Primary Amine-2-Aminopyrimidine Chiral Organocatalysts for the Enantioselective Conjugate Addition of Branched Aldehydes to Maleimides

Article abstract of DOI:10.1055/s-0034-1380718

Chiral primary amines containing the (R,R)- and (S,S)-trans-cyclohexane-1,2-diamine scaffold and a pyrimidin-2-yl unit are synthesized and used as general organocatalysts for the Michael reaction of α-branched aldehydes to maleimides. The reaction takes place with 10 mol% organocatalyst loading and hexanedioic acid as cocatalyst in aqueous N,N-dimethylformamide at 10 °C affording the corresponding succinimides in good yields and enantioselectivities. DFT calculations support the stereochemical results and the role played by the solvents.

Full text of DOI:10.1055/s-0034-1380718

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2199–2206
2199
special topic
P. Vízcaíno-Milla et al.
Special Topic
Synthesis
Primary Amine–2-Aminopyrimidine Chiral Organocatalysts for
the Enantioselective Conjugate Addition of Branched Aldehydes
to Maleimides
R1
Pascuala Vízcaíno-Millaa
José M. Sansanoa
Carmen Nájera*a
Béla Fiserb
Enrique Gómez-Bengoa*b
O
N
H
R2
CHO
δ+
R3
N
N
N
N
N
+
OHC
R1
δ–
N
O
H2N
HN
O
R2
H
O
S,S
PhN
R
N
R3
DMF–H2O, 0–5 °C
high yields
up to 93% ee
O
transition state
O
a Departamento de Química Orgánica and Centro de
Innovación, en Química Avanzada (ORFEO-CINQA),
Universidad de Alicante, Apdo. 99, 03080 Alicante,
Spain
cnajera@ua.es
b Departmento de Química Orgánica I, Facultad de
Química, Universidad del País Vasco, Apdo. 1072,
20080 San Sebastián, Spain
enrique.gomez@ehu.es
Received: 26.03.2015
Accepted after revision: 13.04.2015
Published online: 26.05.2015
an excellent rigid chiral scaffold to anchor a moiety able to
activate the electrophile by hydrogen bonding lowering the
LUMO.7 Since the pioneering studies performed by
Jacobsen,8 Schreiner,9 and Takemoto,10 primary amine-
thiourea derivatives have become the most popular organo-
catalysts.4b,c
Organocatalyzed conjugate addition of α,α-disubstitut-
ed aldehydes to maleimides is one of the most studied reac-
tions using primary amine catalysts. This process allows
easy access to enantiomerically substituted succinimides,
which are interesting core structural units in natural prod-
ucts and biologically active compounds, such as andrimid,
moiramide B, and hirsutellones A–E with antibacterial ac-
tivity, haterumaimides A–Q with antitumor activity, and
tandospirone, which is an anxiolytic and antidepressant
drug.11 In addition, enantioenriched succinimides can be
used as chiral building blocks as they are easily transformed
into pyrrolidines, γ-lactams, and γ-lactones.12
Bifunctional primary amine derived organocatalysts
from trans-cyclohexane-1,2-diamine (R,R)-1 and its enan-
tiomer, bearing a thiourea unit 2,13 3,14 the guanidine deriv-
ative 4,15 the starting diamine 1,16 and its N-Boc-monopro-
tected derivative 5,17 efficiently promoted the Michael-type
addition of α,α-disubstituted aldehydes to maleimides
(Figure 1). Recently, we demonstrated that the 2-amino-
benzimidazole18 and 2-aminopyrimidine19 units are excel-
lent hydrogen bond donors, the corresponding bifunctional
organocatalysts 618 and 719 were used in Michael and aldol
reactions, respectively (Figure 1).
DOI: 10.1055/s-0034-1380718; Art ID: ss-2015-c0196-st
Abstract Chiral primary amines containing the (R,R)- and (S,S)-trans-
cyclohexane-1,2-diamine scaffold and a pyrimidin-2-yl unit are synthe-
sized and used as general organocatalysts for the Michael reaction of α-
branched aldehydes to maleimides. The reaction takes place with 10
mol% organocatalyst loading and hexanedioic acid as cocatalyst in
aqueous N,N-dimethylformamide at 10 °C affording the corresponding
succinimides in good yields and enantioselectivities. DFT calculations
support the stereochemical results and the role played by the solvents.
Key words asymmetric organocatalysis, maleimides, succinimides, al-
dehydes, Michael addition
Enamine1 and iminium2 activation modes of carbonyl
compounds have promoted the development of asymmet-
ric organocatalysis in the last 15 years. Initially chiral sec-
ondary amines were used predominantly in amino cataly-
sis, but more recently primary amines have appeared that
are based on the chemistry of type I aldolases with lysine
residues.3 Chiral primary amines derived organocatalysts
are crucial for enamine formation of hindered carbonyl
compounds, namely α,α-disubstituted aldehydes.4 Several
problems have to be overcome with α-branched aldehydes
apart from steric hindrance,5 the formation of low reactive
enamines,6 and Z/E mixture of diastereomeric enamines.
