A practical and enantioselective synthesis of tapentadol

Article abstract of DOI:10.1016/j.tetasy.2012.03.012

A practical and enantioselective synthetic method for tapentadol has been described. Starting from inexpensive and readily available (E)-3-(3-(benzyloxy) phenyl)acrylic acid, tapentadol was prepared in seven steps (44% overall yield and 99.9% de) in more than 100 g batches, without any chromatographic purification. An Evans' chiral auxiliary based conjugate addition and alkylation were used as the key steps.

Full text of DOI:10.1016/j.tetasy.2012.03.012

Tetrahedron: Asymmetry 23 (2012) 577–582
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
A practical and enantioselective synthesis of tapentadol
Qiang Zhang a, , Jian-Feng Li a, , Guang-Hui Tian b, Rong-Xia Zhang a, Jin Sun b, Jin Suo a,
a,b
Xin Feng c, Du Fang c, Xiang-Rui Jiang a, , Jing-Shan Shen
⇑
a Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China
b Topharman Shanghai Co., Ltd, Shanghai 201209, PR China
c College of Pharmaceutical, Hunan University of Traditional Chinese Medicine, Changsha 410208, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and enantioselective synthetic method for tapentadol has been described. Starting from inex-
pensive and readily available (E)-3-(3-(benzyloxy)phenyl)acrylic acid, tapentadol was prepared in seven
steps (44% overall yield and 99.9% de) in more than 100 g batches, without any chromatographic purifi-
cation. An Evans’ chiral auxiliary based conjugate addition and alkylation were used as the key steps.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 13 March 2012
Accepted 26 March 2012
Available online 27 April 2012
Introduction
were limited due to their unsatisfactory yields, high reagent costs,
and complicated column chromatography procedures. Herein we
Tapentadol 1 (Fig. 1) is a novel centrally acting analgesic with a
dual mode of action: -opioid receptor agonism and noradrenaline
report an efficient, scalable, and enantioselective synthetic route
to 1.
l
reuptake inhibition. It was recently reported that tapentadol ex-
erted analgesic effects in patients undergoing moderate to acute,
inflammatory, and chronic neuropathic pain.1–3
Results and discussion
As outlined in the retrosynthetic strategy (Scheme 1), key inter-
mediate 2 can be transformed into tapentadol via amination,
reduction, and debenzylation. And substituted cinnamic derivative
3 can be prepared effectively from the commercially available
material 4. The most important step is the construction of the
two contiguous stereogenic centers by asymmetric conjugate addi-
tion and methylation from intermediate 3 to 2.
HO
N
tapentadol 1
Despite the popularity of catalytic enantioselective b-conjugate
Figure 1. Structure of tapentadol 1.
additions7 and
a
-alkylations8 of carbonyl compounds in recent
years, many of these methods are still far from practical due to
their substrate limitations. In comparison, Evans’ chiral oxazolidi-
none auxiliaries9 have demonstrated high levels of diastereoselec-
Due to the clinical attractiveness of 1 along with its structural
uniqueness, its synthesis has attracted the increasing research
interest of organic chemists from both academic and industrial lab-
oratories. A variety of synthetic processes for 1 have been devel-
oped in recent years. In most of these reports, the attainment of
the two contiguous alkyl asymmetric centers in 1 was based on
resolution techniques (fractional crystallization or chiral HPLC sep-
aration).4 In such procedures, equivalent amounts of unwanted
isomers were also produced, leading to high material waste and
low atom efficiency. To the best of our knowledge, only two ap-
proaches have been reported for the enantioselective synthesis of
1.5,6 However, the industrial applications of these two processes
tivity in a great number of b-conjugate additions10 and
a-enolate
alkylations.11,12 Moreover, commercially available oxazolidinone
auxiliaries can be conveniently recovered and recycled. In view
of this potential for future industrial applications, we decided to
use the Evans’ auxiliary protocol for the preparation of 1.
