Asymmetric synthesis of both the enantiomers of antidepressant venlafaxine and its analogues

Article abstract of DOI:10.1016/j.tetlet.2012.02.025

Chemoenzymatic asymmetric synthesis of antidepressant agent venlafaxine and its analogue have been reported in this communication. The main highlight of the reported synthesis is the stereoselective synthesis of cyanohydrins by (S)-hydroxynitrile lyase (Hevea brasiliensis) followed by lipase catalyzed kinetic resolution.

Full text of DOI:10.1016/j.tetlet.2012.02.025

Tetrahedron Letters 53 (2012) 1990–1992
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric synthesis of both the enantiomers of antidepressant
venlafaxine and its analogues
⇑
Rajib Bhuniya, Samik Nanda
Department of Chemistry, IIT-Kharagpur, Kharagpur 721302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Chemoenzymatic asymmetric synthesis of antidepressant agent venlafaxine and its analogue have been
reported in this communication. The main highlight of the reported synthesis is the stereoselective syn-
thesis of cyanohydrins by (S)-hydroxynitrile lyase (Hevea brasiliensis) followed by lipase catalyzed kinetic
resolution.
Received 9 December 2011
Revised 2 February 2012
Accepted 6 February 2012
Available online 13 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Antidepressants
Hydroxynitrile lyase
Lipase catalyzed kinetic resolution
Asymmetric synthesis
Venlafaxine hydrochloride belongs to a class of well known
antidepressant agents generally known as SNRIs (serotonin-nor-
epinephrine reuptake inhibitor). It is widely known by its brand
name EffexorXRÒ, which was first introduced by Wyeth and now
marketed globally by Pfizer, is approved for the effective treatment
of major depressive disorder (MDD) and generalized anxiety disor-
der (GAD). Effexor XRÒ made history when it became Wyeth’s larg-
est selling drug accounting for 16–18% of net revenue from 2006 to
2008. The reported synthetic routes for racemic venlafaxine mainly
involve the condensation of cyclohexanones with 4-methoxy-
phenyl acetic acids or 4-methoxyphenyl acetonitriles followed by
functional group manipulation.1 There is also another report which
involves an efficient HDA (Hetero Diels–Alder) reaction of an
azadiene followed by transketalization and hydroxymethylation
reaction.2 Recently an efficient enzymatic resolution of ( )-venla-
faxine has been reported by Kochetkov et al.3 We are interested
to develop an asymmetric synthetic route for both the enantiomers
of venlafaxine, as both the enantiomers have a role in its antide-
pressant activity [(+)-enantiomer inhibiting serotonin reuptake
and the (ꢀ)-enantiomer inhibiting norepinephrine reuptake]. We
thought that cyanohydrins generated from cyclohexanones and
its analogues can be synthetically manipulated to both the enanti-
omers of venlafaxine (1). Our retrosynthetic scheme is outlined be-
low (Scheme 1). The cyanohydrins are easily synthesized from the
corresponding ketone by an enzymatic route applying (S)-
hydroxynitrile lyase (HNL) from Hevea brasiliensis (HbHNL).4 We
have also decided to synthesize two venlafaxine analogues (2
and 3) by the same strategy.
For the synthesis of (R)-venlafaxine (1) we have started from
cyclohexanone. Cyclohexanone is converted to its corresponding
cyanohydrin (4) by an enzymatic transcyanation reaction with ace-
tone cyanohydrin and HbHNL as the enzyme. Chemistry of the cya-
nohydrin formation by similar HNL is well established in our
laboratory and elsewhere.5,6 By applying a transcyanation protocol
with acetone cyanohydrins as a cyanide source cyclohexanone cya-
nohydrin is synthesized on a 10 g scale by using crude the enzy-
matic extract of HNL from rubber tree (Hevea brasiliensis). The
role of enzyme in this particular reaction is unique as the biocata-
lytic reaction is very fast and high yielding (almost quantitative
conversion is achieved) than the corresponding chemical reaction.
The biocatalytic reaction is also highly stereoselective in the case of
cyanohydrins’ formation from 4-methyl cyclohexanone (for syn-
thesis of 3), as it yields only one diastereomer (syn addition of
CN ion; Me is equatorial). Syn addition of CN ion to cyclohexanone
analogue by similar (S)-HNL is reported by Effenberger co-work-
ers.7 This fixes the alcohol functionality in axial and CN group in
the equatorial position of the cyclohexane ring in the case of 4-
methylcyclohexanone. The free hydroxyl group in compound 4
was protected as its EOM ether by treatment with EOM-Cl (ethoxy-
methyl chloride) with DIPEA (diisopropyl ethyl amine) to afford
EOM-protected cyanohydrin 7 in a 90% yield. Addition of Grignard
reagent (generated from 4-bromo anisole) on compound 7 fol-
lowed by acidic work-up afforded ketone 10 in an 85% yield. Wittig
reaction with ketone 10 and triphenylphosphonium methyl iodide
in the presence of KOtBu afforded the olefin 13 in an 82% yield.
Asymmetric hydroboration reaction with (ꢀ)-Ipc2BH was
⇑
Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.02.025

