An expedient total synthesis of cis-(+)-sertraline from D-phenylglycine

Article abstract of DOI:10.1016/S0040-4020(99)01067-4

An efficient and practical total synthesis of cis-(+)-Sertraline is developed involving intramolecular Friedel-Crafts cyclization of an appropriately tailored D-phenylglycine. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(99)01067-4

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1111–1114
An Expedient Total Synthesis of cis-(ϩ)-Sertraline
from d-Phenylglycine
*
S. Chandrasekhar and M. Venkat Reddy
Indian Institute of Chemical Technology, Hyderabad 500007, India
Received 2 September 1999; revised 15 November 1999; accepted 2 December 1999
Abstract—An efficient and practical total synthesis of cis-(ϩ)-Sertraline is developed involving intramolecular Friedel–Crafts cyclization
of an appropriately tailored d-phenylglycine. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Depression is a serious and horrifying mental disorder and
only a few drugs have been discovered with minimal side
effects.1 The slow onset of clinical improvement with
these antidepressants has led to recent proposals that
compounds8 has prompted us to investigate the total synth-
esis of Sertraline. Described herein is an altogether different
approach starting from cheap and readily accessible
d-phenylglycine for the first time (Scheme 1).9
Scheme 1.
desensitization of norepinephrine transmission is involved
in the therapeutic activity of the antidepressant.2 Other
investigations have suggested a role for serotonin in
depression.3,4 The search for more selective serotonin
uptake blockers with reduced anticholinergic and cardio-
vascular liabilities of the tricyclic antidepressants has
resulted in newer agents.5 Sertraline 1 is one such clinical
compound that acts on the central nervous system as a selec-
tive serotonin reuptake inhibitor (SSRI).6 Sertraline 1,
which is marketed as Zoloft᭨, is one of the best selling
second generation antidepressants.7 The total synthesis of
Sertraline has attracted quite a few synthetic organic
chemistry laboratories, however, most efforts involve the
synthesis of a racemic version and later resolution into the
required cis-(ϩ) form. Chiral syntheses of Sertraline are
reported by Corey,9a and Lautens,9c involving asymmetric
catalysis. Our continued interest in the development of new
and efficient synthetic routes to clinically significant amino
Reaction of the methyl ester of N,N-dibenzylphenylglycine
310 with LiAlH4 in anhydrous THF for 3 h afforded the
glycinol derivative 4. A one-pot11 Swern oxidation and
Wittig reaction with ethyltriphenylphosporane in CH2Cl2
yielded the unsaturated ester 5 (72%). To circumvent the
poor yielding one step reduction of 5 to 7 with LiAlH4, a
high yielding two step protocol was adapted. Accordingly,
the unsaturation in 5 is reduced with Mg in MeOH followed
by reduction of the ester group with LiAlH4 (76%) (Scheme
2).
The dichlorophenyl group was introduced through a
Grignard reaction between in situ generated 3,4-dichloro-
phenylmagnesium bromide12 and 4-N,N-dibenzyl-4-phenyl-
n-butanal obtained upon oxidation of 7. The crucial intra-
molecular Friedel–Crafts cyclization was attempted with
various Lewis acids, however, AlCl3 turned out to be best
in yields and stereoselectivity (AlCl3, CH2Cl2, RT, 78%
yield from 2, ds 80%).13 The minor trans-isomer 8a was
eliminated by column chromatography using ethyl acetate/
hexane (2:98). The cis tricyclic intermediate 8 upon
debenzylation (Pd-(OH)2/H2),14 protection of the free
Keywords: Friedel–Crafts cyclization; serotonin; antidepressants.
