Water-Enabled Catalytic Asymmetric Michael Reactions of Unreactive Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with All-Carbon Quaternary Stereogenic Centers

Article abstract of DOI:10.1002/anie.201611466

Water enables new catalytic reactions for otherwise unreactive substrate systems. Under the “on water” reaction conditions, extremely unreactive β,β-disubstituted nitroalkenes smoothly underwent enantioselective Michael addition reactions with dithiomalonates using a chiral squaramide catalyst, affording both enantiomers of highly enantioenriched Michael adducts with all-carbon-substituted quaternary centers. The developed “on water” protocol was successfully applied for the scalable one-pot syntheses of chiral GABA analogs with all-carbon quaternary stereogenic centers at the β-position, which might show highly interesting pharmaceutical properties.

Full text of DOI:10.1002/anie.201611466

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201611466
German Edition: DOI: 10.1002/ange.201611466
Organocatalysis
Hot Paper
Water-Enabled Catalytic Asymmetric Michael Reactions of Unreactive
Nitroalkenes: One-Pot Synthesis of Chiral GABA-Analogs with All-
Carbon Quaternary Stereogenic Centers
Jae Hun Sim and Choong Eui Song*
Abstract: Water enables new catalytic reactions for otherwise
unreactive substrate systems. Under the “on water” reaction
conditions, extremely unreactive b,b-disubstituted nitroalkenes
smoothly underwent enantioselective Michael addition reac-
tions with dithiomalonates using a chiral squaramide catalyst,
affording both enantiomers of highly enantioenriched Michael
adducts with all-carbon-substituted quaternary centers. The
developed “on water” protocol was successfully applied for the
scalable one-pot syntheses of chiral GABA analogs with all-
carbon quaternary stereogenic centers at the b-position, which
might show highly interesting pharmaceutical properties.
T
he simplest g-amino acid, g-aminobutyric acid (GABA), is
Figure 1. Pharmaceutically important GABA analogs.
the major inhibitory neurotransmitter in the central nervous
system (CNS) of mammals. GABA deficiency is associated
with several important neurological disorders such as Hun-
tington and Parkinson disease, epilepsy, as well as psychiatric
disorders, such as anxiety and pain.[1] Thus, synthesis of many
structurally diverse GABA analogs has attracted a great deal
of interest in the pharmaceutical field, especially with the aim
to increase their lipophilicity, thus allowing them to gain
access to the central nervous system.[1] In particular, a number
of GABA analogs bearing a tertiary chiral carbon center at
the b-position such as phenibut,[2] baclofen,[3] pregabalin[4] and
rolipram[5] have been developed as important therapeutic
agents for a range of CNS-disorders (Figure 1). Moreover,
radioactive isotope-labelled b-substituted g-lactams such as
[11C]-labeled UCB-J was shown to have excellent PET
(positron emission tomography) imaging properties for in
vivo quantification of synaptic density with several potential
applications in diagnosis and therapeutic monitoring of
neurological and psychiatric disorders (Figure 1).[6]
without an introduction of activating groups.[9] In this report,
the authors developed a catalytic reaction for the synthesis of
chiral b,b-disubstituted g-amino acids via peptide-catalyzed
asymmetric Michael addition of nitromethane to b-disubsti-
tuted a,b-unsaturated aldehydes (Scheme 1a).[8] Alterna-
In this regard, more lipophilic, chiral acyclic b,b-disub-
stituted g-aminoacids and their lactam analogs with all-
carbon quaternary stereogenic centers are expected to
expand the pharmaceutical library with potential bioactivi-
ties. However, synthetic difficulties with creating all-carbon
quaternary stereogenic centers[7] at the b-position of g-
aminoacids have prevented their implementation in drug
discovery. For example, there is only one reported catalytic
enantioselective synthesis[8] of b,b-disubstituted g-amino acids
Scheme 1. a) Previous work for the synthesis of g-amino acids with an
all-carbon quaternary center. b) Proposal for the synthesis of chiral
GABA analogs with all-carbon quaternary center at b-position by
employing “on water” catalytic conditions.
tively, a g-aminobutyric acid precursor with an all-carbon
quaternary stereogenic center, in principle, could be directly
accessed through a catalytic asymmetric Michael addition of
malonates 2 to b,b-disubstituted nitroalkenes 1 (Scheme 1b).
However, to the best of our knowledge, Michael addition of
b,b-disubstituted nitroalkenes 1 with malonate derivatives
have so far not been realized, presumably due to the lack of
reactivity associated with the steric and electronic nature of b-
carbon.[10]
[*] J. H. Sim, Prof. C. E. Song
Department of Chemistry, Sungkyunkwan University
Suwon, 440-746 (Korea)
E-mail: s1673@skku.edu
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201611466.
