Asymmetric Michael addition organocatalyzed by α,β-dipeptides under solvent-free reaction conditions

Article abstract of DOI:10.3390/molecules22081328

The application of six novel α,β-dipeptides as chiral organocatalysts in the asymmetric Michael addition reaction between enolizable aldehydes and N-arylmaleimides or nitroolefins is described. With N-arylmaleimides as substrates, the best results were achieved with dipeptide 2 as a catalyst in the presence of aq. NaOH. Whereas dipeptides 4 and 6 in conjunction with 4-dimethylaminopyridine (DMAP) and thiourea as a hydrogen bond donor proved to be highly efficient organocatalytic systems in the enantioselective reaction between isobutyraldehyde and various nitroolefins.

Full text of DOI:10.3390/molecules22081328

molecules
Article
Asymmetric Michael Addition Organocatalyzed by
α,β-Dipeptides under Solvent-Free
Reaction Conditions
C. Gabriela Avila-Ortiz 1 ID , Lenin Díaz-Corona 1, Erika Jiménez-González 1
and
ID
Eusebio Juaristi 1,2,
*
ID
1
Departamento de Química, Centro de Investigación y de Estudios Avanzados, Avenida IPN 2508, Ciudad de
México 07360, Mexico; gabriela@relaq.mx (C.G.A.-O.); lenindc8@relaq.mx (L.D.-C.); erika@relaq.mx (E.J.-C.)
El Colegio Nacional, Luis González Obregón 23, Centro Histórico, Ciudad de México 06020, Mexico
Correspondence: juaristi@relaq.mx; Tel.: +52-55-5747-3722
2
*
Received: 7 June 2017; Accepted: 27 July 2017; Published: 10 August 2017
Abstract: The application of six novel α,β-dipeptides as chiral organocatalysts in the asymmetric
Michael addition reaction between enolizable aldehydes and N-arylmaleimides or nitroolefins is
described. With N-arylmaleimides as substrates, the best results were achieved with dipeptide
2
as a catalyst in the presence of aq. NaOH. Whereas dipeptides 4 and 6 in conjunction with
4-dimethylaminopyridine (DMAP) and thiourea as a hydrogen bond donor proved to be highly
efficient organocatalytic systems in the enantioselective reaction between isobutyraldehyde and
various nitroolefins.
Keywords: peptides; Michael addition; asymmetric organocatalysis; solvent-free reactions
1. Introduction
Organocatalysis has become a powerful method in organic synthesis as can be appreciated by the
rapidly increasing number of publications on this topic [
of organocatalytic processes that are environmentally friendly [15
is by employing alternative activation techniques such as microwaves, ultrasound irradiation and
mechanochemistry [18 20]. Furthermore, removal of the solvent in the reaction leads to a reduction of
the generated waste [21 25]. There are several examples in literature of organocatalytic reactions in
1
–14]. Of special interest is the implementation
–
17]. One way to achieve this goal
–
–
the absence of solvent [26–33].
In this context, the Michael addition reaction is a particularly powerful method for C–C bond
formation. Nevertheless, the enantioselective Michael addition reaction between enolizable aldehydes
and maleimides [34
–
47] or nitroolefins [28
–
30
,48
–
53] has rarely been studied in relation to the reaction
with cyclohexanone (Scheme 1).
O
O
O
R
Ar
*
O
R
R
NO2
N
O
Ar
Cat*
Cat*
O
H
H
H
*
R
R
R
Ar
NO2
N
O
Ar
Scheme 1. Asymmetric Michael addition reaction of aldehydes to nitroolefins and N-arylmaleimides
as acceptor substrates. Cat*, chiral catalyst; *, chiral carbon; Ar, aryl.
Molecules 2017, 22, 1328; doi:10.3390/molecules22081328
www.mdpi.com/journal/molecules

Molecules 2017, 22, 1328
2 of 14
In 2007, Cordova’s research group [54] was the first to study the addition reaction of
isobutyraldehyde to maleimides. More recently, Nájera’s group [55 56] studied the reaction employing
several chiral 1,2-diamines as catalysts, while Kokotos used different - or -amino acids as
organocatalysts in the presence of CsCO3 [57]. Finally, Nugent [58 59] examined the use of isoleucine
,
α
β
,
or threonine as organocatalyst in the presence of a hydrogen bond donor (sulfamide) and a base
(4-dimethylaminopyridine, DMAP) (Figure 1).
Figure 1. Examples of organocatalysts and additives employed in the Michael addition reaction of
aldehydes to maleimides and/or nitroolefins, reported by Nájera et al. [55,56], Kokotos [57], and
Nugent et al. [58,59]. ee, enantiomeric excess.
A few years ago, our research group reported the synthesis of a family of
which were used as precursors in the synthesis of 7-membered heterocyclic type ([1,4]-diazepin-2,5-
diones, that is homodiketopiperazines) derivatives (Scheme 2) [60]. The desired -dipeptides were
readily obtained by the coupling of protected -alanine ( -Ala) and the N-tert-Butoxycarbonyl (N-Boc)
protected amino acid, followed by the removal of the protecting groups. Yields for the coupling step
went from moderate to good, depending on the side chain present in the -amino acid. Deprotection
α,β-dipeptides 1–6,
α,β
β
β
α
of these peptides with trifluoroacetic acid and subsequent isolation using an ion exchange column
with Dowex resin afforded the desired α,β-dipeptides 1–6.
Scheme 2. Synthetic route to the
α,β-peptides of interest in the present work. Me, methyl; Bn,
benzyl; Ph, phenyl; iPr, isopropyl; iBu, isobutyl; sBu, sec-butyl; iBBCl, isobutyl chloroformate; THF,
tetrahydrofuran; rt, room temperature; TFA, trifluoroacetic acid.
Given the proven efficiency of small peptides in asymmetric organocatalysis [61
access to the -peptides depicted in Scheme 2, we deemed it of interest to test their potential
as catalysts in the asymmetric Michael addition reaction. In this regard, -amino acids have been
used successfully as organocatalysts in asymmetric Michael addition reactions [57 64], thus their
incorporation in dipeptidic organocatalysts was anticipated to result in more efficient activation modes.
–63], and having
α,β
β
,

