Pyrrolidinyl-camphor derivatives as a new class of organocatalyst for direct asymmetric Michael addition of aldehydes and ketones to β-nitroalkenes

Article abstract of DOI:10.1002/chem.201000483

Practical and convenient synthetic routes have been developed for the synthesis of a new class of pyrrolidinyl-camphor derivatives (7a-h). These novel compounds were screened as catalysts for the direct Michael addition of symmetrical αα-disubstituted ald

Full text of DOI:10.1002/chem.201000483

DOI: 10.1002/chem.201000483
Pyrrolidinyl–Camphor Derivatives as a New Class of Organocatalyst for
Direct Asymmetric Michael Addition of Aldehydes and Ketones to
AHCTUNGTREGbNNUN -Nitroalkenes
Ying-Fang Ting, Chihliang Chang, Raju Jannapu Reddy, Dhananjay R. Magar, and
Kwunmin Chen*[a]
Abstract: Practical and convenient syn-
thetic routes have been developed for
the synthesis of a new class of pyrroli-
dinyl–camphor derivatives (7a–h).
These novel compounds were screened
as catalysts for the direct Michael addi-
tion of symmetrical a,a-disubstituted
aldehydes to b-nitroalkenes. When this
asymmetric transformation was cata-
lyzed by organocatalyst 7 f, the desired
Michael adducts were obtained in high
chemical yields, with high to excellent
stereoselectivities (up to 98:2 diaste-
reomeric ratio (d.r.) and 99% enantio-
meric excess (ee)). The scope of the
catalytic system was expanded to en-
compass various aldehydes and ketones
as the donor sources. The synthetic ap-
plication was demonstrated by the syn-
thesis of a tetrasubstituted-cyclohexane
derivative from (S)-citronellal, with
high stereoselectivity.
Keywords: camphor · citronellal ·
Michael addition · nitroalkenes ·
organocatalysis
Introduction
and broadly applicable asymmetric carbon–carbon bond-
forming reactions, with a wide variety of donors and accept-
ors, can be employed.[5] In recent years, many methods have
been developed for the direct asymmetric Michael additions
of unmodified carbonyl compounds to nitroalkenes to pro-
duce enantiomerically enriched nitroalkanes.[6] Among these
reactions, the Michael addition of a, a-disubstituted alde-
hydes to b-nitrostyrenes is of particular interest due to the
all-carbon quaternary stereocenter possessed by the Michael
products.[7] The synthesis of quaternary stereogenic centers
is considered a challenging task in asymmetric synthesis.[8]
In our continued synthetic efforts toward the develop-
ment of new organocatalysts,[9] we envision that a well-de-
fined, rigid, bicyclic camphor scaffold can serve as an effi-
cient stereocontrol element.[10] The assembly of pyrrolidine
and camphor frameworks with an appropriate linker can
constitute a new class of bifunctional organocatalysts.[11] Pre-
viously, we have designed and synthesized a series of cam-
phor-based pyrrolidine organocatalysts for direct asymmet-
ric aldol reactions on water.[9a,b] Recently, we have devel-
oped camphor-containing pyrrolidine derivatives that could
serve as efficient bifunctional organocatalysts in the asym-
metric Michael addition of aldehydes with b-nitroalkenes to
produce Michael adducts with high chemical yields and ster-
eoselectivities.[9c,d] Minor modifications to the structure of
the organocatalysts may contribute significantly to the ste-
reochemical outcome of a reaction. The pyrrolidine structur-
Nature is a master of asymmetric synthesis and enzymes are
highly efficient biocatalysts in living systems. Besides en-
zymes and transition-metal complexes, organocatalysis is
now renowned as a third powerful tool for the synthesis of
potentially important optically active compounds.[1] In
recent years, much attention has been paid to the develop-
ment of asymmetric organocatalysis, with remarkable advan-
ces made by means of enamine or iminium catalysis.[2] There
are many advantages to using small chiral molecules to cata-
lyze asymmetric reactions: they are often inexpensive and
readily available from natural resources (e.g., amino acids,
alkaloids), stable in air and water, robust, and more impor-
tantly, they are environmentally friendly.[3]
The conjugate (Michael) addition is one of the most effi-
cient and powerful atom-economical carbon–carbon bond-
forming reactions in synthetic chemistry.[4] Organocatalytic
conjugate addition is one of the most important strategies
[a] Y.-F. Ting, C. Chang, Dr. R. J. Reddy, D. R. Magar, Prof. K. Chen
Department of Chemistry
National Taiwan Normal University
Taipei, 116, ROC (Taiwan)
Fax : (+886)2-29324249
E-mail: kchen@ntnu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000483.
7030
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Chem. Eur. J. 2010, 16, 7030 – 7038

FULL PAPER
al unit and the camphor scaffold were linked with appropri-
ate functionalities, such as sulfide and sulfone linkers, as il-
lustrated in Scheme 1. In addition, the pyrrolidine C4-posi-
ed tosylate analogues (4a–c) and (1S)-1-(mercaptomethyl)-
7,7-dimethylbicycloACTHNUTRGNEUNG
[2.2.1]heptan-2-one (5)[13] (Scheme 3).
The common intermediates, ketone sulfides 6a–c, were ob-
Scheme 1. Retrosynthesis of pyrrolidinyl–camphor-derived organocata-
lysts.
tion can be substituted with a hydroxyl group or a bulky
silyl ether functionality. Furthermore, the camphor C2-
carbon atom can be varied as a carbonyl group or an exo-
hydroxyl group. In this context, we report the synthesis of a
new class of organocatalysts, 3 and 7a–h, and their applica-
tions for direct asymmetric Michael addition of a wide
range of aldehydes and ketones to various nitroalkenes. The
desired Michael products were obtained with high chemical
yields and enantioselectivities when organocatalyst 7 f was
used.
Scheme 3. Synthesis of novel pyrrolidinyl–camphor organocatalysts 7a–h.
Na2EDTA=disodium ethylenediamine tetraacetate, TBDPS=tert-butyl-
diphenylsilyl.
tained by the nucleophilic-substitution reaction of N-Boc-O-
tosyl prolinol derivatives (4a–c) with 5 in the presence of
NaH as a base in 72–88% yield. Subsequently, N-Boc-de-
protection of 6a–c with TFA provided the desired organoca-
talysts 7a–c in good to high chemical yields (60–94%). The
sulfone-linked organocatalyst 7d was obtained by oxidation
of N-Boc-protected 6c with Oxone in the presence of diso-
dium ethylenediamine tetraacetate (Na2EDTA) followed by
cleavage of the Boc group. Reduction of N-Boc-protected
6a–c with NaBH4 afforded the corresponding C2-exo alco-
hols (camphor numbering) as a single diastereomers. This
was followed by TFA treatment in CH2Cl2 to give the de-
sired organocatalysts 7e–g with high to excellent overall
yields (82–98%). Sulfone organocatalyst 7h was prepared
with an overall yield of 86%, in a three-step reaction se-
quence from 6c: oxidation, reduction, and deprotection.
The structures of organocatalysts 3 and 7a–h were fully
characterized by IR, 1H, and 13C NMR spectroscopy, and
HRMS techniques. The structure of catalyst 7b was further
confirmed by single-crystal X-ray data analysis (see the Sup-
porting Information).[14]
Results and Discussion
The design and synthesis of a readily accessible, highly ste-
reoselective, and tunable catalyst is always desirable for
asymmetric catalysis. We have developed an efficient syn-
thesis of pyrrolidinyl–camphor organocatalyst 3. We began
with the known tert-butoxycarbonyl (Boc)-protected (S)-2-
aminomethylpyrrolidine (1),[12] which was treated with keto-
pinic acid chloride (2) (derived from ketopinic acid and
SOCl2) in the presence of Et3N (Scheme 2). NaBH4 reduc-
With success in synthesizing the above organocatalysts,
we tested the efficacy of 7a–h in asymmetric reactions. Iso-
butyraldehyde and trans-b-nitrostyrene were used as model
substrates for the Michael reaction under neat conditions in
the presence of 20 mol% of 7a–h at ambient temperature
(Table 1). We first evaluated the pyrrolidinyl–camphor de-
rivatives with a C2-ketone functionality (7a–d). Despite the
high chemical yield obtained, only moderate enantioselectiv-
ity was observed when catalyst 7a was used (Table 1,
entry 1). The stereoselectivity was significantly improved by
the presence of the trans-4-hydroxy group of pyrrolidine cat-
Scheme 2. Synthesis of pyrrolidinyl–camphor organocatalyst 3.
tion of the N-Boc-protected amide afforded the correspond-
ing C2-exo-alcohol (camphor numbering), which was treated
with trifluoroacetic acid (TFA) in CH2Cl2 to provide the de-
sired organocatalyst 3. The synthetic route to 3 is quite
straightforward and can be scaled up to gram quantities.
