Hydrodeamination of β-enamino ketones to 1,2-dideoxy-d-threo-3-hexulose via palladium

Article abstract of DOI:10.1016/j.tetlet.2009.06.112

β-Enamino ketones were successfully synthesized in good to excellent yields by reaction of hex-1-en-3-uloses with amines. After hydrogenation on palladium catalyst, β-enamino ketones effectively underwent hydrodeamination and were converted to the corresp

Full text of DOI:10.1016/j.tetlet.2009.06.112

Tetrahedron Letters 50 (2009) 5120–5122
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Hydrodeamination of b-enamino ketones to 1,2-dideoxy-D-threo-3-hexulose
via palladium
a
a
b
c
Zi-Ping Lin a, Hui-Chang Lin a, , Hsu-Hsuan Wu , Hsiu-Wen Chou , Shao-Kai Lin , Kuan-Chin Sung ,
*
Fung Fuh Wong a
a Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung, Taiwan 40402, Taiwan, ROC
b Sustainable Environment Research Center, National Cheng Kung University, No. 500, Sec. 3, An-ming Rd., Tainan City, Taiwan 709, Taiwan, ROC
c Department of Surgery, Attending Physician Neurosurgery, No. 201, Taikang Village, Liouying Township, Taiwan 709, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
b-Enamino ketones were successfully synthesized in good to excellent yields by reaction of hex-1-en-3-
uloses with amines. After hydrogenation on palladium catalyst, b-enamino ketones effectively underwent
Received 27 April 2009
Revised 19 June 2009
Accepted 23 June 2009
Available online 30 June 2009
hydrodeamination and were converted to the corresponding 1,2-dideoxy-
in 89–95% yields.
D-threo-3-hexulose derivatives
Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
Keywords:
Hydrodeamination
b-Enamino ketones
b-Mannosidase
Hex-1-en-3-ulose
1. Introduction
H
O
OH
N
X
In 2007, Wong and co-workers reported the (2R,3R,4R)-2-
(hydroxymethyl)pyrrolidine-3,4-diol compound 1 as quite spe-
cific and slightly more potent inhibitor of b-mannosidase.1
(4S,5R)-6-Azido-4,5-dihydroxy-hexan-3-one (2)1 and 1,2-dide-
HO
HO
OH
2. X = NH2, 3. X = OH
1
oxy-D
-threo-3-hexulose (3)2 can be used as the precursors to
Figure 1.
prepare 1 (see Fig. 1). Herein, we report an efficient and conve-
nient methodology to synthesize 3 from hex-1-en-3-ulose start-
ing materials.
Hydrodeamination3 was widely applied in the field of organic
functional group transformation, including diazotization,4 amina-
tion of the toluenesulfonamide,5 nitrosation,6 difluoroamine,3b
and nucleophilic aromatic substitutions.7 Many hydrodeamina-
tions of benzylic amines, benzoyl amines, or primary amines have
been investigated by catalytic hydrogenation, dissolving metal
reduction,8 or other reducing agents.9 There have been a few
directed hydrodeamination methods reported for the conversion
of b-enamino ketones to ketones.10 In this work, we reported the
novel hydrodeamination of b-enamino ketones by hydrogenation
on palladium catalyst to generate the corresponding 1,2-dideoxy-
2. Results and discussion
b-Enamino ketones 9–21 were prepared as the reference mate-
rials following the previous publication procedure via Michael
addition of hex-1-en-3-uloses.11 Hex-1-en-3-uloses 4–8 reacted
with two equivalents of primary amines, including benzylamine,
n-butylamine, and n-octylamine in MeOH for two hours to give
the corresponding b-enamino ketones 9–21 in 80–96% yields (see
Table 1).11 The addition reactions were clean and smooth to give
the high diastereoselective Z-geometry of the products due to the
intramolecular hydrogen bonding.12 All of b-enamino ketone struc-
tures were identified and determined by DEPT, NOESY, and other
spectroscopic methods. For example, compound 10 possessed a
characteristic broad singlet resonance at d 10.11 for the amino pro-
ton, a doublet doublet resonance at d 6.81 (J = 7.2, 13 Hz) for the
alkene proton on C1, and a doublet at d 5.27 (J = 7.2 Hz) for the
alkene proton on C2.
D-threo-3-hexulose products.
* Corresponding author. Tel.: +886 4 2205 3366x5612; fax: +886 4 2207 8083.
E-mail addresses: lhc550005@yahoo.com.tw, huichang@mail.cmu.edu.tw (H.-C.
Lin).
0040-4039/$ - see front matter Crown Copyright Ó 2009 Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.112

