Asymmetric reduction of prochiral ketones using in situ generated oxazaborolidine derived from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol. An efficient synthesis of enantiopure (R)-tomoxetine

Article abstract of DOI:10.1016/j.tetlet.2004.11.052

In this work, we report our results on the asymmetric reduction of prochiral aromatic and aliphatic ketones 3, 5-8 catalyzed by the novel in situ generated oxazaborolidine 2 derived from (1S,2S,3R,4R)-3-amino-7,7- dimethoxybornan-2-ol (1) and BH₃?Me₂S. This methodology was applied to the synthesis of the anti-depressant drug (R)-tomoxetine in three steps and 47% overall yield from 3-chloropropiophenone (3h). Catalytic asymmetric reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalyst 2 prepared in situ from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol (1). The optically active secondary alcohols were generally obtained in moderate to high enantiomeric excesses (ee 43-95%) and good yields (75-94%), except for ketones bearing electron-withdrawing groups. The methodology was applied to the synthesis of enantiopure (R)-tomoxetine, a potent anti-depressant drug.

Full text of DOI:10.1016/j.tetlet.2004.11.052

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 495–498
Asymmetric reduction of prochiral ketones using
in situ generated oxazaborolidine derived from
(1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol.
An efficient synthesis of enantiopure (R)-tomoxetine
a
Alexandre A. M. Lapis, Angelo de Fatima, Jose E. D. Martins,
a
b
^
´
´
Valentim E. U. Costab,* and Ronaldo A. Pillia,*
a
´
Instituto de Quımica, UNICAMP, PO Box 6154, 13084-971, Campinas, SP, Brazil
´
Instituto de Quımica, UFRGS, Av. Bento Gonc¸alves, 9500, 91501-970, Porto Alegre, RS, Brazil
b
Received 24 July 2004; revised 6 November 2004; accepted 9 November 2004
Available online 7 December 2004
Abstract—Catalytic asymmetric reduction of prochiral ketones was examined in the presence of chiral oxazaborolidine catalyst 2
prepared in situ from (1S,2S,3R,4R)-3-amino-7,7-dimethoxynorbornan-2-ol (1). The optically active secondary alcohols were gen-
erally obtained in moderate to high enantiomeric excesses (ee 43–95%) and good yields (75–94%), except for ketones bearing elec-
tron-withdrawing groups. The methodology was applied to the synthesis of enantiopure (R)-tomoxetine, a potent anti-depressant
drug.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Asymmetric reduction of prochiral ketones to obtain the
corresponding optically active alcohols is among the
most fundamental subjects in modern organic chemis-
try.1 The discovery of oxazaborolidines as catalytic re-
agents for the enantioselective reduction of prochiral
ketones has been an important milestone in organic
chemistry. This methodology was pioneered by Itsuno
et al.2 and developed further by Corey et al.3 who have
introduced the CBS oxazaborolidines obtained from
a,a-diphenylprolinol and boranes or boronic acids. Parti-
cularly, the B–Me oxazaborolidines prepared from
methylboronic acid rank among the most general and
efficient catalytic system for the enantioselective reduc-
tion of prochiral aryl and alkyl ketones.4 Occasionally,
difficulties have been reported for the preparation of
the B–H oxazaborolidines5 and from the several differ-
ent experimental protocols reported for the preparation
of the catalyst, the most convenient one appears to be
stirring the chiral aminoalcohol with excess of
BH3ÆMe2S at room temperature.6 Additionally, a great
number of studies have been reported over the last dec-
ade aiming to develop stable, efficient and wide scope
CBS catalysts derived from aminoalcohols prepared
from naturally and non-naturally occurring compounds.7
In a previous work, we reported the enantioselective
synthesis of a new chiral norbornane-derived aminoal-
cohol 1 in both enantiomeric forms.8 Herein, we report
the use of chiral exo-aminoalcohol (1S,2S,3R,4R)-1 for
the in situ generation of the corresponding oxazaboroli-
dine 2 (Scheme 1), evaluation of its catalytic ability in
OMe
OMe
MeO
MeO
H
N
BH3.Me2S
THF
NH2
OH
O
BH
OH
1
2
O
catalyst
2
BH3.Me2S, THF
2h, 25 oC
Keywords: Oxazaborolidine; 3-Amino-7,7-dimethoxynorbornan-2-ol;
Asymmetric reduction; Tomoxetine.
3a
4a
*
Corresponding authors. Tel.: +55 1937883083; fax: +55
1937883023; e-mail: pilli@iqm.unicamp.br
Scheme 1.
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.052

