An efficient synthesis of (R)- and (S)-baclofen via desymmetrization

Article abstract of DOI:10.1016/j.tetlet.2009.08.079

A short and highly enantioselective synthesis of both enantiomers of GABA agonist baclofen in four steps with total yields of 32.8% [for (S)-isomer] and 35.1% [for (R)-isomer] is reported. The key step involved desymmetrization of cyclic anhydride with mo

Full text of DOI:10.1016/j.tetlet.2009.08.079

Tetrahedron Letters 50 (2009) 6166–6168
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Tetrahedron Letters
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An efficient synthesis of (R)- and (S)-baclofen via desymmetrization
a
Lei Ji a, Yuheng Ma a, Jin Li b, Liangren Zhang a, , Lihe Zhang
*
a State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China
b Shenogen Pharm Group, Beijing 100085, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2009
Revised 18 August 2009
Accepted 25 August 2009
Available online 27 August 2009
A short and highly enantioselective synthesis of both enantiomers of GABA agonist baclofen in four steps
with total yields of 32.8% [for (S)-isomer] and 35.1% [for (R)-isomer] is reported. The key step involved
desymmetrization of cyclic anhydride with modified cinchona alkaloids.
Ó 2009 Elsevier Ltd. All rights reserved.
4-Aminobutanoic acid (GABA) is the major inhibitory neuro-
transmitter in the mammalian central nervous system (CNS), and
it operates through ionotropic (GABAA and GABAC) as well as G pro-
tein-coupled (GABAB) receptors.1–3 The dysfunction of the central
GABA system is responsible for the development and outbreak of
epilepsy, Huntington’s and Parkinson’s diseases, and other
psychiatric disorders, such as anxiety and pain.4 ( )-4-Amino-3-
(4-chlorophenyl)butanoic acid (1, baclofen), which interacts stereo-
specifically with GABAB receptor, is a selective and therapeutically
available GABAB agonist.5–7 It is used in the treatment of paroxys-
mal pain of trigeminal neuralgia as well as spasticity of spinal, a
serious disease characterized by an increase in muscle tone usually
perceived as muscle tightness or achiness in limbs.8,9 Although
commercialized in its racemic form, the (R)-enantiomer has been
found to be more active.10 Many methods on the syntheses of (R)-
baclofen have been reported, including resolution,11–13 and chemo-
enzymatic14–18 or enantioselective synthesis.19–25 In general, the
syntheses required more than six steps and proceed with a rela-
tively low overall yield.
sis of various cyclic anhydrides.31,32 In particular, a highly enantio-
selective (83–91%) desymmetrization of prochiral monocyclic
anhydrides was obtained by using bis-cinchona alkaloids such as
(DHQD)2AQN and (DHQ)2AQN.31
With these encouraging results, we then attempted this appli-
cation as a key step in the synthesis of (R)-baclofen. Two strategies
for the synthesis of (R)-baclofen were put forward. The first strat-
egy was based on a Curtius rearrangement of the key intermediate
ester (R)-4 and the second one involved a Hoffmann rearrange-
ment of ester (S)-4.
In order to prepare chiral hemiester 4, (DHQD)2AQN- and
(DHQ)2AQN-catalyzed enantioselective alcoholysis of prochiral
anhydride 3 was attempted. 3-(4-Chlorophenyl)glutaric acid anhy-
dride 3 was prepared according to the procedure described33 from
the commercially available 3-(4-chlorophenyl)glutaric acid 2 and
acetic anhydride under refluxing condition in 81% yield.
Consequently, reaction of 1 equiv of anhydride 3 with 10 equiv of
methanol in ethyl ether using 30 mol % of (DHQD)2AQN or
(DHQ)2AQN as catalyst affected the desymmetrization of anhy-
dride 3 to furnish chiral hemiester 4 (Scheme 1). The chiral catalyst
was conveniently recovered quantitatively by basifying the aque-
ous phase followed by extraction with ethyl acetate and concentra-
tion under reduced pressure. It is worthy of note that the recovered
catalyst could be used for another preparative scale reaction to af-
ford the desired product without any loss of efficiency in terms of
yield and enantioselectivity.
Cl
NH2
HO2C
1
In this letter, we report a very short and efficient synthesis of both
enantiomers of baclofen, obtained in highly enantiomeric excess
(ee) and good yield by a four-step sequence involving desymmetri-
zation of cyclic anhydride.
