Enantioselective synthesis of β-aryl-γ-amino acid derivatives via Cu-catalyzed asymmetric 1,4-reductions of γ-phthalimido-substituted α,β-unsaturated carboxylic acid esters

Article abstract of DOI:10.1021/jo800794p

(Chemical Equation Presented) A series of chiral β-aryl-substituted γ-amino butyric acid derivatives were synthesized in good enantioselectivities via the Cu-catalyzed asymmetric conjugate reduction of γ-ph-thalimido-α,β-unsaturated carboxylic acid esters

Full text of DOI:10.1021/jo800794p

Enantioselective Synthesis of ꢀ-Aryl-γ-amino
Acid Derivatives via Cu-Catalyzed Asymmetric
γ-amino acid derivatives have been reported in the past few
years, the search for new and efficient catalytic asymmetric
synthetic methods remains a significant challenge.
3
1
,4-Reductions of γ-Phthalimido-Substituted
r,ꢀ-Unsaturated Carboxylic Acid Esters
Very recently, we have reported a Rh-catalyzed asymmetric
hydrogenation of γ-phthalimido-R,ꢀ-unsaturated carboxylic acid
esters, in which a variety of chiral ꢀ-aryl-γ-amino acid deriva-
†
,‡
,‡
†,‡
Jun Deng, Xiang-Ping Hu,* Jia-Di Huang,
†,‡
4
tives can be obtained with good enantioselectivities. However,
†
,‡
†,‡
Sai-Bo Yu, Dao-Yong Wang, Zheng-Chao Duan, and
,
†,‡
this method has the disadvantages of demanding reaction
conditions (60 atm of H2 pressure), the use of the expensive
Rh catalyst, and the relatively high catalyst loadings (1 mol
%). These shortcomings prompted us to seek for an alternative
approach to synthesize chiral ꢀ-substituted γ-amino acids.
Zhuo Zheng*
Dalian Institute of Chemical Physics, Chinese Academy of
Sciences, Dalian 116023, China, and Graduate School of
Chinese Academy of Sciences, Beijing 100039, China
In the past decade, copper hydride (Cu-H) with chiral ligands
has emerged as a powerful reagent for effecting asymmetric
zhengz@dicp.ac.cn; xiangping@dicp.ac.cn
5
reductions of various R,ꢀ-unsaturated compounds such as
ReceiVed April 10, 2008
6
7
8
enones, R,ꢀ-unsaturated esters, nitroalkenes, R,ꢀ-unsaturated
9
10
sulfones, and R,ꢀ-unsaturated nitriles. Since the copper salts
is very cheap in comparison with the Rh catalyst precursor, we
therefore envisioned that an asymmetric 1,4-reduction of γ-ph-
thalimido-R,ꢀ-unsaturated esters via copper hydride catalysis
should be an attractive alternative to these chiral compounds.
Herein, we report our studies on this new strategy for construct-
ing chiral ꢀ-aryl substituted γ-amino acid derivatives.
We started our studies on the catalytic asymmetric conjugate
reduction of ethyl (Z)-4-phthalimido-3-phenylbut-2-enoate (1a)
by surveying a number of copper salts, silanes, diphosphine
ligands, and solvents in order to identify a suitable catalyst
A series of chiral ꢀ-aryl-substituted γ-amino butyric acid
derivatives were synthesized in good enantioselectivities via
the Cu-catalyzed asymmetric conjugate reduction of γ-ph-
thalimido-R,ꢀ-unsaturated carboxylic acid esters using
(
2) (a) Olpe, H.-R.; Demieville, H.; Baltzer, V.; Bencze, W. L.; Koella, W. P.;
Wolf, P.; Haas, H. L. Eur. J. Pharmacol. 1978, 52, 133–136. (b) Sytinsky, I. A.;
Soldatenkov, A. T. Prog. Neurobiol. 1978, 10, 89–133. (c) Allan, R. D.; Bates,
M. C.; Drew, C. A.; Duke, R. K.; Hambley, T. W.; Johnston, G. A. R.; Mewett,
K. N.; Spence, I. Tetrahedron 1990, 46, 2511–2524. (d) Ong, J.; Kerr, D. I. S.;
Doolette, D. J.; Duke, R. K.; Mewett, K. N.; Allen, R. D.; Johnston, G. A. R.
