A facile synthesis of 4,6-O-benzylidene-d-glycals via 1,5-anhydro-4,6-O-benzylidene-d-hex-1-en-3-ulose

Article abstract of DOI:10.1016/j.carres.2008.05.018

Benzylidenation of readily available 1,5-anhydro-d-hex-1-en-3-ulose, followed by sodium borohydride reduction, afforded the title compounds in high yields. Separation of 4,6-O-benzylidene-d-allal and -d-glucal was accomplished by selective acetylation wit

Full text of DOI:10.1016/j.carres.2008.05.018

Carbohydrate Research 343 (2008) 2740–2743
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A facile synthesis of 4,6-O-benzylidene-D-glycals via
1,5-anhydro-4,6-O-benzylidene-D-hex-1-en-3-ulose
*
Tohru Sakakibara , Tsubasa Ito, Chika Kotaka, Yasuhiro Kajihara, Yuhya Watanabe, Aki Fujioka
Department of Chemistry, Graduate School of Integurated Science, Yokohama City University, Seto Kanazawa-ku, Yokohama 236, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 April 2008
Received in revised form 20 May 2008
Accepted 22 May 2008
Available online 14 June 2008
Benzylidenation of readily available 1,5-anhydro-
D
-hex-1-en-3-ulose, followed by sodium borohydride
reduction, afforded the title compounds in high yields. Separation of 4,6-O-benzylidene-
-glucal was accomplished by selective acetylation with lipase PS.
Ó 2008 Elsevier Ltd. All rights reserved.
D-allal and
-
D
Keywords:
Glycal
Benzylidenation
1-En-3-ulose
Lipase PS
1. Introduction
2. Results and discussion
Glycals (1,5-anhydro-1-enitols) have proven to be excellent
starting materials for various syntheses of sugar derivatives. Parti-
cularly noteworthy in this regard is their use as substrates for
oligosaccharide synthesis,1 for Ferrier rearrangement (glycosida-
tion),2 and for Danishefsky’s glycosylation method.3 Selective 4,6-
O-protection of a glycal is useful since it allows modification of
the remaining 3-hydroxyl group. In this context, 4,6-O-benzylidene
glucal is extremely desirable since the regioselective cleavage of
the protecting group has already been established to afford the de-
sired 4-O-benzyl (6-hydroxyl)4 or the 6-O-benzyl (4-hydroxyl)
derivative.5 4,6-O-Benzylidene glucal was originally prepared from
the free glucal under standard, acidic conditions.6 However, the
yield was low because of the acid sensitivity of the glucal. Im-
proved methods for preparation of these target compounds have
thereafter been reported from methyl,7 thiophenyl,8 selenophe-
nyl,9 sulfone,8,10 and sulfinyl glycosides.11
Treatment of
dimethylacetal in the presence of ( )-10-camphorsulfonic acid
afforded 4,6-O-benzylidene- -threo-hex-1-en-3-ulose (2) in 94%
D-threo-hex-1-en-3-ulose (1) with benzaldehyde
D
yield. However, a similar reaction of the erythro isomer 5 did not
go to completion, and starting material 5 still remained, even when
the reaction time was prolonged and additional benzaldehyde
dimethylacetal was added. Thus, the acid sensitivities for the threo
2 and erythro isomer 6 seem to be fairly different. In fact when
erythro isomer 6 was treated with ( )-10-camphorsulfonic acid in
the presence of benzaldehyde dimethylacetal and methanol (gen-
erated as the benzylidenation occurs) for 3 h at 80 °C, about half
the amount of 6 was debenzylidenated, whereas similar treatment
of threo isomer 2 resulted in the recovery of 2.
To get some information about stability, we performed an ab
initio calculation (B3LYP/6-31+G*)15 of starting materials 1 and 5
as well as benzylidene derivatives 2 and 6. The most stable con-
formers calculated are shown in Figure 1, in which, as expected,
hydrogen bonding was observed between the hydroxyl group at
C-4 (4-OH) and the carbonyl group as well as between 6-OH and
O-4. For the 4,6-O-benzylidene derivative, the threo isomer 2 is
more stable than erythro one 6 by 1.1 kcal/mol, whereas for start-
ing materials threo isomer 1 is less stable than the erythro isomer 5
by 1.5 kcal/mol. These results are not in conflict with the experi-
mental results.
We have employed 1,5-anhydro-hex-1-en-3-uloses 1 and 5 for
the preparation of 4,6-O-benzylidene-D-glycals, because these
compounds, which are readily prepared from per-O-acetyl-
D
-gly-
cals in high yield,12 should withstand acidic conditions. Although
expensive Pd/C was used as a catalyst in the preparation of 1 and
5, it is recycled at least three times.13 Furthermore, a very recently
improved method, using nitrobenzene as hydrogen acceptor, is
reported.14
When less acidic pyridinium p-toluenesulfonate (PPTS)16 was
used instead of ( )-10-camphorsulfonic acid, the intended 6 was
obtained in 80% yield (Scheme 1).
* Corresponding author. Tel.: +81 45 787 2183.
E-mail address: baratoru@yokohama-cu.ac.jp (T. Sakakibara).
0008-6215/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2008.05.018

