Application of amide-stabilized sulfur ylide reactivity to the stereodivergent synthesis of (R,S)- and (S,R)-reboxetine

Article abstract of DOI:10.1016/j.tetasy.2009.12.004

A simple access to (R,S)- and (S,R)-reboxetine from a single chiral sulfonium salt 4 is reported. This approach, based on a stabilized sulfur ylide-mediated epoxidation, followed by a regioselective opening reaction, enables the preparation of these two p

Full text of DOI:10.1016/j.tetasy.2009.12.004

Tetrahedron: Asymmetry 20 (2009) 2764–2768
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Application of amide-stabilized sulfur ylide reactivity
to the stereodivergent synthesis of (R,S)- and (S,R)-reboxetine
*
David M. Aparicio, Joel L. Terán , Dino Gnecco, Alberto Galindo, Jorge R. Juárez, María L. Orea,
Angel Mendoza
Centro de Química. Benemérita Universidad Autónoma de Puebla, Edif. 194 Complejo de Ciencias, C. U., 72570 Puebla, Pue., Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple access to (R,S)- and (S,R)-reboxetine from a single chiral sulfonium salt 4 is reported. This
approach, based on a stabilized sulfur ylide-mediated epoxidation, followed by a regioselective opening
reaction, enables the preparation of these two potentially biologically active compounds in 35.6% and
13.7% overall yield.
Received 29 October 2009
Accepted 9 December 2009
Available online 6 January 2010
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
ylides, which usually react in high yield with non-enolizable alde-
hydes to give the corresponding trans epoxides, have been exten-
Reboxetine is an important noradrenaline reuptake inhibitor
used in the treatment of depressive disorder and marketed as a
racemic mixture of the (R,R) and (S,S) enantiomers. Recently, sev-
eral research groups have discovered that esreboxetine 1 is more
potent than its enantiomer with a better affinity and selectivity
for the noradrenaline transporter (NAT).1 Numerous methods have
been reported to isolate the (S,S)-enantiomer, including resolu-
tion,2 capillary electrophoresis,3 and chiral HPLC.4 Asymmetric
syntheses based on chiral starting materials,5 Sharpless epoxida-
tions,6 or dihydroxylations7 have also been reported.
While much research has been carried out for the preparation of
reboxetine, its (S,S) enantiomer, and their pharmacological proper-
ties, very little is known about the biological properties of the cor-
responding diastereomers (R,S)-2a and (S,R)-2b (Fig. 1). Only
recently, Sutherland et al. have reported that iodinated (R,S)-
reboxetine 3a has a high affinity for the NAT (Ki = 58.2 nM), very
close to the affinity of iodinated (S,S)-reboxetine (Ki = 53.8 nM).
Its enantiomer 3b was much less potent in the same binding assay
(Ki = 320 nM).8 These results strongly suggest that isomers 2a and
2b could also possess interesting inhibitory properties.
sively investigated by Aggarwal et al.10 Thus, trans epoxide 5
should enable the rapid construction of the reboxetine skeleton.
Chiral sulfonium salt 4 was prepared in two steps from (S)-(ꢀ)-
phenylethylamine in quantitative yield (Scheme 2).
Condensation with benzaldehyde was then investigated (Ta-
ble 1). The ylide was first generated under our previously estab-
lished conditions (entry 1),11 but the reaction proved to be
sluggish. The best results were obtained in THF, using potassium
tert-butoxide as a base, leading to the quantitative formation of a
73/27 diastereomeric mixture of trans epoxides 5a and 5b (entry
12). The exclusive formation of the trans adducts was confirmed
by the magnitude of the coupling constants of the epoxides
(J = 2.1 and 1.6 Hz).12
O
O
O
O
benzaldehyde, solvent
base, temperature
Ph
Ph
4
H3C
NH
H3C
NH
Ph
Ph
5a
+ 5b
As the separation of the diastereomers proved to be difficult at
this stage, the nucleophilic opening of epoxides was conducted on
the diastereomeric mixture. Our first attempts using NaH or t-
BuOK were unsuccessful, leading to only trace amounts of the
desired amido-alcohols. Finally, the diastereomeric mixture of
compounds 6a+6b13 was obtained in 95% yield by a slight modifi-
cation of the original reaction conditions reported by Kim et al.,14
which consisted of the addition of 20 mol % of ether 18-crown-6
(Scheme 3).