It is widely accepted that 4-phenyloxazolidin-2-one induces
higher levels of stereoselectivity and reactivity compared to 4-ben-
zyloxazolidin-2-one10 or 4-isopropyloxazolidin-2-one13 in copper-
catalyzed asymmetric 1,4-addition reactions, because of the
unique steric hindrance of the phenyl ring. Thus, as shown in
Scheme 2, (R)-4-phenyloxazolidin-2-one was employed as the chi-
ral auxiliary and acylated by 30-benzyloxy cinnamoyl chloride14 in
CH2Cl2 in the presence of triethylamine (TEA); intermediate 5 was
⇑
Corresponding author. Tel./fax: +86 21 20231000 2407.
E-mail address: xrjiang@mail.shcnc.ac.cn (X.-R. Jiang).
These authors contributed equally to this paper.
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.03.012

578
Q. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 577–582
O
O
O
conjugate
3
BnO
HO
addition
(R)
BnO
BnO
OH
N
X
X
(R)
2
alkylation
4
3
1
2
Scheme 1. Retrosynthesis of tapentadol 1.
i. (COCl)2, CH2Cl2
CuBr·Me2S, EtMgBr,
BF3·Et2O, THF,
O
O
O
ii.(R)-4-phenyl-2-oxazolidinone,
BnO
TEA, CH2Cl2, 0 °C, 4 h
BnO
-40 °C to-20 °C
N
OH
O
93%
88%
Ph
4
5
O
O
O
O
H2O2, LiOH,
NaHMDS, -78 °C, 30 min,
then MeI, -20 °C, 4 h, THF
BnO
BnO
BnO
THF/H2O, rt, 4 h
N
N
O
O
86%
86%
Ph
O
Ph
6
7
(COCl)2, CH2Cl2, 40 °C, 2 h
O
LiAlH4, THF
then TEA, Me2NH·HCl,
BnO
0 °C, 3 h
CH2Cl2, 0 °C,1 h
N
OH
90%
90%
9
8
5% Pd/C, H2, MeOH, rt, 8 h
then conc. HCl
HO
BnO
N
·HCl
N
90%
1
10
Scheme 2. Synthesis of tapentadol 1.
obtained in 93% yield after crystallization,15 requiring no column
chromatography purification.16
slow addition of substrate 5 to the organocuprate reagents was
also crucial in guaranteeing reproducible yields and excellent dia-
stereoselectivities. It is noteworthy that only one recrystallization
was needed for the purification of 6, meaning that the reaction
can be easily scaled up to hundreds of grams batch.
The copper-assisted conjugate addition of Grignard reagents to
5 was investigated next, and the results are summarized in Table 1.
When we treated 5 with an organocuprate prepared from a
CuBrꢀMe2S complex and ethylmagnesium bromide in THF at
ꢁ20 °C, intermediate 6 was obtained in 49% yield after recrystalli-
zation with moderate diastereoselectivity (entry 1). It has been
previously reported that when LiCl is used as an additive, it has a
remarkable influence on the diastereoselectivity of many asym-
metric conjugate addition reactions.17 However, excess LiCl only
slightly enhanced the yield and diastereoselectivity (entry 2) in
our case. Further screening of different additives showed a stronger
Lewis acid, such as BF3ꢀEt2O, could dramatically enhance the dia-
stereoselectivity (entry 3 vs entries 1 and 2). When CuBr was used
instead of CuBrꢀMe2S, excellent diastereoselectivity was obtained,
although the yield of 6 was lower (entry 4 vs entry 3). We also
found that both the diastereoselectivity and the yield benefited
from lower temperature (entry 5 vs entry 1, entry 6 vs entry 3).
