Novel C2-symmetric chiral O,N,N,O-tetradentate 2,2-bipyridyldiolpropane ligands: Synthesis and application in asymmetric diethylzinc addition to aldehydes

Article abstract of DOI:10.1016/j.tetasy.2013.12.020

First synthesis of C₂-symmetric chiral O,N,N,O-tetradentate 2,2-bipyridyldiolpropane ligands is described. The Mukaiyama-Michael reaction was applied as an important reaction for the synthesis of 2,2-bipyridylpropane 9. Among the ligands synthesized, ligand 11 exhibits excellent chiral induction (up to 97% ee) in diethylzinc addition to various aldehydes. The use of additional Lewis acid such as Ti(OⁱPr)₄ in diethylzinc addition reaction is not required for the present catalytic system.

Full text of DOI:10.1016/j.tetasy.2013.12.020

Tetrahedron: Asymmetry 25 (2014) 327–333
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Novel C2-symmetric chiral O,N,N,O-tetradentate
2,2-bipyridyldiolpropane ligands: synthesis and application
in asymmetric diethylzinc addition to aldehydes
b
Shih Yi-Shan a, Ramalingam Boobalan a, Chinpiao Chen a, , Gene-Hsian Lee
⇑
a Department of Chemistry, National Dong Hwa University, Soufeng, Hualien 974, Taiwan, ROC
b Instrumentation Center, College of Science, National Taiwan University, Taipei 106, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 11 November 2013
Accepted 16 December 2013
First synthesis of C2-symmetric chiral O,N,N,O-tetradentate 2,2-bipyridyldiolpropane ligands is described.
The Mukaiyama–Michael reaction was applied as an important reaction for the synthesis of 2,2-bipyr-
idylpropane 9. Among the ligands synthesized, ligand 11 exhibits excellent chiral induction (up to 97%
ee) in diethylzinc addition to various aldehydes. The use of additional Lewis acid such as Ti(OiPr)4 in
diethylzinc addition reaction is not required for the present catalytic system.
Ó 2014 Elsevier Ltd. All rights reserved.
up to 98% ee
1. Introduction
O
OAc
R
H
Over the last three decades, numerous developments in the
field of asymmetry synthesis made the synthesis of enantioen-
riched compounds easier.1 Plenty of chiral ligands/catalysts have
been applied for stereoselective reactions; they are mostly either
available from natural sources or synthesized from naturally avail-
able chiral starting materials by chiral pool synthesis.1 Although
many catalytic systems are available for enantio/diastereoselective
reactions, synthetic research is still in search of new catalysts for
the advancement of the field. We have been studying the synthesis
and application of O,N,N,O-tetradentate-bipyridyldiol ligands
(Scheme 1) towards various stereoselective reactions.2 These
R
CN
O
1. Ti(OiPr)4,TMSCN,
DCM, -78 oC. 2. HCl
3. Ac2O, Py, DCM
R
R
up to 99% ee
OH
Ti(OiPr)4
PhSH
R
R
1
R: Me
R: Ph
2
ACN, rt PhS
OH
R
Ti(OiPr)4
Et2Zn
Toluene, rt
R
N
N
up to 64% ee
O
OH
O
P
HO
Ph
Ph
bipyridyldiol ligands are synthesized from
a-pinene and provide
R
R
R
R
H
N
moderate to excellent chiral induction for many asymmetric reac-
tions especially in the case of Nozaki–Hiyama–Kishi allylation2a of
aldehydes where the ligand 1 serves as one of the best ligands pro-
viding an excellent ee of homoallylic alcohols.
O,N,N,O-tetradentate
bipyridyldiol ligands
Zr(OtBu)4,
TMSCN,
R
DCM, -78 oC
1. CrCl3/Mn, TEA
Allyl chloride
For the further advancement of catalytic activity of these bipyr-
idyldiol ligands, its skeleton modification was considered.3 Thus,
we envisioned that the introduction of an additional carbon be-
tween the two pyridine rings in bipyridyl ligands 1 and 2 would
change the ring size of the resulting metal complexes (Scheme 2)
from 6,5,6-membered rings (a,b,c) to either 6,6,6-membered rings
(d,e,f) with a tetravalent metal or 6,7,6-membered rings (g,h,i) with
a bivalent metal. These possible metal complexes would have
advantages of having less steric hindrance between the rings and
would afford more stability and also the possibility of close prox-
O
OH
TMSCl, THF
Ph
Ph
2. TBAF/THF
O
P
HN
R
CN
R
H
up to 78% ee
up to 99% ee
R
Scheme 1. Application of bipyridyldiol ligands in the asymmetric synthesis.
imity incoming substrates. It was considered that changes in the
environment of bipyridyldiolmethane ligands would have the im-
pact of stronger chiral induction in stereoselective reactions.
The asymmetric addition of diethylzinc to carbonyl compounds
is a synthetically very useful reaction and it is a bench mark reac-
tion for the assessment of the ability to transfer the inherent chi-
rality of any catalyst to a prochiral carbonyl compound especially
⇑
Corresponding author. Tel.: +886 3 863 3597; fax: +886 3 863 0475.
E-mail address: chinpiao@mail.ndhu.edu.tw (C. Chen).
0957-4166/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.12.020

328
Y.-S. Shih et al. / Tetrahedron: Asymmetry 25 (2014) 327–333
NaH, MeI
DMSO, rt
TMSCl, NaI
M
b
N
N
N
O
N
Et3N, MeCN, rt
O
O
O
O
a
M
c
3
4
OH
HO
O
TiCl4
R
R
R
R
R
R
R
R
CH2Cl2, 78 oC
−
6,5,6-
Inserting a carbon
between two pyridine
membered rings
Me3SiO
OSiMe3
O
5
7
N
N
OH
HO
NH4OAc
M
h
R
R
N
AcOH, 120 o
N
N
R
R
C
M
O
M
O
g
i
M
O
O
O
O
8
R
R
R
R
e
6,7,6-
membered rings
N
M
d
f
O
R
R
O
R
1. LDA, R2CO
N
N
R
R
THF, −78 o
C
HO
R
6,6,6-
HO
N
R
membered rings
2. LDA, R2CO
N
THF, −78 o
C
R
Scheme 2. Proposed model and possible metal complexes of the bipyridyldiolme-
thane ligands.
9
10:
11:
R = Ph
R = Me,
to aldehydes.4,7 Herein, we report the synthesis of O,N,N,O-tetra-
dentate bipyridyldiol methane type ligands and their application
towards the enantioselective addition of diethylzinc to aldehydes.
Scheme 3. Synthesis of O,N,N,O-tetradentate 2,2-dipyridyldiolpropane ligands.
