Solvent-induced reversal of enantioselectivity in the synthesis of succinimides by the addition of aldehydes to maleimides catalysed by carbamate-monoprotected 1,2-diamines

Article abstract of DOI:10.1002/ejoc.201403415

A simple change in the polarity of the solvent allows both enantiomers of substituted succinimides to be obtained in the enantioselective conjugate addition reaction of aldehydes, mainly disubstituted, to maleimides catalysed by chiral carbamate-monoprote

Full text of DOI:10.1002/ejoc.201403415

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FULL PAPER
DOI: 10.1002/ejoc.201403415
Solvent-Induced Reversal of Enantioselectivity in the Synthesis of Succinimides
by the Addition of Aldehydes to Maleimides Catalysed by Carbamate-
Monoprotected 1,2-Diamines
Jesús Flores-Ferrándiz,[a] Béla Fiser,[b] Enrique Gómez-Bengoa,[b] and Rafael Chinchilla*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Michael addition / Enantioselectivity / Solvent effects / Transition
states
A simple change in the polarity of the solvent allows both
enantiomers of substituted succinimides to be obtained in the
enantioselective conjugate addition reaction of aldehydes,
mainly α,α-disubstituted, to maleimides catalysed by chiral
carbamate-monoprotected trans-cyclohexane-1,2-diamines.
in high yields by simply changing the reaction solvent from
aqueous DMF (up to 84% ee) to chloroform (up to 86% ee).
Theoretical calculations are used to explain this uncommon
reversal of the enantioselectivity; two transition state orienta-
tions of different polarities are differently favoured in polar
or nonpolar solvents.
Using
a single enantiomer of the organocatalyst, both
enantiomers of the resulting Michael adducts are obtained
of enantioselectivity was discovered in the enantioselective
Michael addition of dimethyl malonate to chalcone
catalysed by a quininium ammonium salt when the reaction
medium was changed from conventional organic solvents
to ionic liquids.[7] A solvent-dependent enantioselectivity re-
versal was also observed when the imidazolidinone salt 1
was used as an organocatalyst in the Michael addition of
an indole to acrolein for the synthesis of a pyrrolo-
indoline.[8] Later, α,α-phenylprolinol silyl ether 2 was shown
to catalyse the enantioselective α-phenylselenenylation of
isovaleraldehyde, and a change in the sense of the
enantioselectivity was observed when the polarity of the
solvent was changed.[9] A similar solvent-influenced rever-
sal of the enantioselectivity of this α-phenylselenenylation
reaction was also reported when polystyrene-supported
imidazolidinone 3 was used as a recoverable organocata-
lyst.[10]
An inversion of enantioselectivity induced by a change
in the solvent has also been observed in the enantioselective
Michael addition of cyclohexanone to chalcones using 1-
ethyl-3-methylimidazolium-(S)-2-pyrrolidinecarboxylic acid
salt as an organocatalyst.[11] Furthermore, some conforma-
tionally flexible organocatalysts have been used in reactions
in which the sense of enantioselectivity is solvent depend-
ent: peptidic system 4 in the aldol reaction between cyclo-
hexanone and p-nitrobenzaldehyde,[12] and bisthiourea/
guanidine 5 in a recent Mannich-type addition of malonates
Introduction
In enantioselective organocatalysis, as in any asymmetric
catalysis, opposite enantiomeric products are typically ob-
tained by using opposite enantiomers of the organocata-
lysts. However, being able to switch the enantioselectivity of
an organocatalytic reaction simply by changing the reaction
conditions is an exciting matter of great potential interest.
One of the main reasons for this is that having both enan-
tiomeric forms of certain organocatalysts can be difficult or
costly.
Although it is rare, there are some reported examples of
enantioselective organocatalytic reactions where both
enantiomers are obtained using a single enantiomer of the
catalyst. These results are always unexpected and serendi-
pitous.[1] Thus, a few examples of switching the enantio-
selectivity of an organocatalytic process by changing the
counteranion in the catalyst,[2] by adding bases,[3] acids,[4]
or other additives,[5] or even by light irradiation[6] have been
reported.