When the reaction proceeded in the presence of BF3ꢀEt2O at
ꢁ40 °C, the conjugate addition reaction product 6 was obtained
in 88% yield after recrystallization with 99.8% ee (entry 6). The
Encouraged by the success in asymmetric conjugated addition,
we focused our efforts toward the optimization of the methylation
conditions. No reaction was observed when 6 was treated with LDA
in THF at ꢁ78 °C (Table 2, entry 1) using MeI as the methylating re-
agent, while enolate formation of 6 with LiHMDS in THF followed
by methylation gave moderate yield and diastereoselectivity (entry
2). The methylation reaction proceeded efficiently to obtain 7 with
excellent diastereoselectivity and high yield when employing NaH-
MDS as the base (entry 3 vs entries 1 and 2). These results are in
accordance with a previously proposed conclusion; i.e. that the
methylation of a sodium enolate is superior to the corresponding
lithium enolate.11 With NaHMDS as the base, we next screened
various methylating reagents, and the experimental results
showed that MeBr can lead to an obvious decrease in both yield
and diastereoselectivity (entries 6 and 7), while other methylating
reagents such as Me2SO4, Me2CO3, and MeSO3Ph, showed no reac-
tivity (entries 8–10). A higher enolate formation temperature could

Q. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 577–582
579
Table 1
Optimization of the asymmetric conjugate addition conditions
O
O
EtMgBr 3 equiv.
O
O
O
O
Lewis acid 1.5 equiv.
Cu Salt 1.5 equiv.
BnO
BnO
BnO
N
N
N
O
O
O
THF, T
Ph
Ph
Ph
6
5
11
Entry
Cu salt
Lewis acid
Temp (°C)
Yielda (%)
eeb (%)
1
2
3
4
5
6
CuBrꢀMe2S
CuBrꢀMe2S
CuBrꢀMe2S
CuBr
—
LiCl
BF3ꢀEt2O
BF3ꢀEt2O
—
BF3ꢀEt2O
ꢁ20 °C to 0 °C
ꢁ20 °C to 0 °C
ꢁ20 °C to 0 °C
ꢁ20 °C to 0 °C
49
58
70
59
75
88
82
86
97
95
96
99
CuBrꢀMe2S
ꢁ40 °C to ꢁ20 °C
ꢁ40 °C to ꢁ20 °C
CuBrꢀMe2S
a
Yields after purification by single recrystallization from i-PrOH.
ee for the corresponding carboxylic acid derivative of 6 after the removal of the oxazolidin-2-one moiety, determined by chiral HPLC.
b
Table 2
Optimization of the asymmetric methylation conditions
O
O
O
O
base, THF, 30 min, T
BnO
BnO
N
N
O
O
then methylating reagent
-20 °C, 2-4 h
Ph
Ph
6
7
Entry
Base
Methylating reagent
Temp of enolate formation (°C)
Yielda (%)
syn:antib
eec (%)
1
2
3
4
5
6
7
8
9
10
LDA
MeI
MeI
MeI
MeI
ꢁ78
ꢁ78
ꢁ78
ꢁ40
ꢁ20
ꢁ78
ꢁ20
ꢁ78
ꢁ78
ꢁ78
NRd
71
86
80
82
74
76
NR
NR
NR
LiHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
NaHMDS
90:10
99.9:0.1
91:9
84:16
91:9
98
99
97
96
97
96
MeI
MeBr
MeBr
Me2SO4
Me2CO3
MeSO3Ph
90:10
a
b
c
Yields after purification by single recrystallization from i-PrOH.
Dr determined on the corresponding carboxylic acid 8 by HPLC.
ee determined on the corresponding carboxylic acid 8 by chiral HPLC.
NR means no reaction.
d
speed up the reaction but resulted in a sharp decrease in diastere-
oselectivity (entries 4 and 5). Taking into consideration the yield,
selectivity, and reaction rate, as well as the costs of the reagents,
we treated 6 with NaHMDS in THF followed by the addition of
yield with excellent dr (>99.9:0.1) after single crystallization from
i-PrOH. The structure of the key intermediate 7 was determined by
single crystal X-ray diffraction.19 The data indicated that the asym-
metric carbons of 7 had a (2R,3R)-configuration (as shown in
Fig. 2). Since imide 7 is the major product in the methylation reac-
tion, we were able to deduce that the conjugate addition of Grig-
nard reagents to 5 furnished 6 as the major isomer.