Molecules 2017, 22, 1328
3 of 14
Furthermore, although
β-amino acids are not found as frequently in nature as their
α
-analogs, they
represent a very important research area in organic synthesis since the 1990s [65
to the present work, it has been discovered that the incorporation of -amino acids in peptides induces
significant conformational changes in the resulting foldamers [67 69], which may prove beneficial in
,66]. Of great relevance
β
–
boosting the enantioinduction in the asymmetric Michael additions of interest here.
2. Results
α
,
β
-Dipeptides
important to mention that the
to their -analogs. In particular, the phenylalanine-glycine (Phe-Gly) dipeptide was synthetized in
1
–
6
were examined as potential catalysts in the present work (Figure 2). It is
β-Ala residue gives certain advantages to these molecules in comparison
α,α
the present work in order to compare its catalytic activity. In the event, the synthetic route resulted in
poor yields (see Supplementary Materials) owing to glycine’s low solubility [70].
CH3
N
OH
N
2
OH
N
OH
H2N
H2N
H2N
O
O
O
O
O
O
1
3
N
OH
N
OH
N
OH
H2N
H2N
H2N
O
O
O
O
O
O
4
5
6
Figure 2. Dipeptides 1–6 examined as potential chiral organocatalysts.
Initially, we conducted Michael additions of isobutyraldehyde to N-phenylmaleimide in the
absence of solvent (neat), as shown in Table 1. It is important to mention that it became evident that
a base is required for the reaction to take place. Based on Kokotos’s observations [57], KOH was
chosen as the base additive in this system. It can be observed that the peptides which afforded better
results in terms of yield and selectivity were phenylalanine-
(Leu- -Ala, ) and isoleucine- -alanine (Ileu- -Ala, ) (Table 1). As peptide
a higher yield [60], this dipeptide was selected for further optimization experiments.
β
-alanine (Phe-
β
-Ala,
can be synthesized in
-Dipeptide
2), leucine-β-alanine
β
5
β
β
6
2
α,α
(Phe-Gly) gave a poor yield of Michael adduct with a lack of enantioselectivity (59% yield, 52:48
enantiomeric ratio (er). See Supplementary Materials).
Table 1. Michael addition reaction of isobutyraldehyde to N-phenylmaleimide organocatalyzed by
α,β-dipeptides 1–6.
Essay a
Cat*
er c
% Yield b
1
2
3
4
5
6
1
2
3
4
5
6
79
64
77
65
75
74
76:24
88:12
77:23
79:21
88:12
85:15
a
Reaction conditions: aldehyde (5.5 mmol), maleimide (0.5 mmol), cat* 10 mol % (0.05 mmol), and KOH, 10 mol
b
c
% (0.05 mmol). Isolated yield. Determined by chiral HPLC. rt, room temperature; er, enantiomeric ratio; Cat*,
chiral catalyst.

Molecules 2017, 22, 1328
4 of 14
With dipeptide
2
as the representative chiral catalyst, we proceeded to optimize the reaction
in terms of several key parameters. The first parameter that was evaluated was catalyst loading.
A screening was performed varying the concentration of catalyst from 1 to 25 mol %, finding that the
optimum amount of dipeptide 2 corresponds to 10 mol % (Table 2). Similar observations have been
made by Berkessel, Gröger and co-workers in related systems [70].
Table 2. Michael addition reaction of isobutyraldehyde to N-phenylmaleimide with different amounts
of catalyst.
O
N
O
Cat* 2
KOH
neat, rt
O
O
N
+
H
H
O
O
7
Essay a
Cat* (mol %)
er c
% Yield b
1
2
3
4
5
6
7
1
2
5
10
15
20
25
66
71
74
73
72
76
56
63:37
62:38
73:27
86:14
67:33
65:35
63:37
a
Reaction conditions: aldehyde (5.5 mmol), maleimide (0.5 mmol), KOH was used in the same amount as catalyst
Isolated yield. Determined by chiral HPLC.
2
.
b
c
Next, various hydroxides, carbonates as well as several amines were tested as base additives.
These bases were used in equimolar amounts relative to catalyst (10 mol %). In Table 3, it can
2
be appreciated that hydroxides are the most efficient base additives, leading to better yields and
stereoselectivities. Among them, sodium hydroxide afforded higher enantioselectivity (Table 3,
entry 3).
Table 3. Michael addition reaction of isobutyraldehyde to N-phenylmaleimide organocatayzed by
phenylalanine-β-alanine (Phe-β-Ala, 2) in the presence of different bases.
Essay a
Base
er c
% Yield b
1
2
3
4
5
6
7
8
9
——
LiOH
n.r.
63
69
54
45
57
31
26
66
n.d.
84:16
90:10
73:27
70:30
65:35
68:32
58:42
55:45
49:51
58:42
NaOH
NaHCO3
KHCO3
Na2CO3
K2CO3
Cs2CO3
NMM
10
11
Et3N
DMAP
10
traces
a
Reaction conditions: aldehyde (2.75 mmol), maleimide (0.5 mmol), KOH was used in the same amount as catalyst
b
c
2
.
Isolated yield. Determined by chiral HPLC. NMM, N-methylmorpholine; DMAP, 4-dimethylaminopyridine.

