An efficient and promising method to prepare Ladostigil (TV3326) via asymmetric transfer hydrogenation catalyzed by Ru-Cs-DPEN in an HCOONa-H 2O-surfactant system

Article abstract of DOI:10.1016/j.tetasy.2012.02.022

The enantiopure multi-functional anti Alzheimer's drug, Ladostigil (TV3326), was prepared by using asymmetric transfer hydrogenation (ATH) as a key step catalyzed by Ru-Cs-DPEN in an HCOONa-H₂O-surfactant system. Good chemical yields with high enantiomeric excess were obtained and the catalyst could be recycled another five times.

Full text of DOI:10.1016/j.tetasy.2012.02.022

Tetrahedron: Asymmetry 23 (2012) 333–338
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Tetrahedron: Asymmetry
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An efficient and promising method to prepare Ladostigil (TV3326) via
asymmetric transfer hydrogenation catalyzed by Ru–Cs-DPEN in an
HCOONa–H2O–surfactant system
⇑
Zonghua Luo, Fangfei Qin, Shilei Yan, Xingshu Li
Institute of Drug Synthesis and Pharmaceutical Processing, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiopure multi-functional anti Alzheimer’s drug, Ladostigil (TV3326), was prepared by
Received 14 January 2012
Accepted 23 February 2012
Available online 4 April 2012
using asymmetric transfer hydrogenation (ATH) as
a key step catalyzed by Ru–Cs-DPEN in an
HCOONa–H2O–surfactant system. Good chemical yields with high enantiomeric excess were obtained
and the catalyst could be recycled another five times.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
yield and high enantioselectivity were obtained (up to 98.0% ee)
in ATH. However, only 62% ee was obtained in the next step of
Ladostigil (TV3326, (R)-3-(prop-2-ynylamino)-2,3-dihydro-1H-
inden-5-yl ethyl(methyl)carbamate, Fig. 1) is the first anti-Alzhei-
mer’s drug with the potential to slow down the progression of
clinical symptoms for sustained periods of time, and modify the
pathology associated with the disease. The drug has been proven
to be safe and well tolerated in Phase I/IIa clinical trials and in
2011 was taking part in Phase IIb during 2011 by Yissum, Pontifax,
and Clal Biotechnology Industries.1 Ladostigil is also the first
multi-functional drug (a novel cholinesterase, brain-selective
monoamine oxidase B inhibitor and neuroprotective agent) to
reach clinical trials for the treatment of Alzheimer’s disease and
other neurodegenerative diseases. However, its (S)-isomer,
TV3279, lacks monoamine oxidase inhibitory activity.2
nucleophilic substitution for obtaining (S)-ethyl-methyl-carme-
bic-acid-3-hydroxy-indan-5-yl ester 3. From a practical point of
view, it is desirable to develop methods for preparing this useful
drug with good stereo-control in each step and recycling of the cat-
alyst so that the related chemistry can be easily applied on a larger
scale.
Since ATH was introduced by Noyori and co-workers in 1995,5 a
number of approaches for the recycling of catalysts have been re-
ported, since the expensive Ru–Ts-DPEN catalyst cannot be easily
obtained. These include anchoring the Ts-DPEN onto silica gel,6–8
insoluble and soluble polymers,9–12 and using unmodified ruthe-
nium catalysts in aqueous micelles and vesicles13 or in PEG and
water systems.14
In our previous studies, we have developed chiral ligands
PEG-BsDPEN15 and N-PEG-Ts-DPEN,16 and examined their applica-
tion in the preparation of (R)-salmeterol with ATH as the key strat-
egy. Herein we report the highly effective preparation of TV3326
by ATH as the key step catalyzed by the Ru–Cs-DPEN/surfactant
system in HCOONa/H2O.
O
N
O
HN
Figure 1. (R)-Ladostigil (TV3326).
2. Results and discussion
Ladostigil (TV3326) was first obtained in several steps using
(R)-(ꢀ)-1-aminoindan as the starting material (Scheme 1).3 This
process was difficult to scale-up to an industrial scale because of
the low yield. A patent, US 2006/0199974 A1 described an asym-
metric preparation of TV3326 (Scheme 2) by asymmetric transfer
hydrogenation (ATH) of the ketone as the key step.4 Catalyzed by
Ru–Ts-DPEN with HCOOH/Et3N as the hydrogen donor, a good
After substrate 2 was obtained according to the reported proce-
dure,4 we chose the HCOONa/H2O system as the hydrogen donor,
which allows us to recycle the catalyst for the screening of ligands
for the Ru-catalyzed ATH (Fig. 2); the results are shown in Table 1.
