Asymmetric conjugate addition of ketones to β-nitrostyrenes by means of 1,2-amino-alcohol-derived prolinamides as bifunctional catalysts

Article abstract of DOI:10.1002/ejoc.200700031

Different L-prolinamides 21, prepared from L-proline and chiral β-amino alcohols are active bifunctional catalysts for the direct nitro-Michael addition of ketones to β-nitrostyrenes. In particular, catalyst 21e, prepared from L-proline and (1S,2R?)-cis-1

Full text of DOI:10.1002/ejoc.200700031

FULL PAPER
DOI: 10.1002/ejoc.200700031
Asymmetric Conjugate Addition of Ketones to β-Nitrostyrenes by Means of
1,2-Amino-Alcohol-Derived Prolinamides as Bifunctional Catalysts
Diana Almasi,[a] Diego A. Alonso,*[a] Enrique Gómez-Bengoa,[b] Yvonne Nagel,[a][‡] and
¸
Carmen Nájera*[a]
Keywords: Asymmetric catalysis / Michael addition / Ketones / Amino acids
Different
L
-prolinamides 21, prepared from
L
-proline and chi-
sumed for the catalytic cycle. The stereochemical control at-
tending Michael addition reactions between ketones and ni-
trostyrenes catalyzed by prolinamide derivatives 21 has been
investigated with computational density functional methods.
Transition-state energies for the rate-limiting C–C bond-
forming step are calculated. Analysis of these structures indi-
cates that hydrogen bonding plays an important role in catal-
ysis, and that the energy barrier for Re-face attack to form
ral β-amino alcohols are active bifunctional catalysts for the
direct nitro-Michael addition of ketones to β-nitrostyrenes. In
particular, catalyst 21e, prepared from L-proline and (1S,2R)-
cis-1-amino-2-indanol, exhibits the highest catalytic per-
formance working in polar aprotic solvents such as NMP, es-
pecially in the presence of 20 mol-% of acid additives such
as p-nitrobenzoic acid or under microwave heating. High syn
diastereoselectivities (up to 94% de) and good enantio- syn-(4S,5R) products is lower than that for Si-face attack
selectivities (up to 80% ee) are obtained at room temp. More-
over, catalyst 21e can be easily recovered and reused. ESI-
MS studies are used to characterize the intermediates as-
leading to syn-(4R,5S) products.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
β-nitrostyrene with -proline (1) as the catalyst with good
yields but very low enantioselectivities (0–23% ee). A re-
lated study by Enders showed a strong solvent effect in the
reaction since in MeOH the enantioselectivity could be in-
creased to 76% for the major syn diastereomer in the reac-
tion between 3-pentanone and trans-β-nitrostyrene em-
ploying 20 mol-% of -proline as the catalyst.[7] Since these
preliminary studies, very effective catalytic systems like 2–
20[8–26] have been developed for the asymmetric Michael re-
action of ketones with nitro alkenes, and the process is gen-
erally syn-selective (Scheme 1). The best improvements to
this reaction have been mostly achieved with pyrrolidine-
based catalytic derivatives. However, chiral acyclic primary
amines such as 10, thiourea-amine bifunctional catalysts
such as 8, 12, 13, 16 and 17, and small dipeptides such as
9 (Scheme 1) have also been shown to be very effective cata-
lysts for the addition of ketones to trans-β-nitrostyrene.
Moreover, some of these catalysts have some important fea-
tures to emphasize such as bipyrrolidine 2, which is a very
active organocatalyst for the anti conjugate addition of α-
Introduction
Organocatalytic asymmetric carbon–carbon and carbon–
heteroatom bond-forming reactions have been extensively
investigated in recent years.[1] The conjugate Michael ad-
dition[2] plays a particularly important role among the nu-
merous asymmetric carbon–carbon bond-forming reactions
since it represents one of the most elegant and attractive
ways to introduce chirality into a Michael acceptor.[3] Par-
ticularly interesting and challenging is the asymmetric con-
jugate addition of a carbon nucleophile to a nitro alkene
since it represents a very useful synthetic method for the
preparation of chiral nitro alkanes with at least two vicinal
stereogenic centres in a single step. Chiral nitro alkanes are
valuable building blocks in organic synthesis because they
can be transformed into a wide variety of different func-
tional groups such as amines, ketones, carboxylic acids, ni-
trile oxides, etc.[4] Barbas[5] and List[6] independently re-
ported the first organocatalytic addition of ketones to trans-
[a] Departamento de Química Orgánica and Instituto de Síntesis hydroxy ketones to nitrostyrenes.[8] A similar sense of rela-
Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante,
tive stereoinduction has been shown by the chiral, primary,
Apdo. 99, 03080 Alicante, Spain
amine-thiourea catalysts 13[19] and 17,[23] developed by Tso-
E-mail: diego.alonso@ua.es
cnajera@ua.es
goeva and Jacobsen, respectively, in the conjugate addition
of acyclic ketones to nitro olefins giving predominantly the
anti Michael adducts due to the participation of a Z-en-
amine intermediate. Catalysts 4,[10b] 16,[22] 19[25] and 20[26]
are very effective systems with which to perform the
Michael addition under aqueous conditions such as brine
[b] Departamento de Química Orgánica I. Facultad de Química.
Universidad del País Vasco,
Apdo. 1072, 20080 San Sebastián, Spain
[‡] Undergraduate student from Albert-Ludwigs-Universität Frei-
burg, Germany
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
2328
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2328–2343

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
Scheme 1. Enantioselective conjugate addition of ketones to trans-β-nitrostyrene.
(catalyst 4) or pure water. On the other hand, the chiral
The initial aim in our organocatalysis program was to
imidazolium salt 15[21] performs much better than other design several amino-alcohol-derived organocatalysts where
chiral pyrrolidine catalysts when the reaction media is an the amide and hydroxy groups were expected to interact
ionic liquid. Furthermore, catalyst 15 and the fluorous sul- by double hydrogen bonding with the nitro group of the
fonamide 19 can be easily recycled by precipitation and electrophile in order to enhance their reactivity as depicted
fluorous solid-phase extraction, respectively, and reused in Scheme 2. A transient activation of the ketone donor
without significant loss of activity and stereoselectivity.
through the formation of an enamine on the secondary
-Prolinamide and derivatives are highly efficient cata- amino group was also anticipated.[33] In a recent prelimi-
lysts for the direct aldol reaction of aldehydes with simple nary paper[34] we indeed reported that amino-alcohol-de-
ketones in organic,[27] ionic[28] and aqueous solvents.[27n,29] rived prolinamides 21 presumably serve as bifunctional or-
This type of organocatalyst also promotes the enantioselec- ganocatalysts for Michael addition reactions between 3-
tive α-hydroxyamination reaction of α-branched aldehydes pentanone and β-nitrostyrenes with high levels of syn dia-
with good yields and moderate enantioselectivities[30] as stereoselectivity (up to 94%) and good enantioselectivities
well as the α-selenylation of aldehydes[31] and ketones[31b] (up to 80% ee) working under room temperature conditions
and the α-chlorination of aldehydes.[32]
and with polar aprotic solvents such as NMP. One of the
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2329

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
main drawbacks of these catalysts was the long reaction in Scheme 3. β-Amino alcohols employed in the prepara-
times required (4 d). Herein, the full account of our studies tion of catalysts 21i[35] and 21n[36] were synthesized accord-
aimed at improving the catalytic performance of the system ing to literature procedures from (1S,2R)-cis-1-amino-2-in-
and exploring the full scope and the mechanism of this pro- danol and (1R,E)-camphorquinone-3-oxime, respectively.
cess is described.
Very recently, Córdova has demonstrated that simple
amides derived from primary amino acids such as alanine
(see 10 in Scheme 1) efficiently catalyze the direct enantiose-
lective addition of ketones to nitrostyrenes.[16] For this
reason, catalyst 23 was also prepared from Boc--alanine
following the synthetic sequence shown in Scheme 4.
We first elucidated the parameters that could play a role
in the selectivity of the reaction. Organocatalysts (20 mol-
%) were then examined for their ability to mediate the
stereoselective Michael addition between 3-pentanone (25a,
4 mmol) and trans-β-nitrostyrene (26a, 0.4 mmol) in a typi-
cal, polar, protic solvent such as MeOH[37] (0.2 mL; 0.5 mL
of solvent/mmol of 26a) at room temp. to give syn and anti
adducts 27aa (Scheme 5 and Table 1). α-Methyl--proline
(28), trans-4-hydroxy--proline (29) and trans-4-TBDMSO-
-proline (30) were also included in the study (Figure 1).
Most of the -prolinamides exhibited high catalytic ac-
tivities for the reaction and gave the syn adduct 27aa as the
favoured product. Prolinamides 21a and 21b, derived from
1,2-diphenyl-2-aminoethanol, which have been successfully
used in the direct aldol reaction of ketones with alde-
hydes,[27a,b,e,i,q] showed good activity with high reaction
conversions, good diastereoselectivity (syn/anti of 92:8 and
85:15, respectively) and enantioselectivity (39% ee and 52%
Scheme 2. -Prolinamide-derived bifunctional organocatalysts.
Results and Discussion
Catalysts 21 were prepared in good to excellent yields
from Cbz- or Fmoc--proline or Cbz-4-hydroxy--proline
and the corresponding commercially available chiral amines
and β-amino alcohols through the reaction sequence shown
Scheme 3. Synthesis of bifunctional organocatalysts 21a–n.
2330
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2328–2343

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
Scheme 4. Synthesis of bifunctional organocatalyst 23.
Figure 1. Proline-derived organocatalysts 28–30.
ee for the major diastereomer, respectively, Table 1, Entries
1 and 2). Catalyst 21c, derived from (R)-2-phenyl-2-amino-
ethanol, with a primary alcohol, showed very high catalytic
activity and afforded, after 1 d, the Michael adduct 27aa in
high yield but with lower diastero- and enantioselectivity
(syn/anti of 83:17 and 36% ee, Table 1, Entry 3). The pres-
ence of the chiral hydroxy moiety seems to be important
for the selectivity of the process. This was further supported
by catalyst 21d, derived from 2-aminophenol, which gave a
42% ee for the syn adduct after 6 d (Table 1, Entry 4). The
reaction time decreased to 3 d, and a noticeable increase in
yield (95%) and enantioselectivity (64% ee) was obtained
with (1S,2R)-cis-1-amino-2-indanol-derived prolinamide
21e (Table 1, Entry 5). This result demonstrated that in-
creasing the conformational rigidity of the amino alcohol
moiety seemed to be beneficial for the selectivity of the pro-
cess. This was probably due to the more favoured double
hydrogen-bonding interactions of the more rigid derivative
21e with the electrophile. Diastereomeric catalysts 21e, 21j,
21l and 21m, showed very high catalytic activities in the 1,4-
addition (Table 1, Entries 5, 11, 13, and 14), the highest
enantioselectivity (64% ee) being observed with prolin-
amide 21e. This finding indicated that the (1S,2R) configura-
tion of the chiral 1-aminoindanol matched the (S)-configu-
ration of the -proline to enhance the stereochemical con-
trol of the reaction. On the other hand, catalyst ent-21e,
prepared from -proline and (1R,2S)-cis-1-amino-2-in-
danol, gave the enantiomeric (4R,5S)-syn adduct 27aa in a
62% ee (Table 1, Entry 6). This experiment also showed
that the enantioselectivity of the process was controlled by
the proline moiety since diastereomeric catalysts ent-21e
and 21l, derived from (1R,2S)-cis-1-amino-2-indanol and -
and -proline, respectively, afforded the enantiomers of the
syn adduct 27aa (Table 1, Entries 6 and 13). Catalysts 21f
and 21k, derived from -proline and (R)- and (S)-1-amino-
Scheme 5. Michael addition between 3-pentanone and trans-β-ni-
trostyrene.
Table 1. Asymmetric 1,4-addition of 3-pentanone to β-nitrosty-
rene–catalyst study.[a]
Entry
Catalyst
T [d]
Conv. [%][b]
dr[b,c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
21a
21b
21c
21d
21e
ent-21e
21f
21g
21h
21i
2
1.5
1
6
3
3
3
3
4.5
3
2
3
3
2
3
6
4
6
87
96
Ͼ99
80
95
99
92:8
85:15
83:17
89:11
93:7
91:9
91:9
87:13
85:15
88:12
88:12
82:18
92:8
39
52
36
42
64
62[e]
48
64
64
34
38
32
53
52
56
48
Ͼ99
Ͼ99
Ͼ99
Ͼ99
48
Ͼ99
Ͼ99
Ͼ99
Ͻ5
Ͻ5
Ͻ5
58
21j
21k
21l
21m
21n
23
86:14
86:14
[f]
[f]
–
–
[f]
[f]
28
–
–
[f]
[f]
29
–
–
30
4.5
9
9
81:19
90:10
90:10
89:11
38
52
58
56
21e[g]
21e[h]
21e[i]
37
98
99
3
[a] A mixture of the catalyst (20 mol-%), 3-pentanone (4 mmol) and
trans-β-nitrostyrene (0.4 mmol) were stirred in MeOH (0.2 mL) at
room temp. for the time indicated in the Table. [b] Determined by
1H NMR and/or GC analysis. [c] syn/anti ratio. [d] ee for the syn
diastereoisomer, as determined by chiral-phase HPLC analysis. [e]
The enantiomer syn-(4R,5S)-27aa was obtained. [f] Not deter-
mined. [g] 5 mol-% of 21e was used. [h] 10 mol-% of 21e was used.
[i] 15 mol-% of 21e was used.
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2331