As a result, both (DHQ)2AQN and (DHQD)2AQN were found to
be effective in desymmetrization of cyclic anhydride 3. Particu-
larly,
a better enantioselectivity was obtained when using
Enantioselective opening of readily accessible prochiral cyclic
anhydrides was proven to be a valuable approach in the synthesis
of chiral hemiesters by Oda and Aitken et al.26–30 Deng recently
discovered that modified cinchona alkaloids were able to function
as effective chiral Lewis base catalysts for asymmetric methanoly-
(DHQD)2AQN (95% ee) as a catalyst than when using (DHQ)2AQN
(75% ee) as a catalyst, which is consistent with the original reports
by Deng et al.31
The configuration of (S)-4 was confirmed by comparing its spe-
cific rotation (½a D25
ꢀ
ꢁ8.0 (c 0.88, CHCl3)) with literature reports34
(½a 2D0
ꢁ9.6 (c 0.88, CHCl3)).
ꢀ
Since the desymmetrization of cyclic anhydride 3 catalyzed
* Corresponding author. Tel.: +86 010 8280 2567; fax: +86 010 8280 2724.
E-mail address: liangren@bjmu.edu.cn (L. Zhang).
by (DHQD)2AQN afforded higher ee, the final synthetic route
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.079

L. Ji et al. / Tetrahedron Letters 50 (2009) 6166–6168
6167
OMe
Et
MeOH
Et
O
O
N
N
N
O
O
O
O
R3N
Cl
MeO
MeO
OMe
OMe
OH
N
N
N
OMe
Me
O
(DHQD)2AQN
H O
R3N
R3N = (DHQ)2AQN
HNR3
Cl
O
Et
Et
O
O
O
O
N
O
O
O
O
Cl
Me
H O
R3N
O
O
O
N
Cl
Cl
R'3N H O
(DHQ)2AQN
O
O
O
Me
Cl
HNR'3
O
O
O
Cl
HO2C
CO2CH3
R'3N = (DHQD)2AQN
Cl
b
Cl
(R)-4
R'3N
H O
a
Me
Cl
OMe
HO2C
CO2H
OH
c
O
O
3
O
O
2
H3CO2C
CO2H
Cl
R'3N
(S)-4
O
MeOH
OMe
Scheme 1. Synthesis of (R)- and (S)-hemiester 4. Reagents and conditions: (a) Ac2O,
reflux, 81%; (b) MeOH, (DHQ)2AQN, ꢁ40 °C, 120 h, 80%, 75% ee; and (c) MeOH,
(DHQD)2AQN, ꢁ40 °C, 120 h, 76%, 95% ee.
Figure 1. General base catalysis mechanism.
is expected to be that of a general base rather than of a nucleo-
phile,26,39–41 as depicted in Figure 1. The first step is anticipated
to form a chiral amine–methanol complex via hydrogen-bonding.
Methanol is activated and attacks the anhydride for the ring open-
ing. The resulting ion pair undergoes proton transfer, forming the
hemiester product and regenerating the chiral amine catalyst.
Limited mechanistic studies have been reported to date on
cinchona alkaloid-catalyzed desymmetrization of prochiral anhy-
drides via alcoholysis, especially on the stereoselectivity. We
hypothesized that the anhydride 3 as a substrate fit into a
U-shaped conformation enzyme-like binding pocket composed of
the two parallel methoxyquinoline units of (DHQD)2AQN as de-
picted in Figure 2. This proposal builds on a transition-state model
which has been developed by Corey for the bis-cinchona alkaloid-
OsO4 system.42–44 The AQN moiety at the bottom of the U-shaped
cavity trended to be oriented so as to allow the substrate 3 to fit
into the packet with a favorable energy. Excellent binding between
the substrate and the catalyst can be expected because of extensive
for the synthesis of (R)-baclofen was carried out as depicted in
Scheme 2.
The hemiester (S)-4 was converted to both (R)-baclofen and (S)-
baclofen hydrochloride through the reaction sequences as shown
in Scheme 2. Ammonolysis of hemiester (S)-4 with ammonium
hydroxide at room temperature furnished amide 6 in 95% yield.
