Access to Chiral GABA Analogues Bearing a Trifluoromethylated All-Carbon Quaternary Stereogenic Center through Water-Promoted Organocatalytic Michael Reactions

Article abstract of DOI:10.1021/acs.orglett.9b02320

Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethyl-β-aryl- or -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably accelerated as

Full text of DOI:10.1021/acs.orglett.9b02320

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Access to Chiral GABA Analogues Bearing a Trifluoromethylated All-
Carbon Quaternary Stereogenic Center through Water-Promoted
Organocatalytic Michael Reactions
Jae Hun Sim,† Jin Hyun Park,† Pintu Maity, and Choong Eui Song*
Department of Chemistry, Sungkyunkwan University, Suwon 16419, Korea
S
* Supporting Information
ABSTRACT: Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethyl-
β-aryl- or -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably
accelerated as a result of enforced hydrophobic interactions between catalysts and reactants. Takemoto-type thiourea catalysts
are very effective for this transformation, affording highly enantioenriched Michael adducts that provide simple access to chiral
γ-aminobutyric acid (GABA) analogues with a β-trifluoromethylated quaternary stereocenter.
γ-Aminobutyric acid (GABA) is a major inhibitory neuro-
transmitter in the human brain.1 Thus, GABA deficiency is
associated with many types of psychiatric and neurological
disorders, such as anxiety, depression, pain, epilepsy,
Huntington’s chorea, Parkinson’s disease, and Alzheimer’s
disease. However, GABA itself is very hydrophilic and thus
cannot be used for the treatment of these diseases since it
cannot penetrate the blood−brain barrier (BBB). Thus, the
synthesis of many structurally modified GABA analogues that
show greater lipophilicity and permeability to cross the BBB
has drawn a lot of interest in the pharmaceutical field.2 In
particular, structural modification of GABA at the β-position
has been the subject of extensive surveys because the potential
activity of the resulting derivatives. For example, β-substituted
GABA derivatives such as pregabalin,3 phenibut,4 baclofen,5
and rolipram6 have been developed as novel therapeutic drugs
for a wide range of central nervous system diseases (Figure 1).
The enantioselective incorporation of fluorine atoms into
therapeutic or diagnostic organic molecules has received
considerable attention in medicinal chemistry since it can
productively influence the pharmacological properties of a
bioactive molecule by enhancing its lipophilicity, metabolic
stability, or even permeability compared with the non-
fluorinated parent compound.7 In particular, the trifluor-
omethyl (−CF3) group is commonly used as the fluorinated
bioisostere of an ethyl7l or isopropyl8 group.
Figure 1. GABA and some of its pharmaceutically important
analogues.
trifluoromethylated quaternary stereogenic center9 at the β-
position would be one outstanding challenge, since the
introduction of the CF3 group might enhance the metabolic
stability and increase the lipophilicity and membrane
permeability.10 However, only very few reports have
accomplished the synthesis of GABA derivatives bearing a
trifluoromethylated quaternary stereocenter at the β-position
that might be of biological interest.11
In principle, a catalytic asymmetric Michael addition of
malonate derivatives to β-CF3-β,β-disubstituted nitroalkenes
would enable efficient access to GABA analogues with a
trifluoromethylated quaternary stereogenic center at the β-
position (Scheme 1). However, β-CF3-β,β-disubstituted nitro-
In this regard, the development of new facile synthetic
Received: July 5, 2019
protocols to access chiral GABA analogues bearing a
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02320
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Proposal for the Synthesis of Chiral GABA
Derivatives with a Trifluoromethylated Quaternary
Stereogenic Center
Scheme 2. Catalyst Screening
alkenes are sterically highly congested and thus are regarded as
poor substrates for Michael addition.12 We recently demon-
strated that the “hydrophobic amplification”13 achieved under
“on-water” conditions14,15 makes it possible to achieve new
catalytic reactions of otherwise completely unreactive sub-
strates.16,17 On-water catalysis usually enables enforced
hydrophobic interactions between catalysts and substrates as
a result of hydrophobic hydration effects.18 Thus, we presumed
that the reactivity limitation of this type of substrate could be
addressed by employing on-water conditions. Herein we report
a practical and versatile synthetic access to chiral GABA
analogues with a trifluoromethylated quaternary stereogenic
center at the β-position via water-promoted organocatalytic
Michael reactions.