Herein we report a stereodivergent and straightforward access
to (R,S) and (S,R)-reboxetine diastereoisomers using sulfur ylide 4
derived from (S)-phenylethylamine (Scheme 1).
2. Results and discussion
Amide-stabilized sulfur ylides are known to be excellent tools
for the construction of epoxides.9 These kinds of semi-stabilized
The diastereomers were easily separated by chromatographic
purification. Fortunately, the major diastereomer 6a crystallized,
* Corresponding author. Tel.: +52 222 229 5500x7277; fax: +52 222 229 55551.
E-mail address: joelluisteran@hotmail.com (J.L. Terán).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.12.004

D. M. Aparicio et al. / Tetrahedron: Asymmetry 20 (2009) 2764–2768
2765
H
N
H
N
H
OH
N
O
OEt
OEt
OEt
O
(S) Ph
O
(S)
OEt
O
6a
5a
5b
O
O
O
Ph
O
O
O
(S)
H3C
NH
H3C
NH
Ph
Na0, 18-crown-6
+
Ph
O
CH3CN, reflux
2-ethoxyphenol
O
OH
X
X
(R)
O
Ph
Ph
OEt
95 %
(R)
(S,S)-reboxetine
esreboxetine 1
X = H 2a
X = I 3a
X = H 2b
X = I 3b
H3C
NH
6b
(S)
H3C
NH
O
Ph
Ph
Figure 1.
Scheme 3. Nucleophilic opening of epoxides.
enabling the determination of its absolute configuration by X-ray
diffraction analysis (Fig. 2).15
O
O
O
O
16
The reduction of 6a by Red-Al5c,e,6a or LiAlH4 only resulted in
the total degradation of the amide, while the use of BH3ꢁTHF affor-
ded compound 7a in a 10% yield. We found that the use of
BH3ꢁMe2S led to 7a, in 75% yield after column chromatography
(Scheme 4).
The completion of the synthesis was performed by the amidifi-
cation of 7a with bromoacetyl bromide to give the corresponding
haloamide 8a which was treated with t-BuOK to afford the mor-
pholinone 9a.
O
N
Ph
CH3
NH
OH
H
O
6
2
Reduction of the resulting morpholinone 9a with BH3ꢁMe2S
gave morpholine 10a in 83% overall yield after three steps.
As expected, typical hydrogenolysis conditions (H2, 10% Pd-C)
for 10a led to a mixture of O- and O,N-debenzylation products.
A fully chemoselective hydrogenolysis was obtained when 10a
was treated under transfer hydrogenation conditions,17 to give the
desired (R,S)-reboxetine in 80% yield (Scheme 4).
O
Ph
O
Ph
(H3C)2S
N
CH3
N
CH3
O
H
H
5
4
Scheme 1. Retrosynthetic analysis.
OEt
OH
(S)
H
Ph
CH3
O
O
Ph
(S)
CH3
N
(S)
Br
Ph
CH3
NH2
HN
O
S(CH3)2
Br
O
Ph
4
CH2Cl2, 4h, rt
quantitative
CH2Cl2, NEt2, 0°C
6a
Br
Scheme 2. Preparation of chiral sulfonium salt 4.
Figure 2.
