Enantioselective michael addition of aldehydes to maleimides organocatalyzed by a chiral primary amine-salicylamide

Article abstract of DOI:10.3390/molecules23123299

A primary amine-salicylamide derived from chiral trans-cyclohexane-1,2-diamine was used as an organocatalyst for the enantioselective conjugate addition of aldehydes, mainly α,α-disubstituted to N-substituted maleimides. The reaction was performed in tolu

Full text of DOI:10.3390/molecules23123299

molecules
Article
Enantioselective Michael Addition
of Aldehydes to Maleimides Organocatalyzed
by a Chiral Primary Amine-Salicylamide
Alejandro Torregrosa-Chinillach 1, Adrien Moragues 1, Haritz Pérez-Furundarena 2,
Rafael Chinchilla 1,
*
, Enrique Gómez-Bengoa 2,
*
and Gabriela Guillena 1,
*
1
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO),
Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain; alextorregrosa96@gmail.com (A.T.-C.);
adrien.moragues@gmail.com (A.M.)
Departamento de Química Orgánica I, Universidad del País Vasco, Apdo. 1072, 20080 San Sebastián, Spain;
hperez017@ikasle.ehu.es
2
*
Correspondence: chinchilla@ua.es (R.C.); enrique.gomez@ehu.es (E.G.-B.); gabriela.guillena@ua.es (G.G.);
Tel.: +34-965-903-822 (R.C.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 26 November 2018; Accepted: 9 December 2018; Published: 12 December 2018
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: A primary amine-salicylamide derived from chiral trans-cyclohexane-1,2-diamine
was used as an organocatalyst for the enantioselective conjugate addition of aldehydes,
mainly
α,α-disubstituted to N-substituted maleimides. The reaction was performed in toluene
as a solvent at room temperature. The corresponding enantioenriched adducts were obtained
with high yields and enantioselectivities up to 94%. Theoretical calculations were used to justify
the stereoinduction.
Keywords: organocatalysis; asymmetric synthesis; Michael addition; maleimides; aldehydes
1. Introduction
Maleimides have been successfully used as building blocks in many asymmetric organocatalytic
transformations for the preparation of compounds of interest [1]. Among the compounds that can be
prepared by the organocatalytic functionalization of maleimides, succinimides are one of the most
important since the succinimide moiety is present in natural products and some clinical drug
candidates [
such as -lactams [
neurological disorders [13].
The most direct way of preparing enantioenriched substituted succinimides is by the organocatalytic
enantioselective conjugate addition of carbon nucleophiles to maleimides [ ]. These carbon nucleophiles
can be generated by the -deprotonation of pro-nucleophiles bearing acidic -hydrogens, such as
1,3-dicarbonyl compounds, by means of chiral organocatalysts that contain both a tertiary amine
suitable to deprotonate the pro-nucleophile as well as an acidic moiety [ ]. The subsequent formation
2–
6
]. Moreover, succinimides can be transformed into other interesting compounds,
γ
7
,8
], which are important in the treatment of HIV [ 10], epilepsy [11 12], and other
9
,
,
1
α
α
1
of a close transition state, which involves the coordination of the maleimide to the catalyst by means of
a hydrogen bond and the enolate generated after deprotonation by the tertiary amine, leads to an efficient
enantioselective process.
However, when aldehydes are used as pro-nucleophiles, the α-deprotonation process becomes
much more difficult. The corresponding conjugate addition can be obtained using primary
amine-bearing organocatalysts that are amenable to create transition states after the formation of
a transient enamine with the pro-nucleophile. Thus, the first organocatalytic Michael addition of
aliphatic aldehydes to N-aryl-maleimides used α,α-phenylprolinol silyl ether 1 as an organocatalyst,
Molecules 2018, 23, 3299; doi:10.3390/molecules23123299
www.mdpi.com/journal/molecules

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affording much lower enantioselectivities when α,α-disubstituted aldehydes were employed [14]
(Figure 1). This type of diarylated prolinol has also been employed as an organocatalyst working in
ionic liquids, although only with linear aldehydes [15].
