Doubly stereocontrolled asymmetric conjugate addition of acetylacetone to nitroolefins catalyzed by bifunctional tertiary amine-thiourea catalysts derived from both acyclic α-amino acids and carbohydrates

Article abstract of DOI:10.1016/j.tet.2010.03.081

A novel class of easily preparative, cheap, and fine-tunable bifunctional chiral tertiary amine-thiourea organocatalysts have been developed by combining both acyclic diamines derived from acyclic α-amino acids and carbohydrates. These organocatalysts pro

Full text of DOI:10.1016/j.tet.2010.03.081

Tetrahedron 66 (2010) 3655–3661
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Doubly stereocontrolled asymmetric conjugate addition of acetylacetone to
nitroolefins catalyzed by bifunctional tertiary amine–thiourea catalysts derived
from both acyclic
a
-amino acids and carbohydrates
*
Xue-Wei Pu, Fang-Zhi Peng, Hong-Bin Zhang, Zhi-Hui Shao
Key Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University), Ministry of Education, School of Chemical Science and Technology, Yunnan University,
Kunming 650091, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel class of easily preparative, cheap, and fine-tunable bifunctional chiral tertiary amine–thiourea
Received 21 January 2010
Received in revised form 18 March 2010
Accepted 23 March 2010
organocatalysts have been developed by combining both acyclic diamines derived from acyclic a-amino
acids and carbohydrates. These organocatalysts promoted the enantioselective conjugate addition
of acetylacetone to various nitroolefins in good yields (up to 93%) with good enantioselectivities (up to
91% ee). The present research demonstrates the advantages of incorporating two stereocontrolling
structures into a single catalyst. Notably, it offers a simple and convenient doubly stereocontrolled ap-
proach for the catalytic asymmetric synthesis of a chiral organic molecule.
Available online 27 March 2010
Dedicated to Professor Albert S.C. Chan on
the occasion of his 60th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Catalyst design
Conjugate addition
Doubly stereocontrolled
a
-Amino acids
Carbohydrates
1. Introduction
As part of our interest in developing novel types of bifunctional
organocatalysts for asymmetric processes,6,7 and in developing
Design of new chiral organocatalysts for efficient asymmetric
transformations has become a focal point of attention in asym-
metric organocatalysis.1 In particular, development of a novel ap-
proach for asymmetric synthesis of both enantiomers2 would be
very useful by designing novel multitasking chiral organocatalysts.
In the past few years, bifunctional tertiary amine–(thio)urea
organocatalysts have emerged as new and efficient organocatalysts
for asymmetric reactions.3,4 Despite their tremendous utility, these
organocatalysts are derived from a very limited range of chiral
structural scaffolds, including cyclohexane-1,2-diamine, 1,10-
binaphthyl-2,20-diamine, and cinchona alkaloids. Moreover, the
potential application of these organocatalysts in doubly stereo-
controlled asymmetric reactions5 has been less explored. There-
fore, development of bifunctional tertiary amine–thiourea
organocatalysts with novel chiral scaffolds for doubly stereo-
controlled asymmetric transformations would be highly desirable.
new approaches for doubly stereocontrolled asymmetric catalysis,8
herein we first report a class of easily preparative, cheap, and fine-
tunable chiral bifunctional tertiary amine–thiourea organocatalysts
by combining both acyclic diamines derived from acyclic a-amino
acids and carbohydrates, and their application in the doubly ster-
eocontrolled catalytic conjugate addition of acetylacetone to
a variety of nitroolefins under mild conditions.9,10
Acyclic
a-amino acids have received growing attention in
organocatalysis as chiral scaffolds.11 In contrast, carbohydrates have
received less attention in the development of chiral organocatalysts
although they are potential chiral scaffolds for the synthesis of
chiral organocatalysts.12 Carbohydrates, i.e., monosaccharides, are
conformationally stable, cheap, and readily available. In addition,
they possess multiple chiral centers and functional groups for
catalyst performance optimization. Therefore, rational assembly of
two stereocontrolling units into a single molecule would lead to
a series of novel cost-effective and fine-tunable chiral organo-
catalysts.13 Surprisingly, despite the enormous potential utility of
this organocatalyst design strategy, few organocatalysts have been
developed with this combining strategy. Recently, Kunz and
co-workers preliminarily explored the utility of this organocatalyst
* Corresponding author. Fax: þ86 871 5035538; e-mail address: zhihui_shao@
hotmail.com (Z.-H. Shao).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.03.081

3656
X.-W. Pu et al. / Tetrahedron 66 (2010) 3655–3661
design strategy by designing an elegant class of bifunctional Schiff
base organocatalysts, which catalyzed enantioselective Strecker
2. Results and discussion
and Mannich reactions.12a In this pioneering work, only one
a
-
2.1. Synthesis and activity of bifunctional chiral tertiary
amine–thiourea catalysts 1
amino acid (L-tert-leucine) was used. Both for scientific interest and
for practical applications, it is desirable to investigate further full
potentials of this organocatalyst design strategy by developing
other types of chiral organocatalysts such as bifunctional tertiary
amine–thiourea organocatalysts (Fig. 1). In particular, it is highly
attractive to explore the new role of carbohydrate motif in the
doubly stereocontrolled asymmetric catalysis.
The chiral organocatalysts 1 were easily synthesized by reaction
of the primary–tertiary diamine 214 derived from acyclic
a
-amino
acids with the isothiocyanate 315 derived from
D-glucopyranose
(Scheme 1).