Ligand L1 [(S,S)-Ts-DPEN-PEG-750] the PEG supported chiral li-
gand which we developed as an immobilized catalyst,16 gave rela-
tively high enantioselectivities (96% ee) but moderate yields (50%).
On the other hand, (S,S)-Ts-DPEN L2, a widely used chiral ligand in
ATH, and (S,S,S)-Cs-DPEN L3, provided high yields with excellent
⇑
Corresponding author. Tel./fax: +86 20 39943050.
E-mail address: xsli219@yahoo.com (X. Li).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.02.022

334
Z. Luo et al. / Tetrahedron: Asymmetry 23 (2012) 333–338
Cl
Cl
O
TFAA
mCPBA, TFA
Cl
CF3
CF3
HN
AlCl3
HN
O
NH2
O
O
N
Cl
O
Cl
K2CO3
Boc2O
O
O
CF3
HO
HO
HN
NH
NH2
Boc
N
O
O
O
O
Br
HCl
·HCl
N
O
N
O
O
NH
NH2
HN
Boc
Scheme 1. The first synthetic route to Ladostigil (TV3326).
N
Cl
[RuCl2(p-cymene)]2
(S,S)-TsDPEN,HCOOH,Et3N
O
O
N
O
HO
CH2Cl2
O
O
1
2
O
step 1.1 (MeSO2)2O
O
N
O
N
O
HN
H2N
step 1.2
OH
3
Scheme 2. The synthesis of Ladostigil (TV3326) by asymmetric transfer hydrogenation (ATH).
Table 1
Preparation of chiral alcohol 3 by asymmetric transfer hydrogenation with different ligandsa
O
O
[RuCl2(p-cymene)]2 Ligand
N
O
N
O
HCOONa·H2O
O
OH
2
3
Entry
Ligand
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
L1
L2
L3
L4
L5
L6
3
3
3
3
3
3
50
99
99
52
90
5
96
99
99
96
98
—
a
b
c
Reactions were carried out on a 1 mmol scale at 40 °C with an S/C = 100.
The yields were determined by HPLC on a C8 column, 1.0 mL/min, MeOH/H2O = 50/50.
The ee values were determined by HPLC on OB-H column, 0.5 mL/min, oven:40 °C, Hex/IPA = 60/40.
enantioselectivities (99% yield, 99% ee). Good enantioselectivities
(96–98% ee) were also obtained when L4 and L5 were used,
although the yields (L4: 52%, L5: 90%) were not as high as those ob-
tained with L2 and L3. A nitro group on the sulfonyl moiety of the
ligands did not seem favorable to the reaction, since when L6 was
used, a very low yield was obtained.
the system. Based on the results of the ligand screen, we chose L2
and L3 as catalysts for recycling by adding various surfactants to
the reaction system; the results are listed in Table 2. With
[RuCl2(p-cymene)]2-(ligand) as the catalyst, the addition of sodium
dodecyl sulfate (SDS, an anionic surfactant) and sodium dodecyl
benzene sulfonate (SDBS) did not influence the yield or enantiose-
lectivity on the first run (99.0% yield with 98% ee, and 97% yield
with 98% ee, respectively), although the yield did decrease in the
In order to attempt a greener approach to enantiopure Ladosti-
gil, we attempted to recycle the catalyst by adding a surfactant to

Z. Luo et al. / Tetrahedron: Asymmetry 23 (2012) 333–338
335
O
O
O
H2N
HN
S
NH HN
S
H2N
HN
S
O
O
O
O
n
O
O
(S,S)-Ts-DPEN-PEG-750 L1
(S,S)-Ts-DPEN L2
(S,S,S)-Cs-DPEN L3
O
H2N
HN
S
O
O
O
H2N
HN
S
NO2
H2N
HN
S
O
O
(S,S)-2,4,6-iPr3-C6H4SO2-DPEN L4
(S,S)-Ms-DPEN L5
Figure 2. The different ligands used in ATH.
