Tunable chiral monophosphines as ligands in enantioselective rhodium-catalyzed ring-opening of oxabenzonorbornadienes with amines

Article abstract of DOI:10.1016/j.tetasy.2014.03.017

A new tunable chiral monophosphine was used as a ligand for asymmetric rhodium-catalyzed ring-opening of oxabenzonorbornadiene with amines, providing a series of chiral ring-opened products in high yields (up to 97%) and with high enantioselectivities (>99%).The reaction can be performed at rt to obtain the desired product with high enantioselectivity.

Full text of DOI:10.1016/j.tetasy.2014.03.017

Tetrahedron: Asymmetry 25 (2014) 709–717
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Tunable chiral monophosphines as ligands in enantioselective
rhodium-catalyzed ring-opening of oxabenzonorbornadienes
with amines
a
a
a
b
Renshi Luo a, , Ling Xie , Jianhua Liao , Hu Xin , Albert S. C. Chan
⇑
a School of Pharmaceutical Sciences, Gannan Medical University, Yi Xue Yuan Road, Ganzhou, Jiangxi 341000, China
b Institute of Creativity, Hong Kong Baptist University, Hong Kong, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A new tunable chiral monophosphine was used as a ligand for asymmetric rhodium-catalyzed ring-
opening of oxabenzonorbornadiene with amines, providing a series of chiral ring-opened products in
high yields (up to 97%) and with high enantioselectivities (>99%).The reaction can be performed at rt
to obtain the desired product with high enantioselectivity.
Received 20 August 2013
Revised 11 March 2014
Accepted 13 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction
a new and efficient rhodium-L2 (Fig. 1) catalyst, which is used in the
asymmetric ring-openings of oxabenzonorbornadiene with amines
Syntheses of chiral substituted dihydronaphthalene compounds
have gained great interest due to their core structural relevance to
different biological activities.1 Although there are different
chemical routes to synthesize such compounds, one of the most
attractive synthetic strategies is the transition metal-catalyzed
asymmetric ring-opening (ARO) of oxabenzonorbornadiene.
Ever since the pioneering study in this field reported by
Lautens,2 great progress has been achieved in the rhodium-
catalyzed asymmetric ring-openings of oxabenzonorbornadiene
with a wide range of nucleophiles.3–10 Other metals such as cop-
per,11 palladium,6,12 iron,13 nickel,14 and iridium15,16 catalyzed
asymmetric ring-opening reactions of oxabicyclic alkenes have
also been reported on.
providing high yields and enantioselectivities.
O
H
H
O
P
O
P
R'
P
R
tBu
t-Bu t-Bu
R
MeO
OMe
MeO
OMe
L1: R = H, R' = H
L5
L2: R = OMe, R' = H
L3: R = OMe, R' = Me
L4: R = OMe, R' = Pt-Bu2
Figure 1. Tunable chiral phosphorus ligands.
Although great progress has been achieved on the metal-cata-
lyzed asymmetric ring-opening of oxabenzonorbornadiene,17 the
development of novel and efficient catalysts with less expensive
transition metals, broader substrate scope, and low catalyst load-
ings continues to be of great importance.
2. Results and discussions
2.1. Effect of ligands and additives
Recently we have developed a series of chiral biaryl monophos-
phorus ligands used for palladium-catalyzed asymmetric
Suzuki–Miyaura coupling reactions18 and the ruthenium-catalyzed
asymmetric additions of arylboronic acids to aryl aldehydes.19 We
speculated that the high tunability of these monophosphorus
ligands could be used to investigate the asymmetric ring-opening
reaction of oxabenzonorbornadiene with amines. Herein we report
At first, we synthesized chiral phosphorus ligands according to
the literature.18 We also synthesized diphosphorus ligands L4 and
L5 to study any differences from the monophosphorus ligand. With
these ligands in hand, we next researched the asymmetric
ring-opening reaction of oxabenzonorbornadiene with piperazine.
The reaction was performed with 2.0 mol % [Rh(cod)Cl]2 and
4.8 mol % of ligand as the catalytic system under nitrogen in THF
at 80 °C for 6 h. Initial screening of the reaction conditions (Table 1,
entries 1–5) demonstrated that the ligand structure (Fig. 1) and
additive play a significant role both in terms of reactivity and
⇑
Corresponding author. Tel./fax: +86 7978169775.
E-mail addresses: renshiluo@126.com, renshiluo@sioc.ac.cn (R. Luo).
http://dx.doi.org/10.1016/j.tetasy.2014.03.017
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

710
R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
Table 1
Optimization of asymmetric rhodium-catalyzed ring-opening of oxabenzonorbornadiene with N-phenylpiperazine
2.0 mol% Rh
O
4.8mol% L1-L5
HN
N
Ph
+
N
N
Ph
THF, 80 o C
6 h
OH
1a
2
3
Entry
Rh precursor
Additive
L⁄
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
[Rh(cod)Cl]2
Rh(NBD)BF4
[Rh(coe)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
[Rh(C2H4)2Cl]2
no
NaI
no
—
—
<5
85
<5
97
95
95
93
81
93
95
97
95
95
91
83
—
—
L1
L1
L2
L3
L4
L5
L2
L2
L2
L2
L2
L2
L2
ND
83
86
12
70
55
90
93
93
78
38
92
93
NaI
NaI
NaI
NaI
NaI
NaI
NaI
NaI
Bu4NI
KI
9
10
11
12
13
14c
15d
NaI
NaI
a
b
c
Yield of the isolated product.
The ee value was determined by HPLC analysis on a chiral phase (Chiralcel Amy-lose 2).
1.0 mol % [Rh(C2H4)Cl]2 and 2.4 mol % L2 were used.
Performed at rt.
d
Table 2
Effects of solvents in the ring-opening reaction of oxabenzonorbornadiene with N-phenylpiperazine
2.0 mol% [Rh(C2H4)2Cl]2
O
4.8 mol% L2
HN
N
Ph
+
N
N
Ph
solvent, temperature
OH
6h
1a
2
3
Entry
Solvent
T (°C)
T (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
10
THF
Et2O
80
40
60
60
80
80
90
40
80
90
8
7
6
6
6
6
8
7
6
8
95
95
95
95
95
95
95
95
95
95
93
92
92
92
86
86
81
87
84
65
MTBE
CHCl3
CH3CN
DCE
dioxane
DCM
hexane
toluene
a
Isolated product.
Determined by HPLC (Chiralcel Lux Amylose-2 column).
b
selectivity.6c,6d Only <5% conversion was observed in the absence
of NaI (Table 1, entries 1 and 3). High yields (85%) were obtained
when 0.2 equiv of NaI were added (Table 1, entry 2). With
[Rh(cod)Cl]2 as the rhodium precursor, ligand L1 gave the desired
product with high yield and good ee (Table 1, entry 4). Upon fur-
ther investigation of ligands, we found that the introduction of a
bulky group at the R position of L2 improved the enantioselectivity
up to 86% (Table 1, entry 5). In contrast, the introduction of bulky
substituents at the R’ position of L3–L5 led to a decrease of enanti-
oselectivities (Table 1, entries 6–8). Having established that L2 was
the best ligand, we next studied rhodium precursors. An enantio-
meric excess of 90% was obtained with Rh(NBD)BF4 as the rhodium
precursor (Table 1, entry 9). The same ees (up to 93% ee) were ob-
served with [Rh(C2H4)2Cl]2 and [Rh(coe)2Cl]2 as the rhodium pre-
cursors (Table 1, entries 10 and 11). This could be due to the fast
complex formation between the rhodium precursors and ligand
L2. Different additives affected the performance of the catalyst.
Only 78% ee and 38% ee were observed using additives such as
Bu4NI and KI, respectively (Table 1, entries 12 and 13). Almost
the same enantioselectivity was observed at a catalyst loading of
1.0 mol % [Rh(C2H4)2Cl]2 and 2.4 mol % L2 (Table 1, entry 14). The
reaction can even be performed at room temperature to give the
desired product with the same enantioselectivity (Table 1, entry
15).
