Stereodivergent synthesis of all the four stereoisomers of antidepressant reboxetine

Article abstract of DOI:10.1039/c7ob01283g

Chiral amino alcohol-copper(ii) catalysts Cu-L_1c and Cu-ent-L_1c were utilized to promote the diastereoselective nitroaldol reactions of chiral aldehydes (S)-3 or (R)-3 with nitromethane, which respectively led to the preferential formation of certain stereoisomer for nitro diol derivatives 4. Using this catalytic protocol, all the four stereoisomers of the antidepressant reboxetine were divergently prepared. The highest overall yield of this synthetic route reached up to 30.5% from aldehyde (S)-3.

Full text of DOI:10.1039/c7ob01283g

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DOI: 10.1039/C7OB01283G
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Stereodivergent Synthesis of All the Four Stereoisomers of
Antidepressant Reboxetine
Cheng Liu, Zhi-Wei Lin, Zhao-Hui Zhou and Hong-Bin Chen*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Chiral amino alcohol-copper(II) catalysts Cu-L1c and Cu-ent-L1c were utilized to promote the diastereoselective
nitroaldol reactions of chiral aldehydes (S)-3 or (R)-3 with nitromethane, which respectively lead to the
preferential formations of certain stereoisomer for nitro diol derivatives 4 . Using this catalytic protocol, all the
four stereoisomers of antidepressant reboxetine are divergently prepared. The highest overall yield of this
synthetic route reached up to 30.5% from aldehyde (S)-3.
some iodinated (R,S)-reboxetines were also found to possess an
affinity for NET which is very comparable to that of (S,S)-
reboxetine.11 These results mean that (S,R)- and (R,S)-reboxetine
analogues should be considered as good candidates for new NRI.
Therefore, a convenient and reliable approach for stereospecific
syntheses of all stereoisomers of reboxetine and their analogues may
greatly facilitate the research and development (R&D) of more
efficacious and safer antidepressants.
Introduction
Reboxetine (1, Scheme 1) is a potent and selective norepinephrine
reuptake inhibitor (NRI) and currently sold as an antidepressant in its
racemic mixture of (S,S)- and (R,R)-enantiomers, under the trade
names of Edronax, Prolift, Vestra, Norebox, and Integrex in over 60
countries.1 In addition, Reboxetine is also found useful for the
treatment of panic disorder, attention deficit/hyperactivity disorder
(ADHD), narcolepsy, as well as cocaine dependence disorder.2
Although its popularity as an antidepressant has continuously grown,
reboxetine may cause several adverse effects, and even its efficacy
was also challenged recently.3
Our interests in biologically active amino alcohols12 as well as the
intriguing pharmacological properties of reboxetine prompt us to
develop a divergent approach to synthesize all its stereoisomers. A
retrosynthetic analysis is performed and outlined in Scheme 2, which
indicates that the diastereoselective nitroaldol reactions of optically
active aldehydes (S)- or (R)-3 with nitromethane are the key steps.
Notably, aldehydes (S)- and (R)-3 can be easily prepared in high yields
from commercially available (S)- or (R)-mandelic acid respectively
(see ESI).
EtO
O
EtO
O
EtO
O
EtO
O
NH
NH
NH
NH
O
O
O
O
(2R,3S)
(2S,3R)
(2S,3S)
(2R,3R)
EtO
Scheme 1. Structures of the four stereoisomers of reboxetine 1
OH
OH
OTBS
O
*
*
O
MeNO2
+
Ph
NH2
Ph
NO2
*
*
Ph
*
*
Ph
NH
*
OH
OH
3
Several studies have shown that (S,S)-reboxetine is significantly
more active and selective for the norepinephrine transporter (NET)
than its (R,R)-enantiomer.4 Therefore great efforts has been made
over the past decade and several methods based on chemical
resolution,5 hydrolytic kinetic resolution,6 optically active starting
materials,7 asymmetric epoxidation5 and dihydroxylation,8 as well as
asymmetric transfer hydrogenation,9 have been developed to the
syntheses of (S,S)-reboxetine. Comparatively, less attention is given
to the preparations of (S,R)- and (R,S)-reboxetine.7a,9a,10 Actually,
O
1
Scheme 2. Retrosynthetic analysis of reboxetine
Results and discussion
Catalytic asymmetric nitroaldol (Henry) reaction is an economic
and powerful tool in organic syntheses because their resulting
β-nitro alcohols can be conveniently converted into β-amino
alcohols and other valuable intermediates,13 which are useful
for the preparations of complex bioactive molecules. Although
great progress has been made over the past two decades, the
Department of Chemistry, College of Chemistry and Chemical Engineering, Xiamen
University, Xiamen, Fujian, 361005, P. R. China.
E-mail: hbchan@xmu.edu.cn
diastereoselective nitroaldol reactions of optically active
-
Electronic Supplementary Information (ESI) available: Preparations of (S)- and (R)-3,
Copies of HPLC and NMR data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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hydroxy-protected aldehydes are rarely investigated,14 which
lead to the formation of nitro diol derivatives.