2. Results and discussion
2.1. Synthesis of O,N,N,O-tetradentate 2,2-dipyridyldiolpropane
ligands
The first target for the synthesis of 2,2-dipyridyldiolpropane li-
gands 10 and 11 was the preparation of 2,2-dipyridylpropane 9
(Scheme 3). Although the synthesis of 9 in low yield had been pre-
viously reported by Chelucci et al. as a double Michael addition of
dilithium enolate of 3,3-dimethylpentane-2,4-dione 4 to pinocarv-
one 7 followed by azaanellation of bis(1,5-diketone) 8 with ammo-
nium acetate and acetic acid,3 in our hands, this procedure afforded
9 in very low yield (ꢀ5%). Thus 2,2-dipyridylpropane were to be
synthesized by a new route that consists of the titanium mediated
Mukaiyama–Michael reaction. The Mukaiyama–Michael reaction
has been known for a long time for the synthesis of 1,5-diketones.5
Our synthetic sequences for the synthesis of tetradentate ligands
10 and 11 commenced with the dimethylation of pentane-2,4-
dione 3 with sodium hydride and methyl iodide in DMSO to give
diketone 4 in good yield (62%).6a Then bis(trimethylsilyl enol ether)
5 was obtained in excellent yield (80%) by treatment of 4 with
in situ generated trimethylsilyl iodide (from TMSCl/NaI) and trieth-
ylamine in acetonitrile at room temperature.6b The obtained silyl
enol ether 5 was then subjected to TiCl4 mediated Mukaiyama–Mi-
Figure 1. X-ray crystal structure of 2,2-dipyridylpropane
system and P6(1) space group; CCDC number: 963556).
9 (hexagonal crystal
After having 9 in hand, its carbanion, generated by reaction
with LDA, was reacted with ketones (with acetone for 10 or with
benzophenone for 11) and the same step was repeated once more
to get the desired tetradentate diol ligands in moderate yields
(36% of 10 and 34% of 11, yield for two steps).2e Due to the bulky
nature of the carbanion, this addition reactions to ketones did not
go to completion, however similar results were found in the liter-
ature especially in the case of the synthesis of simple bipyridyldi-
ols 1 and 2 where the steric hindrance is significant. Thus, an
ample amount of 2,2-dipyridyldiolpropane ligands 10 and 11
were synthesized by the present synthetic route. The structure
of the prepared ligands was confirmed by X-ray crystallography
(Fig. 2).
chael reaction with the
that was prepared from a photooxygenation–elimination reaction
of
-(+)-pinene 6 with singlet oxygen.6c The crude bis(1,5-dike-
a,b-unsaturated ketone, (ꢁ)-pinocarvone 7
a
tone) 8 afforded by the Mukaiyama–Micheal reaction was next re-
acted with ammonium acetate and acetic acid at refluxing
temperature to give azaanellated product, 2,2-dipyridylpropane 9
in 20% yield (two steps).3 Although the overall yield of the Mukaiy-
ama–Micheal and azaanellation reaction was low, it was consistent
and reproducible in our hands. In addition to the spectroscopic
data, X-ray crystallography of the product confirmed that the ob-
tained product was 2,2-dipyridylpropane 9 (Fig. 1).

Y.-S. Shih et al. / Tetrahedron: Asymmetry 25 (2014) 327–333
329
Table 2
Optimization of diethylzinc addition reaction catalyzed by 11a
OH
O
11
solvent, temp
H
Et2Zn
+
12
Entry 11 (mol %) Solventb Temp (°C) Time (h) Yieldc (%) eed (%)
12a
1
2
3
4
5
6
7
8
10
10
10
10
10
1
Toluene
CH2Cl2
THF
rt
rt
rt
rt
rt
rt
rt
rt
rt
24
24
24
24
24
24
24
24
24
57
57
88 95
73 92
31 88
85 94
88 93
46 34
84 93
91 95
90 95
82 96
84 97
Ether
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
5
Figure 2. X-ray crystal structure of O,N,N,O-tetradentate ligand, 2,2-dipyridyldiol-
propane 11 (monoclinic crystal system, P2(1) space group; CCDC number: 963355).
15
20
10
10
9
10
11
0
ꢁ20
2.2. Optimization of reaction condition for diethylzinc addition
to aldehydes
a
b
c
All reactions were carried under an argon atmosphere.
All solvents were dried before use.
The yields represents that of column purified compounds.
Application of the catalytic properties of ligands 10 and 11 were
was then examined for the benchmark reaction of diethylzinc addi-
tion to benzaldehyde. The optimization of the reaction condition
was started with the screening of ligands as shown in Table 1. At
first, 10 mol % of ligand was treated with diethylzinc in toluene
at room temperature, followed by the addition of benzaldehyde
12 to give the corresponding secondary alcohol 12a. Although both
ligands 10 (tetramethyl substituted 2,2-bipyridyldiolpropane), and
11 (tetraphenyl substituted 2,2-bipyridyldiolpropane) catalyze this
model reaction to render 12a in good yield, the selectivity varies
drastically from one another, which wherein ligand 11 exhibits
excellent ee (95%), however, ligand 10 shows very less ee (24%).
Therefore, among the two ligands, 11 was chosen as a better cata-
lyst and further possible reaction conditions using 11 were then
optimized.
The results of screening of various solvents (Table 2, entries 1–
5) for the 11 catalyzed diethylzinc addition to benzaldehyde
shown that toluene is the optimal solvent for thi catalytic system.
Further, the mol % of 11 was studied for the possible improvement
in the enantioselectivity of 12a. When the catalyst loading was re-
duced to 5 mol % (Table 2, entry 7), the selectivity and yield of the
reaction were reduced very slightly (93% ee and 84% yield) as com-
pared to the result of 10 mol % (95% ee and 88% yield, Table 2, entry
1). However, when the catalyst loading was reduced further with
1 mol % the ee and yield of the reaction at rt decreased (Table 2, en-
try 6; 34% ee and 46% yield). Conversely, the increase of mol % of 11
to 15 as well as to 20 mol % did not increase the ee rather it slightly
increases the yield (Table 2, entries 8 and 9, respectively). Thus
10 mol % of ligand 11 was selected as an optimal catalyst loading
for this reaction. Next, the reaction temperature was optimized.
d
Ee of the compounds measured by HPLC using a Chiralcel OD-H column.
When the reaction was conducted at ꢁ20 °C there was 2% ee
improvement with little extended reaction time, however, when
the temperature was further reduced there was no significant
amplification in ee, thus ꢁ20 °C was selected as a suitable reaction
temperature. Therefore the optimal reaction conditions were an
addition of diethylzinc (2 equiv) to ligand 11 (10 mol %) in toluene
(1 mL) at rt, stirred for 10 min, then cool to ꢁ20 °C followed by the
addition of benzaldehyde (1 equiv) (Table 2, entry 11).
