Regioselective reductive ring opening of benzylidene acetals using triethylsilane and iodine

Article abstract of DOI:10.1055/s-0029-1219798

Novel reaction conditions have been developed for the regioselective reductive ring opening of benzylidene acetals in carbohydrate derivatives using triethylsilane and molecular iodine. The reaction is fast, compatible with most of the functional groups e

Full text of DOI:10.1055/s-0029-1219798

LETTER
1193
Regioselective Reductive Ring Opening of Benzylidene Acetals Using
Triethylsilane and Iodine
Regioselective
R
a
j
ngOpe
i
ningo
b
f
Benzylidene
Acet
P
als anchadhayee, Anup Kumar Misra*
Division of Molecular Medicine, Bose Institute, P-1/12, C. I. T. Scheme VII M, Kolkata 700054, India
Fax +91(33)23553886; E-mail: akmisra69@gmail.com
Received 22 January 2010
lated derivatives. However, in some cases we obtained
poor yields because of the instability of some functional
groups under the reaction conditions. Alternative use of
NaBH3CN–HCl·Et2O requires repeated purification of the
Abstract: Novel reaction conditions have been developed for the
regioselective reductive ring opening of benzylidene acetals in car-
bohydrate derivatives using triethylsilane and molecular iodine.
The reaction is fast, compatible with most of the functional groups
encountered in the oligosaccharide synthesis, and yields were excel- products to remove borate salts, and the Et3SiH–TFA sys-
lent. The reaction conditions are equally effective in thioglycosides.
tem did not work in D-galactose derivatives. Thus we
sought to explore other possible reagent combinations for
the reductive ring opening of benzylidene acetals of D-
glucose and D-galactose derivatives. We envisaged that
use of a Et3SiH and molecular iodine combination could
serve to improve the yield of the products. We disclose
herein convenient reaction conditions for the regioselec-
tive ring opening of 4,6-O-benzylidene acetals of carbo-
hydrate derivatives into 6-O-benzylated derivatives using
Key words: carbohydrate, benzylidene acetal, regioselective,
iodine, triethylsilane
Judicious protection of hydroxyl groups in the polyhy-
droxylated carbohydrate skeleton plays an important role
in the synthesis of complex oligosaccharides and natural
products.1 Although chemistry for the selective protection
and deprotection of carbohydrates has been extensively
studied, there is still a need for improved methodology.
Benzylidene acetals have found extensive application in
oligosaccharide synthesis because of the group’s utility
for the simultaneous protection of two hydroxyl groups
and its removal under acidic or neutral conditions.2 Trans-
formation of a benzylidene acetal to a benzyl or benzoyl
group are useful conversions in the synthesis of oligosac-
charides. The 4,6-O-benzylidene acetal in carbohydrate
derivatives can be regioselectively opened to give either
6-O-benzylated or 4-O-benzylated derivatives depending
on the reducing agent used.2 For the selective removal of
benzylidene acetasl a number of methods are available in
the literature, including NaBH3CN–HCl,3 NaBH3CN–
a
combination of triethylsilane–molecular iodine
(Scheme 1).
OBn
Ph
O
O
O
O
Et3SiH, I2, MeCN
0–5 °C, 10–30 min
HO
R3O
OR1
R3O
OR1
OR2
OR2
Scheme 1 Regioselective ring opening of benzylidene acetal using
triethylsilane and iodine.
In a set of initial experiments, methyl 2,3-di-O-acetyl-4,6-
O-benzylidene-a-D-glucopyranoside (1) was allowed to
stir with triethylsilane and iodine in MeCN at room tem-
perature, varying the quantity of reagents. It was observed
that treatment of compound 1 with 1.5 equiv. of Et3SiH
and 0.2 equiv. of iodine in MeCN could efficiently pro-
duce methyl 2,3-di-O-acetyl-6-O-benzyl-a-D-glucopyra-
noside (14) in 10 min at room temperature. Reducing the
quantity of reagents resulted in an incomplete transforma-
tion even after 5 h. Use of other organic solvents such as
CH2Cl2, THF produced a similar result in the formation of
compound 14. Following these reaction condition, a series
of 4,6-O-benzylidene acetal derivatives derived from D-
glucose and D-galactose was transformed into the corre-
sponding 6-O-benzylated derivatives (Scheme 1,
Table 1). Noteworthy features are the absence of forma-
tion of 4-O-benzylated derivatives and stability of the ma-
jority of the functional groups used for the protection of
hydroxy and amino groups in carbohydrates. Furthermore
benzylidene acetals of thio- and selenoglycosides can also
be regioselectively opened without any side reaction
(Table 1, entries 8, 10 and 12); despite the fact that iodine
has been used for thioglycoside activation.14 The reaction
conditions were equally effective in D-glucose and D-
6
TFA,4 Et3SiH–TFA,5 Et3SiH–BF3·OEt2 for the prepara-
tion of 6-O-benzylated derivatives and AlCl3–LiAlH4,7
DIBAL-H,8 Me3NBH3–AlCl3,4 BH3·THF–TMSOTf,9
Bu2BOTf–BH3·THF,10 CoCl2–BH3·THF11 and others12
for the preparation of 4-O-benzylated derivatives. Never-
theless, many of these methods for the preparation of 6-O-
benzylated carbohydrate derivatives have shortcomings
such as formation of byproducts, use of expensive re-
agents, incompatibility with other functional groups, and
harsh reaction conditions. Therefore, development of
mild, efficient, and metal-free methodology for the re-
gioselective ring opening of benzylidene acetals is still
attractive. During the synthesis of complex
oligosaccharides13 we applied Et3SiH–TFA5 or Et3SiH–
6
BF3·OEt2 to the regioselective opening of 4,6-O-ben-
zylidene acetals in sugar derivatives to obtain 6-O-benzy-
SYNLETT 2010, No. 8, pp 1193–1196
x
x.
x
x.
2
0
1
0
Advanced online publication: 23.03.2010
DOI: 10.1055/s-0029-1219798; Art ID: D02210ST
© Georg Thieme Verlag Stuttgart · New York

