Kinetic resolution of secondary carbinols by a chiral N,N-4-dimethylaminopyridine derivative containing a 1,1′-binaphthyl unit: Hydrogen bonding affects catalytic activity and enantioselectivity

Article abstract of DOI:10.1246/bcsj.20160135

We developed an acylative kinetic resolution of secondary carbinols using a binaphthyl-based N,N-4-dimethylaminopyridine (DMAP) derivative 1d with tert-Alcohol substituents. The reaction proceeded with a wide range of carbinols with moderate to high selectivity (s) (up to s = 79.5). Kinetic studies revealed that catalyst 1d was more catalytically active than the corresponding bis-methyl ether 1d′ or DMAP. Hydrogen bonding between tert-Alcohols of the catalyst and secondary carbinols was responsible for the enhanced reaction rate and high enantioselectivity.

Full text of DOI:10.1246/bcsj.20160135

Kinetic Resolution of Secondary Carbinols by a Chiral
N,N-4-Dimethylaminopyridine Derivative Containing a
1,1¤-Binaphthyl Unit: Hydrogen Bonding Affects
Catalytic Activity and Enantioselectivity
Kazuki Fujii, Koichi Mitsudo, Hiroki Mandai,* and Seiji Suga*
Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University,
3-1-1 Tsushima-naka, Kita-ku, Okayama 700-8530
E-mail: suga@cc.okayama-u.ac.jp
Received: April 20, 2016; Accepted: May 23, 2016; Web Released: May 30, 2016
Hiroki Mandai
Hiroki Mandai received his Ph.D. from Tokyo University of Science in 2006 under the supervision of
Professor Teruaki Mukaiyama. After a postdoctoral fellowship at Boston College (Professor Amir H.
Hoveyda), he joined Okayama University as an assistant professor in 2008, and moved to a his current
laboratory in 2010. His current research focuses on the development of nucleophilic organocatalysts with
extremely high catalytic activity and their application to the synthesis of biologically important molecules.
Seiji Suga
Seiji Suga studied organic chemistry at Nagoya University under the direction of Professor Ryoji Noyori.
After earning his Ph.D. in 1995, he worked as a postdoctoral fellow (JSPS Postdoctoral Fellowship for
Research Abroad) with Prof. Sir Jack E. Baldwin at University of Oxford. He then joined the Prof. Jun-ichi
Yoshida group at Kyoto University as an Instructor (1996), and was subsequently promoted to Lecturer
(1999) and Associate Professor (2004). In 2008, he was appointed Professor at Okayama University. His
research interests have focused on electron-transfer reactions of organic compounds and the development
of reaction processes.
Abstract
transfer catalysts.9,10 Detailed studies have been performed on
the reaction mechanism11 and the reactivity of DMAP deriv-
atives.12-16 The development of chiral variants has been exten-
sively studied in response to pioneering studies by Vedejs17 and
Fu,18 and these are used in various enantioselective transforma-
tions, such as the kinetic resolution of racemic alcohols5,19-36
or amines,37,38 desymmetrization of meso-compounds,39,40
Steglich rearrangement41-44 and many other examples.45 How-
ever, most DMAP- or PPY-based chiral catalysts show high
enantioselectivity for only a limited range of substrates or reac-
tions. Thus, the development of a chiral nucleophilic catalyst
that can be used in various transformations with high enantio-
selectivity is of great interest in synthetic organic chemistry.
Recently, we developed several acyl-transfer reactions pro-
moted by two classes of chiral DMAP derivatives.46-49 Partic-
ularly, binaphthyl-based DMAP derivatives 1d with hydrogen-
bonding substituents at the 3,3¤-positions were shown to re-
markably accelerate the rate of the reaction and to exhibit high
enantioselectivity in the Steglich rearrangement (intramolec-
ular acyl-transfer) of various O-acylated oxindole derivatives
(eq 1).49 This reaction only required 0.5 mol % of catalyst to
We developed an acylative kinetic resolution of secondary
carbinols using a binaphthyl-based N,N-4-dimethylamino-
pyridine (DMAP) derivative 1d with tert-alcohol substituents.
The reaction proceeded with a wide range of carbinols with
moderate to high selectivity (s) (up to s = 79.5). Kinetic studies
revealed that catalyst 1d was more catalytically active than
the corresponding bis-methyl ether 1d¤ or DMAP. Hydrogen
bonding between tert-alcohols of the catalyst and secondary
carbinols was responsible for the enhanced reaction rate and
high enantioselectivity.
Introduction
Nucleophilic catalysts (i.e., chiral phosphines,1 diamines,2
imidazoles,3,4 isothioureas,5 N-heterocyclic carbenes,6,7 and
combination of chiral thiourea and DMAP8) for enantio-
selective acyl-transfer reaction have been actively studied for
two decades. Among them, DMAP and 4-pyrrolidinopyridine
(PPY) have been recognized as very powerful and useful acyl-
Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan | 1081

Ar
Ar
Ar
OH
OH
R2
OCOR
R2
OH
R2
catalyst, RCO2O, base
+
N
N
R1
racemate
R1
R1
acylative kinetic resolution
OH
Ar
catalyst
R
R1
R2
H
R1
R2
R1
R2
H
R
:base
O
O
Ar
Ar
Ar
O
Ar
Ar
Ar
Ar
Ar
O
N
O
O
O
O
H
H
H
H
O
O
or
or
R
R
R
N
N
N
N
N
O
O
O
OH
Ar
OH
Ar
O
O
R
H
Ar
Ar
O
TS I
TS II
TS III
Figure 1. Our working hypotheses regarding the transition state.
give the desired products in >98% yield with high enantio-
selectivity (up to 99:1 er). Several verification experiments and
computational studies have clearly indicated that hydrogen
bonding between the catalyst and the counteranion of N-
acylpyridinium ion (nucleophile) stabilizes the transition state
of the reaction (oxyanion stabilization)50 to enhance the
catalytic activity and enantioselectivity. These catalysts were
broadly applicable to kinetic resolutions of secondary carbi-
nols and d,l-1,2-diols, and desymmetrization of meso-1,2-diols
(intermolecular acyl-transfer), however, the origin of the rate
acceleration and the enantioselectivity have not been system-
atically investigated.49
Table 1. Initial screening of catalystsa)
Ar
Ar
OH
N
N
OH
Ar
1a–1g (5 mol %)
Ar
OH
Me
OAc
Me
OH
Me
Ac2O (0.75 equiv), Et3N (0.75 equiv)
+
toluene (0.03 M), –60 ˚C, 15 h
Ph
Ph
Ph
2a
racemate
3a
2a
1a: Ar = Ph
1e: Ar = 4-(i-Pr)3Si-C6H4
1f : Ar = 3,5-(MeO)2-C6H3
1g: Ar = 3,5-(t-Bu)2-4-MeO-C6H2
1b: Ar = 4-MeO-C6H4
1c: Ar = 4-Ph-C6H4
1d: Ar = 4-t-Bu-C6H4
Ar
Ar
OH
N
N
Entry Catalyst Conv/%b) Er of 3ac) Er of 2ac) Sd)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
65
32
42
58
51
49
68
52:48
60:40
60:40
70:30
65.6:33.5 67:33
41:59
59:41
54:46
45.5:54.5 1.6
57.5:42.5 1.7
1.2
OH
Ar
1d (0.5 mol %)
O
Me
O
O
Me
Ar
OPh
OPh
O
77:23
3.8
2.7
1.7
2.1
ð1Þ
N
THF (0.4 M), –20 ºC, 5 h
N
Ar = 4-t-BuC6H4
OPh
OPh
42:58
70:30
O
O
13 examples
1g
>98%yield in all cases
up to 99:1 er
a) Reactions were performed on a 0.10 mmol scale under an
argon atmosphere. b) Conversions were calculated from the
enantioselectivity of the substrate and product. c) Enantio-
selectivities were determined by HPLC analysis. d) S-factors
were calculated by Kagan’s equation.52
Based on these considerations for Steglich rearrangement,
we also expected that such an attractive electrostatic interaction
would enhance the catalytic activity and enantioselectivity in
the acylation of alcohols through hydrogen bonding between
the catalyst and substrate. We hypothesized that a tert-alcohol
moiety of the catalyst would pull in either a carbinol (Figure 1,
Results and Discussion
¹
TS I) or a counteranion of N-acylpyridinium ion ( OCOR,
Figure 1, TS II). Another model that includes the simultaneous
interaction between two tert-alcohol moieties and both a car-
binol and a counteranion, and an outer base to deprotonate the
carbinol, would be possible (Figure 1, TS III). We expected
that such a transition states should lead to high enantioselec-
tivity and accelerate the rate of the reaction. In this paper, we
describe the acylative kinetic resolution of secondary benzylic
alcohols, and the results of several experimental studies to
elucidate the reaction mechanism.