2.3. Scope of the ligand 11 catalyzed diethylzinc addition reaction
The catalytic property of 11 was then examined for various aro-
matic, polycyclic aromatic and aliphatic aldehydes (Table 3). All of
these aldehydes provided excellent enantioselectivities (up to 97%
ee) in moderate to excellent yields (up to 99%). In the case of tolu-
aldehyde, the effect of the position of the substituent was tested
(Table 3 entries 2–4); ortho-substitution showed a little more
enantioselectivity (96% ee) compared to meta (93% ee) that showed
slightly more selectivity than para-substitution (90% ee). Other
substituents such as methoxy, chloro and cyano (Table 3 entries
5–8) were also checked and found to be suitable substituents of
benzaldehyde for the present catalytic system. Polycyclic aromatic
aldehyde such as 1- and 2-naphthaldehyde (20 and 21) were also
found to afford the corresponding secondary alcohol 20a and 21a
in excellent ee (97%).
a,b-Unsaturated aldehydes (22 and 23) and
aliphatic aldehydes (24 and 25) were also transformed into the
corresponding diethylzinc addition product in high ee, however,
the rate of reaction of these aldehydes were was slow, and there-
fore the yields obtained were only low to moderate.
Table 1
Screening of liganda
3. Conclusion
O
OH
∗
Et2Zn, ligand 10 mol %
toluene, rt
Two novel chiral C2-symmetric O,N,N,O-tetradentate 2,2-dipyr-
idyldiolpropane ligands 10 and 11 were synthesized. 2,2-Dipyr-
H
idylpropane
9 was synthesized for the first time using a
12
12a
Mukaiyama–Michael addition route. Among these ligands, the li-
gand 11 was found to be an effective catalyst for the diethylzinc
addition to various aldehydes. The idea of insertion of an extra car-
bon to dipyridyldiol ligands 1 and 2 to modify the resulting metal
complexes ring size had a decisive influence on the enantioselec-
tivity of secondary alcohols obtained (up to 97% ee). The present
catalytic system is a very useful addition to the existing catalytic
Entry
Ligand
eeb (%)
1
2
10
11
24
95
a
PhCHO/Et2Zn/ligand ratio = 1:2:0.1.
Ee checked by chiral HPLC using a Chiralcel OD-H column.
b

330
Y.-S. Shih et al. / Tetrahedron: Asymmetry 25 (2014) 327–333
Table 3
tral silica gels. The reported spectroscopic data are recorded on
Bruker 300 and 400 NMR spectrometers. Chemical shifts (d) are re-
ported in parts per million (ppm) relative to CDCl3 (7.26 and
77.0 ppm), the coupling constants are reported in Hertz (Hz) and
the multiplicities are indicated as br = broad, s = singlet, d = dou-
blet, dd = doublet of doublet, t = triplet, m = multiplet. Infrared
spectra were recorded using a Perkin Elmer FT/IR spectrometer.
Enantiomeric excesses were determined on a Lab Alliance Series
III high performance liquid chromatography (HPLC) with Chiracel
OD-H, OJ and Chiralpak AD chiral columns. Optical rotations were
measured on a JASCO P-1010 polarimeter at the indicated temper-
ature with a sodium lamp (D line, 589 nm). (ꢁ)-Pinocarvone 7 and
3,3-dimethylpentane-2,4-dione 4 were synthesized according to
literature procedures.
Scope of 11 catalyzed diethylzinc addition to various aldehydes in 57 ha
OH
11
O
(10 mol%)
toulene, - 20 o
C
+
Et2Zn
R
R
H
(S)-isomer
Entry
1
Aldehydeb
Product/config.
Yieldc (%)
eed (%)
96
CHO
12a/(S)
84
82
95
63
69
12
CHO
2
3
4
5
6
13a/(S)
14a/(S)
15a/(S)
16a/(S)
17a/(S)
96e
93
13
14
4.2. Synthesis of bis(trimethylsiyl enol ether) 5
CHO
CHO
90
To a stirred solution of 2,4-diketone 4 (12.0 g, 93.6 mmol) in
acetonitrile (100 mL) under argon were added Et3N (32.6 mL,
234.0 mmol), TMSCl (29.6 mL, 234.0 mmol), and NaI (35.0 g,
234.0 mmol) and stirred at room temperature for overnight. Then,
it was diluted with hexane (100 mL) and the acetonitrile layer was
extracted twice with hexane (2 ꢂ 100 mL). The combined organic
layers were washed with a saturated NaHCO3 solution (100 mL)
and brine (100 mL), dried (MgSO4) and evaporated under reduced
pressure. The residue was purified by vacuum distillation (60 °C
at 1 mmHg) to afford 5 (21.3 g, 80%). 1H NMR (400 MHz, CDCl3,
d): 4.17 (s, 2H), 4.02 (s, 2H), 1.16 (s, 6H), 0.19 (s, 18H). 13C NMR
(100.6 MHz, CDCl3, d): 163.6, 88.0, 46.0, 24.9, 0.1. IR (KBr): 3125
15
93e
96
16
MeO
Cl
CHO
17
18
99
79
CHO
CHO
7
8
18a/(S)
19a/(S)
96
Cl
CHO
92
93f
19
(CH), 2964 (CH), 1254 (C–O) cmꢁ1
([M+H]+, 70), 147 (31), 73 (100). HRMS-FAB (m/z): [M]+ calcd for
13H28O2Si2, 272.1628; found, 272.1625.
. LRMS-FAB (m/z): 273
NC
CHO
C
9
20a/(S)
21a/(S)
86
90
97
97
20
CHO
4.3. Synthesis of 2,20-(propane-2,2-diyl)bis(6,6-dimethyl-5,6,7,8-
tetrahydro-5,7-methanoquinoline) 9
10
21
22
To a DCM (73 mL) solution of TiCl4 (9.0 mL, 80.7 mmol) were
added a solution of (ꢁ)-pinocarvone 7 (11.0 g, 73.4 mmol) in
DCM (73 mL) and solution of silyl enol ether (10.0 g, 36.7 mmol)
in DCM (36 mL) at ꢁ78 °C under an argon atmosphere. After 4 h
of stirring (TLC monitored), it was quenched with 10% K2CO3
(100 mL) and extracted three times with DCM. The combined
DCM layer was washed with brine, dried with MgSO4, filtered,
and concentrated under reduced pressure to give the crude
bis(1,5-diketone) 8.
CHO
CHO
11
12
22a/(S)
23a/(S)
63
52
85
90
Ph
Ph
23
CHO
13
14
24a/(S)
25a/(S)
15
15
86g
83g
24
CH3(CH2)5CHO 25
a
Reagent ratio; aldehyde/Et2Zn/ligand 11 = 1:2:0.1.
All the aldehydes used as purchased except benzaldehyde which was freshly
b
To this crude product 8 were added acetic acid (184 mL) and
ammonium acetate (45.7 g, 587.2 mmol) and refluxed for 12 h.
