Enantioselective synthesis of (+)-(S,S)-reboxetine

Article abstract of DOI:10.1055/s-2006-944210

An efficient enantioselective synthesis leading directly to (+)-(S,S)-reboxetine has been described from commercially available trans-cinnammyl bromide using Sharpless asymmetric dihydroxylation as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944210

LETTER
1771
Enantioselective Synthesis of (+)-(S,S)-Reboxetine
E
nantioselecti
h
a
of (+)-(S,S
f
)-Reboxe
i
tine A. Siddiqui, Umesh C. Narkhede, Rajgopal J. Lahoti, Kumar V. Srinivasan*
Division of Organic Chemistry: Technology, National Chemical Laboratory, Dr. Homi Bhabha Road, Pune – 411 008, India
E-mail: kv.srinivasan@ncl.res.in
Received 7 March 2006
synthesis via asymmetric Sharpless epoxidation,10 and
from (S)-2-(hydroxymethyl)morpholine as a chiral start-
ing material.11 Synthesis of arylthiomethyl morpholine
analogues of reboxetine was also reported.12
Abstract: An efficient enantioselective synthesis leading directly
to (+)-(S,S)-reboxetine has been described from commercially
available trans-cinnammyl bromide using Sharpless asymmetric di-
hydroxylation as the key step.
Key words: dihydroxylation, hydrogenation, coupling, reboxetine, The Sharpless asymmetric dihydroxylation and subse-
trans-cinnamyl bromide
quent transformation of the diol formed can be envisioned
as powerful tools offering considerable opportunities for
synthetic manipulations.13 Herein we report a new and
enantioselective synthesis of (S,S)-reboxetine from com-
mercially available trans-cinnamyl bromide employing
Sharpless asymmetric dihydroxylation procedure as the
source of chirality. Our retrosynthetic strategy for the
synthesis of reboxetine is outlined in Scheme 1.
Depression is a common psychiatric disorder and one of
the most frequent illnesses in the world, affecting people
of all gender, ages and backgrounds. a-Aryloxybenzyl
derivatives of morpholine are an important class of com-
pounds owing to their impact on the central nervous sys-
tem,1 as well as potential treatments for depression and
attention deficit/hyperactivity disorder (ADHD). Rebox-
etine is a classical example of such a-aryloxybenzyl de-
rivatives having a mixture of (2R,3R)- and (2S,3S)-2[a-(2-
ethoxyphenoxy)phenylmethyl]morpholine, known to be a
potent selective norepinephrine reuptake inhibitor (NRI)
and widely studied for its pharmacological properties.2
O
OH
O
NH
O
NH
O
3
(S,S)-reboxetine
OEt
OEt
OH
O
Br
Br
O
OH
NH
NH
5
4
O
O
Scheme 1 Retrosynthetic analysis for (S,S)-reboxetine.
2
1
(R,R)-reboxetine
(S,S)-reboxetine
We envisioned that the morpholine intermediate 3 could
be prepared from the diol 4, which in turn would be ob-
tained from trans-cinnamyl bromide (5) by Sharpless
asymmetric dihydroxylation.
Figure 1 (S,S)-Reboxetine and (R,R)-reboxetine.
Reboxetine has been marketed as a mixture of two enan-
tiomers (S,S and R,R) under the brand name EdronaxTM
,
The synthesis of reboxetine was effected via the synthetic
route as shown in Scheme 2. The enantioselective syn-
thesis of (S,S)-reboxetine started with the commercially
available trans-cinnamyl bromide (5) on subjecting it to
asymmetric dihydroxylation under Sharpless condition
using osmium tetroxide and K3Fe(CN)6 as co-oxidant in
the presence of the chiral ligand (DHQ)2PHAL and
NaHCO3 as a buffering agent to afford (2R,3S)-1-bromo-
3-phenylpropane-2,3-diol (4) in 84% yield with 95% ee14
and [a]D25 –8.66 (c 1.16, EtOH).15 Nucleophilic displace-
ment of the bromo group with sodium azide furnished the
azido alcohol 6 in 80% yield. The azide group was then
converted to amine 7 using 10% Pd/C in 90% yield. The
free amine 7 was then treated with chloroacetyl chloride
to furnish amide 8 in 70% yield, which was readily
for the treatment of depressive illness in several European
countries.3 It has comparable efficacy to that of imi-
pramine, desipramine and fluoxetine, and has an im-
proved side-effect profile.4 However, (S,S)-reboxetine (1,
Figure 1) is approximately 24 times more potent than the
(R,R)-reboxetine (2),5 and presents the best affinity and
selectivity for norepinephrine transporter (NET).6 So far,
methods described in the literature to prepare reboxetine
involve separation of reboxetine enantiomers by optical
resolution,7 capillary electrophoresis8 or chiral HPLC,9
SYNLETT 2006, No. 11, pp 1771–1773
1
2
.0
7
.2
0
0
6
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-944210; Art ID: G08706ST
© Georg Thieme Verlag Stuttgart · New York