496
A. A. M. Lapis et al. / Tetrahedron Letters 46 (2005) 495–498
the enantioselective reduction of aromatic and aliphatic
ketones and application in the asymmetric synthesis of
the anti-depressant (R)-tomoxetine (also known as atom-
oxetine, brand name Stratteraꢁ), which is twice more
potent than its racemate and nine times more potent
than its (S)-enantiomer9,10 and has been recently ap-
proved as a non-stimulant drug for the treatment of
attention deficit hyperactivity disorder (ADHD) in both
children and adults.11
OH
R2
O
BH3.Me2S, THF, rt, 2h
R2
R1
R1
2 (5 mol%)
3a-j
4a-j
O
O
O
O
O
O
( )n
7a: n=0
7b: n=1
5
6
8
In order to optimize the catalytic system, we varied the
reaction temperature and the amount of catalyst in the
reduction of acetophenone (3a). In our hands, oxaza-
borolidine 2 was conveniently prepared in situ after stir-
ring exo-aminoalcohol 1 at 45ꢂC with excess of
BH3ÆMe2S (Scheme 1).12 The catalyst (10mol%) was
immediately employed at the same temperature in the
reduction of ketone 3a, which was added over 20min
to the solution of the catalyst via syringe pump. (S)-
sec-Phenethyl alcohol (4a) was obtained in good yield
but moderate enantiomeric excess (63%, Table 1, entry
1). Reduction of the amount of catalyst to 5mol% led
to a moderate increase in the enantiomeric excess (Table
1, entry 2). Based on some previously reported results,
which pointed out the beneficial effect of lowering the
reaction temperature in the enantiomeric excess,13 the
oxazaborolidine catalyst 2 was prepared at 25ꢂC and
the reduction of acetophenone (3a) was carried out at
the same temperature with 10mol% of catalyst load to
provide (S)-sec-phenethyl alcohol (4a) in 88% ee (Table
1, entry 3). As observed before, lowering the catalyst
amount to 5mol% increased the enantiomeric excess
to 92% (Table 1, entry 4). Further decrease in the reac-
tion temperature to 0ꢂC led to a significant reduction of
the enantiomeric excess (61%). Therefore, the best
experimental conditions found for the asymmetric
reduction of acetophenone (3a) required the use of
5mol% of catalyst 2, prepared by stirring exo-amino-
alcohol 1 with BH3ÆMe2S in THF at 25ꢂC, followed by
dropwise addition (20min) of the substrate via syringe
pump at the same temperature.
Scheme 2.
Table 2. Enantioselective reduction of prochiral aromatic and ali-
phatic ketones 3a–j and 5–8 with catalyst 2
Entry Ketone R1
R2
Ee (%)a Conf.b Yieldd
(%)
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
Br
CH3
CH3
CH3
CH3
92
93
91
7
Sc
Sc
S
S
S
R
S
S
S
S
S
S
S
S
S
89
94
88
93
80e
94
91
89
85
85
75
68
84
87
90
2
3
CH3
CN
4
5
OCH3 CH3
H
78
95
60
6
CH2Br
CH2CH3
7
H
8
H
CH2CH2Cl 82
9
Cl
F
CH2CH3
CH2CH3
76
76
77
49
43
57
4
10
11
12
13
14
15
3j
5
—
—
—
—
—
—
—
—
—
—
6
7a
7b
8
a Enantiomeric excesses were determined by capillary chiral GC.
b Absolute configurations determined by comparison of optical rota-
tion with those described in the literature.
c Absolute configurations determined by comparison retention time by
chiral GC analyses (Chirasil-DEX CB 25m · 0.32mm · 0.25lm).
d Chemical yields of isolated products.
e 8% of starting material recovered.
by the increase in the reaction rate of the uncatalyzed
reduction reaction. While 2-bromoacetophenone (3f)
provided the corresponding alcohol with good enantio-
meric excess (95%) (Table 2, entry 6), the enantioselec-
tive reduction of propiophenone proceeded with lower
enantioselectivity (Table 2, entry 7).
After establishing the best reaction conditions for the
reduction of acetophenone (3a) with our catalytic sys-
tem,14 we evaluated its scope in the reduction of ali-
phatic and aromatic ketones (Scheme 2). The results
are summarized in Table 2. Good enantiomeric excess
were observed for para substituted acetophenones, ex-
cept for 3d bearing the electron-withdrawing cyano sub-
stituent (Table 2, entries 1–5), which may be rationalized
Halogen substitution on the alkyl side chain (Table 2,
entry 8) or in the aromatic ring (Table 2, entries 9 and
10) of propiophenone provided moderate enantiomeric
excesses. Steric bulkiness around the prochiral carbonyl
group plays an important role in the enantiomeric dis-
crimination as revealed by the low enantiomeric excess
observed in the reduction of 4-methyl-2-pentanone (6)
(Table 2, entry 12) when compared to pinacolone (5)
(Table 2, entry 11). The catalytic asymmetric reduction
of 2-indanone (7a) and a-tetralone (7b) (Table 2, entries
13 and 14) provided low enantiomeric excesses. The
reduction of 3-keto-4,4-dimethylfuranone (8) provided
(S)-pantolactone in low enantiomeric excess (Table 2,
entry 15), which may be the result of competitive reduc-
tion via a uncatalyzed pathway, which leads to the race-
Table 1. Enantioselective reduction of acetophenone (3a) with catalyst
2
Entry
Catalyst (mol%)
T (ꢂC)
Yield (%)a
Ee (%)b
1
2
3
4
10
5
45
45
25
25
84
87
86
89
63
73
88
92
10
5
a Chemical yields (two runs) of isolated products after column
chromatography.
b Enantiomeric excesses were determined by capillary chiral GC with
Chirasil-DEX CB (25m · 0.32mm · 0.25lm).

