Concise enantioselective synthesis of (+)-sertraline and (-)-CP-52002 using proline catalysis

Article abstract of DOI:10.1016/j.tetlet.2016.01.085

A short enantioselective synthesis of (+)-sertraline and its C₄ epimer (-)-CP-52002 with an overall yield of 30%, respectively, as its hydrochloride has been described. The key steps are the proline catalyzed Mannich reaction of acetaldehyde and acid catalyzed intramolecular Friedel-Crafts' alkylation reaction of olefin proceeding with high optical purities.

Full text of DOI:10.1016/j.tetlet.2016.01.085

Tetrahedron Letters 57 (2016) 1053–1055
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Concise enantioselective synthesis of (+)-sertraline and (À)-CP-52002
using proline catalysis
⇑
Rupali Kalshetti, V. Venkataramasubramanian, Sanjay Kamble, Arumugam Sudalai
Chemical Engineering & Process Development Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune, Maharashtra 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A short enantioselective synthesis of (+)-sertraline and its C4 epimer (À)-CP-52002 with an overall yield
of 30%, respectively, as its hydrochloride has been described. The key steps are the proline catalyzed
Mannich reaction of acetaldehyde and acid catalyzed intramolecular Friedel–Crafts’ alkylation reaction
of olefin proceeding with high optical purities.
Received 8 December 2015
Revised 22 January 2016
Accepted 24 January 2016
Available online 25 January 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Sertraline
Tametraline
Indatraline
Proline catalysis
Mannich reaction
Introduction
NHMe
R'
NHMe
R'
NHMe
R'
Selective serotonin re-uptake inhibitors (SSRIs) are a class of
compounds typically used as antidepressants in the treatment of
major depressive disorder and anxiety-related disorders.1 These
are believed to increase the extracellular level of the neurotrans-
mitter serotonin by limiting its reabsorption into presynaptic cell
and increasing the level of serotonin in the synaptic cleft available
to bind to the postsynaptic receptor. In general, optically active
molecules with amine functionality at the C1 position of a tetralin
or indane framework (1–3) play a major role in pharmaceutical
and medicinal chemistry field due to their high profile bioactivity
as selective monoamine reuptake inhibitors by inhibiting a partic-
ular monoamine neurotransmitter such as serotonin (5-HT), dopa-
mine and norepinephrine. Among these, sertraline [(+)-1a] is an
antidepressant of SSRI class.1 Sertraline hydrochloride [(+)-1aÁHCl]
selectively blocks serotonin reuptake and is used for the treatment
of depression, as well as dependency and other anxiety-related dis-
orders2a (see Fig. 1).
R
R
R
1a
1b
, R = 3,4-Cl2-Ph; R' = H
, R = H, R' = 3,4-Cl2-Ph
3a
2a,
2b
, R = 3,4-Cl2-Ph; R' = H
R = Ph; R' = H
, R = H; R' = Ph 3b, R = H; R' = 3,4- Cl2-Ph
Figure 1. Structure of antidepressant drugs.
NHMe
NHBoc
Ar
NHBoc
NBoc
H
O
Ar
1
4
6
5
Ar = 3,4-Cl2 phenyl
Also, (+)-tametraline (+)-2a is a norepinephrine–dopamine
Scheme 1. Retrosynthetic analysis of (+)-sertraline (1).
reuptake inhibitor,2 while (+)-indatraline (3b) is
a potent
psychoactive compound that acts as a monoamine reuptake
inhibitor and affects the dopamine and serotonin transporters
(see Scheme 1).3
Due to the potential biological importance of (+)-sertraline as
an anti-depressant drug, several synthetic routes were established
using various organic transformations. For example, Quallich et al.
have reported the first asymmetric synthesis of (+)-sertraline
employing asymmetric CBS reduction followed by SN2 substitution
as the key reactions.4 Industrially, it is produced via the classical
⇑
Corresponding author. Tel.: +91 20 25902565; fax: +91 20 25902676.
E-mail address: a.sudalai@ncl.res.in (A. Sudalai).
http://dx.doi.org/10.1016/j.tetlet.2016.01.085
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

