Efficient synthesis of rare sugar D-allal via reversal of diastereoselection in the reduction of protected 1,5-anhydrohex-1-en-3-uloses: Protecting group dependence of the stereoselection

Article abstract of DOI:10.1021/jo801596q

(Chemical Equation Presented) D-Allal was selectively obtained by reducing bulky-silyl-protected 1,5-anhydrohex-1-en-3-uloses using the NaBH₄ - CeCl₃·7H₂O system. The crucial point of this synthesis is the nature of the pr

Full text of DOI:10.1021/jo801596q

require many steps and relatively expensive starting materials.
Therefore, the development of a simple and efficient method
has been much awaited. Several methods have been reported
for the synthesis of protected D-allal, a glycal type of D-allose.5
However, to our knowledge, there are only a handful of reports
of the efficient synthesis of D-allal. Danishefsky’s method
involves the stereospecific oxygenation at C-3 of tri-O-acetyl-
D-glucal-derived sulfoxides in a [2,3]-sigmatropic rearrangement,
followed by base-catalyzed acetyl migration from O-4 to O-3.6
Diaz and Castillon recently reported a synthetic route to allal
and glucal derivatives, which is based on a sequential process
involving olefination-cyclization-elimination, using pentoses as
starting material.7 Danishefsky and co-workers reported oli-
gosaccharide synthesis based on glycosidation using glycal as
glycosyl donor/acceptor.8 Therefore, the development of an
efficient method for the synthesis of D-allose is also important
from the viewpoint of the synthesis of oligosaccharides contain-
ing a rare sugar. We describe in this communication the facile
synthesis of D-allal based on the chemo- and diastereoselective
reduction of protected 1,5-anhydrohex-1-en-3-uloses.
Efficient Synthesis of Rare Sugar D-Allal via
Reversal of Diastereoselection in the Reduction of
Protected 1,5-Anhydrohex-1-en-3-uloses:
Protecting Group Dependence of the
Stereoselection
Takashi Fujiwara and Masahiko Hayashi*
Department of Chemistry, Graduate School of Science, Kobe
UniVersity, Nada, Kobe 657-8501
mhayashi@kobe-u.ac.jp
ReceiVed July 31, 2008
In 1999, we were the first to report a Pd/C-ethylene system
for the oxidation of benzylic and allylic alcohols to correspond-
ing ketones.9 A representative example of this reaction is shown
below. Treatment of D-glucal (1,5-anhydro-2-deoxy-D-arabino-
hex-1-enitol) with a catalytic amount of Pd/C under hydrogen
atmosphere in ethanol gave “normal” hydrogenated 2-deoxy-
1,5-anhydroglucitol (D-r-2-hydroxymethyl-tetrahydropyran-t-3,
c-4-diol) in 92% yield. In contrast, when the same reaction was
employed under ethylene atmosphere, dehydrogenated 1,5-
anhydro-2-deoxy-D-erythro-hex-1-en-3-ulose was obtained in
97% yield (Scheme 1).10 It should be mentioned that the reaction
under argon atmosphere gave hydrogenated and dehydrogenated
products in almost the same ratio.
D-Allal was selectively obtained by reducing bulky-silyl-
protected
1,5-anhydrohex-1-en-3-uloses
using
the
NaBH4sCeCl3 · 7H2O system. The crucial point of this
synthesis is the nature of the protecting group. When bulky
silyl group such as t-butyldiphenylsilyl was used as substrate,
protected D-allal was obtained in >99% selectivity. In
contrast, when acetylated enone was used, protected D-glucal
was obtained exclusively. The addition of CeCl3 · 7H2O was
also found to influence selectivity.
SCHEME 1. Treatment of D-Glucal with a Catalytic
Amount of Pd/C under Ethylene Atmosphere
Rare sugars have received much attention from the viewpoint
of biological activity, such as their ability to act as inhibitors
of various glycosidases.1 However, in spite of their potential
importance in medicine and pharmacy, studies of their biological
effects are limited because of low natural abundance and
difficulty in synthesis. In the synthesis of D-allose, an enzymatic
method2 and several chemical methods have been reported. As
examples of the chemical method, Humoller reported in 1962 a
method starting from D-ribose using cyanohydrins,3 while Baker
et al. reported the reduction of 1,2,5,6-di-O-isopropylidene-R-
D-ribo-hexofuranos-3-ulose hydrate.4 Those methods generally
Our strategy for the preparation of D-allal is to reduce the
carbonyl moiety of 1,5-anhydrohex-1-en-3-ulose that can be
easily obtained according to the above method in a chemose-
lective and stereoselective manner. If the hydride attack takes
place from the ꢀ-face of the carbonyl group, D-allal will be
obtained efficiently (Scheme 2).