Aldehyde (S)-3 was used as the model substrate to screen the
Table 1. Optimizations of the diastereoselective Henry reactions a
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DOI: 10.1039/C7OB01283G
OTBS
OTBS
Cat
OTBS
solvent
+
NO2
catalysts and to optimize the reaction conditions. In the initial
experiments, organic base NEt3 (Table 1, entry 1) and inorganic
base K2CO3 (Table 1, entry 2) were used as catalysts to check
whether certain configured nitroaldol product can be
preferentially formed. However, it is found that the reactions
proceeded slowly and only low diastereoselectivities (syn/anti)
are observed, which suggests that chiral catalysts are needed to
activate the substrate and concomitantly direct the asymmetric
nitroaldol orientation. Thus we turn to the chiral amino alcohol-
copper(II) catalysts,12,15 which are in situ generated from the
Ph
NO2
CH3NO2
Ph
+
O
rt, 3d
Ph
OH
anti
OH
syn
(S)-3
(1S,2S)-4
(1S,2R)-4
Entry
Cat (mmol)
solvent
Yield
(%) b
8
dr
(syn/anti) c
1.7:1
1
2
3
4
5
6
7
8
9
10
11
12
13
14
NEt3 (5%)
K2CO3 (5%)
Cu*-L1a (5%)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
54
60
53
54
35
56
45
9
2.4:1
2.0:1
1:4.3
1.7:1
1:3.7
5.9:1
1:5.0
2.5:1
1:3.9
10.5:1
1:8.1
9.0:1
1:6.9
Cu*-ent-L1a (5%)
Cu*-L1b (5%)
coordination of amino alcohol ligands L1 or ent-L1 (Figure 1) with
Cu*-ent-L1b (5%)
Cu*-L1c (5%)
Cu(OAc)2·H2O in 1:1 ratio respectively. Based on the known
structures of copper complexes with chelated amino alcohols,
the composition of the catalyst is temporarily assigned as
CuL1(OAc)2·H2O or its mixture with different ratios of amino
Cu*-ent-L1c (5%)
Cu*-L1d (5%)
Cu*-ent-L1d (5%)
Cu*-L1c (5%)
Et2O
9
6
alcohol.1
MeNO2
MeNO2
MeNO2
MeNO2
85
69
68
42
Ph
Ph
Ph
Ph
a: R1 = R2 = Me
Cu*-ent-L1c (5%)
Cu*-L1c (2.5%)
Cu*-ent-L1c (2.5%)
b: R1, R2 = -(CH2)4-
c: R1, R2 = -(CH2)5-
d: R1, R2 = -(CH2)2O(CH2)2-
R1
N
R2
ent-L1
OH
R1
N
OH
R2
L1
Figure 1. Chiral amino alcohol ligands
[a] All reactions were performed at 1-mmol scale; [b] isolated yield;
[c] determined by chiral HPLC. Cu* = Cu(OAc)2·H2O.
L
1 and ent-L1
With the optimized reaction conditions in hand, larger scale of Cu-
catalyzed nitroaldol reactions were performed (30.0 mmol). The
results are listed in Scheme 3, which clearly showed that four
stereoisomers of the nitroaldol adducts 4 were respectively formed
with satisfied isolated yields as well as syn/anti ratios.
The Cu-catalyzed nitroaldol reactions were summarized in Table 1
(entries 3-10), which clearly showed that catalysts Cu-L1c (entry 7,
syn/anti 5.9:1) and Cu-ent-L1c (entry 8, syn/anti 1:5.0) were superior
to the other catalysts. Further studies showed that solvent and
catalyst loading were also crucial for the reaction. When pure MeNO2
was used as solvent, both reactivity and diastereoselectivity were
improved largely (entries 11-12). Catalyst Cu-L1c gave a syn/anti ratio
up to 10.5:1 (entry 11), while Cu-ent-L1c gave a syn/anti ratio of 1:8.1
(entry 12); when the catalyst loading was reduced to 2.5 mmol%,
both the reactivity and diastereoselectivity were simultaneously
decreased (entries 13-14). Detail analysis of these data revealed that
the yield as well as diastereoselectivity (syn/anti) from Cu-L1c are
higher than that from Cu-ent-L1c. This experimental observation can
be explained by matched/mismatched pair between chiral substrate
and the chiral catalyst (double diastereoselection).17 In the matched
case, the substrate (S)-3 and the catalyst Cu-L1c are cooperatively
formed in transition state of the reaction with less steric hindrance;15
by contrary, the mismatched pair between the substrate (S)-3 and
the catalyst Cu-ent-L1c diminished the diastereoselectivity, producing
not only the catalyst controlled product, but also minor product due
to the inherent stereogenic carbon center of (S)-3. Nevertheless, the
product is still formed in good diastereoselectivity (entry 12).
OTBS
OTBS
ent-L1c (5%)
CuOAc.H2O (5%)
MeNO2, rt, 3d
L1c (5%)
CuOAc.H2O (5%)
MeNO2, rt, 3d
OTBS
O
Ph
NO2
Ph
NO2
Ph
OH
(1S,2R)-4
OH
(1S,2S)-4
(S)-3
yield:86%
yield: 68%
syn/anti = 10.4:1
syn/anti = 1:8.4
OTBS
OTBS
ent-L1c (5%)
CuOAc.H2O (5%)
MeNO2, rt, 3d
L1c (5%)
CuOAc.H2O (5%)
MeNO2, rt, 3d
OTBS
Ph
NO2
Ph
NO2
O
Ph
OH
(1R,2R)-4
OH
(1R,2S)-4
(R)-3
yield: 87%
yield: 64%
syn/anti = 10.9:1
syn/anti = 1:9.5
Scheme 3. Henry reactions performed at 30.0 mmol scale
Next (1S,2S)-4 was selected as a model reactant for the synthesis
of (2S,3S)-reboxetine, and only the optimized reaction sequences
were illustrated in Scheme 4. Removal of TBS group in aqueous HCl-
methanol18 afforded almost quantitative yield of nitro diol (1S,2S)-5,
which was then recrystallized from diethyl ether-petroleum ether in
84% yield. Subsequent catalytic hydrogenation of the nitro group of
(1S,2S)-5 into amino group and followed reaction with chloroacetyl
chloride in the presence of two equivalents of potassium carbonate
afforded chloroacetamide (2S,3S)-6 in a yield of 71%. This compound
t
was transformed into morpholinone by treatment with BuOK (2.5
t
equiv) in BuOH.7b The reaction proceeded well and the resulting
morpholinone was not separated and directly reduced by LiAlH4 into
morpholine, which was protected into Boc-amide (2S,3S)-7 in 70%
2 | J. Name., 2012, 00, 1-3
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yield over three steps. Finally, following the literature methods6,9a removed under reduced pressure, and the residue was purified by
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with small modifications, (2S,3S)-7 was transformed into (2S,3S)- flash column chromatography on silica gelDeOluI:ti1n0g.10w3i9t/hC7pOeBtr0o1l2e8u3mG
reboxetine 1 in 85% yield. Notably, the overall yield of this synthetic ether-ethyl acetate (20:1, v/v) to give the nitroaldol product 4 as a
route reached up to 30.5% from aldehyde (S)-3.
