Practical synthesis of 1,2-O-benzylidene and 1,2-O-p-methoxybenzylidene hexopyranoses

Article abstract of DOI:10.1081/CAR-120020483

An improved and practical synthesis of 1,2-O-benzylidene and 1,2-O-p-methoxybenzylidene hexopyranoses as useful synthons in carbohydrate chemistry is described. The reaction of 2-benzoyloxyglycosyl bromide with sodium borohydride using excess amount of po

Full text of DOI:10.1081/CAR-120020483

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Practical Synthesis of 1,2‐O‐Benzylidene and
1,2‐O‐p‐Methoxybenzylidene Hexopyranoses
Katsuhiko Suzuki a , Toshihumi Mizuta a & Masanori Yamaura a
a Department of Enviromental Science , Faculty of Science and Engineering , Iwaki Meisei
University , 5‐5‐1 Iino, Chuohdai, Iwaki‐shi, Fukushima, 970‐8551, Japan
Published online: 16 Aug 2006.
To cite this article: Katsuhiko Suzuki , Toshihumi Mizuta & Masanori Yamaura (2003) Practical Synthesis of 1,2‐O‐Benzylidene
and 1,2‐O‐p‐Methoxybenzylidene Hexopyranoses, Journal of Carbohydrate Chemistry, 22:2, 143-147, DOI: 10.1081/
CAR-120020483
To link to this article: http://dx.doi.org/10.1081/CAR-120020483
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JOURNAL OF CARBOHYDRATE CHEMISTRY
Vol. 22, No. 2, pp. 143–147, 2003
Practical Synthesis of 1,2-O-Benzylidene and
1,2-O-p-Methoxybenzylidene Hexopyranoses
*
Katsuhiko Suzuki, Toshihumi Mizuta, and Masanori Yamaura
Department of Enviromental Science, Faculty of Science and
Engineering, Iwaki Meisei University, Fukushima, Japan
ABSTRACT
An improved and practical synthesis of 1,2-O-benzylidene and 1,2-O-p-methoxy-
benzylidene hexopyranoses as useful synthons in carbohydrate chemistry is described.
The reaction of 2-benzoyloxyglycosyl bromide with sodium borohydride using excess
amount of potassium iodide proceeded smoothly to give the corresponding 1,2-O-
benzylidene derivative in good yields.
Key Words: Benzylidene; Reductive acetalization; Protecting group.
INTRODUCTION
The benzylidene group has been widely used in organic synthesis to protect two
hydroxyl groups selectively and provide conformational stability.[1] A number of
studies involving regioselective ring-opening reactions have been performed in
carbohydrate chemistry[2] using 4,6-O-benzylidene protected sugars. In contrast, 1,2-
O-benzylidene sugar derivatives have not been frequently utilized.[3] The general nature
of the 1,2-O-benzylidene group is not well known, but this group is attractive as a
*
Correspondence: Masanori Yamaura, Department of Environmental Science, Faculty of Science
and Engineering, Iwaki Meisei University, 5-5-1 Iino, Chuohdai, Iwaki-shi, Fukushima 970-8551,
Japan; Fax: +81-246-29-0577; E-mail: yamaura@iwakimu.ac.jp.
143
DOI: 10.1081/CAR-120020483
0732-8303 (Print); 1532-2327 (Online)
www.dekker.com
Copyright D 2003 by Marcel Dekker, Inc.