* Corresponding author. Tel.: ϩ91-40-7170512; fax: ϩ91-40-7173387;
e-mail: srivaric@iict.ap.nic.in
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(99)01067-4

1112
S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 1111–1114
Scheme 2.
amino group with (Boc)2O and methylation (NaH, MeI)
followed by Boc removal furnished uneventfully the desired
targeted compound (ϩ)-1 whose data was comparable with
literature.9
ethyl acetate/hexane) 0.5; [a]2D5ˆϪ116.7 (c 2, CHCl3); IR
1
(neat): 3500, 3030, 1600, 1350 cmϪ1; H NMR (200 MHz,
CDCl3); d 7.45–7.25 (15H, m, 3×Ph–CH2N) 4.15 (1H, t,
Jˆ10.6 Hz, CH–NBn2), 3.95 (2H,
d
AB system,
Jˆ13.8 Hz, N–CH2–Ph), 3.6 (2H, dd, Jˆ4.2, 10.6 Hz,
In conclusion, a practical and enantiopure synthesis of cis-
(ϩ)-Sertraline is described starting from chiral pool
d-phenylglycine for the first time.15
CH2–OH), 3.15 (2H,
d
AB system, Jˆ13.8 Hz,
N–CH2Ph); EI MS m/z: 299[MϪ18]ϩ, 286, 91.
(4S)-Ethyl-4-N,N-(Dibenzyl)-4-amino-4-phenyl-(E)-2-
butenoate (5). To a stirred solution of oxalyl chloride
(2.14 g, 17 mmol) in dichloromethane (15 mL) at Ϫ78ЊC
under nitrogen atmosphere was added DMSO (1.6 mL,
18.9 mmol) dropwise. After stirring for 30 min a solution
of the amino alcohol 4 (3 g, 9.46 mmol) in dichloromethane
(25 mL) was added over 15 min. The mixture was warmed
to Ϫ45ЊC and stirring was continued for 1 h at this tempera-
ture, then triethylamine (4.8 g, 47 mmol) was added. The
reaction mixture was brought to 0ЊC and maintained
for 15 min, then ethyltriphenyl phosphorane (3.9 g,
11.3 mmol) in benzene (15 mL) was added and the resulting
solution was stirred for 15 h at room temperature. The
solvent was removed under vacuum, the residue was washed
with water, brine solution and dried over Na2SO4. The
residue was purified by column chromatography (ethyl
acetate/hexane 4:96) to yield the amino a,bunsaturated
ester 5 (2.62 g, 72%) as a pale yellow viscous oil. [Anal.
Calcd for C26H27NO2: C, 81.01; H, 7.06; N, 3.63. Found: C,
81.05; H, 7.10; N, 3.53]; Rf (15% ethyl acetate/hexane)
0.75; [a]2D5ˆϩ0.80 (c 2, CHCl3); IR (neat): 3030, 1700,
Experimental
General methods
Crude products were purified by column chromatography on
Silica gel (60–120 mesh). 1H NMR were obtained in CDCl3
at 200 MHz. Chemical shifts are given in ppm, with respect
to internal TMS, J values are quoted in Hz. Infrared spectra
were obtained neat, only the most significant absorptions in
cmϪ1 are indicated. DMSO, triethylamine and CH2Cl2 were
distilled from CaH2 and stored over molecular sieves. Ben-
zene and THF were dried over sodium, benzophenone. All
reactions were carried out under nitrogen atmosphere using
dry glassware.
(2S)-N,N-(Dibenzyl)-2-amino-2-phenyl-1-ethanol (4). A
solution of ester 3 (15 g, 43 mmol) in THF (20 mL) was
added to a suspension of LiAlH4 (2 g, 52 mmol) in dry
THF (100 mL) at 0ЊC. The suspension was stirred for
30 min at the same temperature and at room temperature
overnight. The reaction mixture was then cooled to 0ЊC
and the excess reagent was quenched by using 15% aqueous
NaOH solution (4 mL) and (water 6 mL). After stirring for
30 min, the solution was filtered through a pad of silica and
Na2SO4 and the filtrate was concentrated under vacuum.
The oily residue was purified by column chromatography
(ethyl acetate/hexane 1:4) to yield 4 (11 g, 80%) as a color-
less viscous oil. [Anal. Calcd for C22H23NO: C, 83.24; H,
7.30; N, 4.41. Found: C, 83.40; H, 7.25; N, 4.50]; Rf (20%
1
1600, 1350 cmϪ1; H NMR (200 MHz, CDCl3): d 7.45–
7.2 (16H, m, 3×Ph–CHyC), 6.0 (1H, d, Jˆ16.2 Hz,
CHyCH), 4.45 (1H, d, Jˆ8.5 Hz, CH–NBn2), 4.25 (2H,
q, Jˆ7.5 Hz, O–CH2), 3.62 (4H, s, 2×CH2Ph), 1.38 (3H,
t, Jˆ7.5 Hz, CH3CH2); EI MS m/z: 294 [MϪ91]ϩ, 131, 91.