Different bifunctional primary amine-bearing organocatalysts are suitable to an additional
coordination to the carbonyl group of the maleimide via hydrogen bonds, and are frequently
prepared from chiral trans-cyclohexa-1,2-diamines. Taking into consideration this enamine-forming
approach, these organocatalysts have been applied to the enantioselective Michael addition of
aldehydes to maleimides, giving good enantioselectivities of the corresponding succinimides (Figure 1).
Thus, the primary amine-thioureas
thiourea 21], the isosteviol-derived thiourea
thioureas [24 25], have been successfully employed. In addition, primary amino acid derivatives [26
2
[
16],
3
[
17
,
18],
4
[
19], and
5
[
20], the beyerane-containing
23], and even the calixarene-based
27
6
[
7
[
22], the squaramide
8 [
,
, ]
and dipeptides have also been used [28], as well as a combination of Cinchona alkaloid-derived
thioureas and primary amino acids [29] or Cinchona alkaloid-derived primary amines [30].
Other bifunctional primary amine-containing compounds used as organocatalysts in this transformation
have been the diaminomethyleneindenedione derivative
the guanidine 11 33 34], the 2-aminopyrimidine 12 35], the 2-benzimidazole 13
14 37 39], and the polymer-supported sulfonamides [40]. Even the simple non-derivatized chiral
9
[31], the ionic liquid-supported amide 10
[32],
[
,
[
[36], the carbamate
[
–
trans-cyclohexa-1,2-diamines have been used as organocatalysts [41].
CF3
CF3
Ph
S
S
S
Ph
Ph
OSiMe3
N
N
N
N
N
H
CF3
N
N
H
CF3
H
H
H
H
H
NH2
NH2
Me
NH2
3
4
2
1
Me
S
Me
C8F17
S
S
Me
N
N
O
N
H
N
H
H
N
N
Me
NH2
H
H
H
NH2
NH2
7
5
6
EtO2C Me
O
O
Me
O
O
NH
HN
O
Me
CF3
N Me
+
N
N
N
N
( )4
-
H
H
PF6
H
NH2
NH2
NH2
EtO2C Me
10
CF3
9
8
O
Me
N
N
N
NiPr
Me
Me
N
O
N
H
N
N
N
H
NHiPr
H
H
H
NH2
NH2
NH2
NH2
14
13
12
11
Figure 1. Chiral organocatalysts employed in the enantioselective Michael addition of aldehydes
to maleimides.
Recently, our research group used a chiral primary amine-monosalicylamide from
trans-cyclohexa-1,2-diamine (15 and ent-15, Figure 2) as an organocatalyst for the enantioselective
Michael addition of
-nitroaldehydes in an excellent chemical yield and with enantioselectivities up to 95% [42].
This study discusses the results that were obtained when this organocatalyst was employed in
α,α-disubstituted aldehydes to β-nitroalkenes, obtaining the corresponding
γ

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the enantioselective Michael addition of aldehydes to N-substituted maleimides. The results are
explained by theoretical calculations.
Figure 2. The organocatalyst employed in this study.
2. Results and Discussion
The primary amine-salicylamide 15 was prepared as reported by the monoamidation of
(1R,2R)-cyclohexane-1,2-diamine with phenyl salicylate in refluxing propan-2-ol [42]. The search for
the most appropriate reaction conditions (Table 1) was carried out using the model Michael addition
reaction of isobutyraldehyde (16a) to N-phenylmaleimide (17a). Thus, the reaction organocatalyzed
by 15 (10 mol%) in toluene as a solvent at room temperature afforded the corresponding substituted
succinimide (R)-18aa almost quantitatively and in an excellent 94% ee after 2 days reaction time
(Table 1, entry 1). The (R) absolute configuration of the final adduct was determined by comparing
the elution order of the corresponding enantiomers in chiral HPLC with those in the literature [38].
The use of chlorinated solvents, such as dichloromethane or chloroform, afforded good yields but lower
enantioselectivities for (R)-18aa (Table 1, entries 2 and 3).
