Highly enantioselective organocatalytic conjugate addition of nitromethane to α,β-unsaturated aldehydes: Three-step synthesis of optically active baclofen

Article abstract of DOI:10.1002/adsc.200700353

An efficient, organocatalytic, highly enantioselective, conjugate addition reaction of nitromethane with α,β-unsaturated aldehydes has been developed. The process serves as the key step for a practical 3-step synthesis of chiral baclofen, an antispastic drug.

Full text of DOI:10.1002/adsc.200700353

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DOI: 10.1002/adsc.200700353
Highly Enantioselective Organocatalytic Conjugate Addition of
Nitromethane to a,b-Unsaturated Aldehydes: Three-Step
Synthesis of Optically Active Baclofen
Liansuo Zu,a Hexin Xie,a Hao Li,a Jian Wang,a and Wei Wanga,*
a
Department of Chemistry and Chemical Biology, University of New Mexico, MSC03 2060, Albuquerque, NM 87131-0001,
USA
Fax : (+1)-505-277-2609; e-mail: wwang@unm.edu
Received: July 17, 2007; Revised: September 22, 2007; Published online: November 21, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: An efficient, organocatalytic, highly enan-
tioselective, conjugate addition reaction of nitrome-
thane with a,b-unsaturated aldehydes has been de-
veloped. The process serves as the key step for a
practical 3-step synthesis of chiral baclofen, an anti-
spastic drug.
synthesis of chiral (R)-baclofen. These methodologies
rely on the use of chiral precursors,[2] chiral auxilia-
ries,[3] and chemical[4] and enzymatic[5] resolutions.
Atom-economic asymmetric catalytic strategies in-
cluding organometallic[6] and organocatalytic[7] sys-
tems also have been developed. However, these ap-
proaches suffer from long synthetic sequences and the
use of not readily available chemicals, thus limiting
their practical application for a large-scale synthesis.
The synthetic significance is further underscored by
the utilization of baclofen as a lead compound for the
design of GABA agonists and antagonists to seek
new therapeutic agents targeting on the central nerv-
ous system (CNS).[1a,8] The analogues of baclofen can
Keywords: asymmetric catalysis; asymmetric syn-
À
thesis; C C bond formation; Michael addition; or-
ganic catalysis
The synthesis of natural products and therapeutics potentially be developed for the treatment of a varie-
has served as a principal driving force for discovering ty of diseases including epilepsy, Huntingtonꢀs and
new synthetic methods. On the other hand, the syn- Parkinsonꢀs diseases, and other psychiatric disorders,
thetic value of useful synthetic methods can be quick- such as anxiety and pain.[1a,8] As a consequence, the
ly established in the context of the efficient prepara- development of general, efficient synthetic strategies
tion of biologically important pharmaceuticals and enabling a facile approach to chiral baclofen and its
natural products. Baclofen (1; Figure 1), a potent analogues is of considerable significance from the
standpoint of the medicinal and organic chemistry.
Driven by the lack of such a facile access to this class
of compounds, in this communication we disclose a
remarkably efficient and practical route for the highly
enantioselective synthesis of optically active baclofen
in 3 steps from the readily available simple achiral
molecules a,b-unsaturated aldehydes and nitroal-
kanes. The key step relies on a highly efficient orga-
nocatalytic enantioselective conjugate addition reac-
Figure 1. The structures of chiral baclofen (1).
tion of nitromethane with a,b-unsaturated aldehydes,
which we have successfully developed in the study.
This efficient synthetic strategy can be further ex-
GABAB receptor agonist, is used for the treatment of plored for the rapid preparation of new chiral baclo-
spinal cord injury-induced spasm.[1] Despite the fact fen analogues in drug discovery.
that the racemic form of baclofen is used in clinical
Our synthetic strategy towards chiral baclofen (1) is
practice,[1a] the (R) enantiomer is the essential active described in Scheme 1. We hypothesized that com-
chemical entity and its (S) form is inactive. Accord- pound 1 could be constructed from chiral g-nitro alde-
ingly, a great deal of effort has been directed to the hyde 2 via the oxidation of the aldehyde and the sub-
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Adv. Synth. Catal. 2007, 349, 2660 – 2664

