Synthesis of hexopyranosyl acetates and 2,3-disubstituted tetrahydropyrans via chemoselective hydrogenation of hex-2-enopyranosyl acetates

Article abstract of DOI:10.1016/j.tetlet.2006.09.091

A simple and easy method for chemoselective synthesis of hexopyranosyl acetates and 2,3-disubstituted tetrahydropyrans from hex-2-enopyranosyl acetates was demonstrated. The former was achieved by hydrogenation catalyzed by Rh/Al₂O₃

Full text of DOI:10.1016/j.tetlet.2006.09.091

Tetrahedron Letters 47 (2006) 8271–8274
Synthesis of hexopyranosyl acetates and 2,3-disubstituted
tetrahydropyrans via chemoselective hydrogenation of
hex-2-enopyranosyl acetates
Kaname Sasaki, Takayuki Wakamatsu, Shuichi Matsumura and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 1 September 2006; revised 13 September 2006; accepted 19 September 2006
Available online 6 October 2006
Abstract—A simple and easy method for chemoselective synthesis of hexopyranosyl acetates and 2,3-disubstituted tetrahydropyrans
from hex-2-enopyranosyl acetates was demonstrated. The former was achieved by hydrogenation catalyzed by Rh/Al2O3 in EtOAc/
toluene solvent at 0 °C, while the latter was carried out using Pd/C in EtOH/AcOH at 25 °C.
Ó 2006 Elsevier Ltd. All rights reserved.
Carbohydrates are most promising, naturally occurring,
raw materials mainly because of their environmentally
sustainable use and their enantio- and diastereomerical
purity. We have so far been working on their fundamen-
tal and important chemical conversions, O- and C-gly-
cosidations, some of which are ecologically friendly
processes within the ambit of ‘Green Carbohydrate
Chemistry’.1 But although carbohydrates are attractive
as starting materials for enantio- and diastereomerically
pure compound syntheses,2 their highly oxygenated nat-
ure is sometimes regarded as an inconvenience due to
the need for appropriate deoxygenation in order to ob-
tain materials with desired functionalization. In this
context, we have demonstrated, through easy, simple,
and classical reactions, a novel chemoselective method
of preparation of highly deoxygenated sugar donors
and chiral tetrahydropyrans by hydrogenation.3
whereas the reductant by two H2, 3, can be used as a chi-
ral material. For example, 2,3-disubstituted chiral tetra-
hydropyran derived from glucose has been used for the
total synthesis of brevetoxin B.6 These results prompted
us to examine the chemoselective hydrogenations of
hex-2-enopyranosyl acetates to selectively produce hexo-
pyranosyl acetates or 2,3-disubstituted tetrahydropyrans.
We first screened several catalysts generally used: 10%
Pd/C, 20% Pd(OH)2/C (Pearlman’s catalyst), 10% Pt/
C, Raney-Ni, and 5% Rh/Al2O3, for the hydrogenations
of the hex-2-enopyranosyl acetate 4 with a hydrogen
balloon in EtOH at 25 °C for 1 h (entries 1–5 in Table
1). It was found that the 2,3-disubstituted tetrahydro-
pyran 6 was produced in good yield in preference to
the hexopyranosyl acetate 5 with Pd/C or Pd(OH)2/C.
Pd/C and Pd(OH)2/C have comparable efficiencies for
this deoxygenation reaction at the C-1 position of 4,
but the latter also gave glycoside 7, which probably re-
sulted from anomeric activation of 4 or 5 by the Lewis
acidity of Pd(OH)2/C and then coupling with the sol-
vent, EtOH.7 Therefore, of the five catalysts examined,
we considered Pd/C to be the best for obtaining 2,3-
disubstituted tetrahydropyrans. In contrast, 5 was
obtained in a slightly greater yield than 6 with Rh/
Al2O3. Thus, it was confirmed that Rh/Al2O3 was suit-
able for converting hex-2-enopyranosyl acetates into
the corresponding hexopyranosyl acetates. Hydrogena-
tion, especially when catalyzed by Pd, may show a ten-
dency to eliminate an allylic heteroatom substituent
hydrogenolytically via a p-allyl palladium complex.
In the course of our synthetic studies of vineomycin B2,4
an anthracycline antibiotic, we found an interesting
reduction reaction of hex-2-enopyranosyl acetate 1,5
which yields the desired hexopyranosyl acetate 2 accom-
panied by 2,3-disubstituted tetrahydropyran 3 (Scheme
1). Compound 2 and its family must work as glycosyl
donors of 2,3-deoxy sugars found in vineomycin B2,
Keywords: Hydrogenation; Hydrogenolysis; Carbohydrates; Chemo-
selectivity; Tetrahydropyrans.
*
Corresponding author. Tel./fax: +81 45 566 1576; e-mail: toshima@
applc.keio.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.091