After examining various reducing agents and reaction condi-
tions, we found that D-allal type 2 was obtained predominantly
by reducing silyl-protected 1,5-anhydrohex-1-en-3-uloses using
(1) (a) Rees, W. D.; Holman, G. D. Biochim. Biophys. Acta 1981, 646, 251–
260. (b) Hossain, M. A.; Wakabayashi, H.; Goda, F.; Kobayashi, S.; Maeta, T.;
Maeta, H. Transplant. Proc. 2000, 32, 2021–2023. (c) Hossain, M. A.; Izuishi,
K.; Maeta, H. J. Hepatobiliary Pancreat. Surg. 2003, 10, 218–225. (d) Murata,
A.; Sekiya, K.; Watanabe, Y.; Yamaguchi, F.; Hatano, N.; Izumori, K.; Tokuda,
M. J. Biosci. Bioeng. 2003, 96, 89–91, and references cited therein.
(2) Tamura, O.; Hashimoto, M.; Kohayashi, Y.; Katoh, T.; Nakatani, K.;
Kamada, M.; Hayakawa, I.; Akiba, T.; Terashima, S. Tetrahedron Lett. 1992,
33, 3487–3490, and references therein.
(5) For the synthesis of benzylidene D-allal: (a) Kaluza, Z.; Chmielewski,
M. Tetrahedron 1989, 45, 7195–7200. (b) Sharma, M.; Brown, R. K. Can.
J. Chem. 1966, 44, 2825–2835. (c) Godage, H. Y.; Fairbanks, A. J. Tetrahedron
Lett. 2003, 44, 3631–3635. For the synthesis of D-allal: (d) Guthrie, R. D.; Irvine,
R. W. Carbohydr. Res. 1979, 72, 285–288.
(6) Wittman, M. D.; Halcomb, R. L.; Danishefsky, S. J.; Golik, J.; Vyas, D.
J. Org. Chem. 1990, 55, 1979–1981.
(3) Humoller, F. L. Methods Carbohydr. Chem. 1962, 1, 102–104.
(4) Baker, D. C.; Horton, D.; Tindall, C. G. Carbohydr. Res. 1972, 24, 192–
197.
10.1021/jo801596q CCC: $40.75
Published on Web 10/14/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9161–9163 9161

TABLE 1. Reduction of 4,6-Diprotected
1,5-Anhydro-2-deoxy-D-erythro-hex-1-en-3-uloses
SCHEME 2. Chemoselective and Stereoselective Reduction
of 1,5-Anhydrohex-1-en-3-ulose
entry
R
methoda
time/h
yield/%b
ratioc 2:3
1
2
3
4
5
6
7
8
H
H
MeCO
A
B
A
B
A
B
A
B
A
B
A
B
A
B
1
1
1
1
5
1
4
1
4
4
5
2
5
2
53
21
73
61
67
62
71
58
64
41
76
23
82
18
23:77
3:97
22:78
0:100
69:31
7:93
42:58
5:95
77:23
22:78
98:2
MeCO
Me3CCO
Me3CCO
PhCO
the NaBH4-CeCl3 ·7H2O system11 (method A). As shown in
Table 1, when t-butyldimethylsilyl ether of 1,5-anhydrohex-1-
en-3-ulose was employed under the conditions for method A,
the ratio of the reduction product, that is, protected D-allal type
(2):protected D-glucal type (3), was 77:23 (entry 9). In contrast,
in the case of acetylated 1,5-anhydrohex-1-en-3-ulose, the ratio
of protected (2):protected (3) was 0:100 (method B, entry 4).
Encouraged by these reversal results, we examined the nature
of the silyl group. We changed the silyl group to a more bulky
group and found that when bulky silyl groups such as triiso-
propylsilyl and t-butyldiphenylsilyl were used, the ratio of D-allal
type (2) increased to afford protected D-allal type in >99%
selectivity (entry 13). The addition of CeCl3 ·7H2O was also
found to influence the direction of the hydride attack. For
example, even when triisopropylsilyl ether and t-butyldiphe-
nylsilyl ether were used, the ratios of 2:3 decreased to 94:6 and
91:9, respectively, in the absence of CeCl3 ·7H2O (method A,
entries 12 and 14), and the chemical yields were also low. When
t-butyldimethylsilyl ether was used, the ratio of 2:3 was reversed
from 77:23 (method A, entry 9) to 22:78 (method B, entry 10).
On the other hand, in the case of acylated 1,5-anhydrohex-1-
en-3-uloses, method B always afforded glucal type 3 in high
selectivity (R ) acetyl, 2b:3b ) 0:100; R ) benzoyl, 2d:3d )
5:95; R ) pivaloyl, 2c:3c ) 7:93).10 It should be mentioned
that when unprotected 1,5-anhydrohex-1-en-3-ulose was treated
with a combination of NaBH4 and CeCl3 ·7H2O, glucal type 3
was obtained predominantly (method A, 23:77; method B, 3:97),
although the chemical yield was moderate or low (53 and 21%,
respectively, entries 1 and 2).
