The synthesis of (R,S)-reboxetine employing a tandem cyclic sulfate rearrangement - Opening process

Article abstract of DOI:10.1016/j.tetasy.2012.04.018

(R,S)-Reboxetine was synthesized in nine steps and with 43% overall yield starting from trans-cinnamyl alcohol. Following silylation and AD steps, the two hydroxyl groups at C-1 and C-2 were simultaneously activated to the cyclic sulfate. A series of tandem reactions initiated by desilylation transposed the activation to C-3, then to C-1, where nucleophilic displacements took place in succession. During this process, the configuration at C-2 was inverted while that at C-1 was retained through a double inversion.

Full text of DOI:10.1016/j.tetasy.2012.04.018

Tetrahedron: Asymmetry 23 (2012) 650–654
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
The synthesis of (R,S)-reboxetine employing a tandem cyclic sulfate
rearrangement—opening process
⇑
Jin Yu, Soo Y. Ko
Department of Chemistry, Ewha Womans University, Seoul 120-750, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
(R,S)-Reboxetine was synthesized in nine steps and with 43% overall yield starting from trans-cinnamyl
alcohol. Following silylation and AD steps, the two hydroxyl groups at C-1 and C-2 were simultaneously
activated to the cyclic sulfate. A series of tandem reactions initiated by desilylation transposed the acti-
vation to C-3, then to C-1, where nucleophilic displacements took place in succession. During this pro-
cess, the configuration at C-2 was inverted while that at C-1 was retained through a double inversion.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 14 March 2012
Accepted 26 April 2012
Available online 8 June 2012
1. Introduction
the AE protocol may seem advantageous in this regard as the AE
product has already one stereocenter activated toward nucleo-
The phenylpropylamino group, with aryloxy substituents at the
benzylic carbon, is a common structural motif in many compounds
acting on the central nervous system. Examples include fluoxetine,
tomoxetine, nisoxetine, and reboxetine (Fig. 1).1 Reboxetine is a
potent selective norepinephrine reuptake inhibitor and displays
an efficacy for the treatment of depression and attention deficit/
hyperactivity disorder (ADHD). It is currently marketed as a
racemic mixture of (S,S)- and (R,R)-stereoisomers, of which the
(S,S)-enantiomer is more potent than the (R,R)-isomer.2
Recently, the diastereomeric (R,S)- and (S,R)-reboxetine isomers
have attracted interest. Some iodine-substituted (R,S)-reboxetine
analogues show an affinity for the norepinephrine transporter
which is very comparable to that of the (S,S)-isomers and much
higher than that displayed by the (S,R)-antipodes. These observa-
tions have led to speculations that the diastereomeric (R,S)-reboxe-
tine might become a useful therapeutic agent.3
Synthetic efforts toward the reboxetines have produced several
approaches.3–8 The strategies for stereochemical control include
asymmetric reactions, the use of enantio-pure starting materials,
and the use of chiral auxiliaries. Of the asymmetric reactions em-
ployed in the enantioselective synthesis of reboxetines, Sharpless’s
asymmetric oxidations, that is, epoxidation (AE) and dihydroxyla-
tion (AD), are popular protocols. It should be noted that both AE
and AD processes have been employed for the synthesis of
syn-(S,S)- or syn-(R,R)-reboxetine and derivatives, while for the
synthesis of anti-(R,S)- or anti-(S,R)-stereoisomers, only AE-based
strategies have been reported so far. It is presumed that the syn-
thesis of the anti-isomers requires a configurational inversion at
one of the stereocenters following the asymmetric oxidation step;
philic displacement. Note that a chiral auxiliary-based approach
has also been reported for the synthesis of (R,S)- and (S,R)-reboxe-
tines (Scheme 1).3
We envisaged an efficient AD-based strategy for the synthesis of
reboxetine, wherein the required activation at C-1 and C-3 (for the
introduction of N-functionality at C-3, and the aryloxy functional-
ity at C-1) would be realized in a single activation step using cyclic
sulfate formation and a subsequent rearrangement—opening pro-
cess. Herein we report the synthesis of diastereomeric (R,S)-
reboxetine.