We envisaged that organocatalysts 7a–h could be easily
prepared from the known l-proline-derived N-Boc-protect-
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K. Chen et al.
Table 1. Catalyst screening for the asymmetric Michael reaction of isobu-
Table 2. Optimization of the Michael reaction of isobutyraldehyde with
tyraldehyde with trans-b-nitrostyrene.[a]
trans-b-nitrostyrene.[a]
Entry
Catalyst
t
Yield [%][b]
ee [%][c]
Entry
Catalyst
[mol%]
Solvent
Additive
[mol%]
t
Yield
[%][b]
ee
G
E
[d]
[%][c]
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7 f
7g
7h
18 h
18 h
3 d
92
91
47
25
91
93
84
32
57
87
51
40
60
91
55
33
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
5
10
15
25
20
20
20
20
H2O
brine
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5.0
1.5
0.5
1.0
3.0
3.0
3.0
3.0
1.0
1.0
1.0
2.0
3.0
1.0
1.0
1.0
3.0
3.0
2.0
1.0
1.0
1.0
3.0
3.0
46
78
93
79
88
81
65
n.d.
n.d.
n.d.
n.d.
88
89
93
93
96
92
94
93
n.d.
93
3 d
MeOH
EtOH
18 h
12h
3 d
84
IPA[d]
<10
<10
<10
<10
88
90
90
83
78
63
80
75
<10
94
96
93
80
81
CH3CN
DMSO
THF
3 d
[a] All reactions were carried out with isobutyraldehyde (4 equiv) and
trans-b-nitrostyrene (1 equiv) in 20 mol% of organocatalyst (7a–h) under
neat conditions at ambient temperature. [b] Isolated yield. [c] Deter-
mined by chiral HPLC analysis.
9
CH2Cl2
hexane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
10
11
12[e]
13[f]
14[g]
15[h]
16[i]
17
18
19
20
21
22
23
24
alyst 7b (Table 1, entry 2). Interestingly, both the reactivity
and stereoselectivity decreased noticeably when the trans-4-
hydroxy group was protected as its TBDPS ether, with
either sulfide- or sulfone-linked catalysts 7c and 7d
(Table 1, entries 3 and 4). The organocatalysts 7e–h were ex-
plored next. High chemical yield (91%) and moderate enan-
tioselectivity (60% enantiomeric excess (ee)) was obtained
with catalyst 7e (Table 1, entry 5). With catalyst 7 f the pres-
ence of a hydroxyl group on the pyrrolidine ring restored
high enantioselectivity (91% ee) (Table 1, entry 6). Both the
reactivity and stereoselectivity diminished when the
TBDPS-protected organocatalysts 7g and 7h were used
(Table 1, entries 7 and 8). The data presented above indi-
cates the importance of the presence of the trans-4-hydroxy
group[6g,9d] (Table 1, entries 2 and 6), which may take part in
the activation of substrates through hydrogen bonding and
thus improve chemical activity and selectivity in the reac-
tion.[15] The pyrrolidinyl–camphor sulfide 7 f, with an exo-hy-
droxyl group at the C2-carbon atom, emerged to be the
most efficient catalyst for the Michael addition.
–
–
–
–
93
92
94
94
n.d.
n.d.
AcOH
PhCOOH
TsOH
TFA
<10
<10
[a] Unless otherwise specified, all reactions were carried out with isobu-
tyraldehyde (4 equiv), trans-b-nitrostyrene (1 equiv), and 7 f (20 mol%)
at ambient temperature. [b] Isolated yield. [c] Determined by chiral
HPLC analysis. [d] IPA= isopropyl alcohol. [e] Reaction was carried out
at 08C–RT. [f] Reaction was carried out at 08C. [g] 2 equiv of isobutyral-
dehyde was used. [h] 6 equiv of isobutyraldehyde was used. [i] 10 equiv of
isobutyraldehyde was used.
isobutyraldehyde under the same reaction conditions result-
ed in a decrease in chemical yields but retained enantiose-
lectivity (Table 2, entries 14–16 versus 11).
A survey of the reaction media was studied with 7 f as the
catalyst. The reactivity was slow when the reaction was car-
ried out in water, but increased when brine was used
(Table 2, entries 1 and 2). Surprisingly, the Michael adduct
8a was obtained after only 12 h in methanol, with excellent
chemical yield and high selectivity (Table 2, entry 3). Both
chemical yield and enantioselectivity decreased when the re-
action was performed in ethanol, and further decreased
when isopropyl alcohol was utilized (Table 2, entries 4 and
5). Similar results were observed when polar solvents, such
as CH3CN, DMSO, and THF, were used (Table 2, entries 6–
8). The desired product 8a was obtained with high chemical
yield and enantioselectivity in CH2Cl2 at ambient tempera-
ture (Table 2, entry 9). Slight improvements on this result
were observed when the reaction was carried out in nonpo-
lar solvents, such as hexane or toluene, at ambient tempera-
ture (Table 2, entries 10 and 11). The stereoselectivity was
further improved when the reaction was carried out at 08C
in toluene (Table 2, entry 13). Deviation of the amount of
Catalyst loading and additive effects were also studied.
Only a trace amount of product 8a was isolated when the
catalyst loading was reduced to 5 mol% (Table 2, entry 17).
Excellent chemical yields, without compromise to the enan-
tioselectivity of the reaction, were obtained using catalyst
loadings of 10 and 15 mol% (Table 2, entries 18 and 19)
however, extended reaction times were required. An in-
crease in catalyst loading to 25 mol% failed to improve the
chemical yield or enantioselectivity (Table 2, entry 20 versus
11). The addition of a catalytic amount of Brønsted acid
may promote the formation of the enamine species and sub-
sequently improve reactivity. To test this, various organic
acids were used as additives (20 mol%) in the reaction mix-
ture. Comparable enantioselectivity but decreased chemical
yields were observed when the reaction was carried out in
the presence of acetic acid or benzoic acid (Table 2, en-
tries 21 and 22). Surprisingly, adduct 8a was obtained in
trace amounts when 20 mol% of p-toluenesulfonic acid
(TsOH) or TFA were used (Table 2, entries 23 and 24). This
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Pyrrolidinyl–Camphor Derivatives as Asymmetric Michael Addition Organocatalysts
FULL PAPER
Table 4. Enantioselective Michael reaction of cyclopentanecarboxalde-
may be due to protonation of the amine catalyst by the acid
that deactivated the formation of the enamine species.
With the optimal reaction conditions realized, the scope
and limitations of this reaction were explored by reaction of
isobutyraldehyde with a variety of nitroalkenes (Table 3).
hyde with nitroolefins in the presence of catalyst 7 f.[a]
Entry
R=
Product
t [d]
Yield [%][b]
ee [%][c]
Table 3. Enantioselective Michael reaction of isobutyraldehyde with ni-
1
2
3
4
5
6
7
8
C6H5
9a
9b
9c
9d
9e
9 f
9g
9h
9i
9j
9k
9l
9m
9n
1.0
1.0
5.0
1.0
2.0
1.0
5.0
2.0
1.5
1.0
1.0
1.0
1.0
5.0
88
96
68
80
85
92
88
86
90
90
95
91
92
54
94
93
69
79
75
95
92
93
91
95
95
88
92
99
troolefins in the presence of catalyst 7 f.[a]
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-CF3C6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-ClC6H4
4-ClC6H4
2-thienyl
2-furyl
Entry
R=
Product
t [d]
Yield [%][b]
ee [%][c]
9
1
2
3
4
5
6
7
8
C6H5
8a
8b
8c
8d
8e
8 f
8g
8h
8i
8j
8k
8l
8m
8n
1.0
1.5
5.0
1.5
2.0
1.0
2.0
2.0
1.0
1.0
1.0
0.5
0.5
5.0
90
92
73
89
88
89
85
88
90
92
90
92
88
43
93
85
72
90
81
94
89
93
92
93
93
87
89
97
10
11
12
13
14
4-MeC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-CF3C6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
3-ClC6H4
4-ClC6H4
2-thienyl
2-furyl
PhCH2CH2
[a] All reactions were carried out with cyclopentanecarboxaldehyde
(4 equiv), nitroolefin (1 equiv), and 7 f (20 mol%) at 08C in toluene.
[b] Isolated yield. [c] Determined by chiral HPLC analysis.
9
10
11
12
13
14
explored. It is notable that this reaction tolerated a range of
functional groups. The reaction proceeded smoothly with a
wide range of aromatic nitroalkenes and gave good chemical
yields and high to excellent levels of enantioselectivity
(Table 4, entries 1–11). The methoxy-substituted aromatic
nitroalkenes afforded only moderate results (Table 4, en-
tries 3–5). To our satisfaction, heteroaromatic nitroalkenes
reacted well with cyclopentanecarboxaldehyde under the
optimal reaction conditions to give 9l and 9m with high
enantioselectivities (Table 4, entries 12 and 13). The alkyl-
substituted nitroalkene (4-nitrobut-3-enyl)benzene is also a
suitable Michael acceptor for this catalytic system and gave
the desired Michael product 9n in moderate yield (54%)
and excellent enantioselectivity (99% ee) (Table 4,
entry 14).