144
Suzuki, Mizuta, and Yamaura
Figure 1. Reductive benzylidenation.
protecting and/or activating group for the anomeric position. The 1,2-O-benzylidene
group has been constructed by acetal exchange reactions of corresponding acetonide[4]
or orthoester[5] derivatives under acidic conditions. In addition, reduction of a 1,2-
trans-2-benzoyloxyglycosyl chloride using sodium borohydride generated the 1,2-O-
benzylidene group as shown in Figure 1.[6] Use of tetra-n-butyl ammonium iodide
(TBAI) in a reductive cyclization system was effective for the synthesis of 1,2-O-
benzylidene from 1,2-cis-2-benzoyloxyglycosyl chloride (A few reports using 1,2-O-
benzylidene derivatives were published. For example; Ref. [7]). However, this reaction
was not successful even if we performed it under similar conditions as previously
described (NaBH4 1.5 mol, TBAI 0.5 mol in MeCN). This result prompted us to
optimize the conditions of this reaction. In this communication, we would like to
report a practical synthesis of 1,2-O-benzylidenehexopyranoses as promising useful
glycosidic synthons.
RESULTS AND DISCUSSION
To compare the difference of the reactivity of 1,2-trans with 1,2-cis-2-ben-
zoyloxyglycosyl halide, two configurationally different types of glycosyl bromide, 1–4,
Table 1. Reductive 1,2-O-benzylidenation reaction.
Entry
Substrate
Condition*
Time
Product (yield %)
1
1
2
3
4
3
4
3
4
3
4
1
2
A
A
A
A
B
B
C
C
D
D
D
D
0.5 h
0.5 h
0.5 h
0.5 h
20 h
20 h
8 h
5 (96%)
6 (86%)
none
2
3
4
none
5
no reaction
no reaction
7 (85%)
8 (76%)
7 (98%)
8 (92%)
5 (94%)
6 (90%)
6
7
8
8 h
9
20 h
20 h
20 h
20 h
10
11
12
*A: NaBH4 (5.0 eq), MeCN, reflux; B: TBAI (0.5 eq), NaBH4 (1.5 ꢀ 5.0 eq), MeCN, rt ꢀ reflux;
C: TBAI (2.5 eq), NaBH4 (2.0 eq), MeCN, rt; D: KI (1.5 eq), NaBH4 (1.0 eq), MeCN, rt.

Practical Synthesis of Hexopyranoses
145
Figure 2. Substrates and products.
manno- and gluco-type, were prepared as substrates. The results of the reductive ben-
zylidenation are shown in Table 1 (Figure 2).
To a solution of manno-type bromide 1 or 2 in acetonitrile was added 5 equiv of
sodium borohydride. The mixture was stirred for 30 min at reflux temperature to afford
1,2-O-benzylidene derivatives 5, 6 (entry 1, 2).a Under these conditions, gluco-type
bromides 3 or 4 were not converted to the corresponding 1,2-O-benzylidene derivatives
but gave complex mixtures.b Apparently, the oxocarbenium-ion intermediate, which is
necessary for the reductive acetalization, did not form when starting from 3 or 4, as it
did from the 1,2-cis glycosyl halide (entry 3,4). Addition of TBAI, which reacts with
the 1,2-cis glycosyl halide to give the 1,2-trans glycosyl halide, should be able to
promote the construction of a 1,2-O-benzylidene derivative from a 1,2-cis glycosyl
halide. However, using the previously reported conditions (NaBH4 1.5 mol, n-Bu4NI
0.5 mol, acetonitrile), the 1,2-O-benzylidene group was not produced at all and starting
materials 3 and 4 were recovered (entry 5, 6).c We thought that excess NaBH4 trapped
the iodide ion necessary for the halogen exchange of 1,2-cis glycosyl halide. This
hypothesis was supported by results of carrying out the reaction using excess TBAI
(entry 7, 8). Use of potassium iodide (KI) as an inexpensive iodide ion source was
much more effective for this reaction (entry 9, 10). In the reactions using KI, manno-
type glycosyl bromide 1 or 2 were converted at room temperature to the corresponding
1,2-O-benzylidene 5 and 6 in a satisfactory yield, respectively (entry 11, 12).
1
The structures of 1,2-O-benzylidene derivatives 5 and 6 were confirmed by H
NMR. A NOE was observed between H-2 and the methine proton of the benzylidene
aSelected spectral data for 3,4,6-tri-O-p-methoxybenzoyl-1,2-O-p-methoxybenzylidene-a-D-man-
nopyranose 6: 1H NMR (CDCl3) d 6.12 (dd, J3,4 = 10.1, J4,5 = 9.9 Hz, H-4), 5.95 (s, ben-
zylidene), 5.67 (dd, J2,3 = 3.5, J3,4 = 10.1 Hz, H-3), 5.58 (d, J1,2 = 1.8 Hz, H-1), 4.80 (dd, H-2),
4.65 (dd, J5,6a = 2.2, J6a,6b = 12.3 Hz, H-6a), 4.36 (dd, J5,6b = 3.3 Hz, H-6b), 4.10 (ddd, H-5);
3,4,6-tri-O-p-methoxybenzoyl-1,2-O-p-methoxybenzylidene-a-D-glucopyranose 8(R): 1H NMR
(CDCl3) d 5.92 (s, benzylidene), 5.87 (d, J1,2 = 5.1 Hz, H-1), 5.71 (dd, J2,3 = 2.9, J3,4 = 1.8
Hz, H-3), 5.50 (ddd, J2,4 = 1.1, J4,5 = 8.8 Hz, H-4), 4.62 (dd, J5,6a = 2.6, J6a,6b = 11.7 Hz,
H-6a), 4.52 (m, H-5), 4.45 (m, H-2), 4.41 (dd, J5,6b = 5.1 Hz, H-6b).
bAll of glycosyl bromides underwent decomposition, and the products were not isolated.
cA small amount of the glycal, 2,3,4,6-tetra-O-benzoyl-D-glucal was obtained in the heating
condition.

