l-Proline derived triamine as a highly stereoselective organocatalyst for asymmetric Michael addition of cyclohexanone to nitroolefins

Article abstract of DOI:10.1016/j.tetasy.2007.05.035

l-Proline derived triamine 4 has been developed as a highly efficient and stereoselective organocatalyst for the asymmetric Michael addition of cyclohexanone to nitroolefins. In the presence of (CF₃SO₂)₂NH, 4 catalyzed the

Full text of DOI:10.1016/j.tetasy.2007.05.035

Tetrahedron: Asymmetry 18 (2007) 1308–1312
L-Proline derived triamine as a highly stereoselective organocatalyst
for asymmetric Michael addition of cyclohexanone to nitroolefins
a,b,c
a,c
a
a,
*
Haibin Chen,
Yu Wang, Siyu Wei and Jian Sun
a
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
b
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
c
Graduate School of Chinese Academy of Sciences, Beijing, China
Received 28 March 2007; revised 29 May 2007; accepted 31 May 2007
Abstract—L-Proline derived triamine 4 has been developed as a highly efficient and stereoselective organocatalyst for the asymmetric
Michael addition of cyclohexanone to nitroolefins. In the presence of (CF SO NH, 4 catalyzed the reaction of cyclohexanone to a vari-
3
2 2
)
ety of nitroolefins with high yields (up to 99%) and excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 98% ee).
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
the asymmetric Michael addition of cyclohexanone to
nitroolefins.
The Michael addition is one of the most important carbon–
carbon bond-forming reactions in organic synthesis. Asym-
metric organocatalytic Michael addition has attracted
intense interests in the recent few years due to its environ-
mental friendliness and the generation of multiple stereo-
O
N
O
N
N
N
OH
NH
NH
N
H
OH
N
H
1
–4
genic centers in a single step. So far quite a number of
chiral small organic molecules have been developed as ste-
1
2
3
4
1
–4
reoselective catalysts for this transformation. L-Proline 1
was first reported to catalyze the intermolecular Michael
addition of carbon nucleophiles to nitroolefins, which,
however, afforded the adducts with poor enantioselectivity,
Figure 1. Structures of the catalysts.
In our previous studies, the cis-4-pyrrolidin-1-yl group on
the pyrrolidine ring was found to have a significantly ben-
eficial effect on the stereoselectivity of catalyst 2 for the
2
albeit with good diastereoselectivity. Later, various cata-
5
lysts were designed and synthesized based on proline and
applied to this reaction, and significantly improved efficien-
cies, diastereoselectivities, and enantioselectivities were ob-
tained.3 Most of these catalysts take advantage of the
carboxylic acid function of proline to install steric shielding
and/or substrate-orienting functional groups.3 Recently,
Palomo presented the first example of highly stereoselective
catalysts that make use of a trans-4-hydroxyl group on the
pyrrolidine ring of proline for the steric orientation of the
asymmetric aldol reaction. We were interested in examin-
ing if such an effect still remains for the Michael addition.
Thus, catalysts 2 and 4 were tested in the Michael addition
of cyclohexanone with nitroolefins. The parent catalysts 1
and 3 were also tested under identical conditions for
comparisons.
,4
2
. Results and discussion
4
a
acceptor. Herein, we report a new catalyst 4 (Fig. 1) that
resorts to the assistance of a cis-4-pyrrolidin-1-yl group on
the pyrrolidine ring for achieving high stereoselectivity in
Compound 4 was easily prepared starting from the com-
mercially available trans-4-hydroxy-L-proline according to
Scheme 1. The preparation commenced with the protec-
tions of the pyrrolidine and the carboxylic acid functions
6
of trans-4-hydroxy-L-proline following known procedures.
*
Corresponding author. Tel.: +86 28 85211220; fax: +86 28 85222753;
e-mail: sunjian@cib.ac.cn
The reduction of the protected intermediate 5 with lithium
aluminum hydride followed by mesylation provided
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.035

H. Chen et al. / Tetrahedron: Asymmetry 18 (2007) 1308–1312
1309
HO
HO
Ref 6
MsO
reactivity, diastereoselectivity, and enantioselectivity in
the presence of TFA, affording 94% yield, 92/8 dr and
89% ee (entry 8).