Table 1
OH
OEt
Effect of base, temperature, and time on conversion and diastereoselectivity
BH3.Me2S
THF, 0°C
H
H3C
N
O
Entry
Solvent
Base
Temp
Time
(h)
Yielda
(%)
drb
(trans)
6a
75%
Ph
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
CH3CN/H2O
CH2Cl2/H2O
MeOH
CH2Cl2/H2O
Et2O/H2O
DMM/H2O
THF/H2O
THF/H2O
THF
THF
THF
THF
THF
KOH
KOH
KOH
NaOH
KOH
KOH
KOH
LiOH
NaH
0 °C to rt
0 °C to rt
ꢀ50 °C
15
15
30
15
15
15
15
15
5
15
3
15
15
15
50
51
92
53
50
50
64
50
50
50
55
100
80
45
55:45
50:50
55:45
50:50
54:46
62:38
63:37
62:38
55:45
50:50
73:27
73:27
73:27
73:27
7a
1) BrCOCH2Br,
CH2Cl2, NEt3, 0°C
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C
83 %
2) t-BuOK, THF, 0°C
OEt
.
3) BH3 Me2S, THF, 0°C to rt
HCO2NH4,
10% Pd-C
EtOH, reflux, 10 min
O
DBU
O
O
OEt
Ph
t-BuOK
t-BuOK
t-BuOK
t-BuOK
H3C
N
O
ꢀ30 °C
80%
N
H
ꢀ50 °C to rt
ꢀ80 °C to rt
Ph
Ph
THF
(R,S)-reboxetine 2a
10a
a
Isolated yield of diastereomeric mixture.
Determined by 1H NMR of the crude.
b
Scheme 4. Synthesis of (R,S)-reboxetine 2a.

2766
D. M. Aparicio et al. / Tetrahedron: Asymmetry 20 (2009) 2764–2768
The (S,R)-reboxetine enantiomer was also obtained using the
same procedure of diastereomer 6b in 51.7% yield.
and the organic phase was separated, dried over anhydrous
Na2SO4, filtered, and the solvent removed in vacuo to give the de-
sired diastereomeric mixture 6a+6b (95% yield, dr = 73:27). The
diastereomeric mixture was separated by column chromatography
on silica gel with petroleum ether/ethyl acetate.
3. Conclusion
We have shown that chiral non-racemic amide-stabilized sulfur
ylide 4 is a valuable starting material for the preparation of the
reboxetine skeleton. Using only six steps, (R,S)-reboxetine was ob-
tained in 35.6% overall yield whereas its enantiomer (S,R)-reboxe-
tine was prepared in 13.7% yield from the same precursor. This
new, versatile, and scalable access to both enantiomers opens the
route to the pharmacological investigation of these promising
compounds as well as the design of analogs.
4.1.3. (10S,2S,3S)-(ꢀ)-3-(2-Ethoxy-phenoxy)-2-hydroxy-3-
phenyl-N-(10-phenyl-ethyl)propionamide 6a
Major diastereoisomer. Mp = 116–118 °C; ½a D20
ꢂ
¼ ꢀ46:0 (c 1.0,
CH2Cl2); IR (film) 3393, 1652, 1498, 1248 cmꢀ1
.
1H NMR (400
MHz, CDCl3) d 1.14 (d, J = 7.2 Hz, 3H), 1.42 (t, J = 7.2 Hz, 3H), 4.02
(m, 2H), 4.44 (b, OH), 4.53 (d, J = 4.4 Hz, 1H), 4.99 (m, J = 7.1,
7.2 Hz, 1H), 5.37 (d, J = 4.4 Hz, 1H), 6.65–7.62 (m, 14H, NH); 13C
NMR (100 MHz, CDCl3) d 14.81, 21.39, 48.11, 64.49, 72.91, 83.15,
113.37, 118.60, 121.47, 123.14, 125.95, 125.96, 127.12, 127.61,
128.01, 128.19, 128.43, 128.44, 136.39, 142.72, 146.20, 149.65,
169.30. HRMS (FAB): Calcd for C25H27NO4: 405.1940. Found:
405.1931.
