Water-compatible iminium activation: Organocatalytic Michael reactions of carbon-centered nucleophiles with enals

Article abstract of DOI:10.1002/anie.200703261

(Chemical Equation Presented) A pool of water-compatible catalysts, namely the chiral prolinol-based catalysts 1, has been developed for highly enantioselective C-C bond-forming Michael reactions in water (see scheme). The synthesis of (S)-Rolipram, a type IV phosphodiesterase inhibitor, was also demonstrated.

Full text of DOI:10.1002/anie.200703261

Angewandte
Chemie
DOI: 10.1002/anie.200703261
Aqueous Organocatalysis
Water-Compatible Iminium Activation: Organocatalytic Michael
Reactions of Carbon-Centered Nucleophiles with Enals**
Claudio Palomo,* Aitor Landa, Antonia Mielgo, Mikel Oiarbide, ngel Puente, and Silvia Vera
Water offers unique characteristics as a solvent. It displays
unparalleled physical properties, is cheap, available in bulk,
and hazardless in handling, and overall it sustains life and
therefore most biosynthetic reactions. In the practice of
chemical synthesis, however, water had been considered a
contaminant for a while. Over the last few decades, chemists
have started to investigate the possibility of using water as
solvent for organic reactions[1] because of potential benefits
with respect to industrial[2] and biological implications. As for
the field of asymmetric synthesis, the development of water-
compatible catalytic methods still remains challenging, essen-
tially because most metal catalysts are unstable toward
hydrolysis.[3] Water can also interfere with organocatalysis[4]
given its capacity for disrupting hydrogen bonds and other
polar interactions. Interestingly, however, chiral secondary
amines have been shown to be viable organocatalysts in
role played by hydrophobic alkyl chains in water-compatible
enamine-mediated catalysis,[5e,h,j] and b) the assumption that
for effective control of iminium geometry and face shielding,
a bulky group should be located near the nitrogen atom of the
catalyst (Figure 1).[12]
varying degrees of an aqueous environment[5] for several C C
À
bond-forming processes known to proceed through activation
of the substrate carbonyl through enamine formation.[6,7]
A
Figure 1. Key design elements of a new family of pyrrolidine catalysts
second major category of amine catalysis relies on activation
of carbonyl Michael acceptors through formation of iminium
species.[8] However, little success has been met in aqueous
systems.[9] Experimental data suggest that iminium activation
is less compatible with the presence of water, and to date no
general catalytic system has been reported fully water-
compatible.[10] Here, we present evidence of the suitability
of organocatalytic asymmetric iminium activation in water-
containing systems by describing highly selective conjugate
additions of several carbon-centered nucleophiles to a,b-
unsaturated aldehydes catalyzed by secondary amines using
water as the only solvent.
for water-compatible iminium catalysis.
At the outset, the conjugate addition of nitromethane to
enals was selected to study the catalysts.[13] Despite the
interest of the resulting adducts as intermediates in syn-
thesis,[14] enantioselective versions of this reaction have been
hardly developed,[15] presumably because of the undesired
competing 1,2-addition process. In particular, by this
approach an atom-economic route to a-unsubstituted g-
amino acids, which exhibit potent activity on the central
nervous system,[16] would be made feasible in a concise and
practical fashion.
To evaluate the catalysts, the reaction of nitromethane
and cinnamaldehyde in the presence of 5 mol% of the
corresponding pyrrolidine 1–8 using water as the only solvent
was carried out at room temperature (Scheme 1 and Table 1).
All tested catalysts were able to promote the reaction, but the
performance varied as a function of the length of the alkyl
side chain (Table 1, entries 1–7). Dimethyl and dipropyl
prolynol derivatives 1 and 2 catalyzed the reaction but led
to only moderate yields and insufficient selectivity. The
dihexyl derivative 3 gave satisfactory reactivity and enantio-
selectivity of 91%. An increase in length of the side chain to
nonyl and dodecyl derivatives 4 and 5, respectively, had a
detrimental effect on both the reaction speed and selectivity
(Table 1, entries 4–7). With the optimal side chain hexyl, the
effect of the silyl group was examined. Thus, the triphenylsilyl
ether 6 gave improved yields and selectivities (Table 1,
entry 8) as compared to the parent trimethylsilyl catalyst.