146
Suzuki, Mizuta, and Yamaura
Scheme 1. Less hindered side attack of H- and the NOE observation with the manno-type 1,2-O-
benzylidene 5 or 6.
group. The highly stereoselective formations of the (R)-benzylidene isomer may be due
to attack by the borohydride ion on the sterically less hindered side of the acyloxonium
ion intermediate (Scheme 1). The gluco-type 1,2-O-benzylidene product mixture 7 and
1
8,a whose H NMR spectrum showed a (R): (S) = 7: 3 diastereomeric mixture at the
benzylidene position, was converted into the known 3,4,6-tri-O-acetate.d Interestingly,
the gluco and manno types of benzylidene derivatives have different pyranose ring
4
conformations. A large coupling of the J3,4 indicates C1 in manno type 5 and 6, but
4
small coupling of the J2,3, J3,4 and the characteristic long-range coupling J2,4 in gluco
type 7 and 8 implies a flexible (skew-boat) conformation.[8] These conformation
differences may account for the different reactivity in ring-opening reactions of the
1,2-O-benzylidene group.
Thus, a practical synthesis of 1,2-O-benzylidenehexopyranoses as useful synthons
in carbohydrate chemistry was accomplished.
REFERENCES
1. Greene, T.W.; Wuts, P.G.M. Protective Groups in Organic Synthesis, 3rd Ed.; John
Wiley & Sons, Inc.: New York, 1999.
2. Hanessian, S. Preparative Carbohydrate Chemistry, 1st Ed.; Marcel Dekker, Inc.:
New York, 1997.
3. Lemieux, R.U.; Detert, D.H. 1,2-O-Alkylidene and 1,2-O-ortholactone derivatives
of 3,4,6-Tri-O-acetyl-a-D-glucose. Can. J. Chem. 1968, 46, 1039–1040.
4. Ress, R.G.; Tatchell, A.R.; Wells, R.D. 1,2-O-Alkylidene a-D-glucopyranoses. Part
I. The diastereoisomeric 1,2-O-(1-Methylpropylidene)-a-D-glucopyranoses. J.
Chem. Soc., C 1967, 1768–1772.
5. Dick, W.E., Jr.; Weisleder, D.; Hodge, J.E. Dioxorane configuration in diaste-
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NMR spectroscopy. Carbohydr. Res. 1972, 23, 229–242.
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amount of sodium methoxide in methanol, then acetylated with acetic anhydride in pyridine to
give 3,4,6-tri-O-acetyl-1,2-O-benzylidene derivative[5] which was separable into its diastereo-
meric components.

Practical Synthesis of Hexopyranoses
147
6. Betaneli, V.I.; Ovchinnikov, M.V.; Backinowsky, L.V.; Kochetkov, N.K. A con-
venient synthesis of 1,2-O-Benzylidene derivatives of carbohydrates. Carbohydr.
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Received July 24, 2002
Accepted January 29, 2003