Dynamic kinetic resolution-based asymmetric transfer hydrogenation of 2-benzoylmorpholinones and its use in concise stereoselective synthesis of all four stereoisomers of the antidepressant reboxetine

Article abstract of DOI:10.1021/jo401102d

Dynamic kinetic resolution-driven, asymmetric transfer hydrogenation reaction of 2-benzoylmorpholin-3-ones (4) proceeds efficiently to give the corresponding (2R,3S)- or (2S,3R)-2-(hydroxyphenylmethyl)morpholin-3-ones (6) with an excellent level of diastereo- and enantioselectivity and simultaneous control of two contiguous stereogenic centers in a single step. This process is employed to prepare all four stereoisomers of the antidepressant reboxetine.

Full text of DOI:10.1021/jo401102d

Article
pubs.acs.org/joc
Dynamic Kinetic Resolution-Based Asymmetric Transfer
Hydrogenation of 2‑Benzoylmorpholinones and Its Use in Concise
Stereoselective Synthesis of All Four Stereoisomers of the
Antidepressant Reboxetine
Se-Mi Son†,‡ and Hyeon-Kyu Lee*,†,‡
†Bio-Organic Science Division, Korea Research Institute of Chemical Technology, PO Box 107, Yuseong, Daejeon 305-600, Korea
‡Department of Medicinal and Pharmaceutical Chemistry, University of Science and Technology, 113 Gwahango, Yuseong, Daejeon
305-333, Korea
S
* Supporting Information
ABSTRACT: Dynamic kinetic resolution-driven, asymmetric transfer hydrogenation reaction of 2-benzoylmorpholin-3-ones (4)
proceeds efficiently to give the corresponding (2R,3S)- or (2S,3R)-2-(hydroxyphenylmethyl)morpholin-3-ones (6) with an
excellent level of diastereo- and enantioselectivity and simultaneous control of two contiguous stereogenic centers in a single
step. This process is employed to prepare all four stereoisomers of the antidepressant reboxetine.
alcohols or amino acids, access to enantiomerically enriched
chiral members of this group is often achieved by using routes
that start from chiral amino alcohols, amino acids, or other
chiral pool sources.1 However, only a limited number of
nonracemic chiral amino alcohols and amino acids are available
in the chiral pool. Moreover, the need to carry out synthetic
sequences to generate specific members of these starting
material families adds to the length of pathways for the
preparation of enantiomerically pure 2-substituted morpho-
lines. Therefore, the development of direct and efficient
methods to synthesize chiral 2-substituted morpholines,
which do not rely on the use of chiral amino alcohols or
amino acids and which utilize well-known chiral catalysts, is a
significant goal of organic chemists interested in devising
efficient routes to biologically important substances containing
the 2-substituted morpholine skeleton.
INTRODUCTION
■
C-Substituted morpholine substructures are found in a variety
of natural products as well as biologically and pharmaceutically
important substances.1 For example, selective norepinephrine
reuptake inhibitors, such as reboxetine (1, A), edivoxetine (B),
and viloxazine (C), possess the 2-substituted morpholine ring
skeleton (Figure 1). In addition, the 2-morpholine structural
In the studies described below, we have developed a new,
highly efficient, and stereoselective method for the synthesis of
(R,S)- and (S,R)-2-(hydroxyphenylmethyl)morpholin-3-ones
(6) starting with the corresponding racemic N-benzyl-2-
benzoylmorpholin-3-ones (4). The process, which enables
simultaneous stereochemical control of two contiguous stereo-
genic centers in a single step, involves dynamic kinetic
resolution (DKR)-driven chiral transition metal-catalyzed
asymmetric transfer hydrogenation (ATH).
Figure 1. Selective norepinephrine reuptake inhibitors possessing the
2-substituted morpholine structure.
scaffold is found in other pharmaceutically active compounds,
such as the NK 1-receptor antagonist aprepitant, antifungal
agent amorofine, and selective GABA β-antagonist SCH-
50911.2
However, despite the importance of these chiral, C-
substituted morpholine-containing substances, only a limited
number of methods have been developed for their nonracemic
synthesis. Because morpholines are often prepared from amino
Received: May 20, 2013
Published: August 5, 2013
© 2013 American Chemical Society
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Asymmetric transfer hydrogenation (ATH), using hydrogen
sources other than molecular hydrogen, has proven to be one of
the most powerful general procedures for asymmetric reduction
of ketone, which yields the corresponding chiral alcohol.3 Major
reasons for this lie in the operational simplicity and excellent
selectivity of the ATH process, the availability of varied
hydrogen sources, and ability to use readily accessible and less
sensitive catalysts. In this context, transition metal-catalyzed
asymmetric transfer hydrogenation of configurationally labile
carbonyl compounds via DKR has emerged as an efficient and
powerful technique for controlling the stereochemistry at two
contiguous stereogenic centers formed in the process. Examples
of this application include ATH of α-substituted β-keto esters,4
β-keto amides,5 β-keto sulfones,6 2-substituted cycloalkanones,7
1,3-diketones,8 1,2-diketones,9 α-keto esters,10 and α-keto
phosphonates.11 Recently, stereoselective ATH-DKR of cyclic
sufamidate imine to the corresponding sulfamidate was also
reported.12 However, there were no previous examples of ATH-
DKR of cyclic α-oxy-β-keto-amides (2-benzoylmorpholine-3-
ones) using chiral Ru- or Rh-catalysts.4,5,13
Table 1. ATH-DKR of N-Benzyl-2-benzoylmorpholin-3-ones
(4)
a
(F/T)
ratio
time
(h)
conv
b
ee
(%)
c
d
entry
4
cat. 5
(%)
dr
1
4a
4a
4a
4a
4a
4a
4a
(R,R)-5a
(R,R)-5b
(R,R)-5c
(R,R)-5d
(R,R)-5e
(R,R)-5e
(R,R)-5e
5:2
5:2
5:2
5:2
5:2
1:1
24
24
24
24
24
12
3
11
−
−
−
−
2
12
3
>99
95/5
96/4
99/1
98/2
99/1
96/4
99/1
99/1
99/1
87
84
99
98
99
95
99
99
4
>99
e
5
>99(96)
>99
6
f
e
e
e
e
e
7
0.2:1
>99(98)
>99(90)
>99(96)
>99(98)
>99(97)
f
8
4b (R,R)-5e
4c (R,R)-5e
4d (R,R)-5e
4a (S,S)-5e
0.2:1
3
f
9
0.2:1
3
f
10
11
0.2:1
3
g
5:2
24
99
RESULTS AND DISCUSSION
■
The racemic N-benzyl-2-aroylmorpholin-3-ones (4), used in
this effort, were easily prepared by employing condensation
reactions of N-benzyl-3-morpholinone (2) with N-aroylmor-
pholines (3) promoted by LDA (Scheme 1).
Scheme 1. Synthesis of N-Benzyl-2-aroylmorpholin-3-ones
(4)
a
4 (1 mmol), 5 (0.5 mol %), F/T (1 mL), CH2Cl2 (10 mL), at 35 °C.
b
c
1
Determined by H NMR. (R,S/S,R)-6a/(R,R/S,S)-6a, determined
d
by chiral HPLC of the crude reaction mixture. Determined by chiral
e
f
HPLC. Isolated yields in parentheses. Neat solution of F/T (0.1 M).
g
%ee of (2S,3R)-6a.
observed that the F/T ratio dramatically affects the time
required for completion of the ATH reaction of 4a catalyzed by
5e (F/T = 5:2, 1:1 and 0.2:1; respective completion time = 24,
12, and 3 h) without deterioration of the dr and ee (entries 5−
7, Table 1).
In preliminary studies, N-benzyl-2-benzoylmorpholin-3-one
(4a) was subjected to ATH reactions using various known
chiral transition metal catalysts 5a−e (0.5 mol %) and a mixture
of formic acid and triethylamine (F/T = 5:2) as the hydrogen
source (Table 1).
