Enantioselective Michael addition of isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines

Article abstract of DOI:10.1016/j.tetasy.2014.02.006

Primary amine-guanidines derived from trans-cyclohexane-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of isobutyraldehyde to arylated and heteroarylated nitroalkenes. The reaction was performed in the presence of imi

Full text of DOI:10.1016/j.tetasy.2014.02.006

Tetrahedron: Asymmetry 25 (2014) 462–467
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Enantioselective Michael addition of isobutyraldehyde to
nitroalkenes organocatalyzed by chiral primary amine-guanidines
b
b
a,
Angel Avila a, Rafael Chinchilla a, , Béla Fiser , Enrique Gómez-Bengoa , Carmen Nájera
⇑
⇑
a Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
b Departamento de Química Orgánica I, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastíán, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 December 2013
Accepted 6 February 2014
Primary amine-guanidines derived from trans-cyclohexane-1,2-diamines are used as organocatalysts for
the enantioselective conjugate addition of isobutyraldehyde to arylated and heteroarylated nitroalkenes.
The reaction was performed in the presence of imidazole as the additive in aqueous DMF as the solvent at
0 °C. The corresponding Michael adducts bearing a new stereocenter were obtained in high yields and
with enantioselectivities of up to 80%. Theoretical calculations are used to justify the observed sense of
the stereoinduction.
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
which is hydrogen bond-coordinated by the nitro group to the NH
groups of the thiourea.
c
-Nitrocarbonyl compounds have gained great importance in
recent years as key precursors of various important compounds,
such as alkaloids,1 aminoacids,2 antitumorals,3 antibiotics,4 pepti-
do mimetics,5 and marine metabolites6 among others.7 Nowadays,
the enantioselective Michael addition reaction of enolizable car-
bonyl compounds to nitroalkenes promoted by a chiral organocat-
alyst is one of the most common and convenient procedures for
CF3
S
S
N
H
N
H
CF3
N
H
N
H
NH2
NH2
NH2
1
2
S
achieving the synthesis of c-nitrocarbonyl compounds in an enan-
N
S
tBu
tiomerically enriched form.8 Thus, organocatalysts with bifunc-
tional characteristics have been most efficient for the
enantioselective addition reaction of aldehydes or ketones to nitro-
olefins, particularly those containing a primary amine and a thio-
urea moiety.9 For instance, the enantioselective Michael addition
reaction of aldehydes to nitroalkenes has been successfully per-
formed using the chiral trans-cyclohexane-1,2-diamine-derived
primary amine-thioureas 1,10 2,11 and 3,12 as organocatalysts as
well as the Cinchona-derived 4,13 the isosteviol-derived 5,14 and
even calix[4]arene-derived compounds.15 When using all of these
primary amine-containing organocatalysts, the enantioselectivity
is induced by the addition of a transient enamine to the nitroolefin,
N
N
NHBn
S
H
H
H
N
H
N
H
OMe
NH2
O
3
4
N
Me
Me
N
H
N
H
NH2
H
H
5
EtO2C Me
We have recently reported on the synthesis of primary amine-
guanidines 6 and ent-6a from chiral trans-cyclohexane-1,2-dia-
mines and their use as organocatalysts in enantioselective Michael
addition reactions of aldehydes, mainly
a,a-disubstituted, to
maleimides.16 Herein we explore the use of these primary
amine-guanidines 6 as chiral organocatalysts in conjugate addition
reactions of
to nitroalkenes, leading to enantioenriched
a
,
a
-disubstituted aldehydes such as isobutyraldehyde
-nitroaldehydes. In
c
⇑
addition, theoretical calculations have been used to explain the
observed enantioselectivity.
Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549.
E-mail addresses: chinchilla@ua.es (R. Chinchilla), cnajera@ua.es (C. Nájera).
http://dx.doi.org/10.1016/j.tetasy.2014.02.006
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

A. Avila et al. / Tetrahedron: Asymmetry 25 (2014) 462–467
463
methyl ether, or methanol gave high yields for (R)-9a in 5 d reac-
tion time, but only 34%, 53%, and 35% ee’s, respectively (Table 1,
entries 4–6), whereas the use of nitromethane as the solvent gave
9a as a racemic mixture (Table 1, entry 7).