(
a), (b)
9%
(c)
OMs
8
83%
CO2H
N3
CO2CH3
NH2
N
H
N
Boc
5
N
Boc
6
To further optimize the reaction conditions, we next exam-
ined the influences of different reaction parameters on the
performance of catalyst 4 in the presence of TFA in the
Michael addition of 10 to 11a. The solvent effects were first
assessed. DMSO, DMF, THF, acetonitrile, diethyl ether,
N3
H2N
N
(f)
(
d)
9%
(e)
4
9
65%
80%
N
N
Boc
N
N
Boc
Boc
i
chloroform, toluene, and PrOH, all afforded similarly
7
8
9
good yields, drs and ee values at room temperature (Table
9
i
2
, entries 1–8). PrOH gave an overall best result with 92%
Scheme 1. Preparation of organocatalyst 4. Reagents and conditions: (a)
LiAlH , THF, 0 °C; (b) MsCl, Et N, CH Cl , 0 °C; (c) NaN , DMF,
0 °C, 12 h; (d) Pd/C (5%), H , MeOH, 35 °C, 5 h; (e) Br(CH Br, Et N,
DMF, 60 °C, 10 h; (f) TFA, CH Cl , rt, 12 h.
yield, 93:7 dr and 90% ee (entry 8). Similarly high drs and
4
3
2
2
3
6
2
2
)
4
3
ee values were also observed in MeOH, H O, and brine
2
2
2
(entries 9–11). However, the reaction is much slower in
these solvents. When the temperature was lowered to
0
°C, the diastereoselectivity and enantioselectivity were
i
both slightly improved with PrOH as the solvent (entry
2). Although the reaction rate did decrease to a large ex-
dimesylate 6 in high yield. Reaction of 6 with sodium azide
afforded the diazido compound 7 in 83% yield. Hydrogen-
olysis of 7 in the presence of 5% Pd/C gave 8 in a nearly
quantitative yield. Treatment of 8 with 1,4-dibromobutane
resulted in the production of 9 in 65% yield. After the re-
moval of the N-Boc protecting group using trifluoroacetic
acid (TFA), the desired catalyst 4 was obtained with an
overall yield of 35%.
1
tent at this temperature, it recovered after the concentra-
tion of 11a was increased from 0.1 to 0.5 M without the
a
Table 2. Optimization of the reaction conditions
Entry Solvent Time (h) Yield (%) dr (syn/anti) ee (syn) (%)
1
2
3
4
5
6
7
8
9
1
1
DMSO
DMF
THF
5
10
10
95
83
95
99
99
99
99
92
65
30
49
80
91
92/8
92/8
96/4
91/9
96/4
93/7
96/4
93/7
95/5
89/11
94/6
96/4
94/6
89
87
85
91
86
89
87
90
90
89
89
94
93
Catalysts 1–4 were first checked in the model reaction of
cyclohexanone 10 with nitrostyrene 11a in DMSO at room
temperature with a catalyst loading of 20 mol %. As illus-
trated in Table 1, Compounds 2 and 4 exhibited signifi-
CH
Et
CHCl
3
CN 10
O
2
10
10
3
Toluene 10
cantly
higher
enantioselectivities,
albeit
similar
i
PrOH
10
diastereoselectivities compared to the parent catalysts 1
and 3, respectively, in the absence of additive (entries 3
and 7 vs 1 and 5, respectively). This clearly indicates that
the cis-4-pyrrolidin-1-yl group has beneficial effects on the
stereoselectivities of catalysts 2 and 4, which became even
more significant when 20 mol % TFA was added to the
CH OH 10
3
0
1
H
2
O
10
10
72
24
Brine
b
i
12
13
PrOH
PrOH
c
i
a
Unless stated otherwise, conditions: [11a] = 0.1 mol/L, 20 mol % 4/TFA,
room temperature, solvent/cyclohexanone = 2:1.