Eur. J. Pharmacol. 1993, 233, 169–172. (e) Costantino, G.; Macchiarulo, A.;
Guadix, A. E.; Pellicciari, R. J. Med. Chem. 2001, 44, 1827–1832. (f) Belliotti,
T. R.; Capiris, T.; Ekhato, V.; Kinsora, J. J.; Field, M. J.; Hrffner, T. G.; Melzer,
L. T.; Schwarz, J. B.; Taylor, C. P.; Thorpe, A. J.; Vartanian, M. G.; Wise,
L. D.; Zhi-Su, T.; Weber, M. L.; Wustrow, D. J. J. Med. Chem. 2005, 48, 2294–
Cu(OAc)
2
2
·H O as a catalyst precursor, (S)-BINAP as a
ligand, PMHS as a hydride source, and t-BuOH as an
additive. The methodology has been applied successfully to
the enantioselective synthesis of a chiral pharmaceutical,
(
R)-baclofen.
2
307.
(
3) For a review, see: Ord oˇ nˇ ez, M.; Cativiela, C. Tetrahedron: Asymmetry
2
007, 18, 3–99.
(
4) Deng, J.; Duan, Z.-C.; Huang, J.-D.; Hu, X.-P.; Wang, D.-Y.; Yu, S.-B.;
γ-Amino butyric acid (GABA) is an important central nervous
Xu, X.-F.; Zheng, Z. Org. Lett. 2007, 9, 4825–4828.
(5) For a review, see: Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed.
2007, 46, 498–504.
system neurotransmitter and has a profound impact on many
1
important biological functions. Hence, many GABA analogues,
(6) (a) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am.
particularly those bearing substituents at the ꢀ-position such as
-amino-3-(4-chlorophenyl)butyric acid (baclofen), have been
Chem. Soc. 2000, 122, 6797–6798. (b) Jurkauskas, V.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 2892–2893. (c) Lipshutz, B. H.; Servesko, J. M. Angew.
Chem., Int. Ed. 2003, 42, 4789–4792. (d) Lipshutz, B. H.; Servesko, J. M.;
Petersen, T. B.; Papa, P. P.; Lover, A. A. Org. Lett. 2004, 6, 1273–1275. (e)
Lipshutz, B. H.; Frieman, B. A.; Tomaso, Jr., A. E. Angew. Chem., Int. Ed 2006,
4
well explored as medicines to treat various diseases associated
2
with GABA receptors. Studies have disclosed that the biological
4
5, 1259–1264.
activities of these GABA analogues resides mainly in the single
enantiomer, and therefore the development of an enantioselective
method for the synthesis of these compounds is highly desirable.
Although some catalytic asymmetric syntheses of ꢀ-substituted
(
7) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9473–9474. (b) Hughes, G.; Kimura, M.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253–11258. (c) Lipshutz, B. H.;
Servesko, J. M.; Taft, B. R. J. Am. Chem. Soc. 2004, 126, 8352–8353. (d) Rainka,
M. P.; Aye, Y.; Buchwald, S. L. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5821–
5
823. (e) Rainka, M. P.; Milne, J. E.; Buchwald, S. L. Angew. Chem., Int. Ed.
†
Dalian Institute of Chemical Physics.
Graduate School of Chinese Academy of Sciences.
2005, 44, 6177–6180. (f) Lipshutz, B. H.; Tanaka, N.; Taft, B. R.; Lee, C.-T.
Org. Lett. 2006, 8, 1963–1966.
‡
(1) (a) Silverman, R. B.; Andruszkiewicz, R.; Nanavati, S. M.; Taylor, C. P.;
(8) (a) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2003, 42, 4793–
4795. (b) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6, 4575–4577. (c)
Czekelius, C.; Carreira, E. M. Org. Process Res. DeV. 2007, 11, 633–636.
(9) Llamas, T.; Array a´ s, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007,
46, 3329–3332.