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In nature, water is used for biosynthetic reactions to
sustain life in enzymatic processes, inducing hydrophobic
interactions between enzyme and substrates.[11] From the
perspective of green chemistry as well as increased scientific
efforts to mimic nature, tremendous effort has recently been
applied to develop asymmetric catalytic reactions in aqueous
environments.[12] Recently, the Schreiner[13] and Rueping[14]
research groups independently reported that hydrogen-bond-
promoted organocatalysis could remarkably be amplified in
aqueous environments by the “hydrophobic hydration
effect”.[15] Soon after, we[16] and Armas research group[17]
also reported successful hydrogen bonding promoted asym-
metric catalytic reactions in aqueous medium. In particular,
we observed that the hydrophobic amplification[13] was
significantly dependent upon the hydrophobicity of the
catalysts.[16b] For example, in the Michael addition reactions
of simple nitroalkenes with malonates, using a hydrophobic
cinchona catalyst, even a highly challenging Michael donor
such as dimethyl methyl malonate could be smoothly
converted to the desired adduct. Thus, we envisioned that
hydrophobic amplification “on water”[18,19] conditions would
enable unprecedented Michael addition of challenging b,b-
disubstituted nitroalkenes with malonate derivatives (Sche-
me 1b).
a Michael donor, no obvious conversion was detected both in
organic solvents and “on water” system. However, dithio-
malonate 2c—a reactivity-enhanced malonate surrogate[20]
—
led to a striking rate difference in the Michael addition
between the reactions in an organic solvent and “on water”
(Figure 2). When the reactions were performed in toluene,
CH2Cl2, or THF, no conversion was observed. However, with
the “on water” condition (on brine[21]), the reaction was
completed after 48 h, presumably due to the hydrophobic
hydration effect. Evidence for the hydrophobic hydration
effect on rate acceleration was obtained using an antihydro-
phobic LiClO4.[15a] In the aqueous LiClO4 solution, less than
5% of conversion was observed after 96 h.
With the promising preliminary results in hand, we next
explored the enantioselective Michael reaction of (E)-a-
methyl-b-nitrostyrene (1a) with dithiomalonate 2c on brine
using a variety of cinchona-based bifunctional organocata-
lysts. However, the use of readily available cinchona-based
bifunctional catalysts, quinine-based sulfonamide QN-SA,
thiourea QN-TU and N-squaramide QN-N-SQA led to
unsatisfactory enantioselectivities (5–66% ee) (Scheme 2).
Here, we report the highly enantioselective organocata-
lytic Michael addition of dithiomalonates to b,b-disubstituted
nitroalkenes in water. The obtained Michael adducts could
smoothly be converted into diverse chiral GABA analogs
with all-carbon quaternary stereogenic centers at the b-
position, which might show interesting pharmaceutical prop-
erties.
Initially, we examined Michael addition reactions of
highly unreactive (E)-a-methyl-b-nitrostyrene (1a) with
dibenzyl malonate (2a), dibenzyl monothiomalonate (2b) or
dibenzyl dithiomalonate (2c) in the presence of triethyl amine
as a catalyst at ambient temperature. As shown in Figure 2,
when malonate 2a or monothiomalonate 2b was employed as
Scheme 2. Preliminary catalyst screening.
Gratifyingly, the squaramide catalyst QN-SQA was found to
be a promising catalyst, showing remarkably higher enantio-
selectivity (77% ee) than those obtained with other catalysts
(Scheme 2, for more results for catalyst screening, see the
Supporting Information). Note that, all catalysts examined in
this study showed no activity in pure organic solvents such as
toluene and CH2Cl2.
Although “on water” reaction conditions enabled the
unprecedented catalytic reaction, ee values achieved with
QN-SQA catalyst and its derivatives were still unsatisfactory.
However, to our delight, the addition of hydrophobic co-
solvents such as, for example, toluene, o-, m- and p-xylene,
mesitylene, hexane, and cyclohexane, yielded enhanced
enantioselectivity (Table 1, see the Supporting Information
for details). For example, the enantioselectivity was increased
from 77% ee to 86% ee by adding 7 equiv of o-xylene (entry 3
in Table 1). However, the reverse mixing of solvents (i.e.,
brine as an additive (7 equiv) in o-xylene) did not promote the
reaction, which is a further evidence of the hydrophobic
hydration effect on the rate acceleration. To further improve
the yields and enantioselectivity, the effect of the substituents
(R) of dithiomalonates 2 in our reaction system was also
Figure 2. Relative reactivity of malonate types in various reaction
media.[a] [a] Reaction was carried out using 1a (0.1 mmol), 2
(1.2 equiv) and NEt3 (20 mol%) in the indicated reaction medium
(2.0 mL) at RT for 48 h. The yield was determined by H NMR
integration.