The reaction temperature is 0 °C.
The reaction temperature is 0 °C and the concentration of 11a is
0.5 mol/L.
7
reaction (entries 4 and 8 vs 2 and 6, respectively). Further-
b
c
more, in the presence of TFA, the diastereoselectivity and
reactivity of catalyst 4 were also significantly improved
8
upon. Thus, catalyst 4 displayed a well-balanced high
a
Table 1. The organocatalytic Michael addition of cyclohexanone to nitrostyrene
O
O
Ph
NO2
20 mol% cat.
NO2
+
Ph
DMSO
10
11a
12a
b
c
d
Entry
Catalyst
Yield (%)
dr (syn/anti)
ee (syn) (%)
1
2
3
4
5
6
7
8
1
94
92
65
49
45
99
61
94
94/6
96/4
95/5
94/6
87/13
93/7
86/14
92/8
33
22
52
55
73
81
80
89
1/TFA
2
2/TFA
3
3/TFA
4
4/TFA
a
b
c
Unless stated otherwise, conditions: [11a] = 0.1 mol/L, solvent/cyclohexanone = 2:1, room temperature, 5 h.
Isolated yield of mixture of syn/anti based on nitrostyrene.
Diastereomeric ratio, determined by chiral-phase HPLC analysis.
d
Enantiomeric excess, determined by chiral-phase HPLC analysis.

1310
H. Chen et al. / Tetrahedron: Asymmetry 18 (2007) 1308–1312
sacrifice of either diastereoselectivity or enantioselectivity
entry 13).
and could be completed within 20 h, affording 95% yield,
99/1 dr and 94% ee (entry 11).
(
The effects of other Brønsted acids were also examined with
catalyst 4 in the Michael addition reaction of 10 to 11a. As
illustrated in Table 3, the reaction rate varies dramatically
with different acids. The reaction is faster with the rela-
tively weak acids such as acetic acid, (CF SO ) NH, ben-
Having established the optimal reaction conditions, we
next examined other nitroolefins to expand the substrate
scope of catalyst 4. As shown in Table 4, high isolated
yields were obtained for all the selected nitroolefins regard-
less of the electronic nature of the aromatic substituent R.
Most of the nitroolefins afforded excellent drs and ee val-
ues. The exception is with the relatively electron-deficient
nitroolefins 11g and 11h. The former gave a moderate ee
value, albeit a high dr (entry 7), whereas both the dr and
the ee value obtained with the latter, tend to be moderate
(entry 8).
3
2 2
zoic acid, and 4-CF C H OH, than with the strong acids
3
6
4
such as TFA, p-TsOH, and D-(+)-camphor sulfonic acid
entries 1–8). However, the reaction dramatically slows
down if the acidity of the acid is too weak (entries 9 and
0). On the other hand, only small deviations of the diaste-
(
1
reoselectivity and enantioselectivity were observed with dif-
ferent acids. The highest dr and ee value were observed
with (CF SO ) NH (entry 5). Although the reaction is
Several other ketones were also examined in the 4-cata-
lyzed Michael addition with 11a. Unfortunately, as de-
picted in Scheme 2, only low to moderate yields and
moderate ee values were obtained.