NiPr
NHiPr
NR
N
H
N
H
NHR
NH2
NH2
However, the use of DMF as a solvent increased dramatically
the reaction rate, quantitatively affording (R)-9a in 48% ee (Table 1,
entry 8). An increasing reaction rate was also observed when water
was used as the solvent, with the enantioselectivity of the process
increasing to 71%, and adduct (R)-9a was isolated in 80% yield
(Table 1, entry 9). Therefore, mixtures of DMF/H2O were assayed
as solvents, in an attempt to combine the beneficial effects of both
solvents. Thus, the use of a DMF/H2O mixture in a 2:1 (v/v) ratio as
the solvent gave rise to a quantitative yield of (R)-9a in 62% ee
(Table 1, entry 10). Increasing the amount of water from 1:2 to
1:4 (v/v) ratios resulted in higher enantioselectivities for (R)-9a
(67% and 70%, respectively) while keeping the quantitative yield
(Table 1, entries 11 and 12).
The use of other basic additives (20 mol %) in the reaction using
the most appropriate solvent [DMF/H2O, 1:4 (v/v)] were was also
assayed. The use of triethylamine or 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) afforded lower enantioselections for (R)-9a (Table 1,
entries 13 and 14), whereas when 1,4-diazabicyclo[2.2.2]octane
(DABCO) was used as the additive, a similar ee to that when using
imidazole was observed, although the reaction was not quantitative
(Table 1, entry 15). In addition, when an acid additive such as ben-
zoic acid was assayed, almost no reaction was observed (Table 1,
entry 16). Moreover, when organocatalyst 6a and the imidazole
additive loadings were lowered down to 10 mol %, adduct (R)-9a
was isolated quantitatively in 70% ee, although the reaction time
increased considerably (Table 1, entry 17).
6a
ent-
6a
, R = iPr
6b, R = Cy
2. Results and discussion
Primary amine-guanidines 6a and 6b were employed as
organocatalysts and were prepared as previously reported16b by
monoguanylation of (1S,2S)-cyclohexane-1,2-diamine with
N,N0-diisopropyl carbodiimide or N,N0-dicyclohexyl carbodiimide,
respectively. The search for the most appropriate reaction condi-
tions (Table 1) began with the Michael addition reaction of isobu-
tyraldehyde 7 to trans-b-nitrostyrene 8a, organocatalyzed by 6a
(20 mol %) in toluene as solvent at room temperature, which affor-
ded the corresponding adduct (R)-9a in only 22% yield and with a
modest 53% ee after 5 d reaction time (Table 1, entry 1). The
(R)-absolute configuration of the final adduct was determined by
comparison of the elution order of the corresponding enantiomers
in chiral HPLC with those in the literature.17
The addition of imidazole as a basic additive, something that
proved beneficial when 6a organocatalyzed the Michael addition
reaction of aldehydes to maleimides,16b was again effective,
increasing the reactivity of the process and allowing the isolation
of (R)-9a in 92% yield in the same reaction time although with a
lower ee (Table 1, entry 2). The use of the dicyclohexyl-containing
primary amine-guanidine 6b as the organocatalyst under these
reaction conditions resulted in a much lower yield and enantiose-
lectivity for (R)-9a (Table 1, entry 3), therefore we continued with
6a. Thus, the use of other solvents such as acetone, tert-butyl
Attempting to increase the enantioselectivity of the process, we
also lowered the reaction temperature. Thus, when the process was
carried out at 0 °C, the reaction time increased to 2 d, but the
Table 1
Screening and optimization of the reaction conditions for the enantioselective Michael addition
cat.
additive
solvent, T
O
O
Ph
*
NO2
Me
NO2
+
Ph
H
H
Me
Me Me
8a
7
9a
Entry
Catalyst (mol %)
Additivea (mol %)
Solvent
T (°C)
t (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
6a (20)
6a (20)
6b (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (20)
6a (10)
6a (20)
ent-6a (20)
—
PhMe
PhMe
PhMe
Acetone
TBME
MeOH
MeNO2
DMF
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
5
5
5
5
5
5
5
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
0.7
3
22
92
30
96
96
99
74
99
80
99
99
99
97
90
85
5
53 (R)
44 (R)
27 (R)
34 (R)
53 (R)
35 (R)
0
48 (R)
71 (R)
62 (R)
67 (R)
70 (R)
60 (R)
33 (R)
70 (R)
63 (R)
70 (R)
80 (R)
80 (S)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
Imidazole (20)
TEA (20)
H2O
DMF/H2Od
DMF/H2Oe
DMF/H2Of
DMF/H2Of
DMF/H2Of
DMF/H2Of
DMF/H2Of
DMF/H2Of
DMF/H2Of
DMF/H2Of
DBU (20)
DABCO (20)
PhCO2H (20)
Imidazole (10)
Imidazole (20)
Imidazole (20)
99
90
87
2
2
0
a
b
c
d
e
f
TEA: triethylamine; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DABCO: 1,4-diazabicyclo[2.2.2]octane.