The catalytic activities of these chiral tertiary amine–thioureas 1
were initially evaluated in the conjugate addition reaction of ace-
tylacetone 4 to trans-b-nitrostyrene 5a in the presence of 10 mol %
of catalyst loading at room temperature, and the results are sum-
marized in Table 1. Several different solvents with the chiral orga-
nocatalyst 1a derived from L-valine and D-glucopyranose were
examined to find optimum reaction media, and the conjugate
addition reaction with the organocatalyst 1a in THF afforded the
best enantioselectivity (85% ee, entry 6). Next, the effect of the
acyclic diamine derived
from α-amino acids
OPG
O
H
N
N
H
N
PGO
PGO
OPG
S
R
carbohydrate
additional chiral unit in
variation of
addition reactions with other organocatalysts 1b–e derived from
-leucine, -phenylalanine, -phenylglycine, and -tryptophan in
THF resulted in lower enantiomeric excess (entries 7–10). Then
the conjugate addition with the organocatalyst 1a0 derived from
a-amino acid moieties was studied. The conjugate
asymmetric adjustment
essential motif in doubly
L
L
L
L
stereo controlled reactions
Figure 1. Key design elements of a new class of bifunctional chiral tertiary amine–
thiourea organocatalysts.
D-valine and D-glucopyranose in THF was examined. The use of
OAc
OAc
O
R
O
H
N
H
N
AcO
AcO
THF
35 °C
N
AcO
+
AcO
NCS
N
NH2
OAc
OAc
R
S
1
2
3
OAc
OAc
O
O
H
H
N
H
H
AcO
AcO
AcO
AcO
N
N
N
N
N
OAc
1a
OAc
S
S
S
1a'
OAc
OAc
O
O
H
N
H
N
H
N
H
N
AcO
AcO
AcO
AcO
N
N
N
N
OAc
1b'
OAc
S
1b
OAc
OAc
OAc
OAc
O
O
H
N
H
N
H
N
H
N
AcO
AcO
AcO
AcO
OAc
OAc
S
S
S
S
Ph
Ph
1c
1c'
O
O
H
N
H
N
H
N
H
N
AcO
AcO
AcO
AcO
N
N
N
N
OAc
OAc
1d
Ph
Ph
1d'
AcO
AcO
H
N
O
H
N
O
H
N
H
N
AcO
AcO
AcO
AcO
OAc
OAc
S
S
NH
NH
1e'
1e
Scheme 1. Synthesis of bifunctional tertiary amine–thiourea organocatalysts 1.

X.-W. Pu et al. / Tetrahedron 66 (2010) 3655–3661
3657
Table 1
Table 2
Enantioselective conjugate addition of acetylacetone 4 to trans-
b
-nitrostyrene 5a
Enantioselective conjugate addition of acetylacetone 4 to trans-
catalyzed by the organocatalysts 1 in THF and PhCH3
b
-nitrostyrene 5a
catalyzed by 1a
a
Yieldb (%)
eec (%)
O
O
Entry
Catalyst
Solvent
O
O
1
2
3
4
5
6
7
8
1a
1a
1a0
1a0
1b
1b
1b0
1b0
1c
THF
PhCH3
THF
PhCH3
THF
PhCH3
THF
PhCH3
THF
PhCH3
PhCH3
THF
PhCH3
PhCH3
THF
PhCH3
THF
88
90
87
90
89
90
86
89
90
89
88
80
90
87
85
87
81
90
89
91
85
85
85 (S)
82 (S)
76 (R)
86 (R)
80 (S)
78 (S)
74 (R)
79 (R)
74 (S)
89 (S)
90 (S)d
70 (R)
87 (R)
90 (R)d
72 (S)
87 (S)
61 (R)
84 (R)
81 (S)
80 (S)
61 (R)
77 (R)
1 (10 mol %)
NO2
+
Ph
NO2
rt, solvent
Ph
5a
4
6a
Entry
Catalyst
Solvent
DCM
PhCH3
Et2O
DMF
MeOH
THF
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1a0
1b0
1c0
1d0
1e0
84
90
72
75
69
88
89
90
85
89
87
86
80
81
85
82 (S)
82 (S)
73 (S)
27 (S)
34 (S)
85 (S)
80 (S)
74 (S)
72 (S)
81 (S)
76 (R)
74 (R)
70 (R)
61 (R)
61 (R)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
1c
1c
1c0
1c0
1c0
1d
1d
1d0
1d0
1e
THF
THF
THF
THF
THF
THF
THF
THF
9
10
11
12
13
14
15
PhCH3
THF
PhCH3
THF
1e
1e0
1e0
THF
a
The reaction was performed with acetylacetone 4 (2 equiv) and trans-b-nitro-
PhCH3
styrene 5a (1 equiv) in the presence of catalyst 1 (10 mol %) at room temperature.
a
The reaction was performed with acetylacetone 4 (2 equiv) and trans-b-nitro-
b
Yields of isolated products.
styrene 5a (1 equiv) in the presence of catalyst 1 (10 mol %) at room temperature.
c
Enantiomeric excess was determined by chiral HPLC analysis (Chiralpak AS-H).
b
Yields of isolated products.
Enantiomeric excess was determined by chiral HPLC analysis (Chiralpak AS-H).
At 0 ꢀC.
c
d
organocatalyst 1a0 in THF provided the product 6a with lower
enantioselectivity (76% ee, entry 11), as well as with a reversal of
the absolute configuration. Moreover, all other chiral tertiary
Development of a novel approach for asymmetric synthesis of
both enantiomers is highly useful in organic synthesis and in the
pharmaceutical industry.2 However, organocatalytic methods for
such a purpose are few.16 On the other hand, reutilization of the
‘useless’ organocatalysts is very attractive in the chiral organo-
catalyst development because of cost-effectiveness and environ-
mental benefits.17 Our findings might offer not only a simple and
convenient route for the reutilization of the ‘useless’ organo-
catalysts in the chiral organocatalyst development, but also a new
approach for doubly stereocontrolled catalytic synthesis.
amine–thiourea organocatalysts 1b0–e0 derived from
D-a-amino
acids exhibited an opposite sense of asymmetric induction (entries
12–15). Interestingly, all these chiral tertiary amine–thiourea
organocatalysts derived from
tioselectivity in THF than those derived from the corresponding
amino acids in THF (entries 6–10 vs 11–15). These results indicate
clearly that the chiral moiety from -amino acids predominated the
absolute configuration of the product 6a. On the other hand, it
seems to indicate that the -configuration of -amino acid moiety
matched the -glucopyranose scaffold of thioureas, enhancing the
stereochemical control in this conjugate addition reaction, whereas
-configuration of -amino acid moiety mismatched the -gluco-
pyranose scaffold of thioureas.