3
2 2
not the most active with this acid, it is reasonably efficient
Table 3. Screening of acids in the Michael addition of cyclohexanone to
nitrostyrene
a
O
Ph
O
4
/(CF3SO2)2NH
NO2
NO2
+
Ph
i-PrOH, 0 oC, 20 h
Entry Acid
Yield dr
ee (syn)
13
11a
14
4% (53% ee)
Ph
(
%) (syn/anti) (%)
2
1
2
3
4
5
6
7
8
9
1
1
TFA
CH COOH
p-TsOH
47
90
65
95/5
93/7
95/5
95/5
99/1
93/7
94/6
92/8
95/5
90/10
99/1
93
92
92
93
93
90
91
90
90
86
94
O
O
3
NO2
4
/(CF3SO2)2NH
NO2
+
Ph
i-PrOH, 0 oC, 20 h
D-(+)-Camphor sulfonic acid 54
1
5
11a
16
10% (66:34 dr, 56% ee)
(CF
C H
6 5
3
SO
COOH
4-NO COOH
4-CF OH
2
)
2
NH
79
81
62
99
29
22
95
<
O
O
Ph
2 6 4
C H
H
NO2
3
C
6
4
3 2 2
4/(CF SO ) NH
i-PrOH, 0 oC, 20 h
NO2
+
Ph
C
6
H
5
OH
4- BuC
2 2
(CF SO )
t
0
1
6
H
4
OH
NH
O
O
O
O
b
3
1
7
11a
18
a
Unless stated otherwise, conditions: [11a] = 0.5 mol/L, 20 mol % 4,
0 mol % acid, solvent/cyclohexanone = 1:1, 0 °C, 10 h.
5
1% (94:6 dr, 77% ee)
2
b
The reaction time is 20 h.
Scheme 2. Michael addition of ketones to 11a.
a
Table 4. Michael addition of cyclohexanone to various nitroolefins catalyzed by 4
O
O
R
NO2
4
/(CF3SO)2NH
i-PrOH, 0 o
NO2
+
R
C
10
11
12
b
c
d
Entry
R (11)
Time (h)
Yield (%)
dr (syn/anti)
ee (%)
1
2
3
4
5
6
7
8
9
Ph (11a)
20
24
24
20
8
24
20
40
8
95
96
95
96
99
95
97
89
94
92
96
97
99/1
98/2
97/3
99/1
99/1
99/1
99/1
85/15
99/1
99/1
99/1
95/5
94
94
93
94
95
98
84
81
94
94
94
91
6 4
4-FC H (11b)
4-BrC
6
H
4
(11c)
(11d)
(11e)
4-ClC
2-ClC
6
H
H
4
6
4
3,4-Cl
4-CNC
4-NO
2
C
6
H
3
(11f)
(11g)
6
H
4
2
C
6
H
4
(11h)
4-CH
3-CH
4-CH
3
3
3
OC
OC
C H (11k)
6 4
6
H
4
(11i)
(11j)
10
11
12
6
H
4
12
12
12
4 3
C H O (11l)
a
b
c
Conditions: [11] = 0.5 mol/L, 20 mol % 4, 20 mol % (CF
Isolated yield of mixture of syn/anti based on the nitroolefin.
Diastereomeric ratio, determined by chiral-phase HPLC analysis.
Enantiomeric excess, determined by chiral-phase HPLC analysis.
3 2 2
SO ) NH, solvent/cyclohexanone = 1:1, 20 h.
d

H. Chen et al. / Tetrahedron: Asymmetry 18 (2007) 1308–1312
1311
The absolute stereochemical results obtained with the pres-
ent catalyst system can be explained by a transition state
model (Fig. 2) similar to those proposed previously.
The Si-face attack of the enamine double bond by the
nitroolefin becomes more unfavorable due to conceivable
steric and/or electronic repulsions between the cis-4-pyrr-
olidin-1-yl group and the nitro group, which might be a
possible reason for the high stereoselectivity of 4.
To a solution of the crude product 6 obtained above was
added NaN (72 g, 1.096 mol). The mixture was stirred at
3
3
b,g,h,m
60 °C for 12 h. The solvents were removed under reduced
pressure. The residue was dissolved in EtOAc and the solu-
tion was washed with brine and dried over anhydrous
MgSO . After removal of the solvents under reduced pres-
4
sure, the residue was purified by flash chromatography on
silica gel to give pure product 7 (23.42 g, 70% over two
steps) as a colorless oil.
A methanol solution of compound 7 (8.10 g, 30.3 mmol)
and 5% Pd/C were charged in a two-necked flask. The mix-
ture was stirred under hydrogen (1 atm) at 35 °C for 5 h,
and was then filtered through Celite. The filtrate was con-
centrated to dryness to give crude product 8 as a brown oil,
which was used for the next step without further
purification.