Vartanian, M. G. J. Med. Chem. 1991, 34, 2295–2298. (b) Yuen, P. W.; Kanter,
G. D.; Taylor, C. P.; Vertanian, M. G. Bioorg. Med. Chem. Lett. 1994, 4, 823–
26. (c) Bryans, J. S.; Davies, N.; Gee, N. S.; Dissanayake, V. U. K.; Ratcliffe,
8
G. S J. Med. Chem. 1998, 41, 1838–1845. (d) Moglioni, A. G.; Brousse, B. N.;
A´ lvarez-Larena, A.; Moltrasio, G. Y.; Ortu n˜ o, R. M. Tetrahedron: Asymmetry
(10) (a) Lee, D.; Kim, D.; Yun, J. Angew. Chem., Int. Ed. 2006, 45, 2785–
2787. (b) Lee, D.; Yang, Y.; Yun, J. Org. Lett. 2007, 9, 2749–2751.
2
002, 13, 451–454.
6
022 J. Org. Chem. 2008, 73, 6022–6024
10.1021/jo800794p CCC: $40.75  2008 American Chemical Society
Published on Web 07/03/2008

a
TABLE 1. Enantioselective Conjugate Reduction of (Z)-4-Phthalimido-3-phenylbut-2-enoate (1a)
c
ee (%)
b
d
entry
Cu-precursor
ligand
silicon reagent
solvent
yield (%)
60
(config)
e
1
2
3
4
5
6
7
8
9
CuCl/t-BuONa
CuF(PPh3)3 ·MeOH
CuF2
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-Tol-BINAP
(R)-MeO-BIPHEP
(S)-SYNPHOS
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
(S)-BINAP
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
PMHS
TMDS
Ph2SiH2
PhSiH3
PMHS
PMHS
PMHS
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
96
f
f
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
Cu(OAc)2 ·H2O
78
57
61
20
24
96 (S)
92
94
60
91
f
97
98
96
f
7
e
10
11
12
13
32
40
72
xylene
CH2Cl2
a
All reactions were conducted using 0.25 mmol of substrate, 5 mol % Cu, 5 mol % ligand, 1.0 mmol of t-BuOH, and 1.0 mmol of silane in 2 mL of
b
c
solvent at room temperature for 24 h, unless otherwise specified. Isolated yields. Values were determined by HPLC on a chiral column (Chiralpak
AD or AD-H). Absolute configuration was determined by comparison of the sign of the optical rotation with the reported data. No added t-BuOH.
Not determined because of low reactivity.
d
e
f
system. The results are summarized in Table 1. Initially, we
7
a
employed the published procedure for the preparation of the
catalyst formed between CuCl, BINAP, and NaOt-Bu. To our
delight, this catalyst promoted the reaction in good enantiose-
lectivity and moderate yield by using PMHS as the stoichio-
metric hydride donor (entry 1). Other copper salts were then
1
1
screened (entries 1-4).
The results suggested that
12
Cu(OAc)2 ·H2O is the best catalyst precursor in terms of yield
and enantioselectivity, providing the reduction product in 78%
yield and 96% ee (entry 4). Since BINAP has proved to be an
efficient ligand for this transformation, some structurally similar
diphosphines were next investigated (Figure 1). Although good
enantioselectivities were obtained in some cases, no results
surpassed that obtained with BINAP (entries 4-7). Subsequent
experiments in an effort to increase yield and enantioselectivity
by the variation of the silane reagents proved unsuccessful. We
found that the use of TMDS, diphenylsilane or phenylsilane in
the reaction resulted in dramatically decreased reaction rates
FIGURE 1. Representative ligands for asymmetric 1,4-reduction.
With these encouraging results, we then selected
Cu(OAc)2 ·H2O as the catalyst precursor, BINAP as the ligand,
PMHS as the silane reagent, and toluene as the solvent for
investigating the scope of this new method on various ethyl
(
Z)-4-phthalimido-3-arylbut-2-enoate (1), and the results are
summarized in Table 2. Initially, a variety of substituted (Z)-
-phthalimido-3-phenylbut-2-enoates (1b-h) were examined,
(entries 8-10). Solvent-screening experiments revealed that the
nature of the solvents had a profound effect on the catalytic
reaction. The reactions performed in THF gave an increased
enantioselectivity, but decreased reaction rate (entry 11). Using
xylene as the solvent, a comparable result was achieved (entry
4
and the results indicated that the electronic properties of the
substituent in the phenyl ring had little effect on the enantiose-
lectivity. All of the substrates were reduced in 93-96% ee
1
2). However, very low reaction rate was observed when the
(entries 1-7). These reduction products can be easily upgraded
reaction was carried out in CH2Cl2 (entry 13).
via recrystallization to higher level of ee values because of their
high crystallinity conferred by the phthalimido group. Good
enantioselectivities were also obtained in the conjugate reduction
of ꢀ-2-naphthyl- and ꢀ-2-thiophenyl-substituted substrates (1i-j,
entries 8 and 9). These results demonstrated the applicability
of this new method in the enantioselective synthesis of γ-amino
acid derivatives.