2.2. Influence of the solvent
In order to obtain better reaction conditions, we next screened
the effects of solvents (Table 2, entries 1–10). Among the solvents
tested, THF was found to be the best solvent to give the best yield
and enantioselectivity (Table 2, entry 1). Slightly lower enantiose-
lectivities but high yields were observed with the solvents Et2O,
MTBE, and CHCl3 (Table 2, entries 2–4). Almost the same enanti-
oselectivities were obtained when the reactions were performed

R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
711
Table 3
Substrates scope of rhodium-catalyzed ring-opening reaction of oxabenzonorbornadiene with piperazines
R
R
R
R
2.0 mol% [Rh(C2H4)2Cl]2
4.8 mol% L2
R1
O
+
HN
N
N
THF, reflux
0.2 eq. NaI
OH
N
R1
1
4
1a
1b
1c
: R = H; : R = F; : R = OMe
Entry
R
R1
T (h)
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
C6H5
8
6
6
10
10
6
6
10
6
10
6
6
6
8
6
6
6
8
6
95 5aa
93(5ab)
95(5ac)
90(5ad)
93(5ae)
95(5af)
95(5ag)
87 5ah
95 5ai
93
95
90
97
95
96
98
>99
96
90
>99
97
96
96
98
>99
97
83
95
2-MeOC6H4
2-CH3C6H4
2-FC6H4
3-ClC6H4
4-CH3C6H4
4-CH3OC6H4
4-CF3C6H4
2,4-di-CH3C6H3
3,4-di-ClC6H3
3-Cl-Bn
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
89 5aj
95 5ak
91 5al
Boc
C6H5
2-FC6H4
93 5ba
91 5bb
95 5bc
97 5bd
97 5be
90 5bf
95 5bg
91 5ca
91 5cb
90 5cc
95 5cd
2-CH3OC6H4
4-CH3C6H4
4-CH3OC6H4
3,4-di-ClC6H3
2,4-di-CH3C6H3
C6H5
2-MeOC6H4
4-CF3C6H4
4-CH3OC6H4
16
12
12
12
94.5
>99
96
98
a
Yield of the isolated product.
The ee value was determined by HPLC analysis on a chiral phase (Chiralcel OD-H, AD-H or Lux Amylose-2 column).
b
with CH3CN, DCE, dioxane, DCM, and hexane (Table 2, entries 5–9).
Reactions in toluene afforded the desired product 3 in only 65% ee
(Table 2, entry 10).
attributed to the hindered ortho-substituted groups and the weak
nucleophilicity of the nucleophiles.
Encouraged by the results of the rhodium-catalyzed ring-
opening reaction of oxabenzonorbornadiene with amines, the
ring-opening reaction of aza-benzonorbornadiene 8 with N-phenyl-
piperazine was also tested with the optimized reaction conditions.
Unfortunately, moderate yields and enantioselectivities were
obtained (Fig. 2). Further studies are currently in progress.
The X-ray structure of 5cc, obtained by solvent evaporation
from its solution in dichloromethane and petroleum ether, con-
firmed its absolute configuration to be (R,R)20 as shown in Figure 3.
2.3. Scope and limitations of the catalytic system
Under the optimized reaction conditions, different oxabenzo-
norbornadienes were converted into the corresponding products
in excellent yields and enantioselectivities (Table 3). As can be seen
in Table 3, with 1,4-dihydro-1,4-epoxynaphthalene 1a as the sub-
strate, various piperazines with either electron-donating or elec-
tron-withdrawing substituents at the position phenyl afforded
high yields and enantioselectivities (Table 3, entries 1–10). Other
piperazines such as N-Boc piperazine and N-Bn piperazine were
also used in this catalyst system and gave high yields and ees
(Table 3, entries 11 and 12). Electron-withdrawing substrates such
as 1,4-dihydro-6,7-difluoro-1,4-epoxynaphthalene 1b could also
be employed to provide high yields and enantioselectivities with
various piperazines (Table 3, entries 13–19). High yields and ees
were also obtained with bigger steric substrates such as 1,4-dihy-
dro-6,7-dimethoxy-1,4-epoxynaphthalene 1c (Table 3, entries
20–23).
3. Conclusion
In conclusion, we have disclosed an efficient method for the Rh-
L2 catalyzed ring-opening of oxabenzonorbornadiene with amines,
leading to the formation of a series of dihydronaphthalenes in high
yields and enantioselectivities. The new monophosphorus ligand
L2 with a large steric chiral phosphine center is key to the success
of this asymmetric transformation. Applications of this methodol-
ogy for the synthesis of biologically active molecules are currently
under investigation and will be reported in due course.
With the optimized catalyst in hand, the asymmetric ring-open-
ing reaction of oxabenzonorbornadiene was screened with other
amines (Table 4). Using 1,4-dihydro-1,4-epoxynaphthalene 1a as
the substrate, various amines including primary or secondary aro-
matic amines (Table 4, entries 1, 2, and 4–8) and aliphatic amines
(Table 4, entries 9 and 10) were used in the reaction to provide the
desired ring-opening products in high yields and enantioselectivi-
ties. However, none of the desired products were observed when
2-chloro-N-methylaniline and pyrrole were employed in the reac-
tion (Table 4, entries 3 and 11). These negative results may be
4. Experimental
4.1. General
All reactions were carried out under a nitrogen atmosphere un-
less otherwise specified. THF (<0.02% water content), Et2O, diox-
ane, MTBE, DCM, DCE, Xylene and toluene were purchased from
Sigma Aldrich and used directly without further purification. Com-
mercialized reagents were used without further purification. 1H,

712
R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
Table 4
Substrate scope of rhodium-catalyzed ring-opening reaction of oxabenzonorbornadiene with amines
R1
N
R2
2.0 mol% [Rh(C2H4)2Cl]2
L2
4.8 mol%
O
R1
H
+
THF, reflux
0.2 eq.NaI, 6h
N
OH
R2
1a
NHR1R2
6
7
Entry
1
Yielda (%)
eeb (%)
96
NH2
95 7aa
H
N
2
3
97 7ab
95
H
N
<5
ND
Cl
H
N
4
90 7ac
94
Cl
H
N
5
6
93 7ad
95 7ae
94
96
Cl
H
N
H3C
H
N
7
8
91 7af
97 7ag
94
97
H
N
9
95 7ah
95 7ai
<5
94
96
ND
NH
N
H
10
H
N
11
a
Yield of the isolated product.
The ee value was determined by HPLC analysis on a chiral phase (Chiralcel OD-H or AD-H).
b
2.0 mol% [Rh(C2H4)2Cl]2
Boc
L2
4.8 mol%
N
+
HN
N
Ph
THF, 80 o C
0.2 eq. NaI
N
N
Ph
NHBoc
onyl 53% ee, 69%yield
Figure 2. Rhodium-catalyzed ring-opening of piperazine to aza-norbornene.
8
9
2
31P, and 13C NMR data were recorded on a Bruker-Topspin DRX400
or 500 NMR Spectrometer with CDCl3 as the solvent. 1H shifts are
referenced to CDCl3 at 7.27 ppm. 31P shifts are referenced to 85%
H3PO4 in D2O at 0.0 ppm as external standard and obtained with
1H decoupling. 13C shifts are referenced to CDCl3 at 77.23 ppm
and obtained with 1H decoupling. MS was measured on Agilent
1100 Series LC/MSD mass spectrometer. Chiral HPLC analyses were
performed on an Agilent 1200 system using a Chiralcel OD-H, Chir-
alpak AD-H column or Chiralcel Lu-Amy lose-2 column. Racemic
compounds were prepared by a reaction using [Rhcod)Cl]2 and
NaI without using the ligand at 80 °C. Optical rotations were re-
corded on a Rudolph Research Automatic Polarimeter.
Figure 3. The X-ray structure of 5cc; the absolute configuration of the stereogenic
centers in 5cc is (R,R).

R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
713
4.2. Procedures for the preparation of ligands
2H), 6.48–6.70 (m, 2H), 4.86 (s, 1H), 3.64 (s, 3H), 3.62 (s, 3H),
0.71 (t, J = 4.0, 8.0 Hz, 9H); 31P NMR (162 MHz, CDCl3) d À0.3; 13C
NMR (100 MHz, CDCl3) d 86.4 (d, J = 7.5 Hz), 56.0, 55.4, 31.6, 30.0
(d, J = 63.2 Hz), 27.1 (t, J = 7.5 Hz); ESI-MS: m/z 659.70 [M+H]+.
4.2.1. Synthesis of ligand L1
Ligand L1 was synthesized from chiral 10 through a coupling
reaction to give compound 12 followed by a stereospecific reduc-
tion of 12 mediated by PMHS/Ti(Oi-Pr)4. The synthetic procedures
were published in a previous paper.18 1H NMR (400 MHz, CD2Cl2):
d 7.71 (m, 2H), 7.42 (m, 2H), 7.35 (m, 2H), 6.99 (m, 1H), 6.90 (dd,
J = 8.1, 0.8 Hz, 1H), 4.87 (dd, J = 12.7, 1.9 Hz, 1H), 4.57 (dd,
J = 25.9, 12.7 Hz, 1H), 0.64 (d, J = 12.1 Hz, 9H); 31P NMR
(162 MHz, CD2Cl2): d À11.2; 13C NMR (100 MHz, CD2Cl2): d
164.8, 146.5, 143.1, 131.9, 129.9, 129.8, 128.9, 127.9, 122.7 (d,
J = 17.9 Hz), 122.3 (d, J = 3.1 Hz), 110.5, 70.5 (d, J = 26.9 Hz), 32.1
(d, J = 20.2 Hz), 27.0 (d, J = 13.8 Hz). ESI-MS: m/z 271 [M+H]+.