Several enantioselective reactions have been performed,
such as conjugate additions, aldol and Mannich reactions,
and α-heterofunctionalization of aldehydes, allowing the
formation of quaternary stereocenters.
Continuing this line of research, and based on the expe-
rience of our group in organocatalyzed asymmetric reac-
tions, we envisaged that a primary amine–2-aminopyrimi-
dine organocatalyst 8 derived from trans-cyclohexane-1,2-
Apart from amino acid derivatives, several bifunctional
primary amine organocatalysts derived from chiral 1,2-di-
amines have been developed. Among them, trans-cyclohex-
ane-1,2-diamine, available in both enantiomeric forms, is
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P. Vízcaíno-Milla et al.
Special Topic
Synthesis
N
N
CF3
, Et3N, i-PrOH
Cl
1.
HN
S
N
H2N
NH2
H2N
HN
2. TFA, CH2Cl2
(65%)
BocHN
NH2
H2N
HN
CF3
1
2
N
ent-5
8
Me
Scheme 1 Synthesis of the organocatalyst 8
HN
S
Me
H2N
HN
in 78% yield as a racemic compound (entry 1). Under the
same reaction conditions using tetrahydrofuran instead of
toluene the reaction failed, and in dichloromethane com-
pound 9a was isolated in 79% yield with a modest 29% ee
and with S-configuration (entries 1–3). However, the use of
water as the solvent gave 9a after three days in 74% yield
and with 44% ee with R-configuration (entry 4). The same
sense of enantiomeric bias was observed in N,N-dimethyl-
formamide, but longer reaction times (ca. 6 d), lower yield
(33%), and higher enantiomeric excess (62% ee) (entry 5).
Therefore, mixtures N,N-dimethylformamide–water (in ra-
tios of 2:1 and 4:1) were examined and these afforded sim-
ilar results, 70% yield and 79% ee (entries 6 and 7).
The reaction failed in the presence of basic additives
such as DABCO or imidazole (entries 8 and 9), which were
beneficial in the case of organocatalysts 116 and 4.15 On the
other hand, when carboxylic acids such as trifluoroacetic,
benzoic, or hexanedioic acid, were used as the additive, the
reaction accelerated only in the case of benzoic and hexane-
dioic acids (entries 10–12). Using 10 mol% hexanedioic acid
as the cocatalyst gave product (R)-9a in 80% yield and with
79% ee; 20 mol% loading of catalyst and cocatalyst gave the
same results (entry 13). Using ent-8 as the catalyst gave the
corresponding product (S)-9a (entry 14).
3
EtO2C
Me
Ot-Bu
NHi-Pr
H2N
HN
H2N
HN
O
Ni-Pr
5
4
6
N
N
N
HN
HN
Me2N
HN
H
N
HN
O
7
N
N
N
N
H2N
HN
ent-8
H2N
HN
8
Figure 1 trans-Cyclohexane-1,2-diamine-derived organocatalysts
Finally, when the temperature was lowered to 0 °C, the
time required for the reaction to go to completion was two
days giving the product in 83% isolated yield and with 88%
ee (entry 15). Under the latter reaction conditions, this con-
jugate addition of isobutyraldehyde was scaled up from 0.3
mmol to ca. 3.5 mmol [N-phenylmaleimide (0.5 g)] afford-
ing (R)-9a after 16 hours reaction time in 99% crude yield
and with 85% ee. Further recrystallization from hexane–
ethyl acetate gave pure succinimide in 75% yield.
Once the optimal reaction conditions had been estab-
lished [catalyst 8 (10 mol%), hexanedioic acid (10 mol%) as
cocatalyst, in N,N-dimethylformamide–water (2:1) as sol-
vents, at 0 to 5 °C], the scope of the reaction was studied
(Scheme 2). The addition of isobutyraldehyde to maleimide
and N-alkylmaleimides such as N-methyl- and N-benzyl-
maleimide, afforded succinimides 9b–d in good yields and
76–82% ee. In the case of the conjugate addition of isobu-
tyraldehyde to N-aryl-substituted maleimides the corre-
sponding products 9e–g were obtained in higher yields
(70–92%) and with 87–86% ee (Scheme 2).
diamine would be able to catalyze the conjugate addition of
α,α-disubstituted aldehydes to maleimides. Density func-
tional theory (DFT) calculations would clarify the role of
the 2-aminopyrimidine unit as rigid guanidine-type func-
tion able to form hydrogen bonds with the carbonyl group
of the maleimide acceptor.
