Enantio- and diastereoselective michael addition reactions of unmodified aldehydes and ketones with nitroolefins catalyzed by a pyrrolidine sulfonamide

Article abstract of DOI:10.1002/chem.200600115

Chiral (S)-pyrrolidine trifluoromethanesulfonamide has been shown to serve as an effective catalyst for direct Michael addition reactions of aldehydes and ketones with nitroolefins. A wide range of aldehydes and ketones as Michael donors and nitroolefins as acceptors participate in the process, which proceeds with high levels of enantioselectivity (up to 99% ee) and diastereoselectivity (up to 50:1 d.r.). The methodology has been employed successfully in an efficient synthesis of the potent H., agonist Sen 50917. In addition, a practical three-step procedure for the preparation of (S)-pyrrolidine trifluorometh-anesulfonamide has been developed. The high levels of stereochemical control attending Michael addition reactions catalyzed by this pyrrolidine sulfonamide, have been investigated by using ab initio and density functional methods. Transition state structures for the rate-limiting C-C bond-forming step, corresponding to re- and si-face addition to the reactive conformation of the key enamine intermediates have been calculated. Analysis of these structures indicates that hydrogen bonding plays an important role in catalysis and that the energy barrier for si-face attack in reactions of aldehydes to form 2R,3S products is lower than that for the re-face attack leading to 2S,3R products. In contrast, the energy barrier for re-face addition is lower than that for si-face addition in reactions of ketones. The computational results, which are in good agreement with the experimental observations, are discussed in the context of the stereo-chemical course of these Michael addition reactions.

Full text of DOI:10.1002/chem.200600115

FULL PAPER
DOI: 10.1002/chem.200600115
Enantio- and Diastereoselective Michael Addition Reactions of Unmodified
Aldehydes and Ketones with Nitroolefins Catalyzed by a Pyrrolidine
Sulfonamide
Jian Wang,[a] Hao Li,[a] Bihshow Lou,*[b] Liansuo Zu,[a] Hua Guo,*[a] and Wei Wang*[a]
Abstract: Chiral (S)-pyrrolidine tri-
fluoromethanesulfonamide has been
shown to serve as an effective catalyst
for direct Michael addition reactions of
aldehydes and ketones with nitroole-
fins. A wide range of aldehydes and ke-
tones as Michael donors and nitroole-
fins as acceptors participate in the
process, which proceeds with high
levels of enantioselectivity (up to
99% ee) and diastereoselectivity (up to
50:1 d.r.). The methodology has been
employed successfully in an efficient
synthesis of the potent H3 agonist
C
G
been calculated. Analysis of these
structures indicates that hydrogen
bonding plays an important role in cat-
alysis and that the energy barrier for
si-face attack in reactions of aldehydes
to form 2R,3S products is lower than
that for the re-face attack leading to
2S,3R products. In contrast, the energy
barrier for re-face addition is lower
than that for si-face addition in reac-
tions of ketones. The computational re-
sults, which are in good agreement
with the experimental observations, are
discussed in the context of the stereo-
chemical course of these Michael addi-
tion reactions.
Sch50917. In addition,
a practical
three-step procedure for the prepara-
tion of (S)-pyrrolidine trifluorometh-
Introduction
alyst can sometimes significantly improve catalytic activity.
As part of a recent, broad effort to search for novel organo-
catalysts, we have discovered that a l-proline surrogate, (S)-
pyrrolidine trifluoromethanesulfonamide (1), promotes a va-
riety of asymmetric organic transformations.[1] Like l-pro-
Herein, we describe the results of an investigation that
proves the tenet that subtle changes in the structure of a cat-
[a] J. Wang, H. Li, L. Zu, Prof. Dr. H. Guo, Prof. Dr. W. Wang
Department of Chemistry, University of New Mexico
Albuquerque, NM 87131–0001 (USA)
Fax : (+1)505-277-2609
E-mail: hguo@unm.edu
wwang@unm.edu
[b] Prof. Dr. B. Lou
Chemistry Division, Center for General Education
Chang Gung University, Tao-Yuan, Taiwan (Republic of China)
Fax : (+886)211-8700
line, compound 1 exhibits high catalytic activity for Man-
A
E-mail: blou@mail.cgu.edu.tw
high levels of enantioselectivity. In some cases, the catalytic
activity of 1 is superior to that of l-proline. For example,
much higher enantioselectivities are observed for asymmet-
ric aldol reactions of a,a-dialkylaldehydes with aromatic al-
dehydes[1c] and conjugate addition processes when 1 is used
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author. It contains proce-
dures for preparation of catalyst 1, characterization of compounds
7a–7m and 8a–8w and computational results for stationary point ge-
ometries.
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as the catalyst.[1d,e] Moreover, compound 1 serves as an ef-
fective catalyst for a-selenenylation[1f] and a-sulfenylation[1g]
reactions, in which l-proline shows poor catalytic activity
and in which more side products are generated. The en-
hanced catalytic activity, enantioselectivity, and/or diastereo-
selectivity associated with reactions promoted by 1 are a
consequence of the acidic and sterically bulky properties of
the NHTf group (Tf=trifluoromethanesulfonyl; respective
pKa in DMSO for NH2Tf and CH3CO2H are 9.7 and 12.3).[2]
Furthermore, the lipophilic character and high stability of
the NHTf group are responsible for the broad solvent com-
patibility of 1 and the need for only relatively low catalyst
loadings.
Herein, the results of studies aimed at exploring the full
scope of this process are described. This effort has demon-
strated that 1 catalyzes Michael additions of b-nitrostyrenes
with both aldehydes and ketones, the process can be applied
to an efficient synthesis of the biologically active potent H3
agonist Sch50917, and ab initio and density functional
theory calculations can be used to identify the source of the
high levels of stereochemical control that attends these reac-
tions.