After successfully developing an asymmetric transforma-
tion for symmetric a,a-disubstituted aldehydes, the scope of
the system was expanded to incorporate various aldehydes
and ketones. The use of unsymmetrical a,a-disubstituted al-
dehydes as nucleophiles remained a challenging task.[7d]
Toward this end, the reaction of 2-phenylpropionaldehyde
with trans-b-nitrostyrene was carried out in the presence of
organocatalysts 7 f and 7g (Table 5). The desired Michael
adduct 10a was obtained in good chemical yield and with
high diastereoselectivity (93:7), but with only 12 and 50%
enantioselectivity, respectively (Table 5, entry 1). Isovaleral-
dehyde and propionaldehyde were also employed as donors
and provided the desired Michael adducts 10b and 10c with
high yields, but low to moderate stereoselectivities (Table 5,
entries 2 and 3). To further examine the generality of this
asymmetric transformation, the organocatalytic asymmetric
Michael addition of ketones to trans-b-nitrostyrene was in-
vestigated in the presence of catalyst 3 or 7 f. Cyclohexa-
none reacted to give the desired product 10d in high chemi-
PhCH2CH2
[a] All reactions were carried out with isobutyraldehyde (4 equiv), nitro-
alkene (1 equiv), and 7 f (20 mol%) at ambient temperature in toluene.
[b] Isolated yield. [c] Determined by chiral HPLC analysis.
All reactions were conducted in toluene at ambient temper-
ature with 20 mol% of dihydroxyl sulfide catalyst 7 f. The
reaction proceeded smoothly to afford Michael products
8a–k in high chemical yields (73–92%) and with high enan-
tioselectivity (72–94% ee) when aryl-substituted nitroal-
kenes were used (Table 3, entries 1–11). The reactivity and
stereoselectivity were dependent on the aromatic substituent
on the nitroalkene. Aromatic nitroalkenes with electron-do-
nating (Table 3, entries 2–5) or -withdrawing (Table 3, en-
tries 6–11) substituents were suitable substrates for the Mi-
chael addition. The reaction of heteroaromatic nitroalkenes
also proceeded well with isobutyraldehyde to give Michael
adducts 8l and 8m with high yields and enantioselectivities
(Table 3, entries 12 and 13). Michael product 8n, derived
from an aliphatic nitrostyrene, was obtained in only 43%
chemical yield, but with excellent enantioselectivity
(97% ee) (Table 3, entry 14).
Encouraged by these results, cyclopentanecarboxaldehyde
was treated with trans-b-nitrostyrene. Michael adduct 9a
was afforded with only a 79% enantioselectivity. The reac-
tion conditions were further optimized to improve the reac-
tivity and selectivity. After several studies, we found that the
reaction proceeded smoothly at 08C in toluene and the de-
sired Michael product 9a was obtained with high yield
(88%) and enantioselectivity (94% ee) (Table 4, entry 1).
The generality of the Michael reaction of cyclopentanecar-
boxaldehyde with various nitroalkenes catalyzed by 7 f was
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K. Chen et al.
Table 5. Diastereo- and enantioselective Michael addition of aldehydes
and ketones to trans-b-nitrostyrene.[a]
Entry
Product
Catalyst
[20 mol%]
t
Yield d.r.[c]
[%][b]
ee
N
[%][d]
7 f[e]
7g[e]
4 d
7 d
92
45
93:7
93:7
12
50
1
Scheme 4. Michael reaction of 11 with trans-b-nitrostyrene, followed by
cyclization.
2
3
4
5
6
7 f[e]
2 d
1 h
86
93
91:9
72
7 f (10 mol%). The desired Michael product 12 was ob-
tained with high chemical yield (93%) and diastereoselectiv-
ity (91:9). Adduct 12 was treated with InBr3 in toluene to
induce Prins-type cyclization. The desired tetrasubstituted-
cyclohexane derivative 13 was obtained in 41% yield with
excellent diastereoselectivity. The structures of 12 and 13
3[f]
65:35 26
89:11 73
3[f]
1 d
1 d
95
87
7 f[f]
98:2
87
were fully characterized by IR, H and 13C NMR spectros-
copies, and HRMS techniques. The structure and stereo-
chemistry of 13 was further confirmed by single-crystal X-
ray data analysis.[14]
The pyrrolidinyl–camphor-based catalysts 3 and 7 f could
serve as bifunctional organocatalysts and share similar ste-
reochemical bias. Although more studies are required to
elucidate the reaction mechanism, the stereochemical out-
come can be explained on the basis of the experimental re-
sults as follows: As proposed in Scheme 5, the pyrrolidine
1
3[f]
2 d
4 d
45
52
99:1
99:1
63
52
7 f[f]
3[f]
12 h 76
12 h 76
70:30 56
50:50 25
7 f[f]
[a] All reactions were carried out using aldehyde/ketone (4 equiv), trans-
b-nitrostyrene (1 equiv), and organocatalyst 3, 7 f, or 7g (20 mol%).
[b] Isolated yield. [c] Determined by 1H NMR spectroscopy and HPLC
analysis. [d] Determined by chiral HPLC analysis. [e] Reaction was car-
ried out in MeOH (with 7 f) and toluene (with 7g) at ambient tempera-
ture. [f] Reaction was carried out with PhCO2H (20 mol%) at ambient
temperature under neat conditions.
cal yield and stereoselectivity, catalyzed by 3 or 7 f in the
presence of benzoic acid under neat reaction conditions
(Table 5, entry 4). 2-Butanone also worked well with cata-
lysts 3 and 7 f and gave Michael adduct 10e with excellent
diastereomeric ratio (d.r.) and moderate chemical yields
(Table 5, entry 5). The use of 2-hydroxy acetone furnished
the corresponding adduct 10 f in a reasonable chemical yield
(76%) with low to moderate stereoselectivity (Table 5,
entry 6).
Citronellal is an important building block in organic syn-
thesis for the synthesis of various pheromones and other
natural products.[16] The base-catalyzed conjugate addition
of citronellal to methyl vinyl ketone has been developed.[17]
More recently, Alexakis and co-workers[18] employed citro-
Scheme 5. Proposed transition-state models for the asymmetric Michael
reaction catalyzed by 3 (left) and 7 f (right).
reacts with a carbonyl compound to form an enamine inter-
mediate. The organocatalyst 3 formed hydrogen bonds be-
tween the camphor C2-hydroxy and/or amide groups and
the nitro functionality of the acceptor substrate. On the
other hand, the nitro group was activated by the 4-hydroxy
functionality in organocatalyst 7 f to organize a favorable
transition model.[6g,9d] The neighboring rigid, bicyclic cam-
phor scaffold serves as an efficient stereocontrol element. It
is believed that the b-nitrostyrene approaches from the less-
hindered bottom face in a favorable electrostatic interaction.
The nucleophilic enamine attacks the nitroolefin from the Si
face to generate the major product.
nellal as a donor for reaction with vinyl bisACHTNUTRGNEUNG(sulfone) with ex-
cellent enantioselectivity. We selected citronellal as a donor
partner for trans-b-nitrostyrene to demonstrate the synthetic
utility of catalysts 3 and 7 f. The reaction of (S)-citronellal
(11) with trans-b-nitrostyrene in the presence of organocata-
lyst 3 or 7 f afforded the desired adduct 12. After extensive
studies (see the Supporting Information), the optimum reac-
tion conditions were realized (Scheme 4). To our delight,
the reaction of 11 with trans-b-nitrostyrene proceeded
smoothly under neat reaction conditions in the presence of
Conclusion
We have presented an efficient and convenient synthesis of
a series of novel organocatalysts, 3 and 7a–h, which contain
a rigid pyrrolidinyl–camphor scaffold. The most promising
7034
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 7030 – 7038

Pyrrolidinyl–Camphor Derivatives as Asymmetric Michael Addition Organocatalysts
FULL PAPER
hol as a yellow solid (2.49 g, 97%). 1H NMR (400 MHz, CDCl3): d=
7.93–7.80 (brs, 1H), 5.90–5.79 (brs, 1H), 4.13–4.06 (m, 1H), 4.06–3.95
(m, 1H), 3.47–3.26 (m, 3H), 3.26–3.12 (m, 1H), 2.16–1.95 (m, 2H), 1.95–
1.79 (m, 4H), 1.79–1.55 (m, 3H), 1.46 (s, 9H), 1.26 (s, 3H), 1.20–1.05 (m,
2H), 1.04 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=175.7, 156.8,
80.1, 79.2, 56.5, 55.9, 49.8, 47.1, 46.3, 45.6, 41.1, 29.7, 29.6, 28.5, 27.4, 23.9,
21.7, 21.0 ppm.
catalyst for the Michael addition (7 f) emerged from the
combination of the installation of a trans-4-hydroxy group
on the pyrrolidine ring, a C2-hydroxyl group on the cam-
phor scaffold, and a sulfide link. We have demonstrated the
practical applications of organocatalyst 7 f for Michael reac-
tion of symmetrical a,a-disubstituted aldehydes with a wide
range of b-nitroalkenes. The products containing an all-
carbon quaternary center were obtained with high to excel-
lent levels of chemical yield and enantioselectivity under the
optimized conditions. This method provides an alternative
route for the efficient synthesis of versatile g-nitro alde-
hydes. Moreover, both 3 and 7 f were found to be effective
catalysts for reaction of various aldehydes and ketones with
b-nitrostyrene to give the corresponding Michael adducts
with moderate to high stereoselectivities. The synthetic ap-
plication of 7 f was demonstrated by the reaction of 11 with
trans-b-nitrostyrene to give tetrasubstituted-cyclohexane de-
rivative 13 with high stereoselectivity.