However, it would be simpler just to change the reaction
solvent, and some examples of solvent-dependent enantio-
selectivity reversal have been reported. Thus, an inversion
[a] Departamento de Química Orgánica, Facultad de Ciencias, and
Instituto de Síntesis Orgánica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
E-mail: chinchilla@ua.es
http://dqorg.ua.es/en/
[b] Departamento de Química Orgánica I, Universidad del País
Vasco,
to N-Boc-protected (Boc
= tert-butoxycarbonyl) ald-
imines.[13] No explanation for why a particular enantiomer
of the final product is obtained using one solvent and the
opposite enantiomer is obtained using another has been
given in any of the reported cases.
Apdo. 1072, 20080 San Sebastián, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403415.
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J. Flores-Ferrándiz, B. Fiser, E. Gómez-Bengoa, R. Chinchilla
FULL PAPER
selectivity of the conjugate addition of aldehydes to maleim-
ides catalysed by chiral carbamate-monoprotected trans-cy-
clohexane-1,2-diamines.[29] In this way, a single enantio-
meric form of a simple organocatalyst can be used for the
preparation of both enantiomeric forms of the correspond-
ing substituted succinimides. The origin of this uncommon
solvent-dependent enantioswitching can be explained by
theoretical calculations.
Results and Discussion
We attempted to explore the behaviour of chiral mono-
Boc-protected diamine 6 as a primary-amine-containing bi-
functional organocatalyst for the enantioselective conjugate
addition reaction of aldehydes to N-substituted maleimides.
This Boc-containing amine 6 was obtained following a
reported procedure involving the reaction of (1S,2S)-
cyclohexane-1,2-diamine with 1 equiv. of hydrogen chloride,
followed by treatment with di-tert-butyl carbonate.[30] The
enantioselective Michael addition of isobutyraldehyde to N-
phenylmaleimide was chosen as a model reaction to test the
efficiency of 6 as an organocatalyst (Table 1).
From the huge array of enantioselective organocatalytic
reactions, those leading to enantioenriched substituted suc-
cinimides have aroused interest in recent years. These
compounds are present in natural products and some clin-
ical drug candidates,[14] and can be transformed into γ-
lactams,[15] which are subunits for the design of pharmaceu-
tical agents important in the treatment of cancer,[16] epi-
Initially, primary amine 6 (20 mol-%) was used in toluene
lepsy,[17] HIV,[18] neurodegenerative disease, and de- as solvent at room temperature, and this gave succinimide
pression.[19]
(S)-9aa almost quantitatively with 67% ee (Table 1, en-
The easiest and most direct way of preparing enantioen- try 1). The absolute configuration for 9aa was determined
riched succinimide moieties is by organocatalytic enantiose- according to the order of elution of the corresponding
lective Michael addition of carbon nucleophiles to maleim- enantiomers in chiral HPLC (see Exp. Section).[24b] When
ides.[20] These carbon nucleophiles can be generated by α- hexane was used as solvent, the enantioselectivity for (S)-
deprotonation of pro-nucleophiles using chiral bifunctional 9aa increased to 73% ee, whereas the use of ethyl ether re-
organocatalysts bearing both a basic tertiary amine and an sulted in a lower ee (Table 1, entries 2 and 3). When CH2Cl2
acidic moiety able to coordinate the maleimide.[20] However, and CHCl3 were used as solvents, 63 and 75% ee values,
when aldehydes are used as pro-nucleophiles, tertiary respectively, for (S)-9aa were observed (Table 1, entries 4
amines are not basic enough to generate an enolate, and the and 5).
enantioselective Michael addition reaction is carried out by
using amine-contaning organocatalysts that can form a enantioselectivity of the process reversed totally, and the
transient enamine with the reacting aldehyde.[21]
oppositely configured succinimide [i.e., (R)-9aa]was ob-
Unexpectedly, when DMF was used as solvent, the
The first organocatalytic Michael addition of aliphatic tained in high yield and with 62% ee, albeit with a much
aldehydes to N-aryl-substituted maleimides used α,α-phen- lower reaction rate (Table 1, entry 6). The use of solvents
ylprolinol silyl ether as an organocatalyst, but the “diffi- such as 1,4-dioxane or acetone also gave (R)-9aa with lower
cult” α,α-disubstituted aldehydes resulted in much lower ee values (Table 1, entries 7 and 8). When water was used
enantioselectivities.[22] Since then, different chiral bifunc- as the solvent, the rate of the reaction increased consider-
tional primary-amine-containing organocatalysts have been ably and (R)-9aa was formed almost quantitatively, albeit
applied to the enantioselective Michael addition of these with only 32% ee (Table 1, entry 9). Therefore, combining
α,α-disubstituted aldehydes to maleimides leading to en- the highest ee and reaction rate, we explored the use of mix-
antioenriched succinimides. Most of the catalysts were pri- tures of DMF and H2O as reaction solvent. Thus, different
mary amine thioureas,[23] but primary amine guanidines,[24] DMF/H2O v/v ratios were tested (Table 1, entries 10–12). A
amino acids,[25] amino acids combined with amine thio- 2:1, v/v mixture of DMF and H2O gave (R)-9aa in 90%
ureas,[26] amines,[27] and 1,2-diamines[28] have also been yield with 84% ee (Table 1, entry 11).