1054
R. Kalshetti et al. / Tetrahedron Letters 57 (2016) 1053–1055
Table 1
R
Boc
N
Acid catalyzed intramolecular Friedel–Crafts’ cyclization of amino alkene 7a
NHBoc
NBoc
H
i
ii
O
NHMe
Ar
NHMe
NHMe
NMeBoc
acid
Ar
6
5
(-)-
(cis/trans = 1.3 : 1)
solvent
SO2Me
Ar
Ar
4, R = H
Ar
iii
1a/1b
9
8
7
7,
R = Me
NHMe
Ar
NHMe
Ar
iv
No. Acids (equiv)
Solvent t (°C) Time (h)
Product yieldb (%)
Ar = 3,4-dichlorophenyl
8
9
1a/1b
1
2
3
4
5
BF3ÁOEt2 (1.5)
CH2Cl2
25
25
80
80
70
10
8
12
12
12
62
—
—
—
57
—
—
—
(+)-1a
(-)-1b
(-)-1b·HCl
(74 % yield; 99% ee)
CH3SO3H (1.5) CH2Cl2
v
v
PPA (1.1)
H3PO4 (1.1)
TFA/AcOH
EDCd
EDCd
—
84 (dr = 1:3)c
(+)-1a·HCl
—
—
52 (dr = 1:3)c
(23% yield; 99% ee)
Complex reaction
mixture
Scheme 2. Reagents and conditions: (i) CH3CHO (5 equiv), L-proline (20 mol %),
a
b
c
CH3CN, 0 °C, 3 h, 55%; (ii) 3,4-Cl2C6H3CH2PPh3Br, n-BuLi or tBuOK, dry THF, 1.5 h,
0 °C, 60% with n-BuLi or 71% with tBuOK, 98% ee; (iii) MeI (2.5 equiv), NaH
(1.5 equiv), dry THF, 7 h, 0–10 °C, 94%; (iv) PPA (1 equiv), EDC, reflux, overnight,
84%, (dr = 1:3); (v) HCl gas, dry Et2O, ꢀ97%.
Amino alkene 7 (5 mmol) and solvent (15 mL).
Isolated yield after column chromatographic purification.
Determined from HPLC analysis.
d
Ethylene dichloride.
Results and discussion
resolution of racemic ( )-sertraline, which in turn could be synthe-
sized from 1-naphthol and 1,2-dichlorobenzene.5 During the last
two decades, a number of other strategies have been reported that
include (i) asymmetric arylation reaction achieved by either ring
opening of chiral cyclopropane using aryl lithium species6a or con-
Accordingly, the synthesis of (+)-sertraline 1 commenced from
N-Boc benzaldimine 6, which was subjected to L-proline catalyzed
Mannich reaction with excess CH3CHO (5 equiv) that gave b-amino
aldehyde 516 in 55% yield; >99% ee (Scheme 2). Aldehyde 5 was
then treated with Wittig phosphorus ylide,17 in the presence of
KOtBu, to afford amino olefin 4 in 71% yield as a mixture of cis
and trans isomers (1.3:1 ratio),18 which were difficult to separate
when attempted to purify through column chromatography.
N-methylation of carbamate in 4 was then carried out to give the
corresponding methyl amino compound 7 in 94% yield.
Intramolecular Friedel–Crafts’ cyclization of amino alkene 7
over a variety of acid catalysts was carried out and the results
are shown in Table 1. Under Lewis acid (BF3ÁOEt2) condition, 7
underwent deprotection to give secondary amine 8 (62% yield);
When Bronsted acid (CH3SO3H) was employed for cyclization, a
simple regioselective addition of CH3SO3H across olefin took place
to give sulfonate 9 (57% yield). However, when polyphosphoric
acid (PPA) was used at 80 °C, the intramolecular cyclization pro-
jugate addition of aryl Grignard reagent onto a,b-unsaturated chi-
ral oxazolidinone,6b (ii) Rh catalyzed allylic C–H insertion,7a and
asymmetric hydrogenation,7b (iii) stereoselective reduction of
ketimines,8 (iv) Pd-catalyzed allyl–aryl cross coupling reaction.9
Further, functionalized tetralin moiety in sertraline was con-
structed using inverse electron-demand Diels–Alder reaction as a
key step.10 Recently, Aggarwal and Jung et al. have employed the
lithiation/borylation–protodeboronation11 and stereoselective
amination of chiral benzylic ethers,12 respectively, as the key chiral
inducing steps for the synthesis of 1a. Quite recently, Santos
Fustero et al. have reported asymmetric allylation/ring closing
metathesis sequence for the synthesis of cyclic homoallylic ami-
nes; and this new methodology has been applied to the formal syn-
thesis of the antidepressant sertraline and the epimer
norsertraline.13 In 2000 Chandrasekhar and Reddy have synthe-
ceeded smoothly to give
a diastereomeric mixture 1a/1b
sized 1a using
D-phenyl glycine as chiral starting material and
(dr = 1:3) in a combined yield of 84%.19 Also, lower yield (52%) of
the product 1a/1b was obtained without affecting the diastere-
omeric ratio when H3PO4 was used. No reaction however took
place when TFA/acetic acid as Lewis acid was used.
finally they used the intramolecular Friedel Crafts cyclization of
benzylic alcohol in the key step.14 However, these reported meth-
ods employ either resolution techniques, which lead to loss of one
of the enantiomers, chiral starting materials or expensive reagents
involving longer reaction sequences, often resulting in poor pro-
duct selectivities. Hence, there is a need for an efficient and highly
enantioselective synthesis of 1-amino-4-aryltetralins (1–2) in a
lesser number of steps circumventing some of the disadvantages
associated with the reported methods. In the literature, no reports
are available for their synthesis using organocatalysis particularly
with proline as the catalyst, which is an inexpensive source of chi-
rality. In continuation of our research directed toward proline cat-
alyzed asymmetric synthesis of bioactive molecules,15 we wish to
report a short enantioselective synthesis of (+)-sertraline (1a)
and its C4 epimer CP-52002 (1b) using proline catalyzed Mannich
reaction and Friedel Crafts’ cyclization as the key steps (Scheme 2).
The retrosynthetic analysis of both (+)-sertraline and (+)-tame-
traline shows that imine 6 can be a common starting material. The
intramolecular Friedel–Crafts’ cyclization of olefin 4 can produce
(+)-sertraline (1a). The olefin 4 in turn can be derived from the
Wittig olefination of chiral b-amino aldehyde 5, which is readily
visualized to be obtained from proline catalyzed Mannich reaction
of N-Boc benzaldimine 6 with acetaldehyde.
Moreover using D-proline as the catalyst, antipode amino alde-
hyde (ent-5) was prepared and subsequently by following a similar
strategy the intramolecular Friedel–Crafts’ cyclization under PPA
conditions gave tametraline as mixture, which was converted to
its hydrochloride (97% yield; cis/trans = 1:1). Nevertheless, the
mixture of (+)-tametraline free base from its C4-epimer can be
separated by following the patented protocol2e via their
treatment with
(+)-tametraline-
D
-(À)-mandelic acid to provide the crystals of
D
-(À)-mandelate selectively.
Conclusion
In conclusion, a short and highly enantioselective method for
the synthesis of (+)-sertraline (+)-1a and (À)-CP-52002 (À)-1b
has been described. The strategy employs proline catalyzed Man-
nich reaction of acetaldehyde and intramolecular Friedel–Crafts
alkylation of amino olefins as the key steps, which are unprece-
dented till now for their synthesis. The overall yield of (+)-1 were
found to be 30%, respectively with 99% ee and maximum