The primary amine–aminopyrimidine organocatalyst 8
was synthesized by reaction of N-Boc-monoprotected de-
rivative ent-5 with commercially available 2-chloropyrimi-
dine in the presence of triethylamine in refluxing propan-
2-ol for 36 hours, followed by trifluoroacetic acid deprotec-
tion at room temperature in dichloromethane (Scheme 1).19
Compound 8 and its enantiomer ent-8 were both obtained
in 65% overall yield.
As model reaction isobutyraldehyde (2 equiv) was re-
acted with N-phenylmaleimide in the presence of 10 mol%
of organocatalyst 8 (Table 1). When the reaction was per-
formed in toluene as the solvent at room temperature for
three days the corresponding succinimide 9a was isolated
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P. Vízcaíno-Milla et al.
Special Topic
Synthesis
Table 1 Optimization of the Reaction Conditionsa
O
O
8 (10 mol%)
N
Ph
N
Ph
+
CHO
OHC
additive (10 mol%)
solvent, T (ºC)
O
O
9a
Entry
Solvent
Additive
Temp (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
toluene
–
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
72
96
72
72
140
72
72
72
72
72
16
16
15
18
48
78
–
rac
THF
–
–
3
CH2Cl2
–
79
74
33
70
71
–
29 (S)
44 (R)
62 (R)
79 (R)
79 (R)
–
4
H2O
–
5
DMF
–
6
DMF–H2O (2:1)
DMF–H2O (4:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
DMF–H2O (2:1)
–
7
–
8
DABCO
imidazole
TFA
9
–
–
10
11
12
13
14f
15
–
–
PhCO2H
HDAd
HDAe
HDAe
HDAe
84
80
80
77
83
75 (R)
79 (R)
79 (R)
79 (S)
88 (R)
a Reaction conditions: isobutyraldehyde (0.6 mmol), N-phenylmaleimide (0.3 mmol), catalyst 8 (10 mol%), additive (10 mol%), solvent (0.6 mL).
b Isolated yield after flash chromatography.
c Determined by chiral HPLC.
d Hexanedioic acid.
e 20 mol%.
f The reaction was carried out using ent-8.
In order to extend this methodology to other aldehydes
such as cyclopentane- and cyclohexanecarbaldehyde were
allowed to react with N-phenylmaleimide. The resulting
succinimides 9h and 9i were isolated in 84 and 89% yield
and with 89 and 93% ee, respectively (Scheme 2). Low dia-
stereoselectivity was observed in the Michael addition of 2-
phenylpropanal and propanal giving products 9j and 9k in
72 and 49% yields and as a mixture 6:1 and 2:1 of diastereo-
mers, respectively; the major isomers 9j and 9k were ob-
tained with 81% and 72% ee, respectively.
The absolute configuration was assigned according to
our previous work using 4 as an organocatalyst.15 The ob-
served enantioinduction indicates that the catalytic process
should take place through a different activation mode of the
2-aminopyrimidine than the thiourea unit in Takemoto’s
catalyst 2.13b Experimental work using catalyst 8 with dif-
ferent enantiomeric excess revealed the absence of a non-
linear effect, it means that in the transition state only one
molecule of the catalyst is involved.
isobutyraldehyde and N-phenylmalemide. Considering that
the bifunctional catalyst 8 bears primary and secondary
amine moieties, the classical mechanism supports the for-
mation of a nucleophilic reacting enamine from the prima-
ry amine and aldehyde. At this point it is reasonable that
this intermediate enamine attacks one of the enantiotopic
faces of the maleimide electrophile. As expected, our pre-
liminary studies showed that this attack is in agreement
with the Seebach’s synclinal model (Figure 2).20 A key fea-
ture of this model is that the reacting face of the enamine
diastereospecifically attacks only one of the faces of the
maleimide. That is, the lower face of the enamine (from our
point of view in Figure 2) is reacting with the Re face of the
maleimide, and the upper face of the enamine must react
with the Si face of the maleimide. The transition structures
found in the present study follow this simple reactivity
model.
The most intriguing experimental data is the solvent-
dependent sense of the enantioselectivity, which affords
the major R-enantiomer in a highly polar reaction medium
(DMF–H2O), a racemic mixture in toluene, and the reversal
In addition, DFT calculations were carried out in order
to get a deeper understanding into the origin of the enan-
tioselectivity with catalyst 8, for the reaction between
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P. Vízcaíno-Milla et al.
Special Topic
Synthesis
At first glance, the secondary NH moiety of the amino-
O
O
R1
pyrimidine group seems to be well suited to H-bond activa-
tion of the maleimide carbonyl oxygen, which could lower
the activation energy of the reaction and increase the reac-
tion rate. Our initial hypothesis is that the model structure
on the left in Figure 2 (Re face of the maleimide) shows a
better disposition of the maleimide and the aminopyrimi-
dine fragments to interact by H-bonding, since they are
both found quite close to each other in the lower face of the
enamine. Thus, apolar and nonprotic solvents that favor the
formation of such internal H-bonds, would induce the gen-
eration of the S-enantiomer. In the inverse situation, the
transition state leading to the formation of the R-enantio-
mer (Figure 2, right) does not show a facile H-bonding pat-
tern, since the pyrimidine and maleimide occupy opposite
faces of the enamine. This structure would be favored in po-
lar, protic solvents that are known to easily solvate polar
transition states, disrupting internal H-bond interactions.