used.
Having established the most appropriate solvents for
In this paper, we describe how a simple change of the achieving a reversal in the enantioselectivity [i.e., CHCl3 for
reaction solvent can produce a reversal of the enantio- (S)-9aa, and DMF/H2O (2:1, v/v) for (R)-9aa], we decided
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Solvent-Induced Reversal of Enantioselectivity
Table 1. Screening and optimization of the reaction conditions for the reversal of the enantioselectivity in the Michael addition reaction.
Entry
Catalyst (mol-%) Additive (mol-%)[a] Solvent
T [°C]
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (20)
6 (10)
6 (10)
6 (5)
–
–
–
–
–
–
PhMe
hexane
Et2O
CH2Cl2
CHCl3
DMF
dioxane
acetone
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
20
14
14
20
20
44
50
44
2
17
20
24
20
20
40
40
48
48
22
20
22
22
22
22
20
20
24
24
48
48
98
85
95
95
99
94
85
92
97
94
90
88
97
95
95
93
94
91
98
86
93
84
97
90
97
94
98
94
97
96
67 (S)
73 (S)
32 (S)
63 (S)
75 (S)
62 (R)
58 (R)
57 (R)
32 (R)
70 (R)
84 (R)
80 (R)
86 (S)
84 (R)
76 (S)
82 (R)
70 (S)
82 (R)
78 (S)
80 (R)
78 (S)
80 (R)
78 (S)
77 (R)
84 (R)
83 (S)
81 (S)
78 (R)
86 (S)
78 (R)
9
–
–
–
–
–
–
–
–
H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
DMF/H2O[d]
DMF/H2O[e]
DMF/H2O[f]
CHCl3
DMF/H2O[e]
CHCl3
6 (5)
DMF/H2O[e]
CHCl3
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
6 (10)
ent-6 (10)
ent-6 (10)
12 (10)
12 (10)
13 (10)
13 (10)
–
–
DMF/H2O[e]
CHCl3
0
HDA (10)
HDA (10)
PhCO2H (10)
PhCO2H (10)
Imidazole (10)
Imidazole (10)
25
25
25
25
25
25
25
25
25
25
25
25
DMF/H2O[e]
CHCl3
DMF/H2O[e]
CHCl3
DMF/H2O[e]
CHCl3
–
–
–
–
–
–
DMF/H2O[e]
CHCl3
DMF/H2O[e]
CHCl3
DMF/H2O[e]
[a] HDA: hexanedioic acid. [b] Isolated yield after flash chromatography. [c] Enantioselectivities and absolute stereochemistry determined
by chiral HPLC[24b] analysis of the crude product mixture. [d] 1:1, v/v. [e] 2:1, v/v. [f] 4:1, v/v.
to lower the organocatalyst loading. Thus, both solvents enantiomer ent-6, following an identical procedure but
were used with 10 and 5 mol-% organocatalyst loadings starting from (1R,2R)-cyclohexane-1,2-diamine. Using this
(Table 1, entries 13–16), and higher enantioselectivities for mono-Boc-protected diamine ent-6 as organocatalyst, un-
both the S and R stereoisomers were observed when a load- der the most convenient reaction conditions [i.e., organocat-
ing of 10 mol-% of 6 was used [86% ee for (S)-9aa, and alyst (10 mol-%), room temperature, CHCl3 or DMF/H2O
84% ee for (R)-9aa] (Table 1, entries 13 and 14). Lowering (2:1, v/v) as solvent], the expected opposite enantio-
the reaction temperature to 0 °C resulted in a diminished selectivities were observed [i.e., (R)-9aa using CHCl3 as sol-
enantioselectivity for 9aa (Table 1, entries 17 and 18).