1194
R. Panchadhayee, A. K. Misra
LETTER
galactose derivatives unlike the Et3SiH–TFA combina- In summary, a novel, mild reaction condition has been de-
tion,5 which can be used in D-glucose derivatives only. Fi- veloped for the regioselective reductive ring opening of
nally, stereochemistry at the anomeric center does not benzylidene acetals in the carbohydrate backbone using
influence the product formation. In order to establish the triethylsilane and molecular iodine. This straightforward
significant advantages of the present protocol, a compara- reaction is rapid and high yielding and can be scaled-up.
tive study was also carried out with the existing literature Use of readily available reagents, without requirement of
reported reaction conditions (Table 2) from which it is heavy metal salts, high boiling solvents or Lewis acids
clear that the present reaction condition produces higher makes this reaction protocol an attractive alternative to
yields of the product in shorter time.
existing methodology.
Table 1 Regioselective Ring Opening of Benzylidene Acetal of Carbohydrate Derivatives Using Et3SiH and I2
Entry
1
Substratesa
Productsa
Time (min)
Yield (%)
9515
OBn
Ph
O
O
O
O
HO
AcO
10
AcO
AcO
AcO
OMe
OMe
OMe
OMe
1
14
OBn
O
Ph
O
O
O
HO
BzO
2
10
9212b
BzO
BzO
BzO
2
15
OBn
O
Ph
O
O
BnO
O
HO
3
4
10
15
9216
OMe
OMe
BnO
BnO
BnO
3
16
OBn
O
Ph
O
O
AcO
O
8717
HO
AcO
OMp
NPhth
OMp
NPhth
4
17
BnO
HO
BnO
OBn
O
OBn
O
Ph
O
O
BnO
5
6
10
10
907
OMe
OMe
5
18
OBn
Ph
O
O
AcO
O
O
HO
AcO
9218
BnO
BnO
OMe
OMe
6
19
OBn
Ph
O
O
O
O
HO
AllO
7
8
10
10
8819
AllO
BnO
BnO
OMe
OMe
7
20
OBn
Ph
O
O
BzO
O
O
8220
HO
BzO
SPh
SPh
BzO
BzO
8
21
Ph
HO
OBn
O
O
O
9
25
90
O
AcO
OMp
AcO
AcO
OMp
AcO
22
9
Synlett 2010, No. 8, 1193–1196 © Thieme Stuttgart · New York