We confirmed this hypothesis in light of the computed
transition state activation energies. For example, a struc-
ture was located (TS-S1, Figure 3), that bears the mentioned
H-bond, leading to the formation of the S-product. It corre-
sponds to a quite apolar TS, and therefore, the computed ac-
tivation values reflect a marginal dependence on the sol-
vent model employed during the calculations. Nonetheless,
as expected, the lowest barrier corresponds to the gas
phase system (15.8 kcal/mol), which also presents the
strongest H-bond (2.00 Å). The H-bonding strength de-
creases in dichloromethane (2.03 Å), and even more in wa-
ter (2.12 Å).
8 (10 mol%)
R3
N
R3
N
+
CHO
R2
OHC
HDA (10 mol%)
DMF–H2O (2:1), 0–5 °C
R2
R1
O
O
9
O
O
O
N
Me
N
Bn
N
H
OHC
Me
OHC
Me
OHC
Me
O
O
O
Me
Me
Me
9b: 72 h, 76%, 76% ee 9c: 60 h, 83%, 76% ee 9d: 48 h, 90%, 82% ee
O
O
N
4-BrC6H4
N
3-ClC6H4
OHC
Me
OHC
Me
O
O
Me
Me
9e: 72 h, 70%, 87% ee
9f: 60 h, 92%, 87% ee
O
O
O
N
Ph
N
Ph
OHC
N
4-ClC6H4
OHC
OHC
Me
O
O
O
Me
9g: 70 h, 87%, 86% ee
9h: 72 h, 84%, 89% ee 9i: 60 h, 89%, 93% ee
O
O
N
Ph
N
Ph
OHC
OHC
Me
O
Me
O
Ph
cyclohexane
apolar TS
9j: 72 h, 6:1 dr, 72%, 81% ee 9k: 72 h, 2:1 dr, 49%, 72%:60% ee
Scheme 2 Synthesis of enantioenriched succinimides 9
N
N
N
H
H
N
pyrimidine
H-bond
Ph
enamine
intramolecular
H-bonding
activation
O
N
O
N
N
N
N
S
maleimide
N
N
TS-S1
H
H
maleimide pro-S approach
gas phase: 15.8 kcal/mol
CH2Cl2: 16.3 kcal/mol
water: 16.2 kcal/mol
proximal
distal
O
O
NH
Ph N
TS-S1
NH
Ph N
gas phase
Figure 3 Computed activation energies for the transition state TS-S1 in
the gas phase, dichloromethane and water models. Structures and val-
ues were obtained at M06-2X/6-311++G** level of theory.
O
O
Re face maleimide
lower face enamine
S product
Si face maleimide
upper face enamine
R product
Figure 2 Faces of enamine and N-phenylmaleimide reacting through
Seebach’s synclinal model
Furthermore, a number of transition states lacking any
internal H-bond were located, and the two lowest in energy
among them are shown in Figure 4. Both structures lead to
the formation of the R-enantiomer. Their charge separation
(developing negative charge in the carbonyl oxygen and
positive in the enamine nitrogen) is quite high, inducing a
polar structure, that would be better stabilized in polar sol-
formation of S-product (although with low ee) in a more
apolar solvent such as dichloromethane. Our computational
data provide a plausible explanation of this interesting ef-
fect.
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P. Vízcaíno-Milla et al.
Special Topic
Synthesis
vents. Indeed, not surprisingly, the activation energy values
show a clear decreasing trend on going from the gas phase
system (>17 kcal/mol), to dichloromethane (ca. 16
kcal/mol) to the lowest one in water (15.4 kcal/mol). The
energy differences between gas phase and water, ca. 2
kcal/mol, are significant and could justify an increase reac-
tivity of around two orders of magnitude. Also, the three
energy values for TS-R1 are lower than the corresponding
values for TS-R2, indicating that the former is operative in
the mechanism leading to the R-enantiomer.
tioselectivity. DFT calculations support that H-bonding ac-
tivation of the maleimide by NH moiety of the aminopy-
rimidine is not taking place in the enantiodiscrimination
stage. The aminopyrimidine unit shows only steric hin-
drance in the transition state. However, under apolar sol-
vents due to H-bonding interactions the opposite enantio-
mer, but with very poor enantioselection, is preferred.
All reagents were purchased from commercial sources and used with-
out further purification. Substrates which were not commercially
available were synthesized according to known literature procedures.