N
O
N
N
O
N
Figure 2. Proposed transition state.
To a solution of Et N (34 mL, 242 mmol) and the crude
3
product 8 obtained above was added 1,4-dibromobutane
3. Conclusion
(14.7 mL, 121 mmol), the mixture was stirred at 60 °C for
10 h. Upon completion, the reaction was quenched with
In conclusion, we have developed L-proline derived
triamine 4 as a highly efficient and stereoselective organo-
catalyst for the asymmetric Michael addition of cyclohexa-
none to nitroolefins. High isolated yields and excellent
diastereoselectivities and enantioselectivities have been ob-
tained for the addition of cyclohexanone to a variety of
nitroolefins under the catalysis of 4. The presence of a
Brønsted acid with proper acidity, such as (CF SO ) NH,
water. The solvent was removed under reduced pressure,
and the residue dissolved in EtOAc, washed with saturated
aqueous NaHCO and brine, and dried over anhydrous
3
MgSO . After removal of the solvents under reduced pres-
4
sure, the residue was purified through column chromato-
graphy on silica gel to give pure product 9 (14.05 g, 64%
over two steps) as a brown oil.
3
2 2
proved to be critical for the excellent performance of this
catalyst system.
(
4
2S,4S)-1-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylmethyl)-
-(pyrrolidin-1-yl)pyrrolidine 9: H NMR (600 MHz,
1
MeOD) d (ppm): 1.48 (s, 9H), 1.83 (m, 9H), 2.45–2.48
(m, 1H), 2.59–2.63 (m, 10H), 2.82–2.97 (m, 1H), 3.02–
4. Experimental
3.06 (m, 1H), 3.78–3.82 (m, 1H), 3.94 (m, 1H).
4
.1. Procedure for the synthesis of catalyst 4
Compound 9 (4.44 g, 13.7 mmol) was treated with a mix-
To an anhydrous THF (1 L) solution of (2S,4R)-1-(tert-
butoxycarbonyl)-4-hydroxyproline methyl ester 5 (33.55 g,
ture of TFA–CH Cl (v/v = 1/2, 120 mL). After stirring
2
2
for 12 h, the reaction mixture was concentrated under re-
duced pressure. The residue was purified through column
chromatography on silica gel to give pure product 4
(2.44 g, 80%) as a yellow oil.
1
37 mmol) was added LiAlH (5.26 g, 137 mmol) in small
4
portions at 0 °C. The resulting mixture was stirred at 0 °C
until the starting material disappeared (monitored by
TLC). The reaction was then quenched with a 15% aqueous
sodium hydroxide solution at 0 °C. After filtration, the vol-
atiles were removed under reduced pressure. The residue
was purified by flash chromatography on silica gel to give
pure (2S,4R)-1-(tert-butoxycarbonyl)-2-hydroxymethyl-4-
hydroxypyrrolidine (27.35 g, 92%) as a yellow oil.
(2S,4S)-2-(Pyrrolidin-1-ylmethyl)-4-(pyrrolidin-1-yl)pyrrol-
2
D
5
1
idine 4: ½aꢀ ¼ 6:4 (c 0.5, CH Cl ), H NMR (600
2
2
MHz, CDCl ) d (ppm): 1.34–1.39 (m, 1H), 1.74–1.81 (m,
3
8H), 2.16–2.21 (m, 1H), 2.41–2.43 (dd, J = 5.4, 11.9 Hz,
1H), 2.50–2.55 (m, 6H), 2.57–2.60 (m, 2H), 2.63–2.66 (m,
1H), 2.68–2.73 (m, 1H), 2.88–2.91 (dd, J = 7.6, 10.9 Hz,
To a stirred solution of Et N (154 mL, 1.096 mol) and
1H), 3.07–3.09 (dd, J = 6.8, 10.5 Hz, 1H), 3.34 (br, 1H),
3
1
3
(
2S,4R)-1-(tert-butoxycarbonyl)-2-hydroxymethyl-4-hydro-
3.35–3.39 (m, 1H).