(4S)-Methyl-N,N-(Dibenzyl)-4-amino-4-phenylbutanoate
(6). To a stirred solution of ester 5 (2.0 g, 5.1 mmol) in
dry methanol (50 mL) was added magnesium turnings
(0.375 g, 15.5 mmol) and stirred for 4 h under nitrogen

S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 1111–1114
1113
atmosphere. The total reaction was taken into water (25 mL)
and to this was added dilute acetic acid and stirred vigor-
ously to get a clear solution. The acidic solution was treated
with NH4OH solution to adjust pH to 8.5 and extracted with
ether (50 mL). The total extracts were washed with water
(25 mL) saturated NaHCO3 solution (20 mL) and dried over
Na2SO4. The solvent was removed under vacuum to get the
crude oily compound and was purified by column chroma-
tography (ethyl acetate/hexane 5:95) to afford the pure ester
6 (1.6 g, 83%) as a yellow viscous oil. [Anal. Calcd for
C25H27NO2: C, 80.40; H, 7.29; N, 3.75. Found: C, 80.52;
H, 7.40; N, 3.92]; Rf (20% ethyl acetate/hexane) 0.6; [a]D25
Ϫ41.4 (c 1, CHCl3); IR (neat): 2990, 1740, 1600,
2:8) to yield 2 (1.0 g, 83%) as a diastereomeric mixture.
[Anal. Calcd for C30H29Cl2NO: C, 73.47; H, 5.96; N, 2.86;
Cl, 14.46 Found: C, 73.50; H, 5.89; N, 2.85; Cl, 14.50]; Rf
(25% ethyl acetate/hexane) 0.4; IR (neat): 3400, 2990, 1600,
1
1350, 825 cmϪ1; H NMR (200 MHz, CDCl3); d 7.4–6.95
(18H, m, 3×Ph, Ph–Cl2), 4.5 (1H, m, CH–PhCl2), 3.75 (2H
dd, AB system, Jˆ6.5, 13.7 Hz, CH2Ph), 3.65 (1H, m,
CH–NBn2), 3.05 (2H, dd, AB system Jˆ6.5 13.7 Hz,
N–CH2Ph), 1.9–1.5 (4H, m, CH2–CH2); HRMS (FAB)
Calcd for C30H29Cl2NO; 490.1691. Found 490.1704.
(1S,4S)-N,N-(Dibenzyl)-4-(3,4-dicholrophenyl)-1,2,3,4-
tetrahydro-1-napthalenamine (8). Compound 2 (0.5 g,
1 mmol) was dissolved in dry dichloromethane (10 mL) to
obtain a clear solution. To this was added a solution of
aluminium chloride (0.1 g, 0.2 mmol) in dry dichloro-
methane (5 mL) and the resulting solution was stirred for
1 h at room temperature, and washed with water (20 mL)
and brine (15 mL) dried over Na2SO4. The solvent was
removed under vacuum. The residue was purified by column
chromatography (ethyl acetate/hexane 2:98) to give the aryl
compounds 8 and 8a, the major being syn 8 (0.375 g, 78%),
as a yellow viscous oil [Anal. Calcd for 8; C30H27Cl2N; C,
76.27; H, 5.76; N, 2.96; Cl, 15.01 Found: C, 76.40; H, 5.65;
N, 2.85; Cl, 15.05]; Rf (15% ethyl acetate/hexane) 0.7;
1350 cmϪ1 1H NMR (200 MHz, CDCl3); d 7.45–7.15
;
(15H, m, 3×Ph), 3.85 (2H, d AB system, Jˆ13.8 Hz,
N–CH2Ph), 3.70 (1H, t, Jˆ7.5 Hz, CH–NBn2), 3.62 (3H,
s, OMe), 3.12 (2H, d AB system, Jˆ13.8 Hz, N–CH2Ph),
2.45–2.30 (2H, m, CH2), 2.15–2.0 (2H, m, CH2–CHN); EI
MS m/z: 373 [M]ϩ.