O
CF3
O
O
O
Ph
tomoxetine
NH
Ph
nisoxetine
NH
Ph
NH
fluoxetine
O
O
O
O
Ph
NH
Ph
NH
O
O
(R,S)-reboxetine
(S,S)-reboxetine
⇑
Corresponding author. Tel.: +82 2 3277 3283; fax: +82 2 3277 2384.
E-mail address: sooyko@ewha.ac.kr (S.Y. Ko).
Figure 1. Aryloxy-substituted phenylpropylamino compounds acting on CNS.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.04.018

J. Yu, S. Y. Ko / Tetrahedron: Asymmetry 23 (2012) 650–654
651
O
O
O
OH
OH
X
X
NH
O
O
X
H
N
O
Br
Ph
X = H, Br, I
NH
Ph
Ph
O
Scheme 1. Synthetic strategies for (R,S)-reboxetine (derivatives) in the literature.
cyclic sulfate rearrangement—opening product was subjected to a
blank reaction (the excess Nꢀ3 having been removed through
extractive work-up and the 2-ethoxyphenol was omitted), epoxide
7 was isolated in >80% yield (Eq. 2). Clearly, the initial product fol-
lowing the cyclic sulfate rearrangement—opening process (E in
Scheme 2) underwent an epoxide ring-closure to give 7, the alkox-
ide at C-2 intramolecularly displacing the sulfate anion at C-1. The
resulting epoxide was then ring-opened by nucleophiles at the
benzylic C-1 site, with an overall double inversion (retention) of
configuration at C-1 taking place. Similar intramolecular nucleo-
philic displacements of a sulfate anion have been reported for b-
amino sulfate and b-malonyl sulfate compounds.11,12
2. Results and discussion
The cyclic sulfate rearrangement—opening process is a series
of tandem reactions that produces anti-diols following AD
reactions (Scheme 2).9 It was originally developed to address
the limitation of the AD protocol, that is, its inability to produce
anti-diols directly since (Z)-alkenes are not good substrates for
the AD. The inversion at C-2 and the introduction of various
nucleophiles at C-3 are reminiscent of the Payne rearrange-
ment—opening process of epoxy alcohols.10 In the original
protocol for a cyclic sulfate rearrangement—opening process, the
reaction mixture was subjected to acidic hydrolysis conditions,
to give anti-diol products F. Before the hydrolysis, intermediate
E has a sulfate anion at C-1. We decided to explore a possible
use for this potential leaving group in our synthetic efforts toward
the reboxetines.
O
1. TBAF
2. NaN3
O
NaOH
Ph
O2S
OTBDMS
Ph
N3
one-pot reaction
then, aq. work-up
O
The trans-cinnamyl alcohol was TBDMS-protected (100%). The
AD (AD-mix-a, 95%, >98% ee), cyclic sulfate formation (SOCl2;
7
4
NaIO4/RuCl3, 100%) sequence proceeded uneventfully (Scheme 3).
Desilylation (TBAF) prompted a rearrangement to the terminal
epoxide, which was then opened by Nꢀ3 . The reaction mixture
was then treated with 2-ethoxyphenol/NaOH. Two products were
isolated after acidic work-up and were the 1-ethoxyphenoxy-3-
azido-2-ol compound 5 (36%) and the 1,3-diazido-2-ol compound
6 (62%) (Eq. 1).
ð2Þ
Optimization of the reaction conditions led to a procedure that
involved an extractive work-up after the cyclic sulfate rearrange-
ment—opening step and subsequent treatment of the crude
Nꢀ3 -opened product E with 2-ethoxyphenol/NaOH. The (1S,2R)-1-
ethoxyphenoxy-3-azido-2-ol compound 5 was obtained in 84%
yield from the cyclic sulfate 4.
O
Reduction of the 3-azido functionality (H2, Pd/C, 88%), amida-
tion of 8 to 9 (chloroacetyl chloride, 84%), cyclization of 9 to 10
(KOtBu, 99%), and reduction of the lactam function of 10 to 11
(BH3ꢁMe2S, 73%) all proceeded smoothly to yield (R,S)-reboxetine
11 (Scheme 3).