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K. Sasaki et al. / Tetrahedron Letters 47 (2006) 8271–8274
AcO
AcO
AcO
H2, Pd/C
O
O
AcO
AcO
AcO
O
EtOH,
25 oC, 1 hr
OAc
OAc
1
2: 18%
3: 71%
Scheme 1. Hydrogenation of 1.
Indeed, Tsuji and Yamakawa reported the preparation
of 1-olefins by the palladium-catalyzed transfer hydrog-
enolysis of allylic acetates with ammonium formates.8
However, no products resulting from cleavage of the
allylic benzoate or the cyclic allylic ether were isolated
in these entries.
5 (Eq. 1 in Scheme 2). Therefore, it is clear that the dou-
ble bond at the C-2 position is the prerequisite for the
cleavage of anomeric acetate. In addition, since methyl
glycoside 10 gave only one H2 adduct 11 under these
conditions, the two H2 reduction requires a substituent
at the C-1 position having appropriate leaving ability
(Eq. 2 in Scheme 2).
With the preliminary results in hand, we next optimized
the reaction conditions, including solvents, reaction
temperature, and reaction time, to selectively obtain
tetrahydropyran 6 (entries 6–9 in Table 1). It was found
that the hydrogenation catalyzed by Pd/C with EtOH
gave better yields of 6 than with THF, EtOAc, and
MeOH. Furthermore, acidic conditions, using EtOH/
AcOH (9/1, v/v) as a solvent to enhance elimination of
an acetoxy group, worked well, giving 6 in good yield
with good chemoselectivity. At this stage, we further
confirmed the following phenomena, as shown in
Scheme 2. The hydrogenation conditions did not affect
the anomeric acetate of the saturated pyranosyl acetate
On the other hand, it was also found that the hydroge-
nation catalyzed by Rh/Al2O3 in THF gave 5 more effec-
tively than that in EtOH (entry 10 in Table 1). However,
the yield was unsatisfactory due to a minor product,
which seemed to result from overreduction (Eq. 3 in
Scheme 2). When the reaction was carried out at 0 °C,
the overreduction was avoided and the yield of 5 was im-
proved. Further, shortening the reaction time sup-
pressed the conversion of 5 to 6, and a better result
was obtained for 40 min than for 60 min. Additionally,
EtOAc proved to be a better solvent for this hydrogena-
tion reaction than EtOH, THF, dioxane, DME, and
Table 1. Hydrogenations of 4 under several conditions
BzO
O
BzO
O
H2, catalyst
BzO
BzO
BzO
BzO
O
OAc
OAc
4
5
6
Entry
Catalyst
Amount of catalyst (wt %)
Solvent
Temperature (°C)
Time (min)
Yielda (%)
5
6
1
2b
3
Pd/C
Pd(OH)2/C
Pt/C
Raney-Ni
Rh/Al2O3
Pd/C
Pd/C
Pd/C
Pd/C
Rh/Al2O3
Rh/Al2O3
Rh/Al2O3
Rh/Al2O3
Rh/Al2O3
Rh/Al2O3
Rh/Al2O3
Rh/Al2O3
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
10
10
EtOH
EtOH
EtOH
EtOH
EtOH
THF
EtOAc
MeOH
EtOH/AcOH (9/1)
THF
THF
Dioxane
DME
Acetone
EtOAc
EtOAc
25
25
25
25
25
25
25
25
25
25
0
10
0
0
0
0
60
60
60
60
60
60
60
60
60
60
40
40
40
40
40
60
60
14
17
4
78
76
63
44
39
59
61
78
80
17
23
24
26
27
21
17
14
4c
5
18
50
37
35
10
13
58
66
69
69
71
77
83
86
6
7
8d
9
10
11
12
13
14
15
16
17
EtOAc/toluene (9/1)
0
BzO
O
BzO
O
BzO
O
BzO
BzO
BzO
OMe
OEt
9
7
8
a Isolated yield.
b Ethyl glycoside 7 was produced in 4% yield.
c 10% of 4 was recovered, and 8 was produced in 21% yield.
d Methyl glycoside 9 was produced in 5% yield.

