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Enantioselective Synthesis of -Aryl-γ-amino
γ-amino acid derivatives have been reported in the past few Acid Derivatives via Cu-Catalyzed Asymmetric
years,3 the search for new and efficient catalytic asymmetric 1,4-Reductions of γ-Phthalimido-Substituted
synthetic methods remains a significant challenge.
Very recently, we have reported a Rh-catalyzed asymmetric , -Unsaturated Carboxylic Acid Esters
hydrogenation of γ-phthalimido-R, -unsaturated carboxylic acidesters, in which a variety of chiral -aryl-γ-amino acid deriva- Jun Deng,†,‡ Xiang-Ping Hu,*,‡ Jia-Di Huang,†,‡ tives can be obtained with good enantioselectivities.4 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 Dalian Institute of Chemical Physics, Chinese Academy of Rh catalyst, and the relatively high catalyst loadings (1 mol Sciences, Dalian 116023, China, and Graduate School of %). These shortcomings prompted us to seek for an alternative Chinese Academy of Sciences, Beijing 100039, China approach to synthesize chiral -substituted γ-amino acids.
In the past decade, copper hydride (Cu-H) with chiral ligands zhengz@dicp.ac.cn; xiangping@dicp.ac.cn has emerged as a powerful reagent for effecting asymmetricreductions of various R, -unsaturated compounds5 such as enones,6 R, -unsaturated esters,7 nitroalkenes,8 R, -unsaturatedsulfones,9 and R, -unsaturated nitriles.10 Since the copper saltsis very cheap in comparison with the Rh catalyst precursor, wetherefore envisioned that an asymmetric 1,4-reduction of γ-ph-thalimido-R, -unsaturated esters via copper hydride catalysisshould 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
-aryl-substituted γ-amino butyric acid derivatives were synthesized in good enantioselectivities via (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.;
the Cu-catalyzed asymmetric conjugate reduction of γ-ph- Soldatenkov, A. T. Prog. Neurobiol. 1978, 10, 89–133. (c) Allan, R. D.; Bates,
thalimido-R, -unsaturated carboxylic acid esters using 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.;
2 H2O as a catalyst precursor, (S)-BINAP as a Doolette, D. J.; Duke, R. K.; Mewett, K. N.; Allen, R. D.; Johnston, G. A. R.
ligand, PMHS as a hydride source, and t-BuOH as an Eur. J. Pharmacol. 1993, 233, 169–172. (e) Costantino, G.; Macchiarulo, A.;
additive. The methodology has been applied successfully to 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,
the enantioselective synthesis of a chiral pharmaceutical, 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–
2307.
(3) For a review, see: Ordoˇnˇez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 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.
system neurotransmitter and has a profound impact on many (5) For a review, see: Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. important biological functions.1 Hence, many GABA analogues, 2007, 46, 498–504.
(6) (a) Moritani, Y.; Appella, D. H.; Jurkauskas, V.; Buchwald, S. L. J. Am. particularly those bearing substituents at the -position such as Chem. Soc. 2000, 122, 6797–6798. (b) Jurkauskas, V.; Buchwald, S. L. J. Am.
4-amino-3-(4-chlorophenyl)butyric acid (baclofen), have been Chem. Soc. 2002, 124, 2892–2893. (c) Lipshutz, B. H.; Servesko, J. M. Angew.
well explored as medicines to treat various diseases associated 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)
with GABA receptors.2 Studies have disclosed that the biological Lipshutz, B. H.; Frieman, B. A.; Tomaso, Jr., A. E. Angew. Chem., Int. Ed 2006,
activities of these GABA analogues resides mainly in the single (7) (a) Appella, D. H.; Moritani, Y.; Shintani, R.; Ferreira, E. M.; Buchwald, enantiomer, and therefore the development of an enantioselective S. L. J. Am. Chem. Soc. 1999, 121, 9473–9474. (b) Hughes, G.; Kimura, M.;
method for the synthesis of these compounds is highly desirable.
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 11253–11258. (c) Lipshutz, B. H.;
Although some catalytic asymmetric syntheses of -substituted 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–
5823. (e) Rainka, M. P.; Milne, J. E.; Buchwald, S. L. Angew. Chem., Int. Ed.
† Dalian Institute of Chemical Physics.
2005, 44, 6177–6180. (f) Lipshutz, B. H.; Tanaka, N.; Taft, B. R.; Lee, C.-T.
‡ Graduate School of Chinese Academy of Sciences.
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–
Vartanian, M. G. J. Med. Chem. 1991, 34, 2295–2298. (b) Yuen, P. W.; Kanter,
4795. (b) Czekelius, C.; Carreira, E. M. Org. Lett. 2004, 6, 4575–4577. (c)
G. D.; Taylor, C. P.; Vertanian, M. G. Bioorg. Med. Chem. Lett. 1994, 4, 823–
Czekelius, C.; Carreira, E. M. Org. Process Res. DeV. 2007, 11, 633–636.