Isolated yield after flash chromatography.
Enantioselectivities and absolute stereochemistry determined by chiral HPLC.8b
2:1, v/v.
1:2, v/v.
1:4, v/v.

464
A. Avila et al. / Tetrahedron: Asymmetry 25 (2014) 462–467
enantioselectivity of adduct (R)-9a increased to 80%, and was iso-
lated in 90% yield (Table 1, entry 18).
In order to gain further insight into the origin of the observed
enantioselectivity, we carried out DFT theoretical calculations.
Our goal was to determine the hydrogen bonding activation pat-
tern of the nitro group, including the role of the pendant guanidine
moiety and the role of water beyond just being the solvent of the
reaction. We assumed that the initial formation of an enamine
between the primary amine of the catalyst 6a and the aldehyde
7 was followed by a nucleophilic attack to nitrostyrene 8a follow-
Expecting to achieve an opposite enantioselection, we also per-
formed the reaction using ent-6a as the organocatalyst, which can
be prepared similarly to its enantiomeric counterpart, but using
(1R,2R)-cyclohexane-1,2-diamine as the chirality source.16b Using
this primary amine-guanidine as the catalyst (20 mol %) under
the most effective reaction conditions [imidazole as additive
(20 mol %), DMF/H2O, 1:4 (v/v), 0 °C], the expected adduct (S)-9a
was isolated in 80% ee (Table 1, entry 19).
Next we explored the addition reaction of isobutyraldehyde to
other trans-b-nitroalkenes 8 under the most favourable reaction
conditions [6a (20 mol %), imidazole (20 mol %), DMF/H2O, 1:4
(v/v), 0 °C], and the results are summarized in Table 2. Thus, when
nitroalkenes 8b and 8c, bearing electron-releasing groups such as
methyl or methoxy in the aromatic ring, were used, the corre-
sponding Michael adducts (R)-9b and (R)-9c were isolated in good
yields and with enantioselectivities of 80% and 75%, respectively
(Table 2, entries 2 and 3). The presence of halogen groups on the
aromatic ring of the nitroalkene such as fluoro 8d, chloro 8e, and
bromo 8f had a certain influence on the enantioselectivity of the
process, with the corresponding adducts (R)-9d, (R)-9e, and
(R)-9f being obtained with diminishing ee’s down to 65% as the
electronegativity of the group was reduced (Table 2, entries 4–6).
This apparent beneficial influence of the presence of electron-with-
drawing groups in the aromatic ring of the nitroalkene was con-
firmed when a nitro group was present 8g, with the reaction
affording adduct (R)-9g in 80% ee (Table 2, entry 7).
18
´
ing Seebachs synclinal model. At that point, the partial negative
charge developing in the nitro group during the CAC bond forming
transition state might be stabilized by hydrogen bonding with the
guanidine (TSH-S and TSH-R, Fig. 1), or alternatively, stabilized and
solvated by the surrounding water molecules (TSW-S).
iPr
H
N
iPr
iPr
N
N
N
iPr
H
iPr
N
H
N
H
N
N
H
N
H
iPr
water
N
N
N
H
H
H
O
O
O
O
O
N
N
N
O
Ph
Ph
TSH- ΔΔGsol = +1.8
Ph
ΔΔGsol = 0
S
R
S
TSW- ΔΔGsol = -1.7
TSH
-
Figure 1. Comparison of the guanidine activated transition states (TSH-S and TSH-R)
with the water activated TSW-S. Free Gibbs energies computed at B3LYP/6-311+
G(d,p) (CPCM, water) level.