D-a-amino acids gave lower enan-
L-a-
a
L
a
D
2.2. Enantioselective conjugate addition of acetylacetone to
nitroolefins in a doubly stereocontrolled manner catalyzed by
bifunctional thiourea catalysts 1c and 1c0 in same solvent
D
a
D
However, we were pleased to find that the conjugate addition
reaction with the ‘mismatched’ organocatalyst 1a0 in PhCH3 gave
the desired product 6a in almost the same enantiomeric excess
with opposite absolute configuration (entry 4 vs entry 1, Table 2).
Triggered by these interesting observations, we made further in-
vestigations. It was found that while the chiral tertiary amine–
The generality of doubly stereocontrolled asymmetric conjugate
addition of acetylacetone 4 to a variety of nitroolefins 5a–h was
examined in the presence of organocatalysts 1c and 1c0 in PhCH3,
respectively, and the results are summarized in Table 3. It is seen
that all reactions of nitroolefins proceed smoothly affording the
desired products of the (S) or (R) configuration9g with good enan-
tioselectivities ((S)-adducts, 86–91% ee, (R)-adducts, 84–91% ee,
Table 3). It appears that the position and the electronic property of
the substituents for aromatic rings of nitroalkenes 5a–g are well
tolerated by the enantioselective conjugate addition reactions.
Whether electron-withdrawing (entries 2–4, Table 3), electron-
donating (entries 5–7, Table 3), or electron-neutral (entry 1, Table 3)
groups on aromatic rings were used, the reactions proceeded
smoothly to give the desired adducts in good yields (80–90%) with
good enantioselectivity (85–91% ee). Notably, the conjugate addi-
tion of challenging aliphatic nitroolefins such as 4-methyl-1-
nitropent-1-ene 5h with acetylacetone 4 afforded the desired
product 6h with 88% ee and ent-6h with 84% ee in the presence of
chiral organocatalysts 1c and 1c0 in PhCH3, respectively (entry 8).
Few examples of the asymmetric addition of acetylacetone to ali-
phatic nitroolefins have been described so far due to lower re-
activity of aliphatic nitroolefins than aromatic nitroolefins7b,9n,s The
thiourea organocatalyst 1c derived from L-phenylalanine in THF
(the optimized solvent, see Table 1) provided lower enantiose-
lectivity (74% ee, entry 8, Table 1 or entry 9, Table 2), the con-
jugate addition reaction with this ‘useless’ organocatalyst 1c in
PhCH3 gave the desired product 6a with higher enantioselectivity
(89% ee, entry 10, Table 2). Moreover, the corresponding orga-
nocatalyst 1c0 from
D-phenylalanine in PhCH3 provided the de-
sired product 6a with the almost same high enantioselectivity
with opposite absolute configuration (87% ee, entry 13, Table 2).
Decreasing the reaction temperature to 0 ꢀC improved the enan-
tioselectivities slightly. Both enantiomers of the desired product
6a were obtained in the same enantiomeric excess (90% ee) by
using the organocatalyst 1c, 1c0 in PhCH3 at 0 ꢀC, respectively
(entries 11, 14, Table 2). Interestingly, all the organocatalysts 1a0–
e0 derived from
with high enantioselectivities than in THF (Table 2).
D-a-amino acids in PhCH3 afforded the product 6a

3658
X.-W. Pu et al. / Tetrahedron 66 (2010) 3655–3661
Table 3
Table 4
Organocatalytic enantioselective conjugate addition of acetylacetone 4 to various
Organocatalytic enantioselective conjugate addition of acetylacetone 4 to various
nitroolefins 5a–h promoted by tertiary amine–thioureas 1a and 1a0 in different
solventsa
nitroolefins 5a–h promoted by tertiary amine–thioureas 1c and 1c0 in same solventa
O
R
O
R
O
O
O
O
1c
(10 mol%), PhCH3, or
(10 mol%), PhCH3, 0 °C
O
O
O
O
NO2
5a-h
or
NO2
+
R
O
O
1a
(10 mol %), THF, rt, or
(10 mol %), PhCH3, rt
NO2
1c'
NO2
5a-h
or
NO2
+
R
4
6a-h
ent-6a-h
NO2
1a'
R
R
4
6a-h
ent-6a-h
Entry
1
R
Catalyst
Product
t (h)
Yieldb (%)
eec (%)
Entry
1
R
Catalyst
Product
t (h)
Yieldb (%)
eec (%)
Ph (5a)
1c
1c0
1c
1c0
1c
1c0
1c
1c0
1c
1c0
1c
1c0
1c
1c0
1c
1c0
6a
ent-6a
6b
ent-6b
6c
ent-6c
6d
ent-6d
6e
ent-6e
6f
ent-6f
6g
ent-6g
6h
19
19
14
16
17
15
19
16
45
43
40
39
60
64
64
60
88
87
83
84
81
80
90
87
83
81
81
80
84
86
84
80
90
90
91
85
89
86
86
90
88
87
91
89
90
91
88d
84d
Ph (5a)
1a
1a0
1a
1a0
1a
1a0
1a
1a0
1a
1a0
1a
1a0
1a
1a0
1a
1a0
6a
ent-6a
6b
ent-6b
6c
ent-6c
6d
ent-6d
6e
ent-6e
6f
ent-6f
6g
ent-6g
6h
17
14
18
15
20
15
18
14
20
20
18
15
36
32
40
48
88
90
80
92
84
93
80
87
86
90
82
89
80
87
81
85
85
86
88
86
86
88
83
88
86
88
90
87
85
88
80
81
2
3
4
5
6
7
8
4-ClC6H4 (5b)
4-BrC6H4 (5c)
2-CF3C6H4 (5d)
4-MeC6H4 (5e)
4-MeOC6H4 (5f)
2-BnOC6H4 (5g)
i-Bu (5h)
2
3
4
5
6
7
8
4-ClC6H4 (5b)
4-BrC6H4 (5c)
2-CF3C6H4 (5d)
4-MeC6H4 (5e)
4-MeOC6H4 (5f)
2-BnOC6H4 (5g)
i-Bu (5h)
ent-6h
ent-6h
a
The reaction was performed with acetylacetone 4 (2 equiv) and nitroolefins
5a–h (1 equiv) in the presence of organocatalyst 1c or 1c0 (10 mol %) at 0 ꢀC.
a
The reaction was performed with acetylacetone 4 (2 equiv) and nitroolefins
5a–h (1 equiv) in the presence of organocatalyst 1a or 1a0 (10 mol %) at room
temperature.
b
Yields of isolated products.
