Fine-tunable organocatalysts bearing multiple hydrogen-bonding donors for construction of adjacent quaternary and tertiary stereocenters via a michael reaction

Article abstract of DOI:10.1002/chem.200801420

The fine-tunable bifunctional amine/thiourea organocatalysts, relying on multipe hydrogen-bonding donors was investigated. A representative set of aryl and alkyl substituted nitroolefins were surveyed under the optimal experimental conditions. The trisubstituted carbon nucleophiles were examined with a 10 mol% of catalyst. The significant role of the multiple hydrogen-bonding donors played in the system was demonstrated through the control experiments using less bulky methylated (1R,2R,1'R,2'R)-II-E, (1R,2R,S)-II-F, and (1R,2R,R)-II-G as the catalyst under the optimized reaction condition. The fine tunable amine/thiourea organocatalysts, relying on multiple hydrogen-binding donors, showed excellent activity, diastereoselectivity, enantioselectivity, and structural scope in asymmetric Michael addition of α-substituted β-ketoesters to nitroolefins.

Full text of DOI:10.1002/chem.200801420

DOI: 10.1002/chem.200801420
Fine-Tunable Organocatalysts Bearing Multiple Hydrogen-Bonding Donors
for Construction of Adjacent Quaternary and Tertiary Stereocenters via a
Michael Reaction
Zhi-Hai Zhang, Xiu-Qin Dong, Dong Chen, and Chun-Jiang Wang*[a]
The Michael addition reaction is widely recognized as one
lectivity and broad scope in the asymmetric Michael addi-
tion of a-substituted b-ketoesters to various nitroolefins.[5c,e]
Although amine/thioureas I were shown to be highly effi-
cient for the addition of various of symmetric and asymmet-
ric 1,3-diketones to nitroolfeins, our initial attempts to apply
I to promote the addition of a-substituted b-ketoesters to ni-
troolefins were unsuccessful (Table 1). The reaction of
methyl 2-oxo-cyclopentanecaboxylate (1a) to nitroolefin
(2a) with catalysts I in CH2Cl2 went to completion at room
temperature in less than 0.5 h, which was consistent with the
case of 1,3-diketone,[6] but the adduct 3a was formed in very
low diastereoselectivity with moderate to good enantioselec-
tivity for the major diastereomer, even at lower temperature
of the most general and versatile methods for formation of
[1]
À
C C bonds in organic synthesis. Therefore, it is not sur-
prising that the development of enantioselective catalytic
protocols for this reaction has attracted much attention.[2]
Efforts aimed at achieving asymmetric Michael addition by
using powerful and environmentally friendly organocatalysts
have been explored intensively in recent years.[3,4] Of partic-
ular interest is the reaction between trisubstituted carbon
nucleophiles and electron-deficient olefins to form Michael
adducts containing adjacent quaternary and tertiary stereo-
centers, which are key units in complex natural products
and highly valuable synthetic building blocks. Despite its
great synthetic potential, only limited successful protocols
have been reported to achieve high levels of enantio- and/or
diastereoselectivity.[5] Compared with other asymmetric cat-
alysis, the reaction simultaneously creating adjacent quater-
nary and tertiary stereocenters in one step is still in its infan-
cy and the development of novel efficient catalysts showing
high reactivity, enantioselectivity and diastereoselectivity
still remains a great challenge.
Table 1. Representative results for Michael addition of a-substituted
b-ketoester 1 and nitroolefin 2a catalyzed by organocatalysts I.[a]
Entry
Catalyst
T [8C]
t [h]
Yield[b] [%]
dr[c]
ee [%][d,e]
Recently, we reported a new class of bifunctional amine/
1
2
3
4
5
I-A
I-B
I-C
I-D
I-D
RT
RT
RT
RT
À45
0.5
0.5
0.5
0.5
10
92
96
91
94
97
74:26
50:50
65:35
59:41
58:42
29
72
80
80
84
thiourea catalysts
I bearing multiple hydrogen-bonding
donors, which showed excellent performance in catalytic
asymmetric addition of acetylactone to nitroolefins and
highly anti-selective nitro-Mannich reaction.[6,7] Extending
the interest of these organocatalyst in asymmetric catalysis,
herein we report that another novel family of readily avail-
able, fine-tunable multiple hydrogen-bonding donor organo-
catalysts II[8,9] results in high enantioselectivity, diastereose-
[a] Unless otherwise noted, the reaction was carried out with 0.22 mmol
of 1a and 0.2 mmol of 2a in 0.25 mL CH2Cl2. [b] Isolated yield. [c] Deter-
mined from crude 1H NMR spectra. [d] Enantiomeric excesses were de-
termined by chiral HPLC analysis. [e] The absolute configuration of 3a
was determined to be (2R,3S) by comparing the retention time of chiral
HPLC analysis with that of the reported date.
