Reductive deprotection of propargyl ether by a SmI2-amine-water system and its application to polymer-supported oligosaccharide synthesis

Article abstract of DOI:10.1016/j.tetlet.2008.06.081

A SmI₂-amine-water system instantaneously deprotected aryl and alkyl propargyl ethers in a reductive manner. The utility of the propargyl group as a protecting group in oligosaccharide synthesis, and its application to polymer-supported oligosaccharide synthesis is described.

Full text of DOI:10.1016/j.tetlet.2008.06.081

Tetrahedron Letters 49 (2008) 5159–5161
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Reductive deprotection of propargyl ether by a SmI2–amine–water system
and its application to polymer-supported oligosaccharide synthesis
b
a,
Shino Manabe a,b, , Akiharu Ueki , Yukishige Ito
*
*
a RIKEN (The Institute of Physical and Chemical Research), Wako-shi, Saitama 351-0198, Japan
b PRESTO, JST, Honcho, Kawaguchi, Saitama 332-0012, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A SmI2–amine–water system instantaneously deprotected aryl and alkyl propargyl ethers in a reductive
manner. The utility of the propargyl group as a protecting group in oligosaccharide synthesis, and its
application to polymer-supported oligosaccharide synthesis is described.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 14 May 2008
Revised 16 June 2008
Accepted 19 June 2008
Available online 22 June 2008
Keywords:
Protecting group
Deprotection reaction
Propargyl ether
SmI2
Oligosaccharide synthesis
The development of protecting groups is highly desirable in
synthetic organic chemistry.1 In the field of carbohydrate chemis-
try, especially, the choice of protecting groups is extremely impor-
tant, because it affects the reactivities and stereoselectivities of the
glycosyl donor and/or acceptor.2 Recently, the utility of propargyl
ethers in carbohydrate chemistry was demonstrated in a b-man-
nosylation reaction, in which this protecting group was especially
effective due to reduced steric buttressing.3 The propargyl glyco-
side was also reported as a novel glycosyl donor activated by
AuCl3.4
To date, the use of the propargyloxy group has been relatively
infrequent in organic synthesis, as well as in carbohydrate chemis-
try, due to the limitations of its deprotection methodology, which
involves extreme reaction conditions,5,6 exotic catalysts,7–9 or
multi-step procedures.10
reaction was complete within 5 min at room temperature, and the
alcohol 2 was obtained in 86% yield (entry 2). The reaction did not
proceed to completion even after 1 h (entry 3) with half the
amount of reductant, namely SmI2 (5 equiv)–i-PrNH2 (20 equiv)–
H2O (15 equiv). Et3N (entry 4) and TMEDA (entry 5) gave satisfac-
tory yields, but a longer reaction time was required, and some allyl
ether 3a was also obtained when TMEDA was employed as the
base. Although the combination of aq 50% NaOH–SmI2 is known
to be an effective reducing reagent,12 these conditions did not give
good results in this deprotection system (entry 6). Similarly,
NaSMe exhibited a slow reaction rate and low yield (entry 7).
Substituents on the propargyl termini also affected the depro-
tection reaction, as shown in Table 2. It is known that alkylsilyl
groups and alkylgermanium groups at the alkyne termini act to
protect the acidic alkyne terminus, and they are cleavable under
different conditions.13 Under our conditions, both trimethylgerma-
nium and trimethylsilyl-substituted alkynes 1b and 1c gave the
deprotected product 2 in 76% and 61% yield, respectively.14,15
Unfortunately, the TIPS-substituted alkyne 1d did not react, and
the starting material was recovered. In the case of methyl-substi-
tuted alkyne 1e, the deprotected product 2 was obtained in 30%
yield together with butenyl ether 3b (19%, 95% E), and 18% of the
starting material 1e.
Hilmersson’s report11 of a SmI2–amine–water system with
powerful reducing ability led us to expect this system to be useful
for the deprotection of propargyl groups. Here, we report the novel,
rapid, room temperature deprotection of propargyl ethers by the
extremely powerful reducing combination SmI2–amine–H2O, and
its application to polymer-supported oligosaccharide synthesis.
Initially, we investigated the effect of amine additives in the
deprotection reaction of glucose-derived propargyl ether 1a (Table
1). In the absence of amine, no reaction occurred after 1 h (entry 1).
When i-PrNH2 was used as an additive in the reaction mixture, the
We then investigated the applicability of this deprotection
method to various propargyl ethers. Representative results are
listed in Table 3, which shows that most of the propargyl ethers
were cleaved within a few minutes. The acid-sensitive protecting
groups MOM and acetonide were stable under these conditions
* Corresponding authors. Tel.: +81 48 467 9432; fax: +81 48 462 4680 (S.M.).
E-mail address: smanabe@riken.jp (S. Manabe).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.081