826. (c) Bryans, J. S.; Davies, N.; Gee, N. S.; Dissanayake, V. U. K.; Ratcliffe, (9) Llamas, T.; Arraya´s, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2007,
G. S J. Med. Chem. 1998, 41, 1838–1845. (d) Moglioni, A. G.; Brousse, B. N.;
´ lvarez-Larena, A.; Moltrasio, G. Y.; Ortun˜o, R. M. Tetrahedron: Asymmetry (10) (a) Lee, D.; Kim, D.; Yun, J. Angew. Chem., Int. Ed. 2006, 45, 2785–
2002, 13, 451–454.
2787. (b) Lee, D.; Yang, Y.; Yun, J. Org. Lett. 2007, 9, 2749–2751.
J. Org. Chem. 2008, 73, 6022–6024
10.1021/jo800794p CCC: $40.75  2008 American Chemical Society Enantioselective Conjugate Reduction of (Z)-4-Phthalimido-3-phenylbut-2-enoate (1a)a
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 solvent at room temperature for 24 h, unless otherwise specified. b Isolated yields. c Values were determined by HPLC on a chiral column (ChiralpakAD or AD-H). d Absolute configuration was determined by comparison of the sign of the optical rotation with the reported data. e No added t-BuOH.
f Not determined because of low reactivity.
system. The results are summarized in Table 1. Initially, weemployed the published procedure7a for the preparation of thecatalyst formed between CuCl, BINAP, and NaOt-Bu. To ourdelight, 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 thenscreened 2 H2O12 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 anefficient ligand for this transformation, some structurally similardiphosphines were next investigated (Figure 1). Although good FIGURE 1. Representative ligands for asymmetric 1,4-reduction.
enantioselectivities were obtained in some cases, no resultssurpassed that obtained with BINAP (entries 4-7). Subsequent experiments in an effort to increase yield and enantioselectivity 2 H2O as the catalyst precursor, BINAP as the ligand, by the variation of the silane reagents proved unsuccessful. We PMHS as the silane reagent, and toluene as the solvent for found that the use of TMDS, diphenylsilane or phenylsilane in investigating the scope of this new method on various ethyl the reaction resulted in dramatically decreased reaction rates (Z)-4-phthalimido-3-arylbut-2-enoate (1), and the results are
(entries 8-10). Solvent-screening experiments revealed that the summarized in Table 2. Initially, a variety of substituted (Z)- nature of the solvents had a profound effect on the catalytic 4-phthalimido-3-phenylbut-2-enoates (1b-h) were examined,
reaction. The reactions performed in THF gave an increased and the results indicated that the electronic properties of the enantioselectivity, but decreased reaction rate (entry 11). Using substituent in the phenyl ring had little effect on the enantiose- xylene as the solvent, a comparable result was achieved (entry lectivity. All of the substrates were reduced in 93-96% ee 12). 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 theirhigh crystallinity conferred by the phthalimido group. Good (11) For copper fluorides as useful catalyst precursors in the Cu-H catalyzed enantioselectivities were also obtained in the conjugate reduction hydrosilylation, see: Sirol, S.; Courmarcel, J.; Mostefai, N.; Riant, O. Org. Lett.
2001, 3, 4111–4113.
of -2-naphthyl- and -2-thiophenyl-substituted substrates (1i-j,
(12) For copper(II) acetate or copper(II) acetate monohydrate as useful entries 8 and 9). These results demonstrated the applicability catalyst precursor in the Cu-H catalyzed hydrosilylation, see: Lee, D.; Yun, J.
of this new method in the enantioselective synthesis of Tetrahedron Lett. 2004
(13) (a) Anada, M.; Hashimoto, S. Tetrahedron Lett. 1998, 39, 79–82. (b)
Resende, P.; Almeida, W. P.; Coelho, F. Tetrahedron: Asymmetry 1999, 10,
To explore the potential synthetic utility of this new method, 2113–2118. (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,
we attempted its application in the synthesis of the chiral 581–586. (e) Meyer, O.; Becht, J.-M.; Helmchen, G. Synlett 2003, 1539–1541.
pharmaceuticals (R)-baclofen (Scheme 1). Although baclofen (f) Becht, J.-M.; Meyer, O.; Helmchen, G. Synthesis 2003, 2805–2810. (g) Belda,
O.; Lundgren, S.; Moberg, C. Org. Lett. 2003, 5, 2275–2278. (h) Felluga, F.;
is commercialized in its racemic form, pharmacological studies Gombac, V.; Pitacco, G.; Valentin, E. Tetrahedron: Asymmetry 2005, 16, 1341–
have shown that its biological activity resides exclusively in its 1345. (i) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. (R)-enantiomer.2a As we have reported, the requisite substrate Chem. Soc. 2005, 127, 119–125. (j) Paraskar, A. S.; Sudalai, A. Tetrahedron
2006, 62, 4907–4916.