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
indane, respectively, mediated the formation of the Michael next screened a range of solvents for the reaction catalyzed
product 27aa in lower yields (48%) and enantioselectivities by prolinamide 21e (Table 2, Entries 5–24). Bulkier, polar,
(48% and 32%, respectively, Table 1, Entries 7 and 12) than protic alcohols such as iPrOH and tBuOH were much less
the corresponding amino-alcohol-derived prolinamides 21e, effective, affording lower conversions and selectivities
21j, 21l and 21m. These results and the very low enantio- (Table 2, Entries 5–6). Non-polar solvents such as toluene
selectivity (34% ee) observed with N-methylated derivative slowed down the reaction to 8 d, affording syn-27aa in a
21i (Table 1, Entry 10) visibly showed that the presence of 56% ee (Table 2, Entry 7). Furthermore, we observed the
the hydroxy group and a hydrogen in the amide group were formation of the regioisomer 31 (Figure 2) in very low
important for a good conversion and selectivity in the 1,4- yields (8%, GC analysis), which resulted from the Michael
addition. Catalysts 21g and 21h, derived from trans--4-hy- addition to the carbon α to the nitro group. This byproduct
droxyproline, afforded levels of enantioselection similar to was not observed when polar protic solvents were used
that of the -proline derivative 21e but lower diastereoselec- (Table 2, compare Entries 1–7). The use of CHCl3 and
tivities (Table 1, Entries 8 and 9). Catalysts 21l and 21n gave CH3CN gave similar results to MeOH with respect to dia-
very similar results in terms of activity and enantio- stereo- and enantioselectivity, and the formation in small
selectivity (Table 1, Entries 13 and 15). This seemed to amounts (5%, GC analysis) of the regioisomeric compound
point to a negligible effect of the steric bulkiness of the 31 (Figure 2, Table 2, Entries 8 and 9) was again detected.
amide group of the organocatalysts in the reaction out- The employment of protic solvents seemed beneficial to
come.
avoid the formation of 31. Notably, increasing the polarity
Although amides derived from simple, primary, amino of the reaction medium with DMF provided a noticeable
acids such as alanine have been shown to efficiently catalyze
the direct enantioselective addition of ketones to nitrosty-
Table 2. Asymmetric 1,4-addition of 3-pentanone to β-nitrostyrene,
renes,[16] the -alanine amide 24 failed to give any product
catalyzed by 21eϪreaction conditions study.[a]
in the 1,4-addition of 3-pentanone to β-nitrostyrene under
Entry
Solvent
T
Conv. [%][b] dr[b,c] ee [%][d]
the tested reaction conditions (Table 1, Entry 16). Proline
has been previously shown to promote the Michael addition
of ketones to nitrostyrene in MeOH.[7] In contrast, α-
methyl--proline (28), a very efficient organocatalyst for the
intramolecular α-alkylation of aldehydes,[38] was not effec-
tive in the 1,4-addition after long reaction periods (Table 1,
Entry 17). Similar result was observed when trans-4-hy-
droxy--proline (29) was used as the promoter, probably
due to solubility problems (Table 1, Entry 18). trans-4-
TBDMSO--Proline (30) has been presented as a valid al-
ternative to proline and proline derivatives in different
asymmetric organocatalytic processes due to its high solu-
bility in organic solvents.[39] However, the catalytic activity
of 30 in the conjugate addition of 3-pentanone to nitrosty-
rene in MeOH was very low, affording 27aa in a 58% con-
version and 38% ee for the major syn isomer (Table 1, En-
try 19).
The effect of catalyst loading on the reaction efficiency
was also evaluated employing 21e. The enantioselectivity of
the process was, in general, slightly sensitive to catalyst
loading, and the best results in terms of yield and selectivity
were obtained with 20 mol-% of the catalyst, as routinely
employed (Table 1, compare Entries 5 and 20–22). In con-
clusion, the catalyst study showed prolinamide 21e was the
most selective organocatalyst in the process. It also demon-
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
MeOH
MeOH[e]
MeOH[g]
MeOH[h]
iPrOH
tBuOH
toluene
CHCl3
3 d
5 d
5 d
7 d
4 d
4 d
8 d
3 d
7 d
10 d
10 d
4 d
7 d
7 d
3 d
5 d
6 d
6 d
6 d
3 d
4 d
3 d
4 d
2.5 h
95
62
30
64
71
93:7
75:25
75:25
93:7
88:12
90:10
91:9
64
[f]
–
–
[f]
58
57
53
56
58
65
76
40
91 (8)
94 (5)
95 (5)
95 (5)
Ͻ5
90 (10)
70 (9)
95 (5)
78 (9)
76 (8)
63 (5)
95 (5)
84 (5)
95
91:9
CH3CN
DMF
90:10
92:8
DMF[i]
–
–
[f]
[f]
DMSO
DMAc
86:14
88:12
90:10
91:9
90:10
90:10
90:10
92:8
73
79
79
77
77
70
72
76
69
75
62
60
72
NMP
NMP[j]
NMP[k]
NMP/H2O[l]
NMP/H2O[m]
NMP/H2O[n]
NMP/MeOH[o]
NMP/DMSO[p]
[bmim][PF6]
–
91:9
94 (5)
90
65
86:14
87:13
87:13
90:10
NMP[q]
99
[a] A mixture of 21e (20 mol-%), 3-pentanone (4 mmol) and trans-
β-nitrostyrene (0.4 mmol) was stirred in the indicated solvent
(0.2 mL) at room temp. for the time indicated. [b] Determined by
1H NMR and/or GC analysis. The yield of compound 31 is shown
in parenthesis, as determined by GC. [c] syn/anti ratio. [d] ee for
strated that the amide and the hydroxy groups are certainly the syn diastereomer, as determined by chiral-phase HPLC analysis.
[e] 5 equiv. of ketone were used. [f] Not determined. [g] 1 equiv. of
involved in the catalysis and stereoselection of the 1,4-ad-
ketone was used. [h] 40 equiv. of ketone were used. [i] 5 mL of
dition, probably through hydrogen-bonding interactions.
DMF/mmol of 26a were used. [j] 26a was added to the reaction
Encouraged by these initial results, and due to the levels
mixture after 20 min. [k] Anhydrous NMP was used. [l] 0.5 mL of
of reaction efficiency observed with prolinamide 21e, we se-
lected this catalyst for further studies of the direct asymmet-
ric addition of ketone 25a to β-nitrostyrene 26a (Scheme 5,
catalyst = 21e and Table 2). With respect to the nucleophile
stoichiometry required for optimal results, a ten-fold excess
solvent (NMP/H2O, 1:1)/mmol of 26a were used (14 equiv. of
H2O). [m] 0.75 mL of solvent (NMP/H2O, 2:1)/mmol of 26a were
used (14 equiv. of H2O). [n] 0.6 mL of solvent (NMP/H2O, 5:1)/
mmol of 26a were used (5 equiv. of H2O). [o] 0.5 mL of solvent
(NMP/MeOH, 1:1)/mmol of 26a were used. [p] 0.5 mL of solvent
(NMP/DMSO, 1:1)/mmol of 26a were used. [q] The reaction was
of ketone gave the best results (Table 2, Entries 1–3). We performed under microwave irradiation (15 W, 48 °C).
2332 Eur. J. Org. Chem. 2007, 2328–2343
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
increase in selectivity (76% ee), and the amount of solvent The representative results are collected in Table 2, Entries
used in the process was very important, since no conversion 17–21. The study demonstrated that the best results were
was observed when 5 mL of DMF/mmol of 26a were used indeed obtained with the commercially available NMP
instead of 0.5 mL/mmol of the limiting reagent (Table 2, (0.05% H2O) which represents 0.014 mmol H2O/mmol 26a
Entries 10 and 11). Again, small amounts (5%) of 31 were (Table 2, Entry 15). Other combinations of solvents such as
detected by GC. Similar ee values were obtained for NMP/MeOH and NMP/DMSO did not improve the results
DMSO, DMAc and NMP, although the best combination (Table 2, Entries 20–21), except that the presence of MeOH
of yield, diastereo- and enantioselectivity was obtained with as cosolvent circumvented the formation of 31 (Table 2, En-
the latter solvent, though longer reaction times were re- try 20). We also tested the ionic liquid [bmim][PF6] as a
quired (Table 2, Entries 12–14).
reaction medium, but lower diastereo- and enantio-
selectivities were obtained (Table 2, Entry 22). Solventless
conditions (Table 2, Entry 23) led to the formation of 27aa
in a 65% conversion and 60% ee for the major syn isomer
(syn/anti of 87:13). Finally, a very fast reaction was achieved
under microwave irradiation (15 W, 48 °C) while good dia-
stereo- and enantioselectivities were preserved (Table 2, En-
try 24). Ultimately, 21e (20 mol-%), NMP (0.5 mL/mmol of
26a) and room temp. were established as the optimal reac-
tion conditions for the conjugate addition of 3-pentanone
(10 mmol) to trans-β-nitrostyrene (1 mmol).[40]
In order to further decrease the long reaction times, we
studied the influence of an acid as an additive in the model
reaction between 3-pentanone and trans-β-nitrostyrene
(Table 3). It has been previously demonstrated that the pres-
ence of an acidic additive in the reaction is beneficial in
terms of activity due to the acceleration of enamine forma-
tion.[27n,33,41] Thus, we started our additive study by em-
ploying substoichiometric amounts (20 mol-%) of different
organic acids (Table 3, Entries 1–10). Among the carboxylic
acids, p-nitrobenzoic acid gave the best results in terms of
rate (1 d), yield (full conversion) and selectivity (Table 3,
compare Entries 1–7). In the presence of this cocatalyst and
anhydrous NMP, the reaction rate and the enantio-
selectivity of the process were lower, which clearly demon-
strated that the water present in the commercially obtained
non-anhydrous NMP was also necessary to obtain good ac-
tivities and selectivities with an acid cocatalyst (Table 3, En-
tries 5 and 6). Interestingly, the acid additives also avoided
Figure 2. Regioisomeric product obtained in non-polar solvents.
The reaction time could be reduced from 7 d to 3 d by
adding the electrophile to the reaction mixture after stirring
the ketone and the catalyst in NMP at room temp for
20 min (Table 2, compare Entries 14 and 15). From this
point on, all subsequent experiments were performed in this
manner. The presence of water has been shown to appreci-
ably accelerate and improve the stereoselectivity in different
organocatalyzed processes by facilitating hydrogen bonding
and proton transfer. When the 21e-catalyzed reaction be-
tween 3-pentanone and β-nitrostyrene was carried out em-
ploying anhydrous NMP (Table 2, Entry 16), similar selec-
tivities were observed, but the 1,4-addition took two extra
days. This showed that the presence of small amounts of
water (H2O content in the initially employed commercial
NMP was 0.05%, Table 2, Entry 15) had a beneficial effect
on the reaction rate.
Since we had demonstrated a dramatic solvent and con-
centration effect in the reaction scope, a deep study was
then performed in NMP, varying the concentration of the
reaction and the amount of water present in the reaction.
Table 3. Asymmetric 1,4-addition of 3-pentanone to β-nitrostyrene catalyzed by 21e (additive study).[a]
Entry
Additive
T [d]
Conv. [%][b]
dr[b,c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
–
3
2
1
6
1
2
2
6
1
1
4
2
4
78
97
75
50
99
97
84
Ͻ5
65
72
91:9
95:5
90:10
97:3
95:5
94:6
93:7
77
75
75
78
78
70
76
AcOH
PhCO2H
PhCO2H[e]
4-NO2C6H4CO2H
4-NO2C6H4CO2H[f]
2,4-(NO2)2C6H3CO2H
PhSO3H
[g]
[g]
–
–
(R)-(–)-2-phenylpropionic acid
(S)-(+)-2-phenylpropionic acid
(R)-1,1Ј-bi(2-naphthol)[h]
(S)-1,1Ј-bi(2-naphthol)[i]
(S)-1,1Ј-bi(2-naphthol)[j]
93:7
93:7
90:10
93:7
91:9
76
74
74
76
73
Ͼ99
Ͼ99
99
[a] A mixture of catalyst 21e (20 mol-%), the additive (20 mol-%) and 3-pentanone (4 mmol) was stirred in NMP (0.2 mL) for 20 min at
room temp. The β-nitrostyrene (0.4 mmol) was then added to the mixture, and the reaction was stirred at room temp. for the time
1
indicated. [b] Determined by H NMR and/or GC analysis. [c] syn/anti ratio. [d] ee for the syn diastereoisomer, as determined by chiral-
phase HPLC analysis. [e] The reaction was performed at 0 °C. [f] Anhydrous NMP was used as solvent. [g] Not determined. [h] 5 mol-%
of (R)-Binol and 5 mol-% of p-nitrobenzoic acid were used. [i] 5 mol-% of (S)-Binol and 5 mol-% of p-nitrobenzoic acid were used. [j]
5 mol-% of (S)-Binol was used.
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2333