The reaction was then cooled to 5 °C, basified with 4 M NaOH
and extracted three times with ethyl acetate. The combined ethyl
acetate was dried with MgSO4, filtered, concentrated, and purified
by column chromatography (5% EtOAc/hexane) to give product 9
distilled.
c
The yields represents that for column purified compounds.
Ee of the compounds measured by HPLC using Chiralcel OD-H, OJ and Chiralpak
AD columns.
Ee was checked by HPLC on its acetate derivative prepared by reaction with
Ac2O and Py.
d
e
f
Ee was checked on its benzoate derivative prepared by reaction with BzCl and
(2.8 g, 20%). Mp: 160ꢁ161 °C. ½a D20:7
ꢃ
¼ þ79:3 (c 1.00, CHCl3). 1H
Py.
g
Ee was checked by 19F NMR for its (R)-(+)-MTPA ester.
NMR (400 MHz, CDCl3, d): 7.03–7.01 (d, J = 7.8 Hz, 2H), 6.72ꢁ6.70
(d, J = 7.8 Hz, 2H), 3.06 (s, 4H), 2.69ꢁ2.62 (m, 4H), 2.35ꢁ2.33 (m,
2H), 1.77 (s, 6H), 1.38 (s, 6H), 1.29ꢁ1.26 (d, J = 9.2 Hz, 2H), 0.63
(s, 6H). 13C NMR (100.6 MHz, CDCl3, d): 165.1, 155.2, 138.3,
132.8, 117.8, 47.5, 46.1, 40.3, 39.4, 36.6, 31.9, 29.0, 26.0, 21.3. IR
system for diethylzinc addition reaction to aldehyde. The applica-
tion of these catalysts to other asymmetric reactions is under
investigation.
(KBr): 2973 (CH), 2921 (CH), 1573 (C@C), 1468 (C@C) cmꢁ1
.
LRMS-EI (m/z): 386 (M+, 100), 371 (45), 343 (20). HRMS-EI (m/z):
4. Experimental
4.1. General
[M]+ calcd for C27H34N2, 386.2720; found, 386.2719.
4.4. 2,20-(2,20-(Propane-2,2-diyl)bis(6,6-dimethyl-5,6,7,8-tetrahy-
dro-5,7-methanoquinoline-8,2-diyl))bis(propan-2-ol) 10
Unless otherwise mentioned, all the reactions were performed
under an argon atmosphere in dried and freshly distilled solvent.
The yields are of column chromatography purified material. The
column chromatography was performed using 230–400 mesh neu-
At first, n-BuLi (0.69 mL, 1.1 mmol, 1.6 M in hexane) was added
to diisopropylamine (0.16 mL, 1.15 mmol) in THF (5 mL) at ice bath

Y.-S. Shih et al. / Tetrahedron: Asymmetry 25 (2014) 327–333
331
temperature to generate lithium diispropylamide (LDA). After
30 min of stirring, LDA solution was cooled to ꢁ78 °C and then a
solution of 2,2-dipyridylpropane 9 (0.39 g, 1.00 mmol) in THF
(2 mL) was added to the above solution. Immediate formation of
a dark brown solution indicates carbanion formation. This was stir-
red for 2 h at the same temperature. Then acetone (0.17 mL,
4 mmol) in THF (10 mL) was added dropwise to the above dark
brown solution. The resulting solution was left to stir overnight;
during this time the temperature of the reaction slowly increased
to room temperature. It was then quenched with water and ex-
tracted with EtOAc (3 ꢂ 30 mL) and the combined EtOAc layer
was dried with MgSO4, filtered and concentrated to obtain crude
mono-acetone addition product of 9 which was dried under high
vacuum and carried on for the next step without purification.
The above reaction was once again repeated for mono-acetone
addition product to give the desired product 10 (0.18 g, 36%, two
steps). The low yield of 10 was noticed when the two reactions
above were conducted as a one pot reaction where a second
equivalent of LDA was generated separately and added to the
mono-acetone addition product of 9 followed by acetone addition.
two steps)). Mp: 178ꢁ179 °C. ½a D22:1
ꢃ
¼ ꢁ303:2 (c 1.00, CHCl3). 1H
NMR (400 MHz, CDCl3, d): 10.05 (s, 2H), 7.38ꢁ7.35 (m, 8H),
7.31ꢁ7.29 (m, 2H), 7.22ꢁ7.20 (d, J = 7.8 Hz, 2H), 7.15ꢁ7.13 (d,
J = 7.8 Hz, 2H), 7.00ꢁ6.97 (m, 2H), 6.93ꢁ6.91 (m, 4H), 6.87ꢁ6.83
(m, 4H), 4.41 (s, 2H), 2.63ꢁ2.62 (m, 2H), 2.55ꢁ2.53 (m, 2H),
2.11ꢁ2.06 (m, 2H), 2.01 (s, 6H), 1.40 (s, 6H), 0.88 (s, 6H), ꢁ0.12
to ꢁ0.14 (d, J = 10.0 Hz, 2H). 13C NMR (100.6 MHz, CDCl3, d):
161.9, 156.4, 146.7, 145.8, 141.1, 134.4, 128.3, 128.1, 128.0,
127.0, 126.8, 126.2, 118.6, 81.9, 47.7, 46.9, 45.4, 43.0, 41.4, 29.1,
28.0, 26.4, 21.3. IR (KBr): 3058 (CH), 2975 (CH), 1575 (C@C),
1444 (C@C), 754 (CH aromatic) cmꢁ1. LRMS-FAB (m/z): 751
([M+H]+, 8), 568 (20), 167 (100). HRMS-FAB: [M]+ calcd for
C53H54N2O2, 750.4185; found, 750.4193.
4.6. General procedure for 11 catalyzed diethylzinc addition to
aldehydes
Under an argon atmosphere, diethylzinc (0.9 mL, 1.0 mmol,
1.1 M in toluene) was added dropwise into a solution of ligand
11 (37 mg, 0.05 mmol) in toluene (1 mL) at room temperature.
After 10 min of stirring, the above solution was cooled to ꢁ20 °C
and followed by the addition of an aldehyde (0.5 mmol). The
resulting reaction mixture was stirred at the same temperature
for 57 h then quenched with 1 M HCl and extracted three times
with EtOAc. The combined EtOAc layer was dried over MgSO4, fil-
tered, concentrated to give a crude material and was purified by
column chromatography (230–400 mesh silica gel) to obtain a
pure product. The ee of this product was then checked by HPLC
using Chiralcel OD-H/OJ/Chiralpak AD chiral columns. The ee of
enantiomeric products that were not separable in the above men-
tioned chiral columns were checked via an acetate or benzoate
derivative. The ee of the product obtained from aliphatic aldehydes
were checked by 19F NMR of its (R)-(+)-MTPA ester.