Initially, to identify a suitable catalyst, kinetic resolution of
the secondary alcohol 2a was carried out in the presence of
5 mol % of catalysts 1a-1g, 0.75 equiv of acetic anhydride and
0.75 equiv of triethylamine in toluene (0.03 M) at ¹60 °C for
15 h (Table 1). Catalysts 1a and 1b showed low selectivity
factors (s = 1.2-1.6, Entries 1 and 2). Therefore, the catalyst
structure was studied further (Entries 3-7). As a result, catalyst
1d (Ar = 4-t-Bu-C6H4) showed the highest selectivity factor
(s = 3.8) among the catalysts examined. Surprisingly, catalyst
1082 | Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan

Table 2. Examination of acylation reagentsa)
Table 3. Solvent screeninga)
1d (5 mol %)
acylation reagent
(0.75 equiv)
1d (5 mol %)
(i-PrCO)2O (0.75 equiv)
Et3N (0.75 equiv)
OH
Me
2a
racemate
OCOi-Pr
OH
Me
+
OH
Me
OR
OH
Me
Et3N (0.75 equiv)
solvent (0.03 M)
–60 ˚C, 15 h
Ph
Ph
Me
Ph
+
toluene (0.03 M)
–60 ˚C, 15 h
Ph
Ph
Me
3a–5a
Ph
4a
2a
2a
2a
racemate
3a: R = Ac, 4a: R = COi-Pr, 5a: R = Bz
Conv
/%b)
Entry Solvent
Er of 4ac) Er of 2ac) Sd)
Acylation
reagent
Conv
Entry
Er of 3a-5ac) Er of 2ac) Sd)
/%b)
1
2
3
4
5
6e)
7f)
toluene
Et2O
t-BuOMe
THF
acetone
60
44
78:22
86:14
78:22
72.5:27.5 64:36
67.5:32.5 55:45
92:8
78:22
89:11
9.2
10.7
8.1
3.4
2.3
1
2
3
4
Ac2O
AcCl
(i-PrCO)2O
Bz2O
58
6
72
70
70:30
51:49
70:30
55:45
77:23
50:50
98:2
3.8
1.0
8.0
1.3
58
38
23
43
42
61:39
DMF
t-amyl alcohol
64:36
72:28
64:36
66:34
2.3
3.4
a) Reactions were performed on a 0.10 mmol scale under an
argon atmosphere. b) Conversions were calculated from the
enantioselectivity of the substrate and product. c) Enantio-
selectivities were determined by HPLC analysis. d) S-factors
were calculated by Kagan’s equation.52
a) Reactions were performed on a 0.10 mmol scale under an
argon atmosphere. b) Conversions were calculated from the
enantioselectivity of the substrate and product. c) Enantio-
selectivities were determined by HPLC analysis. d) S-factors
were calculated by Kagan’s equation.52 e) This reaction was
conducted at ¹50 °C. f) This reaction was conducted at 0 °C.
1f (Ar = 3,5-(MeO)2-C6H3) gave an opposite enantioselectivity
even though it had the same chiral scaffold (s = 1.7). Accord-
ing to these results, we selected catalyst 1d as the optimal
catalyst for further optimization of the reaction conditions.
Next, the effects of the acylation reagent were examined
with the optimal catalyst 1d (Table 2). While acetic anhydride
gave a moderate s-factor (s = 3.8, Entry 1), acetyl chloride
showed an astonishingly low conversion, and gave racemates
of 3a and 2a (s = 1.0, Entry 2). These results showed that the
leaving group of the acylation reagent ( OAc vs. Cl), which
serves as a counteranion of N-acylpyridinium ion in the transi-
tion state (Figure 1), profoundly affected the reactivity51 and
enantioselectivity. Further examination showed that isobutyric
anhydride gave the highest s-factor (s = 8.0, Entry 3). Con-
sequently, isobutyric anhydride was used as the optimal
acylation reagent in this reaction.
We next investigated various solvents with optimal catalyst
1d to explore the optimal conditions (Table 3). Toluene, diethyl
ether and tert-butyl methyl ether could be used for this reac-
tion and showed good conversions with moderate s-factors
(Entries 1-3, s = 8.1-10.7, 44-60% conv), however the use
of polar or protic solvents such as tetrahydrofuran, acetone,
dimethylformamide and tert-amyl alcohol gave low s-factors,
probably because of the weak hydrogen bond networks
between the catalyst and substrate (Entries 4-7). Thus, we
selected toluene, which showed the highest s-factor, as the
optimal solvent.
Finally, to improve the s-factor, we screened several bases
(Table 4). Surprisingly, the reaction proceeded while retaining
a moderate s-factor in the absence of base (Entry 1). These
results suggest that TS III would have little impact. While we
continued to screen various organic and inorganic bases, the
s-factors and conversions were not dramatically improved
(Entries 2-8). Thus, we selected cesium carbonate as the opti-
mal base, which showed the highest s-factor and conversion
among the bases tested (Entry 8). Further studies of the cata-
lyst loading, substrate concentration, reaction temperature, and
reaction time did not provide additional insights. Accordingly,
Table 4. Screening of basesa)
1d (5 mol %)
(i-PrCO)2O (0.75 equiv)
OH
Me
OCOi-Pr
OH
Me
base (0.75 equiv)
+
toluene (0.03 M)
–60 ˚C, 15 h
Ph
Ph
Me
Ph
2a
4a
2a
racemate
Conv
/%b)
¹
¹
Entry
Base
Er of 4ac) Er of 2ac)
Sd)
1
2
3
4
5
6
7
8
none
Et3N
i-PrEtN
pyridine
KOAc
K3PO4
K2CO3
Cs2CO3
29
44
88:12
86:14
88:12
84:16
88:12
88:12
88:12
84:16
65.5:34.5
78:22
71:29
70:30
66.5:33.5
72:28
10.3
10.7
11.0
7.9
10.5
11.4
10.6
11.4
36
37
30
37
31
53
67:33
88:12
a) Reactions were performed on a 0.10 mmol scale under an
argon atmosphere. b) Conversions were calculated from the
enantioselectivity of the substrate and product. c) Enantio-
selectivities were determined by HPLC analysis. d) S-factors
were calculated by Kagan’s equation.52
the optimal conditions were considered to be 5 mol % of cata-
lyst 1d, 0.75 equiv of isobutyric anhydride, and 0.75 equiv of
cesium carbonate in diethylether (0.03 M) at ¹60 °C for 15 h
(Entry 8).