The scope of the ATH reaction was explored using the para-
substituted benzoylmorpholin-3-ones 4b−d with the optimized
conditions described above. The results of this effort show that
ATH reactions of the electron-donating group substituted
substrates 4c and 4d generate the corresponding alcohols
(2R,3S)-6c and (2R,3S)-6d with excellent dr and ee (99:1 dr,
99% ee, entries 9 and 10, Table 1) but that, in contrast, the
reaction of the electron-withdrawing group substituted
morpholin-3-one 4b produces (2R,3S)-6b with slightly
decreased dr and ee (96:4 dr, 95% ee, entry 8, Table 1).
In a further exploratory study, we found that ATH reaction
of 4a with the enantiomeric catalyst (S,S)-5e produces the
enantiomeric alcohol (2S,3R)-6a as the major product with
excellent levels of stereoselectivity (99:1 dr, 99% ee). This
observation indicates that the source of dynamic kinetic
resolution in this process is the configurational lability of the
hydrogen at C-2 of 4a, which results in rapid racemization of
the substrate under the ATH reaction conditions (Scheme 2).
As a consequence, the absolute stereochemistry of the major
reduction product depends on the chirality of the Ru-catalysts
used in a manner such that (2R)-4a is preferentially reduced
with (R,R)-5e to afford alcohol (2R,3S)-6a, and (2S)-4a is
preferentially reduced with (S,S)-5e to give alcohol (2S,3R)-6a.
ATH reactions of 4a in CH2Cl2 using the rhodium 5a or
iridium catalyst 5b do not proceed to completion in 24 h at 35
°C (entries 1, 2, Table 1). However, when Noyori’s (R,R)-
RuCl(TsDPEN)(p-cymene) ((R,R)-5c) catalyst is employed,3f
ATH reaction of 4a takes place completely in 24 h to give
(2R,3S)-6a as major product with high levels of diastereo- and
enantioselectivity (95:5 dr, 87% ee, entry 3, Table 1). Similar
observations were made in a study of the ATH reaction of 4a
using Ru-catalyst 5d,5 which has an electron-deficient
pentafluorophenyl sulfonyl group on the chiral ligand. In this
case, (2R,3S)-6a was generated as the major product in 24 h
with a high dr (96:4) but a decreased ee (84%) (entry 4, Table
1). The results of a further effort revealed that ATH reaction of
4a using the catalyst (R,R)-RuCl(TsDPEN)(mesitylene)
((R,R)-5e),3g,4a which possesses an η6-arene = mesitylene
ligand, produces (2R,3S)-6a in the highest yield (>99%), dr
(99:1), and ee (99%) (entry 5, Table 1). (Results of solvent
effect studies are given in the Supporting Information.)
The results of a recent study have shown that the F/T ratio
has a significant effect on both the rates and enantioselectivities
of ATH reactions of ketones.14 In the current effort, we
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a
Scheme 2. Dynamic Kinetic Resolution in ATH of rac-4a
Scheme 3. Synthesis of (S,S)-Reboxetine (1)
a
(a) BH3·THF, THF, 60 °C 2 h, then MeOH, 97%; (b) Ph3PBr2,
CH2Cl2, 50 °C, 95%; (c) 2-EtO-phenol, KOBu-t, t-BuOH/THF (3:1),
80 °C, 24 h, 91%; (d) α-chloroethyl chloroformate, (i-Pr)2NEt,
CH2Cl2, 50 °C, 4 h, then MeOH, reflux, 2 h, 86%.
a
Scheme 4. Synthesis of (S,S)-Reboxetine (1)
Moreover, single recrystallizations of the products (2R,3S)-6a
and (2S,3R)-6a arising from the respective reactions promoted
by (R,R)-5e and (S,S)-5e produce the corresponding optically
pure substances (dr and ee >99%). The absolute stereo-
chemistry of (2S,3R)-6a was determined by using X-ray
crystallographic analysis (deposited, CCDC 898360, see
Supporting Information).
a
(a) i. NaH, DMF, rt, 2 h; ii. I2, THF, 0 °C to rt, 1 h, 88%; (b) see
Scheme 3.
The resulting optically pure morpholine alcohols, (2R,3S)-6a
and (2S,3R)-6a, could potentially serve as valuable late stage
intermediates in routes for the preparation of biologically
important substances possessing the 2-substituted morpholine
ring system and, in particular, those that are selective
norepinephrine and dual serotonine/norepinephrine reuptake
inhibitors.15 Reboxetine (1) is a potent selective norepinephr-
ine reuptake inhibitor, currently marketed in over 60 countries
for the treatment of depression under the trade names Edronax,
Prolift, Vestra, Norebox, and Integrex.16 While reboxetine is
commercially sold as a racemic mixture of (2S,3S)- and
(2R,3R)-enantiomers, recent studies have shown that the
(2S,3S)-isomer, named as (S,S)-reboxetine, is significantly
more active and selective for the norepinephrine transporter
(NET) than is the racemate.17,18 In addition, (S,S)-reboxetine
succinate is currently undergoing advanced clinical evaluation
as a drug for the treatment of neurophatic pain, fibromyalgia,
and other indications.19
One early pathway developed for (S,S)-reboxetine synthesis
relied on the use of a S-(+)-mandelic acid-promoted, chiral
resolution of racemic reboxetine.20 Other strategies uncovered
for the synthesis of (S,S)-reboxetine are based on the use of
optically active starting materials17 or Sharpless epoxidation/
dihydroxylation steps.18 However, most of these methods
require the utilization of stoichiometric amounts of expensive
chiral starting materials or long (9−10 steps) reaction
sequences.17−19,21,22 Only recently, a highly efficient, stereo-
selective synthesis of (S,S)-reboxetine, which employs a key
BINAP-based, Ru-catalyst promoted asymmetric hydrogenation
(10−50 atm) step was described.13
is then converted to the corresponding morpholine bromide
(2S,3R)-8a using Ph3PBr2, a process that takes place with
inversion of configuration. Bromide displacement of (2S,3R)-8a
with 2-ethoxyphenol in the presence of KOBu-t provides the N-
benzyl-protected (S,S)-reboxetine (2S,3S)-9a. It should be
noted that the use of t-BuOH/THF (3:1) as a solvent for this
process causes an improvement in the yield reported earlier
(80%) when t-BuOH alone is used as solvent to 91%. This
enhancement is likely a result of the improved solubility of
bromide (2S,3R)-8a in t-BuOH/THF. Treatment of (2S,3S)-9a
with α-chloroethyl chloroformate followed by methanolysis of
the intermediate α-chloroethyl carbamate promotes selective
removal of the N-benzyl group and generates (S,S)-reboxetine
(1) in a four-step route from optically pure alcohol (2R,3S)-6a
in 72% overall yield and without deterioration of optical purity
(Scheme 3). (R,R)-Reboxetine (1) was also prepared from
optically pure (2S,3R)-6a (67% overall yield) using essentially
the same procedure as employed for the production of (S,S)-
reboxetine (see Experimental Section).
In an alternative synthetic route, the 2-ethoxyphenyl group in
the target is directly incorporated into the morpholine benzyl
alcohol (2S,3S)-7a with retention of stereochemistry at the
benzylic alcohol position (Scheme 4). Thus, reaction of
morpholine benzyl alcohol (2S,3S)-7a with the tricarbonyl-
chromium complex of 1-ethoxy-2-fluorobenzene17 in the
presence of NaH, followed by subsequent oxidative dechromi-
nation with iodine, provides N-benzyl-protected (S,S)-rebox-
etine (2S,3S)-9a.
To demonstrate the usefulness of the ATH-DKR reaction of
2-benzoylmorpholinones, herein we describe a concise syn-
thesis of (S,S)-reboxetine (1) starting with the optically pure
alcohol (2R,3S)-6a (Scheme 3).
The sequence used for this purpose utilizes a yield improving
modification of the one previously described for the trans-
formation of racemic (R,S/S,R)-6a to racemic (R,R/S,S)-
reboxetine (1).15 First, reduction of the lactam moiety in
(2R,3S)-6a with BH3·THF smoothly produces the morpholine
benzyl alcohol (2S,3S)-7a in excellent yield (97%). This alcohol
While great attention has been given to the synthesis and
pharmaceutical evaluation of (2S,3S)-reboxetine, much less is
known about the preparation and biological properties of its
(2S,3R)- and (2R,3S)-diastereomers.23,24 Therefore, the devel-
opment of convenient routes for stereoselective synthesis of
(R,S)- and (S,R)-reboxetine could benefit research programs
focusing on norepinephrine transporter (NET) modulators.