PhCO
9
t-BuMe2Si
t-BuMe2Si
i-Pr3Si
i-Pr3Si
t-BuPh2Si
t-BuPh2Si
10
11
12
13
14
94:6
>99:1<
91:9
a Method A: 1.0 equiv of CeCl3 ·7H2O was added. Method B:
CeCl3 ·7 H2O was not added. b Isolated yield after silica gel column
chromatography. c Ratio was determined by 1H NMR analysis afer
peracetylation of a crude mixture.
In the case of protected D-galactal (1,5-anhydro-2-deoxy-D-
threo-hex-1-en-3-ulose), the protecting group did not have a
marked effect on stereoselectivity, as shown in Table 2.
Regardless of the nature of the protecting group at 4 and 6
positions, galactal type 6 was obtained.10
TABLE 2. Reduction of 4,6-Diprotected
1,5-Anhydro-2-deoxy-D-threo-hex-1-en-3-uloses
entry
R
methoda
time/h
yield/%b
ratioc 5:6
1
2
3
4
CH3CO
CH3CO
t-BuPh2Si
t-BuPh2Si
A
B
A
B
1
1
4
3
77
58
79
63
2:98
0:100
5:95
The isolated yield was determined after reduction by silica
gel column chromatography. The ratio of 2 to 3 was determined
1
0:100
by H NMR analysis after desilylation and peracetylation in
a Method A: 1.0 equiv of CeCl3 ·7 H2O was added. Method B:
CeCl3 ·7 H2O was not added. b Isolated yield after silica gel column
chromatography. c Determined by 1H NMR analysis afer peracetylation
of a crude mixture.
the case of silylated substrates, whereas in the case of acylated
substrates, deacylation (if necessary) and peracetylation were
performed to estimate the ratio correctly by derivatizing to
3-epimers of peracetylated products.
(7) Bouturelia, O.; Rodriguez, M. A.; Mathey, M. I.; Diaz, Y.; Castillon, S.
Org. Lett. 2006, 8, 673–675.
As for reaction mechanism, the conformation of substrate
enone should be important for consideration of stereoselective
reduction, especially to explain the effect of protecting groups
and reducing agents on stereoselectivity, steric environment at
3-position should affect the course of stereoselective reduction.
The detailed study is now ongoing.
In summary, NaBH4 reduction in the presence of 1 equiv of
CeCl3 ·7H2O (method A) and NaBH4 reduction in the absence
of 1 equiv of CeCl3 ·7H2O (method B) of 4,6-di-O-acetyl-1,5-
anhydro-2-deoxy-D-erythro-hex-1-en-3-ulose and 4,6-di-O-di-
phenyl-t-butylsiloxy derivatives gave the glucal type and its
3-epimer allose derivative in >99% selectivity, respectively.
(8) (a) Danishefsky, S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl.
1996, 35, 1380–1419. (b) Seeberger, P. H.; Bilodeau, M. T.; Danishefsky, S. J.
Aldrichim. Acta 1997, 30, 70–92. (c) Roberge, J. Y.; Beebe, X.; Danishefsky,
S. J. J. Am. Chem. Soc. 1998, 120, 3915–3927. See also: (d) MacDonald, F. E.;
Zhu, H. Y. H. J. Am. Chem. Soc. 1998, 120, 4246–4247. (e) Thiem, J.; Gerken,
M. J. Org. Chem. 1985, 50, 954–958.
(9) (a) Hayashi, M.; Yamada, K.; Arikita, O. Tetrahedron Lett. 1999, 40,
1171–1174. (b) Hayashi, M.; Yamada, K.; Nakayama, S.; Hayashi, H.; Yamazaki,
S. Green Chem. 2000, 257–260. (c) Hayashi, M.; Kawabata, H. Environmentally
Benign Oxidation of Alcohols Using Transition Metal Catalysts. In AdVances
in Chemistry Research; Gerard, F. L., Ed.; Nova Science Publishers, Inc: New
York, 2006; pp 45-64.
(10) Hayashi, M.; Yamada, K.; Arikita, O. Tetrahedron. 1999, 55, 8331–
8340.
(11) Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226–2227.
9162 J. Org. Chem. Vol. 73, No. 22, 2008

was added slowly. The mixture was stirred at 0 °C for 4 h; after
confirmation of the consumption of the starting material by TLC,
the mixture was quenched with H2O (5 mL). After allowing the
reaction mixture to cool to room temperature, the precipitates were
removed by filtration, and the filtrate was extracted with ethyl
acetate (15 mL × 3). The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and evaporated to afford
the crude product, which was purified by silica gel column
chromatography using 40:1 mixture of hexane:ethyl acetate to give
Studies of oligosaccharide synthesis containing rare sugar allose
are ongoing.