Catalysts 8 were synthesized as previously described.19 Melting
points were determined with a Reichert Thermovar hot plate appara-
tus and are uncorrected. IR spectra were recorded on a Jasco FT-IR
4100 LE (Pike Miracle ATR) and only the structurally most relevant
peaks are listed. NMR spectra were performed on a Bruker AC-300 or
Bruker Avance-400 using CDCl3 as solvent and TMS as internal stan-
dard unless otherwise stated. LR-MS (EI) mass spectra were obtained
at 70eV on Agilent GC/MS-5973N apparatus equipped with a HP-5MS
column (Agilent technologies, 30 m × 0.25 mm) and HRMS-ESI were
obtained on a Waters LCT Premier XE apparatus equipped with a time
of flight (TOF) analyzer and the samples were ionized by ESI tech-
niques and introduced through an ultra-high pressure liquid chroma-
tography (UPLC) model Waters Acquity H class. Optical rotations were
measured on a Jasco P-1030 Polarimeter with a 5-cm cell (c given in
g/100 mL). Enantioselectivities were determined by HPLC analysis
(Agilent 1100 Series HPLC) equipped with a G1315B diode array de-
tector and a Quat Pump G1311A equipped with the corresponding
Daicel chiral column. Analytical TLC was performed on Merck silica
gel plates and the spots visualized with UV light at 254 nm. Flash
chromatography employed prepackaged columns (12 mm i.d ×7.5 or
15 cm) using Merck silica gel 60 (0.040–0.063 mm) and a chromatog-
raphy pump Büchi Controller C-610-Module C-601. Silica gel 60 F254
containing gypsum was employed for preparative layer chromatogra-
phy.
polar TS
water solvated
δ–
N
Ph
H
O
δ+
N
N
N
δ–
O
N
N
O
H
H
R
N
N
H
N
PhN
R
O
TS-R1
TS-R2
maleimide pro-R face approach
gas phase: 17.2 kcal/mol
CH2Cl2: 15.9 kcal/mol
maleimide pro-R approach
gas phase: 18.3 kcal/mol
CH2Cl2: 16.4 kcal/mol
water: 16.2 kcal/mol
water: 15.4 kcal/mol
Figure 4 Computed activation energies for the transition states TS-R1
and TS-R2 in the gas phase, dichloromethane and water models. Struc-
tures and values were obtained at M06-2X/6-311++G** level of theory.
The main outcome of this study is that if the reaction is
carried out in polar solvents such as the N,N-dimethylform-
amide–water mixture, any possible internal H-bond would
be disrupted, resulting in the lowest activation energy (in a
water model) for TS-R1 (15.4 kcal/mol). In the opposite di-
rection, TS-S1, which bears an internal H-bond, is predicted
to be the most favorable structure in the absolutely apolar
gas phase model (15.8 kcal/mol). Both data are in agree-
ment with the experimental trend, R-enantiomer in polar
and S-enantiomer in apolar systems. The calculations in di-
chloromethane are between those of water and gas phase.
Whilst it is true that the lowest energy value in dichloro-
methane erroneously corresponds to TS-R1 (15.9 kcal/mol),
its difference to TS-S1 is very low (0.4 kcal/mol) and can be
considered within the calculation error limits. Taking also
into account that the 24% excess of S compound in dichloro-
methane corresponds to an experimental energy difference
of 0.29 kcal/mol, and that the reaction in the similar solvent
toluene produces racemic product, the agreement between
experiment and theory at this point is also significant.
In conclusion, trans-cyclohexane-1,2-diamine derived
primary amine–2-aminopyrimidine organocatalysts 8 pro-
mote the conjugate addition of aldehydes to maleimides
with 10 mol% loading and using hexanedioic acid as cocata-
lyst in good yield and up to 93% ee. The best solvent is N,N-
dimethylformamide and the presence of water as cosolvent
has a beneficial effect on the yield, reaction time, and enan-
(S,S)-2-(Pyrimidin-2-ylamino)cyclohexaneamine (8);19 Typical
Procedure
A mixture of ent-5 (3.27 g, 15.25 mmol), Et3N (2.53 mL, 18.31 mmol),
and 2-chloropyrimidine (2.09 g, 18.31 mmol) in i-PrOH was stirred
for 36 h at 80 °C under argon atmosphere. The mixture was concen-
trated in vacuo and the residue was dissolved in CH2Cl2 (10 mL) and
washed with H2O (3 × 20 mL). After removal of the solvent under re-
duced pressure the resulting reside was purified by flash chromatog-
raphy (hexane–EtOAc) to give Boc-protected 8 (3.52 g). The resulting
solid residue was dissolved in CH2Cl2 (110 mL) and TFA (9.08 mL, 120
mmol) was added and the mixture was stirred for 4 h. The solvents
were removed under reduced pressure and the residue was dissolved
in CH2Cl2 (30 mL) and extracted with H2O (3 × 30 mL). The aqueous
layer was treated with 2 M NaOH solution until basic pH and extract-
ed with CH2Cl2 (3 × 60 mL). The combined organic layers were dried
(MgSO4) and filtered, and the solvents were removed under reduced
pressure to yield 8 (2.64 g, 71% overall yield) as a yellow solid; mp
75°C; [α]D26 +51.4 (c 1, CHCl3).