pale yellow oil.
Using the same procedure described above, (2R,3S)-, (2R,3R)-, and
(2S,3R)-reboxetines were also prepared from their corresponding
nitroaldol adducts 4 (Scheme 4).
(1S,2S)-1-(tert-Butyldimethylsilyloxy)-3-nitro-1-phenylpropan-2-ol
[(1S,2S)-4]
i) 10% Pd/C
Reaction using L1c and (S)-3, 8.03 g, 25.8 mmol, 86%. []D20 +44.7 (c
1.0 in CHCl3); 1H NMR (CDCl3, 500 MHz)  7.38-7.31 (m, 5H), 4.67 (d,
J = 5.96 Hz, 1H), 4.39-4.33 (m, 2H), 4.27 (dd, J = 8.78, 12.76 Hz, 1H),
2.83 (br s, 1H), 0.90 (s, 9H), 0.06 (s, 3H), -0.15 (s, 3H);13C NMR (CDCl3,
126 MHz)  139.3, 128.6(5), 128.6(3), 126.8, 77.3, 75.6, 73.4, 25.7,
18.1, -4.6, -5.2; HRMS (ESI): m/z calcd for C15H25NO4Si [M+Na]+
334.1445, found 334.1447; HPLC (Chiralpak OD-H, 95:5 Hex:iPrOH,
1.0 mL/min, 20 oC, 208 nm): syn (major) = 9.8 min, anti (minor) = 6.9
min, dr (syn/anti) = 10.4:1.
OH
O
OTBS
OH
H2 (10 atm)
MeOH, rt
Cl
3N HCl
MeOH
*
*
Ph
*
*
*
*
N
Ph
NO2
Ph
NO2
ii) ClCH2COCl
K2CO3, 0 °C
H
OH
OH
OH
(2S,3S)-6, 71%
(2R,3S)-6, 73%
(2R,3R)-6, 70%
(2S,3R)-6, 70%
(1S,2S)-4
(1S,2R)-4
(1R,2R)-4
(1R,2S)-4
(1S,2S)-5, 84%
(1S,2R)-5, 95%
(1R,2R)-5, 85%
(1R,2S)-5, 94%
EtO
i) CBr4-PPh3, imi, DCM
OH
i) tBuOK, tBuOH
ii) LiAlH4, THF
iii) Boc2O, THF
ii) 2-ethoxyphenol, tBuOK
tBuOH-THF, reflux
NBoc
O
*
*
Ph
*
*
O
Ph
NH
iii) TFA, DCM, rt, 6h
O
(2S,3S)-7, 70%
(2R,3S)-7, 72%
(2R,3R)-7, 71%
(2S,3R)-7, 70%
(2S,3S)-1, 85%
(2R,3S)-1, 50%
(2R,3R)-1, 84%
(2S,3R)-1, 48%
(1S,2R)-1-(tert-Butyldimethylsilyloxy)-3-nitro-1-phenylpropan-2-ol
[(1S,2R)-4]
Scheme 4. Syntheses of all four stereoisomers of reboxetine
1
Reaction using ent-L1c and (S)-3, 6.35 g, 20.4 mmol, 68%. []D20 +62.3
(c 1.0 in CHCl3), [lit19: []D +48.2 (c 0.5 in CHCl3)]; H NMR (CDCl3,
500 MHz)  7.39-7.35 (m, 2H), 7.34-7.29 (m, 3H), 4.76 (d, J = 5.33 Hz,
1H), 4.47 (dd, J = 4.25, 13.00 Hz, 1H), 4.44 (dd, J = 7.55, 13.00 Hz, 1H),
2.50 (br s, 1H), 0.91 (s, 9H), 0.07 (s, 3H), -0.15 (s, 3H);13C NMR (CDCl3,
126 MHz)  139.9, 128.7, 128.4, 126.5, 77.1, 76.3, 73.6, 25.8, 18.1, -
4.7, -5.1; HRMS (ESI): m/z calcd for C15H25NO4Si [M+Na]+ 334.1445,
found 334.1451; HPLC (Chiralpak OD-H, 95:5 Hex:iPrOH, 1.0 mL/min,
20
1
Conclusions
In summary, we have successfully utilized copper catalysts Cu-
L1c and Cu-ent-L1c to promote the diastereoselective nitroaldol
reactions of chiral aldehydes (S)- or (R)-
which lead to the preferential formation of certain
stereoisomer for nitro diol derivatives respectively. Using this
3 with nitromethane,
4
o
20 C, 208 nm): syn (minor) = 10.2 min, anti (major) = 7.0 min, dr
catalytic protocol, all four stereoisomers of antidepressant
reboxetine were divergently prepared. Furthermore by using
the synthetic approach developed herein, structurally diverse
reboxetine analogues can be conveniently prepared because
phenols are plentiful and commercially available. We wish this
work may help the research and development of novel NRIs.