4.3. General procedure for the asymmetric ring-opening of
oxabenzonorbornadiene with amines
At first, THF (2.0 mL) was added to a mixture of oxabenzonor-
bornadiene 1 (0.347 mmol, 1.0 equiv), amine 4 or 6 (1.041 mmol,
3.0 equiv), NaI (10.34 mg, 0.069 mmol, 0.2 equiv), ligand L2
(4.5 mg, 0.0167 mmol, 4.8 mol %) and [Rh(C2H4)2Cl]2 (2.7 mg,
0.0069 mmol, 2.0 mol %) under N2. The mixture was then stirred
at RT for 1 h and heated at reflux for 6–12 h after which the residue
was subjected directly to silica gel column chromatography [ethyl
acetate/hexanes (1:1–2:1 v/v) as the eluent] to afford the desired
alcohol product 5 or 7. The enantioselectivity was determined by
chiral HPLC on a chiralcel OD-H, chiralcel AD-H, or Lux Amylose-
2 column.
4.2.2. Synthesis of ligand L2
Ligand L2 was synthesized from the chiral compound 10 by a
coupling reaction to give compound 13 followed by a stereospecific
reduction of 13 mediated by PMHS/Ti(Oi-Pr)4. The synthetic proce-
dures were published in a previous paper.18 1H NMR (400 MHz,
CDCl3): d 7.29 (m, 2H), 6.87 (m, 2H), 6.65 (d, J = 8.2 Hz, 1H), 6.59
(d, J = 8.3 Hz, 1H), 4.81 (dd, J = 12.5, 1.8 Hz, 1H), 4.53 (dd, J = 25.2,
12.5 Hz, 1H), 3.77 (s, 3H), 3.71 (s, 3H), 0.73 (d, J = 12.1 Hz, 9H);
31P NMR (162 MHz, CDCl3): d À7.9; 13C NMR (100 MHz, CDCl3): d
163.4, 157.9. 157.1, 138.4 (d, J = 22.3 Hz), 130.5, 129.0, 125.0 (d,
J = 16.4 Hz), 123.8 (d, J = 5.4 Hz), 119.6, 109.5, 104.5, 103.6, 70.4
(d, J = 33.8 Hz), 55.9, 55.4, 30.9 (d, J = 23.2 Hz), 26.6 (d,
J = 18.1 Hz); ESI-MS: m/z 331 [M+H]+.
4.3.1. (1R,2R)-2-(4-Phenylpiperazin-1-yl)-1,2-dihydronaphtha-
len-1-ol 5aa
White solid (95% yield); 93% ee; [
a]
27 = À158.92 (c 0.53, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.50 (d, J = 7.1 Hz, 1H), 7.14–7.21 (m,
4H), 6.99–7.01 (m, 1H), 6.77–6.86 (m, 3H), 6.47 (dd, J = 2.5 Hz,
J = 9.9 Hz, 1H), 6.04 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.84 (d,
J = 11.6 Hz, 1H), 3.45 (td, J = 2.5 Hz, J = 11.5 Hz, 1H), 3.28 (br, 1H),
3.08–3.19 (m, 4H), 2.85–3.08 (m, 2H), 2.60–2.65 (m, 2H); 13C
NMR (100 MHz, CDCl3) 151.42, 137.17, 131.91, 129.60, 129.32,
128.09, 127.65, 126.40, 124.97, 124.58, 120.13, 116.43, 67.91,
67.62 (d, J = 2.9 Hz), 49.98, 49.13; ESI-MS: m/z 307 [M+H]+. Chiral
HPLC conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hex-
ane/isopropanol: 90:10, 254 nm, 12.22 min (minor), 13.22 min
(major).
4.2.3. Synthesis of ligand L3
Ligand L3 was synthesized from chiral compound 13 by a LDA-
mediated homo-coupling reaction to give compound 14 followed
by a stereospecific reduction of 14 mediated by PMHS/Ti(Oi-Pr)4.
The synthetic procedures were published in a previous paper.18
1H NMR (400 MHz,CD2Cl2): d 7.35–7.20 (m, 2H), 6.85–6.75 (m,
2H), 6.64 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 8.4 Hz,1H), 4.97 (q,
J = 7.0 Hz, 1H), 3.73 (s, 3H), 3.71 (s, 3H), 1.40 (dd, J = 16.4, 7.0 Hz,
3H), 0.71 (d, J = 12.0 Hz, 9H); 31P NMR (162 MHz, CD2Cl2): d 9.9;
13C NMR (100 MHz, CD2Cl2): d 163.1, 158.2, 157.4, 139.5 (d,
J = 17 Hz), 130.7, 129.4, 125.78, 125.0 (d, J = 6 Hz), 124.0, 120.0,
109.9, 104.6, 104.0, 79.2 (d, J = 24 Hz), 56.0 (d, J = 2 Hz), 31.1 (d,
J = 19 Hz), 25.6, 21.6 (d, J = 29 Hz); HRMS calcd for C20H26O3P
[M+H]+: 345.1614; found: 345.1605.
4.3.2. (1R,2R)-2-(4-(2-Methoxyphenylpiperazin-1-yl)-1,2-dihydro-
naphthalen-1-ol 5ab
White solid (93% yield); 95% ee; [
a]
27 = À131.8 (c 0.57, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.50 (d, J = 7.1 Hz, 1H), 7.12–7.20 (m,
2H), 6.98–7.00 (m, 1H), 6.90–6.94 (m, 1H), 6.81–6.87 (m, 2H),
6.76–6.78 (m, 1H), 6.46 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 6.09 (dd,
J = 2.5 Hz, J = 9.9 Hz, 1H), 4.84 (d, J = 11.5 Hz, 1H), 3.77 (s, 3H),
3.70 (s, 1H), 3.42 (td, J = 2.5 Hz, J = 11.5 Hz, 1H), 2.89–3.03 (m,
6H), 2.64–2.69 (m, 2H); 13C NMR (100 MHz, CDCl3) 152.31,
141.23, 137.21, 131.92, 129.44, 127.95, 127.55, 126.31, 124.94,
124.91, 123.21, 121.11, 118.37, 112.21, 67.75, 67.55 (d,
J = 2.9 Hz), 55.44 (d, J = 5.8 Hz), 51.27, 49.22; ESI-MS: m/z 337
[M+H]+. Chiral HPLC conditions: Chiralcel OD-H, 25 °C, flow rate:
1.0 mL/min, hexane/isopropanol: 90:10, 254 nm, 11.07 min (ma-
jor), 12.11 min (minor).
4.2.4. Synthesis of ligand L4
Ligand L4 was synthesized from chiral compound 13 by a LDA-
mediated homo-coupling reaction to give compound 15 followed
by a stereospecific reduction of 15 mediated by PMHS/Ti(Oi-Pr)4.
The synthetic procedures were published in a previous paper.18
1H NMR (400 MHz, CD2Cl2) d 7.42 (m, 1H), 7.25 (m, 1H), 6.90 (m,
1H), 6.81 (d, J = 8.0 Hz, 1H), 5.60 (dd, J = 5.4, 4.4 Hz, 1H), 1.37 (d,
J = 11.0 Hz, 9H), 1.18 (d, J = 11.1 Hz, 9H), 0.96 (d, J = 12.2 Hz, 9H);
4.3.3. (1R,2R)-2-(4-o-Tolylpiperazin-1-yl)-1,2-dihydronaphtha-
3
31P NMR (162 MHz, CD2Cl2): d 52.0 (d, JPP = 146.1 Hz), 12.2 (d,
len-1-ol 5ac
3JPP = 146.4 Hz); 13C NMR (100 MHz, CD2Cl2)
d
164.7, 131.5,
White solid (95% yield); 90% ee; [
a
]
D
27 = À122.2 (c 0.37, CHCl3);
131.3, 121.1 (dd, J = 64.3, 6.4 Hz), 121.0 (d, J = 6.1 Hz), 111.3, 80.2
(dd, J = 45.3, 37.4 Hz), 34.6 (d, J = 24.4 Hz), 34.1 (dd, J = 22.4,
11.3 Hz), 32.0 (dd, J = 22.5, 7.6 Hz), 31.5 (dd, J = 12.2, 3.6 Hz), 31.4
(d, J = 12.5 Hz), 26.3 (d, J = 14.7 Hz).
1H NMR (400 MHz, CDCl3) 7.52 (d, J = 7.2 Hz, 1H), 7.07–7.210 (m,
4H), 6.89–7.01 (m, 3H), 6.47 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 6.11
(dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.84 (d, J = 11.8 Hz, 1H), 3.42 (td,
J = 2.4 Hz, J = 11.8 Hz, 1H), 3.27 (br, 1H), 2.85–2.91 (m, 6H), 2.59–
2.63 (m, 2H), 2.23 (s, 3H); 13C NMR (100 MHz, CDCl3) 151.42,
137.19, 132.59, 131.86, 131.16, 129.33, 127.92, 127.48, 126.67,
126.24, 124.90, 127.77, 123.29, 119.05, 67.78, 67.58 (d,
J = 3.2 Hz), 52.30, 49.51, 17.98; ESI-MS: m/z 321 [M+H]+. Chiral
HPLC conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hex-
ane/isopropanol: 90:10, 254 nm, 7.37 min (minor), 8.37 min
(major).