IR: 3243, 2927, 2859, 1583, 1528, 1449, 1418, 1136, 959, 920, 798.
1H NMR: δ = 8.22 (d, J = 4.8 Hz, 2 H), 6.46 (t, J = 4.8 Hz, 1 H), 5.65 (d, J =
9.1 Hz, 1 H), 3.64 (dtd, J = 11.2, 9.6, 4.1 Hz, 1 H), 2.46 (td, J = 10.5, 4.1
Hz, 1 H), 2.10–1.90 (m, 2 H), 1.75–1.62 (m, 2 H), 1.55 (br s, 2 H), 1.43–
1.03 (m, 4 H).
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13C NMR: δ = 162.94, 158.03, 110.46, 57.67, 55.97, 35.02, 32.74, 25.27,
25.19.
(R)-2-(1-Benzyl-2,5-dioxopyrrolidin-3-yl)-2-methylpropanal
(9d)13b
HRMS (ES): m/z [M + H]+ calcd for C6H16N4: 193.1453; found:
Following the general procedure gave 9d (70.00 mg, 90%) as colorless
prisms; 82% ee.
193.1448.
HPLC (Chiralpak AD-H, 210 nm, n-hexane–i-PrOH, 80:20, 1.0
mL/min): tR = 8.0 (minor), 17.0 min (major).
(R,R)-2-(Pyrimidin-2-ylamino)cyclohexaneamine (ent-8); Typical
Procedure
1H NMR: δ = 9.49 (s, 1 H), 7.39–7.27 (m, 5 H), 4.72–4.57 (m, 2 H), 3.03
(dd, J = 9.4, 5.4 Hz, 1 H), 2.82 (dd, J = 18.3, 9.4 Hz, 1 H), 2.45 (dd, J =
18.3, 5.4 Hz, 1 H), 1.17 (s, 3 H), 1.16 (s, 3 H).
Following the typical procedure using 5 (3.27 g, 15.25 mmol) gave
ent-8 (2.64 g, 71% overall yield) as a yellow solid.
13C NMR: δ = 202.81, 177.55, 175.48, 135.77, 128.83, 128.77, 128.10,
48.17, 45.05, 42.59, 31.60, 20.08, 19.23.
Substituted Succinimides 9; General Procedure
To a solution of 8 or ent-8 (0.03 mmol), maleimide (0.3 mmol), and
hexanedioic acid (0.03 mmol, 10% mol) in DMF–H2O (2:1, 0.6 mL) was
added the aldehyde (0.6 mmol) and the mixture was stirred at 0 °C
until completion of the reaction (TLC) (times are given in Scheme 2).
Then, aq 2 M HCl (10 mL) was added and the mixture was extracted
with EtOAc (3 ×10 mL). The combined organic phases were washed
with H2O (2 × 10 mL), dried (MgSO4), filtered, and evaporated (20
mbar). The resulting crude was purified by flash chromatography (n-
hexane–EtOAc) to afford adduct 9.
(R)-2-[1-(4-Bromophenyl)-2,5-dioxopyrrolidin-3-yl]-2-methyl-
propanal (9e)14
Following the general procedure gave 9e (68.07 mg, 70%) as colorless
prisms; 87% ee.
HPLC (Chiralpak OD-H, 230 nm, n-hexane–i-PrOH, 75:25, 0.9
mL/min): tR = 30.7 (minor), 52.3 min (major).
1H NMR: δ = 9.48 (s, 1 H), 7.65–7.50 (m, 2 H), 7.22–7.12 (m, 2 H), 3.10
(dd, J = 9.5, 5.5 Hz, 1 H), 2.96 (dd, J = 18.2, 9.5 Hz, 1 H), 2.61 (dd, J =
18.2, 5.5 Hz, 1 H), 1.35 (s, 3 H), 1.28 (s, 3 H).
13C NMR: δ = 202.80, 176.70, 174.51, 132.48, 130.94, 128.19, 122.70,
48.83, 45.12, 32.11, 20.62, 20.08.
Compound 9a was also prepared on a larger scale (starting from 0.5 g,
2.8 mmol of NPM). Isolation by recrystallization (hexane–EtOAc) led
to 0.531 g (75%) of the product that maintained the same optical puri-
ty.
(R)-2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)-2-methylpropanal
(R)-2-[1-(3-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl]-2-methylpro-
(9a)13b
panal (9f)14
Following the general procedure gave 9a (68.43 mg, 93%) as colorless
Following the general procedure gave 9f (77.20 mg, 92%) as colorless
prisms.
prisms; 87% ee.