(syn/anti) = 1:8.4.
(1R,2R)-1-(tert-Butyldimethylsilyloxy)-3-nitro-1-phenylpropan-2-ol
[(1R,2R)-4]
Reaction using ent-L1c and (R)-3, 8.12 g, 26.1 mmol, 87%. []D20 -45.2
(c 1.0 in CHCl3); 1H NMR (CDCl3, 500 MHz)  7.38-7.35 (m, 2H), 7.34-
7.31 (m, 3H), 4.67 (d, J = 5.96 Hz, 1H), 4.40-4.33 (m, 2H), 4.27 (dd, J =
8.82, 12.80 Hz, 1H), 2.83 (br s, 1H), 0.90 (s, 9H), 0.06 (s, 3H), -0.15 (s,
3H); 13C NMR (CDCl3, 126 MHz)  139.3, 128.6(6), 128.6(3), 126.8,
77.3, 75.6, 73.4, 25.7, 18.1, -4.6, -5.2; HRMS (ESI): m/z calcd for
C15H25NO4Si [M+Na]+ 334.1445, found 334.1448; HPLC (Chiralpak
OD-H, 95:5 Hex:iPrOH, 1.0 mL/min, 20 oC, 208 nm): syn (major) = 8.2
min, anti (minor) = 6.2 min, dr (syn/anti) = 10.9:1.
Experimental sections
General: Unless otherwise noted, reagents and solvents were
commercially available and used as received without any further
purification. Tetrahydrofuran (THF) was distilled from sodium wire
prior to use. Dichloromethane (DCM) was distilled from calcium
1
hydride prior to use. H and 13C NMR spectra were determined in
deuterated solvents on a Bruker av500 NMR spectrometer. Chemical
shifts were reported in delta () units, parts per million (ppm)
downfield from TMS. High resolution mass spectra were recorded on
a Bruker Apex ultra 7.0T FT-MS. Optical rotations were measured in
a MCP500 automatic polarimeter, sodium lamp, 1 dm cuvette
lengths, c in g/100 mL. Analytical HPLC was performed on a Shimadzu
liquid chromatography equipped with a SPD-M20A diode array
detector, using a ChiralcelTM OD-H column (4.6 mm × 250 mm, 5 m).
(1R,2S)-1-(tert-Butyldimethylsilyloxy)-3-nitro-1-phenylpropan-2-ol
[(1R,2S)-4]
20
Reaction using L1c and (R)-3, 5.98 g, 19.2 mmol, 64%. []D -67.0 (c
1.0 in CHCl3); 1H NMR (CDCl3, 500 MHz)  7.39-7.35 (m, 2H), 7.34-7.30
(m, 3H), 4.77 (d, J = 5.27 Hz, 2H), 4.48-4.43 (m, 2H), 4.40-4.36 (m, 1H),
2.45 (br s, 1H), 0.91 (s, 9H), 0.07 (s, 3H), -0.14 (s, 3H);13C NMR (CDCl3,
126 MHz)  139.8, 128.7, 128.4, 126.5, 77.1, 76.3, 73.6, 25.8, 18.1, -
4.7, -5.1; HRMS (ESI): m/z calcd for C15H25NO4Si [M+Na]+ 334.1445,
found 334.1447; HPLC (Chiralpak OD-H, 95:5 Hex:iPrOH, 1.0 mL/min,
20 oC, 208 nm): syn (minor) = 8.0 min, anti (major) = 6.1 min, dr
(syn/anti) = 1:9.5.
General procedure for diastereoselective Henry reaction
A solution of L1c or ent-L1c (420 mg, 1.5 mmol), Cu(OAc)2·H2O (300 mg,
1.5 mmol) and aldehyde (S)-3 or (R)-3 (7.50 g, 30.0 mmol) in MeNO2
(45 mL) was stirred at room temperature for 3 days. The solvent was
This journal is © The Royal Society of Chemistry 20xx
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General procedure for transformation of compound 4 into 5
concentrated under reduced pressure, and the residuVeiewwaAsrtipcluerOifnileinde
by flash column chromatography on silica geDl eOlIu: t1i0n.g10w39it/hC7pOeBtr0o1l2e8u3mG
ether-ethyl acetate (1:2, v/v), which afforded the product 6 as a pale
yellow oil.
A solution of 4 (6.22 g, 20.0 mmol) in a mixture of methanol (50 mL)
and diluted HCl (3N, 50 mL) was stirred at room temperature until
the starting material consumed (as monitored by TLC). Methanol was
removed under reduced pressure, and the aqueous solution was 2-Chloro-N-((2S,3S)-2,3-dihydroxy-3-phenylpropyl)acetamide
extracted with ethyl acetate (3 × 20 mL). The combined organic layers [(2S,3S)-6]
were washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was purified by
1.73 g, 7.1 mmol, 71%. []D20 +18.0 (c 1.0 in CHCl3); 1H NMR (CDCl3,
500 MHz)  7.38-7.29 (m, 5H), 6.97 (br s, 1H), 4.52 (d, J = 6.21 Hz, 1H),
3.98 (s, 2H), 3.82 (td, J = 4.25, 6.97 Hz, 1H), 3.38 (ddd, J = 4.23, 6.26,
14.00 Hz, 1H), 3.24 (ddd, J = 5.49, 7.24, 12.75 Hz, 1H);13C NMR (CDCl3,
126 MHz)  167.3, 140.3, 128.7, 128.3, 126.7, 75.4, 74.1, 42.4(9),
42.4(5); HRMS (ESI): m/z calcd for C11H14ClNO3 [M+Na]+ 266.0560,
found 266.0558.
flash column chromatography on silica gel eluting with petroleum
ether-ethyl acetate (2:1, v/v) [and followed recrystallization from
diethyl ether-petroleum ether (1:10, v/v) for syn-isomer] to give the
nitro diol 5.
