Asymmetric total synthesis of (-)-venlafaxine using an organocatalyst

Article abstract of DOI:10.1016/j.tetlet.2013.02.029

An asymmetric total synthesis of (-)-venlafaxine using an organocatalyst has been achieved via a unified strategy employing organcatalytic Michael addition, regio-selective dehydration and selective epoxide ring opening.

Full text of DOI:10.1016/j.tetlet.2013.02.029

Tetrahedron Letters 54 (2013) 2137–2139
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Asymmetric total synthesis of (ꢀ)-venlafaxine using an organocatalyst
⇑
Subhash P. Chavan , Sumanta Garai, Kailash P. Pawar
Division of Organic Chemistry, CSIR-NCL (National Chemical Laboratory), Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An asymmetric total synthesis of (ꢀ)-venlafaxine using an organocatalyst has been achieved via a unified
strategy employing organcatalytic Michael addition, regio-selective dehydration and selective epoxide
ring opening.
Received 10 January 2013
Revised 5 February 2013
Accepted 9 February 2013
Available online 16 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Antidepressent
Organocatalyst
Asymmetric synthesis
Venlafaxine
Michael addition
Venlafaxine 1, a new generation antidepressant drug, was first
introduced by Wyeth in 1993 and it is marketed by Pfizer with
the trade name of EffexorXRÒ (Fig. 1). It is being used for the treat-
ment of major depressive disorder (MDD), generalized anxiety dis-
order and comorbid indications in certain anxiety disorders for
depression. In 2007, venlafaxine was the sixth most commonly
prescribed antidepressant in the U.S. retail market, with 17.2 mil-
lion prescriptions. Although venlafaxine is sold as a racemate, (ꢀ)-
venlafaxine is a more potent inhibitor of norepinephrine synapto-
somal uptake while (+)-venlafaxine is more selective in serotonin
uptake. The biological activity of venlafaxine is different from other
antidepressants in that it has no or little activity on a variety of
tion because the (ꢀ) and (+) enantiomers of venlafaxine exhibit dif-
ferent biological activities.
To overcome these problems and as a part of our continued
interest in antidepressant agents, we thought to develop an effi-
cient, simple and practical strategy for the asymmetric synthesis
of (ꢀ)-venlafaxine 1 by using an organocatalyst derived from
L-pro-
line. Simply by switching the stereocenter of the -proline catalyst
L
one could synthesize both the enantiomers of venlafaxine and
there would be no loss of material in the form of unwanted
enantiomer.
Our retrosynthetic analysis is outlined in Scheme 1. In principle,
the tertiary hydroxyl group in venlafaxine could be installed by
epoxidation of 2 followed by selective epoxide ring opening. The
required olefin 2 could be obtained by the reduction of ketone 3
followed by elimination. The keto compound 3 in turn could be
readily accessed by asymmetric organocatalyzed Michael reaction7
of cyclohexanone with nitrostyrene 4.
neuroreceptors1 (e.g.,
a or b-adrenergic receptors, muscarinic
receptors, cholinergic receptors, histaminic receptors).
There are a number of racemic syntheses reported in the litera-
ture2 including a few reports from our group3 and the resolution of
racemic venlafaxine by kinetic enzymatic resolution has been re-
cently reported in the literature.4 According to our knowledge, only
two asymmetric syntheses have been reported so far. Davies and
Ni5 have reported an asymmetric synthesis of (+)-venlafaxine by
using a Rh-catalyzed Mannich reaction as a key step while Nanda
and Bhuniya6 have very recently reported an asymmetric synthesis
of both enantiomers of venlafaxine by using an enzymatic resolu-
tion as the key step. The aforementioned two asymmetric synthe-
ses have delivered venlafaxine in chiral form but the Rh-catalyzed
Mannich reaction involved use of environmentally hazardous,
expensive Rh-catalyst while there is loss of 50% material in the
form of unwanted enantiomer in case of kinetic enzymatic resolu-
Accordingly, our synthesis of (ꢀ)-venlafaxine began with the
nitrostyrene 48 which was synthesized by condensation of
O
NMe2
OH
(-)-Venlafaxine, 1
⇑
Corresponding author. Fax: +91 20 5892629.
E-mail address: sp.chavan@ncl.res.in (S.P. Chavan).
Figure 1. Structure of (ꢀ)-venlafaxine.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.029