HPLC [Chiralpak OD-H, 230 nm, n-hexane–i-PrOH, 70:30, 0.9
mL/min): tR = 17.4 (minor), 22.7 min (major).
HPLC (Chiralcel OD-H, 210 nm, n-hexane–i-PrOH, 75:25, 0.6
mL/min): tR = 24.0 (minor), 28.1 min (major).
1H NMR: δ = 9.52 (s, 1 H), 7.52–7.35 (m, 3 H), 7.31–7.24 (m, 2 H), 3.15
(dd, J = 9.5, 5.5 Hz, 1 H), 2.98 (dd, J = 18.2, 9.5 Hz, 1 H), 2.62 (dd, J =
18.2, 5.5 Hz, 1 H), 1.33 (s, 3 H), 1.29 (s, 3 H).
1H NMR: δ = 9.48 (s, 1 H), 7.44–7.31 (m, 2 H), 7.21 (m, 2 H), 3.11 (dd,
J = 9.5, 5.5 Hz, 1 H), 2.96 (dd, J = 18.2, 9.5 Hz, 1 H), 2.65–2.57 (dd, J =
18.2, 9.5 Hz, 1 H), 1.35 (s, 3 H), 1.27 (s, 3 H).
13C NMR: δ = 202.82, 176.97, 174.85, 131.95, 129.31, 128.85, 126.66,
13C NMR: δ = 202.8, 176.6, 174.4, 134.7, 132.9, 130.2, 128.9, 126.9,
48.66, 45.16, 32.02, 20.44, 19.79.
124.8, 48.7, 45.0, 32.0, 20.5, 19.9.
(R)-2-(2,5-Dioxopyrrolidin-3-yl)-2-methylpropanal (9b)15b
(R)-2-[1-(4-Chlorophenyl)-2,5-dioxopyrrolidin-3-yl]-2-methylpro-
panal (9g)13b
Following the general procedure gave 9b (38.53 mg, 76%) as colorless
prisms; 76% ee.
Following the general procedure gave 9g (73.00 mg, 87%) as colorless
prisms; 86% ee.
HPLC (Chiralpak AD-H, 210 nm, n-hexane–i-PrOH, 85:15, 1.0
mL/min): tR = 27.5 (major), 38.6 min (minor).
1H NMR: δ = 9.49 (s, 1 H), 8.73 (br s, 1 H), 3.10 (dd, J = 9.4, 5.8 Hz, 1 H),
2.85 (dd, J = 18.4, 9.4 Hz, 1 H), 2.51 (dd, J = 18.4, 5.8 Hz, 1 H), 1.25 (s, 3
H), 1.23 (s, 3 H).
HPLC (Chiralcel OD-H, 210 nm, n-hexane–i-PrOH, 75:25, 0.9
mL/min): tR = 22.4 (minor), 37.1 min (major).
1H NMR: δ = 9.49 (s, 1 H), 7.48–7.41 (m, 2 H), 7.29–7.22 (m, 2 H), 3.12
(dd, J = 9.5, 5.4 Hz, 1 H), 2.98 (dd, J = 18.1, 9.5 Hz, 1 H), 2.62 (dd, J =
18.1, 5.4 Hz, 1 H), 1.36 (s, 3 H), 1.29 (s, 3 H).
13C NMR: δ = 202.9, 178.3, 176.2, 48.0, 46.3, 32.8, 20.1, 19.4.
13C NMR: δ = 202.8, 176.7, 174.6, 134.6, 130.4, 129.5, 127.9, 48.8, 45.1,
32.1, 20.6, 20.0.
(R)-2-Methyl-2-(1-methyl-2,5-dioxopyrrolidin-3-yl)propanal
(9c)13b
(R)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclopentanecarbalde-
Following the general procedure gave 9c (45.61 mg, 83%) as a color-
less oil; 76% ee.
hyde (9h)14
Following the general procedure gave 9h (68.37 mg, 84%) as colorless
prisms; 89% ee.
HPLC (Chiralpak AS-H, 210 nm, n-hexane–i-PrOH, 80:20, 1.0
mL/min): tR = 15.6 (major),17.7 min (minor).
HPLC (Chiralcel OD-H, 210 nm, n-hexane–i-PrOH, 75:25, 0.5
mL/min): tR = 37.0 (minor), 49.9 min (major).
1H NMR: δ = 9.38 (s, 1 H), 7.50–7.44 (m, 2 H), 7.39 (m, 1 H), 7.33–7.28
(m, 2 H), 3.05 (dd, J = 9.6, 5.2 Hz, 1 H), 2.97 (dd, J = 17.6, 9.6 Hz, 1 H),
2.59 (dd, J = 17.6, 5.2 Hz, 1 H), 2.36–1.73 (m, 8 H).
