Rh-catalyzed asymmetric hydrogenation of γ-phthalimido-substituted α,β-unsaturated carboxylic acid esters: An efficient enantioselective synthesis of β-aryl-γ-amino acids

Article abstract of DOI:10.1021/ol702193v

(Chemical Equation Presented) A series of chiral β-aryl-γ-amino acid ester derivatives were synthesized in high enantioselectivities (93-97% ee) via the Rh-catalyzed asymmetric hydrogenation of γ-phthalimido-α, β-unsaturated carboxylic acid esters using highly modular chiral BoPhoz-type phosphine-aminophosphine ligands. The method has been applied successfully to the synthesis of several chiral pharmaceuticals including (R)-baclofen and (R)-rolipram with high enantioselectivities.

Full text of DOI:10.1021/ol702193v

ORGANIC
LETTERS
2007
Vol. 9, No. 23
4825-4828
Rh-Catalyzed Asymmetric Hydrogenation
of -Phthalimido-Substituted
-Unsaturated Carboxylic Acid
Esters: An Efficient Enantioselective
Synthesis of -Aryl- -amino Acids
γ
r,â
â
γ
Jun Deng,†,‡ Zheng-Chao Duan,†,‡ Jia-Di Huang,†,‡ Xiang-Ping Hu,*,†
Dao-Yong Wang,†,‡ Sai-Bo Yu,†,‡ Xue-Feng Xu,† and 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
zhengz@dicp.ac.cn; xiangping@dicp.ac.cn
Received September 6, 2007
ABSTRACT
A series of chiral
hydrogenation of
â
γ
-aryl-
γ
-amino acid ester derivatives were synthesized in high enantioselectivities (93
−
97% ee) via the Rh-catalyzed asymmetric
-phthalimido-r,â-unsaturated carboxylic acid esters using highly modular chiral BoPhoz-type phosphine−aminophosphine
ligands. The method has been applied successfully to the synthesis of several chiral pharmaceuticals including (R)-baclofen and (R)-rolipram
with high enantioselectivities.
Chiral γ-amino acids and their derivatives, in particular those
analogues bearing substituents at the â-position, have been
the subject of extensive investigations in past decades for
their promising therapeutic use in the treatment of a range
of central nervous system disorders and their useful applica-
tion as building blocks in organic synthesis.1 Although some
catalytic asymmetric syntheses of â-substituted γ-amino acid
derivatives have been reported,2 the development of new and
efficient catalytic asymmetric synthetic methods with proper-
ties superior to their predecessors for enantioselective
synthesis of γ-amino acid derivatives remains a significant
challenge. Given its inherent efficiency and atom economy,
the catalytic asymmetric hydrogenation of γ-dehydroamino
acid derivatives would seem to be an ideal approach to
prepare enantiopure γ-amino acids. Indeed, such methods
are among the most studied and widely applied for the
(1) (a) Bowery, N. G.; Hill, D. R.; Hudson, A. L.; Doble, A.; Middemiss,
N. D.; Shaw, J.; Turnbull, M. Nature 1980, 283, 92-94. (b) Silverman, R.
B.; Andruszkiewicz, R.; Nanavati, S. M.; Taylor, C. P.; Vartanian, M. G.
J. Med. Chem. 1991, 34, 2295-2298. (c) Woll, M. G.; Lai, J. R.; Guzei, I.
A.; Taylor, S. J. C.; Smith, M. E. B.; Gellman, S. H. J. Am. Chem. Soc.
2001, 123, 11077-11078. (d) Amor´ın, M.; Castedo, L.; Granja, J. R. J.
Am. Chem. Soc. 2003, 125, 2844-2845. (e) Amor´ın, M.; Castedo, L.;
Granja, J. R. Chem. Eur. J. 2005, 11, 6543-6551. (f) Brea, R. J.; Amor´ın,
M.; Castedo, L.; Granja, J. R. Angew. Chem., Int. Ed. 2005, 44, 5710-
5713. (g) Farrera-Sinfreu, J.; Giralt, E.; Castel, S.; Albericio, F.; Royo, M.
J. Am. Chem. Soc. 2005, 127, 9459-9468. (h) Vasudev, P. G.; Shamala,
N.; Ananda, K.; Balaram, P. Angew. Chem., Int. Ed. 2005, 44, 4972-4975.
(i) Baldauf, C.; Gu¨nther, R.; Hofmann, H.-J. J. Org. Chem. 2006, 71, 1200-
1208.
† Dalian Institute of Chemical Physics.
(2) For a review: Ordo´nˇez, M.; Cativiela, C. Tetrahedron: Asymmetry
2007, 18, 3-99.
‡ Graduate School of Chinese Academy of Sciences.
10.1021/ol702193v CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/12/2007