LETTER
Regioselective Reductive Ring Opening of Benzylidene Acetals
1195
Table 1 Regioselective Ring Opening of Benzylidene Acetal of Carbohydrate Derivatives Using Et3SiH and I2 (continued)
Entry
10
Substratesa
Productsa
Time (min)
20
Yield (%)
8021
Ph
HO OBn
O
O
O
O
AcO
SEt
AcO
AcO
SEt
AcO
23
10
Ph
O
HO
OBn
O
O
11
12
25
8822
O
BzO
OMp
BzO
OBn
BzO
OMp
BzO
24
11
Ph
O
O
O
AcO
O
HO
AcO
SePh
SePh
AcO
AcO
12
25
OBn
O
Ph
O
O
AcO
O
HO
AcO
O
O
AcO
AcO
AcO
AcO
AcO
AcO
13
30
85
O
O
AcO
AcO
OMe
OMe
13
26
a Mp: 4-methoxyphenyl, NPhth: N-phthalimido, All: allyl, Bn: benzyl, Bz: benzoyl. Known compounds gave 1H NMR and 13C NMR spectra
that matched the data reported in the cited references.
Table 2 Comparison of Reaction Conditions for the Preparation of 6-O-Benzyl Carbohydrate Derivatives
Substrate
Product
Reagent
Time (min)
5
Yield (%)
873
NaBH3CN–HCl·Et2O
OBn
Ph
O
805
84a
92a
180
240
10
Et3SiH–TFA
Et3SiH–BF3·OEt2
Et3SiH–I2
O
O
O
HO
OMe
BnO
OMe
BnO
BnO
BnO
3
16
a This study.
Typical Experimental Conditions
Acknowledgment
To a solution of compound 1 (1 mmol) in MeCN (5 mL) were added
triethylsilane (1.5 mmol) and iodine (0.2 mmol) at 0–5 °C, and the
reaction mixture was allowed to stir at the same temperature for the
appropriate time (Table 1). After completion of reaction (TLC), the
reaction mixture was diluted with CH2Cl2 (20 mL). The organic lay-
er was successively washed with sat. NaHCO3 and H2O, dried
(Na2SO4), and concentrated under reduced pressure. The crude
product was purified using hexane–EtOAc (4:1) as eluent to furnish
pure compound 14 (95%).23
R.P. thanks CSIR, New Delhi for providing a Senior Research
Fellowship. This project was funded by Ramanna Research
Fellowship, DST, New Delhi, India (AKM) (Project no. SR/S1/
RFPC-06/2006).
References and Notes
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Ed. 2001, 40, 1576.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Synlett 2010, No. 8, 1193–1196 © Thieme Stuttgart · New York