We observed that (2S,3R)-reboxetine can be conveniently
prepared from the same intermediate (2S,3S)-7a used in the
(2S,3S)-reboxetine synthetic pathway (Scheme 5).
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a
1. General Procedure for the Synthesis of 2-Benzoyl-4-
benzylmorpholin-3-one (4). A solution of LDA (2.0 M, 13.75 mL,
27.5 mmol) in THF (60 mL) was cooled to −78 °C and treated with
4-benzylmorpholin-3-one15 (2, 4.78 g, 25 mmol) in THF (20 mL) and
stirred for 30 min at that temperature to give a pale yellow solution. N-
Benzoylmorpholine (3, 5.5 g, 28.7 mmol) in THF (20 mL) was added
dropwise to the above solution. The reaction was allowed to slowly
warm to 10 °C and then quenched by addition of saturated aqueous
NaHCO3 solution. The reaction mixture was extracted with EtOAc
(70 mL × 2), and the combined organic layers were washed with
brine, dried over MgSO4, and concentrated under reduced pressure.
The residue was purified by flash chromatography (SiO2, hexane/
EtOAc 8:1 to 5:1) to give 2-benzoyl-4-benzylmorpholin-3-one (4a, 6.9
g, 93%) as pale yellow oil.
Scheme 5. Synthesis of (2S,3R)-Reboxetine
a
(a) DIAD, PPh3, THF, 0 °C to rt, 24 h, 72%; (b) see d of Scheme 3,
75%.
Thus, reaction of (2S,3S)-7a with 2-ethoxyphenol under
Mitsunobu conditions affords (2S,3R)-9a with inversion of
stereochemistry at benzylic position. Subsequent N-debenzyla-
tion of (2S,3R)-9a produces (2S,3R)-reboxetine (99% ee, 54%
yield over two steps). (2R,3S)-Reboxetine was also prepared
(99% ee, 45% overall yield) starting with optically pure
(2R,3R)-7a using essentially the same procedure (see
Experimental Section).
1.1. 2-Benzoyl-4-benzylmorpholin-3-one (4a).
In summary, we have successfully achieved the first example
of dynamic kinetic resolution-driven chiral Ru-catalyzed
asymmetric transfer hydrogenation reactions of readily available
racemic 2-benzoylmorpholin-3-ones (4) that give the corre-
sponding (R,S)- and (S,R)-2-(hydroxyphenylmethyl)-
morpholin-3-ones (6). In this process, stereochemistry at two
contiguous stereogenic centers is controlled simultaneously
with excellent levels of diastereo- and enantioselectivity. In
addition, this study has resulted in the development of efficient,
highly stereoselective routes for the preparation of all four
stereoisomers [(S,S)-, (R,R)-, (S,R)-, (R,S)] of reboxetine from
the common intermediates, (2R,3S)-6a and (2S,3R)-6a, which
are produced by chiral Ru-catalyzed ATH-DKR of racemic N-
benzyl-2-benzoyl-3-morpholinone (4a).
Yield: 93% (6.9 g), pale yellow oil. Keto and enol mixture; enol
1
form:keto form = 1:0.4−0.9 by H NMR analysis.
1
Enol form: H NMR (500 MHz, CDCl3) δ 13.17 (s, 1H), 7.99 (d,
2H, J = 7.6 Hz), 7.32−7.44 (m, 8H), 4.74 (s, 2H), 4.05 (t, 2H, J = 4.9
Hz), 3.43 (t, 2H, J = 4.9 Hz).
Keto form: 1H NMR (500 MHz, CDCl3) δ 8.1 (d, 2H, J = 7.5 Hz),
7.62 (t, 1H, J = 7.4 Hz), 7.51 (t, 2H, J = 7.8 Hz), 7.32−7.44 (m, 5H),
5.64 (s, 1H), 4.87 (d, 1H, J = 14.6 Hz), 4.54 (d, 1H, J = 14.6 Hz),
4.16−4.21 (m, 1H), 3.94−3.90 (m, 1H), 3.42−3.34 (m, 2H).
13C NMR (75 MHz, CDCl3) δ 193.9, 165.8, 164.2, 153.7, 136.1,
135.9, 135.2, 133.9, 133.5, 129.7, 129.5, 129.0, 128.9, 128.7, 128.5,
128.4, 128.2, 128.0, 127.9, 125.2, 77.9, 64.0, 62.2, 49.9, 49.6, 45.8, 45.5.
HRMS (EI): m/z calcd for C18H17NO3 295.1208, found 295.1208.
1.2. 2-(4-Chlorobenzoyl)-4-benzylmorpholin-3-one (4b).
EXPERIMENTAL SECTION
■
General Methods. Dichloromethane, ether, THF were dried and
purified using a solvent purification system. Flash column chromatog-
raphy was carried out on silica gel (38−75 μm). Analytical thin layer
chromatography (TLC) was performed on silica gel 60 F254 plates.
Preparative thin layer chromatography (PLC) was performed on silica
gel 60 F254 2 mm plates. Visualization of the developed chromatogram
was accomplished with UV light and by staining with ethanolic
phosphomolybdic acid (PMA) solution or ninhydrin solution followed
by heating.
Yield: 93% (2 g), pale yellow solid, mp: 107.7−109.6 °C.
1
Predominantly exist as enol form by H NMR analysis. Enol
1
form: H NMR (500 MHz, CDCl3) δ 13.13 (s, 1H), 7.94 (d,
2H, J = 8.8 Hz), 7.40−7.33 (m, 7H), 4.74 (s, 2H), 4.07 (t, 2H, J
= 4.9 Hz), 3.46 (t, 2H, J = 5.0 Hz). 13C NMR (75 MHz,
CDCl3) δ 165.5, 152.3, 135.9, 135.2, 131.9, 129.8, 128.9, 128.1,
128.1, 127.9, 125.3, 64.0, 49.6, 45.6. HRMS (EI): m/z calcd for
C18H16ClNO3 329.0819, found 329.0812.
Nuclear magnetic resonance (NMR) spectra were recorded using a
500 MHz NMR instrument (1H NMR at 500 MHz and 13C NMR at
125 MHz) or a 300 MHz NMR instrument (1H NMR at 300 MHz
1.3. 2-(4-Methylbenzoyl)-4-benzylmorpholin-3-one (4c).
1
and 13C NMR at 75 MHz). H NMR data are reported as follows:
chemical shift (δ, ppm), multiplicity (s = singlet, d = doublet, t =
triplet, q = quartet, m = multiplet, br = broad), integration, coupling
constants (Hz). Data for 13C NMR are reported in terms of chemical
shift (δ, ppm). High performance liquid chromatography (HPLC) was
carried out on a HPLC system equipped with a Chiralpak IB,
Chiralpak IC, or Chiralpak AD-H column. HR-MS were measured
with electron impact (EI) ionization via double focusing mass analyzer
(magnetic and electric fields) or electrospray ionization (ESI) via time
of flight (TOF) analyzer.
The formic acid/triethylamine mixtures (molar ratio = 5:2 or 1:1)
are commercially available. The formic acid/triethylamine mixture
(molar ratio = 0.2:1) was prepared by slow addition of formic acid to
triethylamine with stirring at rt according to the literature procedure.14
N-Benzoylmorpholine derivatives27 (3a−d) were prepared from the
condensation reaction of the corresponding benzoyl chloride and
excess morpholine in CH2Cl2 (90−97%). Chiral catalysts (R,R)-5c,
(R,R)-5d, and (R,R)-5e are commercially available. (R,R)-5a25 and
(R,R)-5b26 were prepared according to the literature procedures.
Yield: 81% (2 g). Keto and enol mixture; enol form:keto form
1
= 1:0.1−0.2 by H NMR analysis.