R. Bhuniya, S. Nanda / Tetrahedron Letters 53 (2012) 1990–1992
1991
OH
OP
OP
Lipase catalyzed
NMe2
kinetic resolution
OH
OMe
(R)-Venlafaxine; 1
OMe
OMe
OP
(S)-HNL
O
CN
P = Ethoxymethyl
OH
OH
Me
NMe2
NMe2
OMe
(R)-Venlafaxine analogue; 2
OMe
(R)-Venlafaxine analogue; 3
Scheme 1. Retrosynthetic analysis for (R)-venlafaxine and two of its structural analogues.
OH
O
HbHNL
OEOM
a
b
R
R
CN
R
n
Me2C(OH)CN
n
CN
n
citrate buffer, pH = 4.5
R = H; n = 1; 4; 100%
R = H; n = 0; 5; 95%
R = Me; n = 1; 6; 96%
R = H; n = 1; 7
R = H; n = 0; 8
R = Me; n = 1; 9
OEOM
O
OEOM
OEOM
R
R
R
OH
n
e
c
n
d
n
R = H; n = 1; 13
R = H; n = 0; 14
R = Me; n = 1; 15
R = H; n = 1; 10
R = H; n = 0; 11
R = H; n = 1; 16
R = H; n = 0; 17
R = Me; n = 1; 18
R = Me; n = 1; 12
OMe
OEOM
OMe
OMe
OEOM
n
OP
R
OAc
R
OH
n
f
R
R'
+
n
R = H; n = 1; (R)-19
R = H; n = 0; (R)-20
R = Me; n = 1; (R)-21
R = H; n = 1; (S)-16
R = H; n = 0; (S)-17
R = Me; n = 1; (S)-18
OMe
OMe
OMe
R' = OTs; R = H, P = EOM; n = 1; (S)-22
R ' = OTs; R = H, P = EOM; n = 0; (S)-23
R' = OTs; R = Me, P = EOM; n = 1; (S)-24
g
R' = NMe2; R = H, P = H; n = 1; (S)-venlafaxine
R ' = NMe2; R = H; P = H; n = 0; (S)-2
OP
R ' = NMe2; R = Me, P = H; n = 1; (S)-3
R
R'
n
OMe
R' = OTs; R = H; P = EOM; n = 1; (R)-22
R ' = OTs; R = H, P = EOM; n = 0; (R)-23
R' = OTs; R = Me, P = EOM; n = 1; (R)-24
R' = NMe2; R = H, P = H; n = 1; (R)-venlafaxine
R ' = NMe2; R = H; P = H; n = 0; (R)-2
R ' = NMe2; R = Me, P = H; n = 1; (R)-3
Scheme 2. Asymmetric synthesis of venlafaxine and its analogues: Reagents and conditions: (a) EOM-Cl, DIPEA, 90%; (b) p-MeOC6H4MgBr, 85%; (c) Ph3P+MeI, KOtBu, 82%; (d)
BH3ꢁSMe2, KOH, H2O2, 84%; (e) CH2@CHOAc, Lipase PS-D, MS 4 Å, 48%; (f) (i) p-TSCl, Et3N, DMAP, 88%; (ii) Me2NH, 80 °C, 48 h; (iii) PTSA, MeOH, 65% (over two steps); (g) (i)
K2CO3, MeOH; then same reaction sequences as in f.

