Solvent-dependent enantioswitching in the Michael addition of α,α-disubstituted aldehydes to maleimides organocatalyzed by mono-N-Boc-protected cyclohexa-1,2-diamines

Article abstract of DOI:10.1016/j.tetasy.2014.06.014

Enantiomerically pure mono-N-Boc-protected trans-cyclohexa-1,2-diamines are used as organocatalysts for the enantioselective conjugate addition of α,α-disubstituted aldehydes to maleimides. Using a single enantiomer of the organocatalyst, both enantiomeri

Full text of DOI:10.1016/j.tetasy.2014.06.014

Tetrahedron: Asymmetry 25 (2014) 1091–1094
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Tetrahedron: Asymmetry
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Solvent-dependent enantioswitching in the Michael addition of
a,a-disubstituted aldehydes to maleimides organocatalyzed by
mono-N-Boc-protected cyclohexa-1,2-diamines
⇑
Jesús Flores-Ferrándiz, Rafael Chinchilla
Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 May 2014
Accepted 19 June 2014
Enantiomerically pure mono-N-Boc-protected trans-cyclohexa-1,2-diamines are used as organocatalysts
for the enantioselective conjugate addition of a,a-disubstituted aldehydes to maleimides. Using a single
enantiomer of the organocatalyst, both enantiomeric forms of the resulting Michael adducts bearing a
new quaternary stereocenter are obtained in high yields, by only changing the reaction solvent from
chloroform (up to 86% ee) to aqueous DMF (up to 84% ee).
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
Taking into consideration this enamine-forming approach,
different bifunctional primary amine-bearing organocatalysts have
The organocatalytic enantioselective Michael addition of carbon
nucleophiles to maleimides is the most direct and easy method for
preparing enantioenriched succinimide moieties,1 which are pres-
ent in natural products and some clinical drug candidates.2 More-
been applied to enantioselective Michael additions of these
‘difficult’
a,a-disubstituted aldehydes to maleimides, giving high
enantioselections in the corresponding succinimides.10 Some
examples include the primary amine–thioureas 1,10a,b 210a,b and
3,10e the beyerane-containing thiourea 4,10f the primary amine–
guanidine 5,10h,j and even the simple trans-cyclohexa-1,2-diamine
6.10k
over, succinimides can be transformed into c
-lactams,3 which are
privileged structural subunits for the design of pharmaceutical
agents that are important in the treatment of cancer,4 epilepsy,5
HIV,6 neurodegenerative disease, and depression.7
Carbon nucleophiles suitable for enantioselective conjugate
additions to maleimides can be generated by
a-deprotonation of
pro-nucleophiles using chiral bifunctional organocatalysts bearing
both an acidic moiety and a tertiary amine.1 Coordination of the
maleimide and the enolate generated after deprotonation to the
chiral organocatalyst leads to an enantioselective process. How-
ever, when aldehydes are used as pro-nucleophiles, tertiary amines
are not basic enough for the efficient generation of an enolate, and
these organocatalysts cannot be employed. In this case, the enan-
tioselective Michael addition reaction can be carried out by using
amine-bearing organo catalysts that are suitable to form a tran-
sient enamine with the reacting aldehyde,8 thus creating a chiral-
ity-inducing transition state after coordination with the
maleimide. The first organocatalytic Michael addition of aliphatic
CF3
CF3
Ph
S
S
Ph
N
H
N
H
CF3
N
H
N
H
CF3
NH2
NH2
2
1
Me
CF3
S
Ph
Me
S
N
H
N
H
NH2
N
N
H
CF3
H
NH2
EtO2C Me
aldehydes to N-aryl-maleimides used
a,a
-phenylprolinol silyl
3
4
ether as the organocatalyst, although a,a-disubstituted aldehydes
resulted in much lower enantioselectivities.9
NiPr
NHiPr
N
H
NH2
NH2
NH2
⇑
Corresponding author. Tel.: +34 965903822; fax: +34 965903549.
E-mail address: chinchilla@ua.es (R. Chinchilla).