4. Experimental
4.1. General methods
Melting points are uncorrected. 1H NMR and 13NMR spectra
were acquired on Varian VX400 (400 MHz), chemical shifts were
given on the delta scale as parts per million (ppm) with tetrameth-
ylsilane (TMS) as an internal standard. IR spectra were recorded on
Nicolet FT-IR Magna 750. Mass spectra were recorded on JEOL JEM-
AX505HA at a voltage of 70 eV. Optical rotations were measured on
Perkin–Elmer 341 polarimeter at room temperature. Column chro-
matography was performed on silica gel (60, 0.063–0.2 mm/70–
230 mesh ASTM). All reagents and solvents were analytically pure.
4.1.4. (10S,2R,3R)-(ꢀ)-3-(2-Ethoxy-phenoxy)-2-hydroxy-3-
phenyl-N-(10-phenyl-ethyl)propionamide 6b
Minor diastereoisomer. Mp = 140–142 °C; ½a D20
ꢂ
¼ ꢀ26:5 (c 1.0,
CH2Cl2); IR (film) 3382, 1654, 1498, 1249 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d 1.35 (d, J = 6.8 Hz, 3H), 1.43 (t, J = 7.2 Hz, 3H),
4.08 (m, 2H), 4.31 (d, J = 3.2 Hz, OH), 4.60 (dd, J = 3.2, 4.4 Hz, 1H),
5.00 (dq, J = 7.1, 7.2 Hz, 1H), 5.41 (d, J = 4.8 Hz, 1H), 6.79–7.42 (m,
14H, NH); 13C NMR (100 MHz, CDCl3) d 14.79, 21.47, 47.85,
64.60, 72.96, 83.50, 113.44, 119.19, 121.59, 123.38, 125.92,
126.93, 127.68, 128.13, 128.16, 128.36, 136.22, 142.49, 146.20,
149.90, 169.21. HRMS (FAB): Calcd for C25H27NO4: 405.1940.
Found: 405.1933.
4.1.1. Synthesis of a diastereomeric mixture of (1S,2R/S,3S/R,)-3-
phenyloxirane-2-carboxylic acid (1-phenyl-ethyl)amides 5a and
5b
To a stirred suspension of potassium tert-butoxide (0.15 g,
1.25 mmol, 1.1 equiv) and sulfonium salt 4 (0.37 g, 1.24 mmol,
1 equiv) in anhydrous THF (30 mL) at ꢀ30 °C was added benzalde-
hyde (0.26 g, 2.48 mmol, 2 equiv). The resulting mixture was stir-
red for 15 h at ꢀ30 °C. The reaction was then quenched by the
successive addition of an aqueous brine solution (25 mL) and the
organic phase was separated, dried over anhydrous Na2SO4, fil-
tered, and the solvent was removed by evaporation. The resulting
diastereomeric mixture was purified via flash column chromatog-
raphy. The diastereomeric mixture of 5a and 5b was obtained as
a white solid in a quantitative yield and dr = 73:27. Spectroscopic
details of the diastereomeric mixture 5a and 5b; IR (film) 3277,
4.1.5. Representative procedure for the reduction of an amide
function with borane dimethyl sulfide complex (BMS)
4.1.5.1. (10S,2R,3S)-(ꢀ)-1-(2-Ethoxy-phenoxy)-1-phenyl-3-(10-
phenyl-ethylamino)-propan-2-ol 7a.
To a stirred solution of
6a (0.1 g, 0.246 mmol) in anhydrous THF (10 mL) at 0 °C was added
a solution of BMS (0.07 mL, 0.055 g, 0.724 mmol, 3 equiv). Then,
the reaction mixture was stirred at room temperature for 8 h.
The reaction was quenched with methanol (2 mL) and stirred for
1 h at room temperature. Finally, the solvents were evaporated un-
der reduced pressure. The product was purified via flash column
chromatography and the corresponding aminoalcohol 7a was ob-
tained as a white oil (0.072 g, 75% yield). ½a D20
ꢂ
¼ ꢀ23:4 (c 1.0,
1654, 1552, 1250 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.46 (d,
.