½
a 2D0:0
ꢃ
¼ ꢁ1:0 (c 4.20, CHCl3). 1H NMR (400 MHz, CDCl3, d): 7.73 (s,
2H), 7.26ꢁ7.14 (d, J = 7.8 Hz, 2H), 6.93ꢁ6.91 (d, J = 7.8 Hz, 2H), 3.07
(s, 2H), 2.64ꢁ2.61 (t, J = 5.6 Hz, 2H), 2.47ꢁ2.43 (m, 2H), 2.23ꢁ2.20
(t, J = 5.6 Hz, 2H), 1.72 (s, 6H), 1.33 (s, 6H), 1.22ꢁ1.18 (m, 8H), 0.82
(s, 6H), 0.60 (s, 6H). 13C NMR (100.6 MHz, CDCl3, d): 162.9, 157.1,
139.9, 133.9, 117.9, 74.0, 52.5, 46.4, 46.1, 42.4, 42.0, 29.2, 29.0,
27.9, 27.1, 26.2, 21.1. IR (KBr): 3315 (O–H), 2974 (CH), 2941
(CH), 2889 (CH), 1575 (C@C), 1471 (C@C) cmꢁ1
.
4.5. 2,20-(Propane-2,2-diyl)bis(6,6-dimethyl-5,6,7,8-tetrahydro-
5,7-methanoquinoline-8,2-diyl)bis(diphenylmethanol) 11
At first, n-BuLi (0.69 mL, 1.1 mmol, 1.6 M in hexane) was added
to diisopropylamine (0.16 mL, 1.15 mmol) in THF (5 mL) at ice bath
temperature to generate lithium diispropylamide (LDA). After
30 min of stirring, LDA solution was cooled to ꢁ78 °C and then a
solution of 2,2-dipyridylpropane 9 (0.39 g, 1.00 mmol) and TMEDA
4.6.1. (S)-1-Phenyl-propan-1-ol 12a7a–c,h–j,l,n
Yield: 84%. ½a D19:9
ꢃ
¼ ꢁ58:8 (c 0.65, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.36ꢁ7.32 (m, 4H), 7.30ꢁ7.27 (m, 1H), 4.58ꢁ4.55 (t,
J = 8.0 Hz, 1H), 2.24 (br, 1H), 1.85ꢁ1.71 (m, 2H), 0.94ꢁ0.90 (t,
J = 8.0 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d): 144.6, 128.4,
127.5, 126.0, 76.0, 31.9, 10.2. IR (KBr): 3365 (O–H), 3029 (CH),
2964 (CH), 2933 (CH), 1492 (C@C), 700 (CH aromatic) cmꢁ1. Ee:
96% (Chiralcel OD-H, flow rate 0.25 mL/min, 10% IPA/hexane,
254 nm, tr (R) = 23.35 min (2.16%), tr (S) = 25.98 min (97.84%)).
(150 lL, 1.0 mmol) in THF (2 mL) was added to above solution.
Immediate formation of a dark brown solution indicates carbanion
formation. This was stirred for 2 h at the same temperature. Then
solution of benzophenone (0.186 g, 1.0 mmol) in THF (10 mL)
was added and stirred overnight at room temperature. Water
was added to quench the reaction, which was extracted with EtOAc
(3 ꢂ 30 mL) and the combined EtOAc layer was dried (MgSO4) and
concentrated to give the crude product of mono-benzophenone
addition product which was purified by column chromatography
using silica gel (230–400 mesh, 6% EtOAc/hexane) to obtain pure
4.6.2. (S)-1-o-Tolyl-propan-1-ol 13a2a
Yield: 82%. ½a D21:1
ꢃ
¼ ꢁ64:3 (c 1.25, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.47ꢁ7.45 (d, J = 8.0 Hz, 1H), 7.26ꢁ7.14 (m, 3H),
4.85ꢁ4.82 (t, J = 4.0 Hz, 1H), 2.35 (s, 3H), 2.18 (br, 1H), 1.78ꢁ1.72
(m, 2H), 1.00ꢁ0.97 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 142.8, 134.6, 130.3, 127.1, 126.2, 125.3, 71.9, 30.9, 19.1, 10.3.
IR (KBr): 3368 (O–H), 3024 (CH), 2933 (CH), 2964 (CH), 2876
(CH), 1487 (C@C), 750 (CH aromatic) cmꢁ1. 1-o-Tolylpropyl acetate
13aa: General procedure for acetylation: pyridine (2.5 equiv) was
added into a solution of 13a (1 equiv) in DCM at ice bath temper-
ature under an argon atmosphere. To this acetic anhydride (2.2
equiv) was added drop wise and the resulting mixture was stirred
at room temperature until TLC showed completion of the reaction.
Then evaporation of the volatiles and purification by column chro-
product (0.33 g, 58%). Mp: 140ꢁ141 °C. ½a D22:5
¼ ꢁ221 (c 1.00,
ꢃ
CHCl3). 1H NMR (400 MHz, CDCl3, d): 10.07 (s, 1H), 7.36ꢁ7.33 (m,
4H), 7.29ꢁ7.26 (m, 1H), 7.16ꢁ7.14 (d, J = 7.7 Hz, 1H), 7.08ꢁ7.02
(m, 4H), 6.97ꢁ6.95 (m, 3H), 6.90ꢁ6.88 (d, J = 7.6 Hz, 1H), 4.35 (s,
1H), 3.11 (s, 2H), 2.75ꢁ2.72 (t, J = 5.4 Hz, 1H), 2.68ꢁ2.59 (m, 2H),
2.47ꢁ2.45 (t, J = 5.4 Hz, 1H), 2.37 (m, 2H), 2.04ꢁ1.98 (m, 1H),
1.89 (s, 3H), 1.88 (s, 3H), 1.40 (s, 3H), 1.37 (s, 3H), 1.33ꢁ1.31 (d,
J = 9.4 Hz, 1H), 0.86 (s, 3H), 0.65 (s, 3H), ꢁ0.23 to ꢁ0.25 (d,
J = 10.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl3, d): 161.9, 156.4,
146.7, 145.8, 141.1, 134.4, 128.3, 128.1, 128.0, 127.0, 126.8,
126.2, 118.6, 81.9, 60.3, 47.7, 46.9, 45.4, 43.0, 41.4, 29.1, 28.0,
26.4, 21.3, 21.0, 14.2. IR (KBr): 3659 (O–H), 3058 (CH), 2974
(CH), 2928 (CH), 1574 (C@C), 1445 (C@C), 756 (CH aromatic)
cmꢁ1. LRMS-FAB (m/z): 569 ([M+H]+, 27), 551 (18), 491 (15).
HRMS-FAB: [M]+ calcd for C40H44N2O1, 568.3454; found, 568.3459.