We next investigated the substrate scope of the reaction
system using various secondary carbinols (secondary alcohol)
under the optimized conditions (Figure 2). The reactions of
carbinols 2a-2d with aryl alkyl substituents showed moderate
to high s-factors (s = 11.4-20.1), and steric hindrance of the
substituent strongly affected the reaction efficiency [R2 = Me
(53% conv) vs. t-Bu (14% conv)]. The effects of the substitu-
ents on the benzene ring were also investigated. While 2e and
2f with ortho- and meta-methoxy groups, respectively, gave
moderate s-factors (s = 7.1-14.8), 2g with a para-methoxy
Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan | 1083

1d (5 mol %)
(i-PrCO)2O (0.75 equiv)
Cs2CO3 (0.75 equiv)
OH
R2
OCOi-Pr
OH
R2
+
R1
R1
R2
R1
toluene (0.03 M), –60 ˚C, 15 h
2a–2n
racemate
4a–4n
2a–2n
OH
Me
OH
Me
OH
Et
OH
OH
MeO
OH
Me
OH
Cl
MeO
t-Bu
Me
MeO
2a
2b
2c
2d
2e
2f
2g
53% conv
35% conv.
14% conv.
73% conv.
18% conv.
37% conv.
61% conv.
s = 11.4
s = 20.1
s = 14.8
s = 15.4
s = 7.1
s = 14.8
s = 29.8
OH
Me
OH
Me
OH
Me
Me OH
Me
Me
OH
Me
OH
OH
Me
F3C
OHC
Me
2h
2i
2j
2k
2l
2m
2n
44% conv.
47% conv.
18% conv.
40% conv
35% conv
11% conv.
18% conv.
s = 22.8
s = 7.1
s = 10.7
s = 79.5
s = 19.0
s = 2.6
s = 5.5
OH
OH
OH
OH
Me
OH
Ph
OH
OBz
Ph
F3C
F3C
OMe
MeO
2r
2s
2t
2o
2p
2q
10% conv
s = 2.1
37% conv
s = 1.6
4% conv
s = 1.0
45% conv
s = 4.2
45% conv
s = 2.2
52% conv.
s = 1.9
Figure 2. Substrate scopea)-d). a) Reactions were performed on a 0.10 mmol scale under an argon atmosphere. b) Conversions were
calculated from the enantioselectivity of the substrate and product. c) Enantioselectivities were determined by HPLC analysis.
d) S-factors were calculated by Kagan’s equation.52
1d or 1d´ (5 mol %)
(i-PrCO)2O (0.75 equiv)
Cs2CO3 (0.75 equiv)
group showed a high s-factor (s = 29.8). In addition, an
electron-withdrawing group on the aryl ring of alcohols did
OH
Me
OCH2Oi-Pr
OH
Me
not significantly decrease the s-factors (2g, s = 29.8 vs. 2h,
s = 22.8). 2i with a para-formyl group can be used without a
loss of functionality under these conditions with a moderate s-
factor (s = 7.1). 2j-2l with sterically demanding substituents,
i.e., mesityl, 2-naphthyl, and 1-naphthyl group, gave moderate
to excellent s-factors (s = 10.7-79.5), while 9-anthryl alcohol
derivative 2m showed a somewhat low s-factor (s = 2.6). To
our great surprise, this reaction system could resolve alcohols
with different aryl substituents 2n-2q in moderate selectivity
(s = 1.9-5.5, respectively) (for selected examples of the syn-
thesis of these compounds by enantioselective addition to alde-
hyde, see Refs 53-57; for selected examples of the synthesis of
these compounds by enantioselective reduction, see Refs 58-
60). To the best of our knowledge, these alcohols have never
been subjected to acylative kinetic resolution with chiral
DMAP or PPY derivatives, probably due to the electrostatic
recognition ability of the catalyst. Unfortunately, the current
reaction system did not give good results except benzylic
alcohols. For example, propargylic alcohol 2r, cyclic alcohols
2s, and 2t resulted in decreased level of conversion with poor
s-factor. In order to solve these issues, a new class of catalysts
suitable for such substrates would be required.
+
Et2O (0.03 M)
–60 ˚C, 15 h
Ph
Ph
Me
Ph
2a
racemate
4a
2a
Ar
Ar
OMe
Ar
Ar
OH
N
N
N
N
OMe
Ar
OH
Ar
Ar
Ar
Ar = 4-t-Bu-C6H4
Ar = 4-t-Bu-C6H4
1d´
1d
49% conv, s = 1.1
53% conv, s = 11.4
Scheme 1. Enantioselectivities with 1d vs. 1d¤.
or bis-methyl ether 1d¤ (where we could neglect the effect
of hydrogen bonding) at ¹60 °C for 15 h (optimal conditions)
proceeded smoothly to give 4a along with unreacted 2a
(Scheme 1). Surprisingly, catalyst 1d gave much a higher s-
factor than 1d¤ despite their nearly identical catalyst structures
(s = 11.4 with 1d, s = 1.1 with 1d¤). These results strongly
suggested that one enantiotopic face of carbinol was recognized
due to not only the steric factors of the 3,3¤-substituents of the
catalyst but also to the electrostatic interaction between the
substrate and a catalyst stemming from the hydrogen bonding
network.
We assumed that hydrogen bonding between the catalyst and
substrate was important for achieving high enantioselectivity
and catalytic activity in this reaction. Thus, we carried out
several key control experiments. The reaction with catalyst 1d
1084 | Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan

1d, 1d´ or DMAP (5 mol %)
(i-PrCO)2O (10 equiv), Cs2CO3 (3 equiv)
R
OH
OCOi-Pr
R1
O
Ar
Ar
Ar
O
O
O
Et2O (0.03 M), –60 ˚C
Ph
Me
(S)-2a
Ph
Me
R2
H
4a
H
R
H
N
N
O
OH
Ar
TS II´
Figure 4. Possible transition state II¤.
the reaction rate and the high enantioselectivity. Although the
mechanism of acceleration is not yet clear, we speculate that
several experimental results, such as the effect of the leaving
¹
¹
group of the acylation reagent ( OAc vs. Cl), the effect of
hydrogen bonding in enantioselectivity (solvent screening), the
effect of base (base screening) and kinetic studies are more
likely to support TS II (Figure 1). In addition, considering the
high enantioselectivity with isobutyric anhydride, TS II¤ (two
hydrogen bondings between the carboxylate anion and both
the ortho-position hydrogen of the pyridine moiety and the
hydroxy group of the catalyst) might be more presumable
according to Spivey,62 Zipse,11 and Kawabata’s explana-
tions63,64 (Figure 4).
Time/min
Figure 3. Kinetic profiles with 1d, 1d¤, and DMAP pseudo-
first-order conditions.
Kinetic experiments were also carried out using (S)-1-
phenylethanol, which is a fast-reacting enantiomer in this
reaction, as a substrate. The reactions were carried out under
pseudo-first-order conditions with 5 mol % of catalyst 1d, 1d¤
or DMAP, 10 equiv of isobutyric anhydride, and 3 equiv of
cesium carbonate in diethylether (0.03 M) at ¹60 °C (Figure 3).