5160
S. Manabe et al. / Tetrahedron Letters 49 (2008) 5159–5161
Table 1
The effect of base in the deprotection of propargyl ethers
SmI2 (10 equiv.)
base (40 equiv.)
H2O (30 equiv.) BnO
OH
OAll
O
O
BnO
BnO
O
+
O
BnO
BnO
BnO
THF
BnO
BnO
OMe
OMe
BnO
1a
OMe
2
3a
Entry
Base
Reaction time
Yield (%) 2
Yield (%) 3a
1
2
3a
4
5
6
7
None
1 h
15 min
1 h
1 h
1 h
0
86
74
84
72
5
0
0
11
0
16
20
30
i-PrNH2
i-PrNH2
Et3N
TMEDA
50% NaOH aq
NaSMe
1 h
18 h
36
a
Sml2 5 equiv, i-PrNH2 20 equiv, H2O 15 equiv.
Table 2
Table 3
The effect of substituents on propargyl termini in propargyl ether deprotection
The deprotection of propargyl ethers in various substrates
SmI2 (10 equiv.)
i-PrNH2(40 equiv.)
H2O (30 equiv.)
R
SmI2 (10 equiv.)
-PrNH2(40 equiv.)
H2O (30 equiv.)
OH
O
i
O
R O
BnO
BnO
BnO
ROH
O
BnO
BnO
BnO
THF
4
5
THF
OMe
OMe
1
2
Entry
1
Time
Yield (%)
92
R O
Ph
R
Reaction time
Yield (%)
5 min
O
4a
1a
1b
1c
1d
1e
H
15 min
1 h
3 h
16 h
10.5 h
86
76
61
0
GeMe3
SiMe3
TIPS
O
2
3
4
5
5 min
10 min
1 h
70
93
43
89
O
O
4b
Me
30
O
MOMO
OTBDPS
O
4c
BnO
BnO
BnO
O
O
OMe
3b
4d
O
15 min
tBu
4e
(entries 2 and 3). After deprotection of the propargyl ether, 4d and
4e were obtained as single diastereomers. Racemization at the chi-
ral centers was negligible. The deprotection yield of 4d was not
satisfactory, and the corresponding allyl ether was obtained in
30% yield (entry 4). Phenolic propargyl ethers were also deprotec-
ted in good yields (entries 6 and 7). Unfortunately, the acetamide-
containing substrate 4g gave a low yield, because reduction to the
methylamine occurred as a competitive reaction.
O
O
6
7
5 min
79
68
OTBS
4f
NHAc
15 min
4g
This methodology was next applied to oligosaccharide synthesis
(Scheme 1). The acceptor 7 was glycosylated with propargyl ether
carrying thioglycoside 6 under NIS–TfOH activation conditions. The
glycosylation reaction proceeded cleanly in quantitative yield with
O
BnO
OH
O
BnO
BnO
i)
O
BnO
BnO
BnO
O
O
O
+
BnO
SPh
O
BnO
a 3:2 a:b ratio, and the propargyl group was not susceptible to I2
BnO
BnO
BnO
BnO
OMe
addition, unlike the allyl group. After separation of the anomeric
stereoisomer, the propargyl group of the b isomer 8b was depro-
tected in 79% yield. These results demonstrated the utility of prop-
argyl ether as a protecting group in oligosaccharide synthesis.
Finally, this methodology was applied to polymer-supported
oligosaccharide synthesis.15 The propargyl ether carrying galactose
thioglycoside 10 was attached to a Wang linker via glycosylation in
OMe
6
7
8a/8b
8a α isomer
8b β isomer
O
O
OH
BnO
BnO
BnO
BnO
O
ii)
O
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
quantitative yield (2:1 a:b). After removal of the acetyl group, the
OMe
OMe
8b
9
resulting phenoxide was immobilized to bromo poly(ethylene gly-
col) methyl ether (average M.W. 750) in the presence of Cs2CO3. As
we previously reported,15a–e PEG’s high polarity enabled purifica-
tion of the PEGylated sugar by passing it through a silica gel pad.
Scheme 1. Glycosylation reaction and deprotection of propargyl-ether-carrying
sugar. Reagents and conditions: (i) NIS, TfOH, CH2Cl2, À40 °C, 15 min, quant., 8a:8b
3:2; (ii) SmI2, i-PrNH2, H2O, THF, rt, 10 min, 79%.