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
the formation of byproduct 31 (Figure 2). Benzenesulfonic the Michael acceptor, the corresponding Michael adduct
acid did not promote the reaction at all (Table 3, Entry 8). 27ag was obtained in 75% yield and 78% ee (Table 4, Entry
Both enantiomers of 2-phenylpropionic acid were also 7). In general, the syn diastereoselectivity was slightly
tested with the aim of detecting a possible influence of a higher when electron-poor nitrostyrenes were used (Table 4,
chiral proton source on the selectivity of the process. Unfor- Entries 5 and 6).
tunately, no improvement on the selectivity was observed
(Table 3, Entries 9 and 10). Very recently, chiral Brønsted
acid 1,1Ј-bi(2-naphthol) has been shown to improve the
enantioselectivity of the -proline-catalyzed direct aldol re-
action through hydrogen-bonding activation when used as
a chiral additive.[42] We then performed the reaction in the
presence of (R)- or (S)-1,1Ј-bi(2-naphthol) (5 mol-%), antic-
ipating a possible multicomponent chiral catalytic system
of higher efficiency. However, very similar results were ob-
tained in both cases, slightly decreasing the rate and selec-
tivity of the reaction (Table 3, Entries 11 and 12). In the
absence of acid, (S)-bi(2-napthol) (5 mol-%) did not show
any improvement (Table 3, compare Entries 12 and 13)
which indicated a negligible effect of this additive in the
reaction scope.
Scheme 6. Michael addition of ketones to β-nitrostyrenes.
Under the established best reaction conditions [21e
Next, we examined other ketone donors in the Michael
(20 mol-%) as the catalyst, p-nitrobenzoic acid (20 mol-%) reaction with trans-β-nitrostyrene (Scheme 6, Table 4). For
as an additive and NMP as the solvent at room temp.], vari- each nucleophile, a full solvent study was carried out, since
ous ketones and nitrostyrenes were evaluated as substrates we observed enormous differences in reactivity and selectiv-
(Scheme 6 and Table 4). The reaction appeared quite gene- ity depending on the solvent.[43] In Table 4, Entries 7–10,
ral with respect to the nature of the aromatic Michael ac- we have recorded the results obtained under the optimized
ceptor. Generally, good yields and good diastereo- and reaction conditions for the new ketones studied. The conju-
enantioselectivities were observed. The introduction of elec- gate addition of cyclohexanone as a Michael donor, cata-
tron-withdrawing or electron-donating groups on the aro- lyzed by 20 mol-% of 21e, proceeded with good diastereo-
matic ring of the nitrostyrene did not affect the enantio- selectivity (syn/anti of 90:10) and moderate enantio-
selectivities. Thus, 4-tolyl-, 4-chloro-, 4-methoxy- and 3,5- selectivity (65% ee) with MeCN as the solvent (Table 4, En-
dichlorosubstituted nitrostyrene derivatives gave com- try 8). Surprisingly, NMP led to a very low 16% ee. The
pounds 27ab–27ae in 64–83% yield, dr values from 91:9 to conjugate reaction between hydroxyacetone and nitrosty-
97:3 and 76% to 81% ee values in a 1.5 d reaction time rene was regioselective for all the studied reaction condi-
(Table 4, Entries 2–5). However, in the case of the 2-(trifluo- tions,[43] CH2Cl2 being the solvent which gave better results
romethyl)phenyl derivative, a 59% ee for the major dia- in terms of enantioselectivity. As depicted in the Entry 9 of
stereoisomer (syn/anti of 99:1) syn-27af was obtained Table 4, the reaction was less syn-selective than previously
(Table 4, Entry 6). When 2-chloronitrostyrene was used as observed, giving a 65:35 syn/anti with low enantioselectivit-
Table 4. Asymmetric 1,4-addition of ketones to nitrostyrenes catalyzed by 21e.[a]
Entry
R1
R2
Ar
Solvent
T [d]
Conv.
[%][b]
Product
syn/anti[c]
ee
[%][d]
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
4-MeC6H4
4-ClC6H4
4-MeOC6H4
3,5-(Cl)2C6H3
2-CF3C6H4
2-ClC6H4
MeCN
NMP
NMP
NMP
NMP
NMP
NMP
NMP
–
1
99 (76)
94 (64)
Ͼ99 (75)
86 (74)
Ͼ99 (83)
Ͼ99 (75)
Ͼ99 (75)
Ͼ99 (80)
Ͼ99 (64)
Ͼ99 (80)
27aa
27ab
27ac
27ad
27ae
27af
27ag
27ba
27ca
27da[h]
95:5
91:9
92:8
93:7
97:3
99:1
97:3
90:10
65:35
90:10
78[e]
76
79
81
78
1.5
1.5
1.5
1.5
1.5
1
1
2
1.5
59
78
–(CH2)4–
Me
Me
65[f]
41[g]
54[i]
OH
Me
Ph
Ph
CH2Cl2
DMSO
10
[a] A mixture of catalyst 21e (20 mol-%), p-nitrobenzoic acid (20 mol-%) and 3-pentanone (4 mmol) was stirred in the indicated solvent
(0.2 mL) for 20 min at room temp. The nitrostyrene (0.4 mmol) was then added to the mixture, and the reaction was stirred at room
1
temp. for the time indicated. [b] Determined by H NMR and/or GC analysis over the crude reaction mixture. The isolated yield after
1
flash chromatography for the mixture of diastereoisomers is shown in brackets. [c] Determined by H NMR and/or GC analysis of the
crude reaction mixture. [d] ee for the syn diastereoisomer, as determined by chiral-phase HPLC analysis. The absolute configuration was
not determined except for 27aa. [e] Similar results were obtained with recycled 21e (88% yield, syn/anti of 91:9, 78% ee). [f] A 16% ee
was obtained when NMP was used as the solvent. [g] 35% ee for the anti isomer. [h] syn/anti/iso of 54:6/40. [i] 5% ee for the anti isomer;
76% ee for the iso isomer.
2334
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2328–2343

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
ies for both isomers (41% ee for syn-27ca and 35% ee for pathway. The existence of the enamine intermediate I in the
anti-27ca). On the other hand, the 21e-catalyzed Michael 21e-catalyzed Michael addition of 3-pentanone to β-nitro-
addition of butanone with nitrostyrene mainly gave the iso styrene was confirmed by ESI-MS (Scheme 8, Figure 3).
isomer and moderate to good enantioselectivities,[43] giving Under the typical reaction conditions, enamine I·H+ (m/z
the best result in DMSO (Table 4, Entry 10, Scheme 7).
= 315.1) was detected after stirring the organocatalyst 21e
Scheme 7. Michael addition of butanone to trans-β-nitrostyrene.
It is worthy to mention that prolinamide catalyst 21e
could be easily recovered (80% recovery) from the reaction
mixture after an extractive acid-base workup and reused
after flash chromatography with similar results (Table 4,
Entry 1) since no loss of optical activity was detected in the
organocatalyst {[α]2D0 = –24.4 (c = 1.0, CH2Cl2)}.
With respect to the reaction mechanism, it is accepted
that when primary or secondary chiral amines are used as
organocatalysts, the reaction clearly involves an enamine (see Scheme 8).
Figure 3. ESI-MS-(+) spectra of the intermediates a) I·H+, b) II+
Scheme 8. Proposed mechanism for the 21e-catalyzed Michael addition.
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2335

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
(20 mol-%), 3-pentanone (1 mmol) and p-nitrobenzoic acid of those reactions, it was also necessary to determine the
(20 mol-%) in MeOH for 20 min (Figure 3, a). To this solu- energies of the reactant hydrogen-bond complexes formed
tion was added trans-β-nitrostyrene (0.1 mmol), and the between the enamines and 1-nitropropene.
mixture was injected after 0.2 min. The formation of inter-
mediate II (Scheme 8) was formed rapidly and was immedi-
ately detected in the mixture by ESI-MS (m/z = 464.3, Fig-
ure 3, b). This meant that enamine I attacked the electro-
phile, which was probably activated by hydrogen bonding
by the amide moiety, to give intermediate II. We could also
intercept[43] the adduct ion III·H+ (m/z = 396.2, Scheme 8),
formed by a reversible Michael addition of 21e to the elec-
trophile. The last step of the catalytic cycle involves the re-
generation of 21e by hydrolysis, facilitated by the small
amounts of water present in the solvent.
Figure 4 indicates the relationship between the ee value
of the catalyst 21e used in the Michael reaction and the ee
value of the Michael adduct 27aa. The observed linearity
suggested that the active catalyst in this process is a mono-
Figure 5. Model reaction used for the DFT computational studies.
meric species.[44] The syn diastereoselectivity and the abso-
lute configuration observed can be reasonably explained
The enamine can be found in two different conforma-
through the acyclic synclinal transition state assembly A tions, syn-34 and anti-34. For each of them, two different
proposed by Seebach,[45] assuming intramolecular hydrogen transition states exist for the approach of the nitropropene
bonding (Scheme 8).
to the diastereotopical Re and Si faces of the enamine, re-
sulting in the formation of four different transition states,
two for each enantiomer (Figure 6). The two transition
states arising from the anti enamine (TSA and TSB) can
benefit from hydrogen-bonding activation between the
amide NH and the hydroxyl group present in the prolin-
amide, and our initial hypothesis was that this interaction
might contribute to a lowering in the energy barriers, re-
sulting in faster reaction rates. Meanwhile, reaction through
syn-enamine conformations would only occur in an uncata-
lyzedway, without the help of hydrogen-bonding activation
(TSC and TSD). We located the four possible transition
Figure 4. Observation of the linear relationship between the ee of
21e and that of 27aa.
Computational Studies
To explain the predominant production of the (4S,5R)-
syn adduct, we have computationally[46] located and studied
the transition states for the formation of both enantiomers
by DFT[47] at the B3LYP/6-31G* level.[48] For computa-
tional simplicity reasons, we have chosen the unsubstituted
prolinamide 32 as a model catalyst for the reaction between
3-pentanone 25a and 1-nitropropene 33 (Figure 5). Since
the formation of the enamine and the final hydrolysis of the
Michael addition adduct are fast and have no effect on the
rate and stereoselectivity of the reaction,[49] we focused on
the study of the transition states involved in the rate-limit-
ing step, the nucleophilic attack of the enamines 34 on 1-
Figure 6. Transition-state geometries and activation energies for the
nitropropene. For the calculation of the activation barriers reaction between 25a and 32, calculated at B3LYP/6-31G* level.
2336 Eur. J. Org. Chem. 2007, 2328–2343
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Asymmetric Addition of Ketones to β-Nitrostyrenes
Table 5. Activation energies and interatomic distances for the transition states calculated at the B3LYP/6-31G* level.
FULL PAPER
Entry
Transition state
Activation energies[a]
Distances[b]
O1···H–O3
C1···C2
N1···N2
O1···H–N3
O2···H–N3
O2···H–O3
1
2
3
4
TSA
TSB
TSC
TSD
15.0
16.4
18.2
27.6
2.129
2.095
2.012
1.945
3.260
3.103
–
2.028
2.109
–
1.885
2.845
–
2.589
2.557
–
2.720
2.093
–
–
–
–
–
–
[a] Activation energies in kcal/mol calculated at the B3LYP/6-31G*+ZPVE level. [b] Distances in Å.
states and found that the lowest in energy (15.0 kcal/mol) ring. We have not included the chirality in the hydroxyeth-
corresponds to TSA, the one that leads to the experimen- ylamino group of the prolinamide. Therefore, by appropri-
tally observed syn-(4S,5R) enantiomer. According to our ate choice of the substituent and the matched relative con-
initial hypothesis, this result shows that both the amide NH figuration we can further modulate the stereoselectivity of
and the hydroxyl group in the catalyst activate the nitro the reaction.
alkene by the concurrence of up to three hydrogen bonds,
favouring the approach of the nitro alkene from the Re face
of the anti enamine. The minor enantiomer syn-(4R,5S) is
formed through a Si approach of the nitro alkene to the
Conclusions
From the studies carried out on the direct, enantioselec-
tive, conjugate addition of ketones to β-nitrostyrenes, cata-
lyzed by 1,2-amino-alcohol-derived prolinamides, we con-
cluded that these organocatalysts promote the syn-dia-
stereo- and enantioselective Michael addition of ketones to
nitrostyrenes in polar aprotic solvents such as NMP. From
a wide variety of prolinamide derivatives, the best catalyst
21e, derived from -proline and (1S,2R)-cis-1-amino-2-in-
danol, gave a diastereomeric excess of up to 94% and up to
80% ee of the syn adduct. High reaction rates could be
achieved employing acid additives such as p-nitrobenzoic
acid or under microwave irradiation conditions. Both the
amide hydrogen and the chiral hydroxy group of the cata-
lysts play an important role in the process. Furthermore,
prolinamide catalysts can be recovered and reused. From
ESI-MS experiments on the Michael reaction between 3-
pentanone and trans-β-nitrostyrene catalyzed by 21e, it was
possible to characterize all the intermediates assumed for
the catalytic cycle. Computational studies at the B3LYP/6-
31G* level have been conducted on a model reaction, con-
firming the initial hypothesis that hydrogen bonding plays
a crucial role in the activation of the nitro alkene and helps
to discriminate between the two diastereofacial approaches.
The computationally favoured transition state TSA presents
the strongest hydrogen bonds and, in accordance with the
experimental results, leads to the observed major syn-
(4S,5R) enantiomer.
anti enamine (TSB), whose activation energy is 16.4 kcal/
mol. The difference between TSA and TSB accounts for
1.4 kcal/mol, corresponding to a computed selectivity of ≈
10:1 (≈ 80% ee) in favour of the syn-(4S,5R) enantiomer.
The other two transition states (TSC and TSD) do not
show hydrogen-bonding activation. Therefore, their acti-
vation barriers are much higher than those of their acti-
vated counterparts (activation energy: TSC ϾϾ TSA and
TSD ϾϾ TSB. Interestingly, there is an inverse relationship
between the distance of the two bond-forming carbons
(C1···C2) and the reaction rate. The fastest reaction corre-
sponds to the earliest transition state TSA (δC1–C2 = 2.13 Å),
and the slowest reaction corresponds to the latest transition
state TSD (δC1–C2 = 1.94 Å).
The reasons for the observed stereoselectivity are under-
standable in view of the hydrogen-bonding differences be-
tween TSA and TSB and the data shown in Table 5. In both
cases, we can distinguish up to three hydrogen bonds (two
of them strong and one weak) between the two oxygens of
the nitro group and the amide NH and hydroxyl group in
the prolinamide. The rigidity and steric congestion of the
proline-based enamine allows for a clear differentiation in
the strength of those interactions. In TSA, one of the oxy-
gens of the nitro group (O1) is able to form two strong
hydrogen bonds with the amide NH (H–N3 2.03 Å) and
especially with the hydroxyl group (H–O3, 1.88 Å), whereas
TSB shows two relatively weaker bonds, with larger dis-
tances for O1···H–N3 (2.11 Å) and O2···H–O3 (2.09 Å). In
both cases, there is a third very weak hydrogen bond with
H-N3 (distance about 2.5 Å), but it can be considered that
this interaction is less important in the activation of the
nitro group. Finally, the distances between O2···H–O3 in
TSA and O1···H–O3 in TSB are too large (Ͼ2.7 Å) to de-
scribe them as hydrogen bonds, although they still can rep-
resent positive electrostatic interactions. These data suggest
that the difference in strength of the hydrogen bonds in TSA
and TSB is responsible for the computed facial selectivity.
Of note is that the source of the chirality in these models is
Further studies on the scope of prolinamide-derived cat-
alysts 21 in Michael and other organocatalytic asymmetric
C–C bond-forming reactions are currently underway.
Experimental Section
General: Melting points were obtained with a Reichert Thermovar
apparatus and were not corrected. IR data were collected with an
FTIR apparatus, Nicolet Impact 400D-FT, and peaks are reported
in cm–1. Specific rotations were determined at 20 °C with a Perkin–
Elmer 341 digital polarimeter. Enantiomeric excesses were deter-
only the stereogenic centre at position 2 of the pyrrolidine mined using a Shimadzu HPLC (LC-10AD pump and SPD-10a
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2337