Molecules 2017, 22, 1328
5 of 14
Furthermore, the reaction was examined in solution, exploring different solvents as reaction
mediums. It transpired that only dichloromethane afforded results comparable in yield and selectivity
(77% yield, 88:12 enantiomeric ratio. Table S1 of Supporting Information) relative to the reaction
carried out under neat conditions. No reaction took place with the rest of the solvents that were
examined (see Supplementary Materials). Taking into account the above observations, it was decided
to continue the work in the absence of solvent to further promote processes which are friendlier to the
environment [15–25]. In this regard, the amount of aldehyde substrate was optimized at this point. To
our benefit, the reaction may proceed well with only 5.5 equivalents of isobutyraldehyde, which is
the minimum quantity required to have a homogeneous reaction mixture—with less equivalents, the
reaction becomes too slow.
It may be argued that isobutyraldehyde being used in excess in the reaction (5.5 equivalents
relative to the N-phenyl maleimide substrate) actually acts as a as solvent and reagent. Nevertheless,
this is one aspect of the area of green chemistry where there is clearly no consensus. In particular,
according to the philosophy of Sheldon [21], who states “the best solvent is no solvent”, one strategy
for the development of more environmentally friendly protocols involves solvent-free reactions. In
some cases, this has been achieved using an excess (up to 20 equivalents) of a liquid reagent [31,71,72].
The potential influence of other additives, in particular hydrogen bond donors such as urea,
thiourea and sulfamide, was also examined; however, these additive acids did not lead to any
significant improvement of the stereoselectivity of the reaction. A similarly disappointing observation
was made when the reaction was performed at a low temperature: the reaction became too slow, and
the enantioselectivity did not actually improve (Table S2 of Supplementary Materials).
Once the reaction conditions had been optimized, the scope of the reaction was evaluated with
different maleimides as electrophilic substrates. Table 4 summarizes the results. It can be observed
that N-donor substituents in the aromatic group on the N-substituted maleimide cause a decrease in
the reactivity, which results in poor reaction yields.
Table 4. Michael addition reaction of aldehydes to different N-substituted maleimide substrates.
Essay a
R
Ar
Product
er c
% Yield b
1
2
3
5
6
8
CH3
CH3
CH3
CH3
–(CH2)5–
CH2CH3
4-Cl-C6H4-
4-Br-C6H4-
2-MeO-C6H4-
3-Cl-C6H4-
C6H5-
9
63
39
traces
70
n.r.
47
81:19
83:17
n.d.
69:31
n.d.
10
11
12
13
14
C6H5-
74:26
a
Reaction conditions: aldehyde (2.75 mmol), N-substituted maleimide (0.5 mmol),
2
and KOH both 10 mol %
b
c
(0.05 mmol). Isolated yield. Determined by chiral HPLC.
The potential of dipeptides
Initially, the optimized conditions of the reaction with N-substituted maleimides were employed,
but surprisingly the reaction did not proceed. Therefore, dipeptides were tested under the
conditions reported by Nugent et al. [58 59] who employ DMAP and a hydrogen bond donor (to
1–6 in the Michael addition to nitroolefins was also studied.
1–6
,
ensure the proximity of both substrates) as additives (Table 5). Catalysts
results and were used in subsequent studies.
4 and 6 provided the best
With dipeptide
6 as the catalyst, the effect of catalyst loading was evaluated. Examination of
Table 6 shows that the most suitable catalyst load is 10 mol % (entry 3). It is important to note that
as in the case of the reaction with maleimides, the use of solvent afforded the desired products in

Molecules 2017, 22, 1328
6 of 14
lower yield and decreased stereoselectivity. It was observed that both dichloromethane (DCM) and
water solvent gave the desired product with high selectivity (93:7 and 94:6 er, respectively, Table S3 of
Supplementary Materials). Finally, yields went from moderate to good (64% and 81%, respectively,
Table S3 of Supplementary Materials). Again, the amount of aldehyde was optimized to 5.5 equivalents
in order to use the minimum quantity to perform the reactions maintaining the same results in yield
and selectivity.
Table 5. Michael addition reaction of isobutyraldehyde to trans-β-nitrostyrene organocatalyzed by
α,β-dipeptides 1–6.
Essay a
Cat*
er c
% Yield b
1
2
3
4
5
6
1
2
3
4
5
6
59
72
70
96
13
98
74:26
82:18
77:23
92:8
88:12
93:7
a
Reaction conditions: aldehyde (5.5 mmol), trans-β-nitrostyrene (0.5 mmol), cat* (10 mol %), DMAP (10 mol %),
b
c
urea (10 mol %). Isolated yield. Determined by chiral HPLC.
Table 6. Michael addition reaction of isobutyraldehyde to trans-
β-nitrostyrene with different amounts
of catalyst.
Essay a
Cat* (mol %)
er c
% Yield b
1
2
3
4
5
2
5
10
15
20
n.r.
42
98
89
81
n.d.
93:7
93:7
92:2
92:2
a
Reaction conditions: aldehyde (2.75 mmol), trans-
β
-nitrostyrene (0.5 mmol) DMAP and urea were used in the
b
c
same amount as cat*: 10 mol % (0.05 mmol). Isolated yield. Determined by chiral HPLC.
Following the methodology reported by Nugent and co-workers [58,59], an analysis of the reaction
was undertaken in the presence of different additives. Specifically, three different hydrogen bond
donors were tested: urea, thiourea and sulfamide. The results turned out to be slightly better with
thiourea, which is also readily accessible. Similar observations were made with dipeptides
as catalysts. The potential effect of temperature was also studied. Nevertheless, at low temperatures
15 ◦C and +2 ◦C) the required reaction times turned out to be too long. Thus, it was concluded that
4 and 6
(
−
the best reaction conditions correspond to the employment of 10 mol % of catalyst in the presence of
equimolar amounts of urea or thiourea and DMAP as additives, at ambient temperature, and in the
absence of solvent. Table 7 summarizes the observations derived from this evaluation.
Once the reaction conditions had been optimized, catalysts
addition reactions with different substrates, in order to establish the scope of the reaction. Table 8
summarizes the results. Generally, both and catalysts provided the desired products with similarly
4 and 6 were used to carry out Michael
4
6

Molecules 2017, 22, 1328
7 of 14
high enantiomeric purity. It is important to note that electron withdrawing groups (EWG) conducts
to lower yields in comparison to electron donating groups (EDG). The most dramatic effect was
produced with 2-Br substituted nitroolefin, which gave the lowest yield but despite that, the product’s
stereoselectivity was good (Table 8, essay 2).
Table 7. Michael addition reaction of isobutyraldehyde to trans-β-nitrostyrene organocatalyzed by
dipeptides 4 and 6 in the presence of different hydrogen bond donors and at various temperatures.
Essay a
Cat*
Hydrogen Bond Donor
Temp ( C)
er c
◦
% Yield b
1
2
3
4
5
6
7
8
9
4
——
——
Urea
25
25
25
25
25
25
25
25
2
n.r.
n.r.
96
79
84
98
98
91
72
57
n.d.
n.d.
4 + NaOH
4
4
4
6
6
6
6
6
90:10
91:9
83:17
93:7
92:8
93:7
94:6
95:5
Thiourea
Sulphamide
Urea
Thiourea
Sulphamide
Urea
10
Urea
−15
a
Reaction conditions: aldehyde (2.75 mmol), trans-β-nitrostyrene (0.5 mmol), additives (DMAP + hydrogen bond
b
c
donor was used in 10 mol %). Isolated yield. Determined by chiral HPLC.
Table 8. Michael addition reaction of aldehydes to different substrates.
Essay a
Cat*
R
Ar
Product
er c
% Yield b
4
6
4
6
4
6
4
6
4
6
4
6
78
77
31
29
52
83
95
56
77
45
69
61
86:14
87:13
85:15
83:13
91:9
91:9
91:9
93:7
85:15
91:9
CH3
CH3
CH3
CH3
CH3
CH3
2-MeO-C6H4-
2-Br-C6H4-
4-MeO-C6H4-
4-Me-C6H4-
4-Cl-C6H4-
4-F-C6H4-
1
2
3
4
5
6
15
16
17
18
19
20
90:10
92:8
a
Reaction conditions: aldehyde (2.75 mmol), trans-
β
-nitrostyrene (0.5 mmol), additives (DMAP + thiourea were
b
c
used in 10 mol %). Isolated yield. Determined by chiral HPLC.
Based on the mechanistic observations reported by Nugent [58,59], we propose a plausible
mechanism for the reaction of isobutyraldehyde with both maleimides and trans-β-nitrostyrenes
(Scheme 3).
3. Discussion
For the Michael addition reaction of aldehydes to N-arylmaleimides, the first step should
correspond to enamine formation. The sodium carboxylate that is generated by the hydroxide base