Enantiomeric excess was determined by chiral HPLC analysis (Chiralpak AS-H,
c
b
Yields of isolated products.
Enantiomeric excess was determined by chiral HPLC analysis (Chiralpak AS-H,
AD-H and Chiralcel OD-H).
c
d
At room temperature.
AD-H and Chiralcel OD-H).
obtained with lower enantioselectivity (Scheme 2). The results
might demonstrate the advantage of incorporating carbohydrate into
chiral tertiary amine–thiourea organocatalysts. Moreover, these re-
sults might highlight the important role of the carbohydrate motif in
the doubly stereocontrolled catalytic conjugate addition reaction of
acetylacetone to nitroolefins. To the best of our knowledge, this is the
first example of catalytic asymmetric reaction in a doubly stereo-
controlled manner catalyzed by chiral organocatalysts possessing
the carbohydrate scaffold.
previous highest enantioselectivty in the asymmetric addition of
acetylacetone to aliphatic nitroolefins reported by Najera0s group in
2009 is 86% ee.9s During the course of our study,10a Zhou0s group
reported the nice application of chiral tertiary amine–thiourea
organocatalysts derived from trans-cyclohexane-1,2-diamine and
D-glucopyranose in the asymmetric conjugate addition of acetyl-
acetone to aromatic nitroolefins.9p However, their organocatalysts
could NOT catalyze the enantioselective addition of acetylacetone
to aliphatic nitroolefins. These results might indicate the advantage of
incorporating acyclic diamines derived from a-amino acids into chiral
tertiary amine–thiourea organocatalysts.
H
N
H
N
N
O
O
S
7
O
O
2.3. Enantioselective addition of acetylacetone to nitroolefins
in a doubly stereocontrolled manner catalyzed by
bifunctional thiourea catalysts 1a and 1a0 in different
solvents10a
NO2
(10 mol%)
+
Ph
NO2
Ph
rt, THF or PhCH3
4
5a
6a
ent-
THF: 83% yield
58% ee
PhCH3: 86% yield
60% ee
The asymmetric conjugate addition reactions of acetylacetone 4
to various nitroolefins 5a–h were investigated in the presence of
organocatalysts 1a and 1a0 in THF and PhCH3, respectively, and the
results are summarized in Table 4. Both organocatalysts exhibited
good enantioselectivity in the conjugate addition reactions. Gen-
erally, both enantiomers of all the desired products can be achieved
in almost the same enantiomeric excess with the organocatalyst 1a
in THF and with organocatalyst 1a0 in PhCH3, respectively (entries
1–8, Table 4). The use of chiral organocatalyst 1a always gave the
conjugate adducts 6a–h with (S)-configuration,9g while the use of
organocatalyst 1a0 afforded ent-6a–h with the (R)-configuration.9g
Scheme 2. Conjugate addition of acetylacetone 4 to trans-
by the chiral tertiary amine–thiourea organocatalyst 7.
b
-nitrostyrene 5a catalyzed
On the basis of previous literatures18 and the observations made
in the present research, a tentative model representing the pro-
totypical addition of acetylacetone 4 to trans-
the presence of organocatalyst 1a derived from
b
-nitrostyrene 5a in
-valine and D-
L
glucopyranose is shown in Figure 2, in which a thiourea moiety of
the catalyst 1a interacts through hydrogen bonding with a nitro
group of the nitroalkene and enhances their electrophilicity while
the tertiary amine deprotonates an acidic proton of acetylacetone,
generating a ternary complex. The re-face approach of the nitro-
olefin accounts for the observed absolute configuration (S) of the
conjugate adduct. As to the results that the ‘mismatched’ catalyst
2.4. Reaction mechanism
To gain an insight into the reaction mechanism of the conjugate
addition of acetylacetone to nitroolefins catalyzed by the chiral
tertiary amine–thiourea organocatalysts derived from both
1a0 derived from
D-valine and D-glucopyranose in THF gave almost
a
-amino acids and carbohydrates, the role of sugar motif was in-
the same enantiomeric excess with opposite absolute configuration
in PhCH3, the solvents might play an important role in the stereo-
chemistry of transition state.19 Probably the interesting solvent
effects come from the introduction of acylated sugar moiety. The
vestigated. The new chiral tertiary amine–thiourea 7 without sugar
motif was synthesized and evaluated in the conjugate addition of
acetylacetone 4 to trans-b-nitrostyrene 5a. The product 6a was

X.-W. Pu et al. / Tetrahedron 66 (2010) 3655–3661
3659
a solution of the isothiocyanate 3 derived from
D
-glucopyranose
S
(1.2 mmol) in dry THF (10 mL) under a nitrogen atmosphere. The
resulting mixture was stirred at 35 ꢀC, and the reaction was mon-
itored by TLC. After removal of solvent, the residue was purified
through column chromatography on silica gel to give the amine–
thiourea catalysts.