2 equiv of MeI18 to deliver the
a,b-disubstituted imide 7 in 86%
Removal of the chiral auxiliary under base hydrolysis conditions
(LiOH/H2O2 in H2O/THF) yielded the
a,b-disubstituted acid 8 in
86% yield. This is particularly noteworthy in that the (R)-4-phenyl-
oxazolidin-2-one could be recovered in 86% yield after a simple
acid-base work-up operation. Treating 8 with oxalyl chloride fol-
lowed by dimethylamine hydrochloride in the presence of TEA in
CH2Cl2 afforded the corresponding dimethylamide 9 in 90% yield.
Subsequent reduction of amide 9 with LiAlH4 in dry THF gave o-
benzyl-tapentadol 10. Debenzylation under a hydrogen atmo-
sphere gave 1 in 90% yield with 99.9% de.20
Conclusion
In conclusion, we have successfully implemented an enantiose-
lective synthesis of tapentadol (seven steps, 44% overall yield, >99%
Figure 2. X-ray crystal structure of 7.

580
Q. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 577–582
chemical purity and enantiomeric excess) by employing (E)-3-(3-
(benzyloxy)phenyl)acrylic acid 4 as the starting material. The
two contiguous stereocenters in 1 were constructed by (R)-4-phe-
nyloxazolidin-2-one induced conjugate addition (88% yield, 99.8%
ee) and methylation (86% yield, 99.8% de). No chromatographic
purification was required for the entire process and the chiral aux-
iliaries could be recovered and recycled, which make this synthetic
process practical for industrial applications.
suspension was filtered over glass wool, which was rinsed with
EtOAc (1 L ꢂ 3). The aqueous layer was separated, and the organic
solution was washed with 10% aqueous NH4OH (1 L ꢂ 3), water
(1 L), and brine (1 L) and dried over Na2SO4. The solvent was evap-
orated off, after which 1.5 kg of 6 was obtained after recrystalliza-
tion in i-PrOH in 88% yield, mp 106–108 °C, ½a D22
¼ ꢁ91:2 (c 1.0,
ꢃ
CHCl3). 1H NMR (300 MHz, CDCl3): d 7.33–7.55 (m, 8H), 7.15–
7.25 (m, 3H), 6.70–6.90 (m, 3H), 5.22 (dd, J = 3.7, 8.6 Hz, 1H),
5.15 (s, 2H), 4.56 (t, J = 8.9 Hz, 1H), 4.22 (dd, J = 3.5, 8.6 Hz, 1H),
3.53 (dd, J = 8.9, 16.4 Hz, 1H), 3.24 (d, J = 5.6 Hz, 1H), 3.15
(m, 1H), 1.54–1.76 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 171.0, 158.8, 153.5, 145.3, 138.9, 136.8,
129.2, 129.1, 129.0, 128.6, 128.5, 128.4, 127.8, 127.6, 127.5,
125.9, 125.8, 120.5, 114.3, 112.5, 69.9, 69.8, 57.4, 43.1, 41.4, 29.4,
Experimental
All reactions, except those involving water, were performed in
flame-dried glass charged with nitrogen. Anhydrous THF was dis-
tilled from Na/benzophenone ketyl under argon in a recycling still.
The copper(I) bromide-dimethyl sulfide complex was purchased
from Aldrich. NMR spectra were recorded on a Mercury 300 spec-
trometer (300 MHz for 1H), and Varian MR-400 (100 MHz for 13C).