The exo alcohol (2.49 g, 6.8 mmol) was dissolved in CH2Cl2 (10 mL) and
TFA (1.0 mL) was added at room temperature. After stirring for 1 h, the
reaction was diluted with CH2Cl2, washed with 2n NaOH, and the mix-
ture was extracted with CH2Cl2 (2ꢂ20 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered, and the solvent was removed
under reduced pressure to give 3 as a pale-yellow solid (1.68 g, 93%).
M.p. 140–1428C; [a]2D5 =+16.49 (c=1.00, CHCl3); 1H NMR (400 MHz,
CDCl3): d=6.81 (s, 1H), 4.02 (dd, J=7.8, 3.5 Hz, 1H), 3.68 (brs, 2H),
3.57–3.46 (m, 1H), 3.38–3.25 (m, 1H), 3.17–2.98 (m, 1H), 2.91 (t, J=
6.8 Hz, 2H), 2.19–1.98 (m, 1H), 1.97–1.88 (m, 2H), 1.86–1.60 (m, 5H),
1.49–1.32 (m, 1H), 1.32–1.19 (m, 4H), 1.16–1.04 (m, 1H), 1.03 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=174.8, 77.9, 58.1, 58.0, 49.0, 46.2,
45.9, 43.0, 41.0, 30.2, 29.0, 27.0, 25.5, 21.6, 21.0 ppm; IR (neat): n˜ =3271,
2953, 2725, 1634, 1557 cmÀ1; HRMS (FAB+): m/z: calcd for C15H27N2O2:
267.2703 [M+H]+; found: 267.2706; crystal data for
3 at 296(2) K;
C15H26N2O2; Mr 266.38; monoclinic; P2l; a=8.0727(3) ꢁ, b=9.2759(4) ꢁ,
c=10.3149(4) ꢁ; a=90.00, b=96.558(2), g=90.00; V=767.34(5) ꢁ3;
F
(MoKa)=0.71073 ꢁ; Z=2; 1=1.153 mgmÀ3; m=0.076 mmÀ1
000 =292; lAHCTUNGRTNEUGN ;
Experimental Section
1389 reflections; 1 restraints; 173 parameters; R=0.0766; Rw=0.2475
for all data.
General remarks: All reagents were used as purchased from commercial
Catalyst 7a: Compound 5 (2.48 g, 13.5 mmol) was added to a stirred sus-
pension of NaH (2.40 g, 56.3 mmol) in anhydrous THF (140 mL) under a
nitrogen atmosphere. The reaction mixture was added dropwise to a solu-
tion of 4a (4.00 g, 11.3 mmol) in anhydrous THF (40 mL) at ambient
temperature. After stirring for 2 h, the reaction was quenched with H2O
at 08C and extracted with CH2Cl2 (2ꢂ50 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4, filtered,
and the solvent was evaporated under reduced pressure. The crude prod-
uct was purified by flash column chromatography on silica gel (hexane/
suppliers without additional purification. IR spectra were recorded on a
1
Perkin–Elmer 500 spectrometer. H and 13C NMR spectra were recorded
on a Bruker Avance 400 NMR spectrometer at 400 and 100 MHz, respec-
tively. Chemical shifts (d) are reported in parts per million (ppm) refer-
enced to an internal TMS standard or CHCl3 (77.0 ppm). Optical rota-
tions were measured on a JASCO P-1010 polarimeter. HRMS were re-
corded on JEOL SX-102A instrument. The X-ray diffraction measure-
ments were carried out at 298 K on a KAPPA APEX II CCD area-detec-
tor system equipped with a graphite monochromator and a MoKa fine-
focus sealed tube (l=0.71073 ꢁ). Routine monitoring of reactions was
performed by using silica gel, glass-backed TLC plates (Merck Kieselgel
60 F254) and visualized by UV light (254 nm). Flash column chromatogra-
phy was performed on silica gel (230–400 mesh) with the indicated elu-
ents. Air- or moisture-sensitive reactions were performed under inert at-
mospheric conditions.
ethyl acetate 2:1) to afford 6a as a colorless viscous liquid (77%). [a]D33
=
À17.6 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=3.99–3.90 (m,
1H), 3.37–3.34 (m, 2H), 2.95–2.82 (m, 2H), 2.56–2.52 (m, 2H), 2.36 (d,
J=18.3 Hz, 1H), 2.10–2.01 (m, 3H), 2.00–1.91 (m, 2H), 1.86 (d, J=
18.3 Hz, 3H), 1.48 (s, 9H), 1.48–1.45 (m, 1H), 1.40–1.38 (m, 1H), 1.05 (s,
3H), 0.91 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=216.9, 154.1,
79.3, 60.7, 56.7, 47.6, 46.4, 43.3, 42.9, 38.1, 30.0, 29.7, 28.4, 26.7, 26.6, 23.5,
Catalyst 3: A solution of 2 (1.5 g, 7.5 mmol) in CH2Cl2 (10 mL) was
added slowly to a stirred solution of 1 (1.5 g, 7.5 mmol) and Et3N
(1.25 mL, 9 mmol) in CH2Cl2 (30 mL) at 08C. The reaction mixture was
stirred for 5 h at ambient temperature and the solvent was removed
under reduced pressure. The residue was dissolved in CH2Cl2 (30 mL),
washed with a saturated aqueous solution of NH4Cl, an aqueous saturat-
ed solution of NaHCO3, and brine. The mixture was extracted with
CH2Cl2 (2ꢂ20 mL); the combined organic layers were dried over anhy-
drous MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash chromatography (hexane/ethyl acetate 2:1)
to give the desired amide as a yellow viscous liquid (2.56 g, 94%).
1H NMR (400 MHz, CDCl3): d=7.73 (brs, 1H), 4.00–3.66 (m, 1H), 3.58–
3.14 (m, 4H), 2.50–2.32 (m, 2H), 2.15–1.96 (m, 2H), 1.93–1.74 (m, 3H),
1.72–1.61 (m, 2H), 1.60–1.49 (m, 1H), 1.48–1.29 (m, 10H), 1.15 (s, 3H),
0.92 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=215.7, 169.2, 155.1,
79.3, 65.0, 56.5, 49.7, 46.7, 43.6, 43.1, 42.4, 28.8, 28.3, 27.9, 27.4, 23.5, 20.6,
20.4 ppm; HRMS (FAB+): m/z: calcd for C20H33N2O4: 365.2440 [MH]+;
found: 365.2439.
22.6, 20.1 ppm; IR (CH2Cl2): n˜ =3469, 2878, 2649, 1742, 1668, 1384 cmÀ1
HRMS (EI): m/z: calcd for C20H33NO3S: 367.2181; found: 367.2180.
;
Compound 6a (1.00 g, 2.72 mmol) in CH2Cl2 (20 mL) was treated with
TFA (4.04 mL, 54.4 mmol) at ambient temperature. After stirring for 1 h,
the reaction mixture was quenched with H2O and the resulting solution
was adjusted to pH 9–10 with aqueous solution of NaHCO3 (1.0m). The
reaction mixture was then extracted with CH2Cl2 (2ꢂ20 mL). The com-
bined organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and the solvent was removed under reduced pressure to
yield 7a as a pale-yellow viscous liquid (0.67 g, 92%). [a]3D3 =+27.1 (c=
1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=3.24–3.20 (m, 1H), 2.98–
2.93 (m, 2H), 2.87–2.80 (m, 2H), 2.78–2.74 (m, 2H), 2.29 (dt, J=6.7,
3.6 Hz, 1H), 2.02–1.83 (m, 4H), 1.82–1.70 (m, 3H), 1.45–1.31 (m, 3H),
0.98 (s, 3H), 0.83 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=217.2,
60.8, 57.8, 47.5, 45.8, 43.2, 42.9, 40.1, 30.7, 29.4, 29.3, 26.6, 26.5, 24.8, 20.0,
19.9 ppm; IR (CH2Cl2): n˜ =3460, 2955, 2881, 1739, 1683, 1538, 1416 cmÀ1
HRMS (EI): m/z: calcd for C15H25NO2S: 267.1657; found: 267.1665.