Results and Discussion
Michael addition reactions of nitroolefins with aldehydes
and ketones are important methods for the synthesis of syn-
thetically useful g-nitrocarbonyl compounds, which serve as
versatile building blocks for the preparation of complex or-
ganic targets.[3,4] The nitro group in these substances can be
readily converted into a variety of new functionalities in-
cluding amines, nitrile oxides, ketones, and carboxylic
acids.[4b] In addition, the trans-
A three-step synthesis of (S)-pyrrolidine trifluoromethane-
sulfonamide (1): Organocatalyst 1 has been proven to be a
valuable catalyst for a variety of organic reactions.[1] Conse-
quently, we have developed an efficient and practical
method for its preparation. The key intermediate in the
route is the N-Cbz-protected (Cbz=benzyloxycarbonyl) pyr-
rolidine primary amine 3 (Scheme 1). The only reported
formations of the aldehyde and
ketone moieties into other
useful functional groups are
possible. Consequently, the de-
velopment of catalytic, asym-
Scheme 1. Three-step synthesis of (S)-pyrrolidine trifluoromethanesulfonamide (1). Reagents and conditions:
a) BH3, THF, reflux, 7 h, 74%; b) Tf2O, TEA, CH2Cl2, 4.5 h, 76%; c) 10% Pd/C, H2, MeOH, 3 h, 93%.
metric versions of Michael ad-
dition reactions of nitroolefins
with aldehydes and ketones is
of great importance. Although
method for the preparation of this substance is lengthy, inef-
several catalytic asymmetric processes have been reported,
most require metal catalysts or restricted reaction condi-
tions.[5] Efforts aimed at achieving asymmetric versions of
the process by using chiral organocatalysts have received
great attention in recent years.[6–14] Among them, processes
promoted by l-proline and its derivatives have been exten-
sively investigated.[10–14] However, these works have led to
mixed results in terms of enantio- and diastereoselectivities
and substrate scope. Several pyrrolidine-based catalysts for
asymmetric Michael reactions have been described, but
moderate enantioselectivities are typically seen in these
processes.[10–14] In some cases, high enantio- and diastereose-
lectivities for the processes have been observed, but only for
a narrow range of substrates. For example, Kotsuki and co-
workers described a chiral pyrrolidine–pyridine catalyst that
promotes highly enantio- and diastereoselective Michael ad-
dition reactions of ketones with nitrostyrenes.[13] However,
poor enantioselectivities (ca. 22% ee) were noted when an
aldehyde was used as substrate. (S)-Diphenylprolinol silyl
ether has been employed as a catalyst for this process and
high levels of enantio- and diastereoselectivity are observed
only when aldehydes are used as substrates.[14]
ficient, and time consuming, taking place in four steps with
a low overall yield of 33% and requiring about one week of
time.[15] Also, it is important to point out that potentially ex-
plosive NaN3 is used in the approach. We envisioned that a
one-step synthesis of the amine 3 would be possible, starting
with commercially available and cheap (S)-2-carbamoyl-1-
N-Cbz-pyrrolidine (2)[16] and relying on the direct amide-to-
amine reduction reported by Brown and Curran
(Scheme 1).[17] In practice, treatment of 2 with BH3 under
the Brown–Curran conditions led to exclusive reduction of
the amide group without affecting the Cbz protecting group
in an optimized yield of 74%. Sulfonylation of the amine
group in 3 with triflic acid anhydride (Tf2O) in the presence
of triethylamine (TEA) gave sulfonamide 4 (76%). It
should be noted that slow addition of Tf2O (over 1 h) at
08C was needed to avoid formation of a bis-sulfonylation
product. Finally the Cbz protecting group in 4 was removed
by Pd-catalyzed hydrogenolysis (93%).
(S)-Pyrrolidine trifluoromethanesulfonamide (1) catalyzed
Michael addition reactions between aldehydes and nitroole-
fins: The efficacy of (S)-pyrrolidine trifluoromethanesul-
In a recent preliminary publication,[1e] we reported that
pyrrolidine sulfonamide 1 serves as a catalyst for Michael
addition reactions between aldehydes and b-nitrostyrenes;
these reactions take place with high levels of enantioselec-
tivity (89–99% ee) and diastereoselectivity (ꢀ20:1 d.r.).
C
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Organocatalysis
FULL PAPER
Table 1. Results of exploratory studies of 1-promoted asymmetric Mi-
chael addition of isobutyraldehyde 5a to trans-b-nitrostyrene 6a.[a]
Table 2. Enantioselective Michael reaction of aldehydes 5 with nitroole-
fins 6 in the presence of catalyst 1.[a]
Entry
Solvent
t [d]
Yield [%][b]
ee [%][c]
Entry
Product 7
t [d]
Yield
[%][b]
ee
d.r.
(syn/anti)[d]
[%][c]
ACHTREUNG
1
2
3
4
5
6
7
8
9
iPrOH
3
4.5
2
3
3
3
3
3
3
89
85
93
87
64
83
90
63
73
73
iPrOH[d]
DMSO
DMF
1
2
4.5
6
85
67
90
90
–
–
CH3CN
CH3NO2
THF
1,4-dioxane
CHCl3
37
71
[e]
<10
<10
43
[e]
79
[a] Reaction conditions: see Experimental Section. [b] Isolated yields.
[c] Enantiomeric excess (ee) determined by chiral HPLC analysis (Chiral-
pak AS-H). [d] At 08C. [e] Not determined.
3
4
5
6
75
89
93
64
–
–
–
1.75
4
89
stereogenic and one quaternary carbon centers, in 89%
yield and 83% ee.[18] The absolute configuration of 7a was
determined to be R, by comparing the specific rotation of
7a with that reported earlier for this substance.[11a] An inves-
tigation of different reaction media revealed that solvent
had a significant impact on the efficiency of this process. Re-
actions in polar solvents, such as iPrOH, DMSO, DMF, and
CH3CN (Table 1, entries 1–5), generally proceeded in higher
yields, whereas those in less polar solvents (CH3NO2, THF,
1,4-dioxane and CHCl3; entries 6–9) took place in low
yields. Despite these differences, generally good to high
enantioselectivities were associated with reactions conduct-
ed in all solvents, but those in protic (e.g., iPrOH) and
acidic solvents (e.g., CHCl3) gave highest enantioselectivities
(entries 1 and 9). This is presumably due to participation of
intermolecular hydrogen bonding between the solvent and
oxygen of the CF3SO2 group, which stabilizes the favored
transition state (see below). Lowering the reaction tempera-
ture to 08C led to further improvement in the enantioselec-
tivity (up to 90%, entry 2) without significantly compromis-
ing the rate of the reaction. The results demonstrate that or-
ganocatalyst 1 displays a more broad solvent compatibility
than proline as a result of the presence of the more lipophil-
ic CF3SO2 group.