1
Enol form: H NMR (500 MHz, CDCl3) δ 13.11 (s, 1H), 7.86 (d,
2H, J = 8.3 Hz), 7.39−7.32 (m, 5H), 7.23(d, 2H, J = 8.2 Hz), 4.74 (s,
2H), 4.06 (t, 2H, J = 5.0 Hz), 3.45 (t, 2H, J = 5.0 Hz), 2.40 (s, 3H).
Keto form: 1H NMR (500 MHz, CDCl3) δ 8.00 (d, 2H, J = 8.2 Hz),
7.41−7.30 (m, 7H), 5.63 (s, 1H), 4.86 (d, 1H, J = 14.8 Hz), 4.56 (d,
1H, J = 14.7 Hz), 4.20−4.18 (m, 1H), 3.94−3.91 (m, 1H), 3.43−3.41
(m, 1H), 3.38−3.37 (m, 1H), 2.45 (s, 3H).
13C NMR (75 MHz, CDCl3) δ 193.4, 165.7, 164.2, 153.9, 144.8,
139.6, 136.1, 135.9, 132.7, 130.6, 129.7, 129.3, 128.9, 128.8, 128.6,
128.3, 128.3, 128.1, 127.8, 124.8, 77.7, 63.9, 62.1, 49.8, 49.5, 45.8, 45.5,
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21.8, 21.5. HRMS (EI): m/z calcd for C19H19NO3 309.1365, found
309.1357.
1.4. 2-(4-Methoxybenzoyl)-4-benzylmorpholin-3-one (4d).
140.6, 135.5, 128.8, 128.1, 128.0, 127.7, 127.6, 126.8, 79.7, 73.6,
63.1, 49.8, 45.7; HRMS (EI): m/z calcd for C18H19NO3
297.1365, found 297.1365.
2.2. (2S,3R)-4-Benzyl-2-(hydroxyphenylmethyl)morpholin-3-one
[(2S,3R)-6a].
Yield: 75% (2 g). Keto and enol mixture; enol form:keto form
1
= 1:0.4−0.5 by H NMR analysis.
1
To 2-benzoyl-4-benzylmorpholin-3-one (4a, 3.3 g, 11.2 mmol)
in CH2Cl2 (60 mL) were added sequentially (S,S)-5e catalyst
(35 mg, 0.056 mmol) and HCO2H/Et3N (5:2) (7 mL), and the
mixture was stirred for 24 h at 35 °C. The reaction mixture was
diluted with CH2Cl2 (50 mL) and washed with saturated
aqueous NaHCO3, H2O, and brine. The solution was dried
over MgSO4 and concentrated under reduced pressure to afford
crystalline solid. The product was fractionated on a short path
column of SiO2 to remove colored impurity to give white
crystals (3.24 g, 97%, dr = 99:1, 99.0% ee). Recrystallization at
EtOAc/n-hexane produced optically pure product (>99% ee
and dr). mp: 117.3−118.2 °C; Chiralpak IB, 10% 2-propanol/
n-hexane, 1.5 mL/min, 254 nm, tR(major) = 8.7 min, tR(minor)
= 10.7 min; [α]D = −96.8 (c 0.8, CHCl3); H NMR (500
MHz, CDCl3) δ 7.49 (d, 2H, J = 7.1 Hz), 7.39−7.32 (m, 3H),
7.30−7.27 (m, 3H), 7.02−6.99 (m, 2H), 5.25 (dd, 1H, J = 9.6
Hz, J = 3.2 Hz), 4.78 (d, 1H, J = 14.8 Hz), 4.57 (d, 1H, J = 3.1
Hz), 4.37−4.34 (m, 2H), 4.00−3.96 (m, 1H), 3.75 (dt, 1H, J =
3.0, 11.6 Hz), 3.26 (dt, 1H, J = 4.1, 12.1 Hz), 2.97−2.93 (m,
1H); 13C NMR (75 MHz, CDCl3) δ 168.3, 140.6, 135.5, 128.8,
128.1, 127.9, 127.7, 127.6, 126.8, 79.7, 73.6, 63.0, 49.8, 45.7;
HRMS (EI): m/z calcd for C18H19NO3 297.1365, found
297.1364.
Enol form: H NMR (500 MHz, CDCl3) δ 13.18 (s, 1H), 8.08 (d,
2H, J = 9.0 Hz), 7.40−7.32 (m, 5H), 6.98(d, 2H, J = 8.9 Hz), 4.74 (s,
2H), 4.07 (t, 2H, J = 4.8 Hz), 3.87(s, 3H). 3.45 (t, 2H, J = 4.7 Hz).
1
Keto form: H NMR (500 MHz, CDCl3) δ 8.09−8.05 (m, 1H),
7.96(d, 1H, J = 9.1 Hz), 7.40−7.32(m, 5H), 7.00−6.96(m, 1H),
6.94(d, 1H, J = 9.0 Hz), 5.62 (s, 1H), 4.86 (d, 1H, J = 14.6 Hz), 4.55
(d, 1H, J = 14.6 Hz), 4.23−4.19 (m, 1H), 3.95−3.91 (m, 1H), 3.91 (s,
3H), 3.46−3.41 (m, 1H), 3.38−3.35 (m, 1H).
13C NMR (75 MHz, CDCl3) δ 192.2, 165.8, 164.4, 164.1, 160.4,
153.7, 136.1, 135.8, 132.2, 132.0, 130.0, 128.8, 128.8, 128.3, 128.2,
128.1, 127.8, 126.0, 124.4, 113.8, 113.7, 113.3, 63.9, 62.0, 55.5, 55.3,
49.8, 49.4, 45.8, 45.5. HRMS (EI): m/z calcd for C19H19NO4
325.1314, found 325.1308.
2. General Procedure for the ATH-DKR Reaction of 2-Benzoyl-4-
benzylmorpholin-3-one (4). With F/T = 5:2: To 2-benzoyl-4-
benzylmorpholin-3-one (4a, 3.48 g, 11.8 mmol) in CH2Cl2 (60 mL)
were added sequentially (R,R)-5e catalyst (37 mg, 0.06 mmol, 0.005
equiv) and HCO2H/Et3N (5:2) (7 mL), and the mixture was stirred
for 24 h at 35 °C. The reaction mixture was diluted with CH2Cl2 (50
mL) and washed with saturated aqueous NaHCO3, H2O, and brine.
The solution was dried over MgSO4 and concentrated under reduced
pressure to afford crystalline solid. The product was fractionated on a
short path column of SiO2 to remove colored impurity to give white
crystals (3.35 g, 96%, dr = 99:1, 99% ee). Recrystallization in EtOAc/
n-hexane produced optically pure product (3.0 g, >99% ee and dr).
Yield: 96%, dr = 99:1, 99% ee.
With F/T = 0.2:1: To 2-benzoyl-4-benzylmorpholin-3-one (4a, 150
mg, 0.51 mmol) in HCO2H/Et3N (0.2:1) mixture (2.4 mL) was added
(R,R)-5e catalyst (1.6 mg, 2.5 μmol 0.005 equiv), and the mixture was
stirred for 3 h at 40 °C. The reaction mixture was diluted with EtOAc
(10 mL) and water (10 mL). Next the organic layer was separated, and
aqueous layer was extracted again with EtOAc (5 mL × 2). The
combined organic layer was washed with saturated aqueous NaHCO3,
H2O, and brine. The solution was dried over MgSO4 and concentrated
under reduced pressure to afford crystalline solid. The product was
fractionated on a short path column of SiO2 to remove colored
impurity to give white crystals (149 mg, 98.4%, dr = 99:1, 99.6% ee).
Recrystallization in EtOAc/n-hexane produced optically pure product
(>99% ee and dr).
19
1
2.3. (2R,3S)-4-Benzyl-2-[hydroxy-(4-chlorophenyl)methyl]-
morpholin-3-one [(2R,3S)-6b].