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
detector), JASCO HPLC (PU-2089 Plus pump, MD-2010 Plus de-
tector, and an AS-2059 Plus automatic injector) or Agilent 1100
Series HPLC (G1311A Quat Pump, DAD G1315B detector and an
automatic injector). For each new compound, the wavelength of
detection, solvent mixture, flow rate, column used, retention time
and major enantiomer are stated. NMR spectra were recorded with
a Bruker AC-300 (300 MHz for H1 NMR and 75 MHz for 13C
NMR) using CDCl3 as the solvent and TMS as the internal stan-
dard unless otherwise noted; chemical shifts are given in δ (ppm)
and coupling constants (J) in Hz. Low-resolution electron impact
(EI) mass spectra were obtained at 70 eV with a Shimadzu QP-
5000 and Agilent 5973 spectrometer and DIP (Direct Insertion
Probe) mass spectra were obtained with an Agilent 5973 spectrome-
ter; fragment ions are listed with relative intensities (%) in parenthe-
sis. HRMS was performed with a Finnigan MAT 95S spectrometer.
ESI-MS experiments were carried out with an Agilent 1100 Series
LC/MSD Trap “SL” mass spectrometer equipped with an ESI
source. Analytical TLC was visualized with UV light at 254 nm.
Thin-layer chromatography was carried out on TLC aluminium
sheets with silica gel 60 F254 (Merck). For flash chromatography,
silica gel 60 (0.040–0.063 mm) was employed in a Büchi Pump sys-
tem (Controller C–610 with Module C–601). Microwave experi-
ments were performed using a CEM DISCOVER Synthesis unit.
Reactions under an inert atmosphere (argon) were performed in
oven-dried glassware, sealed with a rubber septum, using anhydrous
solvents.
1.0, MeOH); R (MeOH/EtOAc, 1:1) = 0.48. IR (KBr): ν = 3325,
˜
f
3299 (N–H, O–H), 1687 (C=O), 1044, 1024 (C–O) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.58–1.67 (m, 2 H, CH2CH2NH), 1.75–
1.85 (m, 1 H, CH2CHCO), 1.96–2.10 (m, 1 H, CH2CHCO), 2.57
(s, 2 H, OH, NH), 2.79–2.87 (dt, J = 10.3, 6.3 Hz, 1 H, CH2N),
2.93–3.01 (dt, J = 10.2, 6.7 Hz, 1 H, CH2NH), 3.72–3.77 (dd, J =
9.0, 5.3 Hz, 1 H, CHCO), 5.4 (d, J = 4.2 Hz, 1 H, CHOH), 5.25–
5.29 (dd, J = 8.6, 4.0 Hz, 1 H, PhCHNH), 6.98–7.26 (m, 10 H,
ArH), 8.43–8.46 (d, J = 8.4 Hz, 1 H, NHCO) ppm. 13C NMR
(75 MHz, CDCl3): δ = 26.1 (CH2CH2NH), 30.5 (CH2CHCO), 47.2
(CH2NH), 59.1 (NCHPh), 60.5 (CHCO), 77.5 (OCHPh), 126.7,
127.48, 127.54, 127.6, 127.8, 128.1 (ArCH), 137.5, 139.7 (ArC),
175.4 (C=O) ppm. MS: m/z (%) = 292 (4) [M – H2O]+, 290 (28),
201 (27), 194 (20), 184 (34), 183 (53), 181 (10), 180 (54), 179 (13),
178 (12), 165 (11), 156 (13), 90 (13), 89 (19), 77 (12), 70 (100).
HRMS: calcd. for C19H22N2O2 [M]+ 310.1681, [M – H2O]+
292.1565; found 292.1546.
(2S)-N-[(1R,2S)-2-Hydroxy-1,2-diphenylethyl]pyrrolidine-2-carbox-
amide (21b): White solid; m.p. 70 °C (EtOAc/MeOH). [α]2D0 = –23.8
(c = 0.52, EtOH); R (MeOH/EtOAc, 1:1) = 0.43. IR (KBr): ν =
˜
f
3325, 3299 (N–H, O–H), 1687 (C=O), 1044, 1024 (C–O) cm–1. H
1
NMR (300 MHz, CD3OD): δ = 1.79–1.95 (m, 3 H, 2 CH2CH2NH,
1 CH2CHCO), 2.21–2.39 (m, 1 H, CH2CHCO), 3.09–3.39 (m, 2 H,
CH2NH), 3.62–3.64 (m, 1 H, CHCO), 5.26 (d, J = 6.5 Hz, 1 H,
CHOH), 5.45 (d, J = 6.5 Hz, 1 H, PhCHNH), 7.56 (br. s, 10 H,
ArH) ppm. 13C NMR (75 MHz, CD3OD): δ = 26.9 (CH2CH2NH),
31.8 CH2CHCO), 47.9 (CH2NH), 59.7 (NCHPh), 61.5 (NCHCO),
77.4 (OCHPh), 128.1, 128.3, 128.6, 128.96, 128.99, 129.1, 129.2
(ArCH), 140.6, 142.7 (ArC), 176.6 (C=O) ppm. MS: m/z (%) = 292
(5) [M – H2O]+, 290 (39), 288 (15), 281 (14), 208 (11), 207 (45), 201
(35), 196 (11), 195 (11), 194 (28), 180 (61), 184 (51), 183 (75), 181
(13), 179 (24), 178 (23), 165 (23), 156 (21), 130 (10), 129 (11), 117
(19), 116 (12), 106 (11), 105 (19), 104 (19), 91 (24), 90 (20), 89 (29),
77 (23), 70 (100). HRMS: calcd. for C19H22N2O2 [M]+ 310.1681;
found 310.1661.
Typical Procedure for the Synthesis of 22 and 24: To a 0 °C solution
of the corresponding N-protected -proline derivative (Scheme 3)
or N-protected -alanine (8.0 mmol, Scheme 4) and TEA
(8.0 mmol) in THF (30 mL), was added dropwise ethyl chloro-
formate (8.0 mmol) for 15 min. After the solution was stirred at
0 °C for 30 min, the corresponding amine (8.0 mmol) was added
dropwise over 15 min. The resulting solution was stirred for 1 h at
0 °C and at room temp. for another 16 h and then heated at reflux
for 3 h. After cooling to room temp., the solution was diluted with
EtOAc. After filtration and removal the solvent under reduced
pressure, the corresponding N-protected amides 22a–n and 24 were
obtained and used in the next step without further purification.
(2S)-N-[(R)-2-Hydroxy-1-phenylethyl]pyrrolidine-2-carboxamide
(21c): White solid; m.p. 125 °C (EtOH/hexane). [α]2D0 = –86.9 (c =
1.0, CH Cl ); R (MeOH/EtOAc, 1:1) = 0.50. IR (KBr): ν = 3306
˜
2
2
f
Experimental Procedure for the Synthesis of Compound 21a: Piperi-
dine (0.56 mL, 5.64 mmol) was added to a 0 °C solution of Fmoc-
22a (1.5 g, 2.82 mmol) in CH3CN (30 mL). The resulting mixture
was maintained at 0 °C for 30 min and at room temp. for 3 h and
then concentrated. The crude residue was purified by recrystalli-
sation from EtOH to give pure 21a.
(N–H, O–H), 1648 (C=O), 1077, 1062 (C–O) cm–1 1H NMR
.
(300 MHz, CD3OD): δ = 1.67–1.84 (m, 2 H, CH2CH2NH), 1.87–
1.98 (m, 1 H, CH2CHCO), 2.01–2.22 (m, 1 H, CH2CHCO), 2.91–
3.04 (m, 2 H, CH2NH), 3.43 (br. s, 2 H, OH, NH), 3.77–3.82 (m,
3 H, 2ϫCH2OH, 1ϫCHCO), 4.97–5.03 (m, 1 H, PhCH), 7.25–
7.37 (m, 5 H, ArH), 8.30 (d, J = 7.8 Hz, 1 H, NHCO) ppm. 13C
NMR (75 MHz, CD3 OD): δ = 26.0 (CH2 CH2 NH), 30.8
(CH2CHCO), 47.1 (CH2NH), 56.1 (CHPh), 60.4 (CHCO), 66.8
(CH2OH), 126.6, 127.7, 128.7 (ArCH), 139.0 (ArC), 175.5 (C=O)
ppm. MS: m/z (%) = 216 (28) [M – H2O]+, 214 (23), 206 (19), 201
(19), 199 (17), 198 (25), 184 (16), 183 (30), 174 (59), 160 (60), 156
(10), 120 (72), 119 (27), 118 (17), 117 (13), 105 (17), 104 (100), 103
(26), 96 (10), 91 (27), 90 (16), 89 (22), 83 (11), 78 (14), 77 (22), 70
(52), 69 (14), 68 (24), 55 (10), 51 (10). C13H18N2O2 (234.29): calcd.
C 66.64, H 7.74, N 11.96, O 13.66; found C 66.65, H 7.94, N 11.84.
Typical Procedure for the Synthesis of Compounds 21b–n: Com-
pounds Cbz-22b–n (1 g), 5% Pd/C (0.1 g, 10 wt.-%) and MeOH
(30 mL) were mixed in a 100 mL, two-necked, round-bottomed
flask. After being stirred under hydrogen (1 atm) overnight, the
solution was filtered through a pad of celite. After removing the
solvent, the resulting residue was purified by recrystallisation (21b,
21c, 21d, 21e, 21g, 21i, 21j, 21l and 21m) or flash chromatography
with EtOAc (21f, 21h, 21k and 21n).
Experimental Procedure for the Synthesis of Compound 23: Boc--
alanine (440 mg, 1.25 mmol) was stirred in hydrogen chloride (4 
solution in dioxane, 5 mL) for 30 min and then extracted with
EtOAc (3ϫ15 mL). The aqueous phase was treated with 15%
NaOH until pH 10 and then extracted with EtOAc (3ϫ15 mL).
The organic layer was dried with anhydrous MgSO4, filtered, and
the solvent was evaporated at low pressure to give product 23,
(S)-N-(2-Hydroxyphenyl)pyrrolidine-2-carboxamide (21d): Yellow
solid; m.p. 170 °C (EtOH). [α]2D0 = –45.6 (c = 1.0, CH2Cl2);
R (EtOAc) = 0.22. IR (KBr): ν = 3220, 3357 (N–H, O–H), 1641
˜
f
(C=O), 1092 (C–O) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ =
1.56–1.65 (m, 2 H, CH2CH2NH), 1.73–1.84 (m, 1 H, CH2CHCO),
1.97–2.09 (m, 1 H, CH2CHCO), 2.71–2.79 (m, 1 H, CH2NH), 2.90–
2.98 (m, 1 H, CH2NH), 3.7 (dd, J = 5.2, 8.9 Hz, 1 H, CHCO),
6.71–6.86 (m, 4 H, ArH), 8.17 (d, J = 7.96 Hz, 1 H, NHCO) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 26.0 (CH2CH2NH), 30.3
1
which was pure by H NMR spectroscopy.
(2S)-N-[(1S,2R)-2-Hydroxy-1,2-diphenylethyl]pyrrolidine-2-carbox-
amide (21a): White solid; m.p. 144 °C (EtOH). [α]2D0 = –19.5 (c =
2338
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2328–2343