Chemical shifts are reported in d ppm referenced to an internal
SiMe4 standard for 1H NMR and CDCl3 (d 77.36) for 13C NMR. Opti-
cal rotations were measured on a Perkin-Elmer 241 MC polarime-
ter. HPLC analysis was performed on an Agilent 1100 series
instrument by using Daicel or DIKMA columns. Melting points
are uncorrected. (E)-3-(3-(Benzyloxy)phenyl)acrylic acid 4 was
prepared from commercially available 3-hydroxybenzaldehyde
and had spectral data in agreement with those reported in the
literature.14
12.0. HRMS (ESI): Calcd for
452.1845. Data for 11:
C
27H27NO4Na: 452.1838. Found:
½
a 2D2
ꢃ
¼ ꢁ57:0 (c 0.5, CHCl3). 1H
NMR(300 MHz, CDCl3): d 7.25–7.45 (m, 5H), 7.15–7.25 (m, 4H),
6.95–7.01 (m, 2H), 6.75–6.86 (m, 3H), 5.35–5.40 (dd, J = 4.1,
8.8 Hz, 1H), 5.05 (s, 2H), 4.60 (t, J = 8.7 Hz, 1H), 4.05 (dd, J = 4.1,
8.9 Hz, 1H), 3.50–3.60 (m, 1H), 3.05–3.15 (m, 2H), 1.55–1.70 (m,
2H), 0.75–0.80 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
171.6, 158.7, 153.6, 145.2, 138.8, 137.0, 129.3, 129.0, 128.9,
128.5, 128.4, 128.3, 127.8, 127.5, 127.4, 125.4, 125.3, 120.4,
114.2, 112.8, 69.3, 69.2, 57.5, 43.7, 41.3, 28.9, 11.9. HRMS (ESI):
Calcd for C27H27NO4Na: 452.1838. Found: 452.1825.The ee of the
corresponding acid from 6 after the removal of the oxazolidin-
2-one moiety was determined to be 99.8% by HPLC analysis
on a DAICEL CHIRALCEL OD-H column (250 ꢂ 4.6 mm, 5
lm),
(R,E)-3-(3-(3-(Benzyloxy)phenyl)acryloyl)-4-phenyloxazolidin-
2-one 5
k = 270 nm, n-hexane/i-PrOH/formic acid = 75:25:0.1, flow rate =
0.30 mL/min, retention time: 13.16 min (major enantiomer),
14.69 min (minor enantiomer).
To a stirred solution of 4 (2 kg, 8 mol) in CH2Cl2 (2 L) was added
oxalyl chloride (1.4 L, 16 mol) dropwise at 0 °C. The resulting
solution was stirred at room temperature for another 4 h and con-
centrated in vacuo. To a stirred solution of (R)-4-phenyloxazolidin-
2-one (1.3 kg, 8 mol) and TEA (1.7 L, 12 mol) in CH2Cl2 (4.8 L) at
0 °C was added the substituted cinnamic chloride in CH2Cl2
(800 mL) dropwise. The mixture was stirred at 0 °C for 1 h and then
raised to room temperature for 3 h when a saturated solution of
NH4Cl (600 mL) was added. The aqueous layer was separated,
and the organic solution was washed with water (600 mL ꢂ 3),
brine (800 mL), and dried over Na2SO4. The organic solution was
evaporated and 2.9 kg of 5 was obtained after recrystallization in
(R)-3-{(2R,3R)-3-[3-(Benzyloxy)phenyl]-2-methylpentanoyl}-4-
phenyloxazolidin-2-one 7
To a solution of 6 (844 g, 2 mol) in dry THF (4 L) at ꢁ78 °C was
added NaHMDS (2.0 M in THF, 1.1 L, 2.2 mol) dropwise under ar-
gon, and the mixture was stirred for 30 min after which MeI
(248 mL, 4 mol) was added dropwise and the resulting mixture
was slowly warmed to ꢁ20 °C. The reaction mixture was quenched
by the addition of a saturated aqueous NH4Cl solution. The vola-
tiles were evaporated and extracted with EtOAc (2 L ꢂ 3). The com-
bined organic layers were washed with brine (1 L) and dried over
Na2SO4. The organic extracts were concentrated in vacuo and
760 g of 7 was obtained after recrystallization in i-PrOH in 86%
EtOH in 93% yield, mp 143–145 °C, ½a D22
ꢃ
¼ þ4:5 (c 1.0, CHCl3). 1H
NMR (300 MHz, CDCl3): d 7.86 (d, J = 15.5 Hz, 1H), 7.75 (d,
J = 15.3 Hz, 1H), 7.30–7.50 (m, 11H), 7.23 (m, 2H), 7.03 (dd,
J = 2.3, 8.6 Hz, 1H), 5.64 (dd, J = 4.0, 9.0 Hz, 1H), 5.15 (s, 2H), 4.85
(t, J = 8.9 Hz, 1H), 4.36 (dd, J = 3.9, 8.8 Hz, 1H). 13C NMR
(100 MHz, CDCl3): d 164.6, 158.9, 153.7, 146.5, 138.9, 136.5,
135.8, 129.8, 129.2, 129.1, 128.6, 128.5, 128.4, 128.1, 127.6,
127.5, 126.0, 125.9, 121.5, 117.4, 117.1, 114.4, 70.0, 69.9, 57.8.