Table 1. Screening and optimization of the reaction conditions for the model enantioselective
Michael addition.
ee (%) b
Entry Catalyst Additive
Solvent
Yield (%) a
1
2
3
15
15
15
-
-
-
PhMe
CH2Cl2
CHCl3
98
96
98
94 (R)
74 (R)
75 (R)
DMF/H2O
4
15
-
91
79 (S)
c
5
6
7
8
15
15
15
19
PhCO2H
LiCl
DMAP
-
PhMe
PhMe
PhMe
PhMe
94
88
45
98
77 (R)
85 (R)
83 (R)
87 (S)
a
b
Isolated yield after flash chromatography. Enantioselectivities and absolute stereochemistry determined by
chiral HPLC. c 2/1 v/v.
When a 2/1 v/v mixture of DMF/H2O was used as a solvent, the enantiomeric (S)-18aa was obtained
in 79% ee (Table 1, entry 4). This inversion in the enantioselectivity of the process was also observed
when the related primary amine-monocarbamate 14 was employed as an organocatalyst, and attributed
to a loss of the bifunctional character of the catalyst due to the competitive hydrogen-bond formation
with water [38].
We also assayed the influence of the addition of some acid or basic additives. Thus, when benzoic
acid (10 mol%) was added to the reaction mixture in toluene, (R)-18aa was obtained in only 77% ee
(Table 1, entry 5), an enantioselectivity that rose up to 85% when LiCl was employed as a non-protic

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acid (Table 1, entry 6). The addition of an organic base, such as 4-N,N-dimethylaminopyridine (DMAP),
gave similar ee than before, but in a much lower chemical yield (Table 1, entry 7).
We were curious to determine if the presence of the phenolic OH on the organocatalyst
was the determinant for achieving a high enantioselectivity. Thus, as the organocatalyst, we employed
the primary amine-containing benzamide 19, obtained by the reaction of (1S,2S)-cyclohexane-1,2-diamine
with phenyl benzoate under similar conditions as 15 (Figure 3) [38]. However, under the above optimal
reaction conditions, this organocatalyst 19 gave rise to adduct (S)-18aa in a lower 87% ee (Table 1, entry 8).
Therefore, the presence of the phenolic OH in organocatalyst 15 had an influence on the enantioselectivity
of the reaction. It is interesting to note that the use of a “related” monocarbamate organocatalyst 14 only
gave a 67% ee for (S)-18aa when using toluene as a solvent [38].
Figure 3. The OH-free organocatalyst employed in this study.
Next, we extended the enantioselective Michael addition reaction to other aldehydes
16 and maleimides 17 under the most favorable reaction conditions [15 (10 mol%), toluene, rt],
the results of which are summarized in Table 2. The absolute configuration of the known succinimides
18 was assigned in accordance with the elution order of the enantiomers in chiral HPLC when compared
to the literature (see Experimental Section).
Table 2. Enantioselective Michael addition of aldehydes to maleimides organocatalyzed by 15.
Entry
Aldehyde
Maleimide
Michael Adduct
Yield (%) a
R1, R2
No.
R3
No.
No.
ee b (%) b
1
2
3
4
5
6
7
8
9
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
Me,Me
16a
16a
16a
16a
16a
16a
16a
16a
Ph
4-MeC6H4
4-MeOC6H4 17c
4-ClC6H4
4-AcC6H4
4-O2NC6H4
17a
17b
(R)-18aa
(R)-18ab
(R)-18ac
(R)-18ad
(R)-18ae
(R)-18af
(R)-18ag
(R)-18ah
(R)-18ba
98
87
77
92
73
78
91
71
93
94
88
89
88
13
70
82
56
82
17d
17e
17f
17g
17h
17a
17a
17a
Me
H
Ph
Ph
Ph
-(CH2)4- 16b
-(CH2)5- 16c
Me,H
10
11
(R)-18ca
84
36
16d
(2S,3R)-,(2R,3R)-18da c
79,89 e
98 d
a Isolated yield after flash chromatography. b Enantioselectivities determined by chiral HPLC. Absolute configuration
assigned by the order of elution of the enantiomers in chiral HPLC (See Experimental Section). c 1/1.2 diastereomer ratio
(1H-NMR). d Combined yield. e Enantioselectivities referred to (2S,3R) and (2R,3R), respectively.