(1S,2S)-3-Nitro-1-phenylpropane-1,2-diol [(1S,2S)-5]
20
1
Colourless solid, 3.31 g, 84%. []D +41.2 (c 1.0 in CHCl3); H NMR 2-chloro-N-((2R,3S)-2,3-dihydroxy-3-phenylpropyl)acetamide
(CDCl3, 500 MHz)  7.42-7.39 (m, 2H), 7.38-7.34 (m, 3H), 4.66 (d, J = [(2R,3S)-6]
5.70 Hz, 1H), 4.49-4.39 (m, 2H), 4.34 (dd, J = 12.37, 2.16 Hz, 1H), 3.07
1.78 g, 73%. []D20 +12.0 (c 1.0 in CHCl3); 1H NMR (CDCl3, 500 MHz) 
7.39-7.35 (m, 4H), 7.34-7.30 (m, 1H), 7.05 (br s, 1H), 4.61 (d, J = 6.18
Hz, 1H), 4.05 (d, J = 1.23 Hz, 2H), 3.87 (td, J = 3.51, 5.90 Hz, 1H), 3.57
(dt, J = 5.86, 14.22 Hz, 1H),3. 47 (ddd, J = 3.50, 6.15, 14.31 Hz, 1H),
2.57 (br s, 2H);13C NMR (CDCl3, 126 MHz)  167.8, 140.1, 128.6, 128.1,
126.6, 75.1, 74.0, 42.5, 41.6; HRMS (ESI): m/z calcd for C11H14ClNO3
[M+Na]+ 266.0560, found 266.0560.
(br s, 1H), 2.80 (br s, 1H);13C NMR (CDCl3, 126 MHz)  138.9, 129.0(3),
128.9(8), 126.5, 77.5, 74.6, 72.7; HRMS (ESI): m/z calcd for C9H11NO4
[M+Na]+ 220.0580, found 220.0584.
(1S,2R)-3-nitro-1-phenylpropane-1,2-diol [(1S,2R)-5]
20
1
Pale yellow oil, 3.75 g, 95%. []D +42.6 (c 1.0 in CHCl3); H NMR
(CDCl3, 500 MHz)  7.47-7.32 (m, 5H), 4.87 (s, 1H), 4.55-4.48 (m, 2H),
4.45-4.39 (m, 1H), 2.90 (d, J = 3.17 Hz, 1H), 2.62 (d, J = 2.26 Hz, 1H); 2-Chloro-N-((2R,3R)-2,3-dihydroxy-3-phenylpropyl)acetamide
13C NMR (CDCl3, 126 MHz)  138.8, 128.9, 128.5, 126.1, 76.7, 74.7, [(2R,3R)-6]
72.7; HRMS (ESI): m/z calcd for C9H11NO4 [M+Na]+ 220.0580, found
220.0582.
21
1.70 g, 70%. []D20 -19.5 (c 1.0 in CHCl3), [lit11a: []D -22.6 (c 1.0 in
CHCl3)]; 1H NMR (CDCl3, 500 MHz)  7.39-7.29 (m, 5H), 6.99 (br s, 1H),
(1R,2R)-3-Nitro-1-phenylpropane-1,2-diol [(1R,2R)-5]
4.52 (d, J = 6.21 Hz, 1H), 3.99 (s, 2H), 3.83 (td, J = 4.25, 6.78 Hz, 1H),
3.39 (ddd, J = 4.23, 6.24, 14.00 Hz, 1H), 3.25 (ddd, J = 5.52, 7.20, 12.75
Hz, 1H), 2.98 (br s, 2H); 13C NMR (CDCl3, 126 MHz)  167.3, 140.3,
128.7, 128.3, 126.7, 75.4, 74.1, 42.4(9), 42.4(5); HRMS (ESI): m/z
calcd for C11H14ClNO3 [M+Na]+ 266.0560, found 266.0561.
20
1
Colourless solid, 3.35 g, 85%. []D -41.5 (c 1.0 in CHCl3); H NMR
(CDCl3, 500 MHz)  7.43-7.34 (m, 5H), 4.67 (d, J = 5.72 Hz, 1H), 4.49-
4.40 (m, 2H), 4.35 (dd, J = 2.32, 12.45 Hz, 1H), 3.04 (br s, 1H), 2.74 (br
s, 1H); 13C NMR (CDCl3, 126 MHz)  138.9, 129.0(3), 128.9(8), 126.5,
77.5, 74.6, 72.8; HRMS (ESI): m/z calcd for C9H11NO4 [M+Na]+ 2-Chloro-N-((2S,3R)-2,3-dihydroxy-3-phenylpropyl)acetamide
220.0580, found 220.0584.