CH2Cl2); IR (film) 3431, 1498, 1251, 1042 cmꢀ1
.
1H NMR
J = 7.2 Hz, 3H), 1.47 (d, J = 7.2 Hz, 3H), 3.45 (d, J = 2 Hz, 1H), 3.50
(d, J = 2 Hz, 1H), 3.77 (d, J = 2 Hz, 1H), 3.90 (d, J = 1.6 Hz, 1H), 5.14
(m, J = 7.2 Hz, 2H), 6.73 (br, NH, 2H), 7.20–7.37 (m, 20H); 13C
NMR (100 MHz, CDCl3) d 21.66, 21.73, 48.24, 48.27, 58.78, 58.91,
125.73, 126.07, 126.12, 127.48, 128.52, 128.57, 128.65, 128.90,
128.61, 128.92, 134.88, 142.46, 142.68, 166.51.
(400 MHz, CDCl3) d 1.36 (d, J = 6.4 Hz, 3H), 1.42 (t, J = 7.6 Hz, 3H),
2.60 (dd, J = 4.2, 12.6 Hz, 1H), 2.71 (dd, J = 6.2, 10.2 Hz, 1H), 3.75
(q, J = 6.4 Hz, 2H), 3.91 (q, J = 6 Hz, 1H), 4.06 (q, J = 6.8 Hz, 2H),
5.10 (d, J = 4 Hz, 1H), 6.69–7.35 (m, 14H); 13C NMR (100 MHz,
CDCl3) d 14.94, 24.29, 47.76, 58.22, 64.37, 72.76, 85.16, 113.38,
117.27, 120.89, 122.16, 126.65, 126.81, 126.85, 127.77, 128.36,
138.18, 145.18, 147.63, 149.46. HRMS (FAB): Calcd for
C25H29NO3: 391.2147. Found: 391.2123.
4.1.2. Opening of epoxide function of diastereomeric mixture
5a and 5b
To a stirred suspension of Na° in anhydrous THF at room tem-
perature was added 2-ethoxyphenol (0.34 g, 2.48 mmol). The mix-
ture was then stirred until the total formation of the corresponding
sodium alkoxy salt (20–30 min). Later, the excess Na° was elimi-
nated by filtration, and the solvent was removed under reduced
pressure to give the 2-ethoxyphenoxy sodium salt. The resulting
4.1.5.2. (10S,2S,3R)-(ꢀ)-1-(2-Ethoxy-phenoxy)-1-phenyl-3-(1-ph
enyl-ethylamino)-propan-2-ol 7b.
The corresponding ami-
noalcohol was obtained as a white oil (0.075 g, 78% yield).
¼ ꢀ18:2 (c 1.0, CH2Cl2); IR (film) 3431, 1498, 1251,
1042 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.37 (m, 6H), 2.69 (dd,
½ ꢂ
a 2D0
.
J = 4.1, 12.2 Hz, 3H), 2.70 (dd, J = 4.2, 12.0 Hz, 1H), 3.25 (s, NH,
OH), 3.69 (q, J = 6.4 Hz, 1H), 3.96 (q, J = 6 Hz, 1H), 4.03 (q,
J = 6.6 Hz, 2H), 5.14 (d, J = 4.1 Hz, 1H), 6.639–7.331 (m, 14H); 13C
NMR (100 MHz, CDCl3) d 14.92, 24.27, 29.86, 47.56, 58.27, 62.38,
64.30, 72.86, 85.11, 113.30, 116.91, 120.85, 122.03, 126.37,
126.62, 126.84, 127.73, 128.39, 128.43, 138.25, 145.30, 147.73,
salt and
a catalytic amount of 18-crown-6-ether (0.13 g,
0.49 mmol, 20%) were placed in anhydrous CH3CN. The mixture
was stirred at room temperature for 30 min. A solution of diaste-
reomeric mixture 5a and 5b (0.33 g, 1.23 mmol) in CH3CN (5 mL)
was then added. The resulting mixture was refluxed for 16 h. The
reaction was quenched with an aqueous brine solution (15 mL)

D. M. Aparicio et al. / Tetrahedron: Asymmetry 20 (2009) 2764–2768
2767
149.23. HRMS (FAB): Calcd for C25H29NO3: 391.2147. Found:
391.2130.