Thus, when 16a reacted with N-arylmaleimides 17b and 17c bearing electron-donating groups on
the phenyl ring, such as 4-methyl and 4-methoxy, the corresponding Michael adducts (R)-18ab and (R).
18ac were obtained with similar enantioselectivities (88% and 89%, respectively) (Table 2, entries 2
and 3). In addition, when the N-arylmaleimide 17d bearing a chloro group at the para-position was used,

Molecules 2018, 23, 3299
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adduct (R)-18ad was obtained in an 88% ee (Table 2, entry 4). The presence of electron-withdrawing
groups on the phenyl ring gave rise to a lower enantioselection. Thus, when the N-substituted
maleimide 17e bearing a 4-acetyl group was employed with isobutyraldehyde, succinimide (R)-18ae
was obtained in only a 13% ee (Table 2, entry 5). This value increased to 70% when maleimide 17f
bearing a 4-nitro group, was used as an electrophile (Table 2, entry 6). In addition, an N-alkylated
maleimide, such as N-methylmaleimide (17g), was also used as an electrophile, affording succinimide
(R)-18ag with a 82% ee (Table 2, entry 7). However, when the simple maleimide (17h) was employed,
the final adduct (R)-18ah was isolated in a lower enantioselectivity (56%) (Table 2, entry 8).
,
We also explored the conjugate addition reaction of other
α,α-disubstituted aldehydes with
maleimide 17a Thus, when cyclopentanecarbaldehyde (16b) was used, the corresponding
.
Michael adduct (R)-18ba was isolated in an excellent yield and with an enantioselectivity of 82%
(Table 2, entry 9). The use of cyclohexanecarbaldehyde (16c) as a pro-nucleophile gave only a 36%
ee (Table 2, entry 10). In addition, when propionaldehyde (16d) was employed as a pro-nucleophile,
a 1/1.2 mixture of diastereomers was isolated and (2S,3R)-18da and (2R,3R)-18da were obtained in 79%
and 89% ee, respectively (Table 2, entry 11).
To acquire further insight into the origin of the enantioselectivity, we carried out theoretical
calculations on the reaction between isobutyraldehyde 16a and maleimide 17a in the presence
of organocatalyst 15. According to our previous computational results on a related process [38],
the reaction proceeds by the formation of an enamine, followed by an attack to the electrophilic
maleimide substrate through an endo transition state (Figure 4). We also considered the possible exo
approach, but the higher activation energies were sufficient enough to discard its participation in
the process. In this situation, the two faces of the enamine were clearly differentiated. If the approach of
the maleimide occurred through the upper face (from our view), as it did in TS-1R, an efficient H-bond
between the C=O group of maleimide and the NH group of the catalyst was formed. This activated
the electrophile and induced a low activation barrier (15.2 kcal/mol) for the formation of the R product.
If the approach of the two reactants was occurring from the other face, as it was in TS-1S, the carbonyl
and NH moieties were far enough to avoid the formation of any effective H-bond, and the activation
energy could not be lowered, resulting in a value of 20.3 kcal/mol. Thus, the high energy difference of
the two transition states nicely explained the formation of the experimental major (R)-18aa isomer.
Meanwhile, the diastereomeric transition states for the reaction organocatalyzed by 19 were
also computed. As mentioned before, catalyst 19 lacked the phenolic OH group, and showed
similar reactivity and moderately lower enantioselectivity under similar conditions as catalyst
15 (Table 1, entries 1 and 8). Interestingly, the optimal transition states for 19 were located
(TS-2S and TS-2R, Figure 5) and showed quite similar activation parameters as catalyst 15,
although with enough differences to explain a moderate decrease in the enantioselectivity. For example,
the Gibbs Free activation barriers leading to the two enantiomers were almost equivalent
(15.2 vs 15.5 kcal/mol and 20.3 vs 20.7 kcal/mol), but the activation enthalpy difference between
TS-1R and TS-1S was 6.3 kcal/mol, while the same value for TS-2S vs TS-2R was 5.2 kcal/mol.