On the other hand, the trans-4-hydroxypyrrolidine derivative
As candidates for water-compatible iminium catalysis,
compounds 1–8 were prepared starting from proline (or trans-
4-hydroxyproline).[11] These molecules were conceived
according to two main design elements: a) the favorable
[*] Prof. Dr. C. Palomo, Dr. A. Landa, Dr. A. Mielgo,
Prof. Dr. M. Oiarbide, . Puente, S. Vera
Departamento de Química Orgµnica I
Universidad del País Vasco
Manuel Lardizabal 3. 20018-San Sebastiµn (Spain)
Fax: (+34)943-015-270
E-mail: claudio.palomo@ehu.es
Homepage: http://www.sc.ehu.es/qpwaiipj/organica.html
[**] This work was supported by The University of the Basque Country
(UPV/EHU), the Ministerio de Educación y Ciencia (MEC, Spain),
and Gobierno Vasco (GV)-Programa Saiotek. A Ramón y Cajal
contract to A.L. from the MEC, and predoctoral grants to S.V. and
A.P. from the MEC and GV, respectively, are acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 8431 –8435
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8431

Communications
A representative selection of enals was evaluated
under the best conditions, and the results are summarized
in Table 2. Good yields, corresponding to two or three
synthetic steps to the final alcohol or ester product,[18]
and regularly high selectivity are attained with neutral,
electron-poor, or electron-rich substituted cinnamalde-
hydes (Table 2, entries 1–6 and 9–12). With crotonalde-
hyde (Table 2, entry 7) slightly lower selectivity was
observed, but by running the reaction at 08C in this case
above 90% ee was attained (Table 2, entry 8). Of
practical importance, lowering the catalyst loading from
5 mol% to only 2 mol% was well tolerated, while the
reaction starting from 5 mmol of substrate enal displayed
no significant loss in reactivity and stereoselectivity
(Table 2, entry 3).
Adduct 12h, which was produced in very high
enantioselectivity, was subsequently transformed into
the S isomer of Rolipram (Scheme 2), a type IV phos-
phodiesterase inhibitor.[16] Thus, the configuration of the
product is consistent with the expected preferential
attack of nitromethane across the rear p face of the
activated iminium species depicted in Figure 1. The
Scheme 1. Enantioselective conjugate addition of nitromethane to enals
catalyzed by pyrrolidines 1–7, and elaboration of the adducts to the
corresponding alcohols and carboxylic esters.
Table 1: Catalyst screening for the reaction of nitromethane with enal 9a
to give 10a.[a]
Table 2: Reaction of nitromethane with a,b-unsaturated aldehydes
catalyzed by 6 (see Scheme 1).[a]
Yield [%][b]
ee [%][c]
Entry
Cat.
t [h]
Conv. [%][b]
Yield [%][c]
ee [%][d]
Entry
R
Product
1
2
3
4
5
6
7
8
1
2
3
4
4
5
5
6
6
7
8
8
3
6
>99
>99
>99
60
>99
50
41
43
65
–
65
–
30
70
66
59
40
55
50
70
91
–
85
–
73
96
94
1
2[d]
3[e]
4
Ph
10a
70
65
61
71
68
66
60
42
57
60
69
62
96
96
95
96
94
97
87
91[g,h]
95
98
95
98
16
16
32
16
32
16
32
16
16
16
4-MeOC6H4
10b
5[d]
6[f]
7[g]
8
4-MeC6H4
Me
10c
10d
80
>99
>99
>99
–
9[e]
10
11
12[f]
9
3-MeOC6H4
4-NO2C6H4
4-ClC6H4
3-cPentO-4-MeOC6H3
12e
12 f
12g
12h
10[f]
11
12
83
À40
–
À87
[a] Reactions performed on 1 mmol scale at room temperature using
[a] Reactions carried out overnight on a 1 mmol scale using nitro-
methane (2 mmol), 6 (5 mol%), benzoic acid (5 mol%), and H2O
(1 mL) unless otherwise stated. [b] Yield after chromatography of the
corresponding alcohol or ester compound. [c] Determined by HPLC.