Three-Step Synthesis of Optically Active Baclofen
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Scheme 1. Retrosynthetic analysis of chiral baclofen (1).
sequent reduction of the nitro group in a straightfor-
In initial exploratory efforts aimed at the develop-
ward manner. This raised a synthetic challenge relat- ment of chiral amine-catalyzed asymmetric conjugate
ed to the assembly of the key intermediate 2. We addition reactions, we screened 4 chiral pyrrolidines
were intrigued by the possibility offered by a catalytic and pyrrolidinones I–IV (Table 1). A model reaction
enantioselective conjugate addition of nitromethane
to an a,b-unsaturated aldehyde, which serves as the
Table 1. Optimization of organocatalytic enantioselective
critical step in the synthesis. If successful, the strategy
conjugate addition reactions.[a]
proposed here would be, to the best of our knowl-
edge, the most efficient approach to chiral baclofen
(1). Moreover, the merit of the method is highlighted
by the use of the readily available simple achiral ni-
troalkanes and a,b-unsaturated aldehydes.
Conjugate addition reactions have been demon-
strated as a powerful tool in organic synthesis.[9] Re-
cently, organocatalytic asymmetric versions of the
processes have been hotly pursued.[10] Notably, stabi-
lized carbanions as nucleophiles for the conjugate ad-
dition to a,b-unsaturated systems, which involve the
À
formation of new C C bonds, have been intensively
Entry Catalyst Solvent t [h] Yield[b] [%]
% ee[c]
studied. Although significant progress has been made
for a,b-unsaturated ketone,[11] ester,[12] amide/imide[13]
and nitrostyrene[14] substrates, the development of a
catalytic method to promote enantioselective conju-
gate additions of stabilized carbanions to a,b-unsatu-
rated aldehydes has proven to be more challenging.
One of the main reasons for this is the greater sus-
ceptibility of a,b-unsaturated aldehydes to 1,2-addi-
tion reactions as compared to other unsaturated sys-
tems. Thus, it is not surprising that only a few success-
ful examples of these reactions have been present-
ed.[15] Prior to our investigation, no study has been re-
ported using nitroalkanes as a nucleophile for the
direct conjugate addition process.[16] During the
course of our study, Arvidsson and co-workers de-
scribed such a process using MacMillanꢀs chiral imida-
1
2
3
4
5
6
7
8
I
II
EtOH
EtOH
EtOH
EtOH
MeOH
i-PrOH
CH2Cl2
toluene 36
THF
MeCN
36
36
36
15
32
9
20
0
0
75
75
60
0
0
0
0
nd[d]
nd[d]
nd[d]
97
III
IV
IV
IV
IV
IV
IV
IV
99
97
36
nd[d]
nd[d]
nd[d]
nd[d]
9
10
36
36
[a]
[b]
[c]
[d]
Reaction conditions: see Experimental Section.
Isolated yields.
Determined by chiral HPLC analysis (Chiralpak AS-H).
Not determined.
zolidinone as promoter.[17] It is noted that the process between trans-cinnamaldehyde 3a and nitromethane
affords products with only moderate enantioselectivi- 4a in the presence of 20 mol% catalyst and PhCO2H
ties (a typical range of ca. 70–80% ee). Even lower ee in EtOH at 08C was conducted (entries 1–4). It was
(47%) was obtained when nitromethane was used. In found that their activities differed significantly.
this context, we reveal an organocatalytic conjugate Among the catalysts probed, (S)-diphenylprolinol
addition protocol which achieves significantly im- TMS ether IV was the best promoter for the process
proved enantioselectivities (87–99% ee). Remarkably, (entry 4).[18] Notably, an excellent level of enantiose-
excellent levels of enantioselectivities (96–99% ee) lectivity (97% ee) and good yield (75%) were achiev-
are achieved for nitromethane as nucleophile. The ed. Encouraged by the promising results, we selected
highly optically active products serve as a useful mo- the catalyst IV for an optimization of the reaction
lecular basis for the synthesis of chiral baclofen and conditions. A survey of solvents revealed that the pro-
its analogues.
cesses were highly solvent-dependent (entries 4–9).
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Table 2. (S)-IV-promoted conjugate addition of nitroalkane
to a,b-unsaturated aldehydes.[a]
The reactions carried out in the protic solvents EtOH,
MeOH and i-PrOH proceeded faster and gave higher
yields (75%, 75% and 60%, respectively entries 4–6).
More importantly, reactions in these solvents were