The scope and limitation of this catalytic process were ex-
plored next by using a wide range of aldehydes and nitroole-
fins. As summarized in Table 2, the reaction catalyzed by 1
has broad applicability with respect to aldehydes as Michael
donors. Reactions of sterically demanding a,a-dialkyl alde-
hydes with trans-b-nitrostyrene (6a), although requiring
longer reaction times, efficiently produced Michael adducts
7a–f that contain quaternary carbon centers (Table 2, en-
tries 1–6). Also, high enantioselectivities (89–93% ee) were
observed for reactions with isobutyraldehyde and cyclopen-
tanecarboxaldehyde (entries 1–4), and cyclohexanecarboxal-
dehyde afforded a product with moderate enantioselectivity
(64%, entry 5). These observations suggest that substrate
42(79)[e]
6
7
3
1
72
77
60(65)[f]
97
1.3:1
12:1
8
0.83
1.16
1
99
63
86
94
91
76
96
94
99
99
97
22
50:1
22:1
20:1
30:1
50:1
50:1
9
10
11
12
13
1
1.08
1
[a] Reaction conditions: see Experimental Section. [b] Isolated yields.
[c] Determined by chiral HPLC analysis (Chiralpak AS-H, or AD and
Chiralcel OD-H). [d] Determined by H NMR spectroscopy. [e] Based on
recovered starting material. [f] Major diastereomer: 60% ee, minor
isomer: 65% ee.
1
conformation plays an important role in governing the enan-
tioselectivity of the process. The Michael addition reaction
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W. Wang, B. Lou, H. Guo et al.
Table 3. Results of organocatalyst 1 promoted Michael addition of cyclic
ketones to trans-b-nitrostyrenes.
of an unsymmetrically substituted a,a-dialkyl aldehyde also
took place to give a Michael adduct (7 f) in a good yield,
but with relatively low ee and poor diastereoselectivity
(entry 6). Studies with linear chain aldehydes revealed that
these substrates reacted much more rapidly than the more
hindered a,a-dialkyl aldehydes (entries 7–12). More signifi-
cantly, reactions with b-nitrostyrenes, bearing both electron-
withdrawing and electron-donating substituents, occurred
with excellent levels of enantio- (94–99% ee) and diastereo-
selectivities (ꢀ20:1 d.r., syn diastereomer major product).
Entry
Product 8
t [h]
Yield
[%][a]
ee
d.r.
(syn/anti)[c]
[%][b]
ACHTREUNG
1
2
3
10
72
96
11
7
97
50:1
When the aliphatic trans-nitroolefin Ph(CH2)2CH=CHNO2
A
was employed as substrate for the process, a high d.r. (50:1)
but low ee (22%) was observed (Table 2, entry 13).
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
Direct (S)-pyrrolidine trifluoromethanesulfonamide (1) cata-
lyzed Michael addition reactions between ketones and nitro-
olefins: As discussed above, previous studies of organocata-
lyzed Michael reactions with nitroolefins have shown that
these processes take place with high levels of enantio- and
diastereoselectivities, but they have a narrow substrate
scope, working only for either aldehydes[14] or ketones.[13]
An ideal catalytic system should be able to promote reac-
tions of a broad spectrum of substrates. Accordingly, we
tested the capacity of compound 1 to catalyze reaction of cy-
clohexanone with 6a under the same reaction conditions
(iPrOH, 08C) found to be optimal for aldehydes. This pro-
168
4
5
6
24
16
24
84
92
83
96
98
99
50:1
50:1
50:1
A
and with remarkably high enantio- (97% ee) and diastereo-
selectivity (50:1 d.r.) (Table 3, entry 1).
The generality of Michael addition reactions between ke-
tones and nitroolefins promoted by 1 was explored. As the
data in Table 3 show, the ring size of cyclic ketones strongly
affects the reaction rate (entries 1–3). Excellent levels of
enantio- (97% ee) and diastereoselectivity (50:1 d.r.) accom-
panied reactions of cyclohexanone, but, in contrast, almost
no reaction occurred for five- and seven-membered ring
cyclic ketones, presumably due to the difficulty of formation
of enamines. A wide range of cyclohexanone derivatives ef-
ficiently reacted with trans-b-nitrostyrenes to give the Mi-
chael adducts with high levels of stereochemical control
(86–99% ee and ꢀ30:1 d.r. favoring syn diastereomers)
(Table 3, entries 4–14). More significantly, b-nitrostyrenes
possessing either electron-donating or electron-withdrawing
groups on their aromatic ring underwent this process (en-
tries 4–9). The electronic nature of substituents on the nitro-
olefins has no effect on stereoselectivity (entries 4–6); excel-
lent levels of enantio- (96–99% ee) and diastereoselectivities
(50:1 d.r.) are observed. The substitution pattern of b-nitro-
styrenes influences enantioselectivities, but not diastereose-
lectivities. For example, when a CF3 group is present at the
ortho- position of b-nitrostyrene, a high d.r. (50:1), but a rel-
atively low ee (88%) is observed (entry 7). Finally, the abso-
lute configuration of 8a was determined to be 2S,3R by
comparing its optical rotation, which is opposite to that of
the known 2R,3S aldehyde.[13] Furthermore, the syn configu-
ration of 8i was determined by X-ray crystallographic analy-
sis (Figure 1).[19]
7
8
34
36
70
79
88
86
50:1
30:1
9
48
91
98
50:1
10
11
24
12
87
95
98
97
50:1
30:1
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Organocatalysis
FULL PAPER
controlled manner (entries 13–14). Unfortunately, a,a-dime-
thylcyclohexanone, 1-indanone, and a-tetralone failed to un-
dergo reaction under these conditions (entries 15–17).
Table 3. (Continued)
Entry
Product 8
t [h]
Yield
[%][a]
ee
d.r.
(syn/anti)[c]
[%][b]
ACHTREUNG
In this investigation, we also probed reactions of acyclic
ketones with b-nitrostyrenes promoted by organocatalyst 1.
Under the reaction conditions described above, reaction of
acetone with trans-b-nitrostyrene proceeded remarkably fast
(8 h) to afford adduct 8r in 96% yield and with a moderate
enantioselectivity (55% ee; Table 4, entry 1). This is the
12
24
83
81
96
95
50:1
50:1
13
18
48
Table 4. Results of organocatalyst 1 promoted Michael addition of acy-
clic ketones to trans-b-nitrostyrenes.
14[e]
93
99
50:1
Entry
Product 8
t [h]
Yield
[%][a]
ee
d.r.
(syn/anti)[c]
[%][b]
ACHTREUNG
15
16
17
96
168
168
<5
<5
<5
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
n.d.[d]
1
2
3
8
36
72
96
85
47
55
93
53
–
50:1
1.1:1
50:1
3:1
[a] Isolated yields. [b] Determined by chiral HPLC analysis (Chiralpak
AS-H, or AD and Chiralcel OD-H). [c] Determined by 1H NMR
spectroscopy. [d] Not determined. [e] Mixture of DMF/iPrOH (1/1, v/v)
4
5
48
48
72
46
77
46
A
used.