The amide 6 was then treated with [bis(trifluoroacetoxy)iodo]ben-
zene (PIFA) at room temperature,35 followed by stirring with HCl
to provide (R)-1 in 60% yield, which was identical to the authentic
sample of (R)-baclofen hydrochloride in 1H NMR, 13C NMR, IR, MS
(ESI), and HRMS spectra. Optical rotation: ½a D23
ꢁ2.6 (c 1.00, H2O)
ꢀ
(lit.23
½
a 2D3
ꢀ
ꢁ1.5 (c 1.00, H2O), for (R)-baclofen hydrochloride).
In addition, (S)-baclofen hydrochloride was also prepared using
hemiester (S)-4 by Curtius rearrangement. The reaction of (S)-4
with diphenylphosphoryl azide (DPPA) and Et3N under reflux for
7 h was followed by addition of methanol to the reaction mixture.
The resulting mixture was further refluxed for 10 h to furnish
methyl ester 5 in 62% yield.36–38 The methyl ester 5 was then
hydrolyzed using HCl/AcOH to provide (S)-baclofen hydrochloride
p-stacking between the phenyl ring with the two methoxyquino-
line units. The methanol activated by (DHQD)2AQN attacks the
nearest carbonyl group of the substrate to give the (S)-hemiester
4. In the same way, the product of opposite configuration was ob-
tained using (DHQ)2AQN as a catalyst. The transition state model
described above accommodates all of the experimental facts which
we have observed.
[(S)-1] in 86% yield, ½a D25
ꢀ
+2.2 (c 1.00, H2O).
It is known that nucleophilic catalysis and general base catalysis
are two plausible mechanistic pathways for the cinchona alkaloid-
catalyzed asymmetric ring opening of cyclic anhydrides.39 The
mechanistic role of the tertiary amine in the cinchona alkaloids
Cl
Cl
a
b
Cl
H3CO2C
NHCO2CH3
HCl
NH2
HO2C
(S)-1
5
Cl
Cl
H3CO2C
CO2H
(S)-4
c
d
H2NOC
CO2H
H2N
CO2H
(R)-1
HCl
6
Scheme 2. Synthesis of both (R)- and (S)-baclofen hydrochloride. Reagents and conditions: (a) DPPA, Et3N, MeOH, 62%; (b) HCl, HOAc, reflux, 10 h, 86%; (c) NH3ꢂH2O, rt, 5 d,
95%; and (d) PIFA, CH3CN, H2O, rt, 24 h; concentrated HCl, rt, 1 h, 60%.

6168
L. Ji et al. / Tetrahedron Letters 50 (2009) 6166–6168
20. Resende, P.; Almeida, W. P.; Coelho, F. Tetrahedron: Asymmetry 1999, 10, 2113.
a
21. Licandro, E.; Maiorana, S.; Baldoli, C.; Capella, L.; Perdicchia, D. Tetrahedron:
Asymmetry 2000, 11, 975.
22. Baldoli, C.; Maiorana, S.; Licandro, E.; Perdicchia, D.; Vandoni, B. Tetrahedron:
Asymmetry 2000, 11, 2007.
b
Me
O
Me
O
Cl
O
23. Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257.
Me
H O
N
N
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1987, 1053.
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H
H
O
O
N
N
O
O
O
O
Et
Et
Figure 2. Two views of the proposed transition-state assembly for methanolytic
desymmetrization of the anhydride substrate 3. Putative intermolecular hydrogen
bonds are highlighted by dashed lines. The AQN spacer unit located behind the
anhydride substrate 3 is shown in gray for clarity.
34. Fryszkowska, A.; Komar, M.; Koszelewski, D.; Ostaszewski, R. Tetrahedron:
Asymmetry 2005, 16, 2475.
35. Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.; Blodgett, J. K.; Boutin, R. H. J.
Org. Chem. 1984, 49, 4272.
Thus, we have developed a convenient and efficient route to
synthesize both enantiomers of baclofen. The desymmetrization
of cyclic anhydride reaction developed by Deng’s group was used
as the key step to give (S)-baclofen hydrochloride in 32.8% overall
yield. Alternatively, the (S)-4 was converted to (R)-baclofen hydro-
chloride in 35.1% overall yield.
36. Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972, 94, 6203.