[d] Using 1 mL of EtOH/H2O (1:1) as solvent. [e] Reaction carried out on
5 mmol scale using 2 mol% catalyst. [f] Full conversion after 6 h.
[g] 5 mmol of nitromethane was used. [h] Reaction performed at 08C.
catalyst 1–8 (5 mol%), benzoic acid (5 mol%), nitromethane (2 equiv,
1
110 mL), and water (1 mL). [b] Measured by H NMR spectroscopy on
crude material. [c] Yield of product (after chromatography) after
reduction to alcohol. [d] Determined by HPLC (Daicel-Chiralpak IB;
eluent 90:10 hexane/2-propanol). [e] In the absence of benzoic acid.
[f] Neat reaction using 10 mol% catalyst without benzoic acid.
7 (Table 1, entry 10) exhibited an inferior performance.
Interestingly, the amino alcohol 8, which contains a free
hydroxy group, is also able to catalyze the reaction either in
neat conditions or with water as solvent and gives rise to a
product of reversed configuration. The stereochemical rever-
sal may be rationalized by assuming that hydrogen bonding is
established between the OH group of the catalyst and the
NO2 group in the transition state.[17] While the above reactions
were generally carried out in the presence of 5 mol% of
benzoic acid, reactions without such an additive were
accompanied with similar levels of enantioselection, although
elapsed reaction times were required (Table 1, compare
entries 8 and 9).
configuration of the remaining adducts was assigned assuming
a uniform reaction mechanism.
Further proof of the capacity of the present catalyst
system can be inferred from its remarkable performance in
the conjugate addition of malonates, a category of Michael
donors previously shown to react poorly in aqueous sys-
tems.[10a] As the results in Table 3 show, the reaction of
dibenzyl malonate with cinnamaldehyde and p-methoxycin-
namaldehyde under similar catalytic conditions, with water as
the sole solvent, led to the corresponding adducts 13 in good
yields and with up to 99% ee. The triphenylsilyl catalyst 6
afforded again slightly improved results as compared with the
TMS derivative 3, even in reactions run at room temperature.
8432
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room temperature in the presence of 20 mol% of the
corresponding catalyst. In all cases, very high diastereoselec-
tivity in favor of the anti adduct and very high enantioselec-
tivities were obtained with catalyst 6. The resulting adducts
could be oxidized to the corresponding glutarates or alter-
natively reduced to 1,5-diols 14, which in turn may be
transformed into cis-3,4-disubstituted tetrahydropyrans by
standard protocols.[21]
The physical appearance of the reaction mixture in the
above developments was in general an easy to stir emulsion.
As a consequence, the yet unanswered question about where
the reaction actually occurs (either in the aqueous or organic
phase, or on the boundary) arises. In this connection, what
seems to be apparent is the tolerance of the present iminium
activation model with a homogeneous aqueous environment
and its robustness, as the same level of catalytic effectiveness
is maintained even in the reactions carried out in water/
ethanol homogeneous solutions (Table 2, entries 2 and 5;
Table 4, entry 3).
Scheme 2. Synthesis of (S)-Rolipram from adduct 12h. [a]2D5 =+26.2
(c=0.6, MeOH) (c.f. [a]2D5 =+24.7 (c=0.23, MeOH)[19]).
Table 3: Reaction of benzyl malonate and enals in water catalyzed by 3 or
6.[a]
Entry
R
Product
Cat.
T [8C]
Yield [%][b]
ee [%][c]
In summary, a new family of prolinol-based catalysts have
been developed that enable iminium-type catalysis of enals in
aqueous systems to provide high enantioselectivies under
practical conditions. With this addition, the emerging pool of
water-compatible organocatalysts is reinforced and the range
of chemical transformations amenable for asymmetric catal-
ysis in water-containing systems is extended.
1
2
3
4
5
H
H
H
MeO
MeO
13a
13a
13a
13b
13b
3
3
6
3
6
25
0
25
0
83
74
77
69
74
82
88
96
92
99
25
[a] Reaction conditions: enal (1 mmol), 3 or 6 (5 mol%), benzoic acid (5
mol%), dibenzyl malonate (0.8 mmol), and water (1 mL). Bn=benzyl.
[b] Yield of adduct 13 after chromatography. [c] Determined by HPLC
after transformation into the corresponding methyl ester.