As could be anticipated from our previous report on the related
Michael addition catalyzed by 6a,16b we found that if only intramo-
lecular H-bonding was taken into account (TSH-S vs TSH-R), a pref-
erence for the transition state leading to the wrong enantiomer,
that is, (S), would be predicted, since TSH-S (Fig. 1) is 1.8 kcal/
mol lower in energy than its isomeric counterpart TSH-R. The log-
ical reason for it is that in TSH-S, the nitrostyrene and the guanidine
subunit are both found in the lower face of the enamine (from our
view), adopting a less strained disposition. In contrast, the nitro-
styrene and the guanidine lyie in opposite faces of the enamine19
in TSH-R, and the structure needs to twist in order to form the
internal H-bonds, adding some strain to the transition structure.
The clear disagreement of this finding with the experimental re-
sults can be understood as the first indication of the absence of
intramolecular H-bonding in the reaction. Furthermore, confirming
this hypothesis, we easily found a preliminary transition state
(TSW-S, Fig. 1), in which the nitro group was activated by the sur-
rounding aqueous solvent (implicit water solvent model), with
1.7 kcal/mol lower activation energy than TSH-S. Water might have
a twofold effect to lower the activation energy: it can solvate better
the more polar transition state (TSW-S vs TSH-S), and it can form
intermolecular hydrogen-bonds with the nitro group, accompanied
by disruption of the intramolecular ones.
Table 2
Enantioselective Michael addition of isobutyraldehyde to nitroalkenes organocata-
lyzed by 6a
O
Ar
6a
O
(20 mol%)
imidazole (20 mol%)
NO2
Me
NO2
+
H
H
Ar
DMF/H2O 1/4 (v/v), 0 ºC
Me Me
Me
7
9
8
Entry
Nitroalkene
t (d)
Adduct no.
Yielda (%)
eeb,c (%)
Ar
Ph
No.
1
2
3
4
5
6
7
8
9
8a
8b
8c
8d
8e
8f
8g
8h
8i
2
2
2
2
2
2
2
2
2
2
(R)-9a
(R)-9b
(R)-9c
(R)-9d
(R)-9e
(R)-9f
(R)-9g
(R)-9h
(R)-9i
(R)-9j
90
75
89
73
90
70
85
75
91
95
80
80
75
80
75
65
80
70
80
70
4-MeC6H4
4-MeOC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
2-Naphthyl
3-Pyridinyl
2-Furanyl
10
8j
a
b
c
Isolated yield after flash chromatography.
Enantioselectivities determined by chiral HPLC.
Absolute configuration assigned by the order of elution of the enantiomers by
chiral HPLC (see Section 4).
If this is so, we should find a polar transition state, lacking intra-
molecular H-bonds, which would thus explain the preferential for-
mation of the (R)-enantiomer. It is worth noting that the flexibility
induced in the catalyst by the lack of internal hydrogen bonding
restrictions, introduces some added difficulty to the calculations,
due to a higher number of possible conformations in the transition
states. Nonetheless, we were able to identify the two most stable
conformations of the reactive enamine (Fig. 2a and b), and finally
the structures responsible for the formation of the (R)-enantiomer.
Two theoretical approaching trajectories of the nitrostyrene to
the catalyst (green arrows) are possible for each enamine. In
Figure 2a, the face of the enamine19 leading to the (S)-enantiomer
is blocked by the guanidine group, and the corresponding TSA-S is
not feasible, whilest in TSA-R the nitrostyrene approaches from
When nitroalkene 9h bearing
a 2-naphthyl group was
employed as a Michael acceptor, the corresponding adduct (R)-
9h was obtained in 70% ee (Table 2, entry 8). In addition, the influ-
ence of the presence of heteroarylated rings in the nitroalkene was
also explored with the use of the 3-pyridinyl- and 2-furanyl-con-
taining nitroalkenes 8i and 8j as Michael acceptors, which gave rise
to adducts (R)-9i and (R)-9j in 80% and 70% ee, respectively (Ta-
ble 2, entries 8 and 10).