Molecules 2017, 22, 1328
8 of 14
orients the approach of the electrophile, the Na+ cation acting as a bridging Lewis acid. Formation of
the new C–C bond takes place with the concomitant creation of the chiral center. Finally, hydrolysis of
the iminium ion intermediate gives the desired product (Scheme 3).
Scheme 3. Proposed mechanism for the Michael addition reaction of isobutyraldehyde to
N-arylmaleimides catalysed by peptide 2 in the presence of sodium hydroxide as a base.
In the case of enolate addition to nitroolefins, the first step should be an acid-base reaction between
the dipeptide and DMAP, followed by enamine formation. In this case, the resulting intermediate
step is activated by the thiourea molecule, which helps orient the approach of the nitroolefin to the
enamine. Final hydrolysis gives the Michael adduct (Scheme 4).
Scheme 4. Proposed mechanism for the Michael addition reaction of isobutyraldehyde to
trans-
β-nitrostyrene catalysed by peptide 4 in the presence of DMAP and thiourea as the hydrogen
bond donor.

Molecules 2017, 22, 1328
9 of 14
4. Materials and Methods
Methyl ((benzyloxy)carbonyl)-L-phenylalanylglycinate (21
)
.
In a round-bottomed flask provided with
nitrogen atmosphere and magnetic stirring was placed 6.0 g (0.02 mol) of N-protected phenylalani◦ne.
The amino acid was disolved in 20 mL of CH3CN and the flask was placed in an ice bath at 0 C
before the addition of 4.8 mL (0.044 mol, 2.2 equiv.) of N-methyl morpholine and 14.28 mL (0.024 mol,
1.2 equiv.) of a 1.68 M solution of propylphosphonic anhydride (T3P). The reaction mixture was stirred
at 0 ◦C before the addition of additional 2.4 mL (0.022 mol, 1.1 equiv.) of N-methyl morpholine and
2.52 g (0.02 mol, 1 equiv.) of de HCl salt of glycine methyl ester, previously dissolved in 20 mL of
CH3CN. The reaction mixture was allowed to reach ambient temperature and stirred for 24 additional
hours. After this time, the solvent was evaporated and the crude was redisolved in 300 mL of EtOAc
and washed with 1N HCl (2
×
150 mL) and saturated solution of sodium and potassium tartrate
(
1 × 100 mL). The organic extracts were dried with Na2SO4 and concentrated under vacuum. The
product was crystallized from EtOAc:hexane (75:25) affording 5.8 g (78% yield) of the desired product
as a white solid. Experimental properties in agreement with reported in literature [73]. Experimental
mp 118–119 ◦C. [α]2D5 = +0.826 (c = 0.363, CHCl3). H-NMR (400 MHz, DMSO-d6, 120 ◦C) (ppm): 2.89
1
(dd, J1 = 9.2, J2 = 14.0 Hz, 1H), 3.11 (dd, J1 = 4.6, J2 = 14.0 Hz 1H), 3.67 (s, 3H), 3.89 (m, 2H), 4.38 (m, 1H),
5.01 (m, 2H), 6.79 (a, 1H), 7.19–7.36 (m, 10H), 7.94 (a, 1H); 13C-NMR (DMSO-d6/100.52 MHz):
δ 38.3,
41.4, 51.9, 56.6, 66.1, 126.6, 127.8, 128.0, 128.4, 128.6, 129.6, 137.6, 138.3, 156.0, 170.3, 172.1; HRESI-MS:
m/z = 371.1598 [M + H]+; calculated for C20H23N2O5 371.1601.
((Benzyloxy)carbonyl)-L-phenylalanylglycine (22). In a round-bottomed flask provided with magnetic
stirring was placed 600 mg (1.6 mmol) of esther 21 and dissolved in 6 mL of THF. The flask was placed
◦
in an ice bath at 0 C before the addition of 134.5 (3.2 mmol, 2 equiv.) of LiOH monohydrate in 2 mL of
water. The reaction mixture was stirred at 0 ◦C and allowed to reach ambient temperature. After 24 h,
the solvent was evaporated under vacuum and the residue was acidulated with conc. HCl to pH = 2
and then extracted with CH2Cl2. The organic extracts were dried with Na2SO4 and concentrated
under vacuum. The product was crystallized from EtOAc:hexane affording 134 mg (23 % yield) of
22 as a white solid. Experimental properties in agreement with those reported in the literature [74],
mp 128-130 ◦C. [α]2D5
(dd, J1 = 9.2, J2 = 14.0 Hz, 1H), 3.12 (dd, J1 = 4.8, J2 = 9.2 Hz 1H), 3.66 (s, 2H), 4.33 (m, 1H), 5.00 (m,
2H), 6.85 (a, 1H), 7.16–7.36 (m, 10H), 7.57 (a, 1H); 13C-NMR (DMSO-d6, 100.52 MHz):
38.3, 42.8, 56.8,
=
−
10.59 (c = 0.34, AcOH). 1H-NMR (400 MHz, DMSO-d6, 120 ◦C) (ppm): 2.87
δ
66.0, 126.5, 127.7, 127.9, 128.4, 128.6, 129.6, 137.6, 138.6, 156.0, 170.3, 171.3; HRESI-MS: m/z = 357.1452
[M + H]+; calculated for C19H21N2O5, 357.1444.
L-Phenylalanylglycine (A). In a round bottomed flask provided with magnetic stirrer and H2 atmosphere
was placed 86 mg of compound 22 with 8.6 mg of Pd/C 10% w/w. Cautiously, 2 mL of methanol
was added and the reaction was stirred at ambient temperature for 24 h. Finally, the mixture was
filtered on Celite and the solid washed with conc. NH4OH affording 56 mg (quantitative yield) of the
desired product as a white solid. Experimental properties were in agreement with those reported in
the literature [75], mp 218–220 ◦C (decomposes). [α]2D5
=
−
5.59 (c = 0.34, AcOH). 1H-NMR (500 MHz,
D2O) (ppm): 2.84 (dd, J1 = 7.1, J2 = 13.6 Hz, 1H), 2.92 (dd, J1 = 6.7, J2 = 13.6 Hz, 1H), 3.42 (d, J = 17.3 Hz,
1H), 3.63 (d, J = 17.5 Hz,1H), 3.74 (dd, J1 = 6.9, J2 = 7.1 Hz 1H), 7.10–7.25 (m, 5H); 13C-NMR (D2O,
125.76 MHz):
δ 38.9, 43.2, 55.6, 127.4, 128.7, 128.9, 129.4, 135.9, 173.4, 176.3; HRESI-MS: m/z = 223.1077
[M + H]+; calculated for C11H14N2O3, 223.1077.
General method for addition of aldehydes to N-arylmaleimides: 15.6 mg (0.05 mmol) of α,β-dipeptide
2
, 2 mg (0.05 mmol) of NaOH, 0.5 mmol (1 equiv.) of the corresponding maleimide and
2.75 mmol (5.5 equiv.) of the aldehyde were placed in a flask equipped with a magnetic
stirrer. The reaction mixture was stirred for up to 24 h at ambient temperature, until thin layer
chromatography (TLC) showed that the reaction was complete. The product was purified by
flash column chromatography with a mixture of hexanes/EtOAc (7:3) as eluent. The absolute