4.1.8. General procedures for the reduction of an amide
function with borane dimethyl sulfide complex (BMS)
4.1.8.1. (10S,2R,2aS)-(ꢀ)-2-[(2-Ethoxy-phenoxy)-phenyl-
4.1.6. Representative procedure for the condensation of the
corresponding aminoalcohol 7a or 7b with bromo acetyl
bromide to give bromo acetamide 8a or 8b
methyl]-4-(10-phenyl-ethyl)-morpholine 10a.
To a stirred
solution of morpholin-3-one 9a (0.077 g, 0.178 mmol) in anhy-
drous THF at 0 °C, under a nitrogen atmosphere, was added BMS
(0.05 mL, 0.040 g, 0.530 mmol). The reaction mixture was stirred
for 8 h at room temperature. Later, the reaction was quenched with
methanol (2 mL) and stirred for 1 h. Finally, the solvent was evap-
orated under reduced pressure, and the crude was purified via flash
chromatography column giving the desired compound 10a as a
4.1.6.1. (10S,2R,3S)-(ꢀ)-2-Bromo-N-[3-(2-ethoxyphenoxy)-2-
hydroxy-3-phenylpropyl]-N-(10-phenyl-ethyl)acetamide
(8a).
To a stirred solution of aminoalcohol 7a (0.07 g,
0.178 mmol) in 20 mL of CH2Cl2 at 0 °C was added dropwise and
alternately a solution of triethylamine (0.017 g, 0.178 mmol) and
bromo acetyl bromide (0.035 g, 0.178 mmol) in CH2Cl2 (1 mL).
The resulting mixture was stirred at 0 °C for 20 min. Finally, the
reaction was quenched with an aqueous solution of HCl (0.5 M,
3 mL). The organic phase was washed with a brine solution
(15 mL) and dried over anhydrous Na2SO4, filtered, and the solvent
was evaporated to yield the desired chiral bromo acetamide 8a
white oil (0.07 g, 95% yield). ½a D20
¼ ꢀ5:5 (c 1.0, CH2Cl2); IR (film)
ꢂ
1496, 1210, 1117 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.32 (t,
.
J = 7.6 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 2.20 (m, 2H), 2.73 (dd,
J = 1.9, 11.2 Hz, 1H), 3.14 (m, 1H), 3.47 (q, J = 6.72 Hz, 1H), 3.60
(m, 1H), 3.90 (m, 4H), 4.96 (d, J = 7 Hz, 1H), 6.63 (m, 2H), 6.79
(m, 2H), 7.30 (m, 12H); 13C NMR (100 MHz, CDCl3) d 15.03,
18.62, 49.76, 52.88, 64.62, 64.70, 67.15, 78.86, 82.32, 114.54–
149.63. HRMS (FAB): Calcd for C27H31NO3: 417.2304. Found:
417.2300.
(0.09 g, 95% yield) as a white oil. ½a D20
¼ ꢀ17:6 (c 1.0, CH2Cl2); IR
ꢂ
(film) 3431, 1640, 1512, 1256 cmꢀ1. The spectroscopic details of
1H NMR and 13C NMR were omitted because their spectra show
the presence of a complex rotameric mixture. HRMS (FAB): Calcd
for C27H30BrNO4: 511.1358. Found: 511.1312.
4.1.8.2. (10S,2S,2aR)-(ꢀ)-2-[(2-Ethoxy-phenoxy)-phenyl-
methyl]-4-(10-phenyl-ethyl)-morpholine 10b.