N
H
O
N
H
O
N
AcO
OAc
-
O
+
4.2.1. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((S)-1-(dimethylamino)-3-
methylbutan-2-yl) thioureido)tetrahydro-2H-pyran-3,4,5-triyl tri-
O
H
N
20
ꢁ9.8 (c 1.0, CHCl3); 1H NMR
AcO
acetate (1a). Yield 431 mg (83%); [
(300 MHz, CDCl3):
a
]
D
O
AcO
d
¼6.15 (br s, 1H), 5.74 (t, J¼8.8 Hz, 1H), 5.32 (t,
J¼9.5 Hz, 1H), 5.07 (t, J¼9.7 Hz, 1H), 4.93 (t, J¼9.3 Hz, 1H), 4.26 (dd,
J¼4.1, 3.9 Hz, 1H), 4.15 (dd, J¼2.0, 2.3 Hz, 1H), 3.88 (m, 1H), 3.28 (br
s, 1H), 2.50–2.46 (m, 2H), 2.32 (s, 6H), 2.04 (s, 6H), 2.02 (s, 6H), 1.83
(m, 1H), 0.96 (d, J¼6.9 Hz, 3H), 0.95 (d, J¼6.9 Hz, 3H); 13C NMR
(75 MHz, CDCl3):
d
¼184.0, 170.5, 170.1, 169.8, 83.9, 73.3, 71.3, 68.5,
63.5, 61.9, 59.7, 44.9, 31.5, 20.8, 20.6, 18.1, 18.0; HRMS (FABþ) calcd
for C22H38N3O9S [Mþ1]þ 520.2329, found 520.2330.
Figure 2. Proposed transition state model.
sugar moiety of bifunctional tertiary amine–thiourea catalysts
might be mainly responsible for the different chiral induction in
different solvents.
4.2.2. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((R)-1-(dimethylamino)-3-
methylbutan-2-yl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl triace-
20
tate (1a0). Yield 420 mg (81%); [
a
]
þ44.0 (c 0.5, CHCl3); 1H
D
NMR (300 MHz, CDCl3):
d
¼5.76 (m, 1H), 5.23 (t, J¼9.4 Hz, 1H),
3. Conclusion
5.01 (t, J¼9.6 Hz, 1H), 4.87 (t, J¼9.4 Hz, 1H), 4.18 (d, J¼12.3 Hz,
1H), 4.06 (d, J¼12.4 Hz, 1H), 3.76 (m, 1H), 2.63–2.37 (m, 2H),
2.24 (s, 6H), 1.99 (s, 3H), 1.98 (s, 3H), 1.96 (s, 3H), 1.94 (s, 3H),
1.19 (m, 1H), 0.88 (d, J¼4.5 Hz, 3H), 0.81 (d, J¼2.5 Hz, 3H); 13C
In summary, two classes of important compounds acyclic
a-
amino acids and carbohydrates in life have been used for the de-
velopment a class of easily preparative, cheap, and fine-tunable
bifunctional tertiary amine–thiourea organocatalysts in chemistry.
These bifunctional thiourea organocatalysts promoted the enan-
tioselective conjugate addition of acetylacetone to various nitro-
olefins at room temperature in good yields (up to 93%) with good
enantioselectivity (up to 91% ee). The present research demon-
strates the advantages of incorporating two stereocontrolling
structures into a single catalyst. Notably, it offers a simple and ef-
ficient doubly stereocontrolled approach for the asymmetric syn-
NMR (75 MHz, CDCl3):
d
¼185.1, 170.6, 170.3, 169.9, 169.7, 83.6,
76.6, 73.5, 73.4, 71.3, 68.4, 62.0, 45.1, 31.6, 20.8, 20.7, 20.6, 18.1;
HRMS (FABþ) calcd for C22H38N3O9S [Mþ1]þ 520.2329, found
520.2330.
4.2.3. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((S)-1-(dimethylamino)-4-
methylpentan-2-yl) thioureido)tetrahydro-2H-pyran-3,4,5-triyl tri-
20
acetate (1b). Yield 426 mg (80%); [
(300 MHz, CDCl3):
a
]
D
ꢁ9.8 (c 1.0, CHCl3); 1H NMR
d
¼6.16 (br s, 1H), 5.71 (br s, 1H), 5.33 (t, J¼9.5 Hz,
thesis of
a chiral organic molecule. Doubly stereocontrolled
1H), 5.08 (t, J¼9.7 Hz, 1H), 4.94 (t, J¼9.5 Hz, 1H), 4.28 (dd, J¼3.6,
3.4 Hz, 1H), 4.15 (d, J¼12.3 Hz, 1H), 3.88 (m, 1H), 3.53 (br s, 1H),
2.57–2.41 (m, 2H), 2.33 (s, 6H), 2.08 (s, 3H), 2.05 (s, 3H), 2.03 (s, 3H),
2.02 (s, 3H), 1.68 (m, 1H), 1.36–1.22 (m, 2H), 0.93 (d, J¼6.5 Hz, 3H),
catalytic conjugate addition of nitroolefins has been achieved with
bifunctional thiourea catalysts 1c and 1c0 in same solvent (PhCH3),
and 1a and 1a0 in different solvents (PhCH3 and THF), respectively.
Further investigation of the efficacy of these organocatalysts in
other catalytic asymmetric reactions and development of other
chiral organocatalysts by this organocatalyst design strategy are in
progress in our laboratory.
0.90 (d, J¼6.2 Hz, 3H); 13C NMR (75 MHz, CDCl3):
¼185.0, 170.6,
d
169.8, 168.7, 168.6, 83.8, 73.3, 73.1, 71.3, 68.5, 66.9, 61.9, 53.4, 45.1,
42.5, 24.7, 22.7, 20.7; HRMS (FABþ) calcd for C23H40N3O9S [Mþ1]þ,
534.2485, found 534.2457.