Molecules 2017, 22, 1328
10 of 14
configuration of the products was assigned by comparison with the available literature [45,55–57,76,77].
The enantiomeric ratio was determined by chiral HPLC. NMR spectra and chromatograms can be
found in Supplementary Materials.
General method for the addition of isobutyraldehyde to nitroolefins: 0.05 mmol of dipeptide
4 or 6,
3.8 mg (0.05 mmol) of (thio)urea, 6.1 mg (0.05 mmol) of DMAP and 0.25 mL (2.75 mmol, 5.5 equiv.)
of isobutyraldehyde were placed in a flask equipped with a magnetic stirrer. The resulting mixture
was stirred for 5 min before the addition of 0.5 mmol (1 equiv.) of the corresponding nitroolefin.
The reaction mixture was stirred for up to 24 h at ambient temperature until TLC showed that the
reaction was complete. The product was purified by flash column chromatography with a mixture of
hexanes/EtOAc (9:1) as eluent. The enantiomeric ratio was determined by chiral HPLC. The absolute
configuration of the products was assigned in accordance with the literature [58,59,76,77].
5. Conclusions
Six novel α,β-dipeptides were evaluated as organocatalysts in the Michael addition reaction
of various aldehydes to different substrates. With N-arylmaleimides or nitroolefins as electrophiles,
the dipeptide alone was not able to promote the reaction, whereas with base NaOH as additive
the asymmetric Michael addition to maleimides proceeds. Similarly, a 1:1 mixture of DMAP and
urea or thiourea promotes the Michael addition reaction to
β-nitrostyrene. The effective use of
additives reported in this work constitutes a clear example of how catalytic activity depends markedly
on non-covalent interactions induced by the additive which are apparently more efficient under
solvent-free reaction conditions. In particular, the sodium salt of the dipeptidic catalyst as well as a
putative supramolecular cluster consisting of dipeptide, DMAP and (thio)urea appear to play a key
role in the stereoselective Michael addition reactions presented here.
Supplementary Materials: The following are available online. References [45,57,59,76–78] are cited in the
supplementary materials.
Acknowledgments: We are grateful to Consejo Nacional de Ciencia Y Tecnología (CONACYT) for financial
support via grant No. 220945. We are also indebted to María Teresa Cortez Picasso, Víctor Manuel González Díaz
and María Luisa Rodríguez Pérez for their assistance in the recording of the NMR spectra.
Author Contributions: C. Gabriela Avila-Ortiz participated in the synthesis of the peptides at large scale, and
performed the experimental work in the organocatalytic reactions with maleimides and the reactions with
Valine-β-Ala as a catalyst in the Michael additions to styrenes. Lenin Díaz-Corona performed the experiments of
the Michael additions to styrenes catalyzed by Ile-β-Ala. Erika Jiménez-González performed the synthesis of the
peptides. Eusebio Juaristi conceived and designed the experiments.
Conflicts of Interest: The authors declare no conflict of interest and the founding sponsors had no role in the
design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the
decision to publish the results.
References
1.
Vetica, F.; de Figueiredo, R.M.; Orsini, M.; Tofani, D.; Gasperi, T. Recent Advances in Organocatalytic Cascade
Reactions toward the Formation of Quaternary Stereocenters. Synthesis 2015, 47, 2139–2184.
Dalko, P.I. Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications, 1st ed.;
John Wiley & Sons: Hoboken, NJ, USA, 2013.
2.
3.
4.
Buckley, B.R. Organocatalysis. Annu. Rep. Sect. B Org. Chem. 2013, 109, 189–206. [CrossRef]
Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev.
2013, 42, 774–793. [CrossRef] [PubMed]
5.
6.
7.
List, B.; Maruoka, K. Science of Synthesis: Asymmetric Organocatalysis, 1st ed.; Thieme Verlag: Stuttgart,
Germany, 2012.
Pellissier, H. Recent Developments in Asymmetric Organocatalysis, 1st ed.; Royal Society of Chemistry:
Cambridge, UK, 2010.
Marqués-López, E.; Herrera, R.P.; Christmann, M. Asymmetric organocatalysis in total synthesis—A trial by
fire. Nat. Prod. Rep. 2010, 27, 1138–1167. [CrossRef] [PubMed]