(4S)-N,N-(Dibenzyl)-4-amino-4-phenyl-1-butanol (7). A
solution of ester 6 (1.5 g, 4 mmol) in THF (20 mL) was
added to a suspension of LiAlH4 (0.25 g, 6.1 mmol) in dry
THF (50 mL) at 0ЊC and stirred for 30 min at the same
temperature and at room temperature for overnight. The
reaction mixture was cooled to 0ЊC and excess reagent
was quenched by careful addition of 15% aqueous NaOH
solution (0.5 mL) and (water 1 mL). After stirring for
30 min the solution was filtered through a pad of silica
and Na2SO4 and filtrate was concentrated under vacuum.
The crude product was purified by column chromatography
(ethyl acetate/hexane 2:8) to afford the pure alcohol 7
(1.05 g, 76%) as a semisolid. [Anal. Calcd for C24H27NO:
C, 83.44; H, 7.88; N, 4.05. Found: C, 83.53; H, 7.90; N,
4.07]; Rf (30% ethyl acetate/hexane) 0.35; [a]2D5ˆϪ49.20 (c
[a]2D5ˆϪ17.60 (c 1, CHCl3); IR: 2990, 1600, 1350, cmϪ1
;
1H NMR (200 MHz, CDCl3); d 7.4–7.0 (15H, m, 3×Ph,
Ph–Cl2), 6.85 (1H, dd, Jˆ8, 2 Hz, Ph–Cl2), 6.7 (1H, d,
Jˆ8 Hz, Ph–Cl2), 4.45–4.0 (2H, m, CH–NBn2,CH–Ph–
Cl2), 3.8 (2H, d, AB system, Jˆ13.7 Hz, N–CH2–Ph),
3.45 (2H, d, AB system, Jˆ13.7 Hz, N–CH2–Ph), 2.25–
2.15 (2H, m, CH2–CHN), 1.9–1.6 (2H, m, CH2–CH–Ph);
HRMS (FAB): Calcd for 472.1443; Found 472.1412.
cis-(1S,4S)-N-(tert-Butoxycarbonyl)-4-(3,4-dichlorophenyl)-
1,2,3,4-tetrahydro-1-napthalenamine (9). Solution of
compound 8 (0.25 g, 0.53 mmol) in methanol (10 mL)
was hydrogenated in presence of Pd(OH)2 under hydrogen
atmosphere. After stirring the mixture vigorously for 3 h,
(Boc)2O (0.138 g, 0.63 mmol) was added to the reaction
mixture and stirred for 3 h. The reaction mass was filtered
and the filtrate was evaporated under vacuum to get the
crude product which was purified by column chroma-
tography (ethyl acetate/hexane 2:8) to afford a white solid
9 (0.162 g, 78%). mp 136–137ЊC; [Anal. Calcd for
C21H23Cl2NO2 C, 64.29; H, 5.91; N, 3.57; Cl, 18.07.
Found: C, 64.35; H, 6.00; N, 3.50; Cl, 18.10]; Rf (25%
ethyl acetate/hexane) 0.5; [a]2D5ˆϪ1.80 (c 1, CHCl3); IR
1, CHCl3); IR (neat): 3500, 3030, 2990, 1600, 1350 cmϪ1
;
1H NMR (200 MHz, CDCl3); d 7.40–7.40 (15H, m, 3×Ph),
3.8 (2H, d AB system, Jˆ13.8 Hz, N–CH2Ph), 3.7 (1H, t,
Jˆ5.9 Hz, CH–NBn2), 3.55 (2H, t, Jˆ5.9 Hz, CH2–OH),
3.15 (2H, d AB system, Jˆ13.8 Hz, N–CH2–Ph), 1.95–1.5
(4H, m, CH2–CH2); HRMS (FAB) Calcd for C24H27NO
346.2129; Found 346.2126.