enantioselective preparation of R- and â-amino acids.3 To
the best of our knowledge, however, the catalytic enantio-
selective hydrogenation of γ-amino acid dehydro precursors
with chiral metal complexes remains a rarely explored area.4
Only one successful example was reported by the researchers
from Pfizer Inc., in which a highly efficient Rh-catalyzed
hydrogenation of a cyano (CN)-substituted precursor to
pregabalin, a chiral â-i-Bu-substituted γ-amino acid phar-
maceutical, was developed.5 Herein we report the first highly
enantioselective synthesis of a series of chiral â-aryl-γ-amino
acid ester derivatives by a rhodium-catalyzed asymmetric
hydrogenation of (Z)-3-aryl-4-phthalimidobut-2-enoates with
highly modular Bophoz-type phosphine-aminophosphine
ligands.
Prochiral γ-dehydroamino acid esters, ethyl (Z)-3-aryl-4-
phthalimidobut-2-enoates, can be easily prepared from aryl
ketones through a three-step transformation as outlined in
Scheme 1. The high crystallinity conferred by the phthal-
Scheme 1. Synthesis of γ-Dehydroamino Acid Esters (Z)-1
Figure 1. Structure of some representative ligands for asymmetric
hydrogenation.
reaction of 1a. For example, bidentate DuPhos, BINAP,
TaniaPhos, and PPFAPhos gave low to moderate enantiose-
Table 1. Asymmetric Hydrogenation of Ethyl
(Z)-4-Phthalimido-3-phenylbut-2-enoate 1aa
imido group makes the purification of the rude substrates
convenient. With easy access to the substrates, the key to
achieving high enantioselectivity in the hydrogenation of
these γ-dehydroamino acid esters, therefore, is to find an
efficient catalyst. We focused our efforts on searching for
an appropriate chiral phosphorus ligand for their demon-
strated track record at effecting Rh-catalyzed asymmetric
hydrogenations. Exploratory ligand screening employed ethyl
(Z)-4-phthalimido-3-phenylbut-2-enoate 1a as the standard
substrate and a diverse array of chiral phosphorus-containing
ligands, which are commercially available or developed
within our research group. A few representative ligands
screened are shown in Figure 1.
Unlike the hydrogenation of R- and â-dehydroamino acid
esters, the hydrogenation of ethyl 4-phthalimido-3-phenylbut-
2-enoate 1a proved to be highly difficult. The data sum-
marized in Table 1 revealed that most of the phosphorus-
ligand/Rh complexes screened, which have proved to be
highly efficient for the asymmetric hydrogenation of func-
tionalized olefins, gave poor results in this hydrogenation
entry
ligand
solvent
convn (%)
ee (%)
1
2
3
4
5
6
7
8
DuPHOS
BINAP
TaniaPhos
PPFAPhos
ManniPhos
BoPhoz 2a
2a
2a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Cl(CH2)2Cl
MeOH
91
62
70
16
40
4
>95
83
b
-
-
>95
>95
83
88
88
11
15
50
75
92
87
93
86
95
93c
9
2a
2a
2a
2b
2c
2d
2e
toluene
THF
33
51
91
10
11
12
13
14
15
16
17
i-PrOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
>95
>95
>95
>95
>95
>95
(SC,RFc,RP)-3
(SC,RFc,RP)-3
(3) Tang, W.; Zhang, X. Chem. ReV. 2003, 103, 3029-3069.
(4) Thakur, V. V.; Nikalje, M. D.; Sudalai, A. Tetrahedron: Asymmetry
2003, 14, 581-586.
(5) (a) Burk, M. J.; de Koning, P. D.; Grote, T. M.; Hoekstra, M. S.;
Hoge, G.; Jennings, R. A.; Kissel, W. S.; Le, T. V.; Lennon, I. C.; Mulhern,
T. A.; Ramsden, J. A.; Wade, R. A. J. Org. Chem. 2003, 68, 5731-5734.
(b) Hoge, G. J. Am. Chem. Soc. 2003, 125, 10219-10227. (c) Hoge, G.;
Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Greene, D. J.; Bao, J. J. Am. Chem.
Soc. 2004, 126, 5966-5967.
a All reactions were carried out with 0.25 mmol of substrate at room
temperature under a H2 pressure of 60 atm in 2 mL of the indicated solvent
for 24 h with a substrate/[Rh(COD)2]BF4/ligand ratio of 1/0.01/0.011.
Conversions were determined by 1H NMR. The ee values were determined
by HPLC on a chiral column (Chiralpak AD). b Not determined because of
low reactivity. c 10 atm of H2, 50 °C, 24 h.
4826
Org. Lett., Vol. 9, No. 23, 2007