Molecules 2017, 22, 1328
11 of 14
8.
9.
Bertelsen, S.; Jørgensen, K.A. Organocatalysis—After the gold rush. Chem. Soc. Rev. 2009, 38, 2178–2189.
[CrossRef] [PubMed]
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Asymmetric aminocatalysis—Gold rush in organic
chemistry. Angew. Chem. Int. Ed. 2008, 47, 6138–6171. [CrossRef] [PubMed]
10. MacMillan, D.W.C. The advent and development of organocatalysis. Nature 2008, 455, 304–308. [CrossRef]
[PubMed]
11. Dondoni, A.; Massi, A. Asymmetric organocatalysis: From infancy to adolescence. Angew. Chem. Int. Ed.
2008, 47, 4638–4660. [CrossRef] [PubMed]
12. Enders, D.; Grondal, C.; Hüttl, M.R.M. Asymmetric organocatalytic domino reactions. Angew. Chem. Int. Ed.
2007, 46, 1570–1581. [CrossRef] [PubMed]
13. Seayad, J.; List, B. Asymmetric organocatalysis. Org. Biomol. Chem. 2005, 3, 719–724. [CrossRef] [PubMed]
14. Dalko, P.I.; Moisan, L. In the golden age of organocatalysis. Angew. Chem. Int. Ed. 2004, 43, 5138–5175.
[CrossRef] [PubMed]
15. Hernández, J.G.; Juaristi, E. Recent efforts directed to the development of more sustainable asymmetric
organocatalysis. Chem. Commun. 2012, 48, 5396–5409. [CrossRef] [PubMed]
16. Chauhan, P.; Chimni, S.S. Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach.
Beilstein J. Org. Chem. 2012, 8, 2132–2141. [CrossRef] [PubMed]
17. North, M. Sustainable Catalysis: With Non-Endangered Metals, 1st ed.; Royal Society of Chemistry: Cambridge,
UK, 2016.
18. Hernández, J.G.; Avila-Ortiz, C.G.; Juaristi, E. Useful Chemical Activation Alternatives in Solvent-Free
Organic Reactions. In Comprehensive Organic Synthesis, 2nd ed.; Molander, G.A., Knochel, P., Eds.; Elsevier:
Oxford, UK, 2014; Volume 9, pp. 287–314.
19. Ranu, B.; Stolle, A. Ball Milling towards Green Synthesis, 1st ed.; Royal Society of Chemistry: Cambridge,
UK, 2015.
ˆ
20. Margetic, D.; Strukil, V. Mechanochemical Organic Synthesis, 1st ed.; Elsevier: Oxford, UK, 2016.
21. Sheldon, R.A. Green solvents for sustainable organic synthesis: State of the art. Green Chem. 2005, 7, 267–278.
[CrossRef]
22. Walsh, P.J.; Li, H.; Anaya de Parrodi, C. A green chemistry approach to asymmetric catalysis: Solvent-free
and highly concentrated reactions. Chem. Rev. 2007, 107, 2503–2545. [CrossRef] [PubMed]
23. Anastas, P.; Eghbali, N. Green chemistry: Principles and practice. Chem. Soc. Rev. 2010, 39, 301–312.
[CrossRef] [PubMed]
24. Varma, R.S. Journey on greener pathways: From the use of alternate energy inputs and benign reaction
media to sustainable applications of nano-catalysts in synthesis and environmental remediation. Green Chem.
2014, 16, 2027–2041. [CrossRef]
25. Gawande, M.B.; Bonifácio, V.D.B.; Luque, R.; Branco, P.S.; Varma, R.S. Solvent-Free and Catalysts-Free
Chemistry: A Benign Pathway to Sustainability. ChemSusChem 2014, 7, 24–44. [CrossRef] [PubMed]
26. Machuca, E.; Juaristi, E. Asymmetric Organocatalytic Reactions under Ball Milling. In Ball Milling towards
Green Synthesis, 1st ed.; Ranu, B., Stolle, A., Eds.; Royal Society of Chemistry: Cambridge, UK, 2015.
27. Hernández, J.G.; Juaristi, E. Asymmetric aldol reaction organocatalyzed by (S)-proline-containing dipeptides:
Improved stereoinduction under solvent-free conditions. J. Org. Chem. 2011, 76, 1464–1467. [CrossRef]
[PubMed]
28. Moles, F.J. N.; Bañón-Caballero, A.; Guillena, G.; Nájera, C. Enantioselective aldol reactions with
aqueous 2,2-dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free conditions.
Tetrahedron Asymmetry 2014, 25, 1323–1330. [CrossRef]
29. Kamal, A.; Sathish, M.; Srinivasulu, V.; Chetna, J.; Shekar, K.C.; Nekkanti, S.; Tangellaa, Y.; Shankaraiahb, N.
Asymmetric Michael addition of ketones to nitroolefins: Pyrrolidinyl-oxazole-carboxamides as new efficient
organocatalysts. Org. Biomol. Chem. 2014, 12, 8008–8018. [CrossRef] [PubMed]
30. Wan, W.; Gao, W.; Ma, G.; Ma, L.; Wang, F.; Wang, J.; Jiang, H.; Zhu, S.; Hao, J. Asymmetric aldol reaction
organocatalyzed by bifunctional N-prolyl sulfinamides under solvent-free conditions. RSC Adv. 2014, 4,
26563–26568. [CrossRef]