K. Sasaki et al. / Tetrahedron Letters 47 (2006) 8271–8274
8273
H2, Pd/C (50 wt%)
6
5
5
(1)
(2)
EtOH:AcOH (9:1)
25 oC, 1 hr
0%
95%
BzO
BzO
BzO
BzO
O
O
H2, Pd/C (50 wt%)
EtOH:AcOH (9:1)
25 oC, 1 hr
OMe
OMe
10
5
11: 95%
H2, Rh/Al2O3 (50 wt%)
6
5
(3)
THF
25 oC, 1 hr
12%
88%
Scheme 2. Hydrogenations of 5 and 10.
acetone. Pursuing milder conditions drives us to de-
crease the amount of the catalyst and add toluene. We
should, therefore, conclude that the hydrogenation of
hex-2-enopyranosyl acetate 4 using 10 wt % Rh/Al2O3
in EtOAc/toluene (9/1, v/v) at 0 °C for 1 h is the optimal
condition for chemoselectively obtaining hexopyranosyl
acetate 5 in high yield.
summarized in Table 2. The D-erythro acetates having
Ac or TBDPS group as protecting groups, 1 and 12,
underwent chemoselective reduction, providing the
corresponding hexopyranosyl acetates 3 or 14 under
condition A, and the corresponding 2,3-disubstituted
tetrahydropyrans 2 or 13 under condition B, in good
yield with good chemoselectivity, respectively. Further-
more, b-acetate 15 and D-threo acetate 17 were both also
converted chemoselectively into two molecular hydro-
gen adducts 3 and 19 with good to high selectivities,
and into one molecular hydrogen adduct 16 and 18 with
excellent selectivities. To demonstrate the feasibility of
the reduction of 6-deoxy sugar, the synthesis of 21 and
22 by hydrogenations of 20 was also investigated. The
We next investigated the hydrogenation of several hex-
2-enopyranosyl acetates under the two optimized condi-
tions: condition A, using Pd/C (50 wt % to starting
materials) in EtOH/AcOH (9/1, v/v) at 25 °C; and con-
dition B, using Rh/Al2O3 (10 wt % to starting materials)
in EtOAc/toluene (9/1, v/v) at 0 °C. These results are
Table 2. Chemoselective hydrogenations of several hex-2-enopyranosyl acetates
Entry
Starting material
Yielda
Conditions Ab
Conditions Bc
1
1
2: 12%
3: 77%
2: 93%, 3: 0%
TBDPSO
TBDPSO
TBDPSO
TBDPSO
TBDPSO
TBDPSO
O
O
O
2
3
4
13: 80%, 14: 16%
16: 91%, 3: 0%
18: 89%, 19: 0%
21: 84%, 22: 4%
OAc
OAc
14: 88%
12
13: 12%
AcO
AcO
AcO
AcO
O
O
OAc
OAc
3: 84%
16: 4%
15
OBz
OBz
OBz
BzO
BzO
BzO
O
O
O
OAc
OAc
OAc
19: 72%
17
18: 18%
OAc
Me
BzO
O
Me
BzO
Me
O
O
5
BzO
22: 73%
21: 15%
20
a Isolated yield.
b Pd/C (50 wt % to starting materials) in EtOH/AcOH (9/1, v/v) at 25 °C for 1 h.
c Rh/Al2O3 (10 wt % to starting materials) in EtOAc/toluene (9/1, v/v) at 0 °C for 1 h.

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K. Sasaki et al. / Tetrahedron Letters 47 (2006) 8271–8274
2. For recent reviews of synthesis of natural products using
carbohydrates as chiral starting materials, see: (a) Chapl-
hydrogenation of 20 under condition A gave 22 in good
yield, while that under condition B resulted in 84% yield
of 21 with good chemoselectivity.
´
eur, Y.; Chretien, F. In The Organic Chemistry of Sugars;
Levy, D. E., Fugedi, P., Eds.; CRC Press: Boca Raton,
¨
2006; pp 489–573; (b) Tatsuta, K.; Hosokawa, S. Chem.
Rev. 2005, 105, 4707–4729; (c) Nicolaou, K. C.; Mitchell,
H. J. Angew. Chem., Int. Ed. 2001, 40, 1576–1624.
3. Hudlicky´, M. Reductions in Organic Chemistry; John Wiley
& Sons: New York, 1984.
4. (a) Omura, S.; Tanaka, H.; Oiwa, R.; Awaya, J.; Masuma,
R.; Tanaka, K. J. Antibiot. 1977, 30, 908–916; (b) Imamura,
N.; Kakinuma, N.; Ikekawa, H.; Tanaka, H.; Omura, S. J.
Antibiot. 1981, 34, 1517–1518.
In conclusion, we demonstrated a novel chemoselective
reduction of hex-2-enopyranosyl acetates to selectively
produce hexopyranosyl acetates or 2,3-disubstituted
tetrahydropyrans, regardless of their configurations
and substituents.
Acknowledgements
5. For synthesis of 1 by a single step from tri-O-acetyl-D-
glucal, see: (a) Inaba, K.; Matsumura, S.; Yoshikawa, S.
Chem. Lett. 1991, 20, 485–488; By an easy and efficient two
steps, see: (b) Baer, H. H.; Siemsen, L. Carbohydr. Res.
1984, 134, 49–61.
6. Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S.
A.; Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J.
P. J. Am. Chem. Soc. 1990, 112, 3040–3054.
This research was supported in part by Grant-in-Aid for
the 21st Century COE Program ‘KEIO Life Conjugated
Chemistry’, for Scientific Research on Priority Areas
18032068 and for JSPS Fellows 18*6013 from the
Ministry of Education, Culture, Sports, Science, and
Technology, Japan.
7. For an example of showing a Lewis acidity of Pd(OH)2/C
in hydrogenolysis, see: Toshima, K.; Yanagawa, K.;
Mukaiyama, S.; Tatsuta, K. Tetrahedron Lett. 1990, 31,
6697–6698.
References and notes
1. For a perspective article, see: Toshima, K. Carbohydr. Res.
2006, 341, 1282–1297.
8. Tsuji, J.; Yamakawa, T. Tetrahedron Lett. 1979, 20, 613–
616.