vent, and (S)-9aa using DMF/H2O (2:1, v/v)] (Table 1, en-
We then explored the influence of the presence of addi- tries 25 and 26).
tives, using an optimized 10 mol-% loading of organocata-
lyst 6, and CHCl3 and DMF/H2O (2:1, v/v) as enantio-
switching solvents. Thus, hexanedioic (HDA) or benzoic
acids were used as additives (10 mol-%), but no increase in
the enantioselectivity was observed for either enantiomer
(Table 1, entries 19–22). Imidazole was also tested as an ad-
ditive (10 mol-%), as its presence has been shown to be ben-
We then explored the possibility of achieving this sol-
eficial in this Michael addition reaction,[24b] but lower vent-dependent reversal of enantioselectivity using chiral
enantioselectivities for both enantiomers of 9aa were also trans-cyclohexane-1,2-diamines monoprotected with other
observed here (Table 1, entries 23 and 24).
carbamates as organocatalysts. We chose the frequently
Attempting to achieve opposite enantioselectivities to used benzyloxycarbonyl (Cbz) and fluorenylmethoxy-
those obtained using organocatalyst 6, we obtained its carbonyl (Fmoc) protecting groups. Thus, Cbz- and Fmoc-
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FULL PAPER
monoprotected diamines 12 and 13, respectively, were pre- reversal in the enantioselectivity of the process was ob-
pared by reaction of N-Boc-monoprotected diamine 6 with served when changing the solvent between CHCl3 (S
the corresponding chloroformates to give diprotected com- enantiomer) and DMF/H2O (2:1, v/v) (R enantiomer).
pounds 10 and 11, followed by trifluoroacetic acid (TFA)- Thus, when mono-Cbz-protected diamine 12 was used as
induced N-Boc deprotection (Scheme 1).
organocatalyst, ee values of 81% ee for (S)-9aa and 78% ee
for (R)-9aa were obtained (Table 1, entries 27 and 28).
When Fmoc-containing primary amine 13 was used as the
organocatalyst, it gave a similar enantioselectivity for (S)-
9aa to when Boc derivative 6 was used, but after a much
longer reaction time, whereas the enantioselectivity for (R)-
9aa was lower (Table 1, entries 29 and 30).
Once the most effective organocatalyst and reaction con-
ditions [i.e., 6 (10 mol-%), CHCl3 for the S enantiomer, and
DMF/H2O (2:1, v/v) for the R enantiomer, room temp.]
were established, we went on to explore the extension of
Scheme 1. (i) CbzCl (for 10) or FmocCl (for 11), NaHCO3 (aq.),
dioxane, room temp.; (ii) TFA, CH2Cl2, r.t.; (iii) NH4OH, CH2Cl2,
r.t.
These Cbz- and Fmoc-monoprotected chiral diamines 12 this organocatalytic solvent-dependent method to other al-
and 13, respectively, were also tested as organocatalysts in dehydes and maleimides (Table 2). As for the model reac-
the model Michael addition reaction, using the most conve- tion, the absolute configurations of the known succinimide
nient reaction conditions as determined above [i.e., organo- products were assigned according to the order of elution of
catalyst (10 mol-%), room temperature, CHCl3 or DMF/ their enantiomers in chiral HPLC when compared to the
H2O (2:1, v/v) as solvent] (Table 1, entries 27–30). Again, a literature (see Experimental section).
Table 2. Solvent-dependent reversal of enantioselectivity in the Michael addition of aldehydes to maleimides catalysed by N-Boc-monopro-
tected 1,2-diamine 6.