The above reaction was repeated once again on the mono-ben-
zophenone addition product (0.33 g) to obtain crude 11 which was
purified by column chromatography (230–400 mesh, 5%
EtOAc/hexane) to give pure ligand 11 (0.255 g, 58%; 34% (over
matography yields 13aa.7o
½
a 2D0:0
ꢃ
¼ ꢁ75:2 (c 0.95, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.35ꢁ7.33 (dd, J = 7.3 and 2.1 Hz, 1H),
7.22ꢁ7.17 (m, 2H), 7.16ꢁ7.13 (m, 1H), 5.92ꢁ5.88 (m, 1H), 2.41
(s, 3H), 2.08 (s, 3H), 1.95ꢁ1.75 (m, 2H), 0.94ꢁ0.90 (t, J = 7.4 Hz,
3H). 13C NMR (100.6 MHz, CDCl3, d): 170.5, 155.9, 139.2, 135.2,
130.3, 127.5, 126.1, 125.8, 108.9, 78.0, 74.0, 65.2, 30.6, 29.7, 28.9,
21.3, 19.3, 10.1. IR (KBr): 2923 (CH), 2851 (CH), 1736 (C@O),
1459 (C@C) cmꢁ1. Ee: 96% (Chiralcel OD-H, flow rate 0.25 mL/

332
Y.-S. Shih et al. / Tetrahedron: Asymmetry 25 (2014) 327–333
min, 10% IPA/hexane, 254 nm, tr (R) = 16.85 min (1.75%), tr
(S) = 16.85 min (98.25%)).
IPA/hexane, 254 nm, tr (R) = 25.62 min (1.84%), tr (S) = 26.22 min
(98.15%)).
4.6.3. (S)-1-m-Tolyl-propan-1-ol 14a7m,n
4.6.8. (S)-4-(1-Hydroxypropyl)benzonitrile 19a7e,g,j
Yield: 95%. ½a D20:0
ꢃ
¼ ꢁ47:4 (c 1.64, CHCl3). 1H NMR (400 MHz,
Yield: 92%. ½a D20:0
ꢃ
¼ ꢁ39:9 (c 3.40, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.26ꢁ7.23 (m, 3H), 7.16ꢁ7.09 (m, 3H), 4.54ꢁ4.51 (t,
J = 6.6 Hz, 1H), 2.38 (s, 1H), 2.35 (br, 1H), 1.85ꢁ1.72 (m, 2H),
0.94ꢁ0.91 (t, J = 7.4, 3H). 13C NMR (100.6 MHz, CDCl3, d): 144.6,
137.9, 128.3, 128.2, 126.7, 123.1, 76.0, 31.8, 21.4, 10.2. IR (KBr):
3370 (O–H), 3026 (CH), 2963 (CH), 2933 (CH), 2875 (CH), 1608
CDCl3, d): 7.54ꢁ7.52 (d, J = 6.7 Hz, 2H), 7.40ꢁ7.38 (d, J = 8.2 Hz,
2H), 4.61ꢁ4.58 (t, J = 6.3 Hz, 1H), 3.06 (br, 1H), 1.73–1.65 (m,
2H), 0.87ꢁ0.83 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d):
150.3, 132.1, 126.6, 118.9, 110.6, 74.8, 31.9, 9.7. IR (KBr): 3435
(O–H), 2967 (CH), 2934 (CH), 2877 (CH), 2227 (CN), 1608 (C@C),
847 (CH aromatic) cmꢁ1. 1-(4-Cyanophenyl)propyl benzoate 19aa:
Pyridine (2.5 equiv) was added to a solution of 19a (1 equiv) in
DCM at ice bath temperature under an argon atmosphere. To this
benzoyl chloride (2.2 equiv) was added dropwise and the resulting
mixture was stirred at room temperature until TLC showed com-
pletion of the reaction. Then evaporation of the volatiles and puri-
(C@C), 1456 (C@C), 703 (CH aromatic) cmꢁ1
.
Ee: 93%
(Chiralcel OD-H, flow rate 0.25 mL/min, 10% IPA/hexane, 254 nm,
tr (R) = 20.84 min (3.36%), tr (S) = 23.34 min (96.63%)).
4.6.4. (S)-1-p-Tolyl-propan-1-ol 15a2a,7l,n
Yield: 63%. ½a D20:0
ꢃ
¼ ꢁ37:8 (c 1.50, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.24ꢁ7.22 (d, J = 8.0 Hz, 2H), 7.18ꢁ7.16 (d, J = 8.1 Hz,
2H), 4.53ꢁ4.50 (t, J = 6.6 Hz, 1H), 2.51 (br, 1H), 2.38 (s, 1H),
1.85ꢁ1.70 (m, 2H), 0.94ꢁ0.90 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 141.7, 137.0, 129.0, 126.0, 75.8, 31.8, 21.1,
10.2. IR (KBr): 3367 (O–H), 3020 (CH), 2963 (CH), 2931 (CH),
fication by column chromatography yields 19aa. ½a D20:0
¼ þ54:7 (c
ꢃ
3.95, CHCl3). 1H NMR (400 MHz, CDCl3, d): 8.09ꢁ8.07 (dd, J = 8.4,
1.3 Hz, 2H), 7.66ꢁ7.64 (d, J = 8.4 Hz, 2H), 7.61ꢁ7.57 (t, J = 7.5 Hz,
1H), 7.52ꢁ7.45 (m, 4H), 5.93ꢁ5.90 (t, J = 7.0 Hz, 1H), 2.10ꢁ1.92
(m, 2H), 1.00ꢁ0.97 (t, J = 7.5 Hz, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 165.7, 146.1, 133.3, 132.4, 129.9, 129.7, 128.5, 128.3, 127.0,
118.7, 111.7, 29.5, 9.8. IR (KBr): 3063 (CH), 2972 (CH), 2937 (CH),
2879 (CH), 2229 (CN), 1451 (C@C), 842 (CH aromatic) cmꢁ1. Ee:
93% (Chiralcel OJ, flow rate 0.50 mL/min, 10% IPA/hexane,
254 nm, tr (R) = 33.01 min (3.67%), tr (S) = 37.77 min (96.33%)).
2875 (CH), 1455 (C@C), 816 (CH aromatic) cmꢁ1
. Ee: 90%
(Chiralpak AD, flow rate 0.20 mL/min, 10% IPA/hexane, 254 nm, tr
(R) = 30.06 min (4.86%), tr (S) = 39.20 min (95.13%)).