(S,S)-o-NO2C6H4SO2-DPEN L6
Table 2
Recycling of the catalyst in the asymmetric transfer hydrogenation of 2 catalyzed by Ru–Ts-DPEN and Ru–Cs-DPENa,b,c,d
O
O
[RuCl2(p-cymene)]2 Ligand L1/L2
N
O
N
O
HCOONa·H2O
OH
O
3
2
Surfactant
Ligand
Run
1
2
3
4
5
Time (h)
Yield/ee (%)
Time (h)
Yield/ee (%)
Time (h)
Yield/ee (%)
Time (h)
Yield/ee (%)
Time (h)
Yield/ee (%)
SDS
L2
L2
L2
L2
L2
L2
L3
L3
L3
3
3
3
3
3
3
3
3
3
99/98
97/98
99/99
99/98
99/99
99/99
99/99
99/99
99/99
12
12
12
12
12
12
12
12
12
79/97
72/98
98/99
99/98
99/98
99/99
99/99
99/98
99/98
36
36
36
36
36
36
36
36
36
56/97
53/98
49/98
96/98
93/98
99/98
93/98
93/98
99/98
—
—
—
48
48
48
48
48
48
—
—
—
—
—
—
72
72
72
72
72
72
—
—
—
SDBS
DDAB
TBAB
CTAB
OTAC
TBAB
CTAB
OTAC
49/98
47/98
69/98
52/97
50/98
85/98
25/95
21/95
50/97
30/97
28/97
63/98
a
b
c
Reactions were carried out on a 0.5 mmol scale at 40 °C with an S/C = 100.
The yields were determined by HPLC on a C8 column, 1.0 mL/min, MeOH/H2O = 50/50.
The ee values were determined by HPLC on an OB-H column,0.5 mL/min, oven:40 °C, Hex/IPA = 60/40.
After each cycle was finished, the reaction system was extracted with hexane 2 mL ꢁ 5.
d
second run (79% and 72% respectively). On the other hand, cationic
surfactants seem to be favorable with regards to the yield. With the
exception of didodecyldimethylammonium bromide (DDAB),
which gave 49% yield on the third run (98% yield on the second
run), the other cationic surfactants achieved more than 90% on
the third run. The best result was obtained from the system com-
posed of OTAC and Ru-L3, which gave 63% yield with 98% ee even
on the fifth run. The ICP-MS analysis of the concentration of ruthe-
nium in both the aqueous and organic layers after the first run was
265.5 and 0.24 mg/L, respectively. More than 90% of the catalyst
remained in the aqueous layer after the fifth run, which indicated
that the catalyst loss could be ignored to some extent.
hol 3 as the substrate4) could be attributed to a concomitant SN1
reaction. Since the solvent is relatively important in the competi-
tion of the alternative reactions of SN1 and SN2, we screened vari-
ous solvents and found that DMF was the optimal choice (Table 3,
and 83% ee).
It is interesting to note that the ee value of the target product
was very low if the intermediate methanesulfonate (step 1.1)
was isolated or purified for the next reaction. We speculated that
this was caused by the rapid racemization of the sulphonate, and
it would be favorable for the enantiomeric purity of the product
if the reaction time was shortened in step 1.1 and the propargyl-
amine (step 1.2) was added in succession. Table 4 shows the opti-
mal reaction time and temperature for step 1.1. Table 4 also shows
that a higher temperature and longer reaction time were unfavor-
able with regards to the ee value. The best result (67% yield with
We next focused on the nucleophilic substitution reaction of a
methanesulfonate by propargylamine. We thought that the moder-
ate ee value (62% ee was obtained with enantiomerically pure alco-

336
Z. Luo et al. / Tetrahedron: Asymmetry 23 (2012) 333–338
Table 3
Preparation of Ladostigil (TV3326) in a different solventa
O
O
step 1.1 MeSO2Cl
N
O
N
O
HN
step 1.2 H2N
OH
3
Ladostigil (TV3326)
Entry
Solvent
Temp. (°C) (step 1.1)
Time (h) (step 1.1)
eeb (%)
Yieldc (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
DMF
THF
Acetone
CH3CN
CH2Cl2 + 10% HMPA
DMF + 10% HMPA
DMF + 20% HMPA
CH3NO2
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ20
2
2
2
2
2
2
2
2
2
65
83
65
56
47
66
75
76
15
60
65
56
42
42
50
60
60
5
a
b
c
Reactions were carried out on a 1 mmol scale and the product of step 1.1 did not require further purification for the next reaction.
The ee values were determined by HPLC on an OB-H column, 0.5 mL/min, oven:40 °C, Hex/IPA = 80/20.