highly enantioselective (97–99% ee). However, no re-
actions occurred in other media probed (entries 7–
10).
Having established the optimal reaction conditions,
we next probed the generality of this asymmetric cat-
alytic conjugate addition reaction of nitroalkanes 4
with a variety of a,b-unsaturated aldehydes 3 in
EtOH at 08C (Table 2). The results show that the re-
actions take place efficiently (65–82%), and excellent
levels of enantioselectivity (96–99%) with nitrome-
thane 4a as nucleophile (entries 1–12) are achieved.
Significant structural variation in the a,b-unsaturated
aldehydes is tolerated in this reaction, which occurs
efficiently, independent of the nature of the substitu-
ents on the aromatic ring, where electron-withdrawing
groups (entries 1–5), electron-donating groups (en-
tries 6–8), neutral groups (entry 9), or combinations
thereof (entry 10) are included. It is also realized that
the reaction is inert to steric hindrance (entries 5 and
8). Furthermore, heteroaromatic (entry 11) and conju-
gated aromatic (entry 12) systems can participate in
the processes as well. Finally, we probed the structural
effect of the nitroalkanes 4 on the conjugate reactions
(entries 13–15). It is found that high ees (87–99%) for
both syn and anti diastereomers are obtained, albeit
with an only poor dr when nitroethane 4b and nitro-
propane 4c are exploited. These results indicate that
the processes described here are superior to those re-
ported by Arvidsson.[17] It is also realized the limita-
tion of the (S)-IV-catalyzed process is that the reac-
tions proceed sluggishly with aliphatic enals.
Entry R, R’, product
t
Yield[b]
% ee[c]
dr[d]
[h] [%]
1
4-ClC6H4, H, 2a
4-ClC6H4, H, 2b
4-NO2C6H4, H, 2c 20 72
15 75
15 73
97
-
-
-
-
-
-
-
2[e]
3[f]
4
À96
99
3-FC6H4, H, 2d 24 80
96
97
99
96
5
2-NO2C6H4, H, 2e 20 65
4-MeOC6H4, H, 2f 20 77
3-MeOC6H4, H,
6[f]
7
20 76
20 70
24 82
2g
8
2-MeOC6H4, H,
97
-
2h
Ph, H, 2i
9
96
99
-
-
10
3-MeO-4-AcC6H3, 20 65
H, 2j
2-furanyl, H, 2k
11[f]
12[f]
34 68
96
96
-
1-naphthyl, H, 2l 20 70
13 g] Ph, Me, 2m
9
92
syn 87[f];
anti 99
syn 92[f];
anti 94
syn 92[f];
anti 99
6/5
3/2
3/1
14 g] 2-NO2C6H4, Me,
12 87
2n
15[f]
2-NO2C6H4, Et, 2o 30 90
[a]
Unless specified, see Experimental Section.
Isolated yields.
[b]
[c]
Determined by chiral HPLC analysis (Chiralpak AS-H
or Chiralcel OD-H).
[d]
[e]
[f]
1
Determined by H NMR.
(R)-IV used.
To determine the absolute configuration of the (S)-
IV-catalyzed conjugate addition process, we converted
compound 2a to carboxylic acid 5a, which had been
converted into baclofen (1).[3c] This also provides an
The ee was determined after converted to corresponding
enone with Ph3P=CHCOPh.
Reaction performed at room temperature.
[g]
opportunity to address the synthetic utility of the re- conveniently converted to (S)-balcofen (1b) HCl salt
action. As shown in Scheme 2, compound 2a can be in two steps (Scheme 2). NaClO2-mediated oxidation
Scheme 2. Synthesis of (S)- and (R)-baclofens (1).
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Three-Step Synthesis of Optically Active Baclofen
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of aldehyde 2a gives rise to 5a in 90% yield,[19] which
can be subsequently reduced to baclofen by hydroge-
nation in the presence of Raney-Ni following the
known procedure.[3c] The analytical data of the syn-
thesized 5a match those previously reported,[3c] thus
confirming the absolute (S) configuration. We also
synthesized the enantiomer 2b in 73% yield and 96%
ee under the same reaction conditions using (R)-IV as
a catalyst (Table 2, entry 2). It is noted that the 4-
chloro enal 3a was readily prepared from commercial-
ly available 4-chlorobenzaldehdye.[20] Moreover, ex-
perimentally, the (R)-2b was demonstrated to be effi-
ciently transformed to (R)-baclofen (1a) HCl salt
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(Scheme 2).
a
gram-scale
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methods for the preparation of therapeutic agent
chiral baclofen and its analogues, we have developed
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[15] For a review of MacMillanꢀs catalyst-catalyzed reac-
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ꢁ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 2660 – 2664