O
Ph
N3
1. TBAF
2. NaN3
O
OH
5
ð1Þ
Ph
O2S
OTBDMS
3. 2-EtOC6H4OH/NaOH
(one-pot reaction)
+
O
3. Conclusion
N3
4
In conclusion, (R,S)-reboxetine was synthesized in nine steps
and with 43% overall yield by starting from trans-cinnamyl alcohol.
Following silylation and AD steps, the two hydroxyl groups at C-1
and C-2 were simultaneously activated in a single operation as the
cyclic sulfate. A series of tandem reactions initiated by desilylation
transposed the activation to C-3, then to C-1, where Nꢀ3 and 2-eth-
oxyphenoxy nucleophiles were introduced, respectively. During
this process, the configuration at C-2 was inverted while that at
C-1 was retained through a double inversion.
Ph
N3
OH
6
The formation of these two products meant that the nucleo-
philic substitutions did take place at C-1, since the sulfate anion
(in the intermediate corresponding to E) was displaced. The forma-
tion of the diazido compound 6 was due to the presence of excess
Nꢀ3 carried over from the epoxide-opening step; the entire se-
quence of the reactions was performed in a single reaction vessel.
Close inspection of the products revealed that they were both the
(1S,2R)-isomers. The inversion of configuration at C-2 from the
4. Experimental
4.1. General
AD-
a product was a consequence of the cyclic sulfate rearrange-
ment. On the other hand, the apparent retention of configuration
at C-1, where the nucleophilic substitutions had also taken place,
seemed surprising at first. Subsequent studies indicated that epox-
ide 7 was probably the precursor for the two products. When the
Reactions were monitored by TLC on silica gel glass-backed
plates. Proton NMR spectra were recorded in ppm relative to TMS

652
J. Yu, S. Y. Ko / Tetrahedron: Asymmetry 23 (2012) 650–654
OH
O
1
AD
R
OTBDMS
R
OTBDMS
R
OTBDMS
2
OH
O
O2S
A
B
C
F
-
-
OSO3
OH
OSO3
Nu
3
H
1
R
R
Nu
R
Nu
2
O
OH
F
OH
D
E
Scheme 2. Cyclic sulfate rearrangement-opening process.
O
OH
TBDMS-Cl
100%
1. SOCl2
AD-mix-α
Ph
OTBDMS
Ph
OTBDMS
Ph
OTBDMS
Ph
OH
95 %
2. NaIO4/RuCl3
O
O2S
OH
100%
4
3
2
1
1. TBAF
2. NaN3,
then aq. work-up
84%
from 4
2-EtOC6H4OH/NaOH
O
O
O
O
ClCH2COCl
84 %
H2, Pd/C
88 %
O
O
Ph
NH
OH
Ph
NH2
Ph
N3
OH
OH
O
5
8
9
Cl
KOtBu
99%
O
O
O
O
BH3·Me2S
73%
Ph
NH
Ph
NH
O
O
O
10
11
Scheme 3. Synthetic pathway for (R,S)-reboxetine.
as an internal standard. The following abbreviations designate split-
ting patterns: s (singlet), d (doublet), t (triplet), q (quartet), dd (dou-
blet of doublet), dt (doublet of triplet), td (triplet of doublet), ddd
(doublet of doublet of doublet), m (multiplet), br (broad). IR spectra
were recorded as thin films on KRS-5 or KBr plates. HRMS were re-
corded by electronspray ionization. Melting points are uncorrected.
mixture was stirred at rt overnight. The mixture was concen-
trated under reduced pressure, and the residue was extractively
worked-up (CHCl3–brine). The combined organic phases were
dried (anhydrous Na2SO4) and concentrated. Flash column chro-
matography (hexane–EtOAc 10:1) yielded the desired product 2
as
a
colorless liquid (8.875 g, 35.74 mmol, 100%). 1H
NMR(CDCl3): d 7.40–7.21 (5H, m, Ar), 6.59 (1H, d, J = 15.9 Hz,
Ph-CH), 6.29 (1H, dt, J = 15.8, 5.0 Hz, Ph-CH@CH), 4.35 (2H, dd,
J = 1.7, 5.0 Hz, CH2–O), 0.94 (9H, s, t-Bu), 0.11 (6H, s, SiMe2)
ppm. IR: 3027(s), 2956(s), 2929(s), 2857(s), 2101(s), 1472(s),
4.1.1. Cinnamyloxy-tert-butyldimethylsilane 213
A solution of trans-cinnamyl alcohol (4.794 g, 35.73 mmol) in
DMF (120 mL) was treated with tert-butyldimethylchlorosilane
(8.076 g, 53.38 mmol) and imidazole (3.649 g, 53.6 mmol). The
1257(s), 835(s), 681(s) cmꢀ1
.