Crude yield.
Table 4
Preparation of Ladostigil (TV3326) in DMF with different temperatures and reaction timesa
O
O
step 1.1 MeSO2Cl
N
O
N
O
HN
H2N
step 1.2
OH
Ladostigil
3
Entry
Temperatureb (°C)
Time (h) (step 1.1)
eec (%)
Yieldd (%)
1
2
3
4
5
6
7
8
0
ꢀ10
ꢀ20
ꢀ40
ꢀ40
ꢀ40
ꢀ40
ꢀ40
0.5
0.5
0.5
0.5
1.0
2.0
4.0
6.0
50
81
85
89
87
83
76
75
40
64
65
67
66
65
60
58
a
b
c
Reactions were carried out on a 1 mmol scale and the product of step 1.1 did note require further purification for the next reaction.
The temperature for step 1.1 was ꢀ40 °C to 0 °C, and for step 1.2 was ꢀ40 °C.
The ee values were determined by HPLC on an OB-H column, 0.5 mL/min, oven:40 °C, Hex/IPA = 80/20.
The yield was tested on crude product.
d
89% ee) was obtained at ꢀ40 °C and 0.5 h for step 1. The NMR spec-
tra confirmed that the sulfonate could be eliminated in the air,
which could be the main cause for its racemization. Finally, Lad-
ostigil (TV3326) Tartrate (99% ee) was obtained after salification
and recrystallization from ethanol.
Column chromatography was carried out using silica gel
(200–300 mesh). TLC was performed on glass-backed plates coated
with Silica Gel 60 with F254 indicator. NMR spectra were recorded
with TMS as the internal standard on a Bruker 400 MHz spectrom-
eter. Coupling constants are given in Hz. Ee values were deter-
mined on a SHIMADZU LC-20AT chromatography using Daicel
Chiral columns (OB-H). Chiral ligands were prepared as described
in our previous work.16
3. Conclusion
In conclusion, we have developed an effective method to pre-
pare the anti Alzheimer’s drug Ladostigil (TV3326) via ATH cata-
lyzed by Ru–Cs-DPEN in a system of HCOONa/H2O/surfactant.
The catalyst could be reused five times with up to 89% ee being ob-
tained for the final product. This efficient and practical approach to
the enantiomerically pure TV3326 provides a very promising pros-
pect for industrial application.
4.2. General procedure for the asymmetric transfer hydrogena-
tion in water with the use of surfactants
A mixture of chiral ligands (0.005 mmol) and [RuCl2(p-cym-
ene)]2 (1.53 mg, 0.0025 mmol) in CH2Cl2 (0.5 mL) was stirred at
40 °C for 1 h under an argon atmosphere. After the solvent was re-
moved under reduced pressure, substrate 2 (116.5 mg, 0.5 mmol),
sodium formate dehydrate (312 mg, 3 mmol), surfactant
(0.05 mmol), and 1.5 mL of H2O were added. The reaction mixture
was stirred at 40 °C under an argon atmosphere, and then ex-
tracted five times with n-hexane (2 mL) after the reaction was
completed (monitored by TLC). The aqueous solution containing
4. Experimental
4.1. General
All reactions were conducted using oven-dried glassware.
Commercial grade reagents were used without further purification.
the catalyst was used with HCOOH (39 ll, 10 equiv) and compound

Z. Luo et al. / Tetrahedron: Asymmetry 23 (2012) 333–338
337
2 (0.1165 g, 0.5 mmol) for the next reaction cycle. The yield was
determined by HPLC on a C8 column. The combined organic phases
were dried over anhydrous Na2SO4, evaporated under vacuum, and
purified by flash chromatography to give chiral alcohol.
40, flow rate = 0.5 mL minꢀ1, (S)-enantiomer t1 = 18.2 min; (R)-
enantiomer: t2 = 27.5 min.