;
Catalyst 7b: Following the procedure described above for 6a, compound
4b was used for the synthesis of 6b, which was isolated as a colorless vis-
cous liquid (88%). [a]3D3 =À18.0 (c=1.00, CHCl3); 1H NMR (400 MHz,
CDCl3): d=4.45–4.41 (m, 1H), 4.19–4.11 (m, 1H), 3.61–3.43 (m, 2H),
2.92 (d, J=12.8 Hz, 1H), 2.87 (d, J=12.8 Hz, 1H), 2.72–2.67 (m, 1H),
2.57 (d, J=12.0 Hz, 1H), 2.36 (dq, J=4.7, 2.6 Hz, 1H), 2.15–2.02 (m,
3H), 2.01–1.95 (m, 3H), 1.86 (d, J=18.3 Hz, 1H), 1.84–1.51 (m, 1H),
1.39 (s, 9H), 1.04 (s, 3H), 0.90 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
The amide (2.56 g, 7.1 mmol) was dissolved in 10:1 CH2Cl2/MeOH
(20 mL) and NaBH4 (2.6 g, 71 mmol) was added portionwise (3 portions)
at room temperature. After stirring for 2 h, the reaction was quenched
with a saturated aqueous solution of NH4Cl, washed with brine, and the
mixture was extracted with CH2Cl2 (2ꢂ20 mL). The combined organic
layers were dried over anhydrous MgSO4, filtered, and concentrated
under reduced pressure. The crude exo-alcohol was purified by flash
chromatography (hexane/ethyl acetate 1:1) to give the desired exo-alco-
Chem. Eur. J. 2010, 16, 7030 – 7038
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7035

K. Chen et al.
d=216.9, 154.3, 79.5, 68.4, 60.5, 55.4, 54.6, 47.4, 43.1, 42.7, 38.7, 37.7, 29.7,
28.1, 26.4, 26.3, 19.9, 19.8 ppm; IR (CH2Cl2): n˜ =3424, 3055, 2959, 2878,
1742, 1668, 1407 cmÀ1; HRMS (EI): m/z: calcd for C20H33NO4S: 383.2130;
found: 383.2138.
1H NMR (400 MHz, CDCl3): d=7.65–7.61 (m, 4H), 7.44–7.41 (m, 3H),
7.40–7.35 (m, 3H), 4.25–4.18 (m, 1H), 3.70 (d, J=15.0 Hz, 1H), 3.37–3.32
(m, 2H), 3.10–3.01 (m, 2H), 2.82 (d, J=15.0 Hz, 1H), 2.45–2.34 (m, 3H),
2.13–2.04 (m, 3H), 1.93 (d, J=18.5 Hz, 1H), 1.85–1.78 (m, 1H), 1.64–1.57
(m, 1H), 1.49–1.43 (m, 1H), 1.06 (s, 12H), 0.88 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=215.5, 135.6 (4C), 133.6 (2C), 129.8 (2C), 127.7
(2C), 72.5, 59.8, 58.8, 55.1, 51.9, 51.4, 48.7, 42.6, 42.5, 41.3, 27.1, 26.8 (3C),
24.9, 19.7, 19.6, 19.0 ppm; IR (CH2Cl2): n˜ =3365, 3063, 2930, 2886, 1746,
Following the procedure described above for 7a, compound 6b (1.00 g,
2.61 mmol) in CH2Cl2 (10 mL) was treated with TFA (3.87 mL,
52.2 mmol) to afford 7b as a yellow solid (0.44 g, 60%). M.p. 96–988C;
[a]3D3 =+34.3 (c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=4.40 (t,
J=5.1 Hz, 1H), 3.61–3.54 (m, 1H), 3.40 (s, 2H), 3.11 (dd, J=11.6,
4.7 Hz, 1H), 2.87 (d, J=11.7 Hz, 1H), 2.82 (d, J=13.0 Hz, 1H), 2.70–2.60
(m, 2H), 2.57 (d, J=13.0 Hz, 1H), 2.39 (dq, J=4.3, 2.6 Hz, 1H), 2.09–
1.93 (m, 4H), 1.86 (d, J=18.3 Hz, 1H), 1.67–1.60 (m, 1H), 1.55–1.49 (m,
1H), 1.41–1.35 (m, 1H), 1.05 (s, 3H), 0.90 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=217.4, 71.9, 60.8, 56.1, 54.6, 47.6, 43.2, 42.9, 41.1,
40.3, 29.4, 26.6 (2C), 20.0, 19.9 ppm; IR (CH2Cl2): n˜ =3424, 2959, 2886,
1738, 1650, 1414 cmÀ1; HRMS (EI): m/z: calcd for C15H25NO2S: 283.1606;
found: 283.1608; crystal data for 7b at 273(2) K: C15H25NO2S; Mr 283.42;
1683, 1587, 1429 cmÀ1
553.2682; found: 553.2689.
; HRMS (EI): m/z: calcd for C31H43NO4SSi:
Catalyst 7e: NaBH4 (1.55 g, 40.8 mmol) was added to a stirred solution
of 6a (1.50 g, 4.08 mmol) in CH2Cl2/MeOH (1:1, 20 mL) at ambient tem-
perature. After stirring for 2 h, the reaction mixture was quenched with
H2O and extracted with CH2Cl2 (2ꢂ20 mL). The combined organic
layers were washed with brine, dried over anhydrous MgSO4, filtered,
and the solvent was removed under reduced pressure. The obtained
crude exo-alcohol (1.37 g, 3.71 mmol) in CH2Cl2 (20 mL) was treated
with TFA (5.51 mL, 74.2 mmol) at ambient temperature for 1 h. The mix-
ture was quenched with H2O and the resulting solution was adjusted to
pH 9–10 with an aqueous solution of NaHCO3 (1.0m). The mixture was
extracted with CH2Cl2 (2ꢂ20 mL), the combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and the solvent
was removed under reduced pressure to afford 7e as a pale-yellow solid
(0.98 g, 98%). M.p. 97–998C; [a]2D5 =+4.8 (c=1.00, CHCl3); 1H NMR
(400 MHz, CDCl3): d=3.97 (q, J=3.8 Hz, 1H), 3.54 (s, 2H), 3.31–3.23
(m, 1H), 2.99–2.95 (m, 2H), 2.87–2.67 (m, 3H), 2.42 (dd, J=13.4, 9.7 Hz,
1H), 1.99–1.64 (m, 7H), 1.51–1.38 (m, 2H), 1.25–1.17 (m, 2H), 1.05 (s,
3H), 0.81 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=75.9, 59.9, 52.7,
47.4, 46.0, 45.3, 40.2, 39.2, 34.2, 31.5, 30.7, 27.1, 25.5, 20.6, 20.0 ppm; IR
(CH2Cl2): n˜ =3364, 2938, 2875, 1680, 1527, 1414 cmÀ1; HRMS (EI): m/z:
calcd for C15H27NO2S: 269.1813; found: 269.1802.
orthorhombic;
31.5723(7) ꢁ;
P2l2l2l;
a=9.0657(2) ꢁ;
Z=8;
b=10.6218(2) ꢁ,
c=
m=
V=3040.23(11) ꢁ3;
1=1.238 mgmÀ3
;
0.212 mmÀ1; 19384 reflections; 0 restraints; 343 parameters; R=0.0939;
Rw=0.1509 for all data.
Catalyst 7c: Following the procedure described above for 7a, compound
4c was used for synthesis of 6c, which was isolated as a colorless viscous
1
liquid (72%). [a]3D3 =À5.5 (c=1.00, CHCl3); H NMR (400 MHz, CDCl3):
d=7.64–7.62 (m, 4H), 7.43–7.40 (m, 3H), 7.39–7.36 (m, 3H), 4.38–4.34
(m, 1H), 4.17 (s, 1H), 3.51 (d, J=10.6 Hz, 1H), 3.22 (dd, J=11.3, 4.2 Hz,
1H), 2.83 (d, J=12.6 Hz, 2H), 2.66 (s, 1H), 2.52 (d, J=12.6 Hz, 1H),
2.34 (dq, J=4.7, 2.2 Hz, 1H), 2.15–2.07 (m, 1H), 2.05–2.00 (m, 1H),
1.99–1.94 (m, 1H), 1.93–1.87 (m, 1H), 1.86–1.72 (m, 3H), 1.47 (s, 9H),
1.45–1.43 (m, 1H), 1.04 (s, 9H), 1.00 (s, 3H), 0.87 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=216.2, 154.2, 135.2 (2C), 133.3 (3C), 129.4 (2C),
127.4 (4C), 79.2, 70.9, 60.4, 55.7, 55.2, 47.3, 43.1, 42.7, 39.7, 38.7, 29.8, 28.2
(2C), 26.5 (6C), 26.3, 19.9, 18.7 ppm; IR (CH2Cl2): n˜ =3077, 2959, 2856,
1746, 1694, 1591, 1392 cmÀ1; HRMS (EI): m/z: calcd for C36H51NO4SSi:
621.3308; found: 621.3315.