In 2017, as mentioned previously, our group demonstrated
that the hydrophobic amplification achieved under on-water
conditions enabled the enantioselective addition of dithiomal-
onates (DTMs)19 to otherwise completely unreactive β,β-
disubstituted nitroalkenes using cinchona-derived organo-
catalysts.16 Thus, we initiated our study by performing the
enantioselective Michael addition of (E)-β-CF3-α-nitrostyrene
(1a) and diethyl dithiomalonate (2a) using different types of
cinchona-derived bifunctional organocatalysts under on-water
conditions as a model reaction (Scheme 2). However, this class
of organocatalysts failed in this model reaction. With quinine
(QN), quinine−sulfonamide (QN-SA), quinine−thiourea
(QN-TU), or quinine−squaramide (QN-SQA) catalysts, the
reaction did not proceed at all. In cinchona-type catalysts,
steric congestion at the bifunctional active site might hinder
the entrance of substrates possessing a sterically demanding
CF3 group to the active site. The van der Waals volume of the
trifluoromethyl group (−CF3) is relatively large, similar to that
of the ethyl group.7l We therefore hypothesized that the use of
catalysts having a larger active-site cavity might address this
low reactivity issue.
a
Reaction conditions: 1a (0.1 mmol), 2a (0.12 mmol), catalyst (0.01
mmol), toluene (0.5 mmol), brine (2.0 mL), rt, 48 h. Conversions
were calculated by 19F NMR integration, and ee values were
determined by HPLC analysis. n.r. = no reaction.
toluene (5.0 equiv) as a hydrophobic cosolvent at 0 °C for 96
h was the most effective protocol for this model reaction
(>99% conversion with 96% ee) (entry 5).20 Here it should
also be noted that in the absence of a hydrophobic cosolvent, a
slightly lower enantioselectivity was obtained (entry 5 vs entry
11). It is probable that some water molecules around the
transition state can interfere with this hydrogen-bonding
catalysis, consequently lowering the enantioselectivity. The
hydrophobic cosolvent can suppress the interaction of water
molecules with transition state by sequestering the transition
state away from water.16,17 Thus, the addition of each of the
hydrophobic cosolvents tested in this study yielded slightly
enhanced enantioselectivity (entries 5−10 vs entry 11). In
addition, to highlight the on-water effect, control experiments
in organic solvents (toluene and DCM) were performed, and
only poor yields were obtained (see the Supporting
Information for experimental details).
Gratifyingly, Takamoto-type catalysts 4 showed some
promising catalytic results. When the model reaction was
carried out using Takemoto catalyst 4a, the desired product
3aa was obtained in 19% yield with 89% ee. Further catalyst
screening revealed Takemoto-type catalyst 4f to be the optimal
catalyst. The presence of the pyrrolidine moiety in 4f provoked
a dramatic change in the reactivity (52% yield) and
enantioselectivity (94% ee). Thus, with 4f as the optimal
catalyst, further optimization studies were performed (Table
1). Further improvements in the conversion and enantiose-
lectivity were simply achieved by increasing the catalyst loading
(15 mol %), lowering the reaction temperature (0 °C), and
prolonging the reaction time (96 h) (entry 3). Furthermore,
screening of different dithiomalonates 2 (see the Supporting
Information) showed that dibenzyl dithiomalonate (2b) was
also a suitable Michael donor (entries 4−11). In particular, the
use of 2.0 equiv of 2b in the presence of 4f (15 mol %) and
With the optimal reaction conditions in hand, the scope of
the enantioselective Michael addition of a variety of β-CF3-β,β-
disubstituted nitroalkenes 1a−w in the presence of a catalytic
amount of 4f was explored to establish the generality of the
process (Scheme 3). A series of trifluoromethylated nitro-
alkene derivatives 1a−o having a variety of different ortho-,
meta-, and para-substituted phenyl groups at the β-position,
including a 2-naphthyl group, were successfully converted into
the corresponding products 3a−o in excellent yields with 93−
96% ee. This reaction also works very well for a range of
trifluoromethylated nitroalkenes with different heteroaryl
(products 3p−r) and alkyl (products 3s and 3t) substituents
at the β-position. Nitroalkene 1u with a CF2H group was also
examined. To our delight, the Michael adduct 3u possessing a
CF2H group at the β-position was also attainable under the
same conditions. However, nitroalkenes 1v and 1w having
sterically more demanding perfluoroalkyl groups (e.g., −C2F5,
B
DOI: 10.1021/acs.orglett.9b02320
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst mol %
DTM (equiv)
cosolvent
temp. (°C)
time (h)
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
15
15
15
15
15
15
15
15
15
15
2a (1.2)
2a (2.0)
2a (2.0)
2b (2.0)
2b (2.0)
2b (2.0)
2b (2.0)
2b (2.0)
2b (2.0)
2b (2.0)
2b (2.0)
toluene
toluene
toluene
toluene
toluene
hexane
cyclohexane
o-xylene
p-xylene
mesitylene
−
rt
rt
0
rt
0
0
0
0
0
0
0
48
48
96
48
96
96
96
96
96
96
96
52
84
82
86
>99
86
98
93
95
89
94
94
96
94
96
94
96
94
95
95
93
10
11
87
a
b
c
Reaction conditions: 1a (0.1 mmol), 2a or 2b, 4f, cosolvent (0.5 mmol), brine (2.0 mL). Calculated by 19F NMR integration. Determined by
HPLC analysis.
