Rhodium-catalyzed asymmetric addition of arylboronic acids to γ-phthalimido-substituted-α,β-unsaturated carboxylic acid esters: An approach to γ-amino acids

Article abstract of DOI:10.1016/j.tetlet.2010.12.044

Efficient Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to ethyl-γ-phthalimidocrotonate by using bis-sulfoxide ligand affords γ-aminobutyric acid (GABA) derivatives with high enantioselectivities (90-96% ee) under mild conditions. Optically pu

Full text of DOI:10.1016/j.tetlet.2010.12.044

Tetrahedron Letters 52 (2011) 830–833
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rhodium-catalyzed asymmetric addition of arylboronic acids
to
c
-phthalimido-substituted-
a,b-unsaturated carboxylic
acid esters: an approach to
c-amino acids
⇑
Fuzhong Han, Jun Chen, Xiangyang Zhang, Jibing Liu, Linfeng Cun, Jin Zhu, Jingen Deng, Jian Liao
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
Natural Products Research Center, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
Graduate School of Chinese Academy of Sciences, Beijing 100049, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient Rh-catalyzed asymmetric 1,4-addition of arylboronic acids to ethyl-
using bis-sulfoxide ligand affords c-aminobutyric acid (GABA) derivatives with high enantioselectivities
(90–96% ee) under mild conditions. Optically pure (S)-Baclofen and (S)-Rolipram have been prepared suc-
cessfully through this synthetic route.
c
-phthalimidocrotonate by
Received 27 October 2010
Revised 30 November 2010
Accepted 10 December 2010
Available online 15 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Bis-sulfoxide ligand
Rh-catalyzed
1,4-Addition
c
-Aminobutyric acids
1. Introduction
addition of arylboronic acids to a,b-unsaturated esters, discovered
by Miyaura and co-workers,8 toward pharmaceutically active
compounds.9
Asymmetric catalyzed synthesis is one of the most powerful
tools to obtain enantiomerically pure pharmaceuticals.1 As a class
of important compounds for therapeutic uses in a range of central
Chiral bis-sulfoxides have been used as ligands in late-transi-
tion-metal catalyzed asymmetric reactions.10 In particular, Dorta
and co-workers disclosed that Rh-disulfoxide complexes can be
nervous system disorders and useful building blocks, c-aminobu-
tyric acids (GABA) and their derivatives, especially those analogs
bearing substituents at the b-position, have been the subject of
intense investigation.2 Moreover, studies have indicated that the
biological activity of these GABA analogs resides exclusively in a
single enantiomer; it is, therefore, desirable to provide an enantio-
selective method for the synthesis of these molecules. Although
much progress has been achieved that uses chiral auxiliaries,3
organocatalysis,4 and metal-catalysis,5 finding a more efficient
pathway of a transition-metal-catalyzed asymmetric transforma-
tion to prepare chiral GABA is still a challenge. Recently, Zheng
and co-workers developed an impressive, highly enantioselective
Rh-catalyzed hydrogenation and copper hydride 1,4-reduction
successfully applied in a
number of transformations.11 Very
recently, we demonstrated that simple chiral tert-butyl sulfoxide,
which is a ubiquitous, privileged structural element of chiral
ligands with only sulfur chirality, can be used in asymmetric reac-
tions (especially in rhodium-catalyzed 1,4-addition of arylboronic
acids to enones) with excellent enantioselectivities.12 Inspired by
the recent success of chiral sulfoxide (P-SOs and bis-sulfoxide)
ligands in asymmetric 1,4-addition, it is anticipated that this
protocol would allow preparation of the GABA derivatives with
excellent enantioselectivities and reactivities. Herein, we report
that alkyl
c-phthalimidocrotonates are excellent substrates for
the chiral rhodium bis-tert-butylsulfoxide complex catalyzed
route to synthesize a variety of chiral b-substituted
c
-amino acid
enantioselective conjugate addition of arylboronic acids under
mild conditions, providing b-substituted c-amino acid derivatives
in high yields and enantioselectivities ranging from 90% to 96% ee.
derivatives.6 Helmchen, on the other hand, described the use of
[Rh(acac)(C2H4)2]/BINAP as an effective catalyst and afforded a
c
-amino ester in 96% yield and 89% ee.7 This is one of the earliest
examples of the application of Rh-catalyzed asymmetric 1,4-
2. Result and discussion
As a starting point in our agenda, we set out to develop an effi-
cient synthetic route to alkyl c-phthalimidocrotonates. These are
⇑
Corresponding author.
E-mail address: jliao@cib.ac.cn (J. Liao).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.044