1196
R. Panchadhayee, A. K. Misra
LETTER
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To aid assignments, data were taken after acetylation of the
products.
4-Methoxyphenyl 2,3,4-Tri-O-acetyl-6-O-benzyl-b-D-
galactopyranoside (Acetylated 22)
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2000, 11, 385.
1H NMR (500 MHz, CDCl3): d = 7.25–7.17 (m, 5 H, ArH),
6.87 (d, J = 9.0 Hz, 2 H, ArH), 6.70 (d, J = 9.0 Hz, 2 H,
ArH), 5.40 (d, J = 3.3 Hz, 1 H, H-4), 5.31 (dd, J = 7.9 Hz
each, 1 H, H-2), 4.99 (dd, J = 10.4, 3.4 Hz, 1 H, H-3), 4.83
(d, J = 7.9 Hz, 1 H, H-1), 4.48 (d, J = 11.9 Hz, 1 H, PhCH2a),
4.36 (d, J = 11.9 Hz, 1 H, PhCH2b), 3.87–3.84 (m, 1 H, H-5),
3.68 (s, 3 H, OCH3), 3.52–3.44 (m, 2 H, H-6a,b), 2.01, 1.99,
1.93 (3 s, 9 H, 3 COCH3). 13C NMR (125 MHz, CDCl3): d =
170.3, 170.1, 169.5 (3 COCH3), 156.0–114.9 (ArC), 101.1
(C-1), 73.9, 72.9, 71.5, 69.4, 67.9, 67.8, 55.8, 21.1, 21.0,
20.9 (3 COCH3). ESI-MS (C26H30O10): m/z = 525.1 [M +
Na]+.
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Asymmetry 2008, 19, 2746. (i) Panchadhayee, R.; Misra, A.
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P. R.; Misra, A. K. Glycoconjugate J. 2008, 25, 511.
(k) Mukherjee, C.; Misra, A. K. Glycoconjugate J. 2008, 25,
611. (l) Tiwari, P.; Misra, A. K. Glycoconjugate J. 2008, 25,
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Phenyl 2,3,4-Tri-O-acetyl-6-O-benzyl-1-seleno-b-D-
glucopyranoside (Acetylated 25)
1H NMR (500 MHz, CDCl3): d = 7.59–7.21 (m, 10 H, ArH),
5.15 (t, J = 9.2 Hz, 1 H, H-3), 5.01 (t, J = 9.8 Hz, 1 H, H-2),
4.97 (t, J = 9.2 Hz, 1 H, H-4), 4.88 (d, J = 9.9 Hz, 1 H, H-1),
4.53–4.46 (2 d, J = 11.8 Hz, 2 H, PhCH2), 3.67–3.63 (m, 1
H, H-5), 3.56–3.54 (m, 2 H, H-6a,b), 2.14, 2.05, 1.96 (3 s, 9
H, 3 COCH3). 13C NMR (125 MHz, CDCl3): d = 170.4,
169.6, 169.4 (3 COCH3), 138.2–127.6 (ArC), 81.4 (C-1),
78.9, 74.4, 73.9, 71.3, 69.4 (2 C), 21.1, 20.9 (2 C) (3
COCH3). ESI-MS (C25H28O8Se): m/z = 559.1 [M + Na]+.
Methyl (2,3,4-Tri-O-acetyl-6-O-benzyl-b-D-
glucopyranosyl)-(1→6)-2,3,4-tri-O-acetyl-a-D-
glucopyranoside (Acetylated 26)
1H NMR (500 MHz, CDCl3): d = 7.33–7.24 (m, 5 H, ArH),
5.43 (t, J = 10.0 Hz each, 1 H, H-3A), 5.16 (t, J = 9.4 Hz
each, 1 H, H-4A), 5.03 (t, J = 9.5 Hz each, 1 H, H-3B), 4.96
(dd, J = 7.9 Hz each, 1 H, H-2B), 4.90 (t, J = 9.4 Hz each, 1
H, H-4B), 4.88 (d, J = 3.6 Hz, 1 H, H-1A), 4.82 (dd, J = 10.1,
3.6 Hz, 1 H, H-2A), 4.55 (d, J = 11.9 Hz, 1 H, PhCH2a), 4.52
(d, J = 7.9 Hz, 1 H, H-1B), 4.48 (d, J = 11.9 Hz, 1 H,
PhCH2b), 3.94–3.89 (m, 2 H, H-6abA), 3.65–3.61 (m, 1 H, H-
5B), 3.55–3.51 (m, 3 H, H-5A, H-6a,bB), 3.37 (s, 3 H, OCH3),
2.06, 2.03, 1.98, 1.89 (4 s, 18 H, 6 COCH3). 13C NMR (125
MHz, CDCl3): d = 170.4, 170.1, 170.0, 169.7, 169.6, 169.4
(6 COCH3), 137.9–128.1 (ArC), 101.2 (C-1B), 96.8 (C-1A),
73.9, 73.7, 73.3, 71.6, 71.2, 70.6, 69.7, 69.4, 69.2, 68.5, 68.3,
55.5 (OCH3), 21.1 (2 C), 21.0 (2 C), 20.9 (2 C). ESI-MS
(C30H40O16): m/z = 679.2 [M + Na]+.
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