6
5
http://dx.doi.org/10.1016/j.tetasy.2014.06.014
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

1092
J. Flores-Ferrándiz, R. Chinchilla / Tetrahedron: Asymmetry 25 (2014) 1091–1094
Table 1
When dealing with enantioselective organocatalysis, as with any
asymmetric catalysis, opposite enantiomeric products are typically
obtained by using opposite enantiomeric organocatalysts. However,
switching the enantioselectivity of an organocatalyst just by varying
the reaction conditions, although potentially very interesting, is not
an easy matter. Thus, only a few examples of switching the enanti-
oselectivity of an organocatalyzed process by changing the countera-
nions of the catalyst,11 adding bases,12 acids,13 or other additives,14
or even by light irradiation,15 have been reported. In addition, exam-
ples of changing the enantioselectivity of organocatalyzed reactions
simply by changing the reaction solvent are scarce, and limited to the
use in some particular cases of some chiral unsupported16a and sup-
Screening and optimization of the reaction conditions for the enantioswitched
Michael addition reaction
O
O
O
O
catalyst
N
Ph
+
N
Ph
H
solvent, T
H
*
O
O
10aa
9a
8a
Entry
Catalyst (mol %)
Solvent
T (°C)
t (h) Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (10)
7 (10)
7 (5)
PhMe
Hexane
Et2O
CH2Cl2
CHCl3
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
20
14
14
20
20
44
2
17
20
24
20
20
40
40
48
48
20
20
98
85
95
95
99
94
97
94
90
88
97
95
95
93
94
91
97
94
67 (S)
73 (S)
32 (S)
63 (S)
75 (S)
62 (R)
32 (R)
70 (R)
84 (R)
80 (R)
86 (S)
84 (R)
76 (S)
82 (R)
70 (S)
82 (R)
84 (R)
83 (S)
ported16b MacMillan’s imidazolidinones or
a,a-diphenyl-2-pyrroli-
dine methanol17 as organocatalysts, as well as conformationally
flexible peptidic18 and guanidine/bisthiourea species.19
DMF
H2O
Herein we report how
enantioselective addition reaction of the particularly ‘difficult’
-disubstituted aldehydes to maleimides allows a single enantio-
a change in the solvent in the
DMF/H2Oc
DMF/H2Od
DMF/H2Oe
CHCl3
9
a,a
10
11
12
13
14
15
16
17
18
mer of N-Boc-monoprotected trans-cyclohexa-1,2-diamines to be
employed as an organocatalyst for the synthesis of both enantio-
mers of the final succinimides.
DMF/H2Od
CHCl3
7 (5)
DMF/H2Od
CHCl3
7 (10)
7 (10)
ent-7 (10)
ent-7 (10)
2. Results and discussion
DMF/H2Od
CHCl3
0
25
25
DMF/H2Od
The (1S,2S)-cyclohexa-1,2-diamine 6 was chosen as a chirality
source; we performed its mono-N-protection with the tert-
butoxycarbonyl (Boc) group via a procedure consisting of a reaction
of 6 with 1 equiv of hydrogen chloride (2 M, Et2O) and subsequent
treatment with di-tert-butyl carbonate.20 The chiral mono-
Boc-protected diamine 7 obtained was explored as a primary
amine-containing organocatalyst for the model enantioselective
Michael addition of isobutyraldehyde to N-phenylmaleimide, under
different reaction conditions (Table 1).
a
b
c
Isolated yield after flash chromatography.
Enantioselectivities and absolute stereochemistry determined by chiral HPLC.
1:1, v/v.
2:1, v/v.
4:1, v/v.
d
e
enantioselections were observed for the (S)- and (R)-stereoisomers
when a loading of 10 mol % was used [86% ee for (S)-10aa and 84%
ee for (R)-10aa] (Table 1, entries 11 and 12). Using this optimized
10 mol % organocatalyst loading, we lowered the reaction temper-
ature to 0 °C, but no increase in the stereoselectivity of the reaction
was observed (Table 1, entries 15 and 16).
NHBoc
NHBoc
Attempting to achieve opposite enantioselections to those
obtained using organocatalyst 7, we prepared the corresponding
enantiomer ent-7 following the same procedure but starting from
(1R,2R)-cyclohexa-1,2-diamines. When mono-N-Boc-protected
diamine ent-7 was used as the organocatalyst under the most con-
venient reaction conditions [10 mol % organocatalyst loading,
room temperature, CHCl3 or DMF/H2O 2:1 v/v as solvent], the
expected opposite enantioselections to those obtained when using
7 were observed [(R)-10aa using CHCl3 as solvent and (S)-10aa
using DMF/H2O 2:1 v/v] (Table 1, entries 17 and 18).