Catalyst 1d showed higher activity than 1d¤ (k1d = 1.5 © 102
min¹1, k1d¤ = 9.1 © 103 min¹1, and k1d/k1d¤ = 1.6). We sur-
mised that the rate acceleration was caused by the appropri-
ate arrangement of carboxylate anion in the transition state61
through hydrogen bonding, to stabilize the transition state.
According to the kinetic experiments and studies of the leaving
We expect that catalyst 1d may be useful in other important
enantioselective transformations, and further investigations in
our laboratory are now underway.
Experimental
General.
Nuclear Magnetic Resonance (NMR) spectra
were recorded on Varian 600 MR (1H 600 MHz, 13C 150
MHz), Varian 400 MR (1H 400 MHz, 13C 100 MHz) and JEOL
ECS-400 (1H 400 MHz, 13C 100 MHz) spectrometers. Chemi-
¹
groups of the acylation reagent (Table 2; Entry 1 vs. 2; OAc
vs. Cl), hydrogen bonding between a tert-alcohol unit and a
carboxylate anion brought about high enantioselectivity and
accelerated the rate of the reaction. Interestingly, 1d bearing a
¹
1
cal shifts for H NMR are reported in parts per million (ppm)
relative to residual CHCl3 in CDCl3 (¤ 7.26 ppm). Data are
reported as follows: chemical shift, multiplicity (s: singlet, d:
doublet, t: triplet, q: quartet, quin: quintet, sext: sextet, sep:
septet, b: broad, m: multiplet), coupling constants, and inte-
gration. Chemical shifts for 13C NMR were reported in parts
per million (ppm) relative to CDCl3 (¤ 77.16 ppm) with com-
plete proton decoupling. Infrared (IR) spectra were recorded on
a JASCO FT/IR-4100 spectrophotometer and Vmax is given in
cm¹1. High-resolution mass spectrometry was performed on a
JEOL JMS-700 MStation (FAB-MS and EI-MS), or Agilent
6520 Accurate Mass Q-TOF LC/MS (ESI-MS). Optical rota-
tions were measured on a JASCO DIP-1000. Melting points
were recorded on a SANSYO SMP-300. Enantiomeric ratios
were determined by analytical liquid chromatography (HPLC)
on a Shimadzu chromatograph (DICEL CHIRALPAKμ AS-3
(4.6 © 150 mm), DICEL CHIRALPAKμ AD-H (4.6 © 250
mm), DICEL CHIRALCEL OJ-H (4.6 © 250 mm) and DICEL
CHIRALCELμ OD-H (4.6 © 250 mm)) with comparison to
authentic racemic materials. Column chromatography was
performed with silica gel 60 N (spherical, neutral, 40-50 ¯m)
purchased from Kanto Chemical. All experiments were carried
out under an argon atmosphere unless otherwise noted.
relatively sterically hindered moiety accelerated the reaction
¹1
more than DMAP (kDMAP = 6.3 © 103 min and k1d/kDMAP
=
2.4). The catalytic activity of 1d¤ was also higher than that
of DMAP, although the substituents of 1d¤ are hindered much
more than those of DMAP. The reasons for this observation are
not yet clear, and more detailed experiments will be needed to
elucidate these acceleration effects.
Conclusion
In summary, we have developed a kinetic resolution of
secondary carbinols with chiral DMAP derivatives having
hydrogen bonding substituents. Catalyst 1d offers moderate to
excellent s-factors (up to s = 79.5) with broad substrate gener-
ality. In addition, this catalyst system could resolve alcohols
with two different aryl groups 2n-2q in moderate enantio-
selectivities (s = 2.2-5.5), which has never been reported in
acylative kinetic resolution. According to our working hypoth-
esis (Figure 1), we proposed that tert-alcohols of the catalyst
would acquire either a carbinol (TS I) or counteranion of N-
acylpyridinium ion (TS II), or simultaneously interact with a
carbinol and counteranion in the transition state (TS III).
The results of kinetic studies strongly support the notion that
hydroxy groups of 1d play an important role in acceleration of
Materials. All reagents were obtained commercially and
used as received unless otherwise noted. CH2Cl2, toluene, and
Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan | 1085

Et3N were distilled over CaH2. Dry tetrahydrofuran [THF]
and dry Et2O were purchased from Wako Pure Chemical
Industries and used without further purification. Dry dimethyl-
formamide [DMF], («)-2,2-dimethyl-1-phenyl-1-propanol
(2c), and («)-4-phenyl-3-butyn-2-ol (2r) were purchased from
Sigma-ALDRICH Japan and used without further purifica-
tion. («)-1-Phenylethanol (2a) was purchased from KANTO
CHEMICAL CO., INC. and used without further purifica-
tion. («)-1-(2-Naphthyl)ethanol (2k) and («)-2-phenylcyclo-
hexan-1-ol (2s) were purchased from Tokyo Chemical Industry
Co., Ltd. and used without further purification. Other alcohols
were synthesized by NaBH4 reduction of the corresponding
ketones and the nucleophilic addition of organolithium rea-
gents or Grignard reagents to the corresponding aldehydes.
trans-2-Hydroxycyclohexyl benzoate (2t) was synthesized by
general benzoylation of trans-1,2-cyclohexanediol purchased
from Sigma-ALDRICH Japan.
Procedure and Analytical Data. General Procedure for
the Acylative Kinetic Resolution of Carbinols: To a solu-
tion of substrate 2a-2t (0.100 mmol), Cs2CO3 (24.4 mg, 75.0
¯mol) and catalyst 1d (4.8 mg, 5.00 ¯mol) in Et2O (3.00 mL)
was added isobutyric anhydride (12.4 ¯L, 75.0 ¯mol) at
¹60 °C. The reaction mixture was stirred for 15 h at ¹60 °C.
MeOH (2 mL) was then added to destroy unreacted isobutyric
anhydride and the mixture was stirred for 30 min as it warmed
to room temperature. The resulting solution was concentrated
in vacuo. The resulting mixture was passed through a short pad
of silica gel (eluent: hexane/Et2O = 1/1, v/v) to give the ester
product and the unreacted alcohol, which were directly ana-
lyzed by chiral HPLC. The enantiomeric ratio (er) and enantio-
meric excess (ee) values of the ester and the unreacted alcohol
were obtained by HPLC analysis. The conversion (C) and s-
factor (s) of kinetic resolution were calculated as follows:52
¤ 176.4, 142.1, 128.6, 127.8, 126.0, 72.0, 34.2, 22.4, 19.0; IR
(KBr) 3034, 2978, 2934, 2876, 1732, 1454, 1192, 1157, 1065,
22
760, 698 cm¹1; ½ꢀꢁD ¹29.7 (c 1.09, CHCl3, 81:19 er).
(R)-1-Phenyl-1-propanol (2b):67
Colorless liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 98/2, v/v, flow
rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 13.5 min
(major) and tR = 14.6 min (minor), 72.5:27.5 er; 1H NMR (400
MHz, CDCl3) ¤ 7.39-7.22 (m, 5H), 4.61 (t, J = 6.6 Hz, 1H),
1.90-1.54 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (100
MHz, CDCl3) ¤ 144.7, 128.5, 127.6, 126.1, 76.1, 31.9, 10.2; IR
(KBr) 3389, 3063, 3028, 2965, 2932, 2876, 1493, 1454, 1202,
24
974, 764, 700 cm¹1; ½ꢀꢁD +4.54 (c 1.03, CHCl3, 72.5:27.5 er)
20
[lit.68 ½ꢀꢁD +45.9 (c 2.0, CHCl3, 94% ee, (R) form)].