lectivity although high conversions were obtained in some
cases (Table 1, entries 1-4), while monodentate ManniPhos
showed no activity for this reaction (Table 1, entry 5). To
our delight, we found that the Rh/Me-BoPhoz complex
afforded nearly full conversions and high enantiomeric excess
(88% ee, Table 1, entry 6). Subsequent experiments in an
effort to attain higher enantioselectivies by optimizing the
reaction conditions proved unfruitful. As shown in Table 1,
a strong solvent dependency was observed in the reaction.
However, no results surpassed that obtained in CH2Cl2 (Table
1, entries 6-11), which was then selected as the standard
reaction media for further investigations.
Table 2. Asymmetric Hydrogenation of Ethyl
(Z)-4-Phthalimido-3-arylbut-2-enoate 1a
entry
substrate (Ar)
1a: Ar ) Ph
ee (%)
1
95 (R)
96 (-)
94 (-)
94 (-)
96 (-)
95 (R)
94 (-)b
93 (-)
97 (R)
94 (-)
94 (-)
97 (-)b
2
3
4
5
1b: Ar ) 2-MeOC6H4
1c: Ar ) 3-MeOC6H4
1d: Ar ) 4-MeOC6H4
1e: Ar ) 4-FC6H4
Since the synthetic method of BoPhoz-type ligands is
highly modular, the optimization of the BoPhoz skeleton was
therefore performed.6 After a systematic investigation of a
number of BoPhoz-type ligands with varying electronic and
steric properties, we determined that those with a trifluo-
romethyl group on the aryl ring of the aminophosphino
moiety tended to give better results than those obtained with
Me-BoPhoz in terms of reactivity and enantioselectivity
(Table 1, entries 12-16). For instance, ligand 2b with a CF3
group on the 4-position of the aryl ring gave 92% ee and
full conversions in the hydrogenation of ester 1a (Table 1,
entry 12). The introduction of two CF3 groups onto the 3,5-
position of the aryl ring also resulted in high enantioselec-
tivity (Table 1, entry 14). In particular, new phosphine-
aminophosphine ligand (SC,RFc,RP)-3, bearing a stereogenic
P center in the phosphino moiety and a 4-CF3 group in the
aryl ring of the aminophosphino moiety, provided the best
result in terms of ee values and conversion (Table 1, entry
16). Lowering the H2 pressure to 10 atm also provided good
enantioselectivity (93% ee); however, an elevated temper-
ature (50 °C) was required to complete the hydrogenation
(entry 17). Ligand (SC,RFc,RP)-3 was synthesized according
to the method developed by Chen et al. very recently, in
which ferrocene-based P-chiral compounds can be easily
prepared in a simple and highly stereoselective way.7
6
1f: Ar ) 4-ClC6H4
7
1g: Ar ) 4-BrC6H4
8
1h: Ar ) 4-CF3C6H4
9
1i: Ar ) 3-cyclopentoxy-4-MeOC6H3
1j: Ar ) 2-naphthyl
1k: Ar ) 2-(6-methoxynaphthyl)
1l: Ar ) 2-thiophenyl
10
11
12
a All reactions were carried out with 0.25 mmol of substrate at room
temperature under a H2 pressure of 60 atm in 2 mL of CH2Cl2 for 24 h,
with a substrate/[Rh(COD)2]BF4/(SC,RFc,RP)-3 ratio of 1/0.01/0.011. Full
conversions were obtained in all reactions. The ee values were determined
by HPLC on a chiral column (Chiralpak AD or Chiralcel OD-H). b The
result was obtained with ligand 2b.
thalimidobut-2-enoate (1i) was hydrogenated with the best
selectivities of 97% ee (Table 2, entry 9). Excellent enan-
tioselectivity (97% ee) was observed in the hydrogenation
of the substrate containing a thiophene-heteroaryl group.
However, in this case, ligand 2b exhibited better ee’s than
(SC,RFc,RP)-3 (Table 2, entry 12).
To explore the potential synthetic versatility of this new
method, we sought to apply it to the synthesis of a range of
chiral pharmaceuticals using asymmetric hydrogenation as
a key step. For this purpose, an enantioselective synthesis
of (R)-baclofen serves as an example (Scheme 2). Baclofen
To demonstrate the flexibility of this method, the hydro-
genation of a series of (Z)-3-aryl-4-phthalimidobut-2-enoates
was studied with the Rh complex of (SC,RFc,RP)-3 under the
optimized conditions (CH2Cl2 as the reaction media, H2
pressure of 60 atm). As shown in Table 2, the hydrogenation
proceeded to completion and provided the corresponding
hydrogenated products with high enantioselectivities (93-
97% ee). The results reveal that there is no major effect on
the substitution pattern of the substituent on the aryl ring of
substrates. For example, all three substrates with a methoxy
group on the aryl ring were reduced in 94-96% ee (Table
2, entries 2-4). Among all substrates with para substituents
tested, ethyl (Z)-3-(3-cyclopentoxy-4-methoxyphenyl)-4-ph-
Scheme 2. Synthesis of (R)-Baclofen
(6) (a) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
Org. Lett. 2002, 4, 2421-2424. (b) Boaz, N. W.; Mackenzie, E. B.;
Debenham, S. D.; Large, S. E.; Ponasik, J. A., Jr. J. Org. Chem. 2005, 70,
1872-1880. (c) Li, X.; Jia, X.; Xu, L.; Kok, S. H. L.; Yip, C. W.; Chan,
A. S. C. AdV. Synth. Catal. 2005, 347, 1904-1908.
(7) (a) Chen, W.; Mbafor, W.; Roberts, S. M.; Whittall, J. J. Am. Chem.
Soc. 2006, 128, 3922-3923. (b) Chen, W.; Roberts, S. M.; Whittall, J.;
Steiner, A. Chem. Commun. 2006, 2916-2918. (c) Chen, W.; McCormack,
P. J.; Mohammed, K.; Mbafor, W.; Roberts, S. M.; Whittall, J. Angew.
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is a lipophilic analogue of γ-aminobutyric acid, and it is
widely used as an antispasmodic agent. Although baclofen
is commercialized in its racemic forms, pharmacological
Org. Lett., Vol. 9, No. 23, 2007
4827