J. Yu, S. Y. Ko / Tetrahedron: Asymmetry 23 (2012) 650–654
653
4.1.2. (1S,2S)-3-(tert-Butyldimethylsilyloxy)-1-phenylpropane-
4.1.5. (1S,2R)-3-Amino-1-(2-ethoxyphenoxy)-1-phenylpropane-
2-ol 8
1,2-diol 313
t
At first, AD-mix-
a
(11.82 g) was dissolved in BuOH and H2O
Azide compound 5 (0.159 g, 0.508 mmol) was dissolved in
EtOAc (20 mL) and Pd/C 10% (0.049 g) was added. The mixture
was subjected to an H2 atmosphere for 30 min. The mixture was
filtered through Celite, which was washed with MeOH. The filtrate
and washings were combined and concentrated. Flash silica col-
umn chromatography (MeOH–EtOAc 9:1) yielded the product 8
(0.128 g, 0.446 mmol, 88%). 1H NMR (CDCl3): d 7.39–7.26 (5H, m,
Ar), 6.88–6.49 (4H, m, OAr), 5.15 (1H, d, J = 4.2 Hz, Ph-CH), 4.09
(2H, q, J = 6.9 Hz, O–CH2–CH3), 3.85 (1H, dd, J = 9.6, 4.2 Hz,
CH(OH)), 2.98 (1H, dd, J = 12.9, 5.7 Hz, CHAHBN), 2.82 (1H, dd,
J = 12.9, 4.2 Hz, CHAHBN), 2.55 (3H, br s, OH, NH2), 1.48 (3H, t,
J = 6.9 Hz, O–CH2–CH3) ppm. IR: 3373(br), 1593(s), 1507(s),
1251(s), 1221(s), 1124(s), 742(s), 697(s) cmꢀ1. Mp: 102–103 °C.
HRMS(EI) calcd for C17H21NO3 [M]+ 287.1521, found 287.1524.
(1:1 v/v, 50 mL). Methanesulfonamide (0.804 g, 8.46 mmol) was
then added and the mixture was cooled at 0 °C. Next, (cinnamyl-
oxy)-tert-butyldimethylsilane 2 (2.163 g, 8.706 mmol) was added
as a tBuOH–H2O (1:1 v/v, 40 mL) solution. The mixture was cooled
at 0 °C and stirred for 9.5 h. The reaction was quenched by adding
Na2SO3 (13.1 g). The mixture was stirred for 1 h at rt, then ex-
tracted with ethyl acetate. The organic phases were combined,
washed with brine, and dried (Na2SO4). Flash silica column
chromatography (hexane–EtOAc 4:1) yielded the product
3
(2.326 g, 8.324 mmol, 95%). Chiral HPLC analysis (Chiralpak
AD-H) indicated the product to be >98% ee. 1H NMR (CDCl3): d
7.41–7.32 (5H, m, Ar), 4.72 (1H, dd, J = 2.8, 5.8 Hz, Ph-CH), 3.75–
3.53 (3H, m, CH(OH)–CH2O), 3.14 (1H, d, J = 2.8 Hz, OH), 2.67 (1H,
d, J = 6.3 Hz, OH), 0.92 (9H, s, t-Bu), 0.07 (6H, s, SiMe2) ppm. IR:
½
a 2D9
ꢂ
¼ þ20:3ðc0:74; EtOHÞ.
3429(br), 2955(s), 2929(s), 2857(s), 1472(s), 1120(s) cmꢀ1
.