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
(CH2CHCO), 46.6 (CH2NH), 60.8 (CHCO), 114.5, 118.6, 119.0,
123.2 (ArCH), 126.3 (NHC), 146.0 (COH), 173.0, (C=O) ppm.
H, OH, CONH), 2.72–2.77 (m, 1 H, CH2N), 2.85–2.89 (m, 1 H,
CH2N), 2.93–2.99 (m, 1 H, CH2CHOH), 3.13–3.20 (m, 1 H,
MS: m/z (%) = 206 (2) [M]+, 70 (100). HRMS: calcd. for CH2CHOH), 4.05 (t, J = 8.3 Hz, 1 H, CHCO), 4.38 (br. s, 1 H,
C11H14N2O2 [M]+ 206.1055; found 206.1064.
OH), 4.63–4.67 (m, 1 H, CHOH), 5.33 (dd, J = 8.6, 5.1 Hz, 1 H,
CHCHN), 7.14–7.26 (m, 4 H, ArH), 8.20 (d, J = 8.4 Hz, 1 H,
NHCO) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.8, –4.7
[Si(CH3)2], 18.0 [C(CH3)3], 25.7, 25.8 [C(CH3)3], 39.6 (CH2N), 40.4
(CH2CHCO), 55.9 (CH2CHOH), 57.0 (CHCHN), 59.9 (CHCO),
73.6 (CHOH), 73.9 (CHOTBDMS), 124.2, 125.4, 127.1, 128.2
(ArCH), 140.2, 140.7 (ArC), 175.9 (C=O) ppm. MS: m/z (%) = 358
(8) [M – H2O]+, 302 (13), 301 (54), 226 (12), 210 (46), 201 (14), 200
(100), 186 (19), 173 (20), 132 (11), 131 (12), 117 (11), 116 (90), 115
(42), 81 (70), 75 (15), 73 (17), 68 (11). HRMS: calcd. for
(2S)-N-[(1S,2R)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]pyrrolidine-
2-carboxamide (21e): White solid, m.p. 169 °C (EtOAc/MeOH).
[α]2D0 = –24.6 (c = 1.0, CH2Cl2); Rf(MeOH/EtOAc, 1:1) = 0.61. IR
(KBr): ν = 3336, 3295 (N–H, O–H), 1633 (C=O), 1066, 1090 (C–
˜
O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.63–1.83 (m, 2 H,
CH2CH2NH), 1.93–2.03 (m, 1 H, CH2CHCO), 2.12–2.21 (m, 1 H,
CH2 CHCO), 2.54 (br. s, 1 H, OH), 2.81–2.98 (m, 3 H,
1 ϫ CH2CHOH, 2 ϫ CH2NH), 3.14 (dd, J = 16.5, 5.1 Hz, 1 H,
CH2CHOH), 3.77 (dd, J = 9.0, 5.3 Hz, 1 H, CHCO), 4.61 (dt, J =
5.1, 2.3 Hz, 1 H, CHOH), 5.31 (dd, J = 8.7, 4.9 Hz, 1 H, NCHCH),
7.14–7.26 (m, 4 H, ArH), 8.13 (d, J = 8.5 Hz, 1 H, NHCO) ppm.
13C NMR (75 MHz, CDCl3): δ = 26.2 (CH2CH2NH), 31.1
(CH2 CHCO), 39.6 (CH2 CHOH), 47.2 (CH2 NH), 57.0
(CHCHNH), 60.7 (CHCO), 73.6 (CHOH), 124.1, 125.3, 127.0,
128.1 (ArCH), 140.2, 140.8 (ArC), 176.2 (C=O) ppm. MS: m/z (%)
= 228 (33) [M – H2O]+, 211 (11), 210 (13), 186 (69), 173 (63), 133
(12), 132 (39), 131 (12), 130 (11), 117 (13), 116 (100), 115 (84), 103
(11), 85 (29), 77 (10), 70 (34), 68 (12). C14H18N2O2 (246.30): calcd.
C 68.27, H 7.37, N 11.37, O 12.99; found C 68.37, H 7.47, N 11.72.
C
20H32N2O3Si [M]+ 376.2182, [M – H2O]+ 358.2088; found
358.2083.
(2S)-N-[(1S,2R)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]-N-methyl-
pyrrolidine-2-carboxamide (21i): Yellow solid; m.p. 156–158 °C
(EtOAc/hexane). [α]2D0 = –29.0 (c = 1.0, CH2Cl2); Rf (MeOH) =
0.27. IR (KBr): ν = 3249, 3065 (N–H, O–H), 1628 (C=O), 1100
˜
1
(C–O) cm–1. H NMR (300 MHz, CDCl3, rotamers mixture): δ =
1.72–2.27 (m, 8 H, 4ϫCH2CH2N, 4 ϫCH2CHCO), 2.62 (s, 3 H,
CH3), 2.73 (s, 3 H, CH3) 2.80–3.09 (m, 4 H, 2 ϫ CH2CHOH,
2ϫCH2N), 3.97 (dd, J = 9.1, 6.3 Hz, 1 H, CHCO), 4.31 (t, J =
7.2 Hz, 1 H, CHCO), 4.76 (m, 2 H, CHOH), 5.30 (d, J = 7.0 Hz,
1 H, NCHCH) 5.85 (d, J = 6.9 Hz, 1 H, NCHCH), 7.19–7.35 (m,
8 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.5, 26.6
(CH2CH2N), 30.0, 30.1 (CH2CHCO), 31.3, 32.1 (CH3), 39.9, 40.1
(CH2CHOH), 47.1, 47.8 (CH2N), 58.2, 58.8 (CHCHN), 61.5, 63.5
(CHCO), 71.8, 72.4 (CHOH), 125.2, 125.4, 125.6, 125.9, 127.2,
128.7, 128.9, (ArCH), 138.0, 138.2, 141.3, 141.6 (ArC), 173.8, 176.1
(C=O) ppm. MS: m/z (%) = 242 (7) [M – H2O]+, 175 (10), 174 (81),
146 (10), 145 (13), 144 (16), 133 (17), 117 (13), 116 (78), 115 (100),
98 (16). HRMS: calcd. for C15H20N2O2 [M]+ , 260.1525,
[M – H2O]+ 242.1408; found 242.1411.
(2S)-N-[(R)-2,3-Dihydro-1H-inden-1-yl]pyrrolidine-2-carboxamide
(21f): Yellow oil; Rf(EtOAc/MeOH, 2:1) = 0.36. [α]2D0 = 23.4 (c =
1.0, CH Cl ). IR (neat): ν = 3294 (N–H), 1654 (C=O) cm–1. 1H
˜
2
2
NMR (300 MHz, CDCl3): δ = 1.67–1.85 (m, 3 H, 2ϫCH2CH2NH,
1ϫCH2CH2C), 1.97–2.26 (m, 3 H, 2ϫCH2CHCO, 1ϫCH2NH),
2.54–2.64 (m, 1 H, CH2CH2C), 2.81–3.03 (m, 4 H, 2ϫCH2CH2C,
2ϫCH2NH), 3.80 (dd, J = 9.2, 5.2 Hz, 1 H, CHCO), 5.46 (dd, J
= 16.7, 8.3 Hz, 1 H, CHNHCO), 7.17–7.26 (m, 4 H, ArH), 7.88
(d, J = 8.11 Hz, 1 H, NHCO) ppm. 13C NMR (75 MHz, CDCl3):
δ = 26.2 (CH2CH2NH), 30.2 (CH2CH2C), 31.1 (CH2CHCO), 34.1
(CH2CH2C), 47.2 (CH2NH), 53.8 (CHNHCO), 60.5 (CHCO),
123.7, 124.7, 126.7, 127.7 (ArCH), 143.2, 143.6 (ArC), 175.2 (C=O)
ppm. MS: m/z (%) = 230 (Ͻ1) [M]+, 115 (10), 70 (100). HRMS:
calcd. for C14H18N2O [M]+ 230.1419; found 230.1430.
(2S)-N-[(1R,2R)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]pyrrolidine-
2-carboxamide (21j): White solid; m.p. 165 °C (EtOAc). [α]2D0 = 78.8
(c = 1.0, CH Cl ); R (MeOH/EtOAc, 1:1) = 0.31. IR (KBr): ν =
˜
2
2
f
3384, 3292 (N–H, O–H), 1659 (C=O), 1080 (C–O) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 1.67–1.76 (m, 2 H, CH2CH2N), 1.93–2.05
(m, 1 H, CH2CHCO), 2.13–2.26 (m, 1 H, CH2CHCO), 2.50–3.50
(br. s, 1 H, OH), 2.82–3.06 (m, 3 H, 1ϫCH2CHOH, 2ϫCH2N),
3.29 (dd, J = 15.8, 7.6 Hz, 1 H, CH2CHOH), 3.85 (dd, J = 8.9,
5.2 Hz, 1 H, CHCO), 4.36 (dd, J = 15.1, 7.6 Hz, 1 H, CHOH),
5.03 (t, J = 5.5 Hz, 1 H, NCHCH), 7.22–7.28 (m, 4 H, ArH), 8.29
(br. s, 1 H, NHCO) ppm. 13C NMR (75 MHz, CDCl3): δ = 26.2
(CH2CH2N), 30.9 (CH2CHN), 38.4 (CH2CHOH), 47.3 (CH2N),
60.3 (CHCHN), 63.4 (CHCO), 81.7 (CHOH), 122.9, 125.2, 127.2,
128.5 (ArCH), 139.3, 140.6 (ArC), 178.0 (C=O) ppm. MS: m/z (%)
= 246 (Ͻ1) [M]+, 70 (100). HRMS: calcd. for C14H18N2O2
[M]+ 246.1368; found 246.1359.
(2S,4R)-N-[(1S,2R)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]-4-hy-
droxypyrrolidine-2-carboxamide (21g): Pale yellow solid; m.p.
142 °C (EtOAc); Rf (EtOAc/MeOH, 2:1) = 0.41. [α]2D0 = 15.3 (c =
1.0, MeOH). IR (KBr): ν = 3358, 3323 (N–H, O–H), 1651 (C=O),
˜
1
1097, 1060, 1039 (C–O) cm–1 . H NMR (300 MHz, CD3OD): δ =
1.78–1.86 (m, 1 H, CH2CHCO), 2.10–2.17 (m, 1 H, CH2CHCO),
2.76–2.81 (m, 3 H, 2ϫCH2NH, 1ϫCHCH2C), 3.02 (dd, J = 16.4,
5.0 Hz, 1 H, CHCH2C), 3.89 (t, J = 16.7 Hz, 1 H, CHCO), 4.24
(br. d, J = 2.5 Hz, 1 H, CH2CHCH2), 4.41 (dt, J = 5.0, 1.3 Hz, 1
H, CH2CHCH), 5.12 (d, J = 5.0 Hz, 1 H, CHCHNH), 7.01–7.13
(m, 4 H, ArH) ppm. 13C NMR (75 MHz, CD3OD): δ = 40.7
(CH2NH), 41.0 (CHCH2CH), 55.9 (CHCH2C), 58.1 (CHCHNH),
60.8 (CH2CHCO), 73.6 (CHOH), 74 (CHOH), 124.8, 126.2, 127.8,
128.9 (ArCH), 141.7, 142.3 (ArC), 177.7 (C=O) ppm. MS: m/z (%)
= 244 (Ͻ1) [M – H2O]+, 216 (24), 215 (19), 211 (24), 210 (37), 201
(10), 188 (26), 187 (75), 186 (64), 133 (20), 132 (21), 131 (11), 117
(13), 116 (100), 115 (81), 87 (13), 86 (34), 85 (28). HRMS: calcd. for
C14H18N2O3 [M]+ 262.1317, [M – 17]+ 245.1296; found 245.1293.
(2S)-N-[(S)-2,3-Dihydro-1H-inden-1-yl]pyrrolidine-2-carboxamide
(21k): Yellow oil. [α]2D0 = –76.4 (c = 1.0, CH2Cl2); Rf (EtOAc/
MeOH, 2:1) = 0.3. IR (neat): ν = 3294 (N–H), 1656 (C=O) cm–1.
˜
1 H NMR (300 MHz, CDCl 3 ) : δ = 1 . 6 5– 1 . 8 2 (m , 3 H ,
2ϫCH2CH2N, 1 ϫCH2CH2C), 1.88–1.99 (m, 1 H, CH2CHCO),
2.10–2.23 (m, 2 H, 1ϫCH2NH, 1ϫCH2CHCO), 2.53–2.64 (m, 1
H, CH2CH2C), 2.80–3.03 (m, 4 H, 2ϫCCH2CH2, 2ϫCH2N), 3.79
(dd, J = 9.0, 5.3 Hz, 1 H, CHCO), 5.42 (dd, J = 16.1, 7.9 Hz, 1 H,
CHNHCO), 7.17–7.27 (m, 4 H, ArH), 7.87 (d, J = 7.2 Hz, 1 H,
N H C O ) p p m . 1 3 C N M R ( 7 5 M H z , C D C l 3 ) : δ = 2 6 . 1
(CH2CH2CH2), 30.2 (CH2CH2C), 30.8 (CH2CHCO), 34.2
(2S,4R)-4-(tert-Butyldimethylsilyloxy)-N-[(1S,2R)-2-hydroxy-2,3-di-
hydro-1H-inden-1-yl]-pyrrolidine-2-carboxamide (21h): White solid;
m.p. 138–140 °C (EtOAc). [α]2D0 = 8.5 (c = 0.65, MeOH); Rf
(EtOAc) = 0.36. IR (KBr) ν = 3408, 3290 (N–H, O–H), 1655
˜
(C=O), 1090, 1053, (C–O) cm–1. 1H NMR (300 MHz, CDCl3): δ =
0.06, 0.08 [2s, 6 H, (CH3)2], 0.87 [s, 9 H, C(CH3)3], 1.92–2.04 (m,
1 H, CH2CHCO), 2.24–2.32 (m, 1 H, CH2CHCO), 2.45 (br. s, 2 (CH2CH2C), 47.2 (NCH2), 53.9 (CONHCH), 60.5 (CHCO), 124.0,
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2339