Entry Aldehyde
Maleimide
R3
Solvent
t [h]
Succinimide
Yield [%][a]
ee [%][b,c]
R1
R2
7
8
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
7a
Ph
8a
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
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
30
30
26
26
32
32
22
22
21
21
17
17
48
48
30
30
48
48
23
23
(S)-9aa
(R)-9aa
(S)-9ab
(R)-9ab
(S)-9ac
(R)-9ac
(S)-9ad
(R)-9ad
(S)-9ae
97
95
99
96
99
97
99
98
92
15
90
92
93
90
94
91
94
88
70
93
99
96
96
96
95[d]
96[e]
86
84
38
76
60
74
70
70
40
80
76
74
30
72
53
68
50
70
55
68
49
61
14
35
36/28
76/73
Me
Me
Me
Me
Me
Me
Me
Me
Et
7a
7a
7a
7a
7a
7a
7a
7a
7b
7c
7d
7e
3-ClC6H4
8b
8c
8d
8e
8f
4-ClC6H4
4-BrC6H4
9
4-AcC6H4
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
(R)-9ae
(S)-9af
(R)-9af
2-MeOC6H4
Bn
Me
H
8g
8h
8i
(S)-9ag
(R)-9ag
(S)-9ah
(R)-9ah
(S)-9ai
(R)-9ai
Ph
Ph
Ph
Ph
8a
8a
8a
8a
(S)-9ba
(R)-9ba
(S)-9ca
–(CH2)4–
–(CH2)5–
Me
(R)-9ca
(S)-9da
(R)-9da
(S,S)/(R,S)-9ea
(R,R)/(S,R)-9ea
DMF/H2O, 2:1
CHCl3
DMF/H2O, 2:1
H
[a] Isolated yield after flash chromatography. [b] Enantioselectivities determined by chiral HPLC analysis of the crude product mixture.
[c] Absolute configuration assigned by the order of elution of the enantiomers in chiral HPLC (see Experimental section). [d] Mixture of
diastereomers 1.4:1, as determined by 1H NMR (300 MHz) spectroscopic analysis of the crude product mixture. [e] Mixture of dia-
1
stereomers 1.2:1, as determined by H NMR (300 MHz) spectroscopic analysis of the crude product mixture.
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Solvent-Induced Reversal of Enantioselectivity
Thus, when CHCl3 was used as solvent, isobutyraldehyde
To get further insight into the origin of this solvent-de-
reacted with N-phenylmaleimides bearing halogens on the pendent enantioselectivity reversal, we carried out theoreti-
phenyl ring, such as a chloro substituent at the 3- or 4- cal calculations on the reaction of N-phenylmaleimide (8a)
position (i.e., 8b and 8c, respectively), or a bromo substitu- and isobutyraldehyde (7a) in the presence of primary-amine
ent at the 4-position (i.e., 8d), and the corresponding suc- catalyst 6. Different computational conditions were envi-
cinimides [i.e., (S)-9ab, (S)-9ac, and (S)-9ad] were obtained sioned (see Exp. Section) Ϫ in the gas phase, in implicit
with 38, 60, and 70% ee, respectively (Table 2, entries 3, 5, solvents (water and chloroform), and also in the presence
and 7). However, when DMF/H2O (2:1, v/v) was used as of a discrete number of explicit water molecules Ϫ in an
the reaction solvent, adducts (R)-9ab, (R)-9ac, and (R)-9ad attempt to reproduce the experimental conditions as closely
were isolated with 76, 74, and 70% ee (Table 2, entries 4, 6, as possible, since the results are highly dependent on the
and 8). In addition, when an acetyl or a methoxy group was reaction medium. Preliminary studies showed that, as ex-
present on the phenyl ring of the maleimide, as in the case pected, the initial formation of an enamine between the cat-
of 8e and 8f, the ee values the corresponding enantiomeric alyst and the aldehyde is followed by nucleophilic attack on
succinimides (S)-9ae/(R)-9ae and (S)-9af/(R)-9af were 40/ the maleimide, according to Seebach’s synclinal model
80% ee and 76/74% ee, respectively, depending on whether (endo attack, Figure 1).[31] A key feature of this model is
CHCl3 or DMF/H2O (2:1, v/v) was used as the solvent that the reacting face of the enamine completely diastereo-
(Table 2, entries 9–12).
selectivelyattacks only one of the faces of the maleimide.
Non-N-arylated maleimides were also used for the conju- Thus, the lower face of the enamine (from our point of view
gate addition with isobutyraldehyde. Thus, N-benzylmale- in Figure 1) reacts with the Re face of the maleimide, and
imide (8g) gave enantiomeric succinimides (S)-9ag and (R)- the upper face of the enamine must react with the Si face
9ag in high yields and with 30 and 72% ee, depending on of the maleimide. This means that each face of the enamine
the solvent used (Table 2, entries 13 and 14). Similarly, N- produces only one of the final enantiomeric products. This
methylmaleimide (8h) gave the S and R enantiomers of ad- fact is crucial to understanding the following discussion,
duct 9ah when CHCl3 and DMF/H2O (2:1, v/v) were used which can be based solely on the reacting face of the en-
as the reaction solvent (53 and 68% ee, respectively; amine. Meanwhile, the exo approaches, like the one involv-
Table 2, entries 15 and 16). In addition, the simple maleim- ing the lower face of the enamine and the Si face of the
ide (8i) was also used as a Michael acceptor, and gave (S)- maleimide (Figure 1), are much higher in energy, and can
9ai (50% ee) when CHCl3 was used as solvent, and (R)-9ai be safely disregarded.