F. Han et al. / Tetrahedron Letters 52 (2011) 830–833
831
O
strates with the phthalimido group can make the purification of
the crude substrates convenient and promote the ee of addition
products because of their high crystallinity. From a synthetic point
COOR
COOR
Potassium phthalimide
DMF, rt, 12 h
N
Br
of view, this type of substrate, alkyl c-phthalimidocrotonates, can
O
be easily prepared from the commercially available (E)-alkyl 4-
bromobut-2-enoate and phthalimide potassium salt through a
one step transformation (Scheme 1).13
With the substrates in hand, we began our investigation by
studying Rh(I)-catalyzed asymmetric 1,4-addition of arylboronic
1a
1b
: R = Et 90%
: R = Me 85%
1c: R = Bu 80%
t
Scheme 1. Synthesis of alkyl
c
-phthalimidocrotonates 1.
acids to alkyl
c-phthalimidocrotonates. The results are summa-
rized in Table 1. In the first set of experiments, addition of phenyl-
boronic acid (2a) to ethyl ester 1a was examined under several
reaction conditions. Treatment of 1a with 2a (3.0 equiv) in
CH2Cl2/H2O (10:1) at 40 °C for 7 h using [L-RhCl]2 (2.5 mol %) and
interesting substrates mainly due to their excellent properties as
Michael acceptors, which allows efficient functionalization at the
b position by treatment with arylboronic acids. In addition, sub-
Table 1
Rhodium-catalyzed asymmetric 1,4-addition of phenylboronic acid to alkyl c
-phthalimidocrotonatesa
O
O
Ph
COOR
COOR
[ -RhCl]2 (2.5 mol %)
L
*
PhB(OH)2
+
N
N
Solvent / H2O (10/1)
KOH (50 mol %), 40 oC
O
O
1a-c
3
S
S
S
O
O
O
MeO
PPh2
L1
(R)-L2
(R,R)-
OMe
Entry
Substrate
Solvent
Time (h)
Yieldb (%)
eec (%)
1
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
1a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
Toluene
THF
1,4-Dioxane
ClCH2CH2Cl
CH2Cl2
7
7
7
7
7
7
7
7
92
60
88
70
95(S)
21
93
95
89
n.d.
n.d
n.d.
n.d.
95
2d
3
4
5
6
7
8
9
10
11
12
20
Trace
n.r.
Trace
Trace
92
7
1.5
1.0
0.5
CH2Cl2
CH2Cl2
83
67
94
94
a
All reactions were carried out with 0.2 mmol of substrate, 0.6 mmol PhB(OH)2 and KOH (1.0 M, 0.1 mL) at 40 °C in 1 mL of the indicated solvent with 2.5 mol % catalyst
([(R,R)-L1-RhCl]2).
b
Isolated yield.
c
The ee values were determined by HPLC on a chiral AD-H column and the absolute configuration was determined by comparison to the literature data.6a
(R)-L2 as ligand.
d
O
O
COOEt
N
[(R,R)-L1-RhCl]2
(2.5 mol %)
O
N
4-ClC6H4B(OH)2
+
COOEt
CH2Cl2 / H2O (10/1)
KOH (50 mol %)
40 oC, 1.5 h
O
Cl
1a
2d
3ad
(S)-
156 mg
90% yield, 95% ee
81% yield, >99% ee (after one
recrystallization)
NH2
HCl
6 N HCl
reflux, 12 h
COOH
93%
Cl
(S)-Baclofen
Scheme 2. Synthesis of (S)-Baclofen.