Experimental Section
All the reactions were performed under an argon atmosphere
using Schlenk tubes techniques and used freshly distilled chemicals
and solvents.
Typical Procedure for Reduction of 4,6-di-O-acetyl-1,5-anhy-
dro-2-deoxy-D-erythro-hex-1-en-3-ulose (entry 4 in Table 1). In a
Schlenk tube were placed 4,6-di-O-acetyl-1,5-anhydro-2-deoxy-D-
erythro-hex-1-en-3-ulose (114.1 mg, 0.5 mmol) and methanol (5
mL). A mixture was cooled to 0 °C, then NaBH4 (19 mg, 0.5 mmol)
was added slowly. The mixture was stirred at 0 °C for 1 h, after
confirmation of the consumption of the starting material by TLC,
the mixture was quenched with H2O (1 mL). After allowing the
reaction mixture to cool to room temperature, the precipitates were
removed by filtration, and the filtrate was extracted with ethyl
acetate (10 mL × 3). The combined organic layers were dried over
anhydrous magnesium sulfate, filtered, and evaporated to afford
the crude product, which was purified by silica gel column
chromatography using 3:1 mixture of hexane:ethyl acetate (3:1) to
give the reduction product 3b (R ) MeCO) (71.4 mg, 61%). [R]D
) 59.9° (c 1.0, CHCl3). IR (thin film): νmax (cm-1) 3467, 2960,
1744, 1650, 1598, 1372, 1238, 1141, 1097, 1045, 910, 815, 733,
the reduction product 2g (R ) t-BuPh2Si) (1.5 g, 80%) [R]D
)
42.9° (c 1.0, CHCl3). IR (thin film): νmax (cm-1) 3559, 3070, 2930,
2857, 1960, 1892, 1645, 1464, 1429, 1112, 998, 822, 699; 1H NMR
(400 MHz, CDCl3): δ 0.98 (s, 9H), 1.00 (s, 9H), 2.1 (br s, 1H),
3.5-3.6 (m, 1H), 3.80 (q, J ) 4.0 Hz, 1H), 3.87 (dd, J ) 3.2, 8.0
Hz, 1H), 3.9-4.0 (m, 1H),4.1-4.2 (m, 1H) 7.2-7.4 (m, 11H),
7.5-7.6 (m, 8H), 7.7-7.8 (m, 1H); 13C NMR (100.6 MHz, CDCl3):
δ 19.3, 19.4, 26.6, 26.9, 27.0, 62.2, 63.5, 69.6, 75.1, 100.0, 127.55,
127.58, 127.7, 127.8, 128.0, 128.3, 129.5, 129.59, 129.64, 130.1,
130.2, 132.7, 133.0, 133.5, 133.6, 134.8, 135.6, 135.7, 135.76,
135.84, 145.7; MS (ESI) m/z: 624 (M + H+) For determination of
2/3 ratio, small part of crude product was desilylated with n-Bu4NF
1
and then peracetylation for H NMR analysis.
Acknowledgment. This work was supported by a Grant-in-
Aid for Scientific Research on Priority Areas ”Advanced
Molecular Transformations of Carbon Resources” and No.
B17340020 from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
1
603; H NMR (400 MHz, CDCl3): δ 2.10 (s, 3H), 2.14 (s, 3H),
2.48 (br s, 1H), 4.11s4.15 (m, 1H), 4.2s4.4 (m, 3H), 4.8s4.9
(m, 1H), 4.96 (dd, J ) 2.4, 6.8 Hz 1H), 6.40 (dd, J ) 1.2, 6.4 Hz,
1H); 13C NMR (100.6 MHz, CDCl3): δ 20.6, 20.8, 61.9, 67.1, 71.6,
73.9, 102.85, 102.88, 144.0, 144.2.
Supporting Information Available: Experimental proce-
dures and spectra data for important compounds including new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Typical Procedure for Reduction of 4,6-di-O-t-butyldiphenyl-
silyl-1,5-anhydro-2-deoxy-D-erythro-hex-1-en-3-ulose (entry 13 in
Table 1). In a Schlenk tube were placed 4,6-di-O-t-butyldiphenyl-
silyl-1,5-anhydro-2-deoxy-D-erythro-hex-1-en-3-ulose (1.86 g, 3.0
mmol), CeCl3 ·7H2O (1.12 g, 3.0 mmol), and methanol (25 mL).
A mixture was cooled to 0 °C, then NaBH4 (113.5 mg, 3.0 mmol)
JO801596Q
J. Org. Chem. Vol. 73, No. 22, 2008 9163