HRMS (ESI): Calcd for C25H21NO4Na: 422.1368. Found: 422.1349.
yield, mp 67–69 °C,
½
a 2D2
ꢃ
¼ ꢁ148:6 (c 0.5, CHCl3). 1H NMR
(300 MHz, CDCl3): d 7.2–7.5 (m, 11H), 6.70–6.95 (m, 3H), 5.10 (s,
2H), 4.82 (dd, J = 3.5, 7.5 Hz, 1H), 4.20–4.30 (m, 1H), 3.92–4.04
(m, 2H), 2.68 (dt, J = 3.7, 10.3 Hz, 1H), 1.82–2.04 (m, 1H), 1.45–
1.65 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H), 0.90 (t, J = 7.4 Hz, 3H). 13C
NMR (100 MHz, CDCl3): d 175.8, 158.5, 153.3, 140.6, 139.1, 137.0,
129.1, 129.0, 128.9, 128.6, 128.5, 128.4, 127.8, 127.6, 127.5,
125.6, 125.5, 120.9, 114.4, 113.1, 69.7, 69.6, 57.5, 51.2, 42.4, 24.9,
15.5, 11.4. HRMS (ESI): Calcd for C28H29NO4Na: 466.1994. Found:
466.2022. Data for (R)-3-(2S,3R)-isomer of 7: mp 120–122 °C,
(R)-3-{(R)-3-[3-(Benzyloxy)phenyl]pentanoyl}-4-
phenyloxazolidin-2-one 6
½
a 2D2
ꢃ
¼ ꢁ1:4:4 (c 0.5, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.31–
To a suspension of CuBrꢀMe2S complex (1.2 kg, 6 mol) in dry
THF (6 L) at ꢁ40 °C under argon was added MgEtBr (4.8 L, 2.5 M
in THF, 12 mol) dropwise and the resulting yellow-green mixture
was stirred for 25 min. Next, BF3ꢀEt2O (760 mL, 6 mol) was added
dropwise. The resulting mixture was stirred for 25 min before
the addition of 5 (1.6 kg, 4 mol) as a solution in THF (12 L), and
the resulting slurries were allowed to warm slowly to ꢁ20 °C
(2 h). A saturated aqueous NH4Cl solution (0.5 L) was added to
quench the reaction and the solvents were evaporated. Next, EtOAc
(6 L) and water (2 L) were added to the residue and the resultant
7.46 (m, 10H), 7.14 (t, J = 7.9 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H), 6.75
(s, 1H), 6.68 (d, J = 7.4 Hz, 1H), 5.47 (dd, J = 3.7, 8.7 Hz, 1H), 5.02
(s, 2H), 4.69 (t, J = 8.7 Hz, 1 H), 4.33 (dd, J = 3.8, 8.9 Hz, 1H), 4.65
(m, 1H), 2.61 (dt, J = 3.3, 10.7 Hz, 1H), 1.48 (m, 1H), 1.16–1.28
(m, 1H), 0.90 (d, J = 6.9 Hz, 3H), 0.48 (t, J = 7.4 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 176.7, 158.6, 153.5, 143.5, 139.0, 136.9,
129.1, 129.0, 128.9, 128.7, 128.6, 128.5, 127.8, 127.7, 127.6,
126.4, 126.3, 121.3, 115.3, 112.4, 69.8, 69.5, 57.9, 51.5, 42.6, 26.9,
16.4, 11.8. HRMS (ESI): Calcd for C28H29NO4Na: 466.1994. Found:
466.2011.