(70% ee) when the solvent was DMF/H2O (2:1, v/v)
(Table 2, entries 17 and 18).
Other α,α-disubstituted aldehydes were used for this en-
antioswitching organocatalytic Michael addition reaction
to N-phenylmaleimide. Thus, 2-ethylbutanal (7b) gave suc-
cinimides (S)-9ba (55% ee) and (R)-9ba (68% ee) using
CHCl3 and DMF/H2O (2:1, v/v) as solvents, respectively
(Table 2, entries 19 and 20). In addition, cyclopentane-
carbaldehyde (7c) and cyclohexanecarbaldehyde (7d) gave
Figure 1. Faces of enamine and maleimide reacting through See-
bach’s synclinal model.
almost quantitative amounts of succinimides (S)-9ca and
(S)-9da with 49 and 14% ee, respectively, when CHCl3 was
the reaction solvent, whereas (R)-9ca and (R)-9da were iso-
The initial optimizations of the enamine structures
lated with 61 and 35% ee, respectively, when DMF/H2O showed that in the most stable conformations (i.e., A and B,
(2:1, v/v) was used as solvent (Table 2, entries 21–24). Figure 2), the NHBoc and enamine groups are in equatorial
Moreover, the use of propanal (7e), an α-monosubstituted positions of the cyclohexane ring. In both cases, the NH
aldehyde, in the two solvents allowed Michael adducts moiety of the NHBoc carbamate is pointing down from our
(R,S)/(S,S)-9ea and (S,R)/(R,R)-9ea, respectively, to be ob- view. The two conformations differ in the orientations that
tained as mixtures of diastereomers, with ee values of up to the NH enamine group can present, pointing up (conforma-
36 and 76% ee, respectively, for the major isomer (Table 2, tion A) or down (conformation B) from the plane of the
entries 25 and 26, see footnotes[d,e]).
cyclohexane ring (Figure 2). According to this picture, the
In an attempt to rule out the possibility that the change fragment NH–C–C–NH shows the two NH groups in anti
in the enantioselectivity could be a consequence of a further (A) or syn (B) relative orientations. The optimization of
transformation of the initially formed product, succinimide these structures showed that they are very similar in energy,
(R)-9aa obtained with 84% ee (Table 2, entry 2) was stirred and both must be taken into account for the transition-
in the presence of organocatalyst 6 (10 mol-%), in CHCl3 as structure search. In fact, structure B is slightly more stable
solvent at room temperature. After 20 h, succinimide (R)-9aa than A in CHCl3 (1.0 kcal/mol difference), whereas they
was recovered unchanged. In addition, the model reaction of have the same energy in water. This means that A is slightly
aldehyde 7a with maleimide 8a in the presence of organocata- better solvated by water than by chloroform. We cautiously
lyst 6 (10 mol-%) in DMF/H2O (2:1, v/v) was carried out for took these data as a first indication of the solvent depen-
4, 8, and 12 h, and the ee for (R)-9aa remained at 84% ee.
dence of the conformational distribution of the initial struc-
Eur. J. Org. Chem. 0000, 0–0
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J. Flores-Ferrándiz, B. Fiser, E. Gómez-Bengoa, R. Chinchilla
FULL PAPER
tures. We thought that this effect could be more dramatic close enough to form an intermolecular hydrogen bond,
during the transition states of the reaction, which are sup- which stabilizes the developing negative charge in the male-
posed to be quite polar, due to the significant charge trans- imide oxygen atom, producing a structure that is much less
fer that takes place from the enamine to the maleimide.
polar than TS-AR, and therefore, less sensitive to the sur-
rounding solvent molecules. This effect can be observed in
the computed energies for TS-BS, which do not show sig-
nificant differences between the different solvent models, or
even the gas phase (TS-BS water: 17.7,[32] TS-BS chloroform:
16.0, TS-BS gas phase: 15.8 kcal/mol, Figure 4).