4.6.5. (S)-1-(3-Methoxyphenyl)propan-1-ol 16a7i,k
Yield: 69%. ½a 20:0
ꢃ
¼ ꢁ48 (c 2.35, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.26ꢁD7.22 (t, J = 8.0 Hz, 1H), 6.89ꢁ6.88 (m, 3H),
6.81ꢁ6.78 (m, 1H), 4.54ꢁ4.51 (t, J = 6.6 Hz, 1H), 3.78 (s, 1H), 2.32
(br, 1H), 1.82ꢁ1.68 (m, 2H), 0.92ꢁ0.88 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 159.6, 146.4, 129.3, 118.3, 112.8, 111.4,
75.8, 55.1, 31.8, 10.1. IR (KBr): 3330 (O–H), 2963 (CH), 2935 (CH),
4.6.9. (S)-1-(Naphthalen-1-yl)propan-1-ol 20a7f,i,k–m
Yield: 86%. ½a D20:0
ꢃ
¼ ꢁ51:2 (c 1.64, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 8.13ꢁ8.10 (t, J = 1.9 Hz, 1H), 7.90ꢁ7.87 (m, 1H),
7.80ꢁ7.78 (d, J = 8.1 Hz, 1H), 7.63ꢁ7.62 (d, J = 7.0 Hz, 1H),
7.54ꢁ7.46 (m, 3H), 5.39ꢁ5.36 (m, 1H), 2.20 (br, 1H), 2.06ꢁ1.89
(m, 2H), 1.05ꢁ1.01 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 140.2, 133.8, 130.5, 128.9, 127.9, 125.9, 125.5, 125.4, 123.3,
122.9, 72.5, 31.1, 10.5. IR (KBr): 3372 (O–H), 3059 (CH), 2931
(CH), 2964 (CH), 2932 (CH), 1510 (C@C), 1455 (C@C), 777 (CH aro-
matic) cmꢁ1. Ee: 97% (Chiralcel OD-H, flow rate 0.50 mL/min, 10%
IPA/hexane, 210 nm, tr (S) = 20.65 min (98.55%), tr (R) = 34.02 min
(1.44%)).
1586 (C@C), 1458 (C@C), 1262 (C–O), 783 (CH aromatic) cmꢁ1
.
1-(3-Methoxyphenyl)propyl acetate 16aa:7o The 13aa synthetic
procedure was followed. ½a D20:0
ꢃ
¼ ꢁ75:3 (c 1.25, CHCl3). 1H NMR
(400 MHz, CDCl3, d): 7.27ꢁ7.23 (d, J = 7.9 Hz, 1H), 6.92ꢁ6.90 (d,
J = 7.8 Hz, 1H), 6.88ꢁ6.87 (t, J = 2.3 Hz, 1H), 6.83ꢁ6.80 (m, 1H),
5.66ꢁ5.63 (t, J = 6.8 Hz, 1H), 3.79 (s, 3H), 2.07 (s, 3H), 1.93ꢁ1.79
(m, 2H), 0.90ꢁ0.87 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3,
d): 170.3, 159.6, 142.2, 129.4, 118.8, 113.0, 112.3, 77.2, 55.1, 29.3,
21.2, 9.9. IR (KBr): 2969 (CH), 2879 (CH), 2837 (CH), 1733 (C@O),
1587 (C@C), 1239 (C–O), 782 (CH aromatic) cmꢁ1. Ee: 93% (Chiral-
cel OD-H, flow rate 0.25 mL/min, 10% IPA/hexane, 254 nm, tr
(R) = 18.86 min (3.30%), tr (S) = 20.16 min (96.67%)).
4.6.10. (S)-1-(Naphthalen-2-yl)propan-1-ol 21a7b,h,j,k,n
Yield: 90%. ½a D20:0
ꢃ
¼ ꢁ37:3 (c 3.65, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.86ꢁ7.82 (m, 3H), 7.76 (s, 1H), 7.52ꢁ7.46 (m, 3H),
4.75ꢁ4.72 (t, J = 6.5 Hz, 1H), 2.29 (br, 1H), 1.95ꢁ1.81 (m, 2H),
0.97ꢁ0.93 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d):
142.0, 133.3, 133.0, 128.2, 127.9, 127.7, 126.1, 125.7, 124.7,
124.2, 76.1, 31.7, 10.1. IR (KBr): 3365 (O–H), 3305 (CH), 2964
(CH), 2932 (CH), 1601 (C@C), 1507 (C@C), 819 (CH aromatic)
cmꢁ1. Ee: 97% (Chiralcel OD-H, flow rate 0.50 mL/min, 10% IPA/
hexane, 210 nm, tr (S) = 22.65 min (98.45%), tr (R) = 25.56 min
(1.54%)).
4.6.6. (S)-1-(3-Chlorophenyl)propan-1-ol 17a2a,7k,l
Yield: 99%. ½a D20:0
ꢃ
¼ ꢁ30:5 (c 3.50, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.31ꢁ7.30 (m, 1H), 7.24ꢁ7.20 (m, 2H), 7.16ꢁ7.14 (m,
1H), 4.51ꢁ4.48 (t, J = 6.5 Hz, 1H), 2.67 (br, 1H), 1.76ꢁ1.66 (m,
2H), 0.89ꢁ0.85 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d):
146.7, 134.2, 129.6, 127.5, 126.1, 124.1, 75.2, 31.8, 9.9. IR (KBr):
3365 (O–H), 3065 (CH), 2960 (CH), 2934 (CH), 2877 (CH), 1598
(C@C), 1575 (C@C), 783 (CH aromatic) cmꢁ1. Ee: 96% (Chiralpak
AD, flow rate 0.50 mL/min, 10% IPA/hexane, 254 nm, tr
(R) = 21.90 min (1.82%), tr (S) = 22.68 min (98.17%)).
4.6.11. (S)-(E)-1-Phenylpent-1-en-3-ol 22a7a,b,f,h–k,n
Yield: 63%. ½a D20:0
ꢃ
¼ ꢁ9:6 (c 1.64, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.40ꢁ7.38 (d, J = 8.4 Hz, 2H), 7.34ꢁ7.30 (t, J = 7.2 Hz,
2H), 7.27ꢁ7.23 (m, 1H), 6.60ꢁ6.56 (d, J = 15.8 Hz, 1H), 6.25ꢁ6.19
(dd, J = 15.9, 6.7 Hz, 1H), 4.23ꢁ4.18 (m, 1H), 1.93 (br, 1H),
1.72ꢁ1.63 (m, 2H), 1.00ꢁ0.96 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 136.8, 132.3, 130.4, 128.6, 127.6, 126.4,
74.4, 30.2, 9.8. IR (KBr): 3365 (O–H), 3059 (CH), 2931 (CH), 2964
(CH), 1493 (C@C), 1450 (C@C), 747 (CH aromatic) cmꢁ1. Ee: 85%
(Chiralcel OD-H, flow rate 0.50 mL/min, 10% IPA/hexane, 254 nm,
tr (R) = 23.09 min (7.61%), tr (S) = 23.09 min (92.38%)).