A. A. M. Lapis et al. / Tetrahedron Letters 46 (2005) 495–498
497
mic alcohol due to the electron-withdrawing nature of
the carboalkoxy group in 8.
syn-coplanar arrangement of the carbonyl group and the
B–H bond allows reduction to take place via a chair-like
transition state through the Re face leading to (S)-4a
preferentially (Fig. 1A).
Having established the scope of the catalytic system pre-
pared from exo-aminoalcohol 1, we proceeded to dem-
onstrate its usefulness in the enantioselective synthesis
of (R)-tomoxetine (Scheme 3).15 As depicted in Table
2, reduction of 3-chloropropriophenone (3h) afforded
(S)-3-chloro-1-phenyl-1-propanol (4h) in 82% ee and
89% yield. Its enantiomeric purity could be enriched to
more than 99% after a single recrystallization from hex-
anes ([a]D À23.5 (c 1, CHCl3)), which afforded (À)-4h in
65% yield from 3-chloropropriophenone (3h). Mitsun-
obu inversion (Ph3P and DEAD) with o-cresol provided
(R)-1-chloro-3-phenyl-3-(2-methylphenoxy)propane (9),
[a]D À21 (c 3.9, CHCl3), in 75% yield, which upon treat-
ment with aqueous methylamine in ethanol furnished
enantiomerically pure (R)-tomoxetine, [a]D À42 (c 0.8,
MeOH) (lit.8 [a]D À43 (c 0.8, MeOH) in 96% yield from
(À)-9 and 47% overall yield from 3-chloropropiophen-
one (3h).
Alternatively, binding of the substrate by the less steri-
cally hindered lone pair but endo to the methoxy group
at C-7, which would lead to reduction through the car-
bonyl Si face seems to be disfavoured based on elec-
tronic repulsion between the lone electron pairs of the
oxygen atoms of the methoxy group and the carbonyl
group (Fig. 1B).
In summary, moderate to high enantiomeric excesses
and good yields were obtained in the reduction of
prochiral aromatic ketones with in situ prepared B–H
oxazaborolidine catalyst derived from norbornane-de-
rived exo-aminoalcohol 1. The catalyst is prepared in
situ and the reduction reaction was carried out in
THF at room temperature. (R)-tomoxetine was pre-
pared in optically pure form in 47% overall yield from
3-chloropropriophenone (3h). This synthetic route
should be amenable for the preparation of other phar-
maceuticals such as fluoxetine and nisoxetine.
The results described above for oxazaborolidine 2 de-
rived from (1S,2S,3R,4R)-1 compare favourably with
those reported for other oxazaborolidines prepared
from exo-1,2-aminoalcohols.13a Although the reason
for the enantiomeric discrimination provided by oxaza-
borolidine 2 is not clear at this point, we speculate that
it may result from a restricted conformation enforced by
a hydrogen bond between one of the methoxy groups at
C-7 and the hydrogen of the B–H bond and binding of
the substrate exo to the methoxy group at C-7 (Fig. 1).
Binding of acetophenone (3a) through its sterically more
accessible electron lone pair (cis to methyl group) with a
Acknowledgements
The authors would like to thank FAPESP (Fundac¸a˜o
`
de Amparo a Pesquisa do Estado de Sa˜o Paulo) for
financial support and fellowship (A.A.M.L. and A.F.)
and CNPq (Conselho Nacional de Desenvolvimento
´
Cientıfico Tecnologico) for fellowship (J.E.D.M.) and
research fellowship (R.A.P. and V.E.U.C.).
´
OH
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b
a
Cl
3h
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(-)-9
Scheme 3. Reagents and conditions: (a) catalyst 2 (5mol%), THF,
25ꢂC, recrystallization from hexanes (two steps, 65%, 99% ee); (b)
Ph3P, DEAD, o-cresol, THF (75%); (c) aq MeNH2 (40%), 130ꢂC,
EtOH (96%).
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14. General procedure for the asymmetric reduction with
catalyst 2: to a solution of aminoalcohol 1 (9.6mg,
0.05mmol) in THF (1.5mL) was added BH3ÆMe2S
(85lL of 10M soln in Me2S, 0.85mmol), under argon
atmosphere, and the mixture was stirred at rt for 1h. A
soln of ketone (1mmol) in THF (2mL) was added
dropwise (using a syringe pump) over a period of 20min.
When the addition was over, the reaction mixture was
continued to stir at rt for 2h. Then, MeOH was added
(1mL) and the solvent was evaporated. The pure alcohol
was obtained after filtration of the crude product on
silicagel (hexane/ethyl acetate as eluent).
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