[(2S,3R)-6]
20
20
(1R,2S)-3-Nitro-1-phenylpropane-1,2-diol [(1R,2S)-5]
1.71 g, 70%. []D -14.5 (c 1.0 in CHCl3), [lit7b: []D -13.6 (c 2.5 in
CHCl3)]; 1H NMR (CDCl3, 500 MHz)  7.39-7.35 (m, 4H), 7.34-7.29 (m,
1H), 7.07 (br s, 1H), 4.61 (d, J = 6.06 Hz, 1H), 4.02 (s, 2H), 3.88-3.82
(m, 1H), 3.56-5.50 (m, 1H), 3.46 (ddd, J = 3.53, 6.00, 14.28 Hz, 1H),
2.75 (br s, 2H);13C NMR (CDCl3, 126 MHz)  167.8, 140.1, 128.6, 128.1,
126.6, 75.1, 74.0, 42.5, 41.6; HRMS (ESI): m/z calcd for C11H14ClNO3
[M+Na]+ 266.0560, found 266.0558.
20
1
Pale yellow oil, 3.71 g, 94%. []D -41.6 (c 1.0 in CHCl3). H NMR
(CDCl3, 500 MHz)  7.43-7.33 (m, 5H), 4.88 (d, J = 1.73 Hz, 1H), 4.55-
4.49 (m, 2H),4.46-4.40 (m, 1H), 2.86 (d, J = 4.28 Hz, 1H), 2.57 (d, J =
2.39 Hz, 1H); 13C NMR (CDCl3, 126 MHz)  138.8, 128.9, 128.6, 126.1,
76.7, 74.7, 72.7; HRMS (ESI): m/z calcd for C9H11NO4 [M+Na]+
220.0580, found 220.0584.
General procedure for transformation of 6 into Boc-amide 7
General procedure for transformation of 5 to chloroacetamide 6
t
To a solution of 6 (2.43 g, 10.0 mmol) in BuOH (20 mL) was added
tBuOK (2.24 g, 20.0 mmol) in one portion. The mixture was stirred at
room temperature for additional 2 hours, quenched with saturated
aqueous ammonium chloride, and then concentrated under reduced
pressure. The resulting solution was extracted with ethyl acetate (3
× 10 mL), and the combined organic layers were washed with brine,
dried over sodium sulfate, filtered and concentrated under reduced
A solution of 5 (1.97 g, 10.0 mmol) in methanol (20 mL) was
catalytically hydrogenated (10 atm) over 10% Pd/C (0.2 g) overnight,
filtered and the filtrate was transferred into a round-bottomed flask.
Powdered potassium carbonate (2.76 g, 20.0 mmol) and chloroacetyl
chloride (1.20 mL, 15.0 mmol) were sequentially added at 0 °C. The
mixture was stirred at the same temperature for additional 1 hour,
filtered and washed with ethyl acetate. The combined filtrate was
4 | J. Name., 2012, 00, 1-3
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pressure. The residue was dissolved in dry THF (10 mL), and was then room temperature for 2 hours, quenched with V1ie0w%ArticsleoOdinulinme
DOI: 10.1039/C7OB01283G
dropwise added into a suspension of LiAlH4 (0.95 g, 25.0 mmol) in thiosulfate and extracted with DCM (2 × 10 mL). The combined
THF (10 mL) at 0 °C. After completion of the addition, the reaction organic layers were washed with brine, dried over sodium sulfate,
mixture was refluxed for additional 6 hours, cooled with an ice bath, filtered and concentrated under reduced pressure. The oily residue
carefully quenched with saturated aqueous potassium carbonate, was dissolved in THF (3 mL), and dropwise added into a solution of
and Boc2O (2.18 g, 10.0 mmol) was then added. The resulting mixture potassium 2-ethoxyphenoxide in tBuOH (6 mL) that was pre-
was vigorously stirred at room temperature overnight, filtered and prepared from 2-ethoxyphenol (552 mg, 4.0 mmol) and potassium
the filtrate was concentrated under reduced pressure. The residue tert-butoxide (448 mg, 4.0 mmol). This mixture was refluxed
was recrystallized from petroleum ether-ethyl acetate (10:1, v/v), overnight, cooled to room temperature, and concentrated under
which afforded the Boc-amide 7 as colourless solid.
reduced pressure. The residue was diluted with water (5 mL) and
extracted with ethyl acetate (3 × 5 mL). The combined organic layers
were washed with brine, dried over sodium sulfate, filtered and
concentrated under reduced pressure. The residue was dissolved in
DCM (10 mL) and TFA (1.0 mL, 13 mmol) was added. The mixture was
stirred at room temperature for additional 6 hours and then
evaporated under reduced pressure. The residue was dissolved in
DCM (10 mL) and then an aqueous solution of NaOH (4N, 3 mL) was
added. After being stirred for 10 min, the organic layer was separated
and the aqueous layer was extracted with DCM (10 mL). The
combined organic layers were dried over sodium sulfate, filtered and
(2S,3S)-2-(-Hydroxyphenylmethyl)morpholine-4-carboxylic acid t-
butyl ester [(2S,3S)-7]
2.06 g, 70%. []D20 +35.5 (c 1.0 in CHCl3), [lit7c: []D20 +34.0 (c 1.24 in
CHCl3)]; 1H NMR (CDCl3, 500 MHz)  7.39-7.28 (m, 5H), 4.53 (dd, J =
2.34, 7.39 Hz, 1H), 3.97 (d, J = 11.44 Hz, 1H), 3.81 (d, J = 11.23 Hz, 1H),
3.67-3.42 (m, 3H), 3.05-2.89 (m, 2H), 2.70 (br s, 1H), 1.39 (s, 9H); 13
C
NMR (CDCl3, 126 MHz)  154.7, 139.3, 128.5, 128.4, 126.9, 80.1, 79.3,
75.0, 66.4, 44.5, 43.7, 28.3; HRMS (ESI): m/z calcd for C16H23NO4
[M+Na]+ 316.1525, found 316.1526.
concentrated
under
reduced
pressure.