The absolute configuration of the known
was assigned according to the elution order of their enantiomers
in chiral HPLC when compared to the literature (see Section 4).
c-nitroaldehydes 9

A. Avila et al. / Tetrahedron: Asymmetry 25 (2014) 462–467
465
1H and 13C NMR spectra were recorded at 25 °C on a Bruker
AC-300 at 300 and 75 MHz, respectively, using TMS as an internal
standard. Nitroalkenes 8 were purchased or prepared according
the literature.21 Absolute configurations for adducts 9 were deter-
mined according to the described order of elution of their enantio-
mers in chiral HPLC. Reference racemic samples of adducts 9 were
obtained by performing the reaction using 4-methylbenzylamine
(20 mol %) as the organocatalyst in toluene as the solvent at 25 °C.
(a)
cyclohexane
R
approach
(7.1)
guanidine
-R = 26.0
TSA
4.2. General procedure for the enantioselective Michael addition
reaction
S
approach
enamine
feasible
S -S un
T
A
nitr ostyrene
To a solution of 6a, ent-6a, or 6b (0.1 mmol), the nitroalkene
(0.5 mmol) and imidazole (6.8 mg, 0.1 mmol) in DMF/H2O (1:4,
nitr ostyrene
v/v) (1.25 mL) was added isobutyraldehyde (228 lL, 2.5 mmol)
(b)
and the mixture was stirred at 0 °C until reaction completion
(TLC). The reaction was quenched with HCl 2 M (10 mL) and the
mixture was extracted with AcOEt (3 ꢀ 10 mL). The organic phase
was washed with H2O (2 ꢀ 10 mL), dried over MgSO4, and the sol-
vent was evaporated (15 Torr) to give a crude product, which was
purified by silica gel chromatography (n-hexane/AcOEt gradients).
Adducts 9 were identified by comparison of their spectroscopic
data with those of the literature. Their enantiomeric excesses were
determined by chiral HPLC.
R
approach
(7.4)
-R = 27.4
TSB
guanidine
S
approach
(6.7)
-S = 27.9
TSB
enamine
cyclohexane
4.2.1. (R)-2,2-Dimethyl-4-nitro-3-phenylbutanal 9a17
1H NMR (300 MHz, CDCl3): dH = 9.53 (s, 1H), 7.37–7.28 (m, 3H),
7.23–7.16 (m, 2H), 4.86 (dd, J = 13.0, 11.2 Hz, 1H), 4.69 (dd, J = 13.0,
4.3 Hz, 1H), 3.78 (dd, J = 11.2, 4.3 Hz, 1H), 1.14 (s, 3H), 1.01 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3): dC = 204.3, 135.4, 129.2, 128.8,
128.3, 76.4, 48.6, 48.3, 21.8, 19.0 ppm; HPLC: Chiralcel OD-H,
nitr ostyrene
Figure 2. 3D-models (based on computed transition states) for the (R)- and (S)-
approaches of styrene to the two most stable conformations of the enamine. Free
Gibbs energies computed at B3LYP/6-311+G(d,p) (CPCM, water) [M06-2X/6-
311+G(d,p) (SMD, water) in parenthesis].
k = 210 nm,
n-hexane/2-propanol,
80:20,
0.7 mL/min,
tr
(major) = 17.8 min, tr (minor) = 24.5 min.
4.2.2. (R)-2,2-Dimethyl-4-nitro-3-(p-tolyl)butanal 9b17
the unhindered side, leadingzto the transition state with the overall
1H NMR (300 MHz, CDCl3): dH = 9.53 (s, 1H), 7.17–7.04 (m, 4H),
4.82 (dd, J = 12.9, 11.3 Hz, 1H), 4.67 (dd, J = 12.9, 4.2 Hz, 1H), 3.74
(dd, J = 11.3, 4.2 Hz, 1H), 2.32 (s, 3H), 1.13 (s, 3H), 1.01 (s, 3H)
ppm; 13C NMR (75 MHz, CDCl3): dC = 204.5, 138.0, 132.2, 129.5,
129.0, 76.5, 48.3 (ꢀ2), 21.7, 21.1, 19.0 ppm; HPLC: Chiralcel
OD-H, k = 210 nm, n-hexane/2-propanol, 75:25, 0.8 mL/min, tr
(major) = 11.3 min, tr (minor) = 15.5 min.
lowest activation energy (
DGsolv ¼ 26:0 kcal/mol, B3LYP functional).