Yield: 95% (170 mg) at F/T = 5:2, 90% at F/T = 0.2:1; mp:
125.8−127.6 °C; dr = 96:4; 95.3% ee (Chiralpak IB, 10% 2-
propanol/n-hexane, 1.0 mL/min, 254 nm, tR(minor) = 13.8
min, tR(major) = 16.5 min); [α]D31 = +62.6 (c 0.3, CHCl3);1H
NMR (500 MHz, CDCl3) δ 7.42 (d, 2H, J = 8.3 Hz), 7.32−
7.29 (m, 5H), 6.92−6.91 (m, 2H), 5.15 (d, 1H, J = 5.6 Hz),
4.85 (d, 1H, J = 14.7 Hz), 4.58 (d, 1H, J = 9.3 Hz), 4.55 (d, 1H,
J = 3.5 Hz), 4.23 (d, 1H, J = 14.7 Hz), 3.96 (dd, 1H, J = 3.1 Hz,
J = 11.9 Hz), 3.78 (dt, 1H, J = 3.0 Hz, J = 11.5 Hz), 3.23 (dt,
1H, J = 4.2 Hz, J = 12.0 Hz), 2.94 (d, 1H, J = 12.3 Hz); 13C
NMR (75 MHz, CDCl3) δ 168.3, 139.1, 135.3, 133.4, 128.9,
128.3, 128.2, 127.9, 127.9, 79.3, 73.0, 63.1, 49.9, 45.7; HRMS
(EI): m/z calcd for C18H18NO3Cl 331.0975, found 331.0972.
2.4. (2R,3S)-4-Benzyl-2-(hydroxy-p-tolylmethyl)morpholin-3-one
[(2R,3S)-6c].
2.1. (2R,3S)-4-Benzyl-2-(hydroxyphenylmethyl)morpholin-3-one
[(2R,3S)-6a].
Yield: 96−98% (3.35 g); mp: 117.3−118.2 °C; dr = 99:1; 99%
ee: Chiralpak IB, 10% 2-propanol/n-hexane, 1.5 mL/min, 254
nm, tR(minor) = 8.9 min, tR(major) = 10.2 min; [α]D18 = +95.6
(c 1.2, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.50−7.48 (m,
2H), 7.39−7.34 (m, 3H), 7.29−7.26 (m, 3H), 7.00−6.98 (m,
2H), 5.24 (dd, 1H, J = 9.7 Hz, J = 3.4 Hz), 4.79 (d, 1H, J = 14.7
Hz), 4.57 (d, 1H, J = 3.4 Hz), 4.35 (d, 1H, J = 14.9 Hz), 4.32
(d, 1H, J = 9.8 Hz), 3.98 (ddd, 1H, J = 1.6, 4.2, 11.9 Hz), 3.76
(dt, 1H, J = 3.1, 11.2 Hz), 3.25 (dt, 1H, J = 4.3, 12.0 Hz), 2.95
(d, 1H, J = 12.3 Hz); 13C NMR (125 MHz, CDCl3) δ 168.4,
Yield: 96% (160 mg); mp: 113.4−115.2 °C; dr = 99:1; 98.9%
ee; Chiralpak IB, 20% 2-propanol/n-hexane, 1.5 mL/min, 254
8400
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nm, tR(minor) = 4.9 min, tR(major) = 5.4 min; [α]D31 = +92.3
(c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.37 (d, 2H, J =
7.9 Hz), 7.29−7.27 (m, 3H), 7.18 (d, 2H, J = 7.9 Hz), 7.02 (m,
2H), 5.22 (dd, 1H, J = 9.5 Hz, J = 3.0 Hz), 4.81 (d, 1H, J = 14.8
Hz), 4.55 (d, 1H, J = 3.2 Hz), 4.36 (d, 1H, J = 14.8 Hz), 4.15
(d, 1H, J = 9.6 Hz), 4.00−3.97 (m, 1H), 3.76 (dt, 1H, J = 3.1
Hz, J = 11.2 Hz), 3.28 (dt, 1H, J = 4.4 Hz, J = 12.2 Hz), 2.96 (d,
1H, J = 12.3 Hz), 2.40(s, 3H); 13C NMR (75 MHz, CDCl3) δ
168.4, 137.7, 137.2, 135.6, 128.9, 128.8, 128.0, 127.8, 126.7,
79.8, 73.5, 63.1, 49.9, 45.8, 21.3; HRMS (EI): m/z calcd for
C19H21NO3 311.1521, found 311.1516.
128.2, 127.3, 127.1, 79.5, 75.6, 66.7, 63.4, 55.2, 52.4; HRMS
(EI): m/z calcd for C18H21NO2 283.1572, found 283.1573.
3.2. (2R,3R)-(4-Benzylmorpholin-2-yl)phenylmethanol [(2R,3R)-
7].
18
Yield: 95.7% (2.0 g); mp: 70.9−72.7 °C; [α]D = +3.7 (c 0.3,
CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.38−7.25 (m, 10H),
4.61 (d, 1H, J = 7.4 Hz), 3.97 (dt, 1H, J = 2.6, 11.3 Hz), 3.72−
3.67 (m, 2H), 3.56 (d, 1H, J = 12.9 Hz), 3.33 (d, 1H, J = 13.0
Hz), 3.21 (brs, 1H), 2.60 (d, 1H, J = 11.4 Hz), 2.48 (d, 1H, J =
11.4 Hz), 2.18 (dt, 1H, J = 3.1, 11.1 Hz), 2.11 (dd, 1H, J = 9.8,
10.9 Hz); 13C NMR (75 MHz, CDCl3) δ 140.1, 137.3 129.3,
128.5, 128.3, 128.1, 127.3, 127.1, 79.4, 75.5, 66.5, 63.3, 55.1,
52.3; HRMS (EI): m/z calcd for C18H21NO2 283.1572, found
283.1574.
2.5. (2R,3S)-4-Benzyl-2-[hydroxy-(4-methoxyphenyl)methyl]-
morpholin-3-one [(2R,3S)-6d].
Yield: 98% (170 mg); mp: 128.4−129.1 °C; dr = >99:1; 99.3%
ee (Chiralpak IB, 20% 2-propanol/n-hexane, 1.5 mL/min, 254
nm, tR(minor) = 6.5 min, tR(major) = 7.3 min); [α]D31 = +75.3
(c 0.3, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.40 (d, 2H, J =
8.7 Hz), 7.29−7.27 (m, 3H), 6.99−6.98 (m, 2H), 6.90 (d, 2H, J
= 8.7 Hz), 5.17 (dd, 1H, J = 9.6 Hz, J = 3.2 Hz), 4.82 (d, 1H, J
= 14.8 Hz), 4.54 (d, 1H, J = 3.3 Hz), 4.32 (d, 1H, J = 14.7 Hz),
4.31 (d, 1H, J = 9.4 Hz), 4.00−3.97 (m, 1H), 3.85(s, 3H), 3.77
(dt, 1H, J = 3.0 Hz, J = 11.5 Hz), 3.25 (dt, 1H, J = 4.2 Hz, J =
12.1 Hz), 2.95 (d, 1H, J = 12.3 Hz); 13C NMR (75 MHz,
CDCl3) δ 168.5, 159.2, 135.6, 132.7, 128.8, 128.0, 128.0, 127.8,
113.5, 79.7, 73.3, 63.1, 55.3, 49.8, 45.8; HRMS (EI): m/z calcd
for C19H21NO4 327.1471, found 327.1466.
4. Conversion of Alcohol to Bromide. 4.1. Synthesis of (2S,3R)-4-
Benzyl-2-(bromophenylmethyl)morpholine [(2S,3R)-8].