Experimental Section
General procedure for the reaction of nitromethane and a,b-
unsaturated aldehydes. Nitromethane (2 mmol, 110 mL) and benzoic
acid (0.05 mmol, 6.1 mg) were added to a mixture of catalyst 3 or 6
(0.05 mmol, 5 mol%) and the corresponding a,b-unsaturated alde-
hyde 9 (1 mmol) in water (1 mL). The resulting emulsion was stirred
for 18 h at room temperature. The mixture was elaborated according
to two alternative procedures. Method A (derivatization to alcohols):
A solution of the above reaction mixture in EtOH (25 mL) was added
dropwise to a cooled solution (À58C) of NaBH4 (47.25 mg, 2.5 mmol)
in EtOH (50 mL). The reaction was stirred at À58C for 20 min (TLC,
1:1 EtOAc/hexane) and afterwards quenched with H2O (20 mL) and
extracted with CH2Cl2 (3 ” 30 mL). The combined organic layers were
washed with brine and dried (MgSO4). The solvent was evaporated,
and the crude product was purified by chromatography (eluent, 1:2
EtOAc/hexane) to obtain 10. Method B (derivatization to carboxylic
acid methyl esters): The crude material was dissolved in a mixture of
MeOH (1.0 mL), CH3CN (1.0 mL), and water (1.0 mL). The resulting
solution was cooled to 08C, and KH2PO4 (63 mg, 0.46 mmol) and
NaClO2 (46 mg, 0.43 mmol) were added. After the injection of H2O2
(35% solution, 0.5 mL), the mixture was warmed to room temper-
ature and stirred for an additional 2 h. The pH was adjusted to pH 3
with 1m HCl, and saturated Na2SO3 (5 mL) was added. The resulting
mixture was extracted with CH2Cl2 (3 ” 10 mL), and the combined
organic layers were washed with 10 mL water and dried over MgSO4.
The organic layer was concentrated in vacuum, and the residue was
dissolved in a toluene/methanol mixture (2.0:5.0 mL). Trimethylsilyl
diazomethane (2.0m in n-hexane) was added dropwise, and the
solution was stirred for an additional 10 min and then quenched with
a drop of concentrated AcOH. The solvents were evaporated under
vacuum. The crude product was subjected to flash chromatography on
silica gel (1:9 EtOAc/n-pentane) to give 12.
Finally, the potential of this family of catalysts in an
aqueous environment was tested for the yet unprecedented
enantioselective amine-catalyzed intermolecular Michael
addition of aldehydes to enals.[20] This reaction bears addi-
tional mechanistical interest, as it likely involves a double
enamine/iminium activation process. As the results in Table 4
show, reactions of propanal and pentanal with cinnamalde-
hyde and 4-methoxycinnamaldehyde took place effectively at
Table 4: Amine-catalyzed Michael additions of aldehydes to enals.[a]
Entry 14
R1
R2
Cat.
t
Yield d.r. [%][c] ee [%][d]
[h] [%][b] anti/syn (anti)
1
2
14a Me Ph
14a Me Ph
14a Me Ph
3[e]
6
6
3
4
20 50
20 62
20 52
48 68
72 45
72 55
72 42[g]
85:15 74
81:19 98
85:15 93
3[f]
4
14b Pr
14b Pr
14b Pr
14c Pr
Ph
Ph
Ph
ꢀ98:2
85
73
97
98
5
6
7
ꢀ98:2
ꢀ98:2
ꢀ98:2
6
6
4-MeOC6H4
[a] Reactions performed on 2 mmol scale at room temperature in the
presence of catalyst (20 mol%), benzoic acid (20 mol%), enal (3 equiv),
and water (2 mL). [b] Yield referred to isolated 14. [c] Measured by NMR
spectroscopy and HPLC. [d] Determined by HPLC. [e] 10 mol% catalyst
used. [f] Using 1 mL of 1:1 EtOH/H2O mixture as solvent. [g] Reaction
conversion 85%.
Received: July 20, 2007
Published online: September 27, 2007
Angew. Chem. Int. Ed. 2007, 46, 8431 –8435
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8433

Communications
D. W. C. MacMillan, J. Am. Chem. Soc. 2000, 122, 9874 – 9875.
For a review, see: b) G. Lelais, D. W. C. MacMillan, Aldrichimica
Acta 2006, 39, 79 – 87. For recent advances in asymmetric
organocatalytic 1,4-additions, see: c) S. B. Tsogoeva, Eur. J.