Meanwhile, the two faces of the other enamine (Fig. 2b) present a
similar hindrance, affording transition states TSB-R and TSB-S of
close energy (27.4 and 27.9 kcal/mol, respectively). Thus, the prefer-
ential formation of the (R)-enantiomer would arise from the pre-
dominance of the sum of TSA-R and TSB-R over TSB-S,20 and the
non-existence of TSA-S. The steric effect of the guanidine group
seems to be the reason behind these observations.
4.2.3. (R)-3-(4-Methoxyphenyl)-2,2-dimethyl-4-nitrobutanal 9c17
1H NMR (300 MHz, CDCl3): dH = 9.53 (s, 1H), 7.15–7.08 (m, 2H),
6.89–6.82 (m, 2H), 4.81 (dd, J = 12.8, 11.3 Hz, 1H), 4.66 (dd, J = 12.8,
4.3 Hz, 1H), 3.79 (s, 3H), 3.73 (dd, J = 11.3, 4.3 Hz, 1H), 1.12 (s, 3H),
1.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): dC = 204.5, 159.4,
130.2, 127.2, 114.2, 76.6, 55.3, 48.5, 48.0, 21.7, 19.0 ppm; HPLC:
Chiralcel OD-H, k = 210 nm, n-hexane/2-propanol, 75:25, 0.8 mL/
min, tr (major) = 13.6 min, tr (minor) = 20.0 min.
3. Conclusion
We conclude that primary amine-guanidines, prepared by a
simple monoguanylation of enantiomerically pure trans-cyclohex-
ane-1,2-diamines act as organocatalysts in the enantioselective
conjugate addition of isobutyraldehyde to nitroalkenes leading to
enantiomerically enriched
c-nitroaldehydes. Good yields and
enantioselectivities can be achieved by working in aqueous
solvents and in the presence of imidazole as a rate-accelerating
additive. Theoretical calculations suggest that the stereoinduction
exerted by the guanidine arises from its capacity to block one of
the faces of the reactive enamine in some of its reactive conforma-
tions, while water molecules activate the nitro group towards
nucleophilic attack by hydrogen bonding and solvation of the polar
transition state.
4.2.4. (R)-3-(4-Fluorophenyl)-2,2-dimethyl-4-nitrobutanal 9d17
1H NMR (300 MHz, CDCl3): dH = 9.51 (s, 1H), 7.19 (m, 2H),
7.05-7.02 (m, 2H), 4.82 (dd, J = 13.1, 11.3 Hz, 1H), 4.68 (dd,
J = 13.1, 4.2 Hz, 1H), 3.81–3.76 (dd, J = 11.3, 4.2 Hz, 1H), 1.13 (s,
3H), 1.01 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): dC = 204.1,
163.7, 161.2, 131.2 (ꢀ2), 130.7 (ꢀ2), 115.9, 115.6, 76.4,
48.2, 47.8, 21.7, 18.9 ppm; HPLC: Chiralcel OD-H, k = 210 nm,
n-hexane/2-propanol, 80:20, 0.8 mL/min, tr (major) = 12.6 min, tr
(minor) = 21.5 min.
4. Experimental
4.1. General
4.2.5. (R)-3-(4-Chlorophenyl)-2,2-dimethyl-4-nitrobutanal 9e17
1H NMR (300 MHz, CDCl3): dH = 9.51 (s, 1H), 7.35–7.29 (m, 3H),
7.19–7.11 (m, 2H), 4.83 (dd, J = 13.1, 11.3 Hz, 1H), 4.69 (dd, J = 13.1,
4.2 Hz, 1H), 3.77 (dd, J = 11.3, 4.2 Hz, 1H), 1.13 (s, 3H), 1.02 (s, 3H)
All of the reagents and solvents employed were of the best
grade available and were used without further purification. The

466
A. Avila et al. / Tetrahedron: Asymmetry 25 (2014) 462–467
ppm; 13C NMR (75 MHz, CDCl3): dC = 203.9, 134.1, 130.5, 129.1,
76.3, 48.3, 48.0, 29.8, 21.9, 19.1 ppm; HPLC: Chiralcel OD-H,
k = 210 nm, n-hexane/2-propanol, 75:25, 0.8 mL/min, tr (major) =
12.9 min, tr (minor) = 20.0 min.