HRMS(EI) calcd for C15H26O3Si [M]+ 282.1651, found 282.1668.
¼ þ11:9ðc1:03; EtOHÞ.
4.1.6. N-[(2R,3S)-3-(2-Ethoxyphenoxy)-2-hydroxy-3-phenylpro-
pyl]-2-chloroacetamide 9
½ ꢂ
a 2D8
Amino compound 8 (0.127 g, 0.443 mmol) was dissolved in
ethyl ether (2 mL). Saturated aq NaHCO3 solution (2 mL) was added
and the mixture was cooled to ꢀ10 °C. Chloroacetyl chloride
(0.0388 mL, 0.487 mmol) was added as an ethyl ether solution
(2 mL) over 5 min. The mixture was stirred at ꢀ10 °C for 10 min
and then warmed to rt where it was stirred for further 10 min.
Extractive work-up (CHCl3–brine), drying (Na2SO4), concentration,
and flash silica column chromatography (hexane–EtOAc 2:3)
yielded the product 9 as a white solid (0.135 g, 0.369 mmol, 84%).
1H NMR (CDCl3): d 7.47–7.31 (5H, m, Ar), 7.16 (1H, s, NH), 7.01–
6.72 (4H, m, OAr), 5.06 (1H, d, J = 4.5 Hz, Ph-CH), 4.21–4.11 (2H,
m, O-CH2-CH3), 4.06–3.98 (3H, m, CH2-Cl, CH(OH)), 3.73 (1H, ddd,
J = 14.4, 7.2, 3.6 Hz, CHAHBN), 3.67 (1H, d, J = 7.2 Hz, OH), 3.35 (1H,
ddd, J = 13.8, 7.5, 4.2 Hz, CHAHBN), 1.53 (3H, t, J = 7.2 Hz, O–CH2–
CH3) ppm. IR: 3537(s), 3398(s), 1679(s) 1503(s), 1251(s), 1125(s),
4.1.3. Formation of the cyclic sulfate 413
Compound 3 (1.809 g, 6.406 mmol) was dissolved in dichloro-
methane (65 mL). Next, Et3N (2.105 mL, 15.12 mmol) was added
followed by SOCl2 (0.5909 mL, 8.136 mmol). The mixture was stir-
red at 0 °C for 10 min. Extractive work-up (CHCl3–brine) was fol-
lowed by concentration. The crude cyclic sulfite thus obtained
was dissolved in CCl4 (18 mL). Next, NaIO4 (2.609 g, 12.2 mmol)
and RuCl3ꢁ3H2O (0.0728 g, 0.351 mmol) were added, and the mix-
ture was diluted by adding H2O (27 mL) and CH3CN (18 mL). The
mixture was stirred at 0 °C for 1 h. The mixture was concentrated
and the residue was isolated by extractive work-up (CHCl3–brine).
Drying (Na2SO4) and concentration yielded the desired cyclic sul-
fate 4 (2.199 g, 6.383 mmol, 100%). 1H NMR(CDCl3) d 7.46 (5H, s,
Ar), 6.20 (1H, d, J = 8.8 Hz, Ph-CH), 4.81 (1H, dt, J = 8.9, 3.2 Hz,
Ph–CH–CH–CH2) 4.03 (1H, dd, J = 12.7, 3.1 Hz, CHAHBO) 3.81 (1H,
dd, J = 12.7, 3.3 Hz, CHAHBO) 0.91 (9H, s, t-Bu) 0.11 (6H, d,
J = 7.1 Hz, SiMe2) ppm.
743(s) cmꢀ1. Mp: 59–63 °C. ½a 2D8
¼ þ36:5ðc0:69; EtOHÞ. HRMS(EI)
ꢂ
calcd for C19H22ClNO4 [M]+ 363.1237, found 363.1238.