4.2.5. Synthesis of ligand L5
Ligand L5 was synthesized from chiral compound 13 by a LDA-
mediated homo-coupling reaction to give compound 16 followed
by a stereospecific reduction of 16 mediated by PMHS/Ti(Oi-Pr)4.
The synthetic procedures were published in a previous paper.18
1H NMR (400 MHz, CDCl3) d 7.15–7.21 (m, 2H), 6.70–6.77 (m,

714
R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
4.3.4. (1R,2R)-2-(4-(2-Fluorophenyl)piperazin-1-yl)-1,2-dihydro-
1H), 6.11 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.96 (d, J = 11.3 Hz, 1H),
3.57 (td, J = 2.4 Hz, J = 11.2 Hz, 1H), 3.33–3.37 (m, 4H), 3.27(br,
1H), 2.97–3.01 (2H, m), 2.73–2.77 (2H, m); 13C NMR (125 MHz,
CDCl3) 153.41, 137.01, 131.85, 129.95, 128.27, 127.84, 126.65 (td,
J = 3.7 Hz), 126.55, 125.98, 125.15, 124.06, 114.96, 67.99, 67.78,
48.97, 48.80; ESI-MS: m/z 375 [M+H]+. Chiral HPLC conditions: Chi-
ralcel AD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopropanol:
90:10, 254 nm, 11.35 min (minor), 11.99 min (major).
naphthalen-1-ol 5ad
White solid (90% yield); 97% ee; [
a]
27 = À154.7 (c 0.67, CHCl3);
D
19F NMR (376 MHz, CDCl3) d À119.71; 1H NMR (400 MHz, CDCl3)
7.49 (d, J = 7.1 Hz, 1H), 7.12–7.19 (m, 2H), 6.82–7.00 (m, 5H),
6.46 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 6.05 (dd, J = 2.5 Hz, J = 9.9 Hz,
1H), 4.84 (d, J = 11.5 Hz, 1H), 3.41 (td, J = 2.5 Hz, J = 11.5 Hz, 1H),
3.25 (br, 1H), 2.98–3.07 (m, 4H), 2.85–2.90 (m, 2H), 2.61–2.66
(m, 2H); 13C NMR (100 MHz, CDCl3) 157.08, 154.64, 140.20,
140.11, 137.16, 131.91, 129.51, 128.02, 127.61, 126.36, 124.96,
124.75, 124.64, 122.78, 122.70, 119.12, 116.37, 116.17, 67.83,
67.60 (d, J = 4.9 Hz), 51.22, 49.13. ESI-MS: m/z 325 [M+H]+. Chiral
HPLC conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hex-
ane/isopropanol: 90:10, 254 nm, 9.87 min (major), 10.85 min
(minor).
4.3.9. (1R,2R)-2-(4-(2,4-Dimethylphenyl)piperazin-1-yl)-1,2-
dihydronaphthalen-1-ol 5ai
White solid (95% yield); 96% ee; [
a]
27 = À160.8 (c 0.55, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.50 (d, J = 7.2 Hz, 1H), 7.11–7.20 (m,
2H), 6.83–7.00 (m, 4H), 6.46 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 6.09
(dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 4.83 (d, J = 11.8 Hz, 1H), 3.41 (td,
J = 2.4 Hz, J = 11.8 Hz, 1H), 3.21 (br, 1H), 2.81–2.87 (m, 6H), 2.57–
2.62 (m, 2H), 2.19 (d, J =4.8 Hz, 6H); 13C NMR (100 MHz, CDCl3)
149.02, 137.25, 132.72, 132.52, 131.88, 129.31, 127.92, 127.48,
127.13, 126.24, 124.97, 124.79, 119.00, 67.79, 67.60 (d,
J = 3.5 Hz), 52.52, 49.62, 20.80 (d, J = 5.0 Hz), 17.84 (d, J = 4.9 Hz).
ESI-MS: m/z 335 [M+H]+. Chiral HPLC conditions: Chiralcel AD-H,
25 °C, flow rate: 1.0 mL/min, hexane/isopropanol: 90:10, 230 nm,
6.58 min (minor), 7.20 min (major).
4.3.5. (1R,2R)-2-(4-(3-Chlorophenyl)piperazin-1-yl)-1,2-dihydr-
onaphthalen-1-ol 5ae
White solid (93% yield); 95% ee; [
a]
27 = À153.7 (c 0.43, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.49 (d, J = 7.1 Hz, 1H), 6.99–7.19 (m,
4H), 6.68–6.79 (m, 3H), 6.47 (dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 6.01
(dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.82 (d, J = 11.4 Hz, 1H), 3.42 (td,
J = 2.3 Hz, J = 11.4 Hz, 1H), 3.20 (br, 1H), 3.09–3.21 (m, 4H), 2.81–
2.86 (m, 2H), 2.57–2.62 (m, 2H); 13C NMR (100 MHz, CDCl3)
152.40, 137.05, 135.10, 131.85, 130.22, 129.66, 128.11, 127.70,
126.42, 125.00, 124.38, 119.64, 116.07, 114.20, 67.89, 67.58,
49.42, 48.91. ESI-MS: m/z 341 [M+H]+. Chiral HPLC conditions: Chi-
ralcel AD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopropanol:
90:10, 254 nm, 14.39 min (minor), 15.65 min (major).
4.3.10. (1R,2R)-2-(4-(3,4-Dichlorophenyl)piperazin-1-yl)-1,2-
dihydronaphthalen-1-ol 5aj
White solid (89% yield); 90% ee; [
a
]
D
27 = À130.95 (c 0.37, CHCl3);
1H NMR (400 MHz, CDCl3) 7.49 (d, J = 7.0 Hz, 1H), 7.14–7.21 (m,
3H), 6.99 (d, J = 6.8 Hz, 1H), 6.85 (d, J = 2.8 Hz, 1H), 6.63 (dd,
J = 2.8 Hz, J = 8.9 Hz, 1H), 6.47 (dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 5.99
(dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.81 (d, J = 11.3 Hz, 1H), 3.42 (td,
J = 2.4 Hz, J = 11.3 Hz, 1H), 3.18 (br, 1H), 3.05–3.10 (m, 4H), 2.80–
2.85 (m, 2H), 2.56–2.61 (m, 2H); 13C NMR (100 MHz, CDCl3)
150.63, 136.88, 132.82, 131.72, 130.51, 129.62, 128.04, 127.64,
126.35, 124.94, 124.16, 122.34, 117.39, 115.50, 67.80, 67.42,
49.27, 48.69. ESI-MS: m/z 375 [M+H]+. Chiral HPLC conditions: Chi-
ralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopropanol:
90:10, 254 nm, 16.12 min (minor), 17.96 min (major).
4.3.6. (1R,2R)-2-(4-p-Tolylpiperazin-1-yl)-1,2-dihydronaphtha-
len-1-ol 5af
White solid (95% yield); 96% ee; [
a]
27 = À120.9 (c 0.38, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.50 (d, J = 7.2 Hz, 1H), 7.15–7.21 (m,
2H), 6.98–7.01 (m, 3H), 6.76–6.78 (m, 2H), 6.47 (dd, J = 2.5 Hz,
J = 9.9 Hz, 1H), 6.04 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.83 (d,
J = 11.6 Hz, 1H), 3.42 (td, J = 2.4 Hz, J = 11.6 Hz, 1H), 3.24 (br, 1H),
3.04–3.12 (m, 4H), 2.85–2.90 (m, 2H), 2.59–2.64 (m, 2H); 13C
NMR (100 MHz, CDCl3) 149.32, 137.20, 131.92, 129.83, 129.65,
129.56, 128.06, 127.63, 126.38, 124.96, 124.64, 116.77, 67.87 (d,
J = 3.5 Hz), 50.53, 49.13, 20.64 (d, J = 10.3 Hz). ESI-MS: m/z 321
[M+H]+. Chiral HPLC conditions: Chiralcel Lu-Amy lose-2, 25 °C,
flow rate: 1.0 mL/min, hexane/isopropanol: 90:10, 254 nm,
12.92 min (minor), 14.33 min (major).