(Z)-3-(4-chlorophenyl)-4-phthalimidobut-2-enoate (1c) was pre-
J. Org. Chem. Vol. 73, No. 15, 2008 Enantioselective Conjugate Reduction of
γ-phthalimido groups, which has led to the asymmetric synthesis (Z)-4-Phthalimido-3-arylbut-2-enoate (1) with a Cu(OAc) ·
of various -aryl-substituted γ-amino acid derivatives in good (S)-BINAP/PMHS Catalytic Systema
enantioselectivities. Interestingly, the results disclosed that theheteroatom in the γ-position seems to be no impact on thedirection of hydride delivery. High crystallinity conferred bythe phthalimido group made the upgrade of ee values of thereduction products possible. This method has been successfullyapplied in the enantioselective synthesis of the chiral pharma- 1b: Ar ) 4-FC6H4
Experimental Section
1c: Ar ) 4-ClC6H4
Ethyl (Z)-4-phthalimido-3-arylbut-2-enoates 1a-j were prepared
1d: Ar ) 4-BrC6H4
1e: Ar ) 4-MeOC6H4
General Procedure for Catalytic Asymmetric 1,4-Reduction.
1f: Ar ) 4-CF3C6H4
1g: Ar ) 3-MeOC
2 H2O (5 mg, 0.025 mmol), (S)-BINAP (15.6 mg, 0.025 1h: Ar ) 3-cyclopentoxy-4-MeOC6H3
mmol), and toluene (1.0 mL) were added into an oven-dried Schlenk 1i: Ar ) 2-naphthyl
tube. The resulting mixture was stirred at room temperature for 30 1j: Ar ) 2-thiophenyl
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- 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/ mmol) in toluene (1.0 mL) was added, followed by t-BuOH (0.191 (S)-BINAP/PMHS/t-BuOH ratio of 1/0.05/0.05/4/4. b Isolated yields.
c Values were determined by HPLC on a chiral column (Chiralpak mL, 2.0 mmol). The reaction vessel was sealed, and the mixture AD-H or chiralcel OD-H). d Absolute configuration was determined by was stirred for 24 h. The reaction mixture was quenched with comparison of the sign of the optical rotation with the reported data.
saturated aqueous ammonium chloride solution, and the aqueouslayer was extracted with Et2O (3 × 20 mL). The combined organic SCHEME 1.
Synthesis of (R)-Baclofen
layers were washed with brine, dried over MgSO4, and concentrated.
The product was purified by chromatography on silica gel.
Ethyl (S)-3-(4-Chlorophenyl)-4-phthalimidobutanoate (2c). 1H
NMR (400 MHz, CDCl3): 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 ) 7.2Hz, 2H), 7.20-7.26 (m, 4H), 7.69-7.71 (m, 2H), 7.79-7.81 (m,2H). 13C NMR (100 MHz, CDCl3): δ 14.1, 38.6, 40.2, 42.9, 60.6,123.3, 128.8, 129.1, 131.8, 133.0, 134.1, 138.9, 168.1, 171.2. HRMS(ESI) m/z calcd for C20H18NO4ClNa+ 394.0822, found 394.0836.
[R]25 - 60.4 (c 0.5, CHCl3). 93% ee was determined by chiral HPLC (Chiralpak AD-H (0.46 cm × 25 cm), i-PrOH/hexane )15/85, UV 254 nm, 40 °C, 1.0 mL/min), retention times (min) 16.4(major, S) and 22.2 (minor, R).
Synthesis of (R)-Baclofen. 13 A mixture of (R)-2c (186 mg, 0.5
mmol, 94% ee) and 6 M HCl (10 mL) was heated under reflux for12 h. The solution was cooled, and the precipitated phthalic acidwas filtered off. The filtrate was evaporated to dryness, and theresulting solid was resuspended in water (10 mL). The filtrate wasevaporated to dryness under reduced pressure and then dried undervacuum to give 112 mg (90.2% yield) of (R)-baclofen as a colorlesssolid, mp 198-199 °C; [R]25 - pared through a three-step transformation from 4′-chloroac- 2O). 1H NMR (400 MHz, D2O): δ 2.73-2.90 (m, 2H), 3.24-3.47 (m, 3H), 7.35-7.48 (m, 4H). 13C NMR (100 MHz, etophenone in good yields (over 60% in total yields). With the D2O): δ 38.3, 39.4, 43.7, 129.3, 129.5, 133.4, 137.1, 175.3.
catalysis of Cu/(R)-BINAP, 1c was reduced in 92% yield and
94% ee. The resulting reduction product 2c was further upgraded
Acknowledgment. We are grateful for financial support from
via recrystallization to over 98% ee and then converted in one the National Natural Science Foundation of China (20472083).
step to (R)-baclofen in a nearly quantitative yield, demonstrating Supporting Information Available: Experimental details,
the potential utility of this method in the synthesis of chiral and analysis of ee-values of products. This material is available free of charge via the Internet at http://pubs.acs.org.
In conclusion, we have developed a method for the asym- metric conjugate reduction of R, -unsaturated esters containing J. Org. Chem. Vol. 73, No. 15, 2008

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