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
124.7, 126.6, 127.7 (ArCH), 143.3, 143.7 (ArC), 175.2 (C=O) ppm.
CH2CH2N), 1.97–2.06 (m, 1 H, CH2CHN), 2.08–2.28 (m, 1 H,
MS: m/z (%) = 230 (Ͻ1) [M]+, 115 (10), 70 (100). HRMS: calcd. CH2CHN), 1.69–2.28 (br. s, 1 H, OH), 2.81–3.05 (m, 3 H,
for C14H18N2O [M]+ 230.1419; found 230.1415.
1ϫCH2CHOH, 2ϫCH2CH2N), 3.18 (dd, J = 16.4, 5.2 Hz, 1 H,
CH2CHOH), 3.84 (dd, J = 9.1, 5.2 Hz, 1 H, CHCO), 4.65 (dt, J =
5.1, 2.3 Hz, 1 H, CHOH), 5.34 (dd, J = 8.7, 5.1 Hz, 1 H, NCHCH),
7.17–7.27 (m, 4 H, ArH), 8.15 (d, J = 7.8 Hz, 1 H, CONH) ppm.
13C NMR (75 MHz, CDCl3): δ = 26.2 (CH2 CH2N), 31.1
(CH2CHN), 39.6 (CH2CHOH), 47.2 (CH2CH2N), 57.0 (NCHCH),
60.7 (CHCO), 73.6 (CHOH), 124.1, 125.3, 127.0, 128.1 (ArCH),
140.2, 140.9 (ArC), 176.2 (C=O) ppm. MS: m/z (%) = 228 (34)
[M – H2O]+, 226 (15), 211 (11), 210 (13), 198 (17), 197 (28), 186
(67), 173 (60), 133 (12), 132 (37), 131 (26), 130 (38), 117 (13), 116
(100), 115 (94), 104 (44), 103 (21), 85 (26), 77 (16), 70 (33), 68 (13).
HRMS: calcd. for C14H18N2O2 [M]+ 246.1368; found 246.1361.
(2S)-N-[(1R,2S)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]pyrrolidine-
2-carboxamide (21l): White solid; m.p. 145 °C (EtOAc/MeOH).
[α]2D0 = –6.9 (c = 1.0, CH2Cl2); Rf (MeOH/EtOAc, 1:1) = 0.27. IR
(KBr): ν = 3302, 3190 (N–H, O–H), 1645 (C=O), 1055 (C–O) cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 1.61–1.82 (m, 2 H, CH2CH2N),
1.89–2.03 (m, 1 H, CH2CHN), 2.08–2.20 (m, 1 H, CH2CHN), 2.85
( br. s, 1 H , O H) , 2 . 8 8– 2 . 9 6 ( m , 3 H , 1 ϫ CH 2 C H O H ,
2ϫCH2CH2N), 3.13 (dd, J = 16.4, 5.1 Hz, 1 H, CH2CHOH), 3.76
(dd, J = 8.7, 5.6 Hz, 1 H, CHCO), 4.59 (dt, J = 5.4, 2.9 Hz, 1 H,
CHOH), 5.27 (dd, J = 8.3, 5.2 Hz, 1 H, NCHCH), 7.22–7.27 (m,
4 H, ArH), 7.93 (d, J = 8.1 Hz, 1 H, NHCO) ppm. 13C NMR
(75 MHz, CDCl3): δ = 26.2 (CH2CH2N), 31.1 (CH2CHN), 39.6 (2S)-2-Amino-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)pro-
(CHCH2C), 47.2 (CH2CH2N), 57.3 (CHCHN), 60.8 (CHCO2), panamide (23): Pale yellow solid; m.p. 143–144 °C (EtOAc). [α]2D0
=
73.5 (CHOH), 124.5, 125.3, 127.0, 128.2 (ArCH), 140.4, 140.8 34.0 (c = 1.0, CH2Cl2); Rf (MeOH/EtOAc, 1:1) = 0.45. IR (KBr):
(CAr), 175.9 (C=O) ppm. MS: m/z (%) = 228 (28) [M – ν = 3295 (N–H, O–H), 1641 (C=O), 1054, 1086 (C–O) cm–1. 1H
˜
H2O]+, 210 (13), 207 (11), 186 (69), 198 (15), 197 (21), 186 (58), NMR (400 Mz, CDCl3): δ = 1.37 (d, J = 6.8 Hz, 3 H, CH3), 2.21
173 (52), 133 (13), 132 (51), 131 (27), 130 (40), 117 (16), 116 (100),
115 (98), 104 (41), 103 (21), 85 (23), 78 (11), 77 (17), 70 (30), 68
(15). HRMS: calcd. for C14H18N2O2 [M]+ 246.1368, [M – H2O]+
228.1274; found 228.1248.
(br. s, 3 H, 2ϫNH2, 1ϫOH), 2.92 (dd, J = 16.4, 1.8 Hz, 1 H,
CH2), 3.14 (dd, J = 16.4, 5.3 Hz, 1 H, CH2), 3.53 (q, J = 6.8 Hz,
1 H, CHCH3), 4.58 (dt, J = 5.2, 2.5 Hz, 1 H, CHOH), 5.29 (dd, J
= 8.5, 5.2 Hz, 1 H, CHNH), 7.21–7.27 (m, 4 H, ArH), 7.75 (d, J
= 8.1 Hz, 1 H, NHCO) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.8 (CH3), 39.6 (CH2), 50.9 (CHNH2), 57.1 (CHNH), 73.5
(CHOH), 124.3, 125.2, 127.0, 128.1 (ArCH), 140.2, 140.7 (ArC),
176.6 (C=O) ppm. MS: m/z (%) = 202 (24) [M – H2O]+, 188 (13),
187 (99), 133 (12), 132 (22), 116 (68), 115 (100), 103 (10). HRMS:
calcd. for C12H16N2O2 [M]+ 220.1212; found 220.1219.
(2S)-N-[(1S,2S)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]pyrrolidine-2-
carboxamide (21m): White solid; m.p. 149–150 °C (EtOAc/MeOH).
[α]2D0 = –78.4 (c = 1.0, CH2Cl2); Rf (MeOH–EtOAc, 1:1) = 0.28. IR
(KBr): ν = 3268, 3073 (N–H, O–H), 1652 (C=O), 1085, 1064 (C–
˜
O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.71–1.89 (m, 2 H,
CH2CH2N), 1.95–2.04 (m, 1 H, CH2CHN), 2.15–2.28 (m, 1 H,
CH2CHN), 1.71–2.04 (br. s, 1 H, OH), 2.90–3.11 (m, 3 H,
1 ϫ CCH2CH, 2 ϫCH2CH2N), 3.29 (dd, J = 15.7, 7.7 Hz, 1 H,
Typical Procedure for the Michael Addition of Ketones to β-Nitro-
styrenes: A mixture of catalyst 21 (0.08 mmol), p-nitrobenzoic acid
CCH2CH), 3.84 (dd, J = 9.0, 5.3 Hz, 1 H, CHCO), 4.39 (dd, J = (0.08 mmol) and the corresponding ketone (4 mmol) in NMP
15.2, 7.9 Hz, 1 H, CHOH), 5.05 (t, J = 5.5 Hz, 1 H, NCHCH), (0.2 mL) was stirred for 20 min at 25 °C. The corresponding nitro-
7.15–7.27 (m, 4 H, ArH), 8.25 (br. s, 1 H, NHCO) ppm. 13C NMR styrene (0.4 mmol) was then added to the mixture, and the reaction
(75 MHz, CDCl3): δ = 26.3 (CH2CH2N), 30.6 (CH2CHN), 38.3 was stirred at 25 °C for the reaction time stated in Tables (Table 1–
(CHCH2C), 47.2 (CH2CH2N), 60.3 (CHCHN), 63.0 (CHCO), 81.4 Table 4). The reaction mixture was quenched with water (2 mL)
(CHOH), 122.7, 125.1, 127.1, 128.3 (ArCH), 139.4, 140.3 (ArC), and extracted with EtOAc (3 ϫ2 mL). The organic layers were
177.6 (C=O) ppm. MS: m/z (%) = 246 (Ͻ1) [M]+, 70 (100). HRMS:
washed with water (3ϫ2 mL) in order to remove NMP, dried with
anhydrous MgSO4 and filtered, and the solvent was evaporated at
low pressure to give crude products, which were purified by flash
chromatography (hexane/EtOAc, 18:1, 3.5 mL/min), giving pure
syn-27.
calcd. for C14H18N2O2 [M]+ 246.1368; found 246.1372.
(2S)-N-(3-Hydroxy-4,7,7-trimethylbicyclo[2.2.1]heptan-2-yl)pyrrol-
idine-2-carboxamide (21n): White solid; m.p. 156 °C (EtOAc). [α]2D0
= 101.5 (c = 0.3 CH2Cl2); Rf (MeOH/EtOAc, 1:1) = 0.32. IR (KBr):
ν = 3410, 3312 (N–H, O–H), 1630 (C=O), 1122, 1099 (C–O) cm–1.
Compounds 27aa,[7] 27ba,[11] 27ca,[8b] 27da,[8a] have been described
previously, and spectroscopic data were in agreement with those
published. See the supporting information for HPLC separation
˜
1H NMR (300 MHz, CDCl3): δ = 0.81 (s, 3 H, CH3CCH3), 0.92
(s, 3 H, CH3CCH3), 1.10 (s, 3 H, CH2CCH3), 1.04–1.2 (m, 2 H,
1 ϫCCH2CH2, 1ϫCCH2CH2), 1.45–1.53 (m, 1 H, CCH2CH2), conditions.
1.63–1.80 (m, 3 H, 1ϫCCH2CH2, 2ϫCH2CH2CH2), 1.87–2.05
syn-4-Methyl-6-nitro-5-p-tolylhexan-3-one (27ab): Colourless oil.
(m, 1 H, NCHCH2), 2.07–2.21 (m, 4 H, 2ϫNCHCH2, 1ϫOH,
1ϫNHCHCH), 2.87–3.04 (m, 2 H, CH2NH), 3.67–3.73 (m, 2 H,
1ϫNCHCH2, 1ϫNCHCH), 3.85 (d, J = 8.1 Hz, 1 H, CHOH),
7.98 (br. s, 1 H, CONH) ppm. 13C NMR (75 MHz, CDCl3): δ =
11.2, 20.8, 21.3 (CH3), 26.2, 26.3 (CCH2CH2, CH2CH2CH2), 31.1
(NCHCH2), 33.4 (CCH2CH2), 47.1 (CH3CCH3), 47.3 (CH2N),
49.1 (CH2CCH3), 50.1 (CHCH3), 57.9, 60.5 (NHCH), 80.6
(CHOH), 175.5 (C=O) ppm. MS: m/z (%) = 266 (Ͻ1) [M]+, 70
(100). HRMS: calcd. for C1 5 H2 6 N2 O2 [M]+ 266.1994,
[M – H2O]+ 248.1878; found 248.1848.
[α]2D0 = 14.8 (c = 1.0, CH2Cl2) for 74% ee; Rf (hexane/EtOAc, 5:1)
= 0.39. IR (neat): ν = 1552 (NO ), 1704 (C=O) cm–1. 1H NMR
˜
2
(400 MHz, CDCl3): δ = 0.96 (d, J = 7.3 Hz, 3 H, CH3CH), 1.07 (t,
J = 7.3 Hz, 3 H, CH3CH2), 2.31 (s, 3 H, CH3Ar), 2.41 (dq, J =
18.2, 7.3 Hz, 1 H, CH2CH3), 2.61 (dq, J = 17.9, 7.1 Hz, 1 H,
CH2CH3), 2.93–3.00 (m, 1 H, CHCH3), 3.65 (dt, J = 9.3, 5.0 Hz,
1 H, CHAr), 4.57 (dd, J = 12.4, 4.8 Hz, 1 H, CH2NO2), 4.64 (dd,
J = 12.4, 9.1 Hz, 1 H, CH2NO2), 7.04 (d, J = 8.1 Hz, 2 H, ArH),
7.12 (dd, J = 7.8 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz,
CDCl3): δ = 7.6 (CH3CH2), 16.2 (CH3CH), 21 (CH3Ar), 35.4
(CH2CO), 45.7 (CHAr), 48.3 (CHCO), 78.4 (CH2NO2), 127.7,
129.6 (ArCH), 134.4, 137.6 (ArC), 213.7 (C=O) ppm. MS: m/z (%)
= 249 (Ͻ1) [M]+, 202 (13), 187 (17), 173 (67), 146 (13), 145 (18),
(2R)-N-[(1R,2S)-2,3-Dihydro-2-hydroxy-1H-inden-1-yl]pyrrolidine-
2-carboxamide (ent-21e): White solid; m.p. 169 °C (EtOAc/MeOH).
[α]2D0 = 24.6 (c = 1.0, CH2Cl2); Rf (MeOH/EtOAc, 1:1) = 0.61. IR
(KBr): ν = 3336, 3295 (N–H, O–H), 1633 (C=O), 1066, 1090 (C– 132 (14), 131 (19), 118 (42), 117 (30), 115 (17), 105 (15), 91 (17),
˜
O) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.69–1.86 (m, 2 H,
57 (100). HRMS: calcd. for C14H19NO3 [M]+ 249.1365; found
2340
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2328–2343