Molecules 2017, 22, 1328
12 of 14
31. Vega-Peñaloza, A.; Sánchez-Antonio, O.; Avila-Ortiz, C.G.; Escudero-Casao, M.; Juaristi, E. An Alternative
Synthesis of Chiral (S)-Proline Derivatives that Contain a Thiohydantoin Moiety and Their Application
as Organocatalysts in the Asymmetric Michael Addition Reaction under Solvent-Free Conditions. Asian J.
Org. Chem. 2014, 3, 487–496. [CrossRef]
32. Avila-Ortiz, C.G.; López-Ortiz, J.M.; Vega-Peñaloza, A.; Regla, I.; Juaristi, E. Use of (R)-Mandelic Acid as
Chiral Co-Catalyst in the Michael Addition Reaction Organocatalyzed by (1S,4S)-2-Tosyl-2,5-diazabicyclo
[2.2.1] heptane under Solvent-Free Conditions. Asymmetric Catal. 2015, 2, 37–44. [CrossRef]
33. Vizcaíno-Milla, P.; Sansano, J.M.; Nájera, C.; Fiser, B.; Gómez-Bengoa, E. Pyrimidine-Derived Prolinamides
as Recoverable Bifunctional Organocatalysts for Enantioselective Inter-and Intramolecular Aldol Reactions
under Solvent-Free Conditions. Eur. J. Org. Chem. 2015, 2015, 2614–2621. [CrossRef]
34. Chauhan, P.; Kaur, J.; Chimni, S.S. Asymmetric organocatalytic addition reactions of maleimides: A promising
approach towards the synthesis of chiral succinimide derivatives. Chem. Asian J. 2013, 8, 328–346. [CrossRef]
[PubMed]
35. Flores-Ferrándiz, J.; Fiser, B.; Gómez-Bengoa, E.; Chinchilla, R. Solvent-Induced Reversal of Enantioselectivity
in the Synthesis of Succinimides by the Addition of Aldehydes to Maleimides Catalysed by
Carbamate-Monoprotected 1,2-Diamines. Eur. J. Org. Chem. 2015, 2015, 1218–1225. [CrossRef]
36. Flores-Ferrándiz, J.; Chinchilla, R. Solvent-dependent enantioswitching in the Michael addition
of
α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected
cyclohexa-1,2-diamines. Tetrahedron Asymmetry 2014, 25, 1091–1094. [CrossRef]
37. Muramulla, S.; Ma, J.A.; Zhao, J.C.G. Michael addition of ketones and aldehydes to maleimides catalyzed by
modularly designed organocatalysts. Adv. Synth. Catal. 2013, 355, 1260–1264. [CrossRef]
38. Orlandi, S.; Pozzi, G.; Ghisetti, M.; Benaglia, M. Synthesis and catalytic activity of fluorous chiral primary
amine-thioureas. New J. Chem. 2013, 37, 4140–4147. [CrossRef]
39. Durmaz, M.; Sirit, A. Calixarene-based chiral primary amine thiourea promoted highly enantioselective
asymmetric Michael reactions of α,α-disubstituted aldehydes with maleimides. Tetrahedron Asymmetry 2013,
24, 1443–1448. [CrossRef]
40. Yang, W.; Jiang, K.Z.; Lu, X.; Yang, H.-M.; Li, L.; Lu, Y.; Xu, L.W. Molecular Assembly of an Achiral Phosphine
and a Chiral Primary Amine: A Highly Efficient Supramolecular Catalyst for the Enantioselective Michael
Reaction of Aldehydes with Maleimides. Chem. Asian J. 2013, 8, 1182–1190. [CrossRef] [PubMed]
41. Gomez-Torres, E.; Alonso, D.A.; Gómez-Bengoa, E.; Nájera, C. Enantioselective Synthesis of Succinimides
by Michael Addition of 1,3-Dicarbonyl Compounds to Maleimides Catalyzed by a Chiral Bis
(2-aminobenzimidazole) Organocatalyst. Eur. J. Org. Chem. 2013, 2013, 1434–1440. [CrossRef]
42. Ma, Z.W.; Liu, Y.X.; Li, P.L.; Ren, H.; Zhu, Y.; Tao, J.C. A highly efficient large-scale asymmetric
Michael addition of isobutyraldehyde to maleimides promoted by a novel multifunctional thiourea.
Tetrahedron Asymmetry 2011, 22, 1740–1748. [CrossRef]
43. Miura, T.; Nishida, S.; Masuda, A.; Tada, N.; Itoh, A. Asymmetric Michael additions of aldehydes to
maleimides using a recyclable fluorous thiourea organocatalyst. Tetrahedron Lett. 2011, 52, 4158–4160.
[CrossRef]
44. Miura, T.; Masuda, A.; Ina, M.; Nakashima, K.; Nishida, S.; Tada, N.; Itoh, A. Asymmetric Michael
reactions of α,α-disubstituted aldehydes with maleimides using a primary amine thiourea organocatalyst.
Tetrahedron Asymmetry 2011, 22, 1605–1609. [CrossRef]
45. Yu, F.; Jin, Z.; Huang, H.; Ye, T.; Liang, X.; Ye, J. A highly efficient asymmetric Michael addition of
α,α-disubstituted aldehydes to maleimides catalyzed by primary amine thiourea salt. Org. Biomol. Chem.
2010, 8, 4767–4774. [CrossRef] [PubMed]
46. Bai, J.-F.; Peng, L.; Wang, L.-L.; Wang, L.-X.; Xu, X.-Y. Chiral primary amine thiourea promoted highly
enantioselective Michael reactions of isobutylaldehyde with maleimides. Tetrahedron 2010, 66, 8928–8932.
[CrossRef]
47. Xue, F.; Liu, L.; Zhang, S.; Duan, W.; Wang, W. A Simple Primary Amine Thiourea Catalyzed Highly
Enantioselective Conjugate Addition of
7979–7982. [CrossRef] [PubMed]
α,α-Disubstituted Aldehydes to Maleimides. Chem. Eur. J. 2010, 16,
48. Wang, Y.; Li, D.; Lin, J.; Wei, K. Organocatalytic asymmetric Michael addition of aldehydes and ketones to
nitroalkenes catalyzed by adamantoyl L-prolinamide. RSC Adv. 2015, 5, 5863–5874. [CrossRef]