1H NMR: δ = 9.51 (s, 1 H), 3.04 (dd, J = 9.3, 5.4 Hz, 1 H), 2.99 (s, 3 H),
2.82 (dd, J = 18.2, 9.3 Hz, 1 H), 1.22 (s, 3 H), 1.21 (s, 3 H).
13C NMR: δ = 202.9, 177.7, 175.8, 48.1, 45.1, 31.6, 24.9, 20.1, 19.1.
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13C NMR: δ = 202.0, 177.8, 175.2, 132.1, 129.2, 128.7, 126.7, 60.1, 43.2,
33.2, 32.7, 32.2, 25.8.
large systems. Besides, solvation factors were introduced with the
CPCM method,24 using CH2Cl2 or water as indicated in the text and
figures, in an attempt to resemble the experimental conditions as
closely as possible, since the results are highly dependent on the reac-
tion medium.
(R)-1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)cyclohexanecarbalde-
hyde (9i)14
The stationary points were characterized by frequency calculations in
order to verify that they have the right number of imaginary frequen-
cies.
The intrinsic reaction coordinates (IRC)25 were followed to verify the
energy profiles connecting each TS to the correct associated local
minima.
Following the general procedure gave 9i (76.18 mg, 89%) as colorless
prisms; 93% ee.
HPLC (Chiralcel OD-H, 210 nm, n-hexane–i-PrOH, 75:25, 0.9
mL/min): tR = 20.1 (minor), 25.6 min (major).
1H NMR: δ = 9.53 (s, 1 H), 7.50–7.42 (m, 2 H), 7.42–7.36 (m, 1 H),
7.31–7.23 (m, 2 H), 3.21 (dd, J = 9.5, 5.9 Hz, 1 H), 2.86 (dd, J = 18.2, 9.5
Hz, 1 H), 2.66 (dd, J = 18.2, 5.9 Hz, 1 H), 1.96–1.84 (m, 3 H), 1.63–1.53
(m, 7 H).
Acknowledgment
13C NMR: δ = 204.7, 177.2, 175.0, 131.9, 129.2, 128.7, 126.7, 52.2, 42.6,
31.6, 28.6, 28.1, 25.1, 21.4, 21.2.
The Spanish Ministerio de Ciencia e Innovación (MICINN) (projects
CTQ2010-20387, and Consolider Ingenio 2010, CSD2007-00006), the
Spanish Ministerio de Economia y Competitividad (MINECO) (projects
CTQ2013-43446-P and CTQ2014-51912-REDC), FEDER, the Generali-
tat Valenciana (PROMETEO 2009/039 and PROMETEOII/2014/017),
the Basque Government (GV Grant IT-291-07), the FP7 Marie Curie
Actions of the European Commission via the ITN ECHONET network
(MCITN-2012-316379), and the Universities of Alicante and Basque
Country are gratefully acknowledged for financial support. We also
thank SGIker (UPV-EHU) for allocation of computational resources.
(R)-2-[(R)-2,5-Dioxo-1-phenylpyrrolidin-3-yl]-2-phenylpropanal
(9j)12
Following the general procedure gave 9j (66.38 mg, 72%) as a colorless
oil; dr 6:1; 81% ee.
HPLC (Chiralpak OD-H, 210 nm, n-hexane–i-PrOH, 80:20, 1 mL/min):
tR = 26.3 (major diastereomer, minor), 44.7 (major diastereomer, ma-
jor), 24.1 (minor diastereomer, minor), 37.7 min (minor diastereomer,
major).
1H NMR: δ (major) = 9.68 (s, 1 H), 7.48–7.35 (m, 2 H), 7.28 (dd, J = 3.9,
1.6 Hz, 1 H), 7.09–7.01 (m, 1 H), 3.82 (dd, J = 9.4, 4.6 Hz, 1 H), 2.98 (dd,
J = 18.9, 9.4 Hz, 1 H), 2.52 (dd, J = 18.9, 4.6 Hz, 1 H), 1.78 (s, 1 H).
13C NMR: δ (minor) = 201.03, 176.77, 174.76, 138.03, 132.00, 129.51,
129.29, 128.82, 128.53, 127.31, 126.75, 56.49, 46.63, 32.72, 19.59.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1380718.
S
u
p
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u
p
p
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1H NMR: δ (minor) = 9.78 (s, 1 H), 7.50–7.33 (m, 6 H), 7.30–7.18 (m, 5
H), 3.44 (dd, J = 9.2, 6.0 Hz, 1 H), 2.65 (ddd, J = 24.4, 18.5, 7.6 Hz, 2 H),
1.84 (s, 3 H).
13C NMR: δ (minor) = 199.19, 176.70, 174.75, 135.68, 131.64, 129.53,
129.22, 128.82, 128.69, 127.56, 126.49, 77.58, 77.16, 76.74, 56.05,
45.08, 32.18, 16.64.
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