4.3.4. Preparation of Ladostigil (TV3326)
A solution of methanesulfonyl chloride (0.229 g, 2 mmol) in
DMF (1 mL) was added to a solution of compound 3 (0.235 g,
1 mmol) and triethylamine (0.404 g, 4 mmol) in DMF (2 mL) at
ꢀ40 °C over 15 min. The reaction was maintained at this tempera-
ture for 0.5 h and then propargylamine (0.55 g, 10 mmol) was
added. The reaction was allowed to slowly return to room temper-
ature and stirred for another 5 h. The solvent and the excess prop-
argylamine were removed under the vacuum to afford the crude
product as a brown oil, which was acidified with aqueous hydro-
chloric acid (1 M, 10 mL) and washed with ether (10 mL). The
aqueous layer was basified with 2 M NaOH (10 mL) and then ex-
tracted with ethyl acetate (20 mL ꢁ 3). The combined organic lay-
ers were dried (Na2SO4), filtered, and concentrated under vacuum
to afford the crude TV3326 (0.19 g, 67%). 1H NMR (400 MHz, CDCl3)
d 7.18 (d, J = 8.1 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 7.8 Hz, 1H), 4.38 (t,
J = 6.1 Hz, 1H), 3.55–3.48 (m, 2H), 3.48–3.37 (m, 2H), 3.04 (d,
J = 9.7 Hz, 1H), 2.99 (m, 3H), 2.83–2.74 (m, 1H), 2.43 (m, 1H),
2.24 (s, 1H), 1.92–1.82 (m, 1H), 1.21 (dd, J = 12.8, 7.0 Hz, 3H); 13C
NMR (400 MHz, CDCl3) d 154.89, 150.29, 145.84, 140.40, 125.10,
121.09, 117.72, 82.42, 71.42, 61.95, 44.02, 36.19, 33.90, 29.89,
13.19, 12.46. LC/MS (EI+APCI) m/z: [M+H]+ 273.2. Analysis of this
4.3. Preparation of Ladostigil (TV3326) tartrate
4.3.1. Preparation of 2
To
a stirred suspension of 6-hydroxy-1-indanone (14.8 g,
100 mmol) and K2CO3 (27.6 g, 200 mmol) in CH3CN (800 mL), eth-
ylmethyl carbamyl chloride (18.22 g, 150 mmol) was added at
room temperature over 20 min and then the reaction mixture
was heated at reflux for 10 h. After the reaction was complete,
the solvent was evaporated and the residue was diluted with water
(250 mL). The mixture was extracted with ethyl acetate
(250 mL ꢁ 3) and the combined organic phase was dried over
Na2SO4. After the solvent was evaporated, the crude product was
purified by recrystallization from ethanol to obtain compound 2.
(22.9 g, 85% yield). 1H NMR (400 MHz, CDCl3) d 7.45 (d, J = 8.4 Hz,
2H), 7.36 (dd, J = 8.2, 2.0 Hz, 1H), 3.51–3.38 (m, 2H), 3.14–3.10
(m, 2H), 3.07 (s, 1H), 2.99 (s, 1H), 2.77–2.67 (m, 2H), 1.22 (dd,
J = 14.7, 6.9 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 205.87, 154.07,
151.59, 151.03, 138.10, 128.65, 127.15, 116.21, 44.08, 36.82,
34.23, 33.77, 25.32, 13.15. LC/MS (EI+APCI) m/z: [M+H]+ 234.1.
4.3.2. Preparation of 3
material by chiral HPLC indicated it to be 89% ee. ½a D20
¼ þ1:1 (c
ꢂ
A
mixture of (S,S,S)-Cs-DPEN (21.3 mg, 0.05 mmol) and
1.46, CHCl3). HPLC conditions: chiralcel OB-H, 40 °C, n-hexane/i-
[RuCl2(p-cymene)]2 (15.3 mg, 0.025 mmol) in CH2Cl2 (5 mL) was
stirred at 40 °C for 1 h under an argon atmosphere. After CH2Cl2
was removed, compound 2 (1.165 g, 5 mmol), sodium formate
dehydrate (3.12 g, 30 mmol), surfactant (0.5 mmol), and 15 mL of
H2O were added. The mixture was stirred at 40 °C for an appropri-
ate period. When the reaction was complete (monitored by TLC),
the mixture was extracted five times with n-hexane (20 mL). The
aqueous solution containing the catalyst was used with HCOOH
propanol = 80/20, flow rate = 0.5 mL minꢀ1
,
(S)-enantiomer
t1 = 28.6 min; (R)-enantiomer: t2 = 36.2 min.
4.3.5. Preparation of Ladostigil (TV3326) tartrate
To a solution of crude TV3326 (2.72 g, 10 mmol) in ethanol
(10 mL) at 70 °C, -(+)-tartrate acid (0.75 g, 5 mmol) was added.