Thus, the presence of the OH induced a slight increase in the enthalpy gap between the two faces
of the maleimide. Also, the critical H-bonding distances differed slightly, being shorter for TS-1R
than for TS-2S (compare δO-H in Figures 4 and 5). Thus, these data indicated that the H-bonding
activation of the maleimide was optimal when the phenolic OH was present, lowering the enthalpy
barrier in TS-1R the effects helped to increase the enantioselectivity observed when organocatalyst
15 was employed, rigidifying the NH-CO-Ar benzamide system, which reduced the conformational
variability of catalyst 19.

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Figure 4. Transition states for the formation of (R)-18aa (a) and the (S)-18aa (b) catalyzed by 15.
3D-Newman projections (left-figures), side views (middle-figures) and 2-D representations are shown.
Figure 5. Transition states for the formation of (S)-18aa (a) and (R)-18aa (b) catalyzed by 19.
3. Experimental Section
3.1. General Information
All of the reagents and solvents employed were of the best grade available and were used without
further purification. The 1H spectra were recorded at room temperature on a Bruker Oxford AV300
at 300 MHz, using TMS as the internal standard. Absolute configuration for adducts 18 was determined
according to the order of elution of their enantiomers in chiral HPLC. Reference racemic samples of
adducts 18 were obtained by performing the conjugate addition reaction using 4-methylbenzylamine
(20 mol%) as an organocatalyst in toluene as a solvent at room temperature.
3.2. General Procedure for the Asymmetric Conjugate Addition Reaction
A solution of 15 (0.02 mmol, 4,7 mg) and the maleimide 17 (0.2 mmol) in toluene (0.5 mL)
was added to the aldehyde 16 (0.4 mmol), and the mixture was stirred at rt for 48 h (TLC). The reaction

Molecules 2018, 23, 3299
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was quenched with HCl 2 N (10 mL) and the mixture was extracted with AcOEt (3
×
10 mL).
The organic phase was washed with saturated NaHCO3 (10 mL) and brine (10 mL), dried over MgSO4,
filtered, and the solvent was then evaporated (15 Torr) to get the crude product, which was purified by
silica gel chromatography (n-hexane/AcOEt gradients). Adducts 18 were identified by the comparison
of their 1H-NMR data with those of the literature. Their enantiomeric excesses were determined by
chiral HPLC using the conditions described in each case.
2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal (18aa) [38]. White solid (48 mg, 98%); 1H-NMR
(CDCl3): δH = 9.52 (s, 1H), 7.48 (m, 2H), 7.40 (m, 1H), 7.28 (m, 2H), 3.16 (dd, J = 9.5, 5.5 Hz,
1H), 2.99 (dd, J = 18.2, 9.5 Hz, 1H), 2.63 (dd, J = 18.2, 5.5 Hz, 1H), 1.34 (s, 3H), 1.29 (s, 3H) ppm;
HPLC: Chiralcel OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (minor) = 23.5 min,
tr (major) = 27.2 min.
2-(2,5-Dioxo-1-(p-tolyl)pyrrolidin-3-yl)-2-methylpropanal (18ab) [23]. White solid (45 mg, 87%); 1H-NMR
(CDCl3): δH 9.52 (s, 1H), 7.27 and 7.15 (AA’BB’ system, 4H), 3.15 (dd, J = 9.5, 5.4 Hz, 1H),
2.96 (dd, J = 18.3, 9.5 Hz, 1H), 2.60 (dd, J = 18.2, 5.4 Hz, 1H), 2.37 (s, 3H), 1.31 (s, 3H), 1.28 (s, 3H) ppm;
HPLC: Chiralcel OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, r (minor) = 18.9 min,
tr (major) = 20.8 min.
2-(1-(4-Methoxyphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal (18ac) [17]. White solid (42 mg, 77%);
1H-NMR (CDCl3): δH = 9.52 (s, 1H), 7.19 and 6.98 (AA’BB’ system, 4H), 3.82 (s, 3H), 3.14 (dd, J = 9.5,
5.4 Hz, 1H), 2.97 (dd, J = 18.2, 9.4 Hz, 1H), 2.60 (dd, J = 18.2, 5.3 Hz, 1H), 1.33 (s, 3H), 1.28 (s, 3H) ppm;
HPLC: Chiralpak AS-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min): tr (minor) = 41.6 min,
tr (major) = 44.4 min.