½
a 2D0
ꢂ
¼ ꢀ18:5
4.1.6.2. (10S,2S,3R)-2-Bromo-N-[3-(2-ethoxyphenoxy)-2-hydro-
xy-3-phenylpropyl]-N-(10-phenyl-ethyl)acetamide
(c 1.0, CH2Cl2); IR (film) 1501, 1250, 1116 cmꢀ1
.
1H NMR
(400 MHz, CDCl3) d 1.36 (t, J = 7.4 Hz, 3H), 1.42 (d, J = 7 Hz, 3H),
2.04 (m, 1H), 2.21 (dd, J = 10.6, 10.6 Hz, 1H), 2.47 (dd, J = 11.2,
2 Hz, 1H), 3.33 (q, J = 6.8 Hz, 1H), 3.53 (m, 2H), 3.74 (m, 1H), 3.98
(m, 3H), 5.04 (d, J = 6.8 Hz, 1H), 6.68 (m, 2H), 6.83 (m, 2H), 7.29
(m, 12H); 13C NMR (100 MHz, CDCl3) d 15.10, 20.22, 51.22, 52.63,
64.56, 65.51, 67.21, 78.96, 82.48, 114.09–149.64. HRMS (FAB):
Calcd for C27H31NO3: 417.2304. Found: 417.2298.
8b.
Amino-alcohol 7b (0.05 g, 0.127 mmol) was converted
into 8b (0.06 g, 95%). ½a D20
¼ ꢀ56:5 (c 1.0, CH2Cl2); IR 3411, 1634,
ꢂ
1501, 1250 cmꢀ1. The spectroscopic details of 1H NMR and 13C
NMR were omitted because their spectra present the presence of
a complex rotameric mixture. HRMS (FAB): Calcd for C27H30BrNO4:
511.1358. Found: 511.1323.
4.1.9. Chemoselective N-debenzylation by a catalytic transfer
hydrogenation process
4.1.7. Representative procedure for the cyclization of
haloamide 8a or 8b to give chiral morpholin-3-one (9a or 9b)
4.1.7.1. (10S,6R)-(+)-6-[(S)-(2-Ethoxy-phenoxy)-phenyl-methyl)-
To a stirred suspension of 10% Pd-C (0.08 g) in absolute ethanol
(6 mL) at room temperature was added the corresponding N-ben-
zylmorpholine (0.08 g, 1 equiv, 0.195 mmol). To the resulting mix-
ture, ammonium formate (0.030 g, 2.5 equiv, 0.475 mmol) was
added and the mixture was refluxed for 10 min. Finally, the mix-
ture was filtered through a path of diatomite and the solvent was
eliminated in vacuo. The corresponding reboxetine was purified
by column chromatography (Silica gel, CH2Cl2/MeOH, 95:5) giving
the desired compound.
4-(10-phenyl-ethyl)-morpholin-3-one 9a.
To a stirred solu-
tion of haloamide 8a (0.097 g, 0.189 mmol) in anhydrous THF
(6 mL) at 0 °C was added solution of t-BuOK (0.023 g,
a
0.207 mmol) in anhydrous THF (2 mL). The reaction mixture
was stirred for 30 min at 0 °C, and then the reaction was
quenched with brine solution (10 mL), and the organic phase
was dried with anhydrous Na2SO4, filtered, and the solvent was
evaporated under reduced pressure to give the corresponding
morpholinone-3-one 9a (0.077 g) as a white oil in a 95% yield.
½
a 2D0
ꢂ
¼ þ4:8 (c 1.0, CH2Cl2); IR (film) 1644, 1495, 1024 cmꢀ1
.
1H
4.1.9.1. (2R)-(+)-2-[(S)-(2-Ethoxy-phenoxy)-phenyl-methyl]-
morpholine.