4.3.11. (1R,2R)-2-(4-(3-Chlorobenzyl)piperazin-1-yl)-1,2-dihyd-
ronaphthalen-1-ol 5ak
White solid (95% yield); >99% ee; [
a
]
D
27 = À146.0 (c 0.68, CHCl3);
1H NMR (400 MHz, CDCl3) 7.47 (d, J = 7.3 Hz, 1H), 7.26 (s, 1H),
7.09–7.18 (m, 5H), 6.96–6.98 (m, 1H), 6.44 (dd, J = 2.5 Hz,
J = 9.9 Hz, 1H), 6.03 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.77 (d,
J = 11.5 Hz, 1H), 3.39 (s, 2H), 3.35 (td, J = 2.5 Hz, J = 11.5 Hz, 1H),
3.18 (br, 1H), 2.71–2.75 (m, 2H), 2.41–2.50 (m, 6H); 13C NMR
(100 MHz, CDCl3) 140.42, 137.24, 134.32, 131.92, 129.63, 129.36,
129.20, 127.94, 127.54, 127.42, 127.35, 126.30, 124.96, 124.90,
67.82, 67.42, 62.52, 53.67, 25.53.. ESI-MS: m/z 354 [M+H]+. Chiral
HPLC conditions: Chiralcel Lu-Amy lose-2, 25 °C, flow rate:
1.0 mL/min, hexane/isopropanol: 85:15, 254 nm, 7.34 min (minor),
8.32 min (major).
4.3.7. (1R,2R)-2-(4-(4-Methoxyphenyl)piperazin-1-yl)-1,2-dihy-
dronaphthalen-1-ol 5ag
White solid (95% yield); 98% ee; [
a]
27 = À162.5 (c 0.43, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.49 (d, J = 7.0 Hz, 1H), 7.13–7.20 (m,
2H), 6.99–7.01 (m, 1H), 6.75–6.83 (m, 4H), 6.47 (dd, J = 2.4 Hz,
J = 9.9 Hz, 1H), 6.05 (dd, J = 2.5 Hz, J = 9.9 Hz, 1H), 4.83 (d,
J = 11.8 Hz, 1H), 3.67 (s, 3H), 3.42 (td, J = 2.3 Hz, J = 11.5 Hz, 1H),
3.21 (br, 1H), 2.99–3.05 (m, 4H), 2.85–2.90 (m, 2H), 2.60–2.65
(m, 2H); 13C NMR (100 MHz, CDCl3) 154.08, 145.72, 137.16,
131.90, 129.54, 128.04, 127.62, 126.37, 124.96, 124.64, 118.52,
114.57, 67.82, 67.53 (d, J = 3.1 Hz), 55.67 (d, J = 5.8 Hz), 51.38,
49.14. ESI-MS: m/z 337 [M+H]+. Chiral HPLC conditions: Chiralcel
AD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopropanol: 90:10,
254 nm, 16.27 min (minor), 18.17 min (major).
4.3.12. tert-Butyl 4-((1R,2R)-1-hydroxy-1,2-dihydronaph-tha-
len-2-yl)piperazine-1-carboxylate 5al
White solid (91% yield); 97% ee; [
a]
27 = À111.05 (c 0.46, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.48 (d, J = 7.3 Hz, 1H), 7.14–7.21 (m,
2H), 6.99–7.01 (m, 1H), 6.46 (dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 5.96
(dd, J = 2.6 Hz, J = 9.9 Hz, 1H), 4.81 (d, J = 11.2 Hz, 1H), 3.34–3.43
(m, 5H), 3.12 (br, 1H), 2.66–2.86 (m, 2H), 2.43–2.44 (m, 2H), 1.39
(s, 9H); 13C NMR (100 MHz, CDCl3) 154.84, 137.04, 131.85,
129.64, 128.11, 127.71, 126.43, 125.03, 124.46, 79.95, 67.93,
67.83, 49.10, 28.60, 25.53. ESI-MS: m/z 331 [M+H]+. Chiral HPLC
conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hexane/
isopropanol: 85:15, 254 nm, 7.71 min (minor), 8.40 min (major).
4.3.8. (1R,2R)-2-(4-(4-(Trifluoromethyl)phenylpiperazin-1-yl)-
1,2-dihydronaphthalen-1-ol 5ah
White solid (87% yield); >99% ee; [
a]
27 = À161.9 (c 0.45, CHCl3);
D
19F NMR (376 MHz, CDCl3) d À58.33; 1H NMR (500 MHz, CDCl3)
7.59–7.61 (m, 1H), 7.50–7.51 (m, 2H), 7.27–7.31(m, 2H), 7.11–
7.12 (m, 1H), 6.94–6.96 (m, 2H), 6.59(dd, J = 2.4 Hz, J = 9.9 Hz,

R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
715
4.3.13. (1R,2R)-6,7-Difluoro-2-(4-phenylpiperazin-1-yl)-1,2-dih-
4.3.17. (1R,2R)-6,7-Difluoro-2-(4-(4-methoxyphenyl)-piperazin-
ydronaphthalen-1-ol 5ba
1-yl)-1,2-dihydronaphthalen-1-ol 5be
White solid (93% yield); 96% ee; [
a
]
D
27 = À72.55 (c 0.28, CHCl3);
White solid (97% yield); 97% ee; [
a]
27 = À113.9 (c 0.89, CHCl3);
D
19F NMR (376 MHz, CDCl3) d À138.43, À140.87; 1H NMR (400 MHz,
CDCl3) 7.41–7.44 (m, 1H), 7.26–7.31 (m, 2H), 6.88–6.96 (m, 4H),
6.45 (dd, J = 2.7 Hz, J = 9.9 Hz, 1H), 6.19 (dd, J = 1.8 Hz, J = 9.9 Hz,
1H), 4.84 (d, J = 12.5 Hz, 1H), 3.48 (td, J = 2.5 Hz, J = 11.5 Hz, 1H),
3.41 (br, 1H), 3.21–3.30 (m, 4H), 2.99–3.03 (m, 2H), 2.70–2.74
(m, 2H); 13C NMR (100 MHz, CDCl3) 151.39, 148.65, 129.39,
127.94, 125.53, 125.52, 120.32, 116.54, 115.22, 115.08, 114.67,
114.52, 67.57, 67.33, 50.05, 49.29. ESI-MS: m/z 343 [M+H]+. Chiral
HPLC conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hex-
ane/isopropanol: 90:10, 254 nm, 12.13 min (major), 15.16 min
(minor).
19F NMR (376 MHz, CDCl3) d À138.47, À140.88; 1H NMR (400 MHz,
CDCl3) 7.31–7.35 (m, 1H), 6.76–6.85 (m, 5H), 6.35 (dd, J = 2.6 Hz,
J = 10.0 Hz, 1H), 6.11 (dd, J = 1.7 Hz, J = 10.0 Hz, 1H), 4.74 (d,
J = 12.5 Hz, 1H), 3.69 (s, 3H), 3.40 (td, J = 2.5 Hz, J = 11.5 Hz, 1H),
3.37 (br, 1H), 3.00–3.10 (m, 4H), 2.88–2.93 (m, 2H), 2.60–2.65
(m, 2H); 13C NMR (100 MHz, CDCl3) 154.20, 150.93 (dd,
J = 13.0 Hz, J = 19.2 Hz), 148.47(dd, J = 12.7 Hz, J = 16.6 Hz),
145.67, 134.36 (dd, J = 3.7 Hz, J = 5.4 Hz), 128.66 (dd, J = 3.9 Hz,
J = 6.2 Hz), 127.84, 125.64, 118.60, 115.09 (d, J = 18.1 Hz), 114.63,
114.44, 67.42, 67.24, 55.72, 51.43, 49.28. ESI-MS: m/z 373
[M+H]+. Chiral HPLC conditions: OD-H, 25 °C, flow rate: 1.0 mL/
min, hexane/isopropanol: 90:10, 254 nm, 13.40 min (major),
15.88 min (minor).
4.3.14. (1R,2R)-6,7-Difluoro-2-(4-(2-fluorophenyl)piperazin-1-
yl)-1, 2-dihydronaphthalen-1-ol 5bb
White solid (91% yield); 96% ee; [
a
]
D
27 = À113.0 (c 0.73, CHCl3);
4.3.18. (1R,2R)-2-(4-(3,4-Dichlorophenyl)piperazin-1-yl)-6,7-
19F NMR (376 MHz, CDCl3) d À122.91, À138.47, À140.86; 1H NMR
(400 MHz, CDCl3) 7.40–7.44 (m, 1H), 7.02–7.10 (m, 2H), 6.91–6.99
(m, 2H), 6.87–6.89 (m, 1H), 6.44 (dd, J = 2.7 Hz, J = 10.0 Hz, 1H),
6.22 (dd, J = 1.9 Hz, J = 10.0 Hz, 1H), 4.84 (d, J = 12.5 Hz, 1H), 3.48
(td, J = 2.5 Hz, J = 11.5 Hz, 1H), 3.43 (br, 1H), 3.12–3.21 (m, 4H),
3.00–3.04 (m, 2H), 2.72–2.76 (m, 2H); 13C NMR (100 MHz, CDCl3)
156.92, 154.96, 150.73 (dd, J = 13.0 Hz, J = 23.4 Hz), 148.76(dd,
J = 13.0 Hz, J = 21.0 Hz), 140.11 (d, J = 8.64 Hz), 134.37 (dd,
J = 3.7 Hz, J = 5.7 Hz), 128.69 (dd, J = 4.0 Hz, J = 6.3 Hz), 127.87,
125.73 (d, J = 2.5 Hz), 124.71 (d, J = 3.6 Hz), 122.93 (d, J = 7.9Hzz),
119.21 (d, J = 3.0 Hz), 116.337 (d, J = 20.8 Hz), 114.84 (dd,
J = 18.60 Hz, J = 70.1 Hz), 67.56, 67.27, 51.26 (d, J = 3.2 Hz), 49.32.