2-(1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal (18ad) [38]. White solid (51 mg, 92%);
1H-NMR (CDCl3): δH = 9.49 (s, 1H), 7.45 and 7.25 (AA’BB’ system, 4H), 3.12 (dd, J = 9.5, 5.4 Hz,
1H), 2.98 (dd, J = 18.1, 9.5 Hz, 1H), 2.62 (dd, J = 18.1, 5.5 Hz, 1H), 1.37 (s, 3H), 1.29 (s, 3H) ppm;
HPLC: Chiralcel OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (minor) = 21.8 min,
tr (major) = 37.0 min.
2-(1-(4-Acetylphenyl)-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal (18ae) [38]. White solid (42 mg, 73%);
1H-NMR (CDCl3): δH = 9.50 (s, 1 H), 8.06 and 7.45 (AA’BB’ system, 4H), 3.14 (dd, J = 9.5, 5.5 Hz, 1H),
3.01 (dd, J = 18.1, 9.6 Hz, 1H), 2.66 (dd, J = 18.2, 5.6 Hz, 1 H), 2.62 (s, 3 H), 1.38 (s, 3 H), 1.31 (s, 3 H) ppm;
HPLC: Chiralpak AS-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 1.0 mL/min): tr (minor) = 31.6 min,
tr (major) = 41.5 min.
2-Methyl-2-(1-(4-nitrophenyl)-2,5-dioxopyrrolidin-3-yl)propanal (18af) [24]. White solid (45 mg, 78%);
1H-NMR (CDCl3): δH = 9.47 (s, 1H), 8.35 and 7.60 (AA’BB’ system, 4H), 3.11 (dd, J = 9.6, 5.2 Hz,
1H), 3.02 (dd, J = 17.7, 9.6 Hz, 1H), 2.66 (dd, J = 17.7, 5.2 Hz, 1H), 1.43 (s, 3H), 1.32 (s, 3H) ppm;
HPLC: Chiralpak AD-H,
λ = 210 nm, n-hexane/2-propanol, 65:35, 1.0 mL/min, tr (minor) = 12.1 min,
tr (major) = 26.6 min.
2-Methyl-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)propanal (18ag) [38]. Colorless oil (33 mg, 91%); 1H-NMR
(CDCl3): δH = 9.51 (s, 1H), 3.03 (dd, J = 9.3, 5.4 Hz, 1H), 2.98 (s, 3H), 2,83 (dd, J = 18.2, 9.3 Hz),
2.41 (dd, J = 18.2, 5.3 Hz, 1H), 1.23 (s, 3H), 1.21 (s, 3H) ppm; HPLC: Chiralpak AS-H,
n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (major) = 12.8 min, tr (minor) = 14.2 min.
λ = 210 nm,
2-(2,5-Dioxopyrrolidin-3-yl)-2-methylpropanal (18ah) [38]. White solid (24 mg, 71%); 1H-NMR (CDCl3):
δH = 9.49 (s, 1 H), 7.95 (br. s, 1 H), 3.09 (dd, J = 9.4, 5.8 Hz, 1H), 2.86 (dd, J = 18.4, 9.4 Hz, 1H),
2.51 (dd, J = 18.4, 5.8 Hz, 1H), 1.26 (s, 3H), 1.25 (s, 3H) ppm; HPLC: Chiralpak AD-H,
n-hexane/2-propanol, 80:20, 1.0 mL/min, tr (major) = 17.3 min, tr (minor) = 23.2 min.