Catalyst 7 f: Following the procedure described above for 7e, NaBH4 re-
duction of 6b in CH2Cl2/MeOH and subsequent treatment with TFA in
CH2Cl2 provided 7 f as a viscous liquid (82%). [a]3D3 =À2.5 (c=1.00,
CHCl3); 1H NMR (400 MHz, CDCl3): d=4.42 (s, 1H), 3.96 (s, 1H), 3.56
(s, 4H), 2.98–2.86 (m, 2H), 2.85–2.65 (m, 3H), 2.38 (t, J=11.6 Hz, 1H),
1.99–1.94 (m, 1H), 1.72–1.65 (m, 4H), 1.61–1.55 (m, 1H), 1.50–1.45 (m,
1H), 1.32–1.16 (m, 2H), 1.04 (s, 3H), 0.81 ppm (s, 3H); 13C NMR
(100 MHz, CDCl3): d=75.7, 72.1, 57.8, 54.2, 52.5, 47.3, 45.2, 41.2, 39.9,
39.3, 33.8, 30.7, 27.0, 20.6, 19.9 ppm; IR (CH2Cl2): n˜ =3392, 2903, 1646,
1428 cmÀ1; HRMS (EI): m/z: calcd for C15H27NO2S: 285.1762; found:
285.1768.
Following the procedure described above for the synthesis of 7a, TFA
(0.36 mL, 4.83 mmol) was added to 6c (1.0 g, 1.61 mmol) in CH2Cl2
(10 mL) to give 7c as a colorless viscous liquid (0.79 g, 94%). [a]3D3 =+3.9
(c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.65–7.61 (m, 4H),
7.43–7.40 (m, 3H), 7.39–7.36 (m, 3H), 5.35 (brs, 1H; NH), 4.48–4.46 (m,
1H), 3.93–3.85 (m, 1H), 3.22 (dd, J=12.0, 4.8 Hz, 1H), 3.07 (d, J=
12.0 Hz, 1H), 2.86 (d, J=13.2 Hz, 1H), 2.81–2.77 (m, 2H), 2.57 (d, J=
13.2 Hz, 1H), 2.36 (dq, J=4.6, 2.1 Hz, 1H), 2.06–1.96 (m, 4H), 1.86 (d,
J=18.4 Hz, 1H), 1.65–1.57 (m, 1H), 1.54–1.49 (m, 1H), 1.38–1.34 (m,
1H), 1.06 (s, 9H), 1.02 (s, 3H), 0.90 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=217.5, 135.5 (4C), 133.5 (2C), 129.71 (2C), 127.7 (4C), 73.2,
61.0, 57.4, 54.5, 47.7, 43.5, 43.0, 40.8, 38.4, 29.4, 26.9 (2C), 26.8 (3C), 20.1,
20.0, 18.9 ppm; IR (CH2Cl2): n˜ =3478, 3070, 2967, 2856, 1742, 1683, 1591,
1429 cmÀ1; HRMS (EI): m/z: calcd for C31H43NO2SSi: 521.2784; found:
521.2782.
Catalyst 7g: Following the procedure described above for 7e, NaBH4 re-
duction of 6c in CH2Cl2/MeOH and subsequent treatment with TFA in
CH2Cl2 provided 7g as a viscous liquid (84%). [a]3D3 =+5.6 (c=1.00,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.64–7.60 (m, 4H), 7.44–7.39
(m, 3H), 7.38–7.32 (m, 3H), 4.44–4.38 (m, 1H), 4.21 (s, 2H), 3.99 (q, J=
3.9 Hz, 1H), 3.63–3.58 (m, 1H), 2.94 (d, J=12.2 Hz, 1H), 2.87–2.77 (m,
3H), 2.66 (d, J=12.2 Hz, 1H), 2.33 (dd, J=13.6, 9.9 Hz, 1H), 1.96 (q, J=
6.8 Hz, 1H), 1.79–1.64 (m, 4H), 1.49–1.38 (m, 2H), 1.22–1.16 (m, 1H),
1.05 (s, 9H), 1.03 (s, 3H), 0.79 ppm (s, 3H); 13C NMR (100 MHz, CDCl3):
d=135.4 (4C), 133.5 (2C), 129.6 (2C), 127.5 (4C), 75.5, 73.7, 58.5, 54.2,
53.2, 52.5, 47.2, 45.2, 41.2, 39.2, 33.9, 30.5, 26.9, 26.7 (3C), 20.5, 19.8,
Catalyst 7d: N-Boc-protected compound 6c was dissolved in a mixture
of CH3CN (90 mL), aqueous Na2EDTA (4ꢂ10À4 m, 60 mL), and acetone
(30 mL) at ambient temperature. Oxone (3.00 g, 4.82 mmol) and
NaHCO3 (1.23 g, 14.46 mmol) were added portionwise and the reaction
mixture was stirred for 30 min. The reaction mixture was quenched with
a saturated aqueous solution of NH4Cl and extracted with CH2Cl2 (2ꢂ
50 mL). The combined organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and the solvent was removed under reduced
pressure. The crude product was purified by flash column chromatogra-
phy on silica gel (hexane/ethyl acetate 4:1) to give the N-Boc-protected
ketone sulfone (1.47 g, 93%). The obtained sulfone was dissolved in
CH2Cl2 (20 mL) and was treated with TFA (0.50 mL, 6.75 mmol) at ambi-
ent temperature and stirred for 1 h. The mixture was quenched with H2O
(10 mL) and the resulting solution was adjusted to pH 9–10 with an aque-
ous solution of NaHCO3 (1.0m). The mixture was extracted with CH2Cl2
(2ꢂ20 mL), the combined organic layer were dried over anhydrous
MgSO4, filtered, and the solvent was removed under reduced pressure to
give 7d as a viscous liquid (1.18 g, 95%). [a]3D3 =+10.1 (c=0.50, CHCl3);
18.8 ppm; IR (CH2Cl2): n˜ =3373, 3077, 2959, 1679, 1591, 1469 cmÀ1
HRMS (EI): m/z: calcd for C31H45NO2SSi: 523.2940; found: 523.2950.
;
Catalyst 7h: Following the procedure described above for the synthesis
of 7d, treatment of 6c with Oxone, NaBH4 in CH2Cl2/MeOH, then TFA
in CH2Cl2 afforded 7h as a colorless viscous liquid (86%). [a]3D3 =À12.1
(c=1.00, CHCl3); 1H NMR (400 MHz, CDCl3): d=7.63 (t, J=6.0 Hz,
4H), 7.46–7.40 (m, 3H), 7.39–7.32 (m, 3H), 4.15–4.10 (m, 2H), 3.66 (d,
J=13.6 Hz, 1H), 3.51 (s, 2H), 3.31–3.22 (m, 1H), 3.07–2.87 (m, 4H),
2.07–2.03 (m, 1H), 1.87–1.78 (m, 2H), 1.77–1.65 (m, 3H),1.57–1.46 (m,
2H), 1.06 (s, 12H), 0.82 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=
135.5 (4C), 133.6 (2C), 129.7 (2C), 127.6 (4C), 75.9, 73.3, 60.6, 55.1, 53.8,
51.6, 50.1, 48.9, 44.0, 41.5, 39.1, 30.3, 27.4, 26.8 (3C), 20.4, 19.8, 18.9 ppm;
IR (CH2Cl2): n˜ =3491, 3077, 2952, 2856, 1653, 1591, 1473, 1307 cmÀ1
HRMS (EI): m/z: calcd for C31H45NO4SSi: 555.2839; found: 555.2830.
;
7036
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Chem. Eur. J. 2010, 16, 7030 – 7038

Pyrrolidinyl–Camphor Derivatives as Asymmetric Michael Addition Organocatalysts
FULL PAPER
Typical procedure for the asymmetric Michael reaction catalyzed by 7 f:
Isobutyraldehyde (0.073 mL, 0.804 mmol), trans-b-nitrostyrene (30 mg,
0.201 mmol), organocatalyst 7 f (11.5 mg, 0.040 mmol), and toluene
(0.5 mL) were added to a round-bottomed flask. The reaction mixture
was stirred at ambient temperature. After the nitroalkene was consumed,
detected by TLC analysis, the reaction was quenched with brine and ex-
tracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and the solvent
was evaporated under reduced pressure. The crude product was purified
by flash column chromatography (hexane/ethyl acetate 6:1) to provide
8a as a colorless liquid (90%). 1H NMR (400 MHz, CDCl3): d=9.53 (s,
1H), 7.36–7.19 (m, 5H), 4.85 (dd, J=13.0, 11.3 Hz, 1H), 4.69 (dd, J=
13.0, 4.2 Hz, 1H), 3.78 (dd, J=11.3, 4.2 Hz, 1H), 1.14 (s, 3H), 1.01 ppm
(s, 3H); 13C NMR (100 MHz, CDCl3): d=204.2, 135.4, 129.1, 128.7, 128.1,
76.3, 48.5, 48.2, 21.7, 18.9 ppm; HPLC: Chiralcel OD-H (hexane/iPrOH:
80/20, flow rate: 0.8 mL/min, l=254 nm); retention time: 16.9 min
(major), 24.4 min (minor).
at NTNU, and the National Center for High-Performance Computing for
providing us with computer time and facilities.