S. Manabe et al. / Tetrahedron Letters 49 (2008) 5159–5161
5161
OAc
BnO
O
O
HO
OPEG
BnO
BnO
O
OAc
BnO
BnO
O
ii), iii)
11
O
O
BnO
BnO
O
O
SPh
i)
BnO
BnO
10
12
13
BnO
O
BnO
O
O
O
BnO
BnO
BnO
BnO
BnO
BnO
iv), v)
vi)
O
O
O
O
OPEG
BnO
O
BnO
OH
BnO
BnO
14
15
Scheme 2. Polymer-supported disaccharide synthesis. Reagents and conditions: (i) NIS, TfOH, CH2Cl2, À40 °C, 30 min, quant.; (ii) NaOMe, MeOH, rt, 2 h, 93%; (iii) MPEG-Br,
Cs2CO3, CH3CN, 14 h, 80 °C, 92%; (iv) SmI2, i-PrNH2, H2O, THF, rt, 15 min, 63%; (v) 6, NIS, TfOH, CH2Cl2, À40 °C, 8 h, 94%; (vi) TFA:CH2Cl2 1:4, rt, 1 h, 64%.
2. (a) Paulsen, H. Angew. Chem., Int. Ed. 1982, 21, 155; (b) Andrews, C. W.;
Again, the propargyl group was deprotected by the SmI2–i-PrNH2–
H2O system within 15 min in 63% yield. Glycosylation with 10 was
Rodebaugh, R.; Frase-Reid, B. J. Org. Chem. 1996, 61, 5280; (c) Zhang, Z.; Ollman,
I. R.; Ye, X.-S.; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121,
carried out and the disaccharide 15 (newly formed glycosyl bond,
:b 1:1) was obtained in 64% yield after cleavage from PEG
(Scheme 2).
Although the mechanism of this reaction is not yet clear,16
novel methodology for the rapid reductive deprotection of propar-
gyl groups has been developed. The methodology was found to be
useful in the construction of simple molecules as well as in oligo-
saccharide synthesis. Our method was effective for both alkyl and
aryl propargyl groups, and was operationally simple.
General procedure for deprotection of propargyl ether: Freshly
prepared SmI2 solution17 (ca. 0.1 M THF solution, 10 equiv) was
added to a mixture of propargyl ether (1 equiv) and i-PrNH2
(40 equiv). Commercially available SmI2 could also be used. H2O
(30 equiv) was added dropwise at room temperature under Ar
atmosphere. The mixture was stirred and the reaction progress
was monitored by TLC at room temperature. After the reaction
was completed, the mixture was quenched with 10% aq citric acid.
The aqueous layer was extracted with CHCl3. The combined layers
were washed with water and brine. After drying the extract over
MgSO4, the solvent was evaporated. The residue was purified by
silica gel column chromatography.
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were stable under the conditions without SmI2 (0.1 M substrate in THF,
40 equiv of i-PrNH2, 30 equiv of H2O).
15. (a) Ando, H.; Manabe, S.; Nakahara, Y.; Ito, Y. J. Am. Chem. Soc. 2001, 123, 3848;
(b) Ando, H.; Manabe, S.; Nakahara, Y.; Ito, Y. Angew. Chem., Int. Ed. 2001, 40,
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S.; Manabe, S.; Inamori, K.-i.; Taniguchi, N.; Ito, Y. Angew. Chem., Int. Ed. 2004,
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4218; (f) Manabe, S.; Ueki, A.; Ito, Y. Chem. Comm. 2007, 3673; (g) Ito, Y.;
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Acknowledgments
We thank Ms. A. Takahashi for her technical assistance. S.M.
thanks the JSPS for a Grant-in Aid for Scientific Research (C) (Grant
No. 19590032).
16. Mechanistic study for SmI2–amine–water reduction system: (a) Chopade, R. R.;
Prasad, E.; Flowers, R. A., II. J. Am. Chem. Soc. 2004, 126, 44; (b) Dahlén, A.;
Hilmersson, G. J. Am. Chem. Soc. 2005, 127, 8340.
References and notes
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