C NMR (150 MHz, CDCl ) d
3
xypyrrolidine (27.35 g, 126 mmol) in chloroform (500 mL)
was added CH SO Cl (43.5 mL, 548 mmol) dropwise at
(ppm): 23.3, 23.4, 37.4, 51.0, 53.5, 54.5, 56.9, 61.8, 66.0.
+
ESI HRMS exact mass calcd for (C H N +H) requires
3
2
13 26
3
0
°C. The resulting mixture was continued to stir at 0 °C
m/z 224.2121. Found: 224.2114.
until the starting material disappeared (monitored by
TLC). 1 M aqueous hydrochloric acid (400 mL) was used
to quench the reaction. The organic layer was separated
and the aqueous layer extracted with dichloromethane.
The combined extracts were washed with brine and dried
4.2. General procedure for the Michael addition of
cyclohexanone to nitroolefins
i
To a mixture of cyclohexanone 10 (0.21 mL) and PrOH
(0.19 mL) were added catalyst (0.04 mmol) and
(CF SO ) NH (0.04 mmol). After stirring at 0 °C for
over anhydrous MgSO , Removal of the solvents under
4
4
reduced pressure gave crude product 6, which was used
for the next step without further purification.
3
2 2
20 min, nitroolefin 11 (0.2 mmol) was introduced. The

1312
H. Chen et al. / Tetrahedron: Asymmetry 18 (2007) 1308–1312
reaction mixture was stirred at the same temperature for 8–
0 h and was then quenched with saturated aqueous
Carrillo, L. Org. Lett. 2006, 8, 6135–6138; (f) Zu, L. S.; Wang,
J.; Li, H.; Wang, W. Org. Lett. 2006, 8, 3077–3079; (g) Zhu, M.
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Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed.
4
NH Cl. EtOAc was added to dilute the mixture. The or-
4
ganic layer was separated, washed with brine, dried over
anhydrous MgSO , and concentrated under reduced pres-
4
sure. The residue was purified through column chromato-
graphy on silica gel to give the corresponding Michael
adduct for further analysis.
2
005, 44, 4212–4215; (j) Wang, W.; Wang, J.; Li, H. Angew.
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Acknowledgment
9
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3
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Catalysis; Horvath, I., Ed.; Wiley: New York, 2002; Vol. 5, pp
9
9–118; (e) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed.
2
003, 42, 1688–1690.
7. It has previously been reported that the addition of an acid can
enhance the catalytic effects of chiral organocatalyst for the
Michael addition, see: Ref. 3b–d, 3g,m,n,p.
8. It should be noted that the addition of one more equivalent of
TFA had little effect on the diastereoselectivity and enantio-
selectivity, but dramatically decreased the reaction rate (36%
yield, 93:7 dr and 88% ee).
9. Such solvent compatibility of this catalyst is quite unusual
compared with the other catalytic systems for the same
reaction, see Refs. 3 and 4.
2
3
. List, B.; Pojarlier, P.; Martin, H. J. Org. Lett. 2001, 3, 2423–
425.
2
. For selected examples, see: (a) Vishnumaya; Singh, V. K. Org.
Lett. 2007, 9, 1117–1119; (b) Luo, S. Z.; Mi, X. L.; Zhang, L.;
Liu, S.; Xu, H.; Cheng, J. P. Angew. Chem., Int. Ed. 2006, 45,
3
2
093–3097; (c) Pansare, S. V.; Pandya, K. J. Am. Chem. Soc.
006, 128, 9624–9625; (d) Mase, N.; Watanabe, K.; Yoda, H.;
Takabe, K.; Tanaka, F.; Barbas, C. F., III. J. Am. Chem. Soc.
006, 128, 4966–4967; (e) Reyes, E.; Vicario, J. L.; Badia, D.;
2