37. Yamada, S.; Ninomiya, K.; Shioiri, T. Tetrahedron Lett. 1973, 14, 2343.
38. Spectroscopic data of compounds 3–6 and (R)-1. Compound 3: 1H NMR
(500 MHz, CDCl3): d 2.81–2.87 (m, 2H), 3.07–3.11 (m, 2H), 3.40–3.45 (m, 1H),
7.16 (d, J = 9.0 Hz, 2H), 7.37 (d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d
33.5, 36.9 (2C), 127.6 (2C), 129.5 (2C), 134.0, 137.5, 165.6 (2C); MS (m/z, %
relative intensity): 226 (M+, 37Cl, 6), 224 (M+, 35Cl, 15), 140 (33), 138 (100), 115
(9), 103 (26), 77 (9); HRMS (ESI): calcd for C11H10ClO3 [M+H]+: 225.0318,
found: 225.0316. Compound (S)-4: ½a D25
ꢁ8.0 (c 0.88, CHCl3); HPLC analysis
ꢀ
Acknowledgments
with
a
Chiracel OD-H column [hexane/i-PrOH/CH3COOH, 185:14:1;
k = 226 nm; 1.0 mL/min; tR(S) = 16.5 min; tR(R) = 20.0 min] 95% ee; 1H NMR
(500 MHz, CDCl3): d 2.59–2.78 (m, 4H), 3.58 (s, 3H), 3.59–3.62 (m, 1H), 7.16 (d,
J = 8.5 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): d 37.3, 40.0,
40.3, 51.7, 128.6 (2C), 128.8 (2C), 132.8, 140.7, 171.7, 176.9; FT-IR (KBr, cmꢁ1):
3035, 1729, 1699, 1435, 1273, 1162, 1096, 825; MS (m/z, % relative intensity):
258 (M+, 37Cl, 4), 256 (M+, 35Cl, 14), 238 (11), 227 (6), 225 (18), 212 (33), 210
(100), 198 (18), 196 (52), 168 (27), 165 (22), 152 (55), 141 (45), 138 (21), 115
(27), 103 (32), 77 (29), 59 (20); HRMS (ESI): calcd for C12H13ClNaO4 [M+Na]+:
279.0400, found: 279.0395. Compound 5: 1H NMR (500 MHz, CDCl3): d 2.46–
2.63 (m, 2H), 3.20–3.22 (m, 2H), 3.38 (m, 1H), 3.49 (s, 3H), 3.51 (s, 3H), 4.70
(brs, 1H), 7.04 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H); 13C NMR (125 MHz,
CDCl3): d 38.0, 41.7, 45.9, 51.7, 52.1, 128.8 (2C), 128.9 (2C), 132.9, 139.5, 156.9,
172.1; FT-IR (KBr, cmꢁ1): 3345, 2953, 1732, 1534, 1256, 1167, 1092, 1014, 828;
HRMS (ESI) calcd for C13H16ClNNaO4 [M+Na]+: 308.0666, found: 308.0664.
We are grateful to Shenogen Pharma Group for the financial
support of this research.
References and notes
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Compound 6: ½a 2D5
ꢀ
+7.3 (c 1.20, MeOH); 1H NMR (500 MHz, MeOH-d4): d 2.46–
2.75 (m, 4H), 3.54–3.59 (m, 1H), 7.26 (br s, 4H); 13C NMR (125 MHz, MeOH-d4):
d 39.7, 41.3, 42.8, 129.5 (2C), 130.3 (2C), 133.5, 143.1, 175.2, 176.5; FT-IR (KBr,
cmꢁ1): 3444, 3327, 2924, 1699, 1634, 1250, 1093, 1040, 1013, 823; MS (m/z, %
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(37), 195 (100), 180 (54), 178 (35), 167 (83); HRMS (ESI) calcd for
C11H12ClNNaO3 [M+Na]+: 264.0403, found: 264.0401. Compound (R)-1: ½a 2D3
ꢀ
ꢁ2.6 (c 1.00, H2O); 1H NMR (500 MHz, DMSO-d6): d 2.54–2.88 (m, 2H), 2.97–
3.11 (m, 2H), 3.35–3.41 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H),
8.07 (s, 3H), 12.24 (s, 1H); 1H NMR (500 MHz, D2O): d 2.73–2.89 (m, 2H), 3.24–
3.28 (m, 1H), 3.38–3.45 (m, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 2H);
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137.8, 176.1; FT-IR (KBr, cmꢁ1): 3030, 1725, 1494, 1411, 1205, 1182, 1127,
1089, 1015, 948, 828; MS (ESI) m/z: 214 [MꢁCl]+; HRMS (ESI) calcd for
C10H13ClNO2 [MꢁCl]+: 214.0635, found: 214.0631.
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