4. Experimental
4.2.4. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((R)-1-(dimethylamino)-4-
methylpentan-2-yl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl
tri-
20
acetate (1b0). Yield 426 mg (80%); [
NMR (300 MHz, CDCl3):
a
]
D
þ41.0 (c 1.0, CHCl3); 1H
4.1. General
d5.81 (m, 1H), 5.33 (t, J¼9.4 Hz, 1H), 5.08 (t,
1H NMR and 13C NMR spectra were recorded at Bruker Avance
300 spectrophotometer. Chemical shifts (d) are expressed in parts
J¼9.7 Hz, 1H), 4.96 (t, J¼9.1 Hz, 1H), 4.28 (dd, J¼4.3, 4.3 Hz, 1H), 4.12
(d, J¼12.3 Hz, 1H), 3.86 (m, 1H), 2.70–2.18 (m, 8H), 2.07 (s, 3H), 2.05
(s, 3H), 2.04 (s, 3H), 2.01 (s, 3H), 1.69 (m, 1H), 1.26 (m, 2H), 0.94 (d,
J¼6.4 Hz, 3H), 0.87 (d, J¼6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3):
per million, and J values are given in hertz. The enantiomeric excess
was determined by HPLC using Chiralpak AS-H, or AD-H and
Chiralcel OD-H column with n-hexane and i-propanol as eluents.
HRMS data were determined on a Bruker Daltonics APEXII 47e FT-
ICR spectrometer. Optical rotations were determined on a JASCO
J-20C polarimeter with 0.2 dm tube using 589 nm at 20 ꢀC. All
chemicals and solvents were used as received without further pu-
rification unless otherwise stated. Flash column chromatography
was performed on silica gel (230–400 mesh).
d
¼185.4, 170.6, 169.9, 169.7, 83.2, 73.4, 71.2, 68.5, 66.1, 62.0, 52.8,
45.2, 42.6, 24.9, 22.7, 20.7, 20.6; HRMS (FABþ) calcd for C23H40N3O9S
[Mþ1]þ, 534.2485, found 534.2457.
4.2.5. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((S)-1-(dimethylamino)-3-
phenylpropan-2-yl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl
tri-
20
acetate (1c). Yield 442 mg (78%); [
(300 MHz, CDCl3):
a
]
D
þ11.0 (c 1.0, CHCl3); 1H NMR
d
7.35–7.23 (m, 3H), 7.19–7.17 (m, 2H), 6.48 (br s,
4.2. General procedure for preparation of bifunctional
tertiary amine–thiourea catalysts 1
1H), 5.71 (m, 1H), 5.32 (t, J¼9.5 Hz, 1H), 5.06 (t, J¼9.8 Hz, 1H), 4.92
(t, J¼9.3 Hz, 1H), 4.28 (dd, J¼3.8, 3.7 Hz, 1H), 4.14 (m, 1H), 3.84 (m,
1H), 2.74 (m, 1H), 2.72 (m, 1H), 2.51 (m, 1H), 2.36 (m, 1H), 2.21 (s,
To a solution of the primary–tertiary diamine 2 derived from
6H), 2.03 (s, 6H), 2.01 (s, 6H); 13C NMR (75 MHz, CDCl3):
d
184.3,
a
-amino acids (1 mmol) in dry THF (5 mL) was added dropwise
170.3, 170.0, 169.6, 169.5, 136.6, 129.0, 128.7, 127.0, 83.6, 73.1, 73.0,

3660
X.-W. Pu et al. / Tetrahedron 66 (2010) 3655–3661
71.2, 68.4, 64.8, 61.7, 55.9, 44.7, 39.0, 20.9, 20.6, 20.4; HRMS (ESI)
4.3. Typical procedure for asymmetric conjugate addition
reaction of acetylacetone 4 to nitroolefins 5 catalyzed by
catalyst 1
calcd for C26H37N3O9S [Mþ1]þ, 568.2323, found 568.2320.
4.2.6. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((R)-1-(dimethylamino)-3-
Catalyst 1a (10.4 mg, 0.02 mmol, 10 mol %) was added to a vial
containing acetylacetone 4 (40 mg, 0.4 mmol) and nitroolefins 5
(0.2 mmol) in dry THF (0.6 mL) at room temperature. The resulting
mixture was stirred at room temperature, and the reaction was
monitored by TLC. The reaction mixture was quenched with 1 M
aqueous HCl solution, extracted with EtOAc, and dried over Na2SO4.
The crude product was purified by flash silica gel chromatography
to give the desired adducts 6. The ee values were determined by
chiral HPLC analysis.
phenylpropan-2-yl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl
20
triacetate (1c0). Yield 431 mg (76%); [
a
]
D
þ14.0 (c 1.0, CHCl3); 1H
NMR (300 MHz, CDCl3): d 7.29–7.27 (m, 2H), 7.22–7.19 (m, 3H), 7.07
(br s, 1H), 5.84 (m, 1H), 5.34 (t, J¼9.4 Hz, 1H), 5.07 (t, J¼9.7 Hz, 1H),
4.95 (m, 1H), 4.35 (dd, J¼4.1, 3.8 Hz, 1H), 4.08 (m, 1H), 3.87
(d, J¼9.9 Hz,1H), 2.99 (m, 2H), 2.47 (m, 2H), 2.17 (s, 6H), 2.04 (s, 6H),
2.02 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 183.6, 170.5, 170.3, 169.8,
169.5, 137.2, 129.4, 128.5, 126.6, 82.8, 73.3, 71.1, 68.3, 61.8, 53.5, 45.1,
38.6, 20.9, 20.5, 20.4; HRMS (ESI) calcd for C26H37N3O9S [Mþ1]þ,
568.2323, found 568.2320.