T. Sakakibara et al. / Carbohydrate Research 343 (2008) 2740–2743
2741
28% yields, respectively, after short column chromatography on sil-
ica gel. Deacetylation of 11 was accomplished by treatment with
NaOMe in methanol to give glucal 7 in 98% yield. Without separa-
tion of these two products, 7 and 9, their acetates should become
substrates for the Ferrier glycosidation, because the reaction is
believed to proceed via the same oxocarbonium ion. To investigate
the reaction mechanism, formation of both glucal 7 and allal 9
from 6 and their facile separation have advantage.
The 3-deuterio-derivatives 4, 8, and 10 were readily prepared
by the use of sodium borodeuteride.
In conclusion, a facile, high-yielding, inexpensive synthesis of
4,6-O-benzylidene glycals has been achieved. Not only the 4,6-O-
benzylideneglycals, but also their precursors, 1,5-anhydro-4,6-O-
benzylidene-D-hex-1-en-3-ulose, have potential utility as glycos-
idation donors.17
3. Experimental
3.1. General methods
All melting points are uncorrected. 1H and 13C NMR spectra
(Bruker Advance 400, 400, and 100.6 MHz, respectively) were
recorded using Me4Si as an internal standard. IR spectra were
recorded for KBr pellets. The reaction mixture was dried over
MgSO4 and evaporated under diminished pressure. Column
chromatography was conducted on silica gel (Wakogel C-300).
Figure 1. Most stable conformers obtained by ab initio calculation.
Sodium borohydride reduction of the enone 2 in the presence of
CeCl3Á7H2O proceeded with high stereoselectivity to afford the
galactal 3 in 86% yield. Similar reduction of erythro isomer 6 gave
a ca. 2.6:1 mixture of glucal 7 and allal 9 in 91% yield.
Although we managed to separate these two products by silica
gel column chromatography, selective acetylation with lipase PS
(Burkholderia) is much superior; only the glucal was acetylated.
Thus, the acetate 11 and 3-O-free 9 were obtained in 72% and
3.2. Preparation of 1,5-anhydro-4,6-O-benzylidene-2-deoxy-D-
threo-hex-1-en-3-ulose (2)
A
solution of 1,5-anhydro-D
-threo-hex-1-en-3-ulose (1)12
(200 mg, 1.39 mmol) in distd MeCN (0.58 mL) and benzaldehyde
dimethyl acetal (320 mg, 2.10 mmol) was warmed at 80–90 °C
under an Ar atmosphere, to which ( )-10-camphorsulfonic acid
Ph
O
Ph
OH
O
HO
O
O
O
O
CeCl3 7H2O, EtOH
PhCH(OMe)2
O
O
O
CSA, MeCN
NaBH4 or NaBD4
86%
HO
80–90 oC, 94%
R
1
3 R = H
2
4
R = D
OH
Ph
O
Ph
O
O
O
CeCl3 7H2O, EtOH
O
O
PhCH(OMe)2
O
R1
HO
NaBH4 or NaBD4
91%
PPTS, MeCN
80–90 oC, 80%
R2
O
O
7 R1 = OH, R2= H
8 R1 = OH, R2= D
5
6
9 R1 = H, R2= OH
10 R1 = D, R2= OH
Ph
O
O
Lipase PS vinylacetate
O
9
9
7
AcO
0.1 M phosphoric acid buffer
40-45 ºC, 4.5 h, ~100%
11
Scheme 1.