Molecules 2017, 22, 1328
13 of 14
49. Ji, Y.; Blackmond, D.G. The role of reversibility in the enantioselective conjugate addition of
α
,
α
-disubstituted
aldehydes to nitro-olefins catalyzed by primary amine thioureas. Catal. Sci. Technol. 2014, 4, 3505–3509.
[CrossRef]
50. He, J.; Chen, Q.; Ni, B. Highly efficient asymmetric organocatalytic Michael addition of α, α-disubstituted
aldehydes to nitroolefins under solvent-free conditions. Tetrahedron Lett. 2014, 55, 3030–3032. [CrossRef]
51. Avila, A.; Chinchilla, R.; Fiser, B.; Gómez-Bengoa, E.; Nájera, C. Enantioselective Michael
addition of isobutyraldehyde to nitroalkenes organocatalyzed by chiral primary amine-guanidines.
Tetrahedron Asymmetry 2014, 25, 462–467. [CrossRef]
52. Kumar, T.P.; Haribabu, K. Enantioselective Michael addition of α,α-disubstituted aldehydes to nitroolefins
catalyzed by a pyrrolidine-pyrazole. Tetrahedron Asymmetry 2014, 25, 1129–1132. [CrossRef]
53. Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Asymmetric Michael Reaction Catalyzed by Proline Lithium Salt:
Efficient Synthesis of L-Proline and Isoindoloisoquinolinone Derivatives. Chem. Eur. J. 2013, 19, 3573–3578.
[CrossRef] [PubMed]
54. Zhao, G.-L.; Xu, Y.; Sundén, H.; Eriksson, L.; Sayah, M.; Córdova, A. Organocatalytic enantioselective
conjugate addition of aldehydes to maleimides. Chem. Commun. 2007, 734–735. [CrossRef] [PubMed]
55. Avila, A.; Chinchilla, R.; Gómez-Bengoa, E.; Nájera, C. Enantioselective Michael addition of aldehydes
to maleimides organocatalysed by chiral 1,2-diamines: An experimental and theoretical study.
Tetrahedron Asymmetry 2013, 24, 1531–1535. [CrossRef]
56. Avila, A.; Chinchilla, R.; Nájera, C. Enantioselective Michael addition of α,α-disubstituted aldehydes to
maleimides organocatalyzed by chiral primary amine-guanidines. Tetrahedron Asymmetry 2012, 23, 1625–1627.
[CrossRef]
57. Kokotos, C.G. An asymmetric Michael addition of α,α-disubstituted aldehydes to maleimides leading to
a one-pot enantioselective synthesis of lactones catalyzed by amino acids. Org. Lett. 2013, 15, 2406–2409.
[CrossRef] [PubMed]
58. Nugent, T.C.; Sadiq, A.; Bibi, A.; Heine, T.; Zeonjuk, L.L.; Vankova, N.; Bassil, B.S. Noncovalent Bifunctional
Organocatalysts: Powerful Tools for Contiguous Quaternary-Tertiary Stereogenic Carbon Formation, Scope,
and Origin of Enantioselectivity. Chem. Eur. J. 2012, 18, 4088–4098. [CrossRef] [PubMed]
59. Nugent, T.C.; Shoaib, M.; Shoaib, A. Practical access to highly enantioenriched quaternary carbon Michael
adducts using simple organocatalysts. Org. Biomol. Chem. 2011, 9, 52–56. [CrossRef] [PubMed]
60. Jiménez-González, E.; Avila-Ortiz, C.G.; González-Olvera, R.; Vargas-Caporali, J.; Dewynter, G.; Juaristi, E.
Solution-phase synthesis of novel seven-membered cyclic dipeptides containing α- and β-amino acids.
Tetrahedron 2012, 68, 9842–9852. [CrossRef]
61. Fingerhut, A.; Grau, D.; Tsogoeva, S.B. Peptides as Asymmetric Organocatalysts. In Sustainable Catalysis:
Without Metals or Other Endangered Elements Part 1, 1st ed.; North, M., Ed.; Royal Society of Chemistry:
Oxford, UK, 2016; pp. 309–353.
62. Colby Davie, E.A.; Mennen, S.M.; Xu, Y.; Miller, S.J. Asymmetric Catalysis Mediated by Synthetic Peptides.
Chem. Rev. 2007, 107, 5759–5812. [CrossRef] [PubMed]
63. Wennemers, H. Asymmetric catalysis with peptides. Chem. Commun. 2011, 47, 12036–12041. [CrossRef]
[PubMed]
64. Dziedzic, P.; Cordova, A. Acyclic β-amino acid catalyzed asymmetric anti-selective Mannich-type reactions.
Tetrahedron: Asymmetry 2007, 18, 1033–1037. [CrossRef]
65. Juaristi, E. Enantioselective Synthesis of β-Amino Acids, 1st ed.; Wiley-VCH: New York, NY, USA, 1997.
66. Juaristi, E.; Soloshonok, V.A. Enantioselective Synthesis of β-Amino Acids, 2nd ed.; John Wiley & Sons, Inc.:
Hoboken, NJ, USA, 2005.
67. Lelais, G.; Seebach, D. β2-amino acids—Syntheses, occurrence in natural products, and components of
β-peptides. Biopolymers 2004, 76, 206–243. [CrossRef] [PubMed]
68. Seebach, D.; Beck, A.K.; Bierbaum, D.J. The world of beta- and gamma-peptides comprised of homologated
proteinogenic amino acids and other components. Chem. Biodivers. 2004, 1, 1111–1239. [CrossRef] [PubMed]
69. Horne, W.S.; Gellman, S.H. Foldamers with Heterogeneous Backbones. Acc. Chem. Res. 2008, 41, 1399–1408.
[CrossRef] [PubMed]
70. Rulli, G.; Duangdee, N.; Baer, K.; Hummel, W.; Berkessel, A.; Gröger, H. Direction of kinetically
versus thermodynamically controlled organocatalysis and its application in chemoenzymatic synthesis.
Angew. Chem. Int. Ed. 2011, 50, 7944–7947. [CrossRef] [PubMed]

Molecules 2017, 22, 1328
14 of 14
71. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Pyrrolidine
−
thiourea as a bifunctional organocatalyst: Highly
enantioselective Michael addition of cyclohexanone to nitroolefins. Org. Lett. 2006, 8, 2901–2904. [CrossRef]
[PubMed]
72. Chua, P.J.; Tan, B.; Zeng, X.; Zhong, G. Prolinol as a highly enantioselective catalyst for Michael addition of
cyclohexanone to nitroolefins. Bioorg. Med. Chem. Lett. 2009, 19, 3915–3918. [CrossRef] [PubMed]
73. Sayyadi, N.; Skropeta, D.; Jolliffe, K.A. N, O-Isopropylidenated threonines as tools for peptide cyclization:
application to the synthesis of mahafacyclin B. Org. Lett. 2005, 7, 5497–5499. [CrossRef] [PubMed]
74. Kanosue, Y.; Kojima, S.; Hiraga, Y.; Ohkata, K. Relationship between the hydrophobicity of dipeptides and
the Michaelis–Menten constant K m of their hydrolysis by carboxypeptidase-Y and carboxypeptidase-A.
Bull. Chem. Soc. Jpn. 2004, 77, 1187–1193. [CrossRef]
75. Ben-Ishai, D. The use of hydrogen bromide in acetic acid for the removal of carbobenzoxy groups and benzyl
esters of peptide derivatives1. J. Org. Chem. 1954, 19, 62–66. [CrossRef]
76. Yoshida, M.; Sato, A.; Hara, S. Asymmetric Michael addition of aldehydes to nitroalkenes using a primary
amino acid lithium salt. Org. Biomol. Chem. 2010, 8, 3031–3036. [CrossRef] [PubMed]
77. Luo, C.; Du, D.-M. Highly enantioselective Michael addition of ketones and an aldehyde to nitroalkenes
catalyzed by a binaphthyl sulfonimide in water. Synthesis 2011, 1968–1973. [CrossRef]
78. Avila, A.; Chinchilla, R.; Gómez-Bengoa, E.; Nájera, C. Enantioselective synthesis of succinimides by Michael
Addition of aldehydes to maleimides organocatalyzed by chiral primary amine-guanidines. Eur. J. Org. Chem.
2013, 2013, 5085–5092. [CrossRef]
Sample Availability: Samples of the compounds are not available from the authors.
©
2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).