4.3.1. (S)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione
NMR (300 MHz, CDCl3): 7.34–7.26 (m, 3H), 7.20–7.17 (m, 2H),
(6a)9g 1H
.
d
4.2.7. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((S)-2-(dimethylamino)-1-
4.67–4.62 (m, 2H), 4.37 (d, J¼10.8 Hz, 1H), 4.28–4.24 (m, 1H), 2.30
phenylethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl
triacetate
20
þ28.0 (c 1.0, CHCl3); 1H NMR
(s, 3H), 1.94 (s, 3H); HPLC (Chiralpak AS-H, i-propanol/hexane¼15/
(1d). Yield 448 mg (81%); [
(300 MHz, CDCl3):
a
]
D
85, flow rate 1.0 mL/min,
tR,minor¼24.3 min.
l¼210 nm): tR,major¼15.5 min,
d
7.39–7.31 (m, 3H), 7.25–7.23 (m, 2H), 6.65 (br s,
1H), 5.76 (m, 1H), 5.33 (t, J¼9.5 Hz, 1H), 5.09 (t, J¼9.9 Hz, 1H), 4.95
(t, J¼9.4 Hz, 1H), 4.30 (dd, J¼4.2, 4.1 Hz, 1H), 4.12 (m, 1H), 3.87
(m, 1H), 2.90 (m, 1H), 2.53 (dd, J¼1.7, 1.7 Hz, 1H), 2.35 (s, 6H), 2.06
4.3.2. (S)-3-(1-(4-Chlorophenyl)-2-nitroethyl)pentane-2,4-dione
(6b)9g 1H NMR (300 MHz, CDCl3):
(s, 3H), 2.04 (s, 3H), 2.01 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 184.4,
.
d
7.31 (d, J¼6.5 Hz, 2H), 7.14 (d,
J¼6.5 Hz, 2H), 4.62 (d, J¼6.6 Hz, 2H), 4.33 (d, J¼10.7 Hz, 1H), 4.27–
170.5, 170.3, 169.8, 169.6, 139.4, 129.2, 128.5, 126.5, 83.6, 73.4, 73.2,
71.1, 68.4, 66.6, 61.8, 58.8, 45.1, 20.6, 20.5; HRMS (ESI) calcd for
C25H35N3O9S [Mþ1]þ, 554.2167, found 554.2178.
4.25 (m, 1H), 2.30 (s, 3H), 1.98 (s, 3H); HPLC (Chiralpak AS-H,
i-propanol/hexane¼15/85, flow rate 1.0 mL/min, ¼210 nm): tR,ma-
l
¼15.8 min, tR,minor¼33.7 min.
jor
4.2.8. (4S,5S,6R)-2-(Acetoxymethyl)-6-(3-((R)-2-(dimethylamino)-1-
4.3.3. (S)-3-(1-(4-Bromophenyl)-2-nitroethyl)pentane-2,4-dione
(6c)9g 1H NMR (300 MHz, CDCl3):
phenylethyl)thioureido)tetrahydro-2H-pyran-3,4,5-triyl
triacetate
.
d
7.47 (d, J¼6.6 Hz, 2H), 7.07 (d,
20
(1d0). Yield 448 mg (81%); [
(300 MHz, CDCl3):
a
]
D
þ3.0 (c 1.0, CHCl3); 1H NMR
J¼6.7 Hz, 2H), 4.62–4.60 (m, 2H), 4.34 (d, J¼10.7 Hz, 1H), 4.26–4.23
d
7.28–7.19 (m, 5H), 5.74 (m, 1H), 5.26
(m, 1H), 2.30 (s, 3H), 1.98 (s, 3H); HPLC (Chiralpak AS-H, i-propanol/
(t, J¼9.5 Hz, 1H), 4.97 (t, J¼9.6 Hz, 1H), 4.86 (m, 1H), 4.20 (dd, J¼4.2,
4.1 Hz, 1H), 4.02 (m, 1H), 3.76 (m, 1H), 2.71 (m, 1H), 2.34 (dd, J¼3.8,
3.7 Hz, 1H), 2.19 (s, 6H), 1.97 (s, 3H), 1.94 (s, 3H), 1.92 (s, 6H); 13C
hexane¼15/85, flow rate 1.0 mL/min,
tR,minor¼32.0 min.
l¼210 nm): tR,major¼16.9 min,
NMR (75 MHz, CDCl3):
d 183.7, 170.8, 170.6, 169.8, 169.6, 139.9,
4.3.4. (S)-3-(2-Nitro-1-(2-(trifluoromethyl)phenyl)ethyl)pentane-
2,4-dione (6d)9g 1H NMR (300 MHz, CDCl3):
128.8, 127.8, 126.5, 82.9, 73.3, 73.0, 71.1, 68.4, 68.2, 67.8, 65.1, 61.8,
56.6, 45.0, 20.6, 20.5; HRMS (ESI) calcd for C25H35N3O9S [Mþ1]þ,
554.2167, found 554.2178.
.
d
7.69 (d, J¼7.6 Hz,1H),
7.46 (t, J¼7.2 Hz, 1H), 7.37 (t, J¼7.6 Hz, 1H), 7.20 (d, J¼7.5 Hz, 1H),
4.81–4.75 (m,1H), 4.62–4.55 (m, 3H), 2.25 (s, 3H),1.94 (s, 3H); HPLC
(Chiralcel OD-H, i-propanol/hexane¼10/90, flow rate 1.0 mL/min,
4.2.9. (3R,5S,6R)-2-(Acetoxymethyl)-6-(3-((S)-1-(dimethylamino)-3-
(1H-indol-3-yl)propan-2-yl)thioureido)tetrahydro-2H-pyran-3,4,5-
l¼210 nm): tR,major¼15.9 min, tR,minor¼17.8 min.