ESI-MS: m/z 361 [M+H]+. Chiral HPLC conditions: Chiralcel OD-H,
25 °C, flow rate: 1.0 mL/min, hexane/isopropanol: 90:10, 254 nm,
8.08 min (major), 9.79 min (minor).
difuoro-1,2-dihydronaphthalen-1-ol 5bf
White solid (90% yield); 83% ee; [
a
]
D
27 = À117.5 (c 0.39, CHCl3);
19F NMR (376 MHz, CDCl3) d À138.27, À140.64; 1H NMR (400 MHz,
CDCl3) 7.30–7.35 (m, 1H), 7.19 (d, J = 8.9 Hz, 1H), 6.87 (d, J = 2.8 Hz,
1H), 6.77–6.82 (m, 1H), 6.64–6.67 (m, 1H), 6.35 (dd, J = 2.6 Hz,
J = 10.0 Hz, 1H), 6.05 (dd, J = 1.8 Hz, J = 10.0 Hz, 1H), 4.73 (d,
J = 12.4 Hz, 1H), 3.38 (td, J = 2.5 Hz, J = 11.5 Hz, 1H), 3.27 (br, 1H),
3.07–3.17 (m, 4H), 2.85–2.90 (m, 2H), 2.57–2.62 (m, 2H); 13C
NMR (100 MHz, CDCl3) 150.95 (dd, J = 13.0 Hz, J = 19.0 Hz),
150.69, 148.49 (dd, J = 13.0 Hz, J = 16.6 Hz), 134.19 (dd, J = 3.7 Hz,
J = 5.7 Hz), 132.97, 130.66, 128.60 (dd, J = 4.0 Hz, J = 6.3 Hz),
128.01, 125.21, 122.61, 117.58, 115.67, 115.15 (d, J = 18.0 Hz),
114.60 (d, J = 19.2 Hz), 67.46, 67.28, 49.41, 48.91. ESI-MS: m/z
411 [M+H]+. Chiral HPLC conditions: Chiralcel OD-H, 25 °C, flow
rate: 1.0 mL/min, hexane/isopropanol: 90:10, 254 nm, 10.60 min
(major), 12.63 min (minor).
4.3.15. (1R,2R)-6,7-Difluoro-2-(4-(2-methoxyphenyl)piperaz-in-
1-yl)-1, 2-dihydronaphthalen-1-ol 5bc
4.3.19. (1R,2R)-2-(4-(2,4-Dimethylphenyl)piperazin-1-yl)-6,7-
White solid (95% yield); 98% ee; [
a]
27 = À110.0 (c 0.68, CHCl3);
difluoro-1,2-dihydronaphthalen-1-ol 5bg
D
19F NMR (376 MHz, CDCl3)
d
À138.59, À140.96; 1H NMR
White solid (95% yield); 95% ee; [
a]
27 = À129.3 (c 0.94, CHCl3);
D
19
(400 MHz, CDCl3) 7.31–7.36 (m, 1H), 6.77–6.97 (m, 5H), 6.33–
6.37 (m, 1H), 6.14–6.17 (m, 1H), 4.75 (d, J = 12.4 Hz, 1H), 3.80 (s,
3H), 3.43 (br, 1H), 3.38 (td, J = 2.5 Hz, J = 11.5 Hz, 1H), 2.94–3.06
(m, 6H), 2.65–2.67 (m, 2H); 13C NMR (100 MHz, CDCl3) 152.39,
150.68(dd, J = 12.9 Hz, J = 22.6 Hz), 148.71(dd, J = 12.9 Hz,
J = 20.2 Hz), 141.22, 134.46 (dd, J = 3.7 Hz, J = 5.6 Hz), 128.71 (dd,
J = 4.0 Hz, J = 6.3 Hz), 127.74, 126.03 (d, J = 2.5 Hz), 123.35,
121.19, 118.43, 115.05 (d, J = 18.0 Hz), 114.52 (d, J = 19.2Hzz),
111.33, 67.51, 67.22, 55.53, 51.34, 49.40. ESI-MS: m/z 373
[M+H]+. Chiral HPLC conditions: OD-H, 25 °C, flow rate: 1.0 mL/
min, hexane/isopropanol: 90:10, 254 nm, 9.50 min (major),
11.03 min (minor).
F
NMR (376 MHz, CDCl3)
d
À138.54, À140.95; 1H NMR
(400 MHz, CDCl3) 7.44–7.47 (m, 1H), 6.89–7.04 (m, 4H), 6.46 (dd,
J = 2.7 Hz, J = 10.0 Hz, 1H), 6.27 (dd, J = 1.7 Hz, J = 9.9 Hz, 1H), 4.85
(d, J = 12.6 Hz, 1H), 3.60 (br, 1H), 3.48 (td, J = 2.5 Hz, J = 11.5 Hz,
1H), 2.93–3.01 (m, 6H), 2.69–2.72 (m, 2H), 2.32 (s, 3H), 2.31 (s,
3H); 13C NMR (100 MHz, CDCl3) 150.68(dd, J = 12.9 Hz,
J = 24.3 Hz), 149.02, 148.71(dd, J = 12.9 Hz, J = 21.9 Hz), 134.51
(dd, J = 3.7 Hz, J = 5.7 Hz), 132.94, 132.64, 132.03, 128.71 (dd,
J = 4.0 Hz, J = 6.2 Hz), 127.68, 127.25, 126.03 (d, J = 2.5 Hz),
119.12, 115.04 (d, J = 18.0 Hz), 114.52 (d, J = 19.2 Hz), 67.53,
67.25, 52.61, 49.76, 20.88, 17.90. ESI-MS: m/z 371 [M+H]+. Chiral
HPLC conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hex-
ane/isopropanol: 90:10, 254 nm, 5.51 min (major), 6.57 min
(minor).
4.3.16. (1R,2R)-6,7-Difluoro-2-(4-p-tolylpiperazin-1-yl)-1,2-dih-
ydronaphthalen-1-ol 5bd
White solid (97% yield); >99% ee; [
a]
27 = À115.55 (c 0.38,
4.3.20. (1R,2R)-6,7-dimethoxy-2-(4-phenylpiperazin-1-yl)-1,2-
D
CHCl3); 19F NMR (376 MHz, CDCl3) d À138.48, À140.92; 1H NMR
(400 MHz, CDCl3) 7.32–7.37 (m, 1H), 7.01–7.03 (m, 2H), 6.78–
6.84 (m, 3H), 6.36 (dd, J = 2.7 Hz, J = 10.0 Hz, 1H), 6.12 (dd,
J = 1.8 Hz, J = 10.0 Hz, 1H), 4.76 (d, J = 12.6 Hz, 1H), 3.39 (td,
J = 2.5 Hz, J = 11.5 Hz, 1H), 3.36 (br, 1H), 3.06–3.17 (m, 4H), 2.90–
2.95 (m, 2H), 2.60–2.66 (m, 2H); 13C NMR (100 MHz, CDCl3)
149.28, 145.87, 134.33, 129.91, 127.89, 125.62, 125.59, 116.87,
115.21, 115.04, 114.65, 114.46, 67.51, 67.29, 50.59, 49.27, 20.66.
ESI-MS: m/z 357 [M+H]+. Chiral HPLC conditions: Chiralcel OD-H,
25 °C, flow rate: 1.0 mL/min, hexane/isopropanol: 90:10, 254 nm,
8.24 min (major), 9.27 min (minor).
dihydronaphthalen-1-ol 5ca
White solid (91% yield); 94.5% ee; [
a
]
D
27 = À225.3 (c 0.62, CHCl3);
1H NMR (400 MHz, CDCl3) 7.17–7.21 (m, 2H), 7.06 (s, 1H), 6.77–
6.86 (m, 3H), 6.56 (s, 1H), 6.39 (dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 5.95
(dd, J = 2.6 Hz, J = 9.9 Hz, 1H), 4.78 (d, J = 11.8 Hz, 1H), 3.84 (s,
3H), 3.78 (s, 3H), 3.39 (td, J = 2.4 Hz, J = 11.2 Hz, 1H), 3.29 (br,
1H), 3.08–3.18 (m, 4H), 2.83–2.88 (m, 2H), 2.60–2.65 (m, 2H);
13C NMR (100 MHz, CDCl3) 151.35, 148.71, 148.12, 129.92,
129.25, 129.05, 124.69, 122.52, 120.06, 116.35, 110.08, 108.77,
67.83, 67.72, 56.17, 56.14, 49.91, 49.11. ESI-MS: m/z 367 [M+H]+.