4.6.7. (S)-1-(4-Chlorophenyl)propan-1-ol 18a7a,b,i,l
Yield: 79%. ½a D20:0
ꢃ
¼ ꢁ34:8 (c 3.25, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.31ꢁ7.28 (dd, J1 = 6.5 Hz, J2 = 2.0 Hz, 2H), 7.25ꢁ7.23
(dd, J = 6.5 and 1.7 Hz, 2H), 4.56ꢁ4.53 (t, J = 6.5 Hz, 1H), 2.13 (br,
1H), 1.80ꢁ1.66 (m, 2H). 13C NMR (100.6 MHz, CDCl3, d): 143.0,
133.0, 128.5, 127.3, 75.2, 31.9, 9.9. IR (KBr): 3360 (O–H), 2965
(CH), 2934 (CH), 2877 (CH), 1489 (C@C), 1092 (C–O), 824 (CH aro-
matic) cmꢁ1. Ee: 96% (Chiralpak AD, flow rate 0.50 mL/min, 10%

Y.-S. Shih et al. / Tetrahedron: Asymmetry 25 (2014) 327–333
333
4.6.12. (S)-(E)-2-Methyl-1-phenylpent-1-en-3-ol 23a7k,n
(CH aromatic) cmꢁ1. Ee: 83% (ee was determined by 19F NMR
(376.49 MHz, CDCl3, d): ꢁ71.27 (R), ꢁ71.35 (S); integration ratio
of R:S = 1.00:11.05).
Yield: 52%. ½a D20:0
ꢃ
¼ þ30:5 (c 1.65, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 7.37ꢁ7.29 (m, 4H), 7.24ꢁ7.22 (t, J = 5.8 Hz, 1H), 6.51 (s,
1H), 4.13ꢁ4.09 (t, J = 6.6 Hz, 1H), 2.16 (br, 1H), 1.88 (s, 3H),
1.73ꢁ1.66 (m, 2H), 0.99ꢁ0.95 (t, J = 7.4 Hz, 3H). 13C NMR
(100.6 MHz, CDCl3, d): 140.1, 137.7, 129.0, 128.1, 126.4, 125.9,
79.5, 27.9, 13.1, 10.1. IR (KBr): 3364 (O–H), 3081 (CH), 3024
(CH), 2962 (CH), 2875 (CH), 1600 (C@C), 1492 (C@C), 746 (CH aro-
matic) cmꢁ1. Ee: 90% (Chiralcel OD-H, flow rate 0.50 mL/min, 3%
IPA/hexane, 254 nm, tr (R) = 33.18 min (5.04%), tr (S) = 36.22 min
(94.95%)).
Acknowledgements
The authors thank Mr. Ping-Kuei Liao, at National Dong Hwa
University, for his help in obtaining X-ray data, and the financial
support from the National Science Council of the Republic of China
(NSC 100-2113-M-259-006-MY3).
References
4.6.13. (S)-1-Cyclohexylpropan-1-ol 24a7a,b,i,g
Yield: 15%. ½a D20:0
ꢃ
¼ ꢁ4:2 (c 0.45, CHCl3). 1H NMR (400 MHz,
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CDCl3, d): 3.30ꢁ3.25 (m, 1H), 1.80ꢁ1.65 (m, 5H), 1.55ꢁ0.98 (m,
9H), 0.97ꢁ0.93 (t, J = 7.4 Hz, 3H). 13C NMR (100.6 MHz, CDCl3, d):
77.5, 43.2, 29.3, 27.8, 26.8, 26.6, 26.4, 26.2, 10.2. IR (KBr): 3371
(O–H), 2925 (CH), 2852 (CH), 1449 (CH bend) cmꢁ1
.
(2S)-1-Cyclohexylpropyl-3,3,3-trifluoro-2-methoxy-2-phenylpro-
panoate 24aa:7o The enantiomeric excess of 24a was determined
by NMR for its (R)-(+)-MTPA ester (Mosher’s ester). General proce-
dure for MTPA ester preparation: A solution of 24a (1 equiv), (R)-(+)-
MTPA ((R)-2-methoxy-3,3,3-trifluoro-2-phenylpropanoic acid) (2
equiv), and DMPA (catalytic) in DCM was cooled with an ice bath.
To this solution was added DCC (4 equiv) and stirred until TLC
showed completion of reaction. Then this was diluted with hexane,
filtered, concentrated, and purified by column chromatography
(230–400 mesh silica gel, 50% EtOAc/hexane) to obtain 24aa. 1H
NMR (400 MHz, CDCl3, d): 7.58ꢁ7.57 (m, 2H), 7.41ꢁ7.38 (m, 4H),
4.91ꢁ4.89 (m, 1H), 3.58ꢁ3.56 (m, 3H), 1.76ꢁ1.58 (m, 8H),
1.23ꢁ1.00 (m, 7H), 0.93ꢁ0.89 (t, J = 7.4 Hz, 2H), 0.81ꢁ0.78 (t,
J = 7.4 Hz, 2H). 13C NMR (100.6 MHz, CDCl3, d): 129.4, 128.2,
127.4, 82.6, 55.7, 55.4, 40.2, 34.9, 28.6, 27.5, 26.3, 26.1, 26.0,
25.5, 24.7, 23.5, 9.8. IR (KBr): 3031 (CH), 3065 (CH), 2932 (CH),
2855 (CH), 1748 (C@O), 1256 (C–O), 716 (CH aromatic) cmꢁ1. Ee:
86% (ee was determined by 19F NMR (376.49 MHz, CDCl3, d):
ꢁ71.16 (R), ꢁ71.20 (S); integration ratio of R:S = 1.00:13.37).
4.6.14. (S)-Nonan-3-ol 25a7a,b,d,i
Yield: 15%. ½a D20:0
ꢃ
¼ þ3:5 (c 0.55, CHCl3). 1H NMR (400 MHz,
CDCl3, d): 3.52ꢁ3.47 (m, 1H), 1.51ꢁ1.27 (m, 13H), 0.93ꢁ0.89 (t,
J = 7.4 Hz, 3H), 0.87ꢁ0.84 (m, 4H). 13C NMR (100.6 MHz, CDCl3,
d): 73.26, 36.9, 31.8, 30.1, 29.4, 25.6, 22.6, 14.0, 9.8. IR (KBr):
3348 (O–H), 2958 (CH), 2930 (CH), 2872 (CH), 1464 (C–O) cmꢁ1
.
(2S)-Nonan-3-yl-3,3,3-trifluoro-2-methoxy-2-phenylpropanoate
25aa:7d,o The MTPA ester was made by following the same proce-
dure as for 24aa. 1H NMR (400 MHz, CDCl3, d): 7.57ꢁ7.55 (m, 2H),
7.41ꢁ7.39 (m, 4H), 5.06ꢁ5.03 (m, 1H), 3.58ꢁ3.56 (m, 3H),
1.70ꢁ1.56 (m, 4H), 1.28ꢁ1.20 (m, 8H), 0.95ꢁ0.82 (m, 6H). 13C
NMR (100.6 MHz, CDCl3, d): 166.4, 132.6, 129.5, 128.3, 127.4,
78.8, 55.4, 33.0, 31.6, 29.0, 26.7, 24.8, 22.5, 14.0, 9.6. IR (KBr):
3065 (CH), 2932 (CH), 2857 (CH), 1744 (C@O), 1452 (C@C), 716