Q. Zhang et al. / Tetrahedron: Asymmetry 23 (2012) 577–582
581
(2R,3R)-3-[3-(Benzyloxy)phenyl]-2-methylpentanoic acid 8
CDCl3): d 7.32–7.58 (m, 5H), 7.25 (t, J = 7.6 Hz, 1H), 6.86 (d,
J = 8.5 Hz, 1H), 6.75 (m, 2H), 5.05 (s, 2H), 2.20–2.34 (m, 2H), 2.21
(s, 3H), 2.14 (s, 3H), 1.80–1.90 (m, 1H), 1.72–1.83 (m, 1H), 1.55–
1.66 (m, 1H), 1.42–1.52 (m, 1H), 1.05 (d, J = 6.2 Hz, 3H), 0.85 (t,
J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): d 158.7, 145.7, 137.1,
129.2, 128.6, 128.5, 127.9, 127.6, 127.5, 121.2, 115.3, 112.1, 69.9,
64.5, 51.6, 45.4, 45.3, 36.3, 24.3, 16.2, 12.3. HRMS (ESI): Calcd for
To a solution of 7 (708 g, 1.6 mol) in THF (4 L) and water (1 L) at
0 °C was added dropwise H2O2 (0.6 L, 30% in H2O, 6.4 mol) followed
by LiOHꢀH2O (114 g, 2.8 mol). The mixture was stirred at 0 °C for
1 h and then raised to room temperature over 1 h. After stirring
at room temperature for 6 h, the reaction mixture was quenched
by the addition of a saturated aqueous Na2S2O3 solution. Next,
THF was removed by rotary evaporation at 30 °C and the resulting
mixture was extracted with CH2Cl2 (1.5 L ꢂ 4). The combined or-
ganic layers were washed with water (500 mL ꢂ 2) and brine
(500 mL ꢂ 2). The organic solution was dried over Na2SO4, filtered,
and evaporated to give 224 g of chiral oxazolidinone in 86% yield.
The aqueous solution was acidified with ice-cooled 1 M aqueous
HCl to pH 1–2 and extracted with EtOAc (1 L ꢂ 4). The combined
organic layers were washed with a saturated solution of NaHCO3
(500 mL) and brine (500 mL), dried over Na2SO4, concentrated to
yield 408 g of 8 as a white powder in 86% yield, mp 75–77 °C,
C21H30NO: 312.2327. Found: 312.2310.
3-[(2R,3R)-1-(Dimethylamino)-2-methylpentan-3-yl] phenol
hydrochloride 1
To a stirred solution of 10 (186 g, 0.6 mol) in MeOH (600 mL)
was added 5% Pd/C (9 g). A hydrogen atmosphere (1 atm) was ap-
plied, and the mixture was stirred at room temperature for 8 h. The
mixture was filtered and the solid residue washed with MeOH
(250 mL ꢂ 3). Next, 12 M HCl (48 mL) was added to the filtrate at
0 °C and then the mixture was stirred for 30 min, concentrated in
vacuo to yield 138 g of 1 as white powders after recrystallization
in MeOH/diisopropyl ether in 90% yield, mp 198–200 °C,
½
a 2D2
ꢃ
¼ ꢁ20:0 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3): d 7.30–
7.50 (m, 5H), 7.24 (t, J = 7.6 Hz, 1H), 6.70–6.94 (m, 3H), 5.05 (s,
2H), 2.84 (m, 1H), 2.77 (m, 1H), 1.77–1.87 (m, 1H), 1.55–1.68 (m,
1H), 1.10 (d, J = 6.8 Hz, 3H), 0.90 (t, J = 7.3 Hz, 3H). 13C NMR
(100 MHz, CDCl3): d 181.8, 158.5, 144.0, 136.8, 129.0, 128.6,
128.5, 127.8, 127.6, 127.5, 120.9, 115.1, 112.4, 69.6, 48.9, 44.8,
23.7, 13.6, 11.7. HRMS (ESI): Calcd for C19H22O3Na: 321.1467.