6
18
89
86
14:1
[a] Isolated yields. [b] Enantiomeric excess (ee) determined by chiral
HPLC analysis (Chiralpak AS-H). [c] Determined by 1H NMR spectros-
copy.
highest % ee achieved for organocatalyzed reaction of ace-
tone thus far.[20] 3-Pentonone reacted with trans-b-nitrostyr-
ene with excellent enantio- (93% ee) and diastereoselectivi-
ty (50:1; Table 4, entry 2). Reactions of unsymmetric ke-
tones took place at the more substituted sites, presumably
because the intermediate enamines were produced under
thermodynamic control (entries 3–6). 2-Butanone gave
product 8t in 53% ee and poor diastereoselectivity (1.1:1
d.r., entry 3). By increasing the size of the ketone side
chain, both the enantio- and diastereoselectivity of the Mi-
chael addition process were significantly improved (Table 4,
entry 4). The same trend is also observed for a-hydroxyl
ketone and its more bulky, protected silyl ether (entries 5
and 6). For example, 86% ee and 14:1 d.r. was achieved for
reaction of TBDMS protected a-hydroxyl acetone (entry 6).
To our knowledge the organocatalyzed processes described
Figure 1. X-ray crystal structure of 8i.
In addition, a wide range of cyclohexanone substrates,
bearing various functionalities (entries 10–14) participate in
1-catalyzed Michael addition reactions with nitrostyrenes
and excellent levels of enantio- and diastereoselectivity (95–
99% ee and ꢀ30:1 d.r.) are observed. Moreover, the mild
reaction conditions needed for this process are compatible
with substrates bearing acid sensitive groups (e.g., ketals)
and highly functionalized g-nitro ketones bearing two ste-
A
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W. Wang, B. Lou, H. Guo et al.
above represent the first examples of efficient asymmetric
Michel addition reactions of acyclic ketones to b-nitrostyr-
enes.[10–14]
synthesized Sch50971 has the correct absolute configuration.
The lower optical rotation of the synthesized Sch50971 is
due to the presence of its minor diastereomer, resulting
from the Michael addition reaction step.
Synthesis of Sch50971: Sch50971 (9) is a potent H3 agonist
with potential use for the treatment of a variety of diseases
including obesity, Alzheimerꢁs disease, and attention defi-
ciency/hyperactivity (Scheme 2).[21,22] This substance was
Mechanistic study: The mechanism of (S)-pyrrolidine tri-
fluoromethanesulfonamide 1 catalyzed Michael addition re-
actions of ketones and aldehydes with b-nitrostyrene should
be similar to that for direct aldol reactions catalyzed by l-
proline, which has been studied earlier by using theoretical
methods.[23] In the first step, the catalyst and the aldehyde or
ketone substrates react to form enamine intermediates.[1f,24]
Stereochemistry of the overall process is believed to be de-
termined by the addition of trans-b-nitrostyrene to these en-
amine intermediates.[1e,f] The bulky sulfonamide group and
the hydrogen bonding between the NH group of pyrrolidine
sulfonamide and the nitro group of b-nitrostyrene are con-
sidered to be important to the high catalytic activity and
enantio- and diastereo-selectivity of the catalyzed reac-
tions.[1e]
Representative transition state models
(Scheme 3) for reactions of energetically favored anti-enam-
ines, formed from 1 and aldehydes (e.g., propanal) and ke-
A
and
B
Scheme 2. Total synthesis of Sch50971 (9). Conditions: a) TrCl, TEA,
CH2Cl2, RT, 14 h, 95%; b) CH3NO2, piperidine, AcOH, RT, 8 h, 79%;
c) propionaldehyde, iPrOH/CH2Cl2 (v/v 1:1) 20 mol% 1, 08C, 24 h,
99% ee, 20:1 d.r., 78%; d) 20% Pd(OH)2, MeOH, 45 psi, RT, 96 h, 65%;
e) 95% TFA, 3 h, 91%.
prepared earlier by applying an Evanꢁs auxiliary controlled
Michael addition reaction as a key step.[21] However, only a
88% d.r. was achieved in this process and, as a result, an ad-
ditional crystallization was needed in order to obtain enan-
tiomerically pure material. We have designed a route to this
target that relies on asymmetric Michael addition reaction
of nitroolefin 12 to propionaldehyde catalyzed by 1 as a key
step.
A synthetic route for preparation of Sch50971, starting
from commercially available 1H-imidazole-4-carboxalde-
hyde (10), is shown in Scheme 2. N-Protection of imidazole
of 10 was achieved by reaction with TrCl (Tr=trityl) in the
presence of TEA (95%). Condensation of aldehyde 11 with
nitromethane in the presence of piperidine and acetic acid
provided the desired trans-nitroolefin 12 in 79% yield. Mi-
chael addition of 12 to propionaldehyde, in the presence of
20 mol% 1 at 08C afforded adduct 13 in 78% yield. In this
reaction, a mixture of iPrOH/CH2Cl2 instead of iPrOH was
used as solvent, owing to the poor solubility of 12 in iPrOH.
Essentially one enantiomer of 13 (99% ee) was obtained,
but with relatively low d.r. (12:1). After silica gel column
purification, the d.r. of the major, desired diastereomer 13
was increased to 20:1. One-pot transformation (65%) of g-
nitro aldehyde 13 into pyrrolidine 14 was promoted by Pd-
catalyzed hydrogenation. Finally, the Tr group was removed
by treatment with trifluoroacetic acid (TFA) to furnish the
target molecule Sch50971 (9) as its HCl salt (91%). Com-
paring the optical rotation of synthetic Sch50971 with that
reported ([a]2D5 =+36.1 (c=0.6 in MeOH), literature
value[21] [a]D25 =+43.5 (c=0.34 in MeOH)) indicates that
Scheme 3. Proposed transition state models A and B.