20
4.3.5. (S)-3-(2-Nitro-1-p-tolylethyl)pentane-2,4-dione
NMR (300 MHz, CDCl3):
(6e)9g 1H
.
triyl triacetate (1e). Yield 467 mg (77%); [
a
]
ꢁ10.0 (c 1.0, CHCl3);
D
1H NMR (300 MHz, CDCl3):
d
8.83 (br s, 1H), 7.47 (br s, 1H), 7.32 (d,
d
7.12 (d, J¼8.0 Hz, 2H), 7.06 (d, J¼8.2 Hz,
J¼7.9 Hz, 1H), 7.15–7.03 (m, 2H), 6.97 (br s, 1H), 6.42 (br s, 1H), 5.64
(d, J¼8.6 Hz, 1H), 5.24 (t, J¼9.5 Hz, 1H), 5.01 (t, J¼9.8 Hz, 1H), 4.87
(m, 1H), 4.17 (dd, J¼3.7, 3.4 Hz, 1H), 4.05 (d, J¼11.5 Hz, 1H), 3.77 (m,
2H), 2.81 (br s, 2H), 2.48 (m, 2H), 2.19 (s, 6H), 1.96 (s, 12H); 13C NMR
2H), 4.62–4.59 (m, 2H), 4.5 (d, J¼10.9 Hz, 1H), 4.22 (m, 1H), 2.30
(s, 3H), 2.29 (s, 3H), 1.94 (s, 3H); HPLC (Chiralpak AS-H, i-propanol/
hexane¼15/85, flow rate 1.0 mL/min,
tR,minor¼19.4 min.
l¼210 nm): tR,major¼12.5 min,
(75 MHz, CDCl3):
d 184.5, 170.6, 169.9, 169.8, 136.6, 126.9, 123.3,
122.2, 119.5, 118.2, 111.6, 110.0, 83.8, 73.2, 71.2, 68.4, 68.2, 67.9, 65.9,
61.8, 54.6, 44.9, 29.6, 20.6; HRMS (ESI) calcd for C28H38N4O9S
[Mþ1]þ, 607.2423, found 607.2438.
4.3.6. (S)-3-(1-(4-Methoxyphenyl)-2-nitroethyl)pentane-2,4-dione
(6f)9g 1H NMR (300 MHz, CDCl3):
.
d
7.10 (d, J¼6.8 Hz, 2H), 6.84
(d, J¼6.8 Hz, 2H), 4.60 (d, J¼6.9 Hz, 2H), 4.34 (d, J¼10.9 Hz, 1H), 4.12
(m, 1H), 3.78 (s, 3H), 2.29 (s, 3H), 1.94 (s, 3H); HPLC (Chiralpak AD-
4.2.10. (3R,5S,6R)-2-(Acetoxymethyl)-6-(3-((R)-1-(dimethylamino)-
H, i-propanol/hexane¼5/95, flow rate 0.8 mL/min,
l
¼210 nm):
3-(1H-indol-3-yl)propan-2-yl)thioureido)tetrahydro-2H-pyran-
tR,major¼40.6 min, tR,minor¼66.5 min.
20
3,4,5-triyl triacetate (1e0). Yield 484 mg (80%); [
a
]
þ30.0 (c 1.0,
D
CHCl3); 1H NMR (300 MHz, CDCl3):
d
8.85 (br s, 1H), 7.58 (br s,
4.3.7. (S)-3-(1-(2-(Benzyloxy)phenyl)-2-nitroethyl)pentane-2,4-di-
one (6g)9g 1H NMR (300 MHz, CDCl3):
7.51–7.40 (m, 5H), 7.26 (m,
1H), 7.36 (d, J¼7.7 Hz, 1H), 7.17–7.05 (m, 2H), 6.99 (br s, 1H), 6.52
(br s, 1H), 5.77 (d, J¼5.8 Hz, 1H), 5.29 (t, J¼9.2 Hz, 1H), 5.03
(t, J¼9.7 Hz, 1H), 4.76 (m, 1H), 4.25 (d, J¼7.3 Hz, 1H), 4.08 (m, 1H),
3.79 (m, 2H), 2.96 (br s, 2H), 2.49 (br s, 2H), 2.09 (s, 6H), 2.03
.
d
1H), 7.10 (m, 1H), 6.98–6.91 (m, 2H), 5.13 (s, 2H), 4.80–4.77 (m, 1H),
4.57–4.53 (m, 3H), 2.18 (s, 3H), 1.91 (s, 3H); HPLC (Chiralpak AS-H,
i-propanol/hexane¼10/90, flow rate 0.8 mL/min,
l¼210 nm):
(s, 6H), 2.02 (s, 6H); 13C NMR (75 MHz, CDCl3):
d 184.2, 171.2,
tR,major¼20.2 min, tR,minor¼22.1 min.
170.7, 169.9, 169.7, 136.4, 127.4, 123.3, 122.2, 119.6, 118.6, 111.5,
110.3, 83.2, 73.3, 71.2, 68.4, 68.2, 65.0, 61.9, 53.5, 45.1, 29.6, 20.7,
20.5; HRMS (ESI) calcd for C28H38N4O9S [Mþ1]þ, 607.2423, found
607.2438.
4.3.8. (R)-3-(4-Methyl-1-nitropentan-2-yl)pentane-2,4-dione
(6h)7b 1H NMR (300 MHz, CDCl3):
4.51 (m, 2H), 3.99 (d, J¼8.4 Hz,
1H), 2.90 (m,1H), 2.28 (s, 3H), 2.25 (s, 3H),1.69 (m,1H),1.35 (m,1H),
.
d

X.-W. Pu et al. / Tetrahedron 66 (2010) 3655–3661
3661
metric conjugate addition of 1,3-dicarbonyl compounds to nitroolefins, see:
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Li, H.; Duan, W.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713; (h) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367; (i) Li, H.; Wang, Y.; Tang, L.;
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105; (j) Terada, M.; Ube, H.; Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454; (k)
Lubkoll, J.; Wennemers, H. Angew. Chem., Int. Ed. 2007, 46, 6841; (l) Andres, J.
M.; Manzano, R.; Pedrosa, R. Chem.dEur. J. 2008, 14, 5116; (m) Malerich, J. P.;
Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008, 130, 14416; (n) Wang, C.;
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0.98 (m, 1H), 0.94 (m, 6H); HPLC (Chiralpak AS-H, i-propanol/
hexane¼4/96, flow rate 1.0 mL/min,
l¼210 nm): tR,major¼10.4 min,
tR,minor¼12.8 min.
Acknowledgements
We thank National Natural Science Foundation of China
(20702044, 20962023) and the Program for New Century Excellent
Talents in University for support of this research.
References and notes
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19. We could not ruled out participation of the solvent in the transition state. We
thank one reviewer’s comments on our manuscript.