1772
S. A. Siddiqui et al.
LETTER
OH
In summary, we have synthesized (+)-(S,S)-reboxetine
enantioselectively from commercially available trans-
cinnamyl bromide by employing Sharpless asymmetric
dihydroxylation as key step with an overall yield of 21%
and nine linear steps.
Br
a
b
d
Br
OH
5
4
OH
OH
Acknowledgment
N3
c
NH2
OH
S.A.S. thanks CSIR, New Delhi, for the award of Senior Research
Fellowship.
OH
6
7
O
OH
OH HN
References and Notes
Cl
NH
f
e
g
(1) Melloni, P.; Della Torre, A.; Lazzari, E.; Mazzini, G.;
Alberto, B.; Matilde, B.; Ottorino, X.; Sante, R.; Alessandro,
R. C. Eur. J. Med. Chem. 1984, 19, 235.
O
OH
O
9
8
OH
(2) (a) Wong, E. H. F.; Sonders, M. S.; Amara, S. G.; Tinholt, P.
M.; Piercey, M. F. P.; Hoffmann, W. P.; Hyslop, D. K.;
Franklin, S.; Porsolt, R. D.; Bonsignori, A.; Carfagna, N.;
McArthur, R. A. Biol. Psychiatry 2000, 47, 818.
(b) Versiani, M.; Cassano, G.; Perugi, G.; Benedetti, A.;
Mastalli, L.; Nardi, A.; Savino, M. J. Clin. Psychiatry 2002,
63, 31. (c) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J.
K.; Brown, M. T.; Wong, E. H. F. CNS Drug Rev. 2004, 10,
23.
(3) Scates, A. C.; Doraiswamy, P. M. Ann. Pharmacotherapy
2000, 34, 1302.
(4) Berzewski, H.; Van Moffaert, M.; Gangiano, C. A. Eur.
Neuropsychopharmacol. 1997, 7, S37.
OH
NBoc
NH
O
O
10
3
Scheme 2 Synthesis of intermediate 10. Reagents and conditions:
a) (DHQ)2PHAL (1 mol%), OsO4 (0.1 mol%), K3Fe(CN)6 (3 equiv),
K2CO3 (3 equiv), NaHCO3 (3 equiv), MeSO2NH2 (1 equiv), H2O–t-
BuOH (1:1), 0 °C, 24 h (84%); b) NaN3 (3 equiv), DMF, 68 °C, 16 h
(80%); c) 10% Pd/C, H2 (1 atm), r.t., 12 h (90%); d) ClCOCH2Cl,
Et3N, CH2Cl2 at –10 °C to r.t., 6 h (70%); e) t-BuOK (2 equiv),
t-BuOH, r.t., 4 h (80%); f) Red-Al®, THF, 0 °C (83%); g) (Boc)2O,
NaOH, CH2Cl2–H20, 0 °C to r.t., 5 h (83%).
(5) Strolin, B. M.; Frigerio, E.; Tocchetti, P.; Brianceschi, G.;
Castelli, M. G.; Pellizzoni, C.; Dostert, P. Chirality 1995, 7,
285.
cyclized to compound 9 using t-BuOK in t-BuOH in 80%
yield. This cyclic amide was reduced using a solution of
Red-Al® at 0 °C, which gave the morpholine intermediate
3 in 83% yield. The reduction of amide was also tried by
other hydride reagent such as LAH in THF or Et2O but
this procedure gave only 25–30% of reduced compound.
The secondary amine was protected with tert-butoxy-
(6) Wong, E. H. F.; Ahmed, S.; Marshall, R. C.; McArthur, R.;
Taylor, D. P.; Birgerson, L.; Cetera, P. WO 2001001973,
2001; Chem. Abstr. 2001, 134, 105849.
(7) (a) Prabhakaran, J.; Majo, V. J.; Mann, J. J.; Kumar, J. S. D.
Chirality 2004, 163, 168. (b) Melloni, P.; Della Torre, A.;
Lazzari, E.; Mazzini, G.; Meroni, M. Tetrahedron 1985, 41,
1393.
(8) Raggi, M. A.; Mandrioli, R.; Sabbioni, C.; Parenti, C.;
Cannazza, G.; Fanali, S. Electrophoresis 2002, 23, 1870.
(9) Ohman, D.; Norlander, B.; Peterson, C.; Bengtsson, F. J.
Chromatogr., A. 2002, 947, 247.
(10) Harding, W. W.; Hodge, M.; Wang, Z.; Woolverton, W. L.;
Parrish, D.; Deschamps, J. R.; Prisinzano, T. E.
Tetrahedron: Asymmetry 2005, 16, 2249.
(11) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005,
7, 937.
(12) Boot, J.; Cases, M.; Clark, B. P.; Findlay, P.; Gallagher, P.
T.; Hayhurst, L.; Man, T.; Montalbetti, C.; Rathmell, R. E.;
Rudyk, H.; Walter, M. W.; Whatton, M.; Wood, V. Bioorg.
Med. Chem. Lett. 2005, 15, 699.
(13) (a) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1994, 94, 2483. (b) Kumar, P.; Naidu, S. V.;
Gupta, P. J. Org. Chem. 2005, 70, 2843. (c) Kumar, P.;
Naidu, S. V. J. Org. Chem. 2005, 70, 4209.
(14) For the measurement of ee, the diol 4 was converted into the
epoxide which was further converted into the corresponding
(S)-Mosher’s ester by reaction with (R)-(–)-a-methoxy-a-
(trifluoromethyl)phenyl acetyl chloride (CH2Cl2–DMAP,
Et3N, 0 °C, 4 h, 90% yield). The enantiomeric purity of the
diol 4 was estimated to be 95%.
25
carbonyl (Boc) group to afford 10 in 83% yield, [a]D
+33.4 (c 1.24, CHCl3) [lit.11 +34 (c 1.24, CHCl3)]. The
physical and spectroscopic data of 10 were in full agree-
ment with literature data.11
The synthesis of the active (+)-(S,S)-reboxetine enantio-
mer was completed as follows. The free hydroxyl group
was coupled with chromium complex of 2-ethoxy
fluorobenzene16 (Scheme 3) as per literature procedure11
followed by cleavage of Boc group by TFA to give the
25
target compound 1 in 88% yield with [a]D +12.81 (c
1.03, MeOH) [lit.11 +13 (c 1.03, MeOH)].
O
O
F
O
ref. 11
10
+
NH
Cr(CO)3
O
Scheme 3 Synthesis of (S,S)-reboxetine.
Synlett 2006, No. 11, 1771–1773 © Thieme Stuttgart · New York