tones (e.g., pentanone), are proposed to account for the
high enantio- and diastereoselectivity of these Michael addi-
tion reactions. In both, the nitro group of trans-b-nitrostyr-
ene is directed toward the CF3SO2NH group by two hydro-
À
À
gen bonds, an intramolecular CF3SO2N H···O N=O and an
À À
À
intermolecular O=S=O···H O H···O N=O involving sol-
vent participation. As observed, 2R,3S configurations are
generated in reactions of aldehydes, while 2S,3R products
derive from ketones. We speculate that the 2R,3S configura-
tion results from a si-face attack, whereas the 2S,3R stereo-
chemical outcome comes from a preferred re-face addition
to the ketone-derived enamine. This difference is presuma-
bly due to the steric hindrance induced by the ketone side
chain (e.g., Et group), which leads to less hindered re face
4326
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Chem. Eur. J. 2006, 12, 4321 – 4332

Organocatalysis
FULL PAPER
approach. It is noted that there is a certain amount of con-
troversy in proposing transition-state models to explain the
stereochemistry observed in the Michael addition reactions
of aldehydes and ketones with olefines. Enders proposed an
anti-enamine, resulting from ketone for re face addition to
nitroolefin.[10b] However, Barbas III,[11d] Alexakis et al.,[11f]
and Kotsuki,[13] developed a syn-enamine for the ketone for
re-face-attacking nitroolefin. In addition, a si-face addition
of anti-enamine for aldehyde to nitroolefin was postulated
by Barbas III[11d] and Alexakis et al.[11f]
To gain a more detailed understanding of the origin(s) of
the high enantio- and diastereoselectivity of the processes
catalyzed by 1 and the opposite stereochemistry associated
with aldehydes and ketones, computational studies were
first carried out by employing ab initio methods and density
functional theory (DFT). For these treatments, we assume
that the enamine formation is a fast process and thus has no
bearing on the rate and stereoselectivity of the overall reac-
tion.[25] The subsequent hydrolysis step to recover the cata-
lyst is also considered to involve a low-energy barrier.[1f] As
for syn-enamines are much higher in energy than those for
anti-enamines. Therefore, only the results for calculations on
pathways arising from the anti-conformation are presented
here. Two possibilities exist for the approach of b-nitrostyr-
ene to the anti-enamine, one from the si face of the enamine
and the other from the re face (Figures 2 and 3). These two
approaches result in formation of the 2R,3S and 2S,3R prod-
ucts, respectively.
As shown in Table 5, the re-face arrangement of the reac-
tant complex has a lower energy than its si counterpart no
matter what type of substrate is involved. For example, the
si complex for 3-pentanone-enamine and b-nitrostyrene is
approximately 4 kcalmolÀ1 higher in energy.
The HF energy barriers for rate-limiting addition to the
propanal enamine intermediate are 33.45 kcalmolÀ1 for the
si-face attack and 34.92 kcalmolÀ1 for the re-face attack.
Thus, there is a significant preference for formation of the
2R,3S product, in accord with the experimental observa-
tion.[1e] This preference is also observed in the B3LYP re-
sults, in which the respective si- and re-face addition barrier
heights are 13.99 and 16.51 kcalmolÀ1, respectively. The
À
a result, the rate-limiting C C bond-forming step involves
formation of the activated reac-
tion complex composed of the
À
enamine intermediate and b-ni-
trostyrene. To simplify the cal-
culations, we have used propa-
nal and 3-pentanone to repre-
sent the aldehyde and ketone
substrates, respectively. In addi-
tion, a water molecule instead
of iPrOH is included in our
transition-state models to pro-
vide hydrogen-bond interac-
tions between the sulfonamide
group in the catalyst and the
nitro group in b-nitrostyrene.
This is justified by the fact that
water is produced in the forma-
tion of enamine intermediate.
To gain insight into the fac-
tors that can affect catalysis and
stereochemistry, we have deter-
mined the energies and struc-
tures of reactant complexes and
transition states using both ab
initio and DFT methods. The
geometric and energetic param-
eters are listed in Table 5 and
structures are displayed in Fig-
ures 2 and 3.
Table 5. Hartree-Fock and DFT results for the rate-limiting C C bond formation step of the Michael addition
reaction of propanal and 3-pentanone to trans-b-nitrostyrene catalyzed by (S)-pyrrolidine sulfonamide 1.
si face (2R, 3S)
transition
state
re face (2S, 3R)
transition
state
reactant
complex
reactant
complex
propanal
energy [kcalmolÀ1] (barrier height given in parentheses)
HF/6–31G* opt + ZPE
B3LYP/6–31G*opt + ZPE
B3LYP/6–31G* + PCM
0.44
1.73
0.72
33.89 (33.45)
15.72 (13.99)
8.26 (7.54)
0
0
0
34.92
16.51
9.38
distances [Š] (HF results given in parentheses)
À
N2 H···O1
1.87 (2.00)
4.03 (4.00)
1.99 (2.13)
5.42
1.80 (1.95)
1.93 (2.08)
2.07 (2.23)
2.04
1.85 (2.01)
1.74 (1.86)
1.96 (2.07)
2.31 (2.55)
2.07
À
À
O1···H O H
3.03 (3.87)
2.09 (2.09)
5.48
À
À
S=O···H O H
C2···C3
N1···N3
4.61
2.94
4.05
3.18
charges [e]
N1/N3
O1/O2
À0.429/+0.441
À0.430/À0.395
À0.380/+0.394
À0.539/À0.481
À0.421/+0.450
À0.441/À0.393
À0.382/+0.412
À0.540/À0.483
3-pentanone
energy [kcalmolÀ1] (barrier height given in parentheses)
HF/6–31G* opt + ZPE
B3LYP/6–31G*opt + ZPE
B3LYP/6–31G* + PCM
4.86
3.83
4.43
42.37 (37.51)
22.26 (18.43)
15.47 (11.04)
0
0
0
34.39
16.24
8.94
distances [Š] (HF results given in parentheses)
À
N2 H···O1
1.89 (1.99)
2.89 (3.21)
1.99 (2.12)
4.91
1.77 (1.89)
1.92 (2.06)
2.38 (2.48)
2.08
1.91 (2.65)
2.56 (3.83)
2.05 (2.26)
5.88
1.79 (1.94)
2.02 (2.08)
2.20 (2.49)
2.11
À
À
O1···H O H
À
À
S=O···H O H
C2···C3
N1···N3
5.02
3.00
4.57
3.22
C5···Cb
3.81
3.12
3.86
3.68
C5···N2
3.63
3.33
3.52
3.24
The enamine intermediates
can adopt anti and syn confor-
mations as shown in Scheme 3.