[a] Z.-H. Zhang, X.-Q. Dong, D. Chen, Prof. Dr. C.-J. Wang
College of Chemistry and Molecular Sciences
Wuhan University, 430072 (PR China)
Fax : (+86)27-68754067
E-mail: cjwang@whu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801420.
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COMMUNICATION
Table 2. Screening studies of asymmetric Michael addition of a-substitut-
ed b-ketoester 1 and nitroolefin 2a catalyzed by organocatalysts II.[a]
(Table 1, entries 1–5). Based on those experimental data and
the study of the reported transition-state models of Michael
reaction of b-ketoesters with nitroolefins,[5e,10] we envisioned
that replacing the bulky sulfonamide NHSO2R with less
bulky OH group in the corresponding organocatalysts could
facilitate forming more favorable transition-state and there-
by significantly enhance the diastereoselectivity and enantio-
selectivity (Scheme 1).
Entry
Catalyst
T [8C]
t [h]
Yield [%][b]
dr[c]
ee [%][d]
1
2
3
4
5
6
II-A
II-B
II-C
II-D
II-D
II-D
RT
RT
RT
RT
À25
À45
1
1
1
1
5
10
95
93
97
95
93
98
93:7
69
78
68
89
97
99
82:18
87:13
90:10
97:3
98:2
[a] Unless otherwise noted, the reaction was carried out with 0.22 mmol
of 1a and 0.2 mmol of 2 in 0.25 mL CH2Cl2. [b] Isolated yield. [c] Deter-
mined from crude 1H NMR spectra. [d] Enantiomeric excess values were
determined by chiral HPLC analysis.
97:3) and high enantioselectivities (90–94% ee) (Table 3, en-
tries 12–15).
Table 3. Asymmetric Michael addition of a-substituted b-ketoester 1 and
nitroolefins 2 catalyzed 2nd generation organocatalysts II.[a]
Entry
R2
Yield [%][b]
dr[c]
ee [%][d]
1
Ph (2a)
Ph (2a)
98
98
97
95
91
95
90
94
90
91
89
89
93
92
89
98:2
98:2
98:2
97:3
99:1
97:3
98:2
97:3
96:4
94:6
97:3
96:4
97:3
97:3
97:3
99
97
99
99
99
99
99
99
98
97
99
94
90
94
90
2[e]
3
o-Me-Ph (2b)
m-Me-Ph (2c)
p-Me-Ph (2d)
o-Cl-Ph (2e)
p-Cl-Ph (2 f)
o-Br-Ph (2g)
Scheme 1. Design of the 2nd generation fine-tunable and less bulky
amine thiourea organocatalysts II bearing multiple hydrogen-bonding
donors.
4
5
6
7
8
9
10
11
12[f]
13[f]
14[f]
15[f]
m-MeO-PhACTHUGNETRNNU(G 2h)
We then investigated the effect of the fine-tunable orga-
nocatalysts II on the model reaction. Gratifyingly, these re-
actions afford good to excellent diastereo- and enantioselec-
tivities with the similar reaction rate at room temperature in
p-MeO-Ph (2i)
p-F-Ph (2j)
amyl (2k)
iPr (2l)
iBu (2m)
Cy (2n)
[11]
CH2Cl2 (Table 2), and catalyst II-D was revealed as the
best one in terms of diastereoselectivity and enantioselectiv-
ity. Interestingly, the reaction temperature remarkably af-
fected the diastereo- and enantioselectivity, which was dif-
ferent from the case of 1,3-diketone.[6] Reducing reaction
temperature to À458C achieved a dr of 98:2 with 99% ee
for the major diastereomer within 10 h[12] (Table 2, entry 6).