832
F. Han et al. / Tetrahedron Letters 52 (2011) 830–833
50 mol % of KOH. First, we studied the enantioselectivity of the
process in the presence of structurally different chiral sulfoxide li-
gands. The [(R,R)-L1-RhCl]2 (L1 = 1,2-bis(tert-butylsulfinyl)ben-
zene, which was reported by us previously12d), provided the best
result in terms of ee value (95%) and yield (92%) (Table 1, entry
1). In contrast, (R)-L2 (also developed by us), which is one of the
best ligands for the Rh-catalyzed asymmetric conjugate addition
of arylboronic acids to enones,12e gave the addition product 3aa
with low yield (60%) and poor enantioselectivity (21% ee) (Table
1, entry 2). Next, the ester group of 1 showed a 93% ee, and tert-
butyl ester (1c) gave 3ca with high ee (95%) but lower yield
(70%) (Table 1, entries 3 and 4).
Then, ethyl c-phthalimidocrotonate (1a) and phenylboronic
acid (2a) were chosen as standard substrates, and some common
factors, such as solvent, reaction time were examined. The enanti-
oselectivities and reactivities were found to be quite sensitive to
the solvent used. When the reaction was carried out at 40 °C in tol-
uene, MeOH, THF, 1,4-dioxane, ClCH2CH2Cl, and CH2Cl2, the results
ranged from no reaction to high yield and excellent ee (Table 1, en-
tries 1 and 5–9). When protic MeOH was used, good enantioselec-
tivity (89% ee) but low yield (20%) was afforded. CH2Cl2 was found
to be the most favorable solvent for this reaction. Thus, thorough
screening experiments were performed to find the best reaction
time. The results indicated that 1.5 h is enough to obtain high yield.
Table 2
Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to ethyl c
-phthalimidocrotonates 1aa
O
O
Ar
[(R,R)-L1-RhCl]2
COOEt
COOEt
(2.5 mol %)
*
ArB(OH)2
+
N
N
CH2Cl2 / H2O (10/1)
KOH (50 mol %)
40 oC, 1.5 h
O
O
1a
2a-2n
3
Entry
Ar (2)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph (2a)
4-MeC6H4 (2b)
4-FC6H4 (2c)
92 (3aa)
91 (3ab)
90 (3ac)
90 (3ad)
96 (3ae)
90 (3af)
94 (3ag)
95(3ah)
80 (3ai)
93 (3aj)
60 (3ak)
95 (3al)
85 (3am)
85 (3an)
95 (S)d
94 (—)
95 (—)
95 (S)d
94 (—)
90 (—)
94 (—)
94 (—)
94 (—)
94 (—)
94 (—)
94 (—)
96 (—)
94 (S)d
4-ClC6H4 (2d)
4-MeOC6H4 (2e)
1-Naphthyl (2f)
2-Naphthyl (2g)
3-MeOC6H4 (2h)
3,5-diMeC6H3 (2i)
3-MeC6H4 (2j)
2-MeC6H4 (2k)
4-tBuC6H4 (2l)
4-CF3C6H4 (2m)
3-Cyclopentoxy-4-MeOC6H3 (2n)
a
All reactions were carried out with 0.2 mmol of substrate, 0.6 mmol ArB(OH)2 and KOH (1.0 M, 0.1 mL) at 40 °C in 1 mL of CH2Cl2 with 2.5 mol % catalyst ([(R,R)-L1-RhCl]2)
for 1.5 h.
b
Isolated yield.
c
The ee values were determined by HPLC on a chiral AD-H or OD-H column. The signs of the optical rotations are indicated in parentheses.
d
The absolute configuration was determined by comparison to literature data.6a
O
B(OH)2
O
N
[(R,R)-L1-RhCl]2
COOEt
(2.5 mol %)
O
+
N
COOEt
CH2Cl2 / H2O (10/1)
KOH (50 mol %)
40 oC, 1.5 h
O
OMe
2n
O
MeO
O
208 mg
1a
(S)-3an
85% yield, 94% ee
78% yield, >99% ee (after one
recrystallization)
O
HN
1) NH2NH2 / THF
2) Et3N, toluene
reflux, 20 h
O
78%
OMe
(S)- Rolipram
Scheme 3. Synthesis of (S)-Rolipram.

F. Han et al. / Tetrahedron Letters 52 (2011) 830–833
833
Reducing the reaction time from 1.5 h to 0.5 h decreases the yield
Supplementary data
to 67%, although a high ee was maintained (Table 1, entries 10–12).
With these optimized reaction conditions identified, we evalu-
ated the scope of this method for various arylboronic acids, apply-
ing (R,R)-L1 as the ligand and 1a as the substrate (Table 2). Several
conclusions are drawn from this study: (a) substituents at the
meta- and para-position do not have an effect on the excellent
enantioselectivity of the reaction. Enantiomeric excesses up to
96% are achieved, which is comparable to the values found in the
unsubstituted case. (b) For each tested arylboronic acid, trifluoro-
methyl as the electron-withdrawing group slowed the reaction,
leading to incomplete conversions (Table 2, entry 13). (c) The steric
hindrance of substituents (Table 2, entries 9, 11, and 14) restricted
the insertion of the substrate and resulted in lower reactivity for
the 1,4-addition.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.044.
References and notes
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ˇ
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acid (2d) and ethyl
c-phthalimidocrotonates (1a) provided the
opportunity to prepare optically pure Baclofen, an antispasmodic
agent, using 1,4-adducts as a key step. Thus, subjection of 3ad
(Table 2, entry 4), which can be upgraded via recrystallization to
over 99% ee, to subsequent hydrolysis (6 N HCl) afforded the (S)-
Baclofen in nearly quantitative yield (Scheme 2), demonstrating
the potential utility of this method in the synthesis of chiral
pharmaceuticals.
Furthermore, we used this method to the synthesis of Rolipram,
which has been known as a cyclic adenosine monophosphate
(cAMP)-specific phosphodiesterase and is employed as an anti-
inflammatory agent and antidepressant.14 Deprotection of the
imide and subsequent preparation of (S)-Rolipram were accom-
plished in 78% overall yield by treatment of 3an (99% ee after
one crystallization) with aqueous hydrazine followed by refluxing
with Et3N in toluene (Scheme 3).
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3. Conclusion
In summary, we document that the asymmetric 1,4-addition of
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c-phthalimidocrotonate proceeds with
high enantioselectivity (90–96% ee) under mild reaction conditions
by using a Rh/(R,R)-1,2-bis(tert-butylsulfinyl)benzene complex as
the catalyst. The method has been successfully applied to obtain
chiral pharmaceuticals, such as enantiomerically enriched Baclofen
and Rolipram.
Acknowledgments
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We are grateful for support from the NSFC (20872139 and
21072186), the West Light Foundation of CAS, the National Basic
Research Program of China (973 Program, 2010CB833300) and
Chengdu Institute of Biology, CAS (Y0B1051100).