Org. Chem. 2007, 1701 – 1716; d) D. Almasi, D. A. Alonso, C.
Nꢁjera, Tetrahedron: Asymmetry 2007, 18, 299 – 365; e) J. L.
Vicario, D. Badꢂa, L. Carrillo, Synthesis 2007, 2065 – 2092.
[9]Epoxidations: a) W. Zhuang, M. Marigo, K. A. Jørgensen, Org.
Biomol. Chem. 2005, 3, 3883 – 3885; b) M. Marigo, J. Franzꢃn,
T. B. Poulsen, W. Zhuang, K. A. Jørgensen, J. Am. Chem. Soc.
2005, 127, 6964 – 6965. Conjugate 1,4-additions of ketoesters:
c) A. Carlone, M. Marigo, C. North, A. Landa, K. A. Jørgensen,
Chem. Commun. 2006, 4928 – 4930. Conjugate additions of
thiols: d) T. Ishino, T. Oriyama, Chem. Lett. 2007, 36, 550 – 551.
[10]For instance, while the conjugate addition of b-keto esters to
enals catalyzed by a diarylprolinol silyl ether has been reported
to occur in aqueous solutions (Ref. [9c]), the parent addition of
malonates and malononitriles appears to work sluggishly if at all:
a) S. Brandau, A. Landa, J. Franzꢃn, M. Marigo, K. A. Jørgen-
sen, Angew. Chem. 2006, 118, 4411 – 4415; Angew. Chem. Int. Ed.
2006, 45, 4305 – 4309; b) A. Carlone, S. Cabrera, M. Marigo,
K. A. Jørgensen, Angew. Chem. 2007, 119, 1119 – 1122; Angew.
Chem. Int. Ed. 2007, 46, 1101 – 1104.
Keywords: aldehydes · amines · asymmetric catalysis ·
iminium activation · organocatalysis
.
[1]General reviews: a) Organic Synthesis in Water (Ed.: P. A.
Grieco), Blackie Academic Profesional, London, 1998;
&
b) U. M. Lindström, Chem. Rev. 2002, 102, 2751 – 2772; c) C.-J.
Li, Chem. Rev. 2005, 105, 3095 – 3165; d) C.-J. Li, L. Cheng,
Chem. Soc. Rev. 2006, 35, 68 – 82.
[2]For a critical recent essay, see: D. G. Blackmond, A. Armstrong,
V. Coombe, A. Wells, Angew. Chem. 2007, 119, 3872 – 3874;
Angew. Chem. Int. Ed. 2007, 46, 3798 – 3800.
[3]For successful metal catalysis in aqueous systems, see: a) Aque-
ous-Phase Organometallic Catalysis (Eds.: B. Cornils, W. A.
Herrman), Wiley-VCH, Weinheim, 1998; b) S. Kobayashi, C.
Ogawa, Chem. Eur. J. 2006, 12, 5954 – 5960; c) S. Kobayashi, M.
Sugiura, H. Kitagawa, W. W. L. Lam, Chem. Rev. 2002, 102,
2227 – 2302; d) D. Sinou, Adv. Synth. Catal. 2002, 344, 221 – 237.
[4]Reviews on organocatalysis: a) P. I. Dalko, L. Moisan, Angew.
Chem. 2001, 113, 3840 – 3864; Angew. Chem. Int. Ed. 2001, 40,
3726 – 3748; b) E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58,
2481 – 2495; c) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248 – 5286; Angew. Chem. Int. Ed. 2004, 43, 5138 – 5175; d) J.
Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719 – 724; e) A.
Berkessel, H. Gröger, Asymmetric Organocatalysis: From Bio-
mimetic Concepts to Applications in Asymmetric Synthesis,
Wiley-VCH, 2005. See also special issues on organocatalysis:
f) Acc. Chem. Res. 2004, 37(8); g) Adv. Synth. Cat. 2004, 346(9–
10).
[11]For details, see the Supporting Information.
[12]For pertinent information on this subject, see: a) Ref. [8b;]b) C.
