TETRAHEDRON:
ASYMMETRY
Tetrahedron: Asymmetry 14 (2003) 581–586 Pergamon
Enantioselective synthesis of (R )-(-)-baclofen via Ru(II)–BINAP
catalyzed asymmetric hydrogenation
Vinay V. Thakur, Milind D. Nikalje and A. Sudalai*
Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
Received 18 November 2002; accepted 2 January 2003
Abstract—A short and efficient enantioselective synthesis of (R )-(-)-baclofen, a selective GABA
B
agonist has been described with
an overall yield of 26% and 90% ee. Ru(II)–(S )-BINAP catalyzed asymmetric hydrogenations of CC and CO groups constitute
the key steps in introducing stereogenic centers into the molecule. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
Baclofen [-amino--(p -chlorophenyl)butyric acid], 1,a
derivative of -aminobutyric acid (GABA), plays an
important role as an inhibitory neurotransmitter in
central nervous system (CNS) of mammalians.
1,2
It
helps to reduce the excitatory effect of active com-
pounds such as benzodiazepine, barbiturates, etc.
3
The
deficiency of GABA is associated with diseases that
exhibit neuromuscular dysfuntions such as epilepsy,
Huntington, Parkinsons’ diseases, etc.
4
Baclofen is also
one of the most promising drugs in the treatment of the
paroxysmal pain of trigeminal neuralgia
5
as well as
spasticity of spinal without influencing the sedation.
6
Although baclofen is commercialized in its racemic
form, it has been reported that its biological activity
resides exclusively in (R )-enantiomer.
7
There are many methods available in the literature on
the synthesis of (R )-(-)-baclofen 1. They are concerned
mostly with resolution,
8
chemoenzymatic
9
or enantiose-
lective synthesis.
10
However, these methods suffer from
disadvantages such as the low overall yields, the need
for separation of diastereoisomers and the use of expen-
sive chiral reagents in stochiometric amounts. In this
context, a more practical approach for the synthesis of
(R )-(-)-baclofen 1 is highly desirable. This article
describes a new enantioselective synthesis of (R )-(-)-
baclofen 1 by employing Ru-catalyzed asymmetric
hydrogenation of ethyl 4-azido-3-(4-chlorophenyl)-2-
butenoate 6 as well as ethyl 4-chlorophenylbenzoyl
acetate 5.
2. Results and discussion
Retrosynthetic analysis (Fig. 1) of (R )-(-)-baclofen 1
reveals that many precursors such as -hydroxy ester 2,
azidoester 6, -cyano ester 3 or nitroketone 7 can be
visualized as the key intermediates. In order to prepare
enantiomerically pure -hydroxy ester 2, Pd-catalyzed
oxidative kinetic resolution
11
of the corresponding
racemic -hydroxyester (±)-4 was attempted. However,
the desired chiral alcohol 2 was obtained in low enan-
tiomeric excess (7% ee). Further, the Michael addition
of nitromethane catalyzed by L-proline on 4-chloroben-
zylideneacetophenone was also attempted to get the
chiral nitroketone 7 (Corey’s intermediate) but with
poor enantioselectivity (15% ee). Ni-catalyzed asymmet-
ric hydrocyanation of 4-chlorobenzylideneacetophe-
none was also attempted using trimethylsilyl cyanide
and acetone cyanohydrin as the HCN source but the
catalyst failed to induce any stereoselectivity although it
gave the racemic product. We then turned our attention
to asymmetric hydrogenation of azidoester 6.
The key precursor, (E )-ethyl 3-(4-chlorophenyl)-2-
butenoate 8, was obtained in 78% overall yield (E :Z=
70:30) by the Reformatsky reaction of
4-chloroacetophenone with ethyl bromoacetate fol-
lowed by p -TSA catalyzed dehydration of the interme-
diate alcohol. The allylic bromination of 8 with
N -bromosuccinimide (NBS) in the presence of 2,2-azo-
bisisobutyronitrile (AIBN) resulted in the formation of
ethyl 4-bromo-3-(4-chlorophenyl)-2-butenoate 9 in 92%
yield. The bromoester 9 was then transformed to ethyl
* Corresponding author. Tel.: +91-020-5893300; fax: +91-20-5893359;
e-mail: sudalai@dalton.ncl.res.in
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00024-7