2138
S. P. Chavan et al. / Tetrahedron Letters 54 (2013) 2137–2139
O
O
O
O
O
NHR
NMeCbz
O
O
NMe2
O
NHCbz
b
a
NO2
OH
9
7
1
2
3
O
NMe2
c
4
O
OH
NO2
NMeCbz
(-)-venlafaxine, 1
Scheme 1. Retrosynthetic analysis of (ꢀ)-venlafaxine.
10
inexpensive and readily available starting material viz. anisalde-
hyde (5) with nitromethane under sonication in 95% yield. Asym-
metric Michael reaction of cyclohexanone with nitrostyrene 4 in
the presence of proline based organocatalyst 89 (20 mol %) fur-
nished the nitroketone 3 in 79% yield with P99% ee. After con-
struction of the main framework of (ꢀ)-venlafaxine, the
remaining tasks were installation of the tertiary hydroxyl group
and introduction of the N,N-dimethyl group. At this stage, the
seemingly simple installation of the tertiary hydroxyl group was
attempted under a variety of reaction conditions, without success,
Scheme 3. Reagents and conditions: (a) MeI, NaH, THF, overnight, rt, 92%; (b) m-
CPBA, NaHCO3, DCM, 2 h, rt; (c) LiAlH4, THF, 5 h, reflux, 60% (over two steps), P99%
ee.
After introduction of the double bond, dihydroxylation reaction
(OsO4, NMO) was carried out on 7 for installation of the tertiary hy-
droxyl group to furnish the corresponding diol (not shown). Selec-
tive removal of the secondary hydroxyl group was attempted
under a variety of conditions but the desired product was not ob-
tained. Therefore for the installation of tertiary hydroxyl group, we
decided to carry out epoxidation followed by reductive epoxide
opening.
due to the highly acidic nature of the nitro a-proton. We then at-
tempted the reduction of both the keto and nitro groups in one
pot but obtained a complex reaction mixture.
Thus, compound 7 was N-methylated with NaH and MeI to af-
ford compound 9 in 92% yield. Compound 9 was subjected to epox-
idation with m-CPBA in the presence of NaHCO3 to afford epoxide
10. The crude epoxide was subjected to selective epoxide opening,
with concomitant carbamate reduction, using lithium aluminum
hydride to afford (ꢀ)-venlafaxine 1 in 60% yield with P99% ee11
(Scheme 3). Spectral data and optical rotation12 for (ꢀ)-venlafaxine
Therefore, it was decided to perform stepwise reduction. Thus,
selective reduction of ketone functionality of compound 3 was
achieved by using NaBH4 in THF/H2O (9:1) as the solvent system
to afford the corresponding nitroalcohol. The crude nitroalcohol
was subjected to reduction10 of nitro group by NiCl2ꢁ6H2O and
NaBH4 in MeOH as a solvent and the amine thus obtained was pro-
tected in situ by benzyl chloroformate (Cbz-Cl) in the presence of
Et3N as a base to furnish Cbz protected amino alcohol 6 in 75%
yield. The hydroxyl group of compound 6 was converted into the
corresponding mesyl derivative by using mesyl chloride (MsCl) in
the presence of Et3N as a base under reflux conditions. The crude
mesylated product on treatment with DBU in acetonitrile,
selectively furnished the more substituted olefin 7 in 68% yield
(Scheme 2).
1
were in good agreement with the data reported in the
literature.13
In conclusion, we have achieved the asymmetric total synthesis
of (ꢀ)-venlafaxine in a very efficient manner from commercially
available, inexpensive starting material by using an environmen-
tally friendly proline-based catalyst. By using different enantio-
mers of proline-based catalyst we can access both the
enantiomers of venlafaxine in a very concise manner. Currently,
work on the synthesis of other antidepressant agents is in progress
in our laboratory and the results will be reported in due course.
O
O
O
Acknowledgments
a
O
c
b
S.G. and K.P.P. thank CSIR, New Delhi, India, for a fellowship and
S.P.C. acknowledges funding from NCL inhouse project [MLP
017226 and MLP 012726]. We thank Ms. S. Kunte for HPLC analysis
and Dr. U.R. Kalkote for helpful discussion.
NO2
CHO
5
3
4
NO2
O
O
Supplementary data
N
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
02.029.
HN
OH
NHCbz
d
NHCbz
N
H
8
7
6
References and notes
Scheme 2. Reagents and conditions: (a) CH3NO2, NH4OAc, glacial acetic acid,
sonication, 3 h, 95%; (b) cyclohexanone, 8, PTSA, DMF, 24 h, 79%, 99% ee; (c) (i)
NaBH4, THF/H2O (9:1), 2 h, (ii) NiCl2ꢁ6H2O, NaBH4, MeOH, 1.5 h, 0 °C then CbzCl,
Et3N, rt overnight, 75% (over two steps); (d) (i) MsCl, Et3N, reflux, 14 h; (ii) DBU,
CH3CN, 24 h, reflux, 68% (over two steps).
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1
;
(m, 8H), 2.28 (dd, J = 12.2, 2.9 Hz, 1H), 2.33 (s, 6H), 2.93 (dd, J = 12.2, 2.9 Hz,
1H), 3.28 (t, J = 12.2 Hz, 1H), 3.79 (s, 3H), 6.79 (d, J = 8.8 Hz, 2H), 7.03 (d,
J = 8.79 Hz, 2H). 13C NMR (50 MHz, CDCl3 + CCl4): 20.70, 21.05, 25.55, 30.72,
37.53, 44.89, 51.20, 54.36, 60.74, 73.48, 112.75, 129.43, 132.00, 157.72. MS
(EI): m/z 278 [M+H]+. ½a D25
ꢃ
ꢀ24.285 (c 1.04, EtOH). Lit.13 R-(ꢀ)-venlafaxine ½a 2D5
ꢃ
ꢀ27.1 (c 1.04, EtOH).
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