2742
T. Sakakibara et al. / Carbohydrate Research 343 (2008) 2740–2743
(64 mg, 0.28 mmol) was added and kept for 10 min. After addition
of Et3N (57.8 L, 0.42 mmol), the solvent was evaporated, and the
residue was extracted with EtOAc. The extracts were washed with
satd aq NaCl, dried, and evaporated. The residue was chromato-
graphed on silica gel with 2:1, v/v, hexane–EtOAc to give 304 mg
(94%) of 2, 1H NMR data of which were identical with an authentic
was added. After stirring for 20 min, aq M HCl was added to the
solution, and the solvent was evaporated. The residue was
extracted with Et2O, and the extracts were washed with water,
satd NH4Cl, and satd NaCl, dried, and filtered. The filtrate was then
concentrated. The residue was chromatographed on silica gel
eluting with 3:1, v/v, hexane–EtOAc to afford a ca. 2.6:1 mixture
l
sample of 2: mp 170–171 °C, lit.18 mp 165–166 °C, [
a]
D 170.4 (c 1.1,
of
D-glucal and
D-allal (895 mg, 91%).
CHCl3), lit.18 186 (c 1, CHCl3);
m
668, 1596 cmÀ1, lit.18 1680, 1600
Similar reduction of 6 (50 mg, 0.2 mmol) with NaBD4 gave a
mixture of 8 and 10. Compounds 7 and 9 were separated by the
following method.
(C@O, C@C); 1H NMR of 6 (CDCl3): d 7.26–7.52 (m, 6H, H-1 and
aryl), 5.36 (dd, 1H, J1,2 6.2, J2,4 1.2 Hz, H-2), 4.21–4.22 (m, 2H,
H-4, H-5), 4.16 (dd, 1H, J5,6a 1.2, J6a,6e 13.0 Hz, H-6a), 4.51 (dd,
1H, J5,6e 1.6 Hz, H-6e), 5.63 (s, 1H, PhCH). 13C NMR (CDCl3): d 186.1,
164.7, 137.3, 129.7, 128.7, 126.6, 105.9, 101.1, 75.6, 73.6, 68.4.
3.6. Separation of 4,6-O-benzylidene-D-glucal 7 and D-allal 9
with lipase PS
3.3. Preparation of 4,6-O-benzylidene-
D
-galactal (3)
To a mixture of 7 and 9 (150 mg, ca. 2.6:1, 0.640 mmol) in vinyl
acetate (13 mL) were added lipase PS (Burkholderia) (172 mg) on
Celite (577 mg) and 0.1 M phosphoric acid buffer solution
To stirred ethanolic solution (7.6 mL) of
a
2 (176 mg,
0.758 mmol) was added CeCl3Á7H2O (423 mg, 1.14 mmol) under
an Ar atmosphere. After the CeCl3Á7H2O was dissolved, the mixture
was cooled with ice-water, sodium borohydride (42.9 mg,
1.13 mmol)19 was added, and the mixture was kept for 5 min with
stirring, to which aq M HCl was added. After evaporation of the sol-
vent, the mixture was extracted with CH2Cl2, and the extracts were
washed with water, satd aq NH4Cl, and satd aq NaCl, dried, and fil-
tered, and then the filtrate was evaporated. The residue was chro-
matographed on silica gel eluting with 2:1, v/v, hexane–EtOAc to
afford 153 mg (86%) of 3: mp 151–152 °C, lit.8 mp 151–152 °C,
(575
l
L) with stirring. (lipase PS on Celite was prepared by stirring
Celite, lipase PS, and 0.1 M phosphoric acid (575
lL) overnight, fol-
lowed by drying over P2O5 under reduced pressure using a vacuum
pump.) The stirred mixture was warmed at 40–45 °C for 4.5 h and
then filtered. The filtrate was concentrated, and the residue was
chromatographed with 6:1, and 3:1, v/v, hexane–EtOAc to give
the acetate 116 (127 mg, 72%) and 3-O-free 9 (42 mg, 28%): mp
81–84 °C, lit.22 mp 83–84 °C, lit.23 mp 83.5 °C, [
a] 208.2 (c 0.5,
D
EtOH), lit.22 219 (c 3.2, EtOH), lit.23 209.5 (c 2, EtOH). Compound
11 is known, but its NMR spectrum was determined in pyridine-
d6. NMR data in CDCl3 are described in the following.
[a]
47.3 (c 1.0, CHCl3), lit.8 47 (c 1, CHCl3). The 1H NMR data for
D
3 were almost the same as those reported in the literature.8 1H
NMR (CDCl3): d 6.49 (dd, 1H, J1,2 6.4, J1,3 1.9 Hz, H-1), 4.80 (ddd,
1H, J2,3 1.7, J2,4 1.8 Hz, H-2), 4.56 (m, 1H, H-3), 4.26 (br d, 1H, J3,4
5.1 Hz, H-4), 3.96 (br s, 1H, H-5), 4.42 (dd, 1H, J5,6a 1.9, J6a,6e
12.4 Hz, H-6a), 4.09 (dd, 1H, J5,6e 0.9 Hz, H-6e), 7.34–7.60 (m, 5H,