To a solution of (2S,3S)-(4-benzylmorpholin-2-yl)-
phenylmethanol (2 g, 7.1 mmol) in anhydrous CH2Cl2 (70
mL) under nitrogen was added PPh3·Br2 (6 g, 14.2 mmol). The
reaction mixture was stirred for 6 h under reflux. The reaction
mixture was cooled to room temperature and washed with
saturated aqueous NaHCO3 solution, dried over MgSO4, and
concentrated under reduced pressure. The resulting residue was
purified by flash chromatography (SiO2, hexane/EtOAc 10:1)
3. Borane Reduction of Morphlin-3-one to Morpholine. 3.1. Syn-
thesis of (2S,3S)-(4-Benzylmorpholin-2-yl)phenylmethanol [(2S,3S)-
7].
to give (2S,3R)-4-benzyl-2-(bromophenylmethyl)morpholine
26
(2.3 g, 95%) as a white solid. Mp: 69.3−71.5 °C; [α]D
=
1
−90.1 (c 1.0, CHCl3); H NMR (500 MHz, CDCl3) δ 7.46−
7.28 (m, 10H), 4.94 (d, 1H, J = 8.0 Hz), 4.11 (dt, 1H, J = 2.1
Hz, J = 9.3 Hz), 3.83 (dt, 1H, J = 2.5, 11.3 Hz), 3.65 (d, 1H, J =
13.0 Hz), 3.61 (dd, 1H, J = 2.3 Hz, J = 11.1 Hz), 3.49 (d, 1H, J
= 13.0 Hz) 3.29 (d, 1H, J = 11.2 Hz), 2.60−2.58 (m, 1H),
2.19−2.15 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 139.3,
137.7, 129.2, 128.7, 128.6, 128.5, 128.4, 127.4, 78.1, 67.1, 63.3,
56.9, 54.0, 52.5; HRMS (EI): m/z calcd for C18H20BrNO
345.0728, found 345.0729.
To a solution of (2R,3S)-4-benzyl-2-(hydroxyphenylmethyl)-
morpholin-3-one (6a, 2.93 g, 9.8 mmol) in anhydrous THF (50
mL) under nitrogen at room temperature was slowly added
BH3·THF (1 M in THF, 39 mL, 39 mmol). The solution was
stirred at 60 °C for 3 h. After cooling to 0 °C, dry MeOH (20
mL) was slowly added to quench excess borane reagent.
Aqueous HCl solution (1 M, 20 mL) was added, and the
reaction mixture was heated to 60 °C for 1 h. The organic
solvents were evaporated under reduced pressure, and the
concentrated solution was poured onto aqueous K2CO3
solution (1 M, 100 mL) and extracted with diethyl ether
(100 mL × 3). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by flash chromatograph
(SiO2, hexane/EtOAc 3:1 to 2:1) to give (2S,3S)-(4-
benzylmorpholin-2-yl)phenylmethanol (2.67 g, 97%) as white
4.2. (2R,3S)-4-Benzyl-2-(bromophenylmethyl)morpholine
[(2R,3S)-8].
Yield: 85.7% (1.2 g); mp: 69.9−72.2 °C; [α]D28 = +89.2 (c 1.0,
1
CHCl3); H NMR (500 MHz, CDCl3) δ 7.45 (d, 2H, J = 7.3
18
1
solid. Mp: 70.1−71.5 °C; [α]D = −3.2 (c 1.2, CHCl3); H
NMR (500 MHz, CDCl3) δ 7.39−7.25 (m, 10H), 4.60 (d, 1H,
J = 7.4 Hz), 3.97 (dt, 1H, J = 2.8, 11.3 Hz), 3.72−3.67 (m, 2H),
3.57 (d, 1H, J = 13.0 Hz), 3.32 (d, 1H, J = 13.0 Hz), 3.19 (brs,
1H), 2.60 (d, 1H, J = 11.5 Hz), 2.49 (d, 1H, J = 11.3 Hz), 2.17
Hz), 7.38−7.28 (m, 8H), 4.94 (d, 1H, J = 8.0 Hz), 4.12−4.08
(m, 1H), 3.83 (dt, 1H, J = 2.6, 11.3 Hz), 3.67−3.59 (m, 2H),
3.48 (d, 1H, J = 13.0 Hz) 3.28 (d, 1H, J = 11.3 Hz), 2.58 (dd,
1H, J = 1.2, 11.5 Hz), 2.19−2.14 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 139.3, 137.7, 129.2, 128.7, 128.6, 128.5, 128.5, 127.4,
78.1, 67.1, 63.3, 56.9, 54.0, 52.5; HRMS (EI): m/z calcd for
C18H20BrNO 345.0728, found 345.0729.
(dt, 1H, J = 3.2 Hz, J = 11.1 Hz), 2.11 (t, 1H, J = 10.4 Hz); 13
C
NMR (125 MHz, CDCl3) δ 140.1, 137.6, 129.3, 128.5, 128.4,
8401
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5. Synthesis of N-Benzylreboxetine. 5.1. Synthesis of (2S,3S)-4-
Benzyl-2-[(2-ethoxyphenoxy)phenylmethyl]morpholine [(2S,3S)-9].
of DMF at room temperature under nitrogen atmosphere. η6-(1-
Ethoxy-2-fluorobenzene)tricarbonylchromium17 (456 mg, 1.65 mmol)
in DMF (3 mL) was added to the mixture and stirred for 2 h at room
temperature. The reaction mixture was cooled to 0 °C, and a solution
of I2 (1.68 g, 6.6 mmol) in 5 mL of THF was added dropwise over 30
min. The reaction mixture was stirred for an additional 30 min at room
temperature, and then 10% Na2S2O3 (50 mL) solution was added. The
mixture was extracted with EtOAc (30 mL × 3), and combined
organic layers were washed with H2O (30 mL × 2), dried over MgSO4,
and concentrated under reduced pressure. The residue was purified by
flash chromatograph (SiO2, hexane/EtOAc 5:1 to 3:1) to give (2S,3S)-
4-benzyl-2-[(2-ethoxyphenoxy)phenylmethyl]morpholine (390 mg,
88%) as a sticky oil. The spectroscopic (1H and 13C NMR) and
optical data of this compound were exactly same as those of the
compound prepared from the above method (section 5.1).
5.4. Synthesis of (2S,3R)-4-Benzyl-2-[(2-ethoxyphenoxy)-
phenylmethyl]morpholine [(2S,3R)-9]. To a solution of (2S,3S)-(4-
benzylmorpholin-2-yl)phenylmethanol (600 mg, 2.12 mmol), Ph3P
(1.12 g, 4.24 mmol), and 2-ethoxyphenol (590 mg, 4.24 mmol) in 20
mL of THF at 0 °C was added diisopropyl azodicarboxylate (860 mg,
4.24 mmol). The reaction mixture was allowed to reach room
temperature and stirred for 24 h. The reaction mixture was evaporated
under reduced pressure and purified by flash chromatography on silica
gel (hexane/EtOAc 7:1 to 5:1) to give (2S,3R)-4-benzyl-2-[(2-
ethoxyphenoxy)phenylmethyl]morpholine (615 mg, 72%) as a sticky
oil.
To a solution of 2-ethoxyphenol (1.32 g, 9.54 mmol) in
anhydrous t-BuOH (10 mL) was added dropwise potassium
tert-butoxide solution (1 M in t-BuOH, 9.6 mL, 9.6 mmol), and
the mixture was stirred for 10 min at room temperature. In
another round-bottomed flask, (2S,3R)-4-benzyl-2-
(bromophenylmethyl)morpholine (1.65 g, 4.77 mmol) was
dissolved in anhydrous t-BuOH (30 mL) and THF (10 mL).
This solution was added dropwise to the potassium 2-
ethoxyphenoxide solution, and the mixture was heated to
reflux for 24 h. The reaction mixture was cooled to room
temperature, and most of solvent was evaporated under
reduced pressure. H2O (50 mL) and EtOAc (50 mL) was
added, and the aqueous layer was extracted again with EtOAc
(30 mL × 2). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated under reduced
pressure. The residue was purified by flash chromatograph
(SiO2, hexane/EtOAc 5:1 to 3:1) to give (2S,3S)-4-benzyl-2-
[(2-ethoxyphenoxy)phenylmethyl]morpholine (1.75 g, 91%) as
29
1
a sticky oil: [α]D = +23.8 (c 1.0, CHCl3); H NMR (500
MHz, CDCl3) δ 7.43−7.41 (d, 2H, J = 7.1 Hz), 7.35−7.26 (m,
8H), 6.87 (d, 2H, J = 4.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 6.76−
6.72 (m, 1H), 5.22 (d, 1H, J = 5.7 Hz), 4.10−4.03 (m, 3H),
3.97 (dt, 1H, J = 2.4, 11.3 Hz), 3.72 (dt, 1H, J = 2.4, 11.1 Hz),
3.55 (d, 1H, J = 13.0 Hz), 3.38 (d, 1H, J = 13.0 Hz), 2.63 (t,
2H, J = 12.8 Hz), 2.20−2.12 (m, 2H), 1.43 (t, 3H, J = 7.0 Hz);
13C NMR (125 MHz, CDCl3) δ 150.1, 148.2, 138.3, 137.9,
129.2, 128.3, 128.2, 128.0, 127.5, 127.2, 122.3, 121.0, 118.6,
114.5, 82.9, 78.5, 66.9, 64.8, 63.5, 55.1, 52.8, 15.1; HRMS (EI):
m/z calcd for C26H29NO3 403.2147, found 403.2145.