Z.-P. Lin et al. / Tetrahedron Letters 50 (2009) 5120–5122
5121
Table 1
The benzylic group is one of the most popular protecting units
for alcohol and carbohydrate compounds.14 By applying the stan-
dard hydrodeamination procedure to benzyl-protected b-enamino
ketones 18 and 19 (R1 = H, R2 = R3 = OBn), the O-deprotected and
The results of Michael addition of hex-1-en-3-uloses
Hex-1-en-3-uloses (4–8)
b-Enamino ketones 9–21
Substrates
R1
R2
R3
Compounds
R4
Yields (%)
hydrodeaminated 1,2-dideoxy-D
-threo-3-hexulose 25 (R1 = H,
4
4
4
5
5
5
6
6
6
7
8
8
8
H
H
H
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
H
H
H
Isopropylidene
Isopropylidene
Isopropylidene
OMe
OMe
OMe
OMe
OMe
OMe
9
10
11
12
13
14
15
16
17
18
19
20
21
Bn
80
97
84
91
96
95
92
89
80
93
90
95
89
R2 = R3 = OH) was afforded in 89% and 93% yield, respectively. Fur-
thermore, we performed the hydrodeamination to benzyl-pro-
tected b-enamino ketones 20 and 21, in which the amino moiety
was linked with Bn and n-Bu groups on nitrogen atom. The corre-
n-Bu
n-Oct
Bn
n-Bu
n-Oct
Bn
n-Bu
n-Oct
Bn
n-Bu
Bn
sponding 1,2-dideoxy-D-erythro-3-hexulose 26 was produced in
89% and 95% yield, respectively, (see Scheme 2). Comparing ben-
zyl-protected b-enamino ketones (18–21) with methyl-protected
b-enamino ketones (9–17), we found that the benzyl-protected
group was easily hydrogenated to hydroxyl group under the same
reaction condition.
H
H
OBn
OBn
OBn
OBn
H
OBn
OBn
OBn
OBn
H
n-Bu
When we treated hex-1-en-3-uloses 5 with N,N-diethylamine
(secondary amine) and acetamide by following the previous pro-
cedure, only the corresponding N,N-diethyl-b-enamino ketone 27
was obtained in 87% yield (see Scheme 3). We applied the same
hydrodeamination to N,N-diethyl-b-enamino ketone 27. The
hydrogenated product 23 also succeeded in generating 90% yield.
We proposed a plausible mechanism for the hydrodeamination
Palladium catalyst was commonly applied in the hydrogenation
of organic compounds.13 In the newly developed hydrodeamina-
tion, various b-enamino ketones 9–17 were treated with a catalytic
amount of palladium in MeOH at room temperature for 4 h
through the atmosphere by a hydrogen-filled balloon. After the
reactions were complete, the normal work-up and purification
with column chromatography on silica gel were performed. The
of b-enamino ketones 28 to 1,2-dideoxy-D-threo-3-hexulose 33 as
shown in Scheme 4, which accounted for our approach and design.
Palladium catalyst underwent hydrogenation toward b-enamino
ketone 28 to give hydrido olefin palladium complex 29 and isomer
desired 1,2-dideoxy-
D-3-hexuloses were isolated in liquid form
(22–24, see Scheme 1 and Table 2).
H
R4
R1
HO H
R3
O
O
NH2R4
O
N
H2/Pd-C
HO H
R3
R2
R3
MeOH, r.t
MeOH, r.t.
R1 R2
O
R1 R2
4-8
R1 = H, OMe, OBn
R2 = H, OMe, OBn, isopropylidene
R3 = OMe, OBn, isopropylidene
9-21
22-24
R4 = Bn, n-Bu, n-Oct
Scheme 1.
Table 2
The results of hydrodeamination of b-enamino ketones 9–17
b-Enamino ketones 9–21
1,2-Dideoxy-
D-threo-3-hexuloses 22–24
Substrates
R1
R2
R3
R4
Compounds
Yields (%)
9
10
11
12
13
14
15
16
17
H
H
H
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
Bn
22
22
22
23
23
23
24
24
24
95
92
94
90
96
89
93
92
90
n-Bu
n-Oct
Bn
n-Bu
n-Oct
Bn
Isopropylidene
Isopropylidene
Isopropylidene
n-Bu
n-Oct
H
R4
O
HO H
O
N
H2/Pd-C
HO H
HO
R3
MeOH, r.t.
R1 R2
R1 R2
18. R1 = H, R2 = R3 = OBn, R4 = Bn
19. R1 = H, R2 = R3 = OBn, R4 = n-Bu
20. R1 = R3 = OBn, R2 = H, R4 = Bn
21. R1 = R3 = OBn, R2 = H, R4 = n-Bu
25. R1 = H, R2 = OH
26. R1 = OH, R2 = H
Scheme 2.

5122
Z.-P. Lin et al. / Tetrahedron Letters 50 (2009) 5120–5122
O
NEt2
O
OMe
HO H
HO H
OMe
O
HNEt2
H2/Pd-C
MeO
MeO
H
O
MeOH, r.t
MeOH, r.t.
MeO H
MeO H
5
27
23
Scheme 3.
Supplementary data
O
NHR
NHR
O
H2/Pd-C
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.112.
W
W
28
33
References and notes
H Pd
W
H
Pd
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32
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In conclusion, b-enamino ketones were prepared as the starting
materials by Michael addition of hex-1-en-3-uloses with primary
amines. They underwent the novel hydrodeamination with a cata-
lytic amount of palladium under hydrogen atmosphere to give 1,2-
dideoxy-D-threo-3-hexuloses in excellent yields (89–93%).
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The authors thank the National Science Council of Taiwan
(NSC95-2314-B-039-046 and NSC96-2113-M-039-002) and China
Medical University, Taiwan for their financial support. The authors
also wish to thank Dr. C. H. Lin and Prof. C. Y. Wu for fruitful dis-
cussion of the work.
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