Chiral HPLC conditions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/

716
R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
min, hexane/isopropanol: 75:25, 254 nm, 14.10 min (major),
18.81 min (minor).
(m, 4H), 7.09–7.11 (m, 1H), 6.94–6.95 (m, 1H), 6.77–6.80 (m,
1H), 6.57 (dd, J = 2.5 Hz, J = 9.8 Hz, 1H), 5.91 (dd, J = 3.0 Hz,
J = 9.8 Hz, 1H), 5.08 (d, J = 9.8 Hz, 1H), 4.72 (td, J = 2.7 Hz,
J = 9.8 Hz, 1H), 2.83 (s, 3H), 2.38 (s, 1H); 13C NMR (125 MHz, CDCl3)
150.44, 136.72, 132.16, 129.86, 129.46, 128.29, 128.13, 127.95,
126.65, 125.80, 118.29, 114.85, 70.27, 63.70, 33.56. ESI-MS: m/z
252 [M+H]+. Chiral HPLC conditions: Chiralcel AD-H, 25 °C, flow
rate: 1.0 mL/min, hexane/isopropanol: 90:10, 254 nm, 9.80 min
(major), 11.30 min (minor).
4.3.21. (1R,2R)-6,7-Dimethoxy-2-(4-(2-methoxyphenyl)-pipera-
zin-1-yl)-1,2-dihydronaphthalen-1-ol 5cb
White solid (91% yield); >99% ee; [
a
]
27 = À199.4 (c 0.82, CHCl3);
D
1H NMR (400 MHz, CDCl3) 7.06 (s, 1H), 6.91–6.94 (m, 1H), 6.84–
6.87 (m, 2H), 6.78 (d, J = 7.8 Hz, 1H), 6.56 (s, 1H), 6.40 (dd,
J = 2.4 Hz, J = 9.9 Hz, 1H), 6.00 (dd, J = 2.7 Hz, J = 9.8 Hz, 1H), 4.79
(d, J = 11.1 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.43
(br, 1H), 3.39 (td, J = 2.4 Hz, J = 11.1 Hz, 1H), 3.02–3.06 (m, 4H),
2.88–2.92 (m, 2H), 2.66–2.70 (m, 2H); 13C NMR (100 MHz, CDCl3)
152.18, 148.57, 148.00, 141.12, 129.90, 128.82, 124.63, 123.05,
122.77, 120.97, 118.21, 111.07, 109.99, 108.76, 67.58, 60.36,
56.03 (d, J = 1.5 Hz), 55.31, 51.15, 21.02, 14.19. ESI-MS: m/z 397
[M+H]+. Chiral HPLC conditions: Chiralcel OD-H, 25 °C, flow rate:
1.0 mL/min, hexane/isopropanol: 75:25, 254 nm, 10.86 min (ma-
jor), 17.55 min (minor).
4.3.26. (1R,2R)-2-((3-Chlorophenyl)(methyl)amino)-1,2-dihydr-
onaphthalen-1-ol 7ac
Colorless liquid (90% yield); 94% ee; [
a]
27 = À143.7 (c 0.92, CH2-
D
Cl2); 1H NMR (500 MHz, CDCl3) 7.54–7.56 (m, 1H), 7.30–7.31 (m,
2H), 7.14–7.18 (m, 2H), 6.91–6.92 (m, 1H), 6.83–6.85 (m, 1H),
6.76–6.77 (m, 1H), 6.64 (dd, J = 2.4 Hz, J = 9.8 Hz, 1H), 5.91 (dd,
J = 3.1 Hz, J = 9.8 Hz, 1H), 5.09 (d, J = 9.3 Hz, 1H), 4.73 (td,
J = 2.8 Hz, J = 9.4 Hz, 1H), 2.84 (s, 3H), 2.27 (s, 1H); 13C NMR
(125 MHz, CDCl3) 151.46, 136.47, 135.37, 132.06, 130.32, 130.20,
128.46, 128.35, 127.45, 126.82, 125.97, 117.85, 114.32, 112.54,
70.40, 63.36, 33.60. ESI-MS: m/z 286 [M+H]+. Chiral HPLC condi-
tions: Chiralcel AD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopro-
panol: 90:10, 254 nm, 9.21 min (minor), 10.27 min (major).
4.3.22. (1R,2R)-6,7-Dimethoxy-2-(4-(4-(trifluoromethyl)-phenyl)-
piperazin-1-yl)-1,2-dihydronaphthalen-1-ol 5cc
White solid (90% yield); 96% ee; [
a
]
27 = À198.4 (c 1.23, CHCl3);19
D
F NMR (376 MHz, CDCl3) d À61.45; 1H NMR (400 MHz, CDCl3) 7.40
(d, J = 8.6 Hz, 1H), 7.06 (s, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.57 (s, 1H),
6.41 (dd, J = 2.1 Hz, J = 9.9 Hz, 1H), 5.91 (dd, J = 2.6 Hz, J = 9.8 Hz,
1H), 4.78 (d, J = 11.0 Hz, 1H), 3.84 (s, 3H), 3.79 (s, 3H), 3.49 (td,
J = 2.4 Hz, J = 11.2 Hz, 1H), 3.27 (br, 1H), 3.17–3.26 (m, 4H), 2.82–
2.86 (m, 2H), 2.61–2.65 (m, 2H); 13C NMR (100 MHz, CDCl3)
153.38, 148.86, 148.29, 129.29, 129.83, 129.26, 126.57, 126.54,
124.71, 122.21, 114.80, 110.21, 108.97, 67.98, 67.78, 56.22, 56.19,
48.91, 48.72. ESI-MS: m/z 435 [M+H]+. Chiral HPLC conditions: Chi-
ralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopropanol:
75:25, 254 nm, 12.46 min (major), 15.23 min (minor).
4.3.27. (1R,2R)-2-((4-Chlorophenyl)(methyl)amino)-1,2-dihydr-
onaphthalen-1-ol 7ad
White solid (93% yield); 94% ee; [
a]
27 = À112.0 (c 0.82, CH2Cl2);
D
1H NMR (500 MHz, CDCl3) 7.53–7.54 (m, 1H), 7.29–7.31 (m, 2H),
7.20–7.22 (m, 2H), 7.14–7.16 (m, 1H), 6.86–6.88 (m, 2H), 6.63
(dd, J = 2.5 Hz, J = 9.8 Hz, 1H), 5.91 (dd, J = 3.1 Hz, J = 9.8 Hz, 1H),
5.08 (d, J = 9.5 Hz, 1H), 4.68 (td, J = 2.8 Hz, J = 9.5 Hz, 1H), 2.82 (s,
3H), 2.38 (s, 1H); 13C NMR (125 MHz, CDCl3) 148.82, 136.37,
131.91, 129.93, 129.04, 128.24, 128.12, 127.32, 126.61, 125.73,
122.81, 115.67, 70.12, 63.57, 33.53. ESI-MS: m/z 286 [M+H]+. Chiral
HPLC conditions: Chiralcel AD-H, 25 °C, flow rate: 1.0 mL/min, hex-
ane/isopropanol: 90:10, 254 nm, 11.09 min (major), 13.05 min
(minor).
4.3.23. (1R,2R)-6,7-Dimethoxy-2-(4-(4-methoxyphenyl)-pipera-
zin-1-yl)-1,2-dihydronaphthalen-1-ol 5cd
Colorless liquid (95% yield); 98% ee; [
a
]
D
27 = À204.2 (c 1.12,
CHCl3); 1H NMR (400 MHz, CDCl3) 7.14 (s, 1H), 6.83–6.91 (m,
4H), 6.64 (s, 1H), 6.47 (dd, J = 2.3 Hz, J = 9.9 Hz, 1H), 6.04 (dd,
J = 2.5 Hz, J = 9.9 Hz, 1H), 4.86 (d, J = 11.3 Hz, 1H), 3.92 (s, 3H),
3.879 (s, 3H), 3.76 (s, 3H), 3.47 (td, J = 2.3 Hz, J = 11.3 Hz, 1H),
3.28 (br, 1H), 3.06–3.14 (m, 4H), 2.92–2.96 (m, 2H), 2.69–2.73
(m, 2H); 13C NMR (100 MHz, CDCl3) 154.06, 148.75, 148.16,
145.74, 130.00, 129.02, 124.74, 122.65, 118.47, 114.57, 110.15,
108.83, 67.84, 67.73, 56.19, 56.17, 55.67, 51.40, 49.22. ESI-MS:
m/z 397 [M+H]+. Chiral HPLC conditions: Chiralcel OD-H, 25 °C,
flow rate: 1.0 mL/min, hexane/isopropanol: 60:40, 254 nm,
10.18 min (major), 12.86 min (minor).