(S)-1-Phenylpropyl Isobutyrate (4b): Pale yellow liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OJ-H (hexane/i-PrOH = 99.9/0.1, v/v, flow
¹1
rate = 1.00 mL min , 30 °C, UV = 254 nm), tR = 6.3 min
(minor) and tR = 8.1 min (major), 93:7 er; 1H NMR (400
MHz, CDCl3) ¤ 7.38-7.21 (m, 5H), 5.65 (t, J = 7.0 Hz, 1H),
2.57 (m, 1H), 1.99-1.72 (m, 2H), 1.18 (d, J = 7.6 Hz, 3H), 1.14
(d, J = 7.6 Hz, 3H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (100
MHz, CDCl3) ¤ 176.5, 141.0, 128.5, 127.8, 126.5, 77.0, 34.3,
29.6, 19.1, 19.0, 10.0; IR (KBr) 2972, 2936, 2878, 1734, 1470,
1456, 1192, 1155, 754, 700 cm¹1; HRMS (FAB+) calculated
21
for C13H19O2 [M+H]+ 207.1379, found 207.1365; ½ꢀꢁD ¹17.4
(c 0.22, CHCl3, 93:7 er).
(R)-2,2-Dimethyl-1-phenyl-1-propanol (2c):
Colorless
solid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OD-H (hexane/i-PrOH = 98/2, v/v,
flow rate = 0.900 mL min¹1, 30 °C, UV = 254 nm), tR = 10.6
min (minor) and tR = 15.9 min (major), 57:43 er; 1H NMR
(400 MHz, CDCl3) ¤ 7.36-7.22 (m, 5H), 4.40 (s, 1H), 1.80 (bs,
0.7H), 0.94 (s, 9H); 13C NMR (100 MHz, CDCl3) ¤ 142.3,
127.7, 127.4, 82.6, 35.7, 26.1; IR (KBr) 3420, 3032, 2995,
ln½1 ꢀ Cð1 þ ee0Þꢁ ln½ð1 ꢀ CÞð1 ꢀ eeÞꢁ
kfast
ln½1 ꢀ Cð1 ꢀ ee0Þꢁ ln½ð1 ꢀ CÞð1 þ eeÞꢁ kslow
s ¼
¼
¼
ð2Þ
22
2955, 2868, 1452, 1005, 899, 735, 702, 648 cm¹1; ½ꢀꢁD +6.3
ee ¼ enantiomeric excess measured for the starting material
20
(c 0.19, CHCl3, 57:43 er) [lit.69 ½ꢀꢁD +19.2 (c 0.48, CHCl3,
ð3Þ
ð4Þ
ð5Þ
99% ee, (R) form)].
ee0 ¼ enantiomeric excess measured for the product
(S)-2,2-Dimethyl-1-phenylpropyl Isobutyrate (4c): Col-
orless liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OD-H (hexane/i-PrOH = 99.9/0.1,
v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR =
ee
C ¼
0 100 ¼ conversion
ee þ ee
(R)-1-Phenylethanol (2a): Colorless liquid. Enantiomeric
ratio was determined by HPLC with DICEL CHIRALCELμ OJ-
H (hexane/i-PrOH = 99/1, v/v, flow rate = 0.500 mL min
1
6.6 min (minor) and tR = 10.2 min (major), 93:7 er; H NMR
¹1
,
(400 MHz, CDCl3) ¤ 7.32-7.20 (m, 5H), 5.47 (s, 1H), 2.61 (sep,
J = 7.1 Hz, 1H), 1.20 (d, J = 7.1 Hz, 3H), 1.18 (d, J = 7.1 Hz,
3H), 0.93 (s, 9H); 13C NMR (100 MHz, CDCl3) ¤ 176.0, 138.7,
30 °C, UV = 254 nm), tR = 57.6 min (minor) and tR = 61.4 min
(major), 88:12 er; 1H NMR (400 MHz, CDCl3) ¤ 7.42-7.30
(m, 4H), 7.30-7.21 (m, 1H), 4.91 (q, J = 6.5 Hz, 1H), 1.51 (d,
J = 6.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 145.9, 128.5,
127.5, 125.5, 70.4, 25.2; IR (KBr) 3354, 2974, 1454, 1282, 899,
127.8, 127.7, 127.5, 82.5, 35.3, 34.5, 26.2, 19.1, 19.0; IR (KBr)
¹1
2972, 2909, 2874, 1736, 1470, 1192, 1155, 735, 702 cm
;
HRMS (FAB+) calculated for C15H23O2 [M+H]+ 235.1692,
20
22
760, 698 cm¹1; ½ꢀꢁD +12.4 (c 0.49, CHCl3, 68:32 er) [lit.65
found 235.1699; ½ꢀꢁD ¹5.8 (c 0.13, CHCl3, 93:7 er).
20
½ꢀꢁD +27.0 (c 0.270, CHCl3, 38% ee, (R) form)].
(S)-2-Chloro-1-phenylethanol (2d):70 Pale yellow liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OJ-H (hexane/i-PrOH = 93/7, v/v, flow
rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 15.7 min
(S)-1-Phenylethyl Isobutyrate (4a):66 Pale yellow liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OJ-H (hexane/i-PrOH = 99/1, v/v, flow rate =
0.500 mL min¹1, 30 °C, UV = 254 nm), tR = 12.1 min (minor)
and tR = 13.7 min (major), 84:16 er; 1H NMR (400 MHz,
CDCl3) ¤ 7.40-7.21 (m, 5H), 5.87 (q, J = 6.7 Hz, 1H), 2.57
(sep, J = 6.9 Hz, 1H), 1.52 (d, J = 6.7 Hz, 3H), 1.18 (d, J = 6.9
Hz, 3H), 1.16 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3)
1
(minor) and tR = 16.9 min (major), >99.9:<0.1 er; H NMR
(400 MHz, CDCl3) ¤ 7.46-7.29 (m, 5H), 4.91 (d, J = 8.9 Hz,
1H), 3.76 (dd, J = 11.2, 3.4 Hz, 1H), 3.66 (dd, J = 11.2, 8.9
Hz, 1H), 2.62 (bs, 1H); 13C NMR (100 MHz, CDCl3) ¤ 140.0,
128.8, 128.6, 126.2, 74.2, 51.0; IR (KBr) 3395, 3032, 2955,
1086 | Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan

23
2893, 1454, 1065, 770, 723, 698, 615 cm¹1; ½ꢀꢁD +18.1 (c
DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 93/7, v/v,
flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 5.2 min
(minor) and tR = 5.7 min (major), 76:24 er; 1H NMR (400
MHz, CDCl3) ¤ 7.30-7.23 (m, 1H), 6.93 (d, J = 8.2 Hz, 1H),
6.89 (s, 1H), 6.82 (dd, J = 8.2, 2.8 Hz, 1H), 5.84 (q, J = 6.5
Hz, 1H), 3.81 (s, 3H), 2.58 (sep, J = 7.1 Hz, 1H), 1.51 (d, J =
6.5 Hz, 3H), 1.22-1.21 (m, 6H); 13C NMR (100 MHz, CDCl3)
¤ 176.4, 159.8, 143.8, 129.7, 118.3, 113.1, 111.8, 71.9, 55.3,
34.3, 22.6, 19.1; IR (KBr) 2978, 2936, 1732, 1470, 1157, 1063,
1049, 781, 698 cm¹1; HRMS (ESI+) calculated for C13H18O3
27
0.05, CHCl3, >99.9:<0.1 er) [lit.71 ½ꢀꢁD +38.5 (c 0.90,
CHCl3, 81% ee, (S) form)].