Flash
column
chromatography on silica gel eluting with ethyl acetate-methanol
(95:5, v/v) afforded reboxetine as a pale yellow oil.
(2R,3S)-2-(-Hydroxyphenylmethyl)morpholine-4-carboxylic acid t-
butyl ester [(2R,3S)-7]
(2S,3S)-Reboxetine [(2S,3S)-1]
2.11 g, 72%. []D20 -0.7 (c 5.0 in CHCl3); 1H NMR (CDCl3, 500 MHz) 
7.40-7.26 (m, 5H), 4.84 (s, 1H), 3.94-3.71 (m, 3H), 3.62-3.50 (m, 2H),
2.96-2.78 (m, 2H), 2.45 (br s, 1H), 1.40 (s, 9H); 13C NMR (CDCl3, 126
MHz)  154.9, 139.6, 128.4, 127.9, 126.4, 80.0, 78.6, 74.4, 66.7, 43.8,
43.0, 28.3; HRMS (ESI): m/z calcd for C16H23NO4 [M+Na]+ 316.1525,
found 316.1523.
532 mg, 85%. []D20 +27.6 (c 1.0 in CHCl3), [lit7b: []D20 +11.5 (c 0.6 in
CHCl3)]; 1H NMR (CDCl3, 500 MHz)  7.41-7.36 (m, 2H), 7.32-7.28 (m,
2H), 7.27-7.23 (m, 1H), 6.90-6.87 (m, 1H), 6.83-6.78 (m, 2H), 6.72-
6.67 (m, 1H), 5.17 (d, J = 6.06 Hz, 1H), 4.09-4.01 (m, 2H), 3.93-3.87
(m, 2H), 3.62 (ddd, J = 5.02, 9.10, 11.58 Hz, 1H), 2.78-2.71 (m, 2H),
2.61 (dd, J = 9.84, 12.57 Hz, 1H), 2.56 (dd, J = 2.98, 12.61 Hz, 1H), 1.41
(t, J = 7.00 Hz, 3H); 13C NMR (CDCl3, 100 MHz)  149.7, 147.8, 137.7,
127.9, 127.8, 127.3, 121.9, 120.7, 117.4, 114.3, 82.5, 78.7, 67.1, 64.5,
46.5, 44.7, 14.0; HRMS (ESI): m/z calcd for C19H23NO3 [M+H]+
314.1756, found 314.1757.
(2R,3R)-2-(-Hydroxyphenylmethyl)morpholine-4-carboxylic acid
t-butyl ester [(2R,3R)-7]
20
28
2.09 g, 71%. []D -35.8 (c 1.0, CHCl3), [lit11a: []D -42.5 (c 1.0 in
CHCl3)]; 1H NMR (CDCl3, 500 MHz)  7.41-7.27 (m, 5H), 4.53 (dd, J =
2.33, 7.38 Hz, 1H), 3.97 (dd, J = 1.15, 11.37 Hz, 1H), 3.81 (d, J = 11.74
Hz, 1H), 3.67-3.42 (m, 3H), 3.05-2.88 (m, 2H), 2.70 (br s, 1H), 1.39 (s,
9H); 13C NMR (CDCl3, 126 MHz)  154.7, 139.3, 128.5, 128.4, 126.9,
80.1, 79.3, 75.0, 66.4, 44.4, 43.7, 28.3; HRMS (ESI): m/z calcd for
C16H23NO4 [M+Na]+ 316.1525, found 316.1525.
(2R,3S)-Reboxetine [(2R,3S)-1]
314 mg, 50%. []D20 +11.6 (c 1.0 in CHCl3), [lit9a: []D29 +33.3 (c 0.3 in
CHCl3)]; 1H NMR (MeOH-d4, 500 MHz)  7.37 (d, J = 7.23 Hz, 2H), 7.29
(t, J = 7.43 Hz, 2H), 7.26-7.22 (m, 1H), 6.92-6.88 (m, 1H), 6.84-6.79 (m,
1H), 6.70-6.64 (m, 2H), 5.08 (d, J = 6.22 Hz, 1H), 4.12-4.03 (m, 2H),
3.83-3.78 (m, 2H), 3.52 (td, J =3.17, 11.24 Hz, 1H), 3.23 (dd, J = 1.88,
12.71 Hz, 1H), 2.86 (dd, J = 10.09, 12.72 Hz, 1H), 2.83-2.77 (m, 1H),
2.77-2.73 (m, 1H), 2.22 (br s, 1H), 1.43 (t, J = 6.99 Hz, 3H); 13C NMR
(MeOH-d4, 126 MHz)  149.6, 147.5, 138.7, 127.8, 127.6, 127.2,
121.9, 120.6, 117.2, 114.1, 82.3, 79.1, 67.1, 64.4, 46.5, 44.8, 14.1;
HRMS (ESI): m/z calcd for C19H23NO3 [M+H]+ 314.1751, found
314.1752.
(2S,3R)-2-(-Hydroxyphenylmethyl)morpholine-4-carboxylic acid t-
butyl ester [(2S,3R)-7]
2.07 g, 70%. []D20 +0.8 (c 5.0 in CHCl3), [lit7b: []D20 +3.45 (c 2.35 in
CHCl3)]; 1H NMR (CDCl3, 500 MHz)  7.39-7.32 (4H), 7.32-7.27 (m, 1H),
4.84 (s, 1H), 3.94-3.70 (m, 3H), 3.63-3.50 (m, 2H), 2.98-2.77 (m, 2H),
2.48 (br s, 1H), 1.40 (s, 9H); 13C NMR (CDCl3, 126 MHz)  154.9, 139.8,
128.4, 127.8, 126.4, 80.0, 78.7, 74.3, 66.7, 43.8, 43.0, 28.3; HRMS
(ESI): m/z calcd for C16H23NO4 [M+Na]+ 316.1525, found 316.1526.