4.1.7. (R)-6-[(S)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholin-
4.1.4. (1S,2R)-3-Azido-1-(2-ethoxyphenoxy)-1-phenylpropan-2-
ol 5
3-one 10
t
To a solution of KOtBu (0.144 g, 1.281 mmol) in BuOH (2 mL)
Cyclic sulfate 4 (1.028 g, 2.984 mmol) was dissolved in THF
(20 mL). Tetrabutylammonium fluoride (1 M in THF, 3.58 mL,
3.58 mmol) was added and the mixture was stirred at rt for
30 min. Next, NaN3 (0.388 g, 5.973 mmol), THF (34 mL), and H2O
(5.4 mL) were added and the mixture was stirred at 70 °C for
21 h. The mixture was concentrated and the residue was parti-
tioned between H2O and CHCl3. Extractive work-up (CHCl3–brine),
drying (Na2SO4), and concentration yielded the crude epoxide ring-
opened product (2.35 g, 2.95 mmol as quantified by NMR with an
external standard, 99%).
was added compound 9 (0.233 g, 0.641 mmol) in tBuOH (5 mL).
The mixture was stirred at rt for 1 h. The reaction was quenched
by adding 0.5 M HCl (10 mL). Extractive work-up (CHCl3–brine),
drying (Na2SO4), concentration, and flash silica column chromatog-
raphy (EtOAc–EtOH 15:1) yielded the desired product 10 as a li-
quid (0.207 g, 0.633 mmol, 99%). 1H NMR (CDCl3): d 7.44–7.33
(5H, m, Ar), 6.91–6.65 (4H, m, OAr), 5.95 (1H, s, NH), 5.13 (1H, d,
J = 6.9 Hz, Ph-CH), 4.30 (1H, d, J = 16.8 Hz, C(@O)-CHAHB), 4.12–
4.03 (4H, m, C(@O)-CHAHB, O–CH2–CH3, Ph–CH–CH–CH2), 3.75–
3.72 (2H, m, CH2–NH), 1.47 (3H, t, J = 7.2 Hz, O-CH2-CH3) ppm.
IR: 3227(br), 1680(s), 1594(s), 1501(s), 1455(s), 1253(s), 1216(s),
2-Ethoxyphenol (0.68 mL, 5.415 mmol) was treated with NaOH
(5.41 mmol) in H2O (4.5 mL). The mixture was stirred at rt for 1 h.
The crude intermediate obtained above (2.16 g, 2.70 mmol) and
H2O (7 mL) were then added. The mixture was heated at reflux
for 5 h. Extractive work-up (CHCl3–brine) was followed by drying
(Na2SO4) and concentration. Flash silica column chromatography
(hexane–EtOAc 4:1) yielded the desired product 5 as a yellow li-
quid (0.719 g, 2.294 mmol, 84% from 4). 1H NMR (CDCl3) d 7.46–
7.26 (5H, m, Ar), 6.98–6.71 (4H, m, OAr), 5.05 (1H, d, J = 5.1 Hz,
Ph-CH), 4.19–4.04 (3H, m, CH(OH)–CH2, O–CH2–CH3), 3.56 (1H,
dd, J = 12.6, 7.8 Hz, CHAHBN3), 3.33 (1H, dd, J = 12.9, 3.3 Hz,
CHAHBN3), 3.25 (1H, d, J = 6.9 Hz, OH), 1.51 (3H, t, J = 6.9 Hz, O–
CH2–CH3) ppm. IR: 3442(br), 2102(s), 1501(s), 1254(s), 1124(s)
744(s) cmꢀ1
.
½
a 2D8
ꢂ
¼ þ67:8ðc0:53; EtOHÞ. HRMS(EI) calcd for
C
19H21NO4 [M]+ 327.1471, found 327.1470.
4.1.8. (R)-2-[(S)-(2-Ethoxyphenoxy)(phenyl)methyl]morpholine
11 [(R,S)-reboxetine]
A solution of compound 10 (0.168 g, 0.513 mmol) in THF (5 mL)
was cooled to 0 °C. Next, BH3ꢁSMe2 (2 M THF, 0.9 mL, 1.8 mmol) was
added over 30 min. The mixture was slowly warmed to rt, then
heated to 70 °C, where it was stirred for 20 h. The mixture was
cooled to rt and H2O (6 mL) was added. The mixture was then con-
centrated. Ethyl acetate (1 mL) and 5 M HCl (18 mL) were added
and the mixture was stirred at rt for 2 h. Aqueous NaOH solution
(10 M, 14 mL) was then added and the mixture extracted with
CHCl3 (20 mL ꢃ 9). The combined organic phases were washed with
cmꢀ1. ½a 2D9
¼ þ33:8ðc1:04; EtOHÞ. HRMS(EI) calcd for C17H19N3O3
ꢂ
[M]+ 313.1426, found 313.1425.