Similar to the results of studies
on proline-catalyzed aldol reac-
tions,[23b,d,e] we found that the
rate-limiting reaction barriers
C5···SO2
4.11
3.80
4.62
4.44
À
C5 H···H2Cb
charges [e]
N1/N3
2.88/4.36
2.09/3.42
3.88/4.20
3.65/3.78
À0.473/+0.439
À0.442/À0.392
À0.455/+0.392
À0.536/À0.474
À0.472/+0.440
À0.441/À0.390
À0.455/+0.409
À0.535/À0.475
O1/O2
dihedral angle [8]
C5-C1-Ca-Cb
43.6
À1.6
À102.9
À80.1
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4327

W. Wang, B. Lou, H. Guo et al.
À
Figure 2. Geometries of stationary points in the rate-determining C C
bond-formation step of the catalyzed Michael addition reaction of propa-
nal with trans-b-nitrostyrene obtained at the B3LYP/6–31G* level of
theory (hydrogen bonds are represented by thin dashed lines).
À
Figure 3. Geometries of stationary points in the rate-determining C C
bond-formation step of the catalyzed Michael addition reaction of 3-pen-
tanone with trans-b-nitrostyrene obtained at the B3LYP/6–31G* level of
theory (hydrogen bonds are represented by thin dashed lines).
lower barrier heights in the DFT results can be attributed to
partial inclusion of the electron correlation effects. The
normal mode associated with the sole imaginary frequency
mainly involves the motion of C2 and C3, corresponding to
À
the formation of a C C bond between the enamine and b-
tions discussed above. This picture is not changed when sol-
vent effects are considered, resulting in barrier heights of
11.04 and 8.94 kcalmolÀ1.
From the structure of the reactant complexes and transi-
tion states, it is clear that hydrogen-bonding interactions
play a key role in the catalysis. As shown in Figures 2 and 3,
nitrostyrene. The addition of solvent further decreases the
barriers to 7.54 and 9.38 kcalmolÀ1, due apparently to the
stabilization of the polar transition states. The lowering of
the reaction barrier in solution is consistent with the experi-
mental observation that the reaction is accelerated in polar
solvents. All the results indicate that the reactive path asso-
ciated with the si-face attack by b-nitrostyrene to the propa-
nal-enamine is more favorable than that associated with the
re-face attack.
À
the N2 H group of the sulfonamide forms a strong hydro-
gen bond with the O1 atom in the nitro group of b-nitrostyr-
ene, whereas a water (solvent) molecule is hydrogen bonded
with an oxygen atom in the sulfonamide group. For propa-
À
On the other hand, the energy barrier for the 3-penta-
none-enamine reaction with b-nitrostyrene follows an oppo-
site trend. The HF barriers for the si and re approaches are
37.51 and 34.39 kcalmolÀ1, respectively, and the correspond-
ing values obtained from the DFT calculations are 18.43 and
16.24 kcalmolÀ1, respectively. Like in the aldehyde case, the
reaction coordinate at the transition state involves primarily
nal–enamine complexes, the N2 H···O1 hydrogen bond
length is 1.87 and 1.85 Š in the si and re arrangements, re-
spectively, and the corresponding values for the hydrogen
bond between water and sulfonamide are 1.99 and 2.09 Š,
respectively. Apparently, the former interaction is stronger,
presumably due to the acidity of the NH proton and the
negative charges carried by the NO2 oxygen. Similar hydro-
gen-bonding patterns are seen for the 3-pentanone–enamine
À
the formation of the C2 C3 bond. The preference of the
À
2S,3R product is also consistent with experimental observa-
complexes, in which the N2 H···O1 hydrogen bond length is
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Chem. Eur. J. 2006, 12, 4321 – 4332

Organocatalysis
FULL PAPER
1.89 and 1.91 Š in the si face and re conformations, respec-
tively, and the water–sulfonamide values are 1.99 and
2.05 Š, respectively.
displayed in Figure 3, in which an ethyl group is much closer
to the sulfonamide group in the si transition state than in
the re counterpart. This is evidenced by the corresponding
À
At transition states, hydrogen bonds are generally
strengthened, due apparently to increased oxygen charges in
the nitro group of b-nitrostyrene as the two C=C bonds are
broken. For propanal, the charge on the oxygen atom
changes from À0.430 (À0.441) in the reactant complex to
À0.539 (À0.540) in the si transition state. As a result, the
C5 Cb distances of 3.12 and 3.68 Š and by other distances
between various atoms belonging to the two groups as listed
in Table 5. The stereo hindrance is further illustrated by the
C5-C1-Ca-Cb dihedral angle, which shows that the re transi-
tion state is much closer to gauche (À80.18) than the si tran-
sition state (À1.68).
À
N2 H···O1 hydrogen bond length is shortened to 1.80 and
1.74 Š in the si and re approaches, respectively. Similarly,
the corresponding hydrogen bond length is reduced to 1.77
and 1.79 Š, respectively, for 3-pentanone, resulting from the
negative charge buildup (q=À0.094 for both si and re reac-
tions) at the nitro oxygen atoms. The role played by intra-
molecular hydrogen bonds in organocatalysis has long been
recognized.[1f,23a,d,e]
More interestingly, the water molecule develops a strong
hydrogen-bond interaction with O1 of the NO2 group, while
maintaining hydrogen bonding with the sulfonamide group.
Conclusion
In conclusion, we have shown that (S)-pyrrolidine trifluoro-
methanesulfonamide (1) is an effective organocatalyst for
promoting direct, highly enantio- and/or diastereoselective
Michael addition of unmodified aldehydes and ketones to b-
nitrostyrenes. The process proceeds under mild reaction
conditions to produce versatile g-nitro aldehydes and ke-
tones. In this investigation, we showed that the Michael ad-
dition reactions have broad applicability with respect to
both the Michael donors and the acceptors; both aldehydes
and ketones and a wide range of nitroolefins can be tolerat-
ed. Furthermore, using the 1-promoted Michael addition as
a key step, we have developed an efficient synthesis of
Sch50971. A practical three-step preparation of organocata-
lyst 1 has also been developed and, as a result, its ready
availability renders it as a valuable catalyst for asymmetric
synthesis.
Computational studies have been conducted to gain an
understanding of the origin of the stereoselectivity of 1-cata-
lyzed the Michael addition process. The results agree quite
well with the observed stereoselectivity of 1-catalyzed Mi-
chael addition reactions of aldehydes and ketones and at-
tribute the activity of the organocatalyst to the formation of
both intramolecular and intermolecular hydrogen bonds.