[1] D. W. C. MacMillan, Nature 2008, 455, 304–308.
[2] For special issues on organocatalysis, see: a) A. Berkessel, H.
Grçger, Asymmetric Organocatalysis: From Biomimetic Concepts to
Applications in Asymmetric Synthesis Wiley-VCH, Weinheim, 2005;
b) P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH, Wein-
heim, 2007.
[3] For selected reviews on organocatalysis, see: a) Chem. Rev. 2007,
107(12); b) Acc. Chem. Res. 2004, 37(8); c) Adv. Synth. Catal. 2004,
346, 9–10; d) B. List, Tetrahedron 2002, 58, 5573–5590; e) P. I.
Dalko, L. Moisan, Angew. Chem. 2004, 116, 5248–5286; Angew.
Chem. Int. Ed. 2004, 43, 5138–5175; f) H. Pellissier, Tetrahedron
2007, 63, 9267–9331; g) A. Dondoni, A. Massi, Angew. Chem. 2008,
120, 4716–4739; Angew. Chem. Int. Ed. 2008, 47, 4638–4660.
[4] P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992.
Compound 12: (S)-Citronellal (11; 0.073 mL, 0.8 mmol), trans-b-nitrostyr-
ene (30 mg, 0.2 mmol), and organocatalyst 7 f (5.7 mg, 0.02 mmol) were
added to a round-bottomed flask. The reaction mixture was stirred at
ambient temperature. After the trans-b-nitrostyrene was consumed, de-
termined by TLC analysis, the reaction was quenched with H2O and ex-
tracted with CH2Cl2 (3ꢂ10 mL). The combined organic layers were
washed with brine, dried over anhydrous MgSO4, filtered, and the solvent
was evaporated under reduced pressure. The crude product was purified
by flash column chromatography (hexane/ethyl acetate 8:1) to provide 12
as a pale-yellow liquid (93%). [a]1D8 =À40.2 (c=1.00, CHCl3); 1H NMR
(400 MHz, CDCl3): d=9.89 (d, J=1.7 Hz, 1H), 7.35–7.26 (m, 3H), 7.16
(d, J=7.2 Hz, 2H), 4.93 (t, J=6.5 Hz, 1H), 4.67 (dd, J=12.4, 4.3 Hz,
1H), 4.52 (dd, J=12.3, 10.1 Hz, 1H), 3.92 (td, J=10.7, 4.3 Hz, 1H), 2.87
(d, J=11.2 Hz, 1H), 2.03–1.90 (m, 2H), 1.62 (s, 3H), 1.52 (s, 3H), 1.50–
1.45 (m, 2H), 1.41–1.31 (m, 1H), 0.85 ppm (d, J=6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=204.2, 136.8, 132.2, 128.9, 127.9, 123.2, 79.2, 56.3,
41.6, 35.4, 32.1, 25.4, 17.6, 14.7 ppm; IR (CH2Cl2): n˜ =2921, 1716, 1557,
[5] For reviews of organocatalytic asymmetric conjugate addition reac-
tions, see: a) K. Tomioka, Y. Nagaoka, M. Yamaguchi in Compre-
hensive Asymmetric Catalysis, Vol. III (Eds.: E. N. Jacobsen, A.
Pfaltz, H. Yamamoto), Springer, New York, 1999, Chapter 31.1 and
K. Tomioka, Y. Nagaoka, M. Yamaguchi in Comprehensive Asym-
metric Catalysis, Vol. III (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yama-
moto), Springer, New York, 1999, Chapter 31.2; b) S. Sulzer-Mossꢃ,
A. Alexakis, Chem. Commun. 2007, 3123–3135; c) J. L. Vicario, D.
Badia, L. Carrillo, Synthesis 2007, 2065–2092; d) S. B. Tsogoeva,
Eur. J. Org. Chem. 2007, 1701–1716; e) J. Christoffers, A. Baro,
Angew. Chem. 2003, 115, 1726–1728; Angew. Chem. Int. Ed. 2003,
42, 1688–1690; f) O. M. Berner, L. Tedeschi, D. Enders, Eur. J. Org.
Chem. 2002, 1877–1894; g) N. Krause, A. Hoffmann-Roder, Synthe-
sis 2001, 171–196; h) M. P. Sibi, S. Manyem, Tetrahedron 2000, 56,
8033–8061.
[6] For examples of asymmetric Michael additions of aldehydes and ke-
tones to nitroolefins, see: a) B. List, P. Pojarliev, H. J. Martin, Org.
Lett. 2001, 3, 2423–2425; b) J. M. Betancort, C. F. Barbas III, Org.
Lett. 2001, 3, 3737–3740; c) A. Alexakis, O. Andrey, Org. Lett. 2003,
5, 3611–3614; d) T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J.
Am. Chem. Soc. 2004, 126, 9558–9559; e) Y. Hayashi, H. Gotoh, T.
Hayashi, M. Shoji, Angew. Chem. 2005, 117, 4284–4287; Angew.
Chem. Int. Ed. 2005, 44, 4212–4215; f) S. Luo, X. Mi, L. Zhang, S.
Liu, H. Xu, J.-P. Cheng, Angew. Chem. 2006, 118, 3165–3169;
Angew. Chem. Int. Ed. 2006, 45, 3093–3097; g) C. Palomo, S. Vera,
A. Mielgo, E. Gomez-Bengoa, Angew. Chem. 2006, 118, 6130–6133;
Angew. Chem. Int. Ed. 2006, 45, 5984–5987; h) S. Mossꢃ, M. Laars,
K. Kriis, T. Kanger, A. Alexakis, Org. Lett. 2006, 8, 2559–2562;
i) S. V. Pansare, K. Pandya, J. Am. Chem. Soc. 2006, 128, 9624–
9625; j) C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8,
2901–2904; k) E. Reyes, J. L. Vicario, D. Badia, L. Carrillo, Org.
Lett. 2006, 8, 6135–6138; l) Y. Xu, A. Cordova, Chem. Commun.
2006, 460–462; m) Y. Chi, L. Guo, N. A. Kopf, S. H. Gellman, J.
Am. Chem. Soc. 2008, 130, 5608–5609; n) P. Garcꢄa-Garcꢄa, A. La-
depeche, R. Halder, B. List, Angew. Chem. 2008, 120, 4797–4799;
Angew. Chem. Int. Ed. 2008, 47, 4719–4721; o) D. Enders, C. Wang,
J. W. Bats, Angew. Chem. 2008, 120, 7649–7653; Angew. Chem. Int.
Ed. 2008, 47, 7539–7542; p) M. Wiesner, J. D. Revell, S. Tonazzi, H.
Wennemers, J. Am. Chem. Soc. 2008, 130, 5610–5611; q) A. Lu, P.
Gao, Y. Wu, Y. Wang, Z. Zhou, C. Tang, Org. Biomol. Chem. 2009,
7, 3141–3147; r) B. Tan, X. Zeng, Y. Lu, P. J. Chua, G. Zhong, Org.
Lett. 2009, 11, 1927–1930; s) M. Laars, K. Ausmees, M. Uudsemaa,
T. Tamm, T. Kanger, M. Lopp, J. Org. Chem. 2009, 74, 3772–3775;
t) H. Uehara, C. F. Barbas III, Angew. Chem. 2009, 121, 10032–
10036; Angew. Chem. Int. Ed. 2009, 48, 9848–9852; u) M. Wiesner,
G. Upert, G. Angelici, H. Wennemers, J. Am. Chem. Soc. 2010, 132,
6–7; v) Z. Zheng, B. L. Perkins, B. Ni, J. Am. Chem. Soc. 2010, 132,
50–51; w) J.-R. Chen, Y.-J. Cao, Y.-Q. Zou, F. Tan, L. Fu, X.-Y.
Zhu, W.-J. Xiao, Org. Biomol. Chem. 2010, 8, 1275–1279.
1455, 1378, 1205, 1089 cmÀ1
;
HRMS (ESI): m/z: calcd for
C18H25NO3+Na+: 326.1732 [M+Na+]; found 326.1740; HPLC: Chiralcel
AD-H (hexane/iPrOH 95:5, flow rate: 0.5 mLminÀ1, l=254 nm); reten-
tion time: 13.61 min (major), 14.61 min (minor).