(
11) For copper fluorides as useful catalyst precursors in the Cu-H catalyzed
hydrosilylation, see: Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant, O. Org. Lett.
001, 3, 4111–4113.
12) For copper(II) acetate or copper(II) acetate monohydrate as useful
2
(
catalyst precursor in the Cu-H catalyzed hydrosilylation, see: Lee, D.; Yun, J.
Tetrahedron Lett. 2004, 45, 5415–5417.
(
13) (a) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79–82. (b)
Resende, P.; Almeida, W. P.; Coelho, F. Tetrahedron: Asymmetry 1999, 10,
113–2118. (c) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257–4259. (d)
Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron: Asymmetry 2003, 14,
81–586. (e) Meyer, O.; Becht, J.-M.; Helmchen, G. Synlett 2003, 1539–1541.
f) Becht, J.-M.; Meyer, O.; Helmchen, G. Synthesis 2003, 2805–2810. (g) Belda,
To explore the potential synthetic utility of this new method,
we attempted its application in the synthesis of the chiral
pharmaceuticals (R)-baclofen (Scheme 1). Although baclofen
is commercialized in its racemic form, pharmacological studies
2
5
(
O.; Lundgren, S.; Moberg, C. Org. Lett. 2003, 5, 2275–2278. (h) Felluga, F.;
Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2005, 16, 1341–
have shown that its biological activity resides exclusively in its
1
345. (i) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119–125. (j) Paraskar, A. S.; Sudalai, A. Tetrahedron
006, 62, 4907–4916.
2a
(
R)-enantiomer. As we have reported, the requisite substrate
2
(Z)-3-(4-chlorophenyl)-4-phthalimidobut-2-enoate (1c) was pre-
J. Org. Chem. Vol. 73, No. 15, 2008 6023

TABLE 2. Enantioselective Conjugate Reduction of
γ-phthalimido groups, which has led to the asymmetric synthesis
of various ꢀ-aryl-substituted γ-amino acid derivatives in good
enantioselectivities. Interestingly, the results disclosed that the
heteroatom in the γ-position seems to be no impact on the
direction of hydride delivery. High crystallinity conferred by
the phthalimido group made the upgrade of ee values of the
reduction products possible. This method has been successfully
applied in the enantioselective synthesis of the chiral pharma-
ceuticals (R)-baclofen.
(
(
Z)-4-Phthalimido-3-arylbut-2-enoate (1) with a Cu(OAc)2 ·H2O/
a
S)-BINAP/PMHS Catalytic System
c
ee (%)
b
d
entry
substrate (Ar)
yield (%)
(config)
1
2
3
4
5
6
7
8
9
1b: Ar ) 4-FC6H4
91
94
71
77
94
92
86
88
92
94(-)
93 (S)
93(-)
95(-)
94(-)
96(-)
94 (S)
95(-)
91(-)
Experimental Section
1c: Ar ) 4-ClC6H4
Ethyl (Z)-4-phthalimido-3-arylbut-2-enoates 1a-j were prepared
according to the known methods.
General Procedure for Catalytic Asymmetric 1,4-Reduction.
1d: Ar ) 4-BrC6H4
1e: Ar ) 4-MeOC6H4
1f: Ar ) 4-CF3C6H4
4
1g: Ar ) 3-MeOC6H4
1h: Ar ) 3-cyclopentoxy-4-MeOC6H3
1i: Ar ) 2-naphthyl
Cu(OAc)
2
2
·H O (5 mg, 0.025 mmol), (S)-BINAP (15.6 mg, 0.025
mmol), and toluene (1.0 mL) were added into an oven-dried Schlenk
tube. The resulting mixture was stirred at room temperature for 30
min. Then, PMHS (0.12 mL, 2.0 mmol) was added to the reaction
mixture, which was stirred for 30 min. A solution of ethyl (Z)-3-
1j: Ar ) 2-thiophenyl
a
Reactions were carried out with 0.5 mmol of substrate in 2 mL of
(
4-chlorophenyl)-4-phthalimidobut-2-enoate (1c) (185 mg, 0.5
toluene at room temperature for 24 h, with a substrate/Cu(OAc)2 ·H2O/
S)-BINAP/PMHS/t-BuOH ratio of 1/0.05/0.05/4/4. Isolated yields.