The current catalysis demonstrated significant improvements
over previous results that gave lower diastereo- and enantio-
selectivity or required longer reaction time (2–4 d).[5c,e]
To evaluate the scope of this Michael reaction, a repre-
sentative set of aryl and alkyl substituted nitroolefins were
surveyed under the optimal experimental conditions. As
shown in Table 3, A variety of aryl nitroolefins (2a–j) react-
ed smoothly with b-ketoesters (1) within 12–20 h to afford
the corresponding adducts (3a–j) in high yields, excellent
diastereoselectivities and enantioselectivities (Table 3, en-
tries 1 and 2–11). It appears that the steric and electronic
properties of the substituents on the aromatic rings have a
very limited effect on the selectivities. Alkyl nitroolefins
(2k–n) also worked well in these reaction to give the desired
products (3k–n) with excellent diastereoselectivities (96:4–
[a] Unless otherwise noted, the reaction was carried out with 0.22 mmol
of 1 and 0.2 mmol of 2 in 0.25 mL of CH2Cl2 at À458C. [b] Isolated yield.
[c] Determined from crude 1H NMR spectra. [d] Enantiomeric excesses
were determined by chiral HPLC analysis. [e] 5 mol% catalyst was used
and the reaction completed in 20 h. [f] Reaction at 08C.
Finally, to explore more deeply the scope and generality
of this catalytic system, other trisubstituted carbon nucleo-
philes were also examined with a 10 mol% of catalyst II-D.
As shown in Figure 1, various cyclic and acyclic compounds
proved to be excellent substrates for this reaction, providing
high diastereoselectivities and enantioselectivities.
The significant role of the multiple hydrogen-bonding
donors played in this system could be demonstrated through
the control experiments using less bulky methylated
(1R,2R,1’R,2’R)-II-E, (1R,2R,S)-II-F and (1R,2R,R)-II-G as
the catalyst under the optimized reaction condition
(Figure 2): the reactions became a little sluggish and the dia-
stereoselectivities of the products still remained at the simi-
lar levels, which was coincident with the proposed transition
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C.-J. Wang et al.
diphenylethanol (1 mmol) in anhydrous THF (10 mL). The solution was
stirred overnight. TLC analysis indicated completion of the reaction. The
reaction mixture was concentrated in vacuo. The residue was purified by
flash silica gel chromatography to yield the corresponding organocatalyst.
General procedure for asymmetric Michael addition of a-substituted b-
ketoesters and nitroolefins catalyzed organocatalysts II-D: The catalyst
II-D (5.0 mg, 0.0126 mmol) was added to a vial containing a-substituted
b-ketoester (0.126 mmol) and nitroolefin (0.25 mmol) in dichloromethane
(0.2–0.6 mL) at À458C, TLC analysis indicated completion of the reac-
tion after about 12–20 h. Then the reaction mixture was concentrated
under vacuum to obtain the crude product. The crude product was puri-
fied by flash silica gel chromatography to afford the product, which was
then analyzed by chiral HPLC to determine the enantiomeric excess.
Figure 1. Results of Michael addition of nitroolefins with other cyclic and
acyclic trisubstituted carbon nucleophiles catalyzed by organocatalysts II-
D.
Acknowledgements
The authors thank Dr. Bo Xu for helpful discussions. This work is sup-
ported by National Natural Science Foundation of China (20642005,
20702039) and the startup fund from Wuhan University.
state mentioned above, however, the enantioselectivities de-
creased remarkably comparing with the results achieved by
the corresponding organocatalyst II-D.
Keywords: asymmetric catalysis · hydrogen bonds · Michael
addition · organocatalysis
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gen-bonding donors played in the fine-tunable organocatalysts II-D.
In summary, elaborately designed fine-tunable bifunction-
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lectivity, enantioselectivity and structural scope in the asym-
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high functional compounds featuring adjacent quaternary
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8782
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Fine-Tunable Organocatalysts
COMMUNICATION
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[11] Results of the solvent screening studies at room temperature:
CH2Cl2 (93% yield, dr 90:10, ee 89%); THF (90% yield, dr 76:24,
ee 73%); CHCl3 (92% yield, dr 75:25, ee 73%); EtOAc (88% yield,
dr 74:26, ee 87%); MeCN (91% yield, dr 87:13, ee 73%); DMSO
(70% yield, dr 64:36, ee 6%); MeOH (87% yield, dr 85:15, ee 0%).
[12] The absoluted configurations of the major products were assigned
by HPLC and optical rotation comparisons with the published re-
sults (see Supporting Information for details).
Received: July 13, 2008
Published online: August 26, 2008
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8783