4.3.28. (1R,2R)-2-(Methyl(p-tolyl)amino)-1,2-dihydro-naphtha-
len-1-ol 7ae
Colorless liquid (95% yield); 96% ee; [
a
]
D
27 = À132.4 (c 0.62, CH2-
Cl2); 1H NMR (500 MHz, CDCl3) 7.58–7.60 (m, 1H), 7.27–7.31 (m,
2H), 7.10–7.15 (m, 3H), 6.91–6.93 (m, 2H), 6.60 (dd, J = 2.5 Hz,
J = 9.8 Hz, 1H), 5.96 (dd, J = 2.9 Hz, J = 9.8 Hz, 1H), 5.13 (d,
J = 10.1 Hz, 1H), 4.69 (td, J = 2.7 Hz, J = 10.1 Hz, 1H), 2.85 (s, 3H),
2.51 (s, 1H), 2.31 (s, 3H); 13C NMR (125 MHz, CDCl3) 148.41,
136.83, 132.19, 129.96, 129.77, 128.22, 128.02, 127.92, 126.59,
125.64, 115.50, 70.11, 64.36, 33.71, 20.47. ESI-MS: m/z 266
[M+H]+. Chiral HPLC conditions: Chiralcel AD-H, 25 °C, flow rate:
1.0 mL/min, hexane/isopropanol: 90:10, 254 nm, 9.61 min (major),
10.28 min (minor).
4.3.24. (1R,2R)-2-(Phenylamino)-1,2-dihydronaphthalen-1-ol 7aa
White solid (95% yield); 96% ee; [
a
]
27 = À138.4 (c 0.32, CH2Cl2);
D
1H NMR (500 MHz, CDCl3) 7.49–7.51 (m, 1H), 7.16–7.33 (m, 5H),
6.73–6.81 (m, 3H), 6.58 (dd, J = 1.7 Hz, J = 9.6 Hz, 1H), 6.04 (dd,
J = 3.6 Hz, J = 9.6 Hz, 1H), 4.87 (d, J = 7.8 Hz, 1H), 4.45 (td,
J = 2.7 Hz, J = 9.8 Hz, 1H), 3.66 (s, 1H), 2.46 (s, 1H); 13C NMR
(125 MHz, CDCl3) 146.85, 135.76, 132.07, 129.65, 128.70, 128.63,
128.13, 127.11, 126.89, 118.57, 114.25, 71.67, 55.75. ESI-MS: m/z
238 [M+H]+. Chiral HPLC conditions: Chiralcel AD-H, 25 °C, flow
rate: 1.0 mL/min, hexane/isopropanol: 90:10, 254 nm, 13.48 min
(minor), 17.51 min (major).
4.3.29. (1R,2R)-2-(Ethyl(phenyl)amino)-1,2-dihydro-naphtha-
len-1-ol 7af
Colorless liquid (91% yield); 94% ee; [
a
]
D
27 = À160.7 (c 0.85, CH2-
Cl2); 1H NMR (500 MHz, CDCl3) 7.56–7.58 (m, 1H), 7.28–7.33 (m,
4H), 7.16–7.18 (m, 1H), 6.99–7.00 (m, 2H), 6.81–6.84 (m, 1H),
6.64 (dd, J = 2.4 Hz, J = 9.8 Hz, 1H), 6.00 (dd, J = 3.2 Hz, J = 9.8 Hz,
1H), 5.15 (d, J = 9.8 Hz, 1H), 4.71 (td, J = 2.8 Hz, J = 9.2 Hz, 1H),
3.39 (q, J = 7.0 Hz, 2H), 2.47 (s, 1H), 5.15 (t, J = 7.08 Hz, 3H); 13C
NMR (125 MHz, CDCl3) 148.40, 136.57, 132.16, 129.61, 129.48,
128.81, 128.24, 128.21, 126.71, 126.19, 117.80, 114.95, 70.47,
63.39, 41.72, 14.67. ESI-MS: m/z 266 [M+H]+. Chiral HPLC condi-
tions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopro-
panol: 90:10, 254 nm, 7.39 min (major), 8.28 min (minor).
4.3.25. (1R,2R)-2-[Methyl(phenyl)amino]-1,2-dihydro-naphtha-
len-1-ol 7ab
Colorless liquid (97% yield); 95% ee; [
a]
D
27 = À112.9 (0.72,
CH2Cl2); 1H NMR (500 MHz, CDCl3) 7.52–7.54 (m, 1H), 7.22–7.27

R. Luo et al. / Tetrahedron: Asymmetry 25 (2014) 709–717
717
4.3.30. (1R,2R)-2-(Allyl(methyl)amino)-1,2-dihydro-naphthalen-
References
1-ol 7ag
Colorless liquid (97% yield); 97% ee; [
27 = À83.4 (c 0.28, CH2-
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D
Cl2); 1H NMR (500 MHz, CDCl3) 7.42–7.44 (m, 1H), 7.14–7.20 (m,
4H), 7.03–7.05 (m, 1H), 6.84–6.86 (m, 2H), 6.68–6.71 (m, 1H),
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254 nm, 13.01 min (minor), 16.84 min (major).
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18. (a) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N. D.; Savoie, J.;
Gao, J. J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.; Krishnamurthy, D.; Yee, N.
K.; Senanayake, C. H. Angew. Chem., Int. Ed. 2010, 49, 5879; (b) Tang, W.; Patel,
N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, M.-H.; Keshipeddy, S.; Capacci, A. G.;
Wei, X.; Zhang, Y.; Gao, J. J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K.;
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19. Li, K.; Hu, N.-F.; Luo, R.-S.; Yuan, W.-C.; Tang, W. J. Org. Chem. 2013, 78, 6350.
20. CCDC 943665 5cb contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB21EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk)
4.3.31. (1R,2R)-2-(3,4-Dihydroisoquinolin-2(1H)-yl)-1,2-dihydr-
onaphthalen-1-ol 7ah
Colorless liquid (95% yield); 94% ee; [
a
]
27 = À134.9 (c 0.82, CH2-
D
Cl2); 1H NMR (500 MHz, CDCl3) 7.62–7.63 (m, 1H), 7.27–7.31 (m,
2H), 7.06–7.18 (m, 4H), 6.60 (dd, J = 2.6 Hz, J = 9.8 Hz, 1H), 6.17
(dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 5.04 (d, J = 12.0 Hz, 1H), 4.04 (d,
J = 14.9 Hz, 1H), 3.83 (d, J = 14.9 Hz, 1H), 3.68 (td, J = 2.5 Hz,
J = 12.0 Hz, 1H), 3.45 (s, 1H), 3.16–3.18 (m, 1H), 2.95–2.98 (m,
2H), 2.81–2.83 (m, 1H), 1.68 (s, 1H); 13C NMR (125 MHz, CDCl3)
137.15, 134.85, 134.48, 131.84, 129.66, 128.86, 127.93, 127.43,
126.71, 126.27, 126.21, 125.75, 124.76, 124.68, 68.12, 67.86,
52.03, 46.97, 30.01. ESI-MS: m/z 278 [M+H]+. Chiral HPLC condi-
tions: Chiralcel OD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopro-
panol: 90:10, 254 nm, 11.04 min (major), 12.74 min (minor).
4.3.32. (1R,2R)-2-(Benzyl(methyl)amino)-1,2-dihydro-naphtha-
len-1-ol 7ai
Colorless liquid (95% yield); 95% ee; [
a
]
27 = À118.2 (c 0.32, CH2-
D
Cl2); 1H NMR (500 MHz, CDCl3) 7.61–7.62 (m, 1H), 7.25–7.36 (m,
7H), 7.09–7.11 (m, 1H), 6.59 (dd, J = 2.7 Hz, J = 9.9 Hz, 1H), 6.16
(dd, J = 2.4 Hz, J = 9.9 Hz, 1H), 4.98 (d, J = 12.0 Hz, 1H), 3.89 (d,
J = 13.3 Hz, 1H), 3.62–3.65 (m, 1H), 3.42 (s, 3H), 2.37 (s, 3H); 13C
NMR (125 MHz, CDCl3) 139.04, 137.30, 132.02, 129.72, 129.03,
128.63, 127.99, 127.50, 127.43, 126.28, 125.20, 124.75, 68.85,
66.43, 58.94, 38.00. ESI-MS: m/z 266 [M+H]+. Chiral HPLC condi-
tions: Chiralcel AD-H, 25 °C, flow rate: 1.0 mL/min, hexane/isopro-
panol: 90:10, 254 nm, 13.61 min (major), 14.20 min (minor).
Acknowledgements
We are grateful to the start fund of the School of Pharmaceutical
Sciences, Gannan Medical University (QD201303).