In order to determine whether the observed ee for (R)-10aa
changed during the process, the model reaction of aldehyde 8a
and maleimide 9a in the presence of organocatalyst 7 (10 mol %)
was carried out in DMF/H2O 2:1 v/v with reaction times of 4, 8,
and 12 h. In all cases the ee for (R)-10aa remained at 84%, the same
value as to when the reaction was completed. In an attempt to rule
out whether the change in the enantioselectivity was due to the
former evolution of the final product, product (R)-10aa (84% ee)
was combined with organocatalyst 7 (10 mol %) in CHCl3 as the
solvent at room temperature. After stirring for 20 h, product (R)-
10aa was recovered with its enantioinduction intact.
NH2
NH2
ent-7
7
The use of a 20 mol % loading of 7 in toluene as solvent at room
temperature gave succinimide (S)-10aa in almost quantitative
yield of 67% ee (Table 1, entry 1). The absolute configuration was
determined according to the order of elution of the corresponding
enantiomers in chiral HPLC (see Experimental).10j Changing the
solvent to hexane gave (S)-10aa with a higher ee, whereas the
use of ether as solvent lowered the enantioselectivity (Table 1,
entries 2 and 3). When CH2Cl2 and CHCl3 were employed as sol-
vents, (S)-10aa was obtained with 63% and 75% ee, respectively
(Table 1, entries 4 and 5).
However, when DMF was used as the solvent the enantioselec-
tivity of the process switched completely and gave (R)-10aa with
62% ee (Table 1, entry 6). The use of water as the solvent consider-
ably increased the reaction rate, affording also (R)-10aa almost
quantitatively in 2 h although with only 32% ee (Table 1, entry
7). Therefore, we explored the possible use of mixtures of DMF/
H2O as the solvent, something that has proven to be effective when
primary amine–guanidines have been used as organocatalysts in
this reaction.10h,j Thus, different DMF/H2O v/v ratios were studied
(Table 1, entries 8–10), with a 2:1 v/v ratio affording (R)-10aa in
90% yield and with 84% ee (Table 1, entry 9).
With the most effective reaction conditions in hand [7
(10 mol %), CHCl3 for (S)-enantiomer and DMF/H2O 2:1 v/v for
(R)-enantiomer, rt] we extended this organocatalytic solvent-
dependent enantioswitching methodology to other aldehydes
and maleimides (Table 2).21 As in the case of the model reaction,
the absolute configuration of the resulting succinimides was
assigned according to the elution order of their enantiomers in chi-
ral HPLC when compared to the literature.22,23
Once the most appropriate solvents for achieving opposite
enantioselectivities were selected [CHCl3 for (S)-10aa and DMF/
H2O 2:1 v/v for (R)-10aa], we explored lowering the organocatalyst
loading. Thus, the amount of organocatalyst 7 was decreased to 10
and 5 mol % using both solvents (Table 1, entries 11–14); higher

J. Flores-Ferrándiz, R. Chinchilla / Tetrahedron: Asymmetry 25 (2014) 1091–1094
1093
Table 2
Solvent-dependent enantioswitched Michael addition of aldehydes to maleimides organocatalyzed by mono-Boc-protected 1,2-diamine 7
O
O
O
O
O
O
7 (10 mol%)
R1
N
R2
N
R2
R2
+
N
H
or
solvent, rt
H
H
R1
R1 R1
(S)-10
R1 R1
O
O
O
8
9
10
(R)-
Entry
Aldehyde
Maleimide
Solvent
t (h)
Adduct No.
Yielda (%)
eeb,c (%)
R1
No.
R2
No.
1
2
3
4
5
6
7
8
Me
8a
Ph
9a
CHCl3
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
CHCl3
20
20
30
30
30
30
26
26
21
21
17
17
48
48
30
30
48
48
(S)-10aa
(R)-10aa
(S)-10ab
(R)-10ab
(S)-10ac
(R)-10ac
(S)-10ad
(R)-10ad
(S)-10ae
(R)-10ae
(S)-10af
(R)-10af
(S)-10ba
(R)-10ba
(S)-10ca
(R)-10ca
(S)-10da
(R)-10da
97
95
99
97
99
98
92
15
94
91
94
88
70
93
99
96
96
96
86
84
60
74
70
70
40
80
53
68
50
70
55
68
49
61
14
35
Me
Me
Me
Me
Me
Et
8a
8a
8a
8a
8a
8b
8c
8d
4-ClC6H4
9b
9c
9d
9e
9f
4-BrC6H4
4-AcC6H4
9
Me
H
10
11
12
13
14
15
16
17
18
Ph
Ph
Ph
9a
9a
9a
–(CH2)4–
–(CH2)5–
DMF/H2O 2:1
CHCl3
DMF/H2O 2:1
a
b
c
Isolated yield after flash chromatography.