Palomo, A. Mielgo, Angew. Chem. 2006, 118, 8042 – 8046;
Angew. Chem. Int. Ed. 2006, 45, 7876 – 7880.
[13]For a review on conjugate additions of nitroalkanes, see: R.
Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini, Chem. Rev.
2005, 105, 933 – 971.
[5]Aldol reactions: a) T. J. Dickerson, K. D. Janda, J. Am. Chem.
Soc. 2002, 124, 3220 – 3221; b) H. Torii, M. Nakadai, K. Ishihara,
S. Saito, H. Yamamoto, Angew. Chem. 2004, 116, 2017 – 2020;
Angew. Chem. Int. Ed. 2004, 43, 1983 – 1986; c) P. Dziedzic, W.
Zou, J. Hafren, A. Cordova, Org. Biomol. Chem. 2006, 4, 38 – 40;
d) P. M. Pihko, K. M. Laurikainen; A. Usano, A. I. Nyberg, J. A.
Kaavi, Tetrahedron 2006, 62, 317 – 328; A. Usano, A. I. Nyberg,
J. A. Kaavi, Tetrahedron 2006, 62, 317 – 328; e) Y. Hayashi, S.
Aratake, T. Okano, J. Takahashi, T. Sumiya, M. Shoji, Angew.
Chem. 2006, 118, 5653 – 5655; Angew. Chem. Int. Ed. 2006, 45,
5527 – 5529; f) D. Font, C. Jimeno, M. A. Pericàs, Org. Lett. 2006,
8, 4653 – 4655; g) Y. Wu, Y. Zhang, M. Yu, G. Zhao, S. Wang,
Org. Lett. 2006, 8, 4417 – 4420; h) N. Mase, Y. Nakai, N. Ohara,
H. Yoda, K. Takabe, F. Tanaka, C. F. Barbas, J. Am. Chem. Soc.
2006, 128, 734 – 735; Mannich reaction: i) L. Cheng, X. Wu, Y.
Lu, Org. Biomol. Chem. 2007, 5, 1018 – 1020; Michael reactions:
j) N. Mase, K. Watanabe, H. Yoda, K. Takabe, F. Tanaka, C. F.
Barbas III, J. Am. Chem. Soc. 2006, 128, 4966 – 4967; k) L. Zu, J.
Wang, H. Li, W. Wang, Org. Lett. 2006, 8, 3077 – 3079; l) Z.-Y.
Yan, Y.-N. Niu, H.-L. Wei, L.-Y. Wu, Y.-B. Zhao, Y.-M. Liang,
Tetrahedron: Asymmetry 2006, 17, 3288 – 3293; m) S. Luo, X. Mi,
S. Liu, H. Xu, J.-P. Cheng, Chem. Commun. 2006, 3687 – 3689;
n) Y.-J. Cao, Y.-Y. Lai, X. Wang, Y.-J. Li, W.-J. Xiao, Tetrahedron
Lett. 2007, 48, 21 – 24; o) V. Singh, V. K. Singh, Org. Lett. 2007, 9,
1117 – 1119.
[6]Reviews on enamine catalysis: a) B. List, Tetrahedron 2002, 58,
5573 – 5590; b) B. List, Acc. Chem. Res. 2004, 37, 548 – 557; c) B.
List, Chem. Commun. 2006, 819 – 824; d) M. Marigo, K. A.
Jørgensen, Chem. Commun. 2006, 2001 – 2011; e) G. Guillena,
D. J. Ramꢀn, Tetrahedron: Asymmetry 2006, 17, 1465 – 1492.
[7]For a recent exchange on the enamine-based organocatalysis
carried out in systems containing water, see: a) A. P. Brogan,
T. J. Dickerson, K. D. Janda, Angew. Chem. 2006, 118, 8278 –
8280; Angew. Chem. Int. Ed. 2006, 45, 8100 – 8102; b) Y.
Hayashi, Angew. Chem. 2006, 118, 8281 – 8282; Angew. Chem.
Int. Ed. 2006, 45, 8103 – 8104; c) see also Ref. [2].
[14]For the chemistry and transformations of the nitro group, see:
a) R. Ballini, M. Petrini, Tetrahedron 2004, 60, 1017 – 1047; b) N.
Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New
York, 2001, pp. 103 – 125.
[15]a) T. Ooi, K. Doda, K. Maruoka, J. Am. Chem. Soc. 2003, 125,
9022 – 9023; b) D. Enders, M. R. M. Hꢄtll, C. Grondal, G. Raabe,
Nature 2006, 441, 861 – 863; c) L. Hojabri, A. Hartikka, F. M.
Moghaddam, P. I. Arvidsson, Adv. Synth. Catal. 2007, 349, 740 –
748. For conjugate additions to enones involving iminium
activation, see: d) S. Hanessian, V. Pham, Org. Lett. 2000, 2,
2975 – 2978; e) S. Hanessian, Z. Shao, J. S. Warrier, Org. Lett.
2006, 8, 4787 – 4790; f) S. Hanessian, S. Govindan, J. S. Warrier,
Chirality 2005, 17, 540 – 543; g) C. E. T. Mitchell, S. E. Brenner,
J. Garcꢂa-Fortanet, S. V. Ley, Org. Biomol. Chem. 2006, 4, 2039 –
2049; h) S. B. Tsogoeva, S. B. Jagtap, Z. A. Ardemasova, Tetra-
hedron: Asymmetry 2006, 17, 989 – 992.
[16]For pertinent information on this subject, see: A. L. L. Garcꢂa,
M. J. S. Carpes, A. C. B. M. de Oca, M. A. G. dos Santos, C. C.
Santana, C. R. D. Correia, J. Org. Chem. 2005, 70, 1050 – 1053.
[17]This hypothesis correlates well with the observed variation in
enantioselectivity from the neat reaction to the aqueous
reaction, as water may disrupt any well-organized hydrogen-
bond network. For computational models supporting hydrogen
bonding between the catalyst OH group and the substrate NO2
group in a related system, see: C. Palomo, S. Vera, A. Mielgo, E.
Gꢀmez-Bengoa, Angew. Chem. 2006, 118, 6130 – 6133; Angew.
Chem. Int. Ed. 2006, 45, 5984 – 5987.
[18]Transformation into the alcohols or ester derivatives was
required to avoid partial decomposition of the aldehyde
products during chromatographic isolation.
[19]J. Barluenga, M. A. Fernꢁndez-Rodrꢂguez, E. Aguilar, F.
Fernꢁndez-Marꢂ, A. Salinas, B. Olano, Chem. Eur. J. 2001, 7,
3533 – 3544.
[20]For amine-catalyzed intramolecular Michael reactions of alde-
hydes, see: a) M. T. E. Fonseca, B. List, Angew. Chem. 2004, 116,
4048 – 4050; Angew. Chem. Int. Ed. 2004, 43, 3958 – 3960; b) J. W.
Yang, M. T. E. Fonseca, B. List, J. Am. Chem. Soc. 2005, 127,
[8]For the uncovering of the iminium activation concept in
asymmetric catalysis, see: a) K. A. Ahrendt, C. J. Borths,
8434
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Angewandte
Chemie
15036 – 15037. For intermolecular versions, see: (to enones) c) Y.
Chi, S. H. Gellman, Org. Lett. 2005, 7, 4253 – 4256; d) T. J.
Peelen, Y. Chi, S. H. Gellman, J. Am. Chem. Soc. 2005, 127,
11598 – 11599; e) P. Melchiorre, K. A. Jørgensen, J. Org. Chem.
2003, 68, 4151 – 4157; (to vinyl sulfones) f) S. Mossꢃ, A. Alexakis,
Org. Lett. 2005, 7, 4361 – 4364; (to maleimides) g) G.-L. Zhao, Y.
Xu, H. Sundꢃn, L. Eriksson, M. Sayah, A. Cꢀrdova, Chem.
Commun. 2007, 734 – 735. Amine-catalyzed Michael addition of
ketones to chalcones: h) J. Wang, H. Li, L. Zu, W. Wang, Adv.
Synth. Catal. 2006, 348, 425 – 428.
[21]A. Bernardi, P. Dotti, G. Poli, C. Scolastico, Tetrahedron 1992,
48, 5597 – 5606, and references therein.
Angew. Chem. Int. Ed. 2007, 46, 8431 –8435
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
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