The preference of the si approach for aldehydes appears to
stem from the alignment of the bulky sulfonamide group
with the b-nitrostyrene, which is in turn determined by the
chirality of the Ca atom in the catalyst. On the other hand,
the preference of the re reaction path in ketone reactions
seems to originate from the stereo hindrance between the
bulky sulfonamide group in the catalyst and an alkyl group
in the enamine intermediate. These results provide valuable
insight into the mechanisms of asymmetric organocatalysis
and might help the design of new and more efficient organo-
catalysts.
À
As shown in Figures 2 and 3, the HO H···O1 hydrogen
bond length is 1.93 and 1.96 Š at the si and re transition
states, respectively, for the propanal reaction and 1.92 and
2.02 Š, respectively, for the 3-pentanone reaction. The par-
ticipation of water-assisted, intermolecular hydrogen bonds
observed here underscores the importance of the sulfona-
mide group in the catalysis, which not only provides an elec-
tron-withdrawing force to the neighboring NH group, but
also electrostatic interaction with the nitro group of b-nitro-
styrene through a water molecule. Such a cooperative hy-
drogen-bond network resembles the “oxyanion hole” com-
monly found in enzymes for stabilizing the transition
state.[26]
It is much more difficult to unequivocally identify the
source of the stereoselectivity in these catalyzed reactions.
Hence, we only offer here some tantalizing evidence based
on the structure of the transition states, which might suggest
possible explanations. It appears that the origin of the ste-
A
substrates. In the former case, it appears that the energy dif-
ference in the transition state correlates with the distance
between the negatively charge nitrogen atom (N1) in the
pyrrolidine ring and the positively charged nitrogen atom
À
(N3) in the nitro group of b-nitrostyrene. The N1 N3 dis-
tance at the re transition state (3.18 Š) is much larger than
that at the si transition state (2.94 Š), rendering a stronger
À
electrostatic interaction in the latter case. The larger N1 N3
distance at the re transition state is apparently due to the
chirality at the Ca position of the catalyst, which pointing
the bulkier sulfonamide group towards the approach b-ni-
trostyrene. In the si approach, however, such stereo-hin-
drance is absent.
Experimental Section
General: Unless specified, all reactions were performed under an aerobic
atmosphere. Commercial, HPLC grade solvents were used directly for re-
actions without further purification. HPLC grade EtOAc and hexanes
were used for column chromatography. Anhydrous THF was obtained
from distillation of Na and benzophenone. Column chromatography was
performed with silica gel (230–400 mesh size). TLC plates with F254 indi-
cator were used for monitoring reactions. The combined organic layers
The opposite stereoselectivity for the Michael addition of
ketones is most likely due to the bulky alkyl group that re-
places the hydrogen in aldehydes, which might cause strong
stereo hindrance at the transition state. Indeed, such hin-
drance can be readily found in the transition state structures
Chem. Eur. J. 2006, 12, 4321 – 4332
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
4329

W. Wang, B. Lou, H. Guo et al.
were dried over MgSO4. Solvents were evaporated under reduced pres-
sure. All yields given refer to as isolated yields. 1H NMR was recorded
on a 500 MHz and 13C on a 125 MHz spectrometer. HRMS experiment
was performed on a high resolution magnetic sector spectrometer. Tetra-
methylsilane (TMS) was used as a reference for 1H NMR experiments.
4-[(3R,4R)-4-Methylpyrrolidin-3-yl]-1-trityl-1H-imidazole (14): Pd(OH)2
(20%; 21 mg, 30%) was added to a solution of compound 13 (70 mg,
0.16 mmol) in methanol (10 mL) and the reaction mixture was reductive-
ly cyclized at 45 psi for 96 h. After reaction mixture was concentrated
under reduced pressure, the resulting residue was then purified by silica-
gel chromatography (methanol/dichloromethane=1:5) and fractions
were collected and concentrated in vacuo to afford a clear solid (41 mg,
65%).
1
Data for H are reported as follows: chemical shift (ppm), and multiplici-
ty (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet). Data for
13C NMR are reported as ppm.
4-[(3R,4R)-4-Methylpyrrolidin-3-yl]-1H-imidazole
(9;
Sch50971):
Typical procedure for Michael addition reaction of aldehydes: Catalyst 1
(10 mg, 0.044 mmol) was added to a vial containing isobutyraldehyde
(0.20 mL, 2.19 mmol) and dry iPrOH (1 mL) at 08C. The mixture was
vigorously stirred for 15 min, and then trans-b-nitrostyrene (33 mg,
0.219 mmol) was added. After 4.5 d stirring, TLC analysis indicated com-
pletion of the reaction. After the reaction mixture was concentrated
under reduced pressure, the resulting residue was then purified by silica-
gel chromatography (ethyl acetate/hexane=1:30 to 1:5) and fractions
were collected and concentrated in vacuo to provide a clear oil (41 mg,
0.186 mmol, 85%). Relative and absolute configurations of the product
were determined by comparison with the known 1H NMR, 13C NMR and
optical rotation data (see Supporting Information).
CF3COOH (95%, 5 mL) was added to compound 14 (70 mg, 0.18 mmol)
and the reaction mixture was stirred for 96 h. After reaction mixture was
concentrated under reduced pressure, HCl (1n, 4 mL) was added to the
reaction mixture and products were extracted with Et2O (3”10 mL). The
aqueous phase was concentrated under reduced pressure to afford a
white solid (22 mg, 91%). [a]2D5 (major)=+36.1 (c=0.6 in MeOH), litera-
ture value[21] [a]2D5 (major)=+43.5 ( c=0.34 in MeOH).
Computational methods: All the calculations, including Hartree–Fock
(HF) and density functional theory (DFT), were carried out using the
Gaussian 03 suite of programs.[27] The stationary points corresponding to
the enamine–nitrostyrene (reactant) complex and the transition state for
À
the C C bond were fully optimized by using both the HF and DFT ap-
Typical procedure for Michael addition reaction of ketones (Tables 3 and
4): Catalyst pyrrolidine sulfonamide 1 (10 mg, 0.044 mmol) was added to
a vial containing cyclohexanone (0.23 mL, 2.19 mmol) and dry iPrOH
(1.0 mL) at 08C. The mixture was vigorously stirred for 15 min, and then
trans-b-nitrostyrene (33 mg, 0.219 mmol) was added. After 10 h stirring,
TLC analysis indicated completion of the reaction. After reaction mix-
ture was concentrated under reduced pressure, the resulting residue was
then purified by silica-gel chromatography (ethyl acetate/hexane=1:30 to
1:5) and fractions were collected and concentrated in vacuo to provide a
white solid (52 mg, 0.210 mmol, 96%). Relative and absolute configura-
tions of the product were determined by comparison with the known
1H NMR, 13C NMR and optical rotation data (see Supporting Informa-
tion).