Found: 321.1472. The dr and ee was determined by HPLC analysis
in comparison with authentic racemic materials respectively.
½
a 2D2
ꢃ
¼ ꢁ29:6 (c 1.1, MeOH).1H NMR (300 MHz, CD3OD): d 7.25 (t,
J = 7.9 Hz, 1H), 6.60–6.82 (m, 3H), 2.82–2.94 (m, 2H), 2.70–2.80
(br s, 6H), 2.23–2.36 (m, 1H), 2.14–2.28 (m, 1H), 1.80–1.90 (m,
1H), 1.55–1.68 (m, 1H), 1.25 (d, J = 6.7 Hz, 3H), 0.85 (t, J = 7.4 Hz,
3H). 13C NMR (100 MHz, CD3OD): d 159.7, 145.8, 131.1, 121.0,
117.2, 115.3, 64.6, 53.3, 46.1, 42.1, 35.6, 26.3, 16.4, 12.7. HRMS
(ESI): Calcd for C14H24NO: 222.1858. Found: 222.1860. The de
was determined as 99.9% by HPLC analysis in comparison with
authentic racemic materials. HPLC: DIKMA CHIRALPAK AD-H col-
HPLC: DIKMA CHIRALPAK AD-H column (250 ꢂ 4.6 mm, 5
lm),
k = 270 nm, n-hexane/i-PrOH/formic acid = 95:5:0.1, flow rate =
0.60 mL/min, retention time: 13.69 min (anti-isomer), 14.37 min
(anti-isomer), 20.02 min (2S,3S), 25.49 min (2R,3R).
umn (250 ꢂ 4.6 mm, 5
lm), k = 270 nm, n-hexane/Et2NH = 100:0.2,
flow rate = 0.80 mL/min, retention time: 42.05 min, 44.35 min,
49.16 min (2R,3R), 54.37 min.
(2R,3R)-3-(3-(Benzyloxy)phenyl)-N,N,2-trimethylpentanamide
9
Acknowledgments
To a stirred solution of 8 (357 g, 1.2 mol) in CH2Cl2 (0.6 L) at
room temperature was added dropwise oxalyl chloride (200 mL,
2.4 mol) and the mixture was stirred at 40 °C for 2 h and then con-
centrated in vacuo. The residue was dissolved in CH2Cl2 (400 mL),
and at 0 °C, was added to a solution of dimethylamine hydrochlo-
ride (196 g, 2.4 mol) and TEA (576 mL, 4 mol) over a period of 1 h.
The mixture was stirred at room temperature for 1 h, and then
acidified with 1 M aqueous HCl at pH 6–7 at 0 °C. The organic layer
was separated and washed with a saturated solution of NaHCO3
(500 mL), brine (500 mL), and dried over Na2SO4. Filtration fol-
lowed by concentration in vacuo afforded 352 g of 9 as a pale yel-
This work was supported by the National Science & Technology
Major Project ‘Key New Drug Creation and Manufacturing Pro-
gram’, China (Number: 2009ZX09301-001).
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low oil in 90% yield, ½a D22
ꢃ
¼ ꢁ46:2 (c 1.0, CHCl3).1H NMR (300 MHz,
CDCl3): d 7.30–7.55 (m, 5H), 7.22 (m, 1H), 6.70–6.82 (m, 3H), 5.05
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¼ ꢁ17:6 (c 1.0, CHCl3). 1H NMR (300 MHz,

582
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18. The addition of 2 equiv of MeI to the reaction resulted in reproducibly
complete conversion of 6 to 7.
19. CCDC 870920.
20. The comparison of the specific rotation {½a D23
¼ ꢁ29:6 (c 1.1, MeOH)} of 1 with
ꢃ
the literature data4f {½a D22
¼ ꢁ27:6 (c 0.97, MeOH)} confirmed its absolute
ꢃ
configuration.