Compound 13: InBr3 (70 mg, 0.19 mmol) was added to a stirred solution
of 12 (40 mg, 0.13 mmol) in toluene (0.5 mL) at ambient temperature.
After 24 h, the reaction was quenched with H2O and extracted with
CH2Cl2 (3ꢂ10 mL). The combined organic layers were washed with
brine, dried over anhydrous MgSO4, filtered, and the solvent was evapo-
rated under reduced pressure. The crude product was purified by flash
column chromatography (hexane/ethyl acetate 4:1) to afford 13 as a
white solid (17 mg, 41%). M.p. 155–1578C; [a]1D8 =À29.2 (c=1.00,
CHCl3); 1H NMR (400 MHz, CDCl3): d=7.33–7.29 (m, 2H), 7.24–7.22
(m, 3H), 5.00 (dd, J=11.6, 4.8 Hz, 1H), 4.63 (t, J=11.2 Hz, 1H), 4.41 (s,
1H), 3.96 (brs, 1H), 3.84 (td, J=11.0, 4.8 Hz, 1H) 1.80–1.75 (m, 2H),
1.64–1.61 (m, 1H), 1.55–1.51 (m, 1H), 1.43–1.41 (m, 2H), 1.41 (s, 3H),
1.31 (s, 3H), 1.26–1.22 (m, 2H), 1.06 ppm (d, J=6.9 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=139.0, 128.7, 128.1, 127.4, 80.1, 74.3, 68.0, 49.6,
46.9, 43.5, 33.4, 29.6, 28.4, 27.7, 15.1 ppm; IR (CH2Cl2): n˜ =3402, 2958,
1640, 1548, 1448, 1376, 1200, 115 0 cmÀ1; HRMS (ESI): m/z: calcd for
C18H27NO4 +Na: 344.1838 [M+Na+]; found: 344.1840; crystal data for 13
at 200(2) K; C18H27NO4; Mr 321.41; orthorhombic; P212121; a=9.6849
(7) ꢁ, b=18.6629 (11) ꢁ, c=29.4837 (19) ꢁ; a=90, b=90, g=90; V=
5329.1 (6) ꢁ3; F000 =2088; l=0.71073 ꢁ; Z=12, 1=1.202 mgmÀ3; m=
0.084 mmÀ1; 28950 reflections; 0 restraints; 622 parameters; R=0.0844;
Rw=0.1265 for all data.
Acknowledgements
We thank the National Science Council of the Republic of China (NSC
96-2113M-003-005-MY3 and NSC 98-2119M-003-003) for financial sup-
port for this work. We are grateful to the Academic Paper Editing Clinic
Chem. Eur. J. 2010, 16, 7030 – 7038
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7037

K. Chen et al.
[7] For the synthesis of all-carbon quaternary stereogenic centers from
a,a-disubstituted aldehydes to nitroolefins, see: a) X.-j. Zhang, S.-p.
Liu, X.-m. Li, M. Yan, A. S. C. Chan, Chem. Commun. 2009, 833–
835; b) A. Sato, M. Yoshida, S. Hara, Chem. Commun. 2008, 6242–
6244; c) S. H. McCooey, S. J. Connon, Org. Lett. 2007, 9, 599–602;
d) M. P. Lalonde, Y. Chen, E. N. Jacobsen, Angew. Chem. 2006, 118,
6514–6518; Angew. Chem. Int. Ed. 2006, 45, 6366–6370; e) J. Wang,
H. Li, B. Lou, L. Zu, H. Guo W. Wang, Chem. Eur. J. 2006, 12,
4321–4332; f) W. Wang, J. Wang, H. Li, Angew. Chem. 2005, 117,
1393–1395; Angew. Chem. Int. Ed. 2005, 44, 1369–1371; g) N. Mase,
R. Thayumanavan, F. Tanaka, C. F. Barbas III, Org. Lett. 2004, 6,
2527–2530; also reference [6w] and [9c].
[8] a) C. L. Rigby, D. J. Dixon, Chem. Commun. 2008, 3798–3800;
b) Z.-H. Zhang, X.-Q. Dong, D. Chen, C.-J. Wang, Chem. Eur. J.
2008, 14, 8780–8783; c) T.-Y. Liu, J. Long, B.-J. Li, L. Jiang, R. Li,
Y. Wu, L.-S. Ding, Y.-C. Chen, Org. Biomol. Chem. 2006, 4, 2097–
2099; d) H. Li, J. Song, X. Liu, L. Deng, J. Am. Chem. Soc. 2005,
127, 8948–8949; e) M. Bella, K. A. Jørgensen, J. Am. Chem. Soc.
2004, 126, 5672–5673.
[9] a) Z.-H. Tzeng, H.-Y. Chen, C.-T. Huang, K. Chen, Tetrahedron
Lett. 2008, 49, 4134–4137; b) Z.-H. Tzeng, H.-Y. Chen, R. J. Reddy,
C.-T. Huang, K. Chen, Tetrahedron 2009, 65, 2879–2888; c) C.
Chang, S.-H. Li, R. J. Reddy, K. Chen, Adv. Synth. Catal. 2009, 351,
1273–1278; d) R. J. Reddy, H.-H. Kuan, T.-Y. Chou, K. Chen,
Chem. Eur. J. 2009, 15, 9294–9298; e) P.-M. Liu, C. Chang, R. J.
Reddy, Y.-F. Ting, H.-H. Kuan, K. Chen, Eur. J. Org. Chem. 2010,
42–46.
[10] For camphor-based catalysts for various asymmetric transformations,
see: a) V. K. Aggarwal, G. Hynd, W. Picoul, J.-L. Vasse, J. Am.
Chem. Soc. 2002, 124, 9964–9965; b) Z. Xu, C. Chen, J. Xu, M.
Miao, W. Yan, R. Wang, Org. Lett. 2004, 6, 1193–1195; c) S. Rajar-
am, M. S. Sigman, Org. Lett. 2005, 7, 5473–5475; d) M. Lemay,
W. W. Ogilvie, Org. Lett. 2005, 7, 4141–4144; e) Y. Langlois, A.
Petit, P. Remy, M.-C. Scherrmann, C. Kouklovsky, Tetrahedron Lett.
2008, 49, 5576–5579; f) H. He, B.-J. Pei, H.-H. Chou, T. Tian, W.-H.
Chan, A. W. M. Lee, Org. Lett. 2008, 10, 2421–2424.
[11] For selected references for bifunctional organocatalysts, see: a) T.
Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125,
12672–12673; b) See also reference [8c]; c) J. M. Andrꢃs, R. Manza-
no, R. Pedrosa, Chem. Eur. J. 2008, 14, 5116–5119.
[12] N. Dahlin, A. Bogevig, A. Adolfsson, Adv. Synth. Catal. 2004, 346,
1101–1105.
[13] V. K. Aggarwal, G. Fang, C. G. Kokotos, J. Richardson, M. G. Un-
thank, Tetrahedron 2006, 62, 11297–11303.
[14] CCDC-702906 (3), 740626 (7b), and 765436 (13) contain the supple-
mentary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] For recent reviews of hydrogen-bonding activation in organocataly-
sis, see: a) S. J. Connon, Chem. Eur. J. 2006, 12, 5418–5427; b) M. S.
Taylor, E. N. Jacobsen, Angew. Chem. 2006, 118, 1550–1573; Angew.
Chem. Int. Ed. 2006, 45, 1520–1543; c) T. Akiyama, J. Itoh, K. Fu-
chibe, Adv. Synth. Catal. 2006, 348, 999–1010; d) C. Bolm, T. Ranta-
nen, I. Schiffers, L. Zani, Angew. Chem. 2005, 117, 1788–1793;
Angew. Chem. Int. Ed. 2005, 44, 1758–1763.
[16] E. J. Lenard¼o, G. V. Botteselle, F. Azambuja, G. Perin, R. G. Jacob,
Tetrahedron 2007, 63, 6671–6712.
[17] a) H. Hagiwara, N. Komatsubara, H. Ono, T. Okabe, T. Hoshi, T.
Suzuki, M. Ando, M. Kato, J. Chem. Soc. , Perkin Trans. 1 2001,
316–322; b) H. Hagiwara, T. Okabe, K. Hakoda, T. Hoshi, H. Ono,
V. P. Kamat, T. Suzuki, M. Ando, Tetrahedron Lett. 2001, 42, 2705–
2707; c) H. Hagiwara, T. Sayuri, T. Okabe, T. Hoshi, T. Suzuki, H.
Suzuki, K.-i. Shimizu, Y. Kitayama, Green Chem. 2002, 4, 461–463.
[18] S. Sulzer-Mossꢃ, A. Alexakis, J. Mareda, G. Bollot, G. Bernardinelli,
Y. Filinchuk, Chem. Eur. J. 2009, 15, 3204–3220.
Received: February 24, 2010
Published online: May 7, 2010
7038
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Chem. Eur. J. 2010, 16, 7030 – 7038