1992
R. Bhuniya, S. Nanda / Tetrahedron Letters 53 (2012) 1990–1992
attempted at the beginning, to our dismay the enantioselectivity in
the product alcohol was found to be very poor (only 20%).8 In gen-
eral none of the chiral boranes developed to date are efficient for
the enantioselective hydroboration of 1,1-disubstituted olefins
such as compound 13–15. At this point we have decided to change
our strategy and we thought to opt for the enzymatic kinetic reso-
lution (EKR) strategy, which will allow the synthesis of both the
enantiomers of venlafaxine in a straightforward way. Hydrobora-
tion of olefinic compound 13 with BH3ꢁSMe2 afforded the corre-
sponding racemic hydroxymethylated compound 16 in an 84%
yield. Compound 16 was subjected to lipase catalyzed EKR (transe-
sterification with active ester) with vinyl acetate. Lipase PS-D
(Burkholderia cepacia, lipase immobilized on diatomaceous earth)
was found to be the best lipase in terms of enantioselectivity.9 Sub-
sequently the fast reacting enantiomer of compound 16 was con-
verted to its (R)-acetate 19 (ee = 94%; yield = 48%) and the slow
reacting enantiomer (ee = 95%; yield = 46%; S) was recovered after
chromatographic separation. The absolute configuration was pre-
dicted by Kazlauskas empirical rule.10
authors (RB) is thankful to CSIR (New Delhi, India) for senior re-
search fellowship.
Supplementary data
Supplementary data (1H and 13C NMR spectra for all new com-
pounds) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2012.02.025.
References and notes
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20090512.; (b) Mahaney, P. E. US 7524846 B2 20090428.; (c) Trybulski, E. J.;
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20090217.; (d) Trybulski, E. J.; Sabatucci, J. P.; Vu, A. T.; Cohn, S. T.; Santilli, A.
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Once the stereocenter has been fixed, the remaining steps in
achieving the target molecules seem to be a routine affair. Com-
pound (S)-16 is converted to its corresponding tosylate derivative
(S)-22 by treatment with p-TsCl and Et3N in an 88% yield. Reaction
of (S)-22 with dimethyl amine (Me2NH, 40% aq solution)11 in a
closed vessel for 48 h at 80 °C followed by the removal of EOM
group with PTSA (para-toluene sulfonic acid), afforded (S)-venla-
faxine in a 65% yield (two steps, overall yield = 14% from cyclohex-
anone. Overall yield of venlafaxine analogue 2 is 10.2% from
cyclopentanone and 3 is 12.8% from 4-methyl cyclohexanone).
The optical rotation value of our synthesized venlafaxine matches
well with the literature value, and that establishes the absolute
configuration of our synthesized venlafaxine.12 Deacetylation with
K2CO3–MeOH and the similar reaction sequences as described
above afforded (R)-venlafaxine from the (R)-acetate 19. The venla-
faxine analogues have also been synthesized by following similar
reaction sequences from (S)-17/18 and (R)-20/21 (Scheme 2).
In conclusion, asymmetric synthesis of both enantiomers of
antidepressant agent venlafaxine and two of its analogues has been
reported here. The main highlight of our synthetic strategy was (S)-
HNL catalyzed synthesis of cyanohydrins from cyclic ketones and
lipase-PS catalyzed kinetic resolution for creation of the stereocen-
ter. Novel synthetic studies for structurally similar analogues are
currently underway in our laboratory.
3. Kochetkov, K. A.; Galkina, M. A.; Galkin, O. M. Mendeleev Commun. 2010, 20,
314–315.
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Pelter, A. In Stereoselective Synthesis; Helmche, G., Hoffmann, R. W., Mulzer, J.,
Schaumann, E., Eds.; Houben-Weyl, Georg Thieme: Stuttgart, 1991; Vol. E21 7,
pp 4396–4420. fourth ed.; (c) Carreira, E. M.; Kvaerno, L. Classics in
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Jadhav, P. K.; Mandal, A. K. Tetrahedron 1981, 37, 3547–3587.
9. Enantioselectivity (ee) of the enzymatic kinetic resolution step was determined
by chiral HPLC analysis (OD-H column, mobile phase: hexane/2-propanol = 9:1,
flow rate: 1 ml/min. tmajor = 22.4; tminor = 28.2 for compound 16. tmajor = 18.6;
tminor = 20.2 for compound 19).
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Couzinier, J. P. J. Med. Chem. 1987, 30, 318–325.
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A.; Muth, E. A.; Andree, T.; Fletcher, H.; James, M. N. G.; Sieleckit, A. R. J. Med.
Acknowledgements
Chem. 1990, 33, 2899–2905. Literature
½
a 2D5
ꢂ
for (S)-venlafaxine = +27.6
(c = 1.07, EtOH); for (R)-venlafaxine ½a D25
ꢂ
ꢀ27.1 (c = 1.04, EtOH)..
We are thankful to DBT (New Delhi, India; Grant No: BT/
PR13830/PID/06/568/2010) for financial support. One of the