Efficient enantioselective synthesis of sertraline, a potent antidepressant, via a novel intramolecular nucleophilic addition to imine

Article abstract of DOI:10.1021/ol990608g

(equation presented) An efficient enantioselective synthesis of sertraline, an antidepressant, utilizing anionic imine ring closure is described.

Full text of DOI:10.1021/ol990608g

ORGANIC
LETTERS
1999
Vol. 1, No. 2
293-294
Efficient Enantioselective Synthesis of
Sertraline, a Potent Antidepressant, via
a Novel Intramolecular Nucleophilic
Addition to Imine
Cheng-yi Chen* and Robert A. Reamer
Process Research Department, Merck Research Laboratories,
Rahway, New Jersey 07065
cheng_chen@merck.com
Received April 20, 1999
ABSTRACT
An efficient enantioselective synthesis of sertraline, an antidepressant, utilizing anionic imine ring closure is described.
Sertraline (1), a selective competitive inhibitor of synapto-
somal serotonin uptake, is an important pharmaceutical agent
for the treatment of depression.1 The commercial production
of sertraline relies on the resolution of the racemate with
D-mandelic acid.2 Two asymmetric syntheses for sertraline
were reported: both focus on the efficient preparation of
the sertraline penultimate, tetralone 2 (equation 1).3 Obvi-
ously, reductive amination is expected to give the desired
product as in the commercial production route. We herein
wish to disclose a different approach to the synthesis of
sertraline utilizing the metal-halide exchange of iodoimine
3 followed by an intramolecular, stereoselective anionic
addition to the imine moiety (eq 1).4
As illustrated in Scheme 1, the stereo center at C4 bearing
two aryl groups was established via a conjugated addition
of arylmagnesium bromide to the imide conjugate derived
from 3,4-dichlorocinnamic acid.5 Incorporation of a chiral
auxiliary such as phenyloxazolidinone allowed us to intro-
duce the stereocenter in a reliable manner. Thus, 2-bro-
mobenzaldehyde (4) was protected as its dimethyl acetal and
subsequently converted to arylmagnesium bromide 5. The
cinnamic imide 7 was prepared in 94% yield from the
corresponding acid 6 and (S)-2-phenyloxazolidine using Ho’s
procedure.6 Addition of arylmagnesium bromide 5 (2 equiv)
mediated by CuBr-SMe2 (0.2 equiv) to the cinnamic imide
7 produced imide 8 in 90% yield with complete diasterose-
lectivity.7 The imide was reduced to alcohol 9 (91% yield)
(1) Welch, W. M.; Kraska, A. R.; Sarges, R.; Coe, K. B. J. Med. Chem.
1984, 27, 1508. Coe, B. K.; Weissman, A.; Welch, W. M.; Broune, R. G.
J. Pharmacol. Exp. Ther. 1983, 226, 686.
(2) Recemate route to sertraline has been reviewed, see: William, M.;
Quallich, G. Chem. Ind. (London) 1990, 10, 315.
(3) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373. Quallich,
G. J.; Woodall, T. M. Tetrahedron 1992, 48, 10239.
(4) The intramolecular addition of the imine is not precedented in the
literature although the intermolecular version has been extensively studied.
For recent reviews, see: Bloch, R. Chem. ReV. 1998, 98, 1407. Enders, D.;
Reinhold, U. Tetrahedron: Asymmetry 1997, 8, 1895.
(5) For an excellent review on asymmetric conjugate addition reaction,
see: Rossiter, B. E.; Swingle, N. M. Chem. ReV. 1992, 92, 771.
(6) Ho, G.-J.; Mathre, D. J. J. Org. Chem. 1995, 60, 2271.
(7) Nicolas, E.; Russell, K. C.; Hruby, V. J. Vane, J. J. Org. Chem. 1993,
58, 766. Hruby, V. J.; Han, Y. Tetrahedron Lett. 1997, 38, 7317. Lin, J.;
Lian, S.; Hruby, V. J. Tetrahedron Lett. 1998, 39, 5373. Anderssen, P. G.;
Schink, H. E.; Osterlund, K. J. Org. Chem. 1998, 63, 8067.
10.1021/ol990608g CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/16/1999

Scheme 1
smoothly using NaBH4/THF-H2O.8 Treatment of alcohol 9
of the acetal moiety was also effected in the reaction to give
the iodoaldehyde 10 directly in 85% overall yield. The ring-
closure precusor, iodoimine 3, was formed quantitatively
from the aldehyde and methylamine (2.0 M in THF). Ring
closure was faciliated with t-BuLi (2.0 equiv) in THF-
toluene (1:1) to give sertraline in 69% yield as a single
diastereoisomer.10
with I2-PPh3-imidazole followed by in situ hydrolysis of
the acetal moiety using 2 N HCl led to the formation of
iodoaldehyde 10 (83%). Alternatively, the alcohol was
converted to its mesylate which was displaced by iodide
using Finkelstein’s conditions.9 Interestingly, deprotection
(8) Prashd, M.; Har, D.; Kim, H.-Y.; Repic, O. Tetrahedron Lett. 1998,
39, 7067.
(9) Finkelstein H. Ber. 1910, 43, 1528.
In summary, the asymmetric synthesis of sertraline was
accomplished in 45% overall yield in six steps from 3,4-
dichlorocinnamic acid. To the best of our knowledge, the
intramolecular anionic ring closure on imine is literature
unprecedented.4 The high efficiency of the stereoselective
ring closure is remarkable and could potentially be extended
to the synthesis of other chiral amines.
(10) The sertraline free base was fully characterized: 1H NMR (500.1
MHz, C6D6) δ 7.18 (br d, J ) 7.6, 1 H), 7.15 (obscured d, 1 H), 7.04 (m,
1 H), 6.99 (d, J ) 8.3, 1 H), 6.96 (m, 1 H), 6.67 (d, J ) 7.6, 1 H), 6.59
(dd, J ) 8.3, 2.4, 1 H), 3.56 (dd, J ) 9.5, 6.0, 1 H), 3.43 (t, J ) 4.4 1 H),
2.26 (s, 3 H), 1.99 (m 1 H), 1.70 (m, 1 H), 1.61 (m, 1 H), 1.45 (m, 1 H);
13C NMR (125.8 MHz, C6D6) δ 148.2, 140.1, 139.0, 132.6, 131.1, 130.6,
130.4, 130.0, 129.5, 128.5, 127.4, 126.7, 57.7, 45.5, 34.3, 28.4, 26.0. The
free base was converted to its hydrochloride salt: mp 241-244 °C (lit.1
mp 243-245 °C).
OL990608G
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Org. Lett., Vol. 1, No. 2, 1999