5.2. (2R,3R)-4-Benzyl-2-[(2-ethoxyphenoxy)phenylmethyl]-
morpholine [(2R,3R)-9].
29
1
Yield: 72%; [α]D = −22.3 (c 0.3, CHCl3); H NMR (500 MHz,
CDCl3) δ 7.45 (d, 2H, J = 7.3 Hz), 7.37−7.20 (m, 8H), 6.87−6.86 (m,
2H), 6.73−6.69 (m, 2H), 5.07 (d, 1H, J = 6.8 Hz), 4.06−3.98 (m,
3H), 3.85 (d, 1H, J = 11.3 Hz), 3.67 (d, 1H, J = 13.1 Hz), 3.62 (dt,
1H, J = 2.4, 11.3 Hz), 3.47 (d, 1H, J = 13.1 Hz), 3.30 (d, 1H, J = 11.4
Hz), 2.64 (d, 1H, J = 11.3 Hz), 2.33 (t, 1H, J = 11.1 Hz), 2.19 (dt, 1H,
J = 3.2, 11.3 Hz), 1.41 (t, 3H, J = 7.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 149.9, 148.0, 139.2, 138.0, 129.2, 128.4, 128.3, 128.0, 127.6,
127.2, 122.1, 121.0, 117.8, 114.5, 82.7, 78.9, 67.2, 64.8, 63.6, 55.7, 52.9,
15.2; HRMS (ESI-TOF): m/z [M + Na]+ calcd for C26H29NO3Na
426.2045, found 426.2031. HRMS (ESI-TOF): m/z [M + H]+ calcd
for C26H30NO3 404.2226, found 404.2227.
5.5. (2R,3S)-4-Benzyl-2-[(2-ethoxyphenoxy)phenylmethyl]-
morpholine [(2R,3S)-9].
Yield: 90.5%, 920 mg; [α]D29 = −21.4 (c 1.0, CHCl3); 1H NMR
(500 MHz, CDCl3) δ 7.41 (d, 2H, J = 7.1 Hz), 7.33−7.25 (m,
8H), 6.86 (d, 2H, J = 4.0 Hz), 6.80 (d, 1H, J = 7.9 Hz), 6.75−
6.72 (m, 1H), 5.21 (d, 1H, J = 5.7 Hz), 4.08−4.04 (m, 3H),
3.96 (d, 1H, J = 11.4 Hz), 3.71 (dt, 1H, J = 2.3, 11.2 Hz), 3.54
(d, 1H, J = 13.0 Hz), 3.37 (d, 1H, J = 13.0 Hz), 2.62 (t, 2H, J =
11.8 Hz), 2.20−2.11 (m, 2H), 1.42 (t, 3H, J = 7.0 Hz); 13C
NMR (125 MHz, CDCl3) δ 150.1, 148.2, 138.3, 137.9, 129.2,
128.3, 128.2, 128.0, 127.6, 127.2, 122.3, 121.0, 118.5, 114.7,
82.9, 78.5, 66.9, 64.9, 63.5, 55.2, 52.8, 15.2; HRMS (EI): m/z
calcd for C26H29NO3 403.2147, found 403.2149.
5.3. Synthesis of (2S,3S)-9 from (2S,3S)-7 and the Tricarbonyl-
chromium Complex of 1-Ethoxy-2-fluorobenzene. To a suspension
of NaH (60% oil dispersion, 66 mg, 1.65 mmol, washed once with n-
hexane) in 1 mL of DMF was added dropwise (2S,3S)-(4-
benzylmorpholin-2-yl)phenylmethanol (312 mg, 1.1 mmol) in 3 mL
29
Yield: 70.2% (340 mg); [α]D = +22.9 (c 0.5, CHCl3);1H
NMR (500 MHz, CDCl3) δ 7.44 (d, 2H, J = 7.3 Hz), 7.36−
7.25 (m, 8H), 6.86−6.85 (m, 2H), 6.73−6.69 (m, 2H), 5.07 (d,
1H, J = 6.8 Hz), 4.06−3.97 (m, 3H), 3.87−3.84 (m, 1H),
3.68−3.65 (d, 1H, J = 13.2 Hz), 3.65−3.59 (dt, 1H, J = 2.3,
11.2 Hz), 3.47 (d, 1H, J = 13.1 Hz), 3.30 (d, 1H, J = 11.3 Hz),
2.63 (d, 1H, J = 11.6 Hz), 2.33 (t, 1H, J = 11.0 Hz), 2.19 (dt,
1H, J = 3.2, 11.4 Hz), 1.41 (t, 3H, J = 7.0 Hz); 13C NMR (75
MHz, CDCl3) δ 149.9, 148.0, 139.2, 138.0, 129.3, 128.4, 128.3,
128.0, 127.6, 127.2, 122.1, 121.0, 117.8, 114.5, 82.7, 79.0, 67.2,
64.8, 63.6, 55.7, 52.9, 15.2; HRMS (ESI-TOF): m/z [M + Na]+
calcd for C26H29NO3Na 426.2045, found 426.2047. HRMS
8402
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Article
(ESI-TOF): m/z [M + H]+ calcd for C26H30NO3 404.2226,
found 404.2226.
CH2Cl2/MeOH 9:1, 2 times elution) to give (2R,3R)-
reboxetine (105 mg, 90%) as colorless oil. Yield: 90%;
>99.9% ee; Chiralpak IC, Hex/EtOH/DEA = 90/10/0.1, 1.0
mL/min, 254 nm, tR(major) = 8.2 min, tR(minor) = 9.8 min;
[α]D29 = −13.9 (c 0.3, MeOH); 1H NMR (500 MHz, CDCl3) δ
7.41 (d, 2H, J = 7.2 Hz), 7.35−7.20 (m, 3H), 6.89−6.85 (m,
2H), 6.80 (d, 1H, J = 7.6 Hz), 6.76−6.71(m, 1H), 5.14 (d, 1H,
J = 5.7 Hz), 4.13−4.05 (m, 2H), 4.03−3.97 (m, 2H), 3.71 (dt,
1H, J = 3.5 Hz, J = 11.5 Hz), 2.93−2.85 (m, 2H), 2.80−2.72
(m, 3H), 1.46 (t, 3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3)
δ 150.1, 148.0, 138.0, 128.4, 128.2, 127.5, 122.4, 121.0, 118.4,
114.4, 83.2, 78.9, 67.7, 64.8, 47.2, 45.5, 15.1; HRMS (EI): m/z
calcd for C19H23NO3 313.1678, found 313.1676.
6. Synthesis of Reboxetine: Selective N-Debenzylation. 6.1. Syn-
thesis of (2S,3S)-Reboxetine [(2S,3S)-1].
To a solution of (2S,3S)-4-benzyl-2-[(2-ethoxyphenoxy)-
phenylmethyl]morpholine (150 mg, 0.37 mmol) and i-
Pr2NEt (260 μL, 1.5 mmol) in anhydrous 1,2-dichloroethane
(10 mL) was added dropwise α-chloroethyl chloroformate (161
μL, 1.5 mmol), and the mixture was stirred for 10 min at room
temperature. The reaction mixture was refluxed for 4 h, and the
solvent was evaporated under reduced pressure. MeOH (20
mL) was added, and the solution was heated to reflux for 2 h.