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Table 1: Reaction condition optimization with squamide-based cata-
lysts.[a]
Figure 3. Reaction progress of the Michael addition of 2d to 1a on
Entry Catalyst
R
Additive
(equiv)[b]
T [8C] t [h] Yield [%][c] ee [%][d]
brine.[a] a) using squaramide catalysts.[a] The reactions were performed
with 1a (0.1 mmol), 2d (1.2 equiv), catalyst (10 mol%) and o-xylene
(5 equiv) on brine (3.0 mL) at RT.
1
2
3
4
5
6
QN-SQA Bn
–
20
20
20
20
20
20
48 61
48 47
48 44
48 36
96 49
96 99
77
84
86
87
87
84
QN-SQA Bn toluene
QN-SQA Bn o-xylene
QN-SQA Et o-xylene
QN-SQA Et o-xylene
HQN-
SQA
racemic tertiary amine catalysts. The more hydrophobic tri-n-
butyl amine (LogP; 3.97) and tri-n-hexyl amine (LogP; 6.47)
exhibited much higher catalytic activity than the less hydro-
phobic triethyl amine (LogP; 1.26) (see the Supporting
Information).
Et o-xylene
7
8
QD-SQA Et o-xylene
HQD-
SQA
20
20
96 47
96 99
85[e]
86[e]
Et o-xylene
Et o-xylene
Et o-xylene
With the optimal catalytic conditions in hand, the
substrate scope of our protocol was investigated, and the
results are shown in Scheme 3. Excellent enantioselectivities
(up to 96% ee) and isolated chemical yields (up to 99%) were
obtained with diverse aryl and heteroaryl substituted nitro-
alkenes 1. In particular, substituents in meta-, or para-
positions were all found to be excellent substrates for the
reaction. Regardless of the electronic nature of the aromatic
substituent, high enantioselectivity was achieved. Although
the sterically demanding ortho-substituted substrate 3d also
gave excellent enantioselectivity, a significantly lower reac-
tion rate was observed, due to steric limitations. Heteroar-
omatic substrates such as 2-furanyl (1q), 2-thienyl (1r) and 3-
thienyl (1s) also gave excellent enantioselectivities (92% ee,
95% ee and 95% ee, respectively). In addition, aliphatic
substrates 1t–1v were also smoothly converted to the
corresponding adducts in moderate to high yields, however
with lower ees. The absolute configuration of 3d was
determined to be (S) by a single crystal X-ray structure
analysis.[22] The absolute configuration of other Michael
adducts 3 were assigned by analogy. It is also noteworthy
that this process is stereoconvergent, a highly desirable
feature for a catalytic asymmetric reaction.[23] E or Z isomer
of 1a afforded the same (S)-enantiomer of the Michael
adduct 3a. Thus, the mixture of E/Z-isomers of 1 can be used
without a purification step.
9
HQN-
SQA
0
0
96 98
96 97
92
10
HQD-
SQA
93[e]
[a] Reactions were performed with 1a (0.1 mmol), 2 (3 equiv) and
catalyst (15 mol%) on brine (2.0 mL). [b] 7 equivalents of additive were
used. [c] The yield was determined by 1H NMR integration. [d] The ee
values were determined by HPLC analysis using a chiral stationary phase.
[e] Using the pseudo-enantiomeric QD-SQA and HQD-SQA, the oppo-
site enantiomer was obtained.