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
249.1356; HPLC: (Chiralcel OD-H, 1 mL/min, hexane/iPrOH:
99:1, 254 nm) tRmaj = 13.3 min, tRmin = 17.7 min.
J = 11.8, 4.0 Hz, 1 H, CH2NO2), 4.82 (dd, J = 11.8, 6.7 Hz, 1 H,
CH2NO2), 7.28 (d, J = 7.8 Hz, 1 H, ArH), 7.41 (t, J = 7.6 Hz, 1
H, ArH), 7.54 (t, J = 7.5 Hz, 1 H, ArH), 7.72 (d, J = 7.8 Hz, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 7.5 (CH3CH2), 16.4
(CH3CH), 35.4 (CH2CO), 40.8 (CHAr), 47.7 (CHCO), 77.9
(CH2NO2), 122.3 (CF3), 125.9 (ArC), 126.7, 127.8 (ArCH), 129.3
(ArC), 132.4 (ArCH), 136.8 (ArC), 213.3 (C=O) ppm. MS:
m/z (%) = 303 (Ͻ3) [M – CH3CH2]+, 199 (42), 186 (17), 178 (11),
159 (13), 151 (10), 57 (100). HRMS: calcd. for C14H16F3NO3
[M]+ 303.1082, [M – CH3CH2]+ 274.0686; found 274.0710; HPLC:
syn-5-(4-Chlorophenyl)-4-methyl-6-nitrohexan-3-one (27ac): Colour-
less oil. [α]2D0 = 5.7 (c = 1.0, CH2Cl2) for 78% ee; Rf (hexane/EtOAc,
5:1) = 0.2. IR (neat): ν = 1553 (NO ), 1711 (C=O) cm–1. 1H NMR
˜
2
(400 MHz, CDCl3): δ = 0.96 (d, J = 7.1 Hz, 3 H, CH3CH), 1.07 (t,
J = 7.1 Hz, 3 H, CH3CH2), 2.41 (dq, J = 17.9, 7.1 Hz, 1 H,
CH2CH3), 2.62 (dq, J = 17.9, 7.1 Hz, 1 H, CH2CH3), 2.95 (dq, J
= 9.3, 7.2 Hz, 1 H, CHCH3), 3.69 (dt, J = 9.3, 4.9 Hz, 1 H, CHAr),
4.58 (dd, J = 12.4, 4.8 Hz, 1 H, CH2NO2), 4.64 (dd, J = 12.4,
9.0 Hz, 1 H, CH2NO2), 7.11 (d, J = 8.3 Hz, 2 H, ArH), 7.31 (dd,
J = 6.6 Hz, 2 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ =
7.6 (CH3CH2), 16.2 (CH3CH), 35.4 (CH2CO), 45.4 (CHAr), 48.1
(CHCO), 78.0 (CH2NO2), 129.2, 129.3 (ArCH), 133.8, 136.0
(ArC), 213.1 (C=O) ppm. MS: m/z (%) = 269 (Ͻ1) [M – CH3CH2]+,
193 (19), 138 (18), 115 (10), 57 (100). HRMS: calcd. for
C13H16ClNO3 [M]+ 269.0819, [M – NO2]+ 223.0884; found
223.0874; HPLC: (Chiralcel OD-H, 1 mL/min, hexane/iPrOH:
99:1, 254 nm) tRmaj = 22.6 min, tRmin = 25.8 min.
(Chiralcel OD-H, 1 mL/min, hexane/iPrOH 99:1, 254 nm) tRmaj
8.8 min, tRmin = 11.5 min.
=
syn-5-(2-Chlorophenyl)-4-methyl-6-nitrohexan-3-one (27ag):
Colourless oil. [α]2D0 = 21.5 (c = 1.0, CH2Cl2) for 78% ee; Rf (hex-
ane/EtOAc, 5:1) = 0.4; IR (neat): ν = 1557 (NO ), 1713 (C=O)
˜
2
cm–1. H NMR (400 MHz, CDCl3): δ = 1.02 (d, J = 7.2 Hz, 3 H,
1
CH3CH), 1.06 (t, J = 7.2 Hz, 3 H, CH3CH2), 2.38 (dq, J = 17.9,
7.2 Hz, 1 H, CH2CH3), 2.62 (dq, J = 17.9, 7.2 Hz, 1 H, CH2CH3),
3.16–3.24 (m, 1 H, CHCH3), 4.30 (dt, J = 9.2, 4.4 Hz, 1 H, CHAr),
4.63 (dd, J = 12.7, 4.4 Hz, 1 H, CH2NO2), 4.85 (dd, J = 12.7,
8.8 Hz, 1 H, CH2NO2), 7.15–7.27 (m, 3 H, ArH), 7.41 (d, J =
9.4 Hz, 1 H, ArH) ppm. 13C NMR (100 MHz, CDCl3): δ = 7.6
(CH3CH2), 16.1 (CH3CH), 35.5 (CH2CO), 42.1 (ArCH), 46.9
(CHCO), 76.6 (CH2NO2), 127.3, 128.9, 128.5, 130.4 (ArCH),
134.5, 135.1 (ArC), 213.3 (C=O) ppm. MS: m/z (%) = 234 (54)
[M – Cl]+, 167 (11), 165 (30), 152 (22), 138 (13), 131 (10), 130 (15),
129 (12), 125 (15), 115 (17), 103 (14), 57 (100). HRMS: calcd. for
C13H16ClNO3 [M]+ 269.0819, [M – Cl]+ 234.1125; found 234.1151;
HPLC: (Chiralcel OD-H, 1 mL/min, hexane/iPrOH 99:1, 210 nm)
tRmaj = 11.2 min, tRmin = 14.3 min.
syn-5-(4-Methoxyphenyl)-4-methyl-6-nitrohexan-3-one (27ad):
White solid; m.p. 124 °C (EtOAc/pentane). [α]2D0 = –10.1 (c = 1.0,
CH Cl ) for 73% ee; R (hexane/EtOAc, 5:1) = 0.29. IR (KBr): ν
˜
2
2
f
= 1245 (Ar–O–C), 1552 (NO2), 1705 (C=O) cm–1 1H NMR
.
(300 MHz, CDCl3): δ = 1.38 (d, J = 7.2 Hz, 3 H, CH3CH), 1.48 (t,
J = 7.3 Hz, 3 H, CH3CH2), 2.83 (dq, J = 18.0, 7.2 Hz, 1 H,
CH2CH3), 3.03 (dq, J = 18.1, 7.2 Hz, 1 H, CH2CH3), 3.37 (dq, J
= 9.5, 7.2 Hz, 1 H, CHCH3), 4.06 (dt, J = 9.0, 5.1 Hz, 1 H, CHAr),
4.2 (s, 3 H, OCH3) 4.95–5.08 (m, 2 H, CH2NO2), 7.27 (d, J =
8.6 Hz, 2 H, ArH), 7.49 (d, J = 8.6 Hz, 2 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 7.6 (CH3CH2), 16.2 (CH3CH), 35.4
(CH2CO), 45.3 (CHAr), 48.5 (CHCO) 55.2 (OCH3), 78.5
(CH2NO2), 114.3, 128.9 (ArCH), 129.4, 159.1 (ArC), 213.7 (C=O)
ppm. MS: m/z (%) = 265 (4) [M]+, 218 (26), 203 (17), 189 (52), 162
(11), 161 (10), 135 (13), 134 (100), 121 (10), 119 (11), 91 (14), 57
(77). C14H19NO4 (265.31): calcd. C 63.38, H 7.22, N 5.28, O 24.12;
found C 63.26, H 7.34, N 5.27. HPLC: (Chiralcel OD-H, 1 mL/
4-Methyl-5-nitro-6-phenylhexan-3-one (31): Yellow oil; Rf (hexane/
EtOAc, 6:1) = 0.49. IR (neat): ν = 1558 (NO ), 1714 (C=O) cm–1.
˜
2
1H NMR (300 MHz, CDCl3): δ = 1.06 (t, J = 7.3 Hz, 3 H,
CH3CH2), 1.18 (d, J = 7.0 Hz, 3 H, CH3CH), 2.30–2.46 (m, 3 H,
2ϫCH2Ph, 1ϫCHCH3), 2.50–2.68 (m, 2 H, CH2CH3), 5.45 (t, J
= 7.64 Hz, 1 H, CHNO2), 7.36–7.47 (m, 5 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 7.7 (CH3CH2), 17.8 (CH3CH), 34.8 (CH2),
36.5 (CH2), 42.6 (CHCO), 89.8 (CH2NO2), 127.6, 129.0, 129.9
(ArCH), 134.3 (ArC), 213.4 (C=O) ppm. MS: m/z (%) = 207 (Ͻ1)
[M – H2O]+, 189 (46), 131 (58), 117 (14), 115 (2), 114 (11), 91 (13),
57 (34). HRMS: calcd. for C13H17NO3 [M]+ 235.1208, [M –
NO2]+ 189.1274; found 189.1265.
min, hexane/iPrOH 99:1, 254 nm) tRmaj = 21.4 min, tRmin
=
27.4 min.
syn-5-(3,5-Dichlorophenyl)-4-methyl-6-nitrohexan-3-one (27ae): Yel-
low oil. [α]2D0 = –24.4 (c = 1.0, CH2Cl2) for 72% ee; Rf (hexane/
EtOAc, 5:1) = 0.31. IR (neat): ν = 1556 (NO ), 1712 (C=O) cm–1.
˜
2
1H NMR (300 MHz, CDCl3): δ = 1.02 (d, J = 7.2 Hz, 3 H,
CH3CH), 1.06 (t, J = 7.2 Hz, 3 H, CH3CH2), 2.39 (dq, J = 18.1,
7.2 Hz, 1 H, CH2CH3), 2.64 (dq, J = 18.1, 7.2 Hz, 1 H, CH2CH3),
3.10–3.20 (m, 1 H, CHCH3), 4.24 (dt, J = 9.0, 4.2 Hz, 1 H, CHAr),
4.61 (dd, J = 12.8, 4.2 Hz, 1 H, CH2NO2), 4.82 (dd, J = 12.8,
8.7 Hz, 1 H, CH2NO2), 7.11 (d, J = 8.4 Hz, 1 H, ArH), 7.22–7.27
(m, 1 H, ArH), 7.44 (d, J = 2.2 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 7.6 (CH3CH2), 16.1 (CH3CH), 35.5
(CH2CO), 41.7 (CHAr), 46.8 (CHCO), 76.4 (CH2NO2), 127.7,
129.4, 130.2 (ArCH), 133.8, 134.2, 135.2 (ArC), 213.0 (C=O) ppm.
MS: m/z (%) = 303 (Ͻ1) [M]+, 261 (14), 199 (11), 186 (11), 172
(11), 57 (100). HRMS: calcd. for C13H15Cl2NO3 [M]+ 303.0429;
found 303.0421; HPLC: (Chiralcel OD-H, 1 mL/min, hexane/
iPrOH 99:1, 254 nm) tRmaj = 13.9 min, tRmin = 17 min.
Supporting Information (see also the footnote on the first page of
this article): Typical procedure for the Michael addition under mi-
crowave irradiation and solvent screening for the Michael addition
of ketones 25b, 25c and 25d to β-nitrostyrene. Typical procedure
for the recovery of catalyst 21e and ESI-MS (+) experiments and
spectra. Cartesian coordinates for transition states and reactant
complexes and HPLC separation conditions are included.
Acknowledgments
This work has been supported by the Dirección General de In-
vestigación of the Ministerio de Educación y Ciencia (CTQ2004-
00808/BQU), by the Generalitat Valenciana (CTIOIB/2002/320,
GRUPOS03/134, GRUPOS05/11 and GV05/157) and the Univer-
sity of Alicante. D. A. thanks the Ministerio de Educación y Cien-
syn-4-Methyl-6-nitro-5-[2-(trifluoromethyl)phenyl]hexan-3-one
(27af): Yellow oil. [α]2D0 = –4.5 (c = 1.0, CH2Cl2) for 50% ee; Rf
(hexane/EtOAc, 5:1) = 0.25. IR (neat): ν = 1556 (NO ), 1713 (C=O)
˜
2
cm–1. H NMR (300 MHz, CDCl3): δ = 0.97 (d, J = 7.2 Hz, 3 H,
1
CH3CH), 1.09 (t, J = 7.3 Hz, 3 H, CH3CH2), 2.48 (dq, J = 18.1, cia for a predoctoral fellowship. We also thank SGI/IZO-SGIker
7.3 Hz, 1 H, CH2CH3), 2.67 (dq, J = 18.1, 7.2 Hz, 1 H, CH2CH3), UPV/EHU for allocation of computational resources and Dr.
3.21–3.31 (m, 1 H, CHCH3), 4.06–4.15 (m, 1 H, CHAr), 4.58 (dd, Pablo Candela for ESI-MS measurements.
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2341