R. Kalshetti et al. / Tetrahedron Letters 57 (2016) 1053–1055
1055
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Acknowledgments
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We sincerely thank CSIR, New Delhi, India (Indus MAGIC project
CSC-0123) and DST-SERB (no. SB/S1/OC-42/2014), for financial
support. R.K. and V.V. thank CSIR, New Delhi, India for fellowship.
R.K. and V.V. contributed equally to this work.
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Supplementary data
Supplementary data (1H and 13C NMR spectra for all com-
pounds, detailed experimental procedures) associated with this
article can be found, in the online version, at http://dx.doi.org/10.
1016/j.tetlet.2016.01.085.
16. Yang, J. W.; Chandler, C.; Stadler, M.; Kampen, D.; List, B. Nature 2008, 452, 453.
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18. Determined based on the 1H NMR and chiral HPLC analysis.
19. (+)-Sertraline (1a) HCl: Yield: 94%, colorless solid; mp: 240–243 °C, (lit.2c mp:
References and notes
25
25
243–245 °C); [
a
]
+46.8 (c 0.4, CHCl3); lit.2c
[a
]
+37.9 (c 2, MeOH); 1H NMR
D
D
(400 MHz, CDCl3): d 1.95–2.17 (m, 2H), 2.26 (br s, 1H), 2.28–2.43 (m, 1H), 2.57
(br s, 3H), 3.85–4.06 (m, 1H), 4.30 (br s, 1H), 6.86 (d, J = 7.6 Hz, 1H), 7.12–7.28
(m, 4H), 7.29–7.43 (m, 2H), 7.76 (d, J = 7.1 Hz, 1H), 9.87 (br s, 1H), 9.99 (br s,
1H); 13C NMR (100 MHz, CDCl3): d 23.1, 27.6, 29.6, 45.0, 56.3, 127.5, 128.6,
129.6, 129.7, 130.4, 130.5, 130.7, 130.9, 131.1, 132.6, 139.9, 145.1; MALDI-MS
(ESI, m/z): calculated for C17H16Cl2N (MÀ1)+ 304.07; found 304.04. (À)-CP-
52002 (1b) HCl: Yield: 92%, colorless solid; mp: 253–255 °C, (lit.2c mp: 257–
1. (a) Pinder, R. M.; Bropden, R. N.; Speight, T. M.; Avery, G. S. Drugs 1977, 13, 321;
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À40.3 (c 0.9, CHCl3); lit.2c
[a]
D
À39.2 (c 2, MeOH); 1H NMR
25
25
258 °C); [
a
]
D
(400 MHz, CDCl3 + DMSO-d6): d 1.74–1.92 (m, 1H), 2.02–2.17 (m, 1H), 2.19–
2.32 (m, 1H), 2.43–2.55 (m, 1H), 2.63 (t, J = 5.3 Hz, 3H), 4.24 (t, J = 6.2 Hz, 1H),
4.55 (br s, 1H), 6.71–6.94 (m, 2H), 7.10 (d, J = 2.0 Hz, 1H), 7.22–7.30 (m, 1H),
7.30–7.40 (m, 2H), 7.88 (d, J = 7.8 Hz, 1H), 9.78 (br s, 1H), 10.0 (br s, 1H); 13C
NMR (100 MHz, CDCl3 + DMSO-d6): d 21.6, 27.8, 28.9, 38.9, 39.1, 39.3, 39.7,
39.9, 40.1, 43.1, 55.2, 126.8, 127.5, 128.7, 128.9, 129.7, 129.8, 129.9, 130.0,
130.2, 131.7, 139.0, 145.7.