(R)-2-Chloro-1-phenylethyl Isobutyrate (4d):
Pale
yellow liquid. Enantiomeric ratio was determined by HPLC
with DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 99.3/
0.7, v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm),
tR = 7.8 min (minor) and tR = 10.4 min (major), 68:32 er;
1H NMR (400 MHz, CDCl3) ¤ 7.43-7.27 (m, 5H), 5.96 (dd,
J = 8.2, 4.6 Hz, 1H), 3.85-3.67 (m, 2H), 2.65 (sep, J = 7.1
Hz, 1H), 1.23 (d, J = 7.1 Hz, 3H), 1.19 (d, J = 7.1 Hz, 3H);
13C NMR (100 MHz, CDCl3) ¤ 176.1, 137.5, 128.9, 128.8,
126.7, 74.8, 46.9, 34.2, 19.1, 19.0; IR (KBr) 2976, 2936,
2878, 1742, 1470, 1456, 1188, 1150, 729, 698 cm¹1; HRMS
(FAB+) calculated for C12H16ClO2 [M+H]+ 227.0833, found
21
[M+H]+ 223.1329, found 223.1322; ½ꢀꢁD ¹17.9 (c 0.36,
CHCl3, 76:24 er).
(R)-1-(4-Methoxyphenyl)ethanol (2g):67 Colorless liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 98/2, v/v, flow
rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 20.9 min
24
227.0816; ½ꢀꢁD ¹6.0 (c 0.38, CHCl3, 68:32 er).
(R)-1-(2-Methoxyphenyl)ethanol (2e):72 Colorless solid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 98/2, v/v, flow
rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 16.7 min
(minor) and tR = 18.2 min (major), 58:42 er; 1H NMR (400
MHz, CDCl3) ¤ 7.34 (dd, J = 7.7, 1.4 Hz, 1H), 7.29-7.22 (m,
1H), 6.97 (t, J = 7.7 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 5.10 (q,
J = 6.5 Hz, 1H), 3.87 (s, 3H), 1.94 (bs, 1H), 1.51 (d, J = 6.5
Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 156.4, 133.6, 128.2,
126.0, 120.7, 110.3, 66.1, 55.2, 23.0; IR (KBr) 3312, 3007,
2967, 2913, 2835, 1601, 1587, 1281, 1234, 1074, 1026, 1007,
(major) and tR = 24.8 min (minor), >99.9:<0.1 er; H NMR
1
(400 MHz, CDCl3) ¤ 7.31 (d, J = 8.6 Hz, 2H), 6.89 (d, J =
8.6 Hz, 2H), 4.87 (q, J = 6.4 Hz, 1H), 3.81 (s, 3H), 1.48 (d,
J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 159.0, 138.1,
126.7, 113.9, 70.0, 55.4, 25.1; IR (KBr) 3441, 2972, 2930,
22
2835, 1612, 1514, 1246, 1175, 1036, 831, 810 cm¹1; ½ꢀꢁD
25
+7.56 (c 0.09, CHCl3, 99.9:0.1 er) [lit.75 ½ꢀꢁD +53.5 (c 1.7,
CHCl3, 94% ee, (R) form)].
(S)-1-(4-Methoxyphenyl)ethyl Isobutyrate (4g): Color-
less liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 99.9/0.1, v/v,
flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 15.2
min (minor) and tR = 18.0 min (major), 82:18 er; 1H NMR
(400 MHz, CDCl3) ¤ 7.28 (dd, J = 6.6, 1.8 Hz, 2H), 6.87 (dd,
J = 6.6, 1.8 Hz, 2H), 5.84 (q, J = 6.5 Hz, 1H), 3.80 (s, 3H),
2.54 (sep, J = 7.1 Hz, 1H), 1.51 (d, J = 6.5 Hz, 3H), 1.16 (d,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 176.5, 159.3,
134.2, 127.5, 113.9, 71.7, 55.4, 34.3, 22.2, 19.1, 19.0; IR (KBr)
2972, 2936, 2837, 1732, 1514, 1470, 1034, 970, 833, 698
cm¹1; HRMS (FAB+) calculated for C13H19O3 [M+H]+
22
897, 748, 733 cm¹1; ½ꢀꢁD +6.6 (c 0.29, CHCl3, 58:42 er) [lit.73
25
½ꢀꢁD +18.5 (c 1.0, CHCl3, 50% ee, (R) form)].
(S)-1-(2-Methoxyphenyl)ethyl Isobutyrate (4e): Color-
less liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OD-H (hexane/i-PrOH = 98/2, v/v,
flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 4.6 min
(minor) and tR = 5.2 min (major), 86:14 er; 1H NMR (400
MHz, CDCl3) ¤ 7.36 (d, J = 7.6 Hz, 1H), 7.30-7.19 (m, 2H),
6.96 (t, J = 7.6 Hz, 1H), 6.87 (d, J = 7.6 Hz, 1H), 6.22 (q, J =
6.8 Hz, 1H), 3.84 (s, 3H), 2.59 (qd, J = 6.9, 1.5 Hz, 1H), 1.47
(dd, J = 6.8, 1.6 Hz, 3H), 2.42 (dd, J = 6.9, 1.5 Hz, 3H), 1.18
(dd, J = 6.9, 1.5 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤
176.3, 156.1, 130.8, 128.6, 125.8, 120.7, 110.6, 66.9, 55.5,
34.3, 21.3, 19.1, 19.1; IR (KBr) 2976, 2936, 1734, 1495, 1466,
12346, 1192, 1157, 1065, 754 cm¹1; HRMS (FAB+) calculated
21
222.1250, found 222.1275; ½ꢀꢁD ¹10.6 (c 0.52, CHCl3,
82:18 er).
(R)-1-(4-(Trifluoromethyl)phenyl)ethanol (2h):76 Color-
less liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 95/5, v/v,
flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 7.3 min
(minor) and tR = 7.8 min (major), 83:17 er; 1H NMR (400
MHz, CDCl3) ¤ 7.61 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.6 Hz,
2H), 4.98 (q, J = 6.4 Hz, 1H), 1.85 (bs, 0.8H), 1.51 (d, J =
6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 149.8, 129.7 (q,
J = 32.1 Hz), 125.8, 125.6, 124.2 (q, J = 271.1 Hz), 69.2, 25.5;
IR (KBr) 3352, 2978, 1622, 1415, 1327, 1165, 1126, 1090,
21
for C13H19O3 [M+H]+ 222.1250, found 222.1250; ½ꢀꢁD +13.3
(c 0.12, CHCl3, 86:14 er).
(R)-1-(3-Methoxyphenyl)ethanol (2f):74
Pale yellow
liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 93/7, v/v,
flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 11.9
min (minor) and tR = 13.1 min (major), 65:35 er; 1H NMR (400
MHz, CDCl3) ¤ 7.31-7.24 (m, 1H), 6.98-6.91 (m, 2H), 6.82
(dd, J = 7.8, 2.2 Hz, 1H), 4.88 (q, J = 6.5 Hz, 1H), 3.82 (s,
3H), 1.69 (bs, 1H), 1.50 (d, J = 6.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) ¤ 159.8, 147.7, 129.6, 117.8, 112.9, 111.0,
70.3, 55.3, 25.2; IR (KBr) 3395, 2972, 2930, 2835, 1603, 1585,
21
1069, 843 cm¹1; ½ꢀꢁD +33.0 (c 0.075, CHCl3, 83:17 er) [lit.77
20
½ꢀꢁD +34.9 (c 1.0, CHCl3, 94% ee, (R) form)].