(1S,R4S)-N,N-(Dibenzyl)-4-amino-1-(3,4-dicholrophenyl)-
4-phenyl-1-butanol (2). To a stirred solution of 7 (1.0 g,
2.8 mmol) in dichloromethane (25 mL) was added pyri-
dinium dichromate (2.1 g, 5.7 mmol) in portions with
stirring at room temperature, after 5 h the reaction mixture
was diluted with ether (50 mL) and filtered through a short
silica gel column. The column was washed with ether
(50 mL) and the filtrates were concentrated at low tempera-
ture to afford the aldehyde (0.85 g, 2.4 mmol). The aldehyde
was added to a solution of 3,4 dichloro phenylmagnesium
bromide {The solution of 3,4-dichloro phenylmagnesium
bromide was prepared from 3,4-dichlorobromo benzene
(1.1 g, 4.9 mmol and magnesium (0.209 g, 8.7 mmol) in
THF (20 mL)}. The reaction mixture was stirred for 5 h,
quenched with saturated ammonium chloride solution
(15 mL), and compound was extracted with ether (50 mL).
The combined extracts were washed with water (25 mL)
brine (25 mL) and dried over Na2SO4. The solvent was
removed under vacuum to get the residue, which was
purified by column chromatography (ethyl acetate/hexane
1
(KBr): 3300, 1697, 1350, 1160 cmϪ1; H NMR (200 MHz,
CDCl3): d 7.4–7.1 (5H, m, Ph–PhCl2), 6.9 (1H, dd, Jˆ8,
2 Hz, Ph–Cl2), 6.8 (1H, d, Jˆ6.8 Hz, Ph–Cl2), 4.9 (1H, bs,
NH Boc), 4.8 (1H, distorted t, Jˆ2.5 Hz, CH–NH), 4.1 (1H,
br t, Jˆ6.8 Hz, CH–PhCl2), 2.25–2.1 (2H, m, CH2CHN),
2.0–1.80 (2H, m, CH2–CHPh), 1.50 (9H, s, O–C– (CH3)3),
EI MS m/z 334 (MϪ57)ϩ, 290, 249, 77.
cis-(1S,4S)-N-(tert-Butoxycarbonyl)-N-methyl-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-1-napthalenamine
(10). A solution of compound 9 (0.15 g, 0.38 mmol) in THF
(2 mL) was added dropwise to a well-stirred suspension of
oil free NaH (0.02 g, 76 mmol) in THF (10 mL). After
30 min, methyl iodide (0.136 g, 0.95 mmol) was added
and the reaction mixture was stirred for 6 h. The reaction

1114
S. Chandrasekhar, M. Venkat Reddy / Tetrahedron 56 (2000) 1111–1114
2. Mobley, P. L.; Sulser, F. Antidepressants. Neurochemical
Behavioural and Clinical Perspectives; Enna, S. J., Malick, J. B.,
Richelson, S. E. Eds.; Raven Press: New York, 1981, pp 31–51.
3. Coppen, A.; Shaw, D. M.; Herzberg, B.; Maggs, R. Lancet
1967, 1178.
4. Carlsson, A.; Corrodi, H.; Fuxe, K.; Hokfelt, T. Eur. J.
Pharmocal. 1969, 5, 357.
5. Weleh, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med.
Chem 1984, 27, 1508 (references cited therein).
mass was quenched with saturated NH4Cl solution (5 mL)
and the solution was extracted with ether (25 mL). The
organic layers was washed with water (15 mL), brine
(10 mL) and dried over Na2SO4. Removal of volatiles
gave the crude compound, which was purified by column
chromatography (ethyl acetate/hexane, 1:9) to give the
compound 10 (0.13 g, 84%) as a semi solid. [Anal. Calcd
for C22H25Cl2NO2; C, 65.03; H, 6.20; N, 3.45; Cl, 17.45.