a
enantiomer of 4f as the catalyst. The absolute configuration of
ent-3ab was established as S by X-ray analysis.22
Scheme 3. Substrate Scope
Finally, the synthetic utility of our catalytic protocol was
showcased by the synthesis of β-CF3-β-aryl- or -alkyl-
functionalized γ-aminobutyric acids (7) from Michael adducts
3. As shown in Scheme 4, the Michael addition reactions of 1a,
Scheme 4. Synthetic Utility of the Michael Adducts 3 To
ab
Obtain β-CF3-GABA Analogues
a
The % ee values in parentheses were obtained after recrystallization.
The corresponding enantiomers of (S)-7a, (S)-7f, (S)-6o, and (R)-
b
7t were also prepared with 3ab, 3f, 3o, and 3t, respectively (see the
Supporting Information).
1f, 1o, and 1t with dibenzyl dithiomalonate (2b) using ent-4f
(15 mol %) as the catalyst on a 2 mmol scale afforded the
corresponding desired Michael products (S)-3ab (96% ee),
(S)-3f (95% ee), (S)-3o (96% ee), and (R)-3t (67% ee),
respectively. The obtained Michael products were then
smoothly converted into the corresponding γ-lactam thioesters
ent-5a, ent-5f, ent-5o, and ent-5t, respectively, under reduction
conditions (Zn, TiCl3·HCl in AcOH). The enantiopurity of
ent-5t was increased above 88% ee after recrystallization from
diethyl ether. Subsequent hydrolysis of γ-lactam thioesters 5
followed by a decarboxylation step provided β-CF3-substituted
a
General reaction conditions: 1a−v (0.3 mmol), 2b (0.6 mmol), 4f
b
(0.045 mmol), toluene (1.5 mmol), brine (4.0 mL), 0 °C, 96 h. ent-
4f was used as the catalyst. 2b (0.3 mmol) was used. n.r. = no
reaction.
c
d
−C3F7) showed no reactivity.21 The opposite enantiomeric
products ent-3ab, ent-3c, ent-3f, ent-3o, and ent-3t were also
obtained in good yields and stereoselectivities using the
C
DOI: 10.1021/acs.orglett.9b02320
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
γ-lactams 6. Enantiomerically pure ent-6a23 and ent-6f could be
obtained by recrystallization from methyl tert-butyl ether.
Notably, ent-6o is the β-trifluoromethylated analogue of
rolipram. Finally, the HCl salts of ent-7a, ent-7f, and ent-7t,
which are the β-trifluoromethylated analogues of phenibut,
baclofen, and pregabalin, respectively, were obtained by
hydrolysis of the corresponding γ-lactams with 6 N HCl.
In summary, we herein have introduced a practical and
versatile synthetic access to CF3-substituted GABA analogues
bearing a quaternary stereogenic center at the β-position via
water-promoted Michael reactions. Under on-water conditions,
the highly challenging enantioselective Michael addition of
sterically congested β-CF3-β,β-disubstituted nitroalkenes with
dithiomalonates as reactivity-enhanced malonate surrogates
has been achieved. As a result of enforced hydrophobic
interactions between catalysts and reactants, the reaction rates
were remarkably accelerated under on-water conditions.
Takemoto-type thiourea catalysts are very effective for this
transformation, and excellent chemical yields with enantiose-
lectivities of over 90% ee were obtained in most cases. Thus,
this approach enables the very efficient asymmetric synthesis of
enantioenriched Michael adducts containing a quaternary
stereogenic center bearing a trifluoromethyl group, which
provide simple access to GABA analogues with a β-
trifluoromethylated quaternary stereocenter.
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Corresponding Author
*E-mail: s1673@skku.edu.
ORCID
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Choong Eui Song: 0000-0001-9221-6789
Author Contributions
†J.H.S. and J.H.P. contributed equally to this work.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF-2017R1A2A1A05001214 and
NRF-2019R1A4A2001440). The authors also thank Ms. S. L.
Park and Mr. Y. J. Chang (Sungkyunkwan University) for their
assistance in the experiments.
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thioesters did not proceed at all (see the Supporting Information).
(21) The sterically highly congested substrates having an ortho-
substituted phenyl (e.g., o-Me, o-OMe) or 1-naphthyl group were not
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E
DOI: 10.1021/acs.orglett.9b02320
Org. Lett. XXXX, XXX, XXX−XXX