(S)-1-(4-(Trifluoromethyl)phenyl)ethyl Isobutyrate (4h):
Colorless liquid. Enantiomeric ratio was determined by HPLC
with DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 99.9/
0.1, v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm),
tR = 6.3 min (major) and tR = 6.9 min (minor), 92:8 er;
1H NMR (400 MHz, CDCl3) ¤ 7.61 (d, J = 8.2 Hz, 2H), 7.45
(d, J = 8.2 Hz, 2H), 5.89 (q, J = 6.5 Hz, 1H), 2.59 (sep,
J = 6.8 Hz, 1H), 1.53 (d, J = 6.8 Hz, 3H), 1.23-1.12 (m, 6H);
13C NMR (150 MHz, CDCl3) ¤ 183.0, 176.3, 146.1, 130.1 (q,
21
1258, 1157, 1045, 856, 785, 700 cm¹1; ½ꢀꢁD +9.5 (c 0.44,
25
CHCl3, 65:35 er) [lit.75 ½ꢀꢁD +51.2 (c 1.0, CHCl3, 96% ee, (R)
form)].
(S)-1-(3-Methoxyphenyl)ethyl Isobutyrate (4f): Color-
less liquid. Enantiomeric ratio was determined by HPLC with
Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan | 1087

J = 32.6 Hz), 126.9, 125.7 (q, J = 3.6 Hz), 124.2 (q, J = 270.6
Hz), 71.4, 34.2, 33.9, 22.5, 19.0, 19.0; IR (KBr) 2980, 2938,
2879, 1738, 1327, 1159, 1126, 1070, 841 cm¹1; HRMS (FAB+)
calculated for C13H16F3O2 [M+H]+ 261.1096, found 261.1125;
(minor) and tR = 52.7min (major), 84:16 er; 1HNMR (400MHz,
CDCl3) ¤ 7.96-7.77 (m, 4H), 7.56-7.41 (m, 3H), 5.09 (q, J =
6.4 Hz, 1H), 1.80-1.53 (m, over rap with water); 13C NMR (100
MHz, CDCl3) ¤ 143.3, 133.5, 133.1, 128.5, 128.1, 127.8, 126.3,
125.9, 123.9, 70.7, 25.3; IR (KBr) 3323, 3053, 2970, 2880,
21
½ꢀꢁD ¹32.6 (c 0.185, CHCl3, 92:8 er).
22
(R)-4-(1-Hydroxyethyl)benzaldehyde (2i):78 Pale yellow
green liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALPAKμ AS-3 (hexane/i-PrOH = 90/10, v/v,
flow rate = 1.000 mL min¹1, 30 °C, UV = 254 nm), tR = 16.4
min (major) and tR = 21.4 min (minor), 77:23 er; 1H NMR (400
MHz, CDCl3) ¤ 10.0 (s, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.55 (d,
J = 8.0 Hz, 2H), 5.00 (q, J = 6.6 Hz, 1H), 1.86 (bs, 1H), 1.52
(d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 192.3,
153.1, 135.3, 130.0, 125.9, 69.6, 25.2; IR (KBr) 3458, 1694,
1599, 1364, 1275, 826, 743 cm¹1; ½ꢀꢁD +14.7 (c 0.35, CHCl3,
20
84:16 er) [lit.77 ½ꢀꢁD +60.4 (c 1.0, CHCl3, 97% ee, (R) form)].
(S)-1-(2-Naphthyl)ethyl Isobutyrate (4k): Pale yellow
liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 95/5, v/v,
flow rate = 0.600 mL min¹1, 30 °C, UV = 254 nm), tR = 11.6
1
min (minor) and tR = 12.6 min (major), 98:2 er; H NMR (400
MHz, CDCl3) ¤ 7.89-7.78 (m, 4H), 7.52-7.45 (m, 3H), 6.04 (q,
J = 6.5 Hz, 1H), 2.60 (sep, J = 6.9 Hz, 1H), 1.61 (d, J = 6.5
Hz, 3H), 1.24-1.15 (m, 6H); 13C NMR (100 MHz, CDCl3) ¤
176.5, 139.4, 133.3, 133.1, 128.5, 128.1, 127.8, 126.3, 126.1,
125.0, 124.2, 72.2, 34.3, 22.4, 19.1; IR (KBr) 2976, 1934,
1732, 1470, 1387, 1155, 1063, 818, 748 cm¹1; HRMS (FAB+)
calculated for C16H19O2 [M+H]+ 243.1379, found 243.1349;
22
1607, 1090, 899, 831, 748 cm¹1; ½ꢀꢁD ¹13.6 (c 0.480, CHCl3,
26
77:23 er) [lit.78 ½ꢀꢁD +34.8 (c 0.979, CHCl3, 90% ee, (R)
form)].
(S)-1-(4-Formylphenyl)ethyl Isobutyrate (4i):
Pale
yellow liquid. Enantiomeric ratio was determined by HPLC
with DICEL CHIRALPAKμ AS-3 (hexane/i-PrOH = 90/10,
v/v, flow rate = 1.000 mL min¹1, 30 °C, UV = 254 nm), tR =
24
½ꢀꢁD ¹31.7 (c 0.33, CHCl3, 98:2 er).
(R)-1-(1-Naphthyl)ethanol (2l):62
Colorless solid.
1
4.5 min (minor) and tR = 5.0 min (major), 81:19 er; H NMR
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 90/10, v/v, flow
rate = 0.300 mL min¹1, 30 °C, UV = 254 nm), tR = 31.3 min
(minor) and tR = 46.1 min (major), 73:27 er; 1H NMR (400
MHz, CDCl3) ¤ 8.13 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.4 Hz,
1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 7.4 Hz, 1H), 7.60-
7.46 (m, 3H), 5.70 (q, J = 6.4 Hz, 1H), 1.89 (bs, 0.6H), 1.69 (d,
J = 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 141.5, 133.9,
130.4, 129.0, 128.0, 126.1, 125.6, 123.3, 122.1, 67.2, 24.5; IR
(400 MHz, CDCl3) ¤ 10.0 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H),
7.50 (d, J = 8.2 Hz, 2H), 5.90 (q, J = 7.0 Hz, 1H), 2.60 (sep,
J = 7.1 Hz, 1H), 1.54 (d, J = 7.0 Hz, 3H), 1.19 (d, J = 7.1 Hz,
3H), 1.71 (d, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤
192.0, 176.3, 149.0, 136.0, 130.2, 126.5, 71.5, 34.2, 22.4, 19.0
(2); IR (KBr) 2976, 2936, 2876, 1732, 1697, 1611, 1470, 1209,
1192, 1157, 1066, 1007, 829 cm¹1; HRMS (FAB+) calculated
24
for C13H17O3 [M+H]+ 221.1172, found 221.1161; ½ꢀꢁD ¹13.5
20
(c 1.04, CHCl3, 81:19 er).