654
J. Yu, S. Y. Ko / Tetrahedron: Asymmetry 23 (2012) 650–654
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N.; Inoue, T.; Ohkuma, T. Adv. Synth. Catal. 1955, 2011, 353.
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10. (a) Payne, G. B. J. Org. Chem. 1962, 27, 3819; (b) Behrens, C. H.; Ko, S. Y.;
Sharpless, K. B.; Walker, F. J. J. Org. Chem. 1985, 50, 5687; (c) Hanson, R. M.
Organic Reactions Vol. 60, Chapter 1 (2002).
11. (a) Lohray, B. B.; Gao, Y.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 2623; (b) Oi,
R.; Sharpless, K. B. Tetrahedron Lett. 1991, 32, 999; (c) Lohray, B. B. Synthesis
1992, 1035.
brine, dried (Na2SO4), and concentrated. Flash silica column chro-
matography (EtOAc–MeOH 1:2) yielded (R,S)-reboxetine 11
(0.117 g, 0.374 mmol, 73%). Chiral HPLC analysis (Chiralcel OD-H)
indicated the product to be >98% ee. 1H NMR (CDCl3): d 7.41–7.33
(5H, m, Ar), 6.85–6.67 (4H, m, OAr), 5.06 (1H, d, J = 6.3 Hz, Ph-CH),
4.07 (2H, td, J = 6.9, 1.2 Hz, O–CH2–CH3), 3.88 (1H, dt, J = 11.1,
2.7 Hz, Ph–CH–CH–CH2), 3.83–3.78 (1H, m, OCHAHB), 3.54 (1H, td,
J = 11.1, 2.7 Hz, OCHAHB), 3.33 (1H, dd, J = 12.3, 2.1 Hz, CHAHB-
NH), 2.99–2.88 (2H, m, CH2-NH), 2.82 (1H, t, J = 12.3 Hz, CHAHB-
NH), 1.74 (2H, s, NH), 1.45 (3H, t, J = 7.2 Hz, O-CH2-CH3) ppm. IR:
3334(br), 2976(br), 1592(s), 1501(s), 1455(s), 1254(s), 1217(s),
1124(s), 1045(s), 746(s) cmꢀ1
.
½
a 2D8
ꢂ
¼ þ16:0ðc0:68; CH2Cl2Þ.
HRMS(EI) calcd for C19H23NO3 [M]+ 313.1678, found 313.1679.
References
1. (a) Kent, J. M. Lancet 2000, 355, 911; (b) Dostert, P.; Benedetti, M. S.; Poggesi, I.
Eur. Neuropsychophamacol. 1997, S23.
2. (a) Melloni, P.; Carniel, G.; Della Torre, A.; Bensignon, A. .; Buonamici, A.; Pozzi,
O.; Ricciardi, S.; Rossi, A. C. Eur. J. Med. Chem. 1984, 19, 235; (b) Hajós, M.;
Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M. T.; Wong, E. H. F. CNS Drug Rev.
2004, 10, 23.
12. A report of b-hydroxyalkyl sulfate anions being converted into epoxides has
appeared in the literature. See (a) Jang, D. O.; Joo, Y. H.; Cho, D. H. Synth.
Commun. 2000, 30, 4489; (b) It may be possible that the epoxide precursors
herein were actually b-hydroxyalkyl methyl sulfate diesters and the leaving
group was a methyl sulfate anion, and not a sulfate dianion.
3. (a) Jobson, N. K.; Spike, R.; Crawford, A. R.; Dewar, D.; Pimlott, S. L.; Sutherland,
A. Org. Biolol. Chem. 2008, 6, 2369; (b) Jobson, N. K.; Crawford, A. R.; Dewar, D.;
13. Ko, S. Y.; Lerpiniere, J. Tetrahedron Lett. 1995, 36, 2101.