gave a lower /b ratio. This
phenomenon probably can be explained by the steric hindrance
of the axial benzyloxyl group at the C-4 position of galactal, which
prevents the attack by acceptors from the top face of the sugar ring,
a
-stereoselec-
(TLC) plates were purchased from Liangchen Chemical Engineering
Co. Ltd (Anhui Province). All compounds were visualized with 5%
H2SO4 in EtOH, followed by heating. Flash column chromatography
was performed on Silica Gel 60 (E. Merck, 0.063–0.200 mm). NMR
spectra were recorded on a Bruker AMX-400 (400 MHz) instru-
ment. Optical rotations were measured at 25 °C using an Optical
Activity AA-10R automatic polarimeter.
a
thus promoting the formation of a-isomer.
2.4. The reaction mechanism
3.2. Typical procedure for preparing 2-deoxyglycoside
derivatives 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b
We demonstrated that TMSI–PPh3 was an effective catalyst sys-
tem for the direct 2-deoxy glycosidation from glycals. Here we pro-
pose a possible mechanism for the reaction. TMSI firstly reacts
with ROH to form PPh3ꢀHI and TMSOR in the presence of Lewis
base PPh3. PPh3ꢀHI serves as a better catalyst than PPh3ꢀHBr to ini-
tiate the protonation of the glycal because of its stronger acidity.
Moreover, TMSOR is a better nucleophile than ROH (Scheme 1).
When the reaction is carried out in the absence of PPh3 a complex
mixture is observed. When TMSOTf is used, PPh3ꢀHOTf and TMSOR
should be formed in a similar way, but the strong acidity of
PPh3ꢀHOTf led to side reactions.
To a stirred solution of glycal (1a and 1b, 1.0 equiv) in CH2Cl2
(2.0 mL) were added alcohol (2 equiv), PPh3 (0.05 equiv), and TMSI
(0.05 equiv). The mixture was stirred at 40 °C for 2–4 h, concen-
trated under reduced pressure, and purified by silica gel chroma-
tography with EtOAc/PE (1:20) to give the products in 56–92%
yields. The 1H NMR and 13C NMR data are listed in the Supplemen-
tary data.
3.3. Typical procedure for preparing 2-deoxyglycoside
derivatives 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b
In summary, we have successfully synthesized a-2-deoxyglyco-
sides in good yield and stereoselectivity by using TMSI–PPh3 as the
catalyst to promote the addition of hydroxylic nucleophiles to gly-
cals. Nucleophiles include simple alcohols, partially protected
monosaccharides, and a phenol. In addition, the acid labile isopro-
pylidene group is tolerated under this condition.
To a stirred solution of glycal (1a and 1b, 1.0 equiv) in CH2Cl2
(2.0 mL) were added glycosyl acceptor (1.5 equiv), PPh3
(0.20 equiv), and TMSI (0.20 equiv). The mixture was stirred at
40 °C for 10 h, concentrated under reduced pressure, and purified
by silica gel chromatography with EtOAc/PE (1:8) to give the prod-
ucts in 67–86% yields. The 1H NMR and 13C NMR of the known
compounds are listed in the Supplementary data.
3. Experimental
3.1. General procedures
3.3.1 Methyl 6-O-(2-deoxy-3,4,6-tri-O-benzyl-
anosyl)-2,3,4-tri-O-benzyl- -mannopyranoside (8a) and methyl
6-O-(2-deoxy-3,4,6-tri-O-benzyl- -arabino-hexopyranosyl)-
2,3,4-tri-O-benzyl- -mannopyranoside (8b)
Compound 8a: [
+47 (c 2.7, CHCl3). 1H NMR (400 MHz,
a-D-lyxo-hexopyr
a-D
All chemicals, reagents, and solvents were purchased from com-
mercial sources where available. Dichloromethane was distilled
over CaH2. When dry conditions were required, the reactions were
performed under an argon atmosphere. Thin-layer chromatography
a-D
a
-D
a]
D
CDCl3): d 7.46–7.28 (m, 30H, Ph), 5.20 (s, 1H, H-10), 4.99 (dd, 2H,
J 11.6 Hz, PhCH2), 4.83–4.43 (m, 11H, PhCH2, H-1), 4.05–3.62 (m,
11H, H-20, H-30, H-40, H-50, H-60, H-3, H-4, H-5, H-6), 3.32 (s, 3H,
OCH3), 2.33–2.27 (m, 1H, H-2a), 2.17–2.11 (m, 1H, H-2b); 13C
NMR (100 MHz, CDCl3): d 139.02, 138.61, 138.55, 138.51, 138.38,
138.20, 128.45–127.48, 98.79, 98.19, 80.26, 75.07, 74.91, 74.79,
74.34, 74.19, 73.39, 73.10, 72.67, 72.14, 71.37, 70.12, 69.93,
69.40, 66.32, 54.65, 31.07. HRMS: m/z Calcd for C50H60O10Na
OBn
OBn
O
OBn
O
OBn
BnO
BnO
favored, stable
I
[M+Na]+, 903.4084. Found 903.4062. Compound 8b: [
a] +53 (c
D
4.9, CHCl3). 1H NMR (400 MHz, CDCl3): d 7.47–7.24 (m, 30H, Ph),
5.22 (s, 1H, H-10), 5.01 (dd, 2H, J 10.8 Hz, PhCH2), 4.85–4.51 (m,
11H, H-1, PhCH2), 4.10–3.63 (m, 11H, H-20, H-30, H-40, H-50, H-60,
H-3, H-4, H-5, H-6), 3.36 (s, 3H, OCH3), 2.46 (dd, 1H, H-2a), 1.82–
1.75 (m, 1H, H-2b); 13C NMR (100 MHz, CDCl3): d 138.82, 138.70,
138.67, 138.54, 138.42, 138.24, 128.44–127.53, 98.88, 97.76,
80.38, 78.26, 77.19, 75.04, 74.91, 74.80, 73.47, 72.74, 72.12,
71.53, 71.39, 70.83, 68.82, 65.96, 54.75, 35.31. HRMS: m/z Calcd
for C50H60O10Na [M+Na]+, 903.4084. Found 903.4090.
PPh3 HI
OBn
BnO
OBn
PPh3
ROH + TMSI
O
unfavored,
reactive
I
ROTMS
Acknowledgements
This work was supported by grants from the National Natural
Science Foundation of China (NSFC No. 21072017) and the National
Basic Research Program of China (Grant No. 2012CB822100).
OBn
O
OBn
Supplementary data
BnO
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.carres.2012.
06.004.
OR
Scheme 1. Possible catalytic cycle of TMSI–PPh3 mediated 2-deoxyglycosidation.

22
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