investigated. Among the tested substrates (R = benzyl, ethyl,
n-butyl, t-butyl, phenyl etc.), the diethyl dithiomalonate 2d
was found to be the most suitable Michael donor (87% ee,
entry 4) (For more results obtained from thiomalonates
screening, see the Supporting Information). However, in
spite of our intensive optimization efforts, we could not obtain
higher than 49% yield even with prolonged reaction times
(entry 5 in Table 1). Recently, we reported that the catalyst
hydrophobicity, which can result in enforced hydrophobic
interactions between catalysts and substrates, is critical for the
reaction rate in some “on water” reactions.[16b] As shown in
Table 1 (entries 5 and 7 vs. entries 6 and 8) and Figure 3, the
reaction rate issue of the present reaction was also addressed
by using more hydrophobic catalysts. When more hydro-
phobic dihydroquinine-derived squaramide HQN-SQA
(LogP; 2.41 for QN-SQA, 2.68 for HQN-SQA)[16b] was
used, an enormous rate acceleration (> 99% conversion) was
observed (entries 6 and 8 in Table 1 and Figure 3). Further
improvement of enantioselectivity was achieved by lowering
the reaction temperature to 08C [92% ee using HQN-SQA
(entry 9) and 93% ee using the HQD-SQA (entry 10)]. The
same trends highlighting the remarkable effect of catalyst
hydrophobicity on the reactivity was also observed with
To demonstrate the synthetic utility and potential large-
scale applications of the present catalytic protocol, gram-scale
one-pot process for the synthesis of chiral GABA analogs
bearing chiral quaternary carbon centers was developed. As
shown in Scheme 4, the Michael addition reactions of 1a, 1g,
1m and 1p with diethyl dithiomalonate (2d) on a 13 mmol
scale afforded multi-gram quantities of the corresponding
desired products, (S)-3a (92% ee), (S)-3g (92% ee), (S)-3m
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clohexane (see the Supporting Information for experimental
details).[16b] After the separation of the organic layer from the
biphasic filtrate and evaporation under reduced pressure, the
crude products were subjected to reduction (Zn/TMSCl),
affording the corresponding chiral g- lactam thioesters 4a, 4g,
4m and 4p, respectively. Subsequent hydrolysis of crude g-
lactam thioesters 4a and 4m with 6n HCl provided the HCl
salt of the corresponding b,b-disubstituted g-amino acid 5a
(83% yield, 3 steps from 1a) and 5m (86% yield, 3 steps from
1m), which are the respective b-methylated analogs of
phenibut and baclofen. On the other hand, the b-methylated
analog of rolipram 7g was prepared by hydrolysis of crude 4g,
followed by a decarboxylation step (83% yield, 91% ee, 4
steps from 1g). In a similar manner, the g-lactam 7p was also
obtained which can be used to synthesize the beta-methylated
analog of [11C]-labeled UCB-J (85% yield, 94% ee, 4 steps
from 1p). The enantioselectivities of the original Michael
adducts 3 were maintained in the g-lactams 7, indicating the
perfect preservation of the stereochemistry during the
reduction and decarboxylation steps. The absolute configu-
ration of g-lactams 7 was also determined by a single crystal
X-ray structure analysis.[22]
In summary, we demonstrated here that on-water catalysis
enables new catalytic reactions for otherwise unreactive
substrate systems. Highly enantioselective organocatalytic
Michael addition of dithiomalonates to unreactive b,b-
disubstituted nitroalkenes, affording both enantiomers of
highly enantioenriched Michael adducts with all-carbon-
substituted quaternary centers, has been achieved by employ-
ing the “on water condition,” which enables enforced hydro-
phobic interactions between catalysts and substrates due to
the hydrophobic hydration effects. The developed “on water”
protocol was successfully applied for the scalable one-pot
syntheses of chiral GABA analogs with all-carbon quaternary
stereogenic centers at the b-position, which might show highly
interesting pharmaceutical properties.
Scheme 3. Substrate scope of the reaction.[a] [a] Unless otherwise
indicated, the reactions were performed with (E)-1 (0.5 mmol), 2d
(3.0 equiv), HQN-SQA (15 mol%), and o-xylene (7.0 equiv) on brine
(4.0 mL) at 08C for 96 h. [b] The yields and % ees in parentheses were
obtained by using HQD-SQA as the catalyst.
Acknowledgements
We are grateful for the financial support provided by the
Ministry of Science, ICT and Future Planning (NRF-
2014R1A2A1A01005794 and NRF-2016R1A4A1011451).
Conflict of interest
The authors declare no conflict of interest.
Keywords: amino acids · asymmetric organocatalysis ·
Michael addition · stereogenic centers · water
Scheme 4. Synthetic applications—one-pot syntheses of chiral beta-
disubstituted GABA analogs.
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Manuscript received: November 23, 2016
Final Article published: && &&, &&&&
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Organocatalysis
J. H. Sim, C. E. Song*
&&& — &&&
Water-Enabled Catalytic Asymmetric
Michael Reactions of Unreactive
Nitroalkenes: One-Pot Synthesis of Chiral
GABA-Analogs with All-Carbon
Quaternary Stereogenic Centers
Hydrophobic hydration: Under aqueous
reaction conditions, extremely unreactive
b,b-disubstituted nitroalkenes smoothly
underwent enantioselective Michael
addition reactions with dithiomalonates
using a chiral squaramide catalyst,
affording both enantiomers of the highly
enantioenriched Michael adducts with all-
carbon-substituted quaternary centers.
6
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