LETTER
Enantioselective Synthesis of (+)-(S,S)-Reboxetine
1773
(15) (2R,3S)-1-Bromo-3-phenylpropane-2,3-diol (4).
To a mixture of K3Fe(CN)6 (25.05 g, 76.1 mmol), K2CO3
(10.5 g, 76.1 mmol), NaHCO3 (6.39 g, 76.1 mmol) and
(DHQ)2PHAL (197 mg, 1 mol%), in t-BuOH–H2O (1:1, 126
mL) cooled to 0 °C, was added OsO4 as a 0.1 M solution in
toluene (0.3 mol%) followed by methanesulfonamide (2.4 g,
25.3 mmol). After stirring for 30 min at 0 °C, the trans-
cinnamyl bromide (5 g, 25.3 mmol) was added in one
portion. The reaction mixture was stirred at 0 °C for 24 h and
then quenched with solid Na2SO3 (40 g). Stirring was
continued for 45 min and the solution was extracted with
EtOAc (3 × 50 mL). The combined organic phase was
washed with brine, dried over Na2SO4, and concentrated.
The residue was purified by silica gel column
chromatography (PE–EtOAc, 8:2) affording the diol 4 (4.9
g, 84%) as a colorless, syrupy liquid: [a]D25 –8.66 (c 1.16,
EtOH). IR (CHCl3): 3368, 3055, 1595, 1452, 1265, 1049,
738, 702 cm–1. 1H NMR (200 MHz, CDCl3): d = 3.11–3.19
(dd, J = 5.69 Hz, 1 H), 3.33–3.40 (dd, J = 3.92 Hz, 1 H),
4.25–4.38 (m, 1 H), 4.66–4.69 (d, J = 6.5 Hz, 1 H), 7.36–
7.38 (m, 5 H). 13C NMR (50 MHz, CDCl3): d = 35.0, 74.5,
75.1, 126.0, 126.4, 127.9, 128.3, 139.5, 139.8. Anal. Calcd
for C9H11BrO2: C, 46.78; H, 4.80; Br, 34.58. Found: C,
46.66; H, 4.67; Br, 34.36. LCMS: 231.07 [M+].
(16) (a) Kamikawa, K.; Watanabe, T.; Daimon, A.; Uemura, M.
Tetrahedron 2000, 56, 2325. (b) Mahaffy, C. A. L. J.
Organomet. Chem. 1984, 262, 33.
Synlett 2006, No. 11, 1771–1773 © Thieme Stuttgart · New York