Values were determined by HPLC on a chiral column (Chiralpak
AD-H or chiralcel OD-H). Absolute configuration was determined by
comparison of the sign of the optical rotation with the reported data.
b
mmol) in toluene (1.0 mL) was added, followed by t-BuOH (0.191
mL, 2.0 mmol). The reaction vessel was sealed, and the mixture
was stirred for 24 h. The reaction mixture was quenched with
saturated aqueous ammonium chloride solution, and the aqueous
(
c
d
layer was extracted with Et
layers were washed with brine, dried over MgSO
The product was purified by chromatography on silica gel.
Ethyl (S)-3-(4-Chlorophenyl)-4-phthalimidobutanoate (2c). H
NMR (400 MHz, CDCl ): δ 1.08 (t, J ) 7.2 Hz, 3H), 2.68-2.72
m, 2H), 3.72-3.75 (m, 1H), 3.86-3.91 (m, 2H), 3.92 (q, J ) 7.2
2
O (3 × 20 mL). The combined organic
4
, and concentrated.
SCHEME 1. Synthesis of (R)-Baclofen
1
3
(
Hz, 2H), 7.20-7.26 (m, 4H), 7.69-7.71 (m, 2H), 7.79-7.81 (m,
1
3
2
1
(
[
H). C NMR (100 MHz, CDCl
3
): δ 14.1, 38.6, 40.2, 42.9, 60.6,
23.3, 128.8, 129.1, 131.8, 133.0, 134.1, 138.9, 168.1, 171.2. HRMS
ESI) m/z calcd for C20
+
H18NO
4
ClNa 394.0822, found 394.0836.
2
5
R]
D
-60.4 (c 0.5, CHCl
3
). 93% ee was determined by chiral
HPLC (Chiralpak AD-H (0.46 cm × 25 cm), i-PrOH/hexane )
5/85, UV 254 nm, 40 °C, 1.0 mL/min), retention times (min) 16.4
major, S) and 22.2 (minor, R).
1
(
1
3
Synthesis of (R)-Baclofen. A mixture of (R)-2c (186 mg, 0.5
mmol, 94% ee) and 6 M HCl (10 mL) was heated under reflux for
2 h. The solution was cooled, and the precipitated phthalic acid
1
was filtered off. The filtrate was evaporated to dryness, and the
resulting solid was resuspended in water (10 mL). The filtrate was
evaporated to dryness under reduced pressure and then dried under
vacuum to give 112 mg (90.2% yield) of (R)-baclofen as a colorless
2
5
13b
solid, mp 198-199 °C; [R]
D
-2.17 (c 0.6, H
O). H NMR (400 MHz, D O): δ 2.73-2.90 (m, 2H),
.24-3.47 (m, 3H), 7.35-7.48 (m, 4H). C NMR (100 MHz,
2
O), lit. -2.0 (c
1
0
3
.6, H
2
2
pared through a three-step transformation from 4′-chloroac-
etophenone in good yields (over 60% in total yields). With the
catalysis of Cu/(R)-BINAP, 1c was reduced in 92% yield and
13
D
2
O): δ 38.3, 39.4, 43.7, 129.3, 129.5, 133.4, 137.1, 175.3.
Acknowledgment. We are grateful for financial support from
the National Natural Science Foundation of China (20472083).
94% ee. The resulting reduction product 2c was further upgraded
via recrystallization to over 98% ee and then converted in one
step to (R)-baclofen in a nearly quantitative yield, demonstrating
the potential utility of this method in the synthesis of chiral
pharmaceuticals.
In conclusion, we have developed a method for the asym-
metric conjugate reduction of R,ꢀ-unsaturated esters containing
Supporting Information Available: Experimental details,
and analysis of ee-values of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO800794P
6
024 J. Org. Chem. Vol. 73, No. 15, 2008