Figure 2. Most stable conformations of the reacting enamine.
We confirmed this hypothesis in the light of the com-
puted transition state activation energies. In conformation
A, the maleimide could hypothetically approach the two
faces of the enamine, as shown in Figure 3. If the attack
takes place from the left-hand side of the enamine, the reac-
tion occurs through TS-AR (Si face of maleimide, R prod-
uct), whereas the approach of the maleimide from the right-
hand side of the enamine (hypothetical TS-AS) is strongly
disfavoured due to steric repulsion from the large Boc
group, which is blocking that face. We could not actually
find any transition state for that approach without severely
distorting the structure. It is noteworthy that TS-AR is a
very polar structure, with a high degree of negative charge
developing in the maleimide oxygen atom. Consequently,
the polarity of the reaction medium must have a great influ-
ence on the activation barrier of the process. Thus, it was
not surprising to find that the lowest free energy for TS-AR
corresponds to the structure computed in a water model
(ΔG‡ = 14.8 kcal/mol),[32] while the chloroform and gas
phase models present higher values (ΔG‡ = 18.7 and
20.7 kcal/mol, respectively). Interestingly, TS-AR leads to
the formation of the R enantiomer, which is experimentally
obtained in the polar aqueous medium.
Figure 4. Representations and energies of transition states TS-BS
and TS-BR, corresponding to conformation B in Figure 2. Struc-
tures and values were obtained at the M06-2X/6-311+G**//M06-
2X/6-31G** level of theory.
Meanwhile, if the maleimide approaches the upper face
of the enamine in conformation B, this leads to transition
state TS-BR (Figure 4). Similarly to TS-AR, this transition
structure is quite polar, and the maleimide oxygen is better
stabilized in the presence of surrounding solvent molecules.
Thus, its lowest energy was measured in water (15.2 kcal/
mol),[32] although this value is higher than the one corre-
sponding to TS-AR (14.8 kcal/mol, Figure 3). This increase
in the energy is probably due to the higher internal strain
that the structure presents as the result of a weak hydrogen
bond formed between the enamine NH and the carbamate
oxygen atom, which does not participate in the activation
of the maleimide.
In summary, the most significant computational data are
that the lowest calculated activation energy in water corre-
sponds to TS-AR (14.8 kcal/mol), a polar structure lacking
intramolecular hydrogen bonds, where the surrounding
water molecules are responsible for intermolecular
hydrogen-bonding activation of the maleimide (Figure 5).
TS-AR produces the R enantiomer of the product, which is
consistent with the experimental results in the polar aque-
ous DMF medium (Table 1). Also, the lowest calculated ac-
Figure 3. Computed activation energies for transition state TS-AR
(corresponding to conformation A in Figure 2) in the gas phase,
chloroform, and water models. Structures and values were obtained
at the M06-2X/6-311+G**//M06-2X/6-31G** level of theory.
On the other hand, two transition states were located for tivation energy in chloroform is TS-BS (16.0 kcal/mol), a
conformation B, following the two possible approaching transition structure containing an intramolecular hydrogen
trajectories (TS-BS and TS-BR, Figure 4). In TS-BS, the Re bond between the maleimide and the NHBoc groups (Fig-
face of the maleimide is attacked by the lower face (from ure 5). This transition state leads to the formation of the S
our view) of the enamine, whereas in TS-BR, the Si face of enantiomer, which is once again consistent with the experi-
the maleimide approaches the upper face of the enamine. mental data in chloroform (Table 1). Furthermore, these re-
In TS-BS, the maleimide oxygen and the HNBoc group are sults agree with chemical common sense, that intramolec-
6
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Solvent-Induced Reversal of Enantioselectivity
Computational Methods: The structures were initially optimized
using density functional theory (DFT) with the B3LYP[33] and the
6-31G* basis set, as implemented in Gaussian 09.[34] Further reop-
timization at the M06-2X/6-31G** level of theory[35] was carried
out to account for the important dispersion forces in such large
systems. The energy values shown in Figures 3 and 4 also include
single-point refinements at the M06-2X/6-311+G** level on the
previously optimized structures (M06-2X/6-31G**), including po-
larization functions for a better description of hydrogen-bond acti-
vations. Additionally, solvation factors were introduced with the
IEF-PCM method,[36] using chloroform or water as indicated in
the text and figures.
ular hydrogen bonds are more significant in nonpolar sol-
vents, whereas intermolecular hydrogen bonds with sur-
rounding water molecules are present in aqueous systems.