aryl), 5.73 (s, 1H, PhCH), 2.55 (br d, 1H, J3,OH 11.0 Hz, OH). 13C
NMR (CDCl3): d 144.2, 137.9, 129.7, 128.7, 126.7, 102.5, 101.7,
72.8, 69.8, 68.5, 63.3.
1H NMR of 11: d 6.39 (dd, 1H, J1,2 6.1, J1,3 1.7 Hz, H-1), 4.80 (dd,
1H, H-2), 5.45 (dt, 1H, J2,3 1.9, J3,4 8.8 Hz, H-3), 4.02 (d, 1H, J4,5
10.2 Hz, H-4), 3.99 (dt, 1H, J5,6a 10.2, J5,6e 4.2 Hz, H-5), 3.84 (t, 1H,
J6a,6e 10.4 Hz, H-6a), 4.39 (dd, 1H, H-6e), 7.49 (d, 2H, Ph), 7.37 (d,
2H, Ph), 5.59 (s, 1H, PhCH), 2.08 (s, 3H, OCOMe). 13C NMR (CDCl3):
d 145.1 (C-1), 100.6 (C-2), 68.8 (C-3), 68.64 (C-4), 68.7 (C-5), 68.2
(C-6), 170.7 (OCO), 21.1 (OCOMe).
Similar reduction of 2 (50 mg, 0.2 mmol) with NaBD4 gave
50.1 mg (99%) of 4.
3.7. Deacetylation of 11 with NaOMe in MeOH
To a stirred methanolic solution of 11 (100 mg, 0.362 mmol)
3.4. Preparation of 1,5-anhydro-4,6-O-benzylidene-2-deoxy-
erythro-hex-1-en-3-ulose (6)
D
-
was added M NaOMe (2 mg, 0.04 mmol). After stirring for
105 min, the solution was deionized with Amberlite IR-120 (H+)
and filtered. The filtrate was concentrated and the residue was
chromatographed on silica gel with 3:1, v/v, hexane–EtOAc to give
83 mg (98%) of 7: mp 144–145 °C, lit.6 mp 142–143 °C, lit.9 mp
A
solution of 1,5-anhydro-D
-erythro-hex-1-en-3-ulose (5)12
(760 mg, 5.27 mmol) and benzaldehyde dimethyl acetal
(1613 mg, 10.60 mmol) in distd MeCN (53 mL) was warmed at
80–90 °C under an Ar atmosphere, to which PPTS (266 mg,
1.06 mmol) was added. After 170 min, an additional benzaldehyde
dimethyl acetal (1613 mg) was added to the mixture, which was
kept for 120 min, and cooled at room temperature. After addition
140–143 °C, [
a]
D
À15.8 (c 2.3, CHCl3), lit.6 À19 (c 0.63, CHCl3),
lit.9 À15.8 (c 0.83, CHCl3).
3.8. Treatment of benzylidene derivatives 2 and 6 with ( )-10-
camphorsulfonic acid
of Et3N (150 lL, 1.1 mmol), the mixture was concentrated, and
the residue was chromatographed on silica gel with 3:1, v/v,
To a stirred solution of 30 mg (0.13 mmol) of the threo isomer 2,
benzaldehyde dimethylacetal (19.7 mg, 0.13 mmol), MeOH (5.0 lL,
0.12 mmol), and MeCN (0.58 mL) at 80 °C under an Ar atmosphere
was added ( )-10-camphorsulfonic acid (6.0 mg, 0.03 mmol), and
hexane–EtOAc to give 975 mg (80%) of 6: mp 127–129 °C, lit.20
mp 128–129 °C, [
a
]
189 (c 0.5, CHCl3), lit.21 189 (c 0.8, CHCl3).
D
The 1H NMR data of which were taken in CDCl3,20 but some signals
were overlapped. The spectrum in C6D6 gave better signals for
analysis. 1H NMR of 6 (C6D6): d 6.39 (d, 1H, J1,2 6.0 Hz, H-1), 5.15
(d, 1H, H-2), 3.83 (d, 1H, J4,5 12.3 Hz, H-4), 3.94 (ddd, J5,6a 9.5,
J5,6e 4.9 Hz, H-5), 3.44 (dd, 1H, J6a,6e 9.6 Hz, H-6a), 4.00 (dd, 1H,
H-6e), 5.23 (s, 1H, PhCH), 7.20–7.75 (m, 5H, aryl).
the solution was kept for 3 h. After addition of Et3N (5.4 lL,
0.39 mmol), the solvents were evaporated. The residue was
extracted with EtOAc and the extracts were washed with satd aq
NaCl, dried, and filtered. The filtrate was concentrated, and the
1H NMR spectrum of the residue revealed the recovery of 2.
Similar treatment of erythro isomer 6 gave ca. 1:1 mixture of 6
and debenzylidenated 5.
3.5. Preparation of 4,6-O-benzylidene-D-glucal (7) and allal (9)
To a stirred ethanolic solution (42 mL) of 6 (975 mg, 4.20 mmol)
under an Ar atmosphere was added CeCl3Á7H2O (2.3 g, 6.2 mmol).
After the addition of CeCl3Á7H2O, the mixture was cooled with
ice-water, and then sodium borohydride (240 mg, 6.35 mmol)
Acknowledgment
We gratefully acknowledge Dr. Masakiko Hayashi for kind
advice to preparation of compounds 1 and 5.

T. Sakakibara et al. / Carbohydrate Research 343 (2008) 2740–2743
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