Found. C, 65.05; H, 6.30; N, 3.40; Cl, 17.60.]; Rf (15% ethyl
acetate/hexane) 0.6; [a]2D5ˆϪ19.0 (c 1, CHCl3); IR (neat):
1693, 1600, 1350, 1160 cmϪ1; 1H NMR (200 MHz, CDCl3):
d 7.4–7.05 (5H, m, Ph, PhCl2). 6.9 (1H, br d, Jˆ8 Hz,
Ph–Cl2), 6.8 (1H, d, Jˆ7 Hz, Ph–Cl2) 5.4 (1H, br t,
Jˆ4.8 Hz, CH–NH), 4.15 (1H, distorted t, CH–PhCl2),
2.65 (3H, s, N–CH3), 2.4–2.2 (2H, m, CH2–CHN), 2.05–
1.9 (2H, m, CH2–CHPh), 1.5 (9H, s, O–C–(CH3)3); FAB
MS m/z 348 (MϪ57)ϩ, 275, 130, 77.
6. Coe, K. B.; Weisman, A.; Weleh, W. M.; Broune, R. G.
J. Pharmoacol. Exp. Ther. 1983, 226, 686.
7. Sertraline is marketed as Zoloft᭨ by Pfizer laboratories.
8. (a) Chandrasekhar, S.; Mohapatra, S. Tetrahedron Lett. 1998,
39, 6415. (b) Chandrasekhar, S.; Mohapatra, S.; Yadav, J. S. Tetra-
hedron 1999, 55, 4763.
9. (a) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373.
(b) Quallich, G. J.; Woodall, T. M. Tetrahedron 1992, 48, 10 239.
(c) Lautens, M.; Rovis, T. J. Org. Chem. 1997, 62, 5246. (d) For a
review of earlier synthetic routes to sertraline see, Williams, M.;
Quallich, G. Chem. Ind. (London). 1990, 10, 315. (e) Davies, H. M.
L.; Douglas, G.; Stafford; Hansen, T. Org. Lett. 1999, 1 (2) 233–
236. (f) Cheng-yi Chen; Reamer, R. A. Org. Lett. 1999, 1 (2) 293–
294. (g) See Ref. 5.
10. Beaulieu, P. L.; Wernic, D. J. Org. Chem. 1996, 61, 3635.
11. (a) Jurczak, J.; GoleBiowski, A. Chem. Soc. Rev. 1989, 89,
149. (b) Hensel, M. J.; Fuchs, P. L. Synth. Commun. 1986, 16,
1285. (c) Davies, S. B.; McKervey, M. A. Tetrahedron Lett.
1999, 40, 1229.
cis-(1S,4S)-N-Methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetra-
hydro napthalenamine hydrochloride (1). The compound
10 (0.1 g, 0.3 mmol) was dissolved in dry dichloromethane
(10 mL) to obtain a clear solution. To this was added a cold
solution of trifluoroacetic acid (0.068 g, 0.6 mmol) in dry
dichloromethane (5 mL). The resulting solution was stirred
for 1 h at room temperature. The reaction mixture was
poured into cold water (10 mL), washed with brine and
dried over Na2SO4. Removal of the volatiles gave
compound 1 (0.064 g, 85%). The compound 1 was dissolved
in dry ether and dry HCl gas was passed through the solution
to form the hydrochloride salt of compound 1 [a]2D5ˆϩ37.9
(c 2, CH3OH). (Lit.9 [a]2D5ˆϩ37.9) mp 242–244ЊC (lit.9
243–245ЊC) The material was found to be identical in all
other aspects to that reported earlier.9
12. Weleh, W. M.; Kraska, A. R.; Sarges, R.; Ceo, K. B. J. Med.
Chem. 1984, 27, 1508.
13. (a) Khallaf; Roberts, R. M. J. Org. Chem. 1972, 37, 4227. (b)
Khallaf; Roberts, R. M. J. Org. Chem. 1969, 34, 3571. (c) The
required 1,4 syn diastereomer was theoretically found to be a
favored one based on MM3 and UFF energy minimization studies.
This is further confirmed by converting 8 to final compound and
comparing the spectral data.
Acknowledgements
One of us (M.V.R.) thanks CSIR, New Delhi, for financial
assistance.
14. (a) Laib, T.; Chastanet, J.; Zhu, J. J. Org. Chem. 1998, 63,
1709. (b) Prugh, J. D.; Rooney, C. S.; Deana, A. A.; Ramjit, H. G.
Tetrahedron Lett. 1985, 26, 2947.
15. IICT Communication no. 4270.
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