D. Almasi, D. A. Alonso, E. Gómez-Bengoa, Y. Nagel, C. Nájera
¸
FULL PAPER
5263; b) Z. Tang, F. Jiang, X. Cui, L.-Z. Gong, A.-Q. Mi, Y.-
Z. Jiang, Y.-D. Wu, Proc. Natl. Acad. Sci. USA 2004, 101,
5755–5760; c) Z. Tang, Z.-H. Yang, L.-F. Cun, L.-Z. Gong,
A.-Q. Mi, Y.-Z. Jiang, Org. Lett. 2004, 6, 2285–2287; d) S. Tan-
imori, T. Naka, M. Kirihata, Synth. Commun. 2004, 34, 4043–
4048; e) Z. Tang, Z.-H. Yang, X.-H. Cheng, L.-F. Cun, A.-Q.
Mi, Y.-Z. Jiang, L.-Z. Gong, J. Am. Chem. Soc. 2005, 127,
9285–9289; f) J.-R. Chen, H.-H. Lu, X.-Y. Li, L. Cheng, J.
Wan, W.-J. Xiao, Org. Lett. 2005, 7, 4543–4545; g) D. Gryko,
R. Lipin´ski, Adv. Synth. Catal. 2005, 347, 1948–1952; h) S.
Samanta, J. Liu, R. Dodda, C.-G. Zhao, Org. Lett. 2005, 7,
5321–5323; i) L. He, Z. Tang, L. F. Cun, A.-Q. Mi, Y.-Z. Jiang,
L. Z. Gong, Tetrahedron 2006, 62, 346–351; j) M. Jiang, S.-F.
Zhu, Y. Yang, L.-Z. Gong, X.-G. Zhou, Q.-L. Zhou, Tetrahe-
dron: Asymmetry 2006, 17, 384–387; k) Z. Tang, L.-F. Cun, X.
Cui, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, Org. Lett. 2006, 8,
1263–1266; l) G. Guillena, M. C. Hita, C. Nájera, Tetrahedron:
Asymmetry 2006, 17, 729–733; m) G. Guillena, M. C. Hita, C.
Nájera, Tetrahedron: Asymmetry 2006, 17, 1027–1031; n) G.
Guillena, M. C. Hita, C. Nájera, Tetrahedron: Asymmetry
2006, 17, 1493–1497; o) D. Gryko, B. Kowalczyk, L. Zawadzki,
Synlett 2006, 1059–1062; p) S. Samanta, C.-G. Zhao, J. Am.
Chem. Soc. 2006, 128, 7442–7443; q) M. Raj, V. S. K. Ginotra,
V. K. Singh, Org. Lett. 2006, 8, 4097–4099; r) J.-R. Chen, X.-
Y. Li, X.-N. Xing, W.-J. Xiao, J. Org. Chem. 2006, 71, 8198–
8202.
[1] a) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2001, 40,
3726–3748; b) B. List, Tetrahedron 2002, 58, 5573–5590; c)
R. O. Duthaler, Angew. Chem. Int. Ed. 2003, 42, 975–978; d)
Acc. Chem. Res. 2004, 37 (8), special issue on organocatalysis;
e) P. I. Dalko, L. Moisan, Angew. Chem. Int. Ed. 2004, 43,
5138–5175; f) A. Berkessel, H. Gröger, in Asymmetric Organ-
ocatalysis: From Biomimetic Concepts to Applications in Asym-
metric Synthesis, Wiley-VCH, Weinheim, 2004; g) P. M. Pihko,
Angew. Chem. Int. Ed. 2004, 43, 2062–2064; h) J. Seayad, B.
List, Org. Biomol. Chem. 2005, 3, 719–724; i) Tetrahedron 2006,
62 (2–3), Tetrahedron Symposium-in-Print on Organocatalysis
in Organic Synthesis.
[2] A. Perlmutter, Conjugative Additions in Organic Synthesis, Per-
gamon Press, Oxford, 1992.
[3] For reviews on catalytic asymmetric Michael additions, see: a)
M. P. Sibi, S. Manyem, Tetrahedron 2000, 56, 8033–8061; b) N.
Krause, A. Hoffmann-Röder, Synthesis 2001, 171–196; c) S. C.
Jha, N. N. Joshi, Arkivoc 2002, vii, 167–196; d) R. Ballini, G.
Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev. 2005,
105, 933–972; e) D. Almasi, D. A. Alonso, C. Nájera, Tetrahe-
¸
dron: Asymmetry 2007, 18, 299–365.
[4] a) N. Ono, The Nitro Group in Organic Synthesis Wiley-VCH:
New York, 2001; b) O. M. Berner, L. Tedeschi, D. Enders, Eur.
J. Org. Chem. 2002, 1877–1894.
[5] K. Sakthivel, W. Notz, T. Bui, C. F. Barbas III, J. Am. Chem.
Soc. 2001, 123, 5260–5267.
[28]
[29]
[30]
[31]
H.-M. Guo, L.-F. Cun, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang,
Chem. Commun. 2005, 1450–1452.
S. S. Chimni, D. Mahajan, V. V. S. Babu, Tetrahedron Lett.
2005, 46, 5617–5619.
H.-M. Guo, L. Cheng, L.-F. Cun, L.-Z. Gong, A.-Q. Mi, Y.-
[6] B. List, P. Pojarliev, H. J. Martin, Org. Lett. 2001, 3, 2423–
2425.
[7] D. Enders, A. Seki, Synlett 2002, 26–28.
[8] a) O. Andrey, A. Alexakis, A. Tomassini, G. Bernardinelli, Adv.
Synth. Catal. 2004, 346, 1147–1168; b) O. Andrey, A. Alexakis,
G. Bernardinelli, Org. Lett. 2003, 5, 2559–2561.
[9] T. Ishii, S. Fujioka, Y. Sekiguchi, H. Kotsuki, J. Am. Chem.
Soc. 2004, 126, 9558–9559.
Z. Jiang, Chem. Commun. 2006, 429–431.
a) W. Wang, J. Wang, H. Li, Org. Lett. 2004, 6, 2817–2820; b)
J. Wang, H. Li, Y. Mei, B. Lou, D. Xu, D. Xie, H. Guo, W.
Wang, J. Org. Chem. 2005, 70, 5678–5687.
[10] a) J. M. Betancort, K. Sakthivel, R. Thayumanavan, F.
Tanaka, C. F. Barbas III, Synthesis 2004, 1509–1521; b) N.
Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F.
Barbas III, J. Am. Chem. Soc. 2006, 128, 4966–4967.
[11] A. J. A. Cobb, D. M. Shaw, D. A. Longbottom, J. B. Gold, S. V.
Ley, Org. Biomol. Chem. 2005, 3, 84–96.
[32]
[33]
N. Halland, A. Braunton, S. Bachmann, M. Marigo, K. A.
Jørgensen, J. Am. Chem. Soc. 2004, 126, 4790–4791.
a) J. Hine, Acc. Chem. Res. 1978, 11, 1–7; b) J. Hine, Y. Chou,
J. Org. Chem. 1981, 46, 649–652; c) S. Saito, H. Yamamoto,
Acc. Chem. Res. 2004, 37, 570–579.
[34]
[35]
D. Almasi, D. A. Alonso, C. Nájera, Tetrahedron: Asymmetry
¸
[12] C. E. T. Mitchell, A. J. A. Cobb, S. V. Ley, Synlett 2005, 611–
2006, 17, 2064–2068.
614.
Z. J. Song, M. Zhao, R. Desmond, P. Devine, D. M. Tschaen,
R. Tillyer, L. Frey, R. Heid, F. Xu, B. Foster, J. Li, R. Reamer,
R. Volante, E. J. J. Grabowski, U. H. Dolling, P. J. Reider, S.
Okada, Y. Kato, E. Mano, J. Org. Chem. 1999, 64, 9658–9667.
[13] D. Terakado, M. Takano, T. Oriyama, Chem. Lett. 2005, 34,
962–963.
[14] S. B. Tsogoeva, D. A. Yalalov, M. J. Hateley, C. Weckbecker,
K. Huthmacher, Eur. J. Org. Chem. 2005, 4995–5000.
[15] Y. Xu, W. Zou, H. Sundén, I. Ibrahem, A. Córdova, Adv.
Synth. Catal. 2006, 348, 418–424.
[16] Y. Xu, A. Córdova, Chem. Commun. 2006, 460–462.
[17] M.-K. Zhu, L. F. Cun, A.-Q. Mi, Y.-Z. Jiang, L.-Z. Gong, Tet-
rahedron: Asymmetry 2006, 17, 491–493.
[18] D. A. Yalalov, S. B. Tsogoeva, S. Schmatz, Adv. Synth. Catal.
2006, 348, 826–, 832.
[19] S. B. Tsogoeva, S. Wei, Chem. Commun. 2006, 1451–1453.
[20] J. Wang, H. Li, B. Lou, L. Zu, H. Guo, W. Wang, Chem. Eur.
J. 2006, 12, 4321–, 4332.
[21] S. Luo, X. Mi, L. Zhang, S. Liu, H. Xu, J.-P. Cheng, Angew.
Chem. Int. Ed. 2006, 45, 3093–3097.
[36]
[37]
R. E. Gawley, P. Zhang, J. Org. Chem. 1996, 61, 8103–8112.
Alcoholic solvents have been previously shown to be very effec-
tive for the organocatalytic addition of ketones to nitro olefins,
see ref.[7]
[38]
[39]
N. Vignola, B. List, J. Am. Chem. Soc. 2004, 126, 450–451.
For the asymmetric α-aminoxylation, O-nitroso-aldol/Michael
and Mannich reactions with carbonyl compounds, see: a) Y.
Hayashi, J. Yamaguchi, K. Hibino, T. Sumiya, T. Urushima,
M. Shoji, D. Hashizume, H. Koshino, Adv. Synth. Catal. 2004,
346, 1435–1439; For the asymmetric Michael reaction of alde-
hydes and nitro alkanes, see: b) Y. Hayashi, H. Gotoh, T. Haya-
shi, M. Shoji, Angew. Chem. Int. Ed. 2005, 44, 4212–4215; For
the asymmetric Mannich reaction, see: c) D. Enders, C. Gron-
dal, M. Vrettou, G. Raabe, Angew. Chem. Int. Ed. 2005, 44,
4079–4083; For the α-fluorination of aldehydes and ketones,
see: d) D. Enders, M. R. M. Hüttl, Synlett 2005, 991–993; For
the asymmetric aldol reaction in the synthesis of carbohydrates,
see: e) C. Grondal, D. Enders, Tetrahedron 2006, 62, 329–337.
[22] C.-L. Cao, M.-C. Ye, X.-L. Sun, Y. Tang, Org. Lett. 2006, 8,
2901–2904.
[23] H. Huang, E. N. Jacobsen, J. Am. Chem. Soc. 2006, 128, 7170–
7171.
[24] S. V. Pansare, K. J. Pandya, J. Am. Chem. Soc. 2006, 128, 9624–
9625.
[25]
[26]
L. Zu, J. Wang, H. Li, W. Wang, Org. Lett. 2006, 8, 3077–3079.
S. Luo, X. Mi, S. Liu, H. Xu, J.-P. Cheng, Chem. Commun.
2006, 3687–3689.
a) Z. Tang, F. Jiang, L.-T. Yu, X. Cui, L.-Z. Gong, A.-Q. Mi,
Y.-Z. Jiang, Y.-D. Wu, J. Am. Chem. Soc. 2003, 125, 5262–
[40]
At this point, catalysts 21f and 21g were also tested in order
to confirm 21e as the best choice. Compound 21f gave a 65%
yield, a syn/anti of 84:14 and a 74% ee after a 6 d reaction,
whereas 21g gave a 45% yield, a syn/anti of 80:20 and a 78%
ee after a 7 d reaction.
[27]
2342
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2328–2343

Asymmetric Addition of Ketones to β-Nitrostyrenes
FULL PAPER
[41] a) M. E. Kuehne, J. Am. Chem. Soc. 1959, 81, 5400–5404; b)
T. A. Spencer, H. S. Neel, D. C. Ward, K. L. Williamson, J.
Org. Chem. 1966, 31, 434–436; c) R. B. Woodward, Pure Appl.
Chem. 1968, 17, 519–547; d) Z. G. Hajos, D. R. Parrosh, J. Org.
Chem. 1974, 39, 1612–1615.
Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morokuma, G. A.
Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzewski, S. Dap-
prich, A. D. Daniels, M. C. Strain, O. Farkas, D. K. Malick,
A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V. Ortiz, Q.
Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B. Stefanov,
G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L. Martin,
D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A. Nanayak-
kara, M. Challacombe, P. M. W. Gill, B. Johnson, W. Chen,
M. W. Wong, C. Gonzalez, and J. A. Pople, GAUSSIAN 03,
Revision C.02, Gaussian, Inc., Wallingford CT, 2004.
[47] R. G. Parr, W. Yang, in Density-Functional Theory of Atoms
and Molecules, Oxford, New York, 1989.
[48] a) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–
789; b) A. D. Becke, Phys. Rev. A 1988, 38, 3098–3100; c) A. D.
Becke, J. Chem. Phys. 1993, 98, 5648–5652; d) W. Kohn, A. D.
Becke, R. G. Parr, J. Phys. Chem. 1996, 100, 12974–12980.
[49] J. L. Reymond, J. Mol. Catal. B 1998, 5, 331–337; see also
ref.[21]
[42] Y. Zhou, Z. Shah, Tetrahedron: Asymmetry 2006, 17, 1671–
1677.
[43] See the supporting information.
[44] C. Girard, H. B. Kagan, Angew. Chem. Int. Ed. 1998, 37, 2922–
2959.
[45] D. Seebach, J. Golinski, Helv. Chim. Acta 1981, 64, 1413–1423.
[46] Calculations were carried out using the GAUSSIAN 03 suite
of programs: M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr,
T. Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyen-
gar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani,
N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima,
Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox,
H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo, R. Gom-
perts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C.
Received: January 15, 2007
Published Online: March 23, 2007
Eur. J. Org. Chem. 2007, 2328–2343
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2343