λ = 210 nm,
1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclopentane-1-carbaldehyde (18ba) [38]. White solid (50 mg, 93%);
1H-NMR (CDCl3): δH = 9.39 (s, 1H), 7.50–7.23 (m, 5H), 3.01 (m, 2H), 2.58 (dd, J = 17.6, 9.6 Hz, 1H),

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2.30 (dd, J = 17.6, 5.2 Hz, 1H), 2.07-1.97 (m, 2H), 1.90-1.73 (m, 5H) ppm; HPLC: Chiralcel OD-H,
λ = 210 nm, n-hexane/2-propanol, 80:20, 0.5 mL/min, tr (minor) = 21.8 min, tr (major) = 27.3 min.
1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexane-1-carbaldehyde (18ca) [38]. White solid (48 mg, 84%);
1H-NMR (CDCl3): δH = 9.55 (s, 1H), 7.50–7.23 (m, 5H), 3.22 (dd, J = 9.4, 5.9 Hz, 1H), 2.88 (dd, J = 18.2,
9.4 Hz, 1H), 2.68 (dd, J = 18.1, 5.9 Hz, 1H), 1.99-1.45 (m, 10H) ppm; HPLC: Chiralcel OD-H,
n-hexane/2-propanol, 80:20, 0.9 mL/min, tr (minor) = 20.8 min, tr (major) = 25.7 min.
λ = 210 nm,
2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)propanal (18da) [38]. Yellow oil (45 mg, 98%); Mixture of
diastereomers (ratio: 1/1.2*, 1H-NMR). 1H-NMR (CDCl3): δH = 9.63/9.54* (s, 1H), 7.43–7.19 (m, 10H),
3.33/3.20 (m, 1H), 3.10/3.00 (m, 1H), 3.02/2.97 (dd, J = 18.5, 9.6 Hz, 1H), 2.61/2.55 (dd, J = 17.9, 5.5 Hz,
1H), 1.30/1.25 (d, J = 7.8 Hz, 3H) ppm; HPLC: Chiralpak AD-H,
λ = 210 nm, n-hexane/2-propanol,
80:20, 0.8 mL/min, diastereomer 1: tr (minor) = 17.5 min, tr (major) = 25.9 min, diastereomer 2:
tr (minor)= 18.9 min, tr (major) = 19.7 min.
3.3. Computational Methods.
All reported structures were optimized at Density Functional Theory level using the B3LYP [43–45]
functional as implemented in Gaussian 09 [46]. Optimizations were carried out with the 6-31G(d,p)
basis set. The stationary points were characterized by frequency calculations to verify that they had
the right number of imaginary frequencies. The reported energy values correspond to Gibbs Free
energies, including single point refinements at M06-2X/6-311 + G(d,p) [47] level of theory in a solvent
model (IEFPCM, toluene) [48–50] on the previously optimized structures (computed structures in
the Supplementary Materials).
4. Conclusions
We conclude that a primary amine-salicylamides, prepared by a simple monoamidation
of an enantiomerically pure trans-cyclohexane-1,2-diamine, acts as an efficient organocatalyst in
the enantioselective conjugate addition of aldehydes to maleimides, leading to enantiomerically
enriched succinimides. Good yields and enantioselectivities can be achieved working in toluene
as a solvent at room temperature. Theoretical calculations suggest that the phenolic OH present in
catalyst 15 helps to preorganize the system, inducing a more effective H-bonding of the benzamide
NH towards the activation of the maleimide. The activation can only be effective in one of the faces of
the maleimide (TS-1R), leading to a high degree of enantioselectivity with 15.
Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/23/12/3299/
s1, NMR spectra, HPLC chromatograms and cartesian coordinates of the computed structures.
Author Contributions: A.T.-C. and A.M. performed the experiments; G.G. and R.C. conceived and designed
the experiments and wrote the paper; H.P.-F. carried out the theoretical calculations; E.G.-B. carried out
the theoretical calculations and wrote the paper.
Funding: We thank the financial support from the Spanish Ministerio de Economía, Industria y
Competitividad (CTQ2015-66624-P and CTQ201788171-P) and the University of Alicante (VIGROB-173).
A.M. thanks SIGMA Clermont Chemistry Engineering Graduate School for an ERASMUS+ fellowship. We also
thank the Basque Government (GIC15/03, IT1033-16) for financial support, and IZO/SGI SGIker of UPV/EHU
for human and technical support.
Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 15 and 19 are available from the authors.
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