L
The mixture was maintained at the same temperature for 2 h,
and then allowed to slowly return to room temperature to give a
light yellow solid. This was filtered, washed with ether, and recrys-
tallized to provide Ladostigil tartrate in 60% yield (2.86 g). 1H NMR
(400 MHz, CDCl3) d 7.19 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 7.2 Hz, 1H),
5.48 (s, 3H), 4.64 (s, 1H), 4.27 (s, 1H), 3.72–3.60 (m, 1H), 3.42
(dd, J = 31.1, 6.4 Hz, 1H), 3.09 (d, J = 8.3 Hz, 1H), 3.05 (s, 1H), 2.96
(s, 1H), 2.85–2.75 (m, 1H), 2.43 (s, 1H), 2.17 (s, 1H), 1.34–1.10
(m, 2H). 13C NMR (400 MHz, CDCl3) d 176.69, 176.69, 154.78,
154.78, 150.28, 141.59, 141.03, 125.44, 122.52, 118.91, 75.04,
72.50, 61.21, 61.21, 44.07, 34.93, 34.20, 31.02, 29.83, 13.17.
(390 lL, 10 equiv) and compound 2 (1.165 g, 5 mmol) for the next
reaction cycle. The yield was determined by HPLC on a C8 column.
The combined organic phases were dried over anhydrous Na2SO4
and evaporated under vacuum, and purified by flash chromatogra-
phy to afford the (S)-enantiomer of the title compound as a gray oil
(0.963 g, 82%). 1H NMR (400 MHz, CDCl3) d 7.13 (d, J = 8.1 Hz, 1H),
7.07 (d, J = 1.0 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 5.04 (t, J = 6.3 Hz,
1H), 3.43 (d, J = 5.5 Hz, 1H), 3.36 (d, J = 5.6 Hz, 1H), 3.10–2.86 (m,
4H), 2.74–2.63 (m, 1H), 2.36 (m, 1H), 1.94–1.79 (m, 1H), 1.19
(dd, J = 22.0, 5.8 Hz, 3H). 13C NMR (400 MHz, CDCl3) d 154.97,
150.38, 146.61, 139.91, 125.09, 121.45, 117.74, 75.83, 44.04,
36.15, 33.97, 29.21, 13.15. LC/MS (EI+APCI) m/z: [M+H]+ 236.1.
Analysis of this material by chiral HPLC indicated it to be 98% ee.
½
a 2D0
ꢂ
¼ þ11:8 (c 1.95, CHCl3). Analysis of the free base by chiral
HPLC indicated it to be 99% ee. HPLC conditions: chiralcel OB-H,
40 °C, n-hexane/i-propanol = 80/20, flow rate = 0.5 mL minꢀ1, (S)-
enantiomer t1 = 28.6 min; (R)-enantiomer: t2 = 36.2 min.
½
a 2D0
ꢂ
¼ þ27:2 (c 2.38, CHCl3). HPLC conditions: chiralcel OB-H,
40 °C, n-hexane/i-propanol = 60/40, flow rate = 0.5 mL minꢀ1, (S)-
enantiomer t1 = 18.2 min; (R)-enantiomer: t2 = 27.5 min.
Acknowledgement
We thank the Natural Science Foundation of China (20972198)
for financial support of this study.
4.3.3. Preparation of racemic 3
Sodium borohydride (0.385 g, 10 mmol) was added to a stirred
suspension of 2 (1.165 g, 5 mmol) in methanol (15 mL) at 0 °C, and
then the mixture was allowed to return to room temperature over
2 h. The solvent was evaporated and the residue was diluted with
water (20 mL) and extracted with ethyl acetate (20 mL ꢁ 3). The
combined organic layers were dried (Na2SO4), filtered, and concen-
trated under vacuum to afford racemic 3 (1.15 g, 98%). 1H NMR
(400 MHz, CDCl3) d 7.14 (d, J = 8.1 Hz, 1H), 7.09 (d, J = 1.7 Hz, 1H),
6.92 (dd, J = 8.1, 1.9 Hz, 1H), 5.04 (dd, J = 11.8, 5.9 Hz, 1H), 3.44
(d, J = 6.4 Hz, 1H), 3.37 (d, J = 6.4 Hz, 1H), 3.14–2.95 (m, 3H), 2.70
(m, 1H), 2.39 (m, 1H), 2.27 (1H), 1.88 (m, 1H), 1.26–1.13 (m, 3H).
HPLC conditions: chiralcel OB-H, 40 °C, n-hexane/i-propanol = 60/
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