Acknowledgments
We thank the financial support from the Spanish Ministerio de
Economía y Competitividad (projects CTQ2010-20387, CTQ2010-
21263-C02 and Consolider Ingenio 2010, CSD2007-00006), FEDER,
the COST Action CM0905 ‘Organocatalysis’, the Generalitat Valen-
ciana (Prometeo/2009/039), the Basque Government (GV Grant
IT-291-07), the FP7 Marie Curie Actions of the European Commis-
sion via the ITN ECHONET Network (MCITN-2012-316379) and the
universities of Alicante and the Basque Country. We also thank SGI/
IZO-SGIker UPV/EHU for allocation of computational resources.
4.2.6. (R)-3-(4-Bromophenyl)-2,2-dimethyl-4-nitrobutanal 9f17
1H NMR (300 MHz, CDCl3): dH = 9.49 (s, 1H), 7.48–7.45 (m, 2H),
7.11–7.08 (m, 2H), 4.81 (dd, J = 13.1, 11.3 Hz, 1H), 4.68 (dd, J = 13.1,
4.2 Hz, 1H), 3.78–3.73 (dd, J = 11.3, 4.2 Hz, 1H), 1.12 (s, 3H), 0.99
(s, 3H) ppm; 13C NMR (75 MHz, CDCl3): dC = 203.9, 134.5, 131.9,
130.8, 122.3, 76.1, 48.1, 47.9, 21.8, 18.9 ppm; HPLC: Chiralcel
OD-H, k = 210 nm, n-hexane/2-propanol, 80:20, 0.8 mL/min, tr
(major) = 16.4 min, tr (minor) = 24.1 min.
References
4.2.7. (R)-2,2-Dimethyl-4-nitro-3-(4-nitrophenyl)butanal 9g17
1H NMR (300 MHz, CDCl3): dH = 9.49 (s, 1H), 8.21 (m, 2H), 7.44
(m, 2H), 4.93 (dd, J = 13.1, 11.3 Hz, 1H), 4.81–4.76 (dd, J = 13.1,
4.2 Hz, 1H), 3.94 (dd, J = 11.3, 4.2 Hz, 1H), 1.16 (s, 3H), 1.05 (s,
3H) ppm; 13C NMR (75 MHz, CDCl3): dC = 203.2, 147.7, 143.4,
130.2, 123.9, 75.8, 48.2, 48.1, 21.8, 19.0 ppm; HPLC: Chiralcel
OD-H, k = 210 nm, n-hexane/2-propanol, 80:20, 0.7 mL/min, tr
(major) = 12.5 min, tr (minor) = 20.9 min.
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7.70 (m, 1H), 7.50–7.45 (m, 2H), 7.28 (m, 1H), 4.97 (dd, J = 13.1,
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1H NMR (300 MHz, CDCl3): dH = 9.51 (s, 1H), 8.58–8.56 (m, 1H),
8.52–8.51 (m, 1H), 7.60–7.57 (m, 1H), 7.31–7.27 (m, 1H), 4.88 (dd,
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4.2.10. (R)-3-(Furan-2-yl)-2,2-dimethyl-4-nitrobutanal 9j17
1H NMR (300 MHz, CDCl3): dH = 9.52 (s, 1H), 7.38–7.37 (d,
J = 1.6 Hz, 1H), 6.32–6.31 (dd, J = 5.2, 4.0 Hz, 1H), 6.22 (d,
J = 3.2 Hz, 1H), 4.7 (dd, J = 12.8, 11.2 Hz, 1H), 4.58 (dd, J = 13.1,
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110.4, 109.7, 74.9, 48.2, 42.3, 21.1, 19.0 ppm; HPLC: Chiralcel OD-
H, k = 210 nm, n-hexane/2-propanol, 75:25, 0.8 mL/min, tr (ma-
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´
19. Seebachs model is diastereospecific (see Ref. 18), meaning that each reacting
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20. It is worth noting the notorious difference in activation energies between
B3LYP (26–28 kcal/mol) and M06-2X (6–7 kcal/mol) functional, and the fact
that the energies of the three transition states are within computational error
with M06-2X (7.1, 7.4 and 6.7 kcal/mol), restricting the explanation with this
functional to the qualitative difference of approaching trajectories drawn in
Figure 2.
4.3. Calculations
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B3LYP and the 6-31G basis set as implemented in Gaussian 09,23
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frequency calculations in order to verify that they have the
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connecting each transition structure to the correct associated local
minima.

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