Enantioselectivities determined by chiral HPLC.22
Absolute configuration assigned by the order of elution of the enantiomers in chiral HPLC.23
Thus, when CHCl3 was used as the solvent, isobutyraldehyde
organocatalysts in the high-yielding enantioselective conjugate
addition of -disubstituted aldehydes to different maleimides,
reacted with N-phenylmaleimides bearing halogens on the phenyl
ring, such as a chloro or a bromo atom at the 4-position of 9b and
9c, and the succinimides (S)-10ab and (S)-10ac were obtained in
60% and 70% ee, respectively (Table 2, entries 3 and 5). However,
when DMF/H2O 2:1 v/v was the reaction solvent, adducts
(R)-10ab and (R)-10ac were isolated in 74% and 70% ee (Table 2,
entries 4 and 6). When an acetyl group was present on the phenyl
ring of the maleimide, as in the case of 9d, the enantioselectivities
for the corresponding enantiomeric succinimides (S)-10ad and
(R)-10ad were 40% and 80%, depending on the use of CHCl3 or
DMF/H2O 2:1 v/v as the solvent, respectively (Table 2, entries 7
and 8).
a,a
giving rise to an uncommon solvent-dependent enantioswitched
reaction. Thus, both the (S)- or (R)-enantioenriched forms of the
Michael adducts can be obtained by employing a single mirror
form of the organocatalyst, by simply changing the reaction sol-
vent from chloroform to aqueous N,N-dimethylformamide. Further
studies devoted to gaining insight into the origin of this solvent-
induced stereoselectivity switch, as well as extending this method-
ology to other organocatalysts and substrates are currently
underway.
Acknowledgments
Non-N-arylated maleimides were also employed for the conju-
gate addition with isobutyraldehyde. Thus, N-methylmaleimide 9e
gave the (S)- and (R)-enantiomer of adduct 10ae depending on the
use of CHCl3 and DMF/H2O 2:1 v/v as the reaction solvent (53% and
68% ee, respectively) (Table 2, entries 9 and 10). Maleimide (9f)
was also used as a Michael acceptor and afforded (S)-10af (50%
ee) when using CHCl3 as the solvent, and (R)-10af (70% ee) when
the solvent was DMF/H2O 2:1 v/v (Table 2, entries 11 and 12).
We thank the financial support from the Spanish Ministerio de
Economía y Competitividad (Project CTQ2011-24151), FEDER, the
COST Action CM0905 ‘Organocatalysis’, and the University of
Alicante.
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21. Typical experimental procedure for the enantioselective Michael addition reaction:
To a solution of 7 or ent-7 (0.04 mmol) and 9 (0.2 mmol) in DMF/H2O (2:1, v/v)
(0.5 mL) was added aldehyde 8 (0.4 mmol) and the reaction was stirred at rt
until completion (TLC). A solution of 2 M HCl (10 mL) was then added and the
mixture was extracted with EtOAc (3 Â 10 mL). The organic phase was washed
with water (2 Â 10 mL), dried (MgSO4), filtered, and evaporated (15 torr). The
resulting crude was purified by flash chromatography (hexane/AcOEt) to afford
adducts 10, which gave consistent spectroscopic data with those reported in
the literature.10j
22. Enantioselectivities were determined by HPLC using n-hexane/2-propanol mixtures
as eluant and the following chiral columns: Chiralcel OD-H for 10aa, 10ab, 10ac,
10ca, 10da, Chiralpak AS-H for 10ad, 10ae, 10ba, and Chiralpak AD-H for 10af.
Reference racemic samples of adducts 10 were obtained by performing the
reaction using 4-methylbenzylamine (20 mol %) as the organocatalyst in
toluene as the solvent at room temperature.
23. The absolute configurations for adducts 10 were determined according to the
described order of elution of their enantiomers in chiral HPLC.10j