MeOH was evaporated under reduced pressure. The residue
was dissolved in EtOAc (10 mL), washed with 1 N NaOH
solution and brine, dried over MgSO4, and concentrated under
reduced pressure. The residue was purified by preparative TLC
(2 mm thickness) (SiO2, CH2Cl2/MeOH 9:1, two times
elution) to give (2S,3S)-reboxetine (100 mg, 86%) as colorless
oil: >99.9% ee (Chiralpak IC, Hex/EtOH/DEA = 90/10/0.1,
1.0 mL/min, 254 nm, tR(minor) = 8.2 min, tR(major) = 9.8
6.3. (2S,3R)-Reboxetine [(2S,3R)-1].
Yield: 74.5%; >99.9% ee (Chiralpak IB, Hex/EtOH/DEA =
80/20/0.1, 1.0 mL/min, 254 nm, tR(major) = 7.5 min,
29
tR(minor) = 8.2 min); [α]D = −16.9 (c 0.2, CH2Cl2),
[α]D29 = −32.0 (c 0.4, CHCl3); 1H NMR (500 MHz, CDCl3) δ
7.42 (d, 2H, J = 7.3 Hz), 7.34 (t, 2H, J = 7.4 Hz), 7.30−7.29
(m, 1H), 6.88−6.86 (m, 2H), 6.72−6.69 (m, 2H), 5.10(d, 1H, J
= 6.5 Hz), 4.12−4.07 (m, 2H), 3.91 (d, 1H, J = 11.4 Hz),
3.86−3.82 (m, 1H). 3.58 (dt, 1H, J = 2.7 Hz, J = 11.2 Hz), 3.35
(d, 1H, J = 11.8 Hz), 3.02−2.92 (m, 2H), 2.85(d, 1H, J = 12.5
Hz), 2.17(brs, 1H), 1.48 (t, 3H, J = 7.0 Hz); 13C NMR (75
MHz, CDCl3) δ 149.7, 147.7, 138.8, 128.2, 127.8, 127.2, 122.0,
121.0, 117.3, 114.1, 82.8, 79.6, 68.1, 64.6, 47.3, 45.8, 15.1;
HRMS (EI): m/z calcd for C19H23NO3 313.1678, found
313.1676.
28
28
min); [α]D = +12.3 (c 0.3, MeOH); [α]D = +22.5 (c 0.75,
CHCl3); lit.17 [α]D = +13.0 (c 1.03, MeOH), 99% ee, lit.22
20
[α]D = +12.59 (c 1.1, MeOH), lit.13 [α]D = +11.8 (c 1.01,
25
21
1
MeOH), 99.4% ee; H NMR (500 MHz, CDCl3) δ 7.41 (d,
2H, J = 7.2 Hz), 7.35−7.26 (m, 3H), 6.86 (d, 2H, J = 4.0 Hz),
6.81 (d, 1H, J = 7.9 Hz), 6.75−6.71 (m, 1H), 5.14 (d, 1H, J =
5.8 Hz), 4.12−4.05 (m, 2H), 4.04−3.94 (m, 2H), 3.70 (dt, 1H,
J = 3.0 Hz, J = 11.2 Hz), 2.92−2.82 (m, 2H), 2.77−2.69 (m,
2H), 2.29 (brs, 1H), 1.46 (t, 3H, J = 7.0 Hz); 13C NMR (75
MHz, CDCl3) δ 150.1, 148.1, 138.0, 128.3, 128.1, 127.5, 122.4,
121.0, 118.4, 114.5, 83.3, 79.2, 68.0, 64.8, 47.4, 45.7, 15.1;
HRMS (EI): m/z calcd for C19H23NO3 313.1678, found
313.1676.
6.4. (2R,3S)-Reboxetine [(2R,3S)-1].
6.2. (2R,3R)-Reboxetine [(2R,3R)-1].
Yield: 64.7%; >99.9% ee (Chiralpak IB, Hex/EtOH/DEA =
80/20/0.1, 1.0 mL/min, 254 nm, tR(minor) = 7.5 min,
29
29
tR(major) = 8.2 min); [α]D = +16.1 (c 0.5, CH2Cl2), [α]D
= +33.3 (c 0.3, CHCl3), lit.24 [α]D28 = +16.0 (c 0.68, CH2Cl2);
1H NMR (500 MHz, CDCl3) δ 7.43 (d, 2H, J = 7.3 Hz), 7.34
(t, 2H, J = 7.4 Hz), 7.30−7.29 (m, 1H), 6.88−6.86 (m, 2H),
6.73−6.69 (m, 2H), 5.09(d, 1H, J = 6.1 Hz), 4.12−4.07 (m,
2H), 3.91 (d, 1H, J = 11.3 Hz), 3.85−3.82 (m, 1H). 3.57 (dt,
1H, J = 2.5 Hz, J = 11.2 Hz), 3.35 (d, 1H, J = 12.3 Hz), 3.02−
2.92 (m, 2H), 2.85(d, 1H, J = 12.3 Hz), 2.22(brs, 1H), 1.48 (t,
3H, J = 7.0 Hz); 13C NMR (75 MHz, CDCl3) δ 149.7, 147.7,
138.8, 128.2, 127.9, 127.2, 122.0, 120.9, 117.3, 114.1, 82.8, 79.6,
68.1, 64.6, 47.3, 45.7, 15.1; HRMS (EI): m/z calcd for
C19H23NO3 313.1678, found 313.1678.
To a solution of (2R,3R)-4-benzyl-2-[(2-ethoxyphenoxy)-
phenylmethyl]morpholine (150 mg, 0.37 mmol) and diisopro-
pylamine (polymer-bound, Aldrich, 2.0−3.5 mmol/g) (370 mg,
0.74 mmol) in anhydrous CH2Cl2 (10 mL) was added
dropwise 1-chloroethyl chloroformate (201 μL, 1.85 mmol),
and the mixture was stirred for 10 min at room temperature.
The reaction mixture refluxed for 4 h with vigorous stirring, and
the reaction mixture was filtered and the resin washed with
CH2Cl2. The combined organic phases were evaporated under
reduced pressure. MeOH (20 mL) was added, and the solution
was heated to reflux for 2 h. MeOH was evaporated under
reduced pressure. The residue was dissolved in EtOAc (10 mL)
and washed with 1 N NaOH solution and brine, dried over
MgSO4, and concentrated under reduced pressure. The residue
was purified by preparative TLC (2 mm thickness) (SiO2,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra, chiral HPLC chromato-
grams of all chiral compounds, and X-ray crystallography data
8403
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The Journal of Organic Chemistry
Article
(17) Brenner, E.; Baldwin, R. M.; Tamagnan, G. Org. Lett. 2005, 7,
937.
for (2S,3R)-6a in CIF format (CCDC 898360). This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Hayes, S. T.; Assaf, G.; Checksfield, G.; Cheung, C.; Critcher,
D.; Harris, L.; Howard, R.; Mathew, S.; Regius, C.; Scotney, G.; Scott,
A. Org. Process Res. Dev. 2011, 15, 1305.
(19) Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007, 11, 354.
(20) Prabhakaran, J.; Majo, V. J.; Mann, J. J.; Dileep Kumar, J. S.
Chirality 2004, 16, 168.
AUTHOR INFORMATION
Corresponding Author
*E-mail: leehk@krict.re.kr
■
Notes
(21) Metro, T.-X.; Pardo, D. G.; Cossy, J. J. Org. Chem. 2008, 73,
707.
The authors declare no competing financial interest.
(22) Reddy, R. S.; Chouthaiwale, P. V.; Suryavanshi, G.; Chavan, V.
B.; Sudalai, A. Chem. Commun. 2010, 46, 5012.
ACKNOWLEDGMENTS
■
This investigation was supported by the Ministry of Science,
ICT & Future Planning of Korea, and the Korea Research
Institute of Chemical Technology.
(23) Aparicio, D. M.; Teran, J. L.; Gnecco, D.; Galindo, A.; Juarez, J.
R.; Orea, M. L.; Mendoza, A. Tetrahedron: Asymmetry 2009, 20, 2764.
(24) Yu, J.; Ko, S. Y. Tetrahedron: Asymmetry 2012, 23, 650.
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(26) Mashima, K.; Abe, T.; Tani, K. Chem. Lett. 1998, 1199.
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