proaches. These stationary points were confirmed by additional frequen-
cy calculations and the transition state was verified by the existence of an
imaginary frequency. The energies reported in this work include the
zero-point energy corrections. To confirm the connectivity between the
reactant and transition state, intrinsic reaction coordinate (IRC)[28] calcu-
lations were performed. In the DFT calculations, the B3LYP exchange-
correlation functional[29,30] was used and its accuracy in studying asym-
metric organocatalysis has been well documented.[12c] Two basis sets,
namely the standard 6–31G* and 6–31G** basis sets, were tested in the
DFT calculations and the results are very close (see Supporting Informa-
tion). As a result, only the 6–31G* results are reported here. Atomic
charges were calculated using the CHelpG method.[31] The solvent effects
for the solution phase reaction were estimated for the stationary points
using the polarized continuum model (PCM),[32] with no further geometry
optimization. In all of the PCM calculations, the UAKS radii and a di-
1-(1,1-Diphenylethyl)-1H-imidazole-4-carbaldehyde (11): Chlorotriphe-
nylmethane (1.73 g, 6.3 mmol) was added to a solution of compound 10
(0.5 g, 5.2 mmol) and triethylamine (0.87 mL, 6.3 mmol) in dichlorome-
thane (15 mL) at room temperature; the reaction mixture was stirred for
14 h. After reaction mixture was concentrated under reduced pressure,
the resulting residue was then purified by silica-gel chromatography
(ethyl acetate/hexane=1:10 to 1:2) and fractions were collected and con-
centrated in vacuo to provide a white solid (1.67 g, 95%).
AHCTREUNG
4-[(E)-2-Nitrovinyl]-1-(1,1-diphenylethyl)-1H-imidazole (12):[12] Piperi-
dine (1 drop) and acetic acid (1 drop) were added to a solution of com-
pound 11 (0.2 g, 0.59 mmol) in nitromethane (3 mL) at room tempera-
ture; the reaction mixture was stirred for 8 h. After reaction mixture was
concentrated under reduced pressure, the resulting residue was then puri-
fied by silica-gel chromatography (ethyl acetate/hexane=1:10 to 1:3) and
fractions were collected and concentrated in vacuo to afford a pale solid
(178 mg, 79%).
Acknowledgements
Financial support from the Department of Chemistry and the Research
Allocation Committee (W.W.), University of New Mexico, the National
Science Foundation (H.G.), and the National Science Council (B.L.) is
gratefully acknowledged. The Bruker X8 X-ray diffractometer was pur-
chased through an NSF CRIF:MU award to the University of New
Mexico, CHE-0443580. The expert X-ray crystallographic measurements
made by Dr. Eileen N. Duesler are greatly appreciated. We thank Profes-
sor Patrick S. Mariano for making critical editorial comments about the
manuscript.
A
lyst 1 (4 mg, 0.02 mmol) was added to a solution of compound 12 (38 mg,
0.1 mmol) and propionaldehyde (73 mL, 1.0 mmol) in dichloromethane
(0.5 mL) and iPrOH (0.5 mL) at 08C; the reaction mixture was stirred
for 24 h. After reaction mixture was concentrated under reduced pres-
sure, the resulting residue was then purified by silica-gel chromatography
(ethyl acetate/hexane=1:10 to 1:3) and fractions were collected and con-
centrated in vacuo to afford a white solid (34 mg, 78%). [a]2D5 (major)=
+44.4 (c=0.8 in CHCl3); 1H NMR (500 MHz, CDCl3, 258C, TMS): d=
9.72 (s, 1H; CHO), 7.39 (s, 1H; Ar), 7.36–7.30 (m, 9H; Ar), 7.11–7.06
[1] (S)-Pyrrolidine trifluoromethansulfonamide (1) has been used for
catalyzing: a) Mannich reactions: W. Wang, J. Wang, H. Li, Tetrahe-
dron Lett. 2004, 45, 7243–7246; b) a-aminoxylation: W. Wang, J.
Wang, H. Li, L.-X. Liao, Tetrahedron Lett. 2004, 45, 7235–7238, H.
SundØn, N. Dahlin, I. Ibrahem, H. Adolfsson, A. Córdova, Tetrahe-
dron Lett. 2005, 46, 3385-; c) aldol: W. Wang, H. Li, J. Wang, Tetra-
hedron Lett. 2005, 46, 5077–5079; d) Michael addition of ketones to
enones: J. Wang, H. Li, L.-S. Zu, W. Wang, Adv. Synth. Catal. 2006,
348, 413–417; e) Michael addition of aldehydes to nitroolefins: W.
Wang, J. Wang, H. Li, Angew. Chem. 2005, 117, 1393–1395; Angew.
Chem. Int. Ed. 2005, 44, 1369–1371; f) a-selenenylation: J. Wang, H.
Li, Y.-J. Mei, B. Lou, D.-G. Xu, D.-Q. Xie, H. Guo, W. Wang, J. Org.
Chem. 2005, 70, 5678–5687; g) a-sulfenylation: W. Wang, H. Li, J.
Wang, L.-X. Liao, Tetrahedron Lett. 2004, 45, 8229–8231.
(m, 6H; Ar), 6.63 (s, 1H; Ar), 4.80 (dd, 3J
CH), 4.72 (dd, 3J(H,H)=12.0 Hz, 5.5 Hz, 1H; CH), 3.88 (dd, 3J
15.0 Hz, 7.5 Hz, 1H; CH), 2.87–2.78 (m, 1H; CH), 1.05 ppm (d, 3J-
(H,H)=7.0 Hz, 3H; CH3); 13C NMR (125 MHz, 258C, CDCl3): d=202.5,
ACHTREUNG
A
ACHTREUNG
ACHTREUNG
142.1, 139.1, 136.5, 129.6, 128.1, 128.0, 75.4, 47.4, 37.5, 11.1 ppm; HRMS
(EI) calcd for [C8H10N3O3+Na]+: 219.0620; found: 219.0626; HPLC
(Chiralpak AD, iPrOH/Hexane=10:90, flow rate 1.0 mLminÀ1
, l=
254 nm): tminor =28.3 min, tmajor =22.1 min, ee=99%, d.r.=12:1 (after fur-
ther silica-gel column purification, d.r. was improved to 20:1).
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Chem. Eur. J. 2006, 12, 4321 – 4332

Organocatalysis
FULL PAPER
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Chem. Eur. J. 2006, 12, 4321 – 4332