We also performed single-point calculations at the B3LYP/6-
311+G** level of theory, and the relative values are similar to those
of the M06-2X energies. Therefore, they have not been included in
the manuscript, and are collected in the Supporting Information.
The stationary points were characterized by frequency calculations
in order to verify that they have the right number of imaginary
frequencies.
Figure 5. 3D representations and energies of transition states TS-
AR-water and TS-BS-chloroform.
The intrinsic reaction coordinates (IRC)[37] were followed to verify
the energy profiles connecting each transition state to the correct
associated local minima.
Conclusions
Easily prepared carbamate-monoprotected chiral trans-
cyclohexane-1,2-diamines can be used as organocatalysts in
the high-yielding enantioselective conjugate addition of
aldehydes, mainly α,α-disubstituted, to different maleim-
ides, in a solvent-dependent enantioswitchable reaction.
Thus, both S- or R-enantioenriched forms of the corre-
sponding succinimides can be obtained using a single
enantiomer of the organocatalyst, just by changing the re-
action solvent from chloroform to aqueous N,N-dimethyl-
formamide. Theoretical calculations are able to show the
reason for this solvent-dependent reversal of enantio-
selectivity. The most polar transition state (i.e., TS-AR)
presents the lowest energy in water, and it is responsible for
the major formation of the R enantiomer. The least polar
transition state (i.e., TS-BS) accounts for the formation of
the S enantiomer in chloroform, consistent with the experi-
mental results.
Acknowledgments
The authors are grateful for the financial support from the Spanish
Ministerio de Economía y Competitividad (MEC) (project number
CTQ2011-24151), Fondos Europeos para el Desarrollo Regional
(FEDER), the COST Action CM0905 “Organocatalysis”, the FP7
Marie Curie Action of the European Commission via the ITN
ECHONET Network (FP7-MCITN-2012-316379), the University
of Alicante and the University of the Basque Country. The authors
also thank SGI/IZO-SGIker (UPV/EHU) and the University of
Szeged, Department of Chemical Informatics for allocation of
computational resources. J. F.-F. acknowledges the Vicerrectorado
de Investigación, Desarrollo e Innovación of the University of Al-
icante for a predoctoral fellowship.
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their physical and spectroscopic data, are described in the Support-
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(0.04 mmol) and 8 (0.2 mmol) in CHCl3 or DMF/H2O (2:1, v/v;
0.5 mL), and the reaction was stirred at room temp. until TLC
showed that it was complete. HCl (2 m aq.; 10 mL) was added, and
the mixture was extracted with EtOAc (3ϫ 10 mL). The organic
phase was washed with water (2ϫ 10 mL), dried (MgSO4), filtered,
and evaporated (15 Torr). The resulting residue was purified by
flash chromatography (hexane/EtOAc) to give adducts 9.
Succinimides 9 have already been described.[24b] Their H and 13C
NMR spectroscopic data and retention times in chiral HPLC for
both enantiomers can be found in the Supporting Information.
1
Eur. J. Org. Chem. 0000, 0–0
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J. Flores-Ferrándiz, B. Fiser, E. Gómez-Bengoa, R. Chinchilla
FULL PAPER
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Received: October 31, 2014
Published Online: ᭿
8
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Date: 14-01-15 18:51:59
Pages: 9
Solvent-Induced Reversal of Enantioselectivity
Organocatalysis
J. Flores-Ferrándiz, B. Fiser, E. Gómez-
Bengoa, R. Chinchilla* ..................... 1–9
Solvent-Induced Reversal of Enantioselec-
tivity in the Synthesis of Succinimides by
the Addition of Aldehydes to Maleimides
Catalysed by Carbamate-Monoprotected
1,2-Diamines
An inversion of enantioselectivity is
achieved by simply changing the solvent in
the enantioselective Michael addition reac-
tion of aldehydes to maleimides catalysed
by carbamate-monoprotected trans-cyclo-
hexane-1,2-diamines. The reasons behind
this uncommon enantioswitch are ex-
plained using theoretical calculations.
Keywords: Asymmetric catalysis / Organo-
catalysis / Michael addition / Enantioselec-
tivity / Solvent effects / Transition states
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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