¼ þ16:1 (c 1.0, CH2Cl2); IR (film) 2919, 1500, 1252, 1119,
744 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.43 (t, J = 7.0 Hz, 3H),
(R,S)-Reboxetine
(0.048 g,
yield
80%)
NMR (400 MHz, CDCl3)
d 1.24 (t, J = 7 Hz, 3H), 1.55 (d,
½ ꢂ
a 2D0
J = 7.1 Hz, 3H), 3.10 (dd, J = 10.1, 12.5 Hz, 1H), 3.61 (dd, J = 2.9,
12.6 Hz, 1H), 3.93 (m, 2H), 4.05 (m, 1H), 4.11 (d, J = 9.8 Hz, 1H),
4.34 (d, J = 16.6 Hz, 1H), 4.92 (d, J = 7.7 Hz, 1H), 6.12 (q,
J = 7.0 Hz, 1H), 6.53–7.36 (m, 14H); 13C NMR (100 MHz, CDCl3)
d 14.87, 15.26, 29.68, 42.61, 49.74, 64.09, 67.93, 76.72, 82.04,
113.44–149.80, 166.34. HRMS (FAB): Calcd for C27H29NO4:
431.2097. Found: 431.2074.
.
2.64 (b, 2H), 2.91 (m, 3H), 3.31 (dd, J = 2.02, 12.54 Hz, 1H), 3.55
(td, J = 2.8, 11.06 Hz, 1H), 3.82 (m, 1H), 3.87 (m, 1H), 4.06 (qd,
J = 2.8, 6.98 Hz, 2H), 5.06 (d, J = 6.16 Hz, 1H), 6.66 (m, 2H), 6.83
(m, 2H), 7.31 (m, 5H); 13C NMR (100 MHz, CDCl3) d 15.06, 29.69,
45.59, 47.12, 64.56, 67.92, 79.46, 82.78, 114.00, 117.27, 120.80,
121.98, 127.20, 127.42, 127.87, 128.24, 138.72, 147.60, 149.64.
HRMS (FAB): Calcd for C19H23NO3: 313.1678. Found: 313.1665.
4.1.7.2. (10S,6S)-(ꢀ)-[(R)-(2-Ethoxy-phenoxy)-phenyl-methyl]-
4-(10-phenyl-ethyl)-morpholin-3-one 9b.
½
a 2D0
ꢂ
¼ ꢀ102:6 (c
4.1.9.2. (2S)-(+)-2-[(R)-(2-Ethoxy-phenoxy)-phenyl-methyl]-
1.0, CH2Cl2); IR (film) 1644, 1495, 1024 cmꢀ1
.
1H NMR
morpholine.
CH2Cl2).
(S,R)-Reboxetine (yield 80%) ½a D20
¼ ꢀ15:9 (c 1.0,
ꢂ
(400 MHz, CDCl3) d 1.32 (t, J = 7.0 Hz, 3H), 1.55 (d, J = 7.2 Hz,
3H), 3.35 (dd, J = 12.3, 2.8 Hz, 1H), 3.51 (dd, J = 10.0, 12.2 Hz,
1H), 3.97 (q, J = 7.0 Hz, 2H), 4.11 (d, J = 16.6 Hz, 1H), 4.33 (d,
J = 16.6 Hz, 1H), 4.99 (d, J = 7.2 Hz, 1H), 6.11 (q, J = 7.1 Hz, 1H),
Acknowledgments
6.56–7.36 (m, 14H); 13C NMR (100 MHz, CDCl3)
d 14.99,
We are grateful to CONACyT (Project 83185) for financial sup-
port. D.M.A.S. thanks CONACyT for the scholarship (169011) and
Dr. Laurent Micouin for careful reading of the manuscript and
suggestions.
15.41, 42.45, 49.68, 64.22, 67.79, 76.47, 81.88, 113.60–149.64,
166.37. HRMS (FAB): Calcd for C27H29NO4: 431.2097. Found:
431.2077.

2768
D. M. Aparicio et al. / Tetrahedron: Asymmetry 20 (2009) 2764–2768
8. (a) Jobson, N. K.; Crawford, A. R.; Dewar, D.; Pimlott, S. L.; Sutherland, A. Bioorg.
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