studies have shown that its biological activity resides
exclusively in its (R)-enantiomer.8 Therefore, several efforts
have been made to prepare enantiomerically pure (R)-
baclofen.9 The requisite hydrogenation substrate, (Z)-3-(4-
chlorophenyl)-4-phthalimidobut-2-enoate (1f), can be easily
prepared from 4′-chloroacetophenone through a three-step
transformation in good yields (over 60% in total yields) as
shown in Scheme 1. With the catalysts generated in situ from
[Rh(COD)2]BF4 and (SC,RFc,RP)-3, N-phthaloyl-protected
amino acid ester 4f can be obtained in quantitative yield and
good enantioselectivity (95% ee). Compound 4f can be
upgraded via recrystallization to over 99% ee (91% recov-
ery). This was converted in one step to (R)-baclofen in nearly
quantitative yield, demonstrating the potential utility of this
method in the synthesis of chiral pharmaceuticals. Second,
we applied this method to the synthesis of rolipram, which
has been known as a selective inhibitor of PDE-IV, a cyclic
adenosine monophosphate (cAMP)-specific phosphodi-
esterase, and is employed as an anti-inflammatory agent and
antidepressant.10-11 For the synthesis of rolipram, 1i was
synthesized from the corresponding ketones and was hydro-
genated with this new method in high enantioselectivity (97%
ee). With deprotection with aqueous hydrazine followed by
treatment with Et3N in toluene at refluxing temperature, the
hydrogenation product 4i could be converted into (R)-
rolipram in 78% yield (Scheme 3).
Scheme 3. Synthesis of (R)-Rolipram
In conclusion, we discovered that a series of chiral γ-amino
acid esters could be synthesized in high enantioselectivity
in the first Rh-catalyzed asymmetric hydrogenation of
γ-phthalimido-R,â-unsaturated carboxylic acid esters using
highly modular chiral BoPhoz-type phosphine-aminophos-
phine ligands. The method has been applied successfully to
the synthesis of several pharmaceuticals including (R)-
baclofen and (R)-rolipram with high enantioselectivities. The
high crystallinity conferred by the phthalimido group pro-
vided a convenient way to upgrade the ee of the hydrogenated
product to a very high level. It is our hope that this work
will provide a new and practical method to prepare chiral
γ-amino acids and their derivatives.
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Acknowledgment. We are grateful for financial support
from the National Natural Science Foundation of China
(20472083).
Supporting Information Available: Experimental de-
tails, optimization data, spectra for new compounds, and
analysis of ee’s of products. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL702193V
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Org. Lett., Vol. 9, No. 23, 2007