(2R,3R)-Reboxetine [(2R,3R)-1]
General procedure for transformation of 7 into reboxetine 1
526 mg, 84%. []D20 -27.7 (c 1.0 in CHCl3), []D20 -10.0 (c 1.0 in MeOH),
[lit9a: []D29 -13.9 (c 0.3 in MeOH)]; 1H NMR (CDCl3, 500 MHz)  7.40-
7.37 (m, 2H), 7.32-7.28 (m, 2H), 7.27-7.23 (m, 1H), 6.88 (dd, J = 1.25,
7.94 Hz, 1H), 6.83-6.78 (m, 2H), 6.72-6.67 (m, 1H), 5.16 (d, J = 6.06
Hz, 1H), 4.10-4.01 (m, 2H), 3.94-3.88 (m, 2H), 3.62 (ddd, J = 4.67, 9.47,
To a stirred solution of (2S,3S)-7 (586 mg, 2.0 mmol), PPh3 (630 mg,
2.4 mmol) and imidazole (164 mg, 2.4 mmol) in DCM (10 mL) was
added CBr4 (795 mg, 2.4 mmol) at 0 °C. The mixture was stirred at
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
10 (a) J. Yu and S. Y. Ko, Tetrahedron: Asymmetry 2012, 23, 650;
11.55 Hz, 1H), 2.78-2.72 (m, 2H), 2.61 (dd, J = 9.81, 12.57 Hz, 1H),
2.57 (dd, J = 3.00, 12.61 Hz, 1H), 1.41 (t, J = 6.99 Hz, 3H); 13C NMR
(MeOH-d4, 126 MHz)  149.7, 147.7, 137.7, 127.9, 127.8, 127.3, 121.9,
120.7, 117.4, 114.3, 82.5, 78.7, 67.1, 64.5, 46.5, 44.7, 14.0; HRMS
(ESI): m/z calcd for C19H23NO3 [M+H]+ 314.1751, found 314.1753.
View Article Online
(b) D. M. Aparicio, J. L. Teran, D. GnDeOccI:o1,0.A10.3G9/aCli7nOdBo0,12J8. 3RG.
Juarez, M. L. Orea and A. Mendoza, Tetrahedron: Asymmetry
2009, 20, 2764.
11 (a) N. K. Jobson, A. R. Crawford, D. Dewar, S. L. Pimlott and A.
Sutherland, Bioorg. Med. Chem. Lett. 2009, 17, 4996; (b) N. K.
Jobson, R. Spike, A. R. Crawford, D. Dewar, S. L. Pimlott, and
A. Sutherland, Org. Biolol. Chem. 2008, 6, 2369; (c) N. K.
Jobson, A. R. Crawford, D. Dewar, S. L. Pimlott and A.
Sutherland, Bioorg. Med. Chem. Lett. 2008, 16, 4940.
(2S,3R)-Reboxetine [(2S,3R)-1]
292 mg, 48%. []D20 -11.7 (c 1.0 in CHCl3), [lit9a: []D29 -32.0 (c 0.4 in
CHCl3)]; 1H NMR (MeOH-d4, 500 MHz)  7.39-7.36 (m, 2H), 7.32-7.27
(m 2H), 7.26-7.22 (m, 1H), 6.892-6.88 (m, 1H), 6.84-6.79 (m, 1H),
6.70-6.64 (m, 2H), 5.08 (d, J = 6.22 Hz, 1H), 4.10-4.04 (m, 2H), 3.83-
3.77 (m, 2H), 3.52 (td, J = 3.14, 11.24 Hz, 1H), 3.22 (dd, J = 1.84, 12.69
Hz, 1H), 2.86 (dd, J = 10.08, 12.72 Hz, 1H), 2.83-2.77 (m, 1H), 2.77-
2.72 (m, 1H), 1.43 (t, J = 6.99 Hz, 3H); 13C NMR (MeOH-d4, 126 MHz)
 149.6, 147.5, 138.6, 128.2, 127.9, 127.1, 122.0, 120.8, 117.2, 114.0,
82.8, 79.3, 67.7, 64.6, 46.8, 45.3, 14.9; HRMS (ESI): m/z calcd for
C19H23NO3 [M+H]+ 314.1751, found 314.1760.
12 (a) W. Chen, Z. H. Chen and H. B. Chen, Org. Biomol. Chem.
2017, 15, 1530; (b) D. D. Qin, W. Yu, J. D. Zhou, Y. C. Zhang, Y.
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,
13 For reviews, see: (a) G. Murugavel, P. Sadhu and T.
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Acknowledgements
This work was financially supported by the fundamental
research funds for the central universities (No. 20720160047
and 20720170022) and NSFC (No. 21502158).
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Organic & Biomolecular Chemistry
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DOI: 10.1039/C7OB01283G
EtO
.
Cu-L1c or
OTBS
OTBS
Cu-ent-L1c
O
Four stereoisomers
of reboxetine
*
O
Ph
NO2
*
MeNO2
Ph
*
*
Ph
NH
*
OH
4
Nitroaldol
3
O
Four stereoisomers of antidepressant reboxetine were divergently prepared via Cu-catalyzed
diastereoselective nitroaldol reactions