(KBr) 3200, 2976, 2903, 1595, 1229, 899, 802, 775 cm¹1; ½ꢀꢁD
25
+32.5 (c 0.47, CHCl3, 73:27 er) [lit.75 ½ꢀꢁD +43.6 (c 1.0,
(R)-1-Mesitylethanol (2j):79 Colorless solid. Enantiomeric
ratio was determined by HPLC with DICEL CHIRALPAKμ
AD-H (hexane/i-PrOH = 99/1, v/v, flow rate = 0.800
mL min¹1, 30 °C, UV = 254 nm), tR = 20.4 min (major) and
CHCl3, 60% ee, (R) form)].
(S)-1-(1-Naphthyl)ethyl Isobutyrate (4l):62 Yellow liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 90/10, v/v, flow
rate = 0.300 mL min¹1, 30 °C, UV = 254 nm), tR = 13.5 min
(minor) and tR = 14.8 min (major), 92:8 er; 1H NMR (400
MHz, CDCl3) ¤ 8.08 (d, J = 8.6 Hz, 1H), 7.87 (d, J = 8.0 Hz,
1H), 7.80 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.57-
7.45 (m, 3H), 6.64 (q, J = 6.4 Hz, 1H), 2.62 (sep, J = 7.3 Hz,
1H), 1.70 (d, J = 6.4 Hz, 3H), 1.21 (d, J = 7.3 Hz, 3H), 1.18 (d,
J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, 40 °C) ¤ 176.4,
137.9, 134.1, 130.5, 129.0, 128.5, 126.3, 125.8, 125.5, 123.4,
123.3, 69.4, 34.4, 21.8, 19.1, 18.9; IR (KBr) 2976, 2934, 1732,
1
tR = 24.5 min (minor), 59:41 er; H NMR (400 MHz, CDCl3)
¤ 6.82 (s, 2H), 5.37 (q, J = 7.0 Hz, 1H), 2.42 (s, 6H), 2.25 (s,
3H), 1.53 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3)
¤ 137.7, 136.3, 135.6, 130.1, 67.3, 21.5, 20.7, 20.5; IR (KBr)
¹1
3232, 2986, 2920, 1611, 1447, 1364, 1211, 895, 851 cm
;
23
25
½ꢀꢁD +27.5 (c 0.090, CH2Cl2, 59:41 er) [lit.80 ½ꢀꢁD +52.5 (c
1.1, CHCl3, 50% ee, (R) form)].
(S)-1-Mesitylethyl Isobutyrate (4j): Pale yellow liquid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALPAKμ AD-H (hexane/i-PrOH = 99.9/0.1, v/v, flow
¹1
21
rate = 1.00 mL min
,
30 °C, UV = 254 nm), tR = 4.5 min
1470, 1387, 1157, 1069, 800, 777 cm¹1; ½ꢀꢁD ¹17.2 (c 0.41,
(minor) and tR = 5.0 min (major), 90:10 er; 1H NMR (400
MHz, CDCl3) ¤ 6.82 (s, 2H), 6.26 (q, J = 6.9 Hz, 1H), 2.55
(sep, J = 7.0 Hz, 1H), 2.51 (s, 6H), 2.24 (s, 3H), 1.54 (d, J =
5.6 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 1.13 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) ¤ 176.5, 137.0, 136.1, 134.6,
CHCl3, 92:7 er).
(R)-1-(9-Anthryl)ethanol (2m):72
Yellow solid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALPAKμ AD-H (hexane/i-PrOH = 96/4, v/v, flow
rate = 0.800 mL min¹1, 30 °C, UV = 254 nm), tR = 31.9 min
(major) and tR = 46.9 min (minor), 52.5:47.5 er; 1H NMR (400
MHz, CDCl3, 50 °C) ¤ 8.67 (d, J = 8.4 Hz, 2H), 8.39 (s, 1H),
8.00 (d, J = 8.6 Hz, 2H), 7.56-7.40 (m, 4H), 6.46 (q, J = 6.8
Hz, 1H), 1.92 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3,
130.1, 69.4, 34.3, 20.9, 20.6, 19.7, 19.2, 18.9; IR (KBr) 2974,
¹1
2934, 2874, 1732, 1470, 1371, 1194, 1155, 1061, 851 cm
;
HRMS (FAB+) calculated for C15H23O2 [M+H]+ 235.1692,
22
found 235.1702; ½ꢀꢁD +11.1 (c 0.095, CHCl3, 90:10 er).
(R)-1-(2-Naphthyl)ethanol (2k):
Colorless solid.
50 °C) ¤ 135.8, 131.7, 129.4, 128.8, 127.9, 125.5, 124.8, 67.2,
¹1
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OJ-H (hexane/i-PrOH = 95/5, v/v, flow
rate = 0.600 mL min¹1, 30 °C, UV = 254 nm), tR = 40.8 min
23.4; IR (KBr) 3290, 2968, 1622, 1115, 889, 791, 729 cm ;
24
½ꢀꢁD +1.76 (c 0.825, CHCl3, 52.5:47.5 er) [lit.81 [α]D +18.5
(c 1, CHCl3, >99% ee, (R) form)].
1088 | Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan

¹1
(S)-1-(9-Anthryl)ethyl Isobutyrate (4m):72 Orange solid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALPAKμ AD-H (hexane/i-PrOH = 96/4, v/v, flow
rate = 0.800 mL min¹1, 30 °C, UV = 254 nm), tR = 5.7 min
(minor) and tR = 7.2 min (major), 71:29 er; 1H NMR (400
MHz, CDCl3) ¤ 8.62 (bd, J = 8.0 Hz, 2H), 8.42 (s, 1H), 8.01
(d, J = 8.0 Hz, 2H), 7.57-7.37 (m, 5H), 2.69-2.55 (m, 1H),
1.94 (dd, J = 6.0, 1.6 Hz, 3H), 1.18 (dd, J = 7.1, 1.9 Hz, 3H),
1.08 (dd, J = 7.1, 2.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤
176.6, 132.5, 131.8, 129.5, 129.1, 128.5, 125.9, 124.9, 68.8,
34.3, 21.7, 19.0; IR (KBr) 2974, 2934, 1732, 1450, 1157, 1086,
IR (KBr) 2974, 2936, 1732, 1514, 1250, 1150, 833, 698 cm ;
HRMS (FAB+) calculated for C18H21O3 [M+H]+ 285.1485,
21
found 285.1457; ½ꢀꢁD ¹11.4 (c 0.64, CHCl3, 74:26 er).
(R)-Phenyl(4-(trifluoromethyl)phenyl)methanol (2p):84
Colorless solid. Enantiomeric ratio was determined by HPLC
with DICEL CHIRALCELμ OD-H (hexane/i-PrOH = 93/7,
v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR =
11.4 min (major) and tR = 12.8 min (minor), 61:39 er; 1H NMR
(400 MHz, CDCl3) ¤ 7.60 (d, J = 8.4 Hz, 2H), 7.51 (d, J =
8.4 Hz, 2H), 7.41-7.27 (m, 5H), 5.87 (s, 1H), 2.36 (bs, 1H);
13C NMR (100 MHz, CDCl3) ¤ 147.5, 143.0, 129.6 (q, J = 32.6
Hz), 128.8, 128.1, 126.7, 125.4 (m), 124.3 (q, J = 271.9 Hz),
21
1040, 731 cm¹1; ½ꢀꢁD +6.49 (c 0.55, CHCl3, 71:29 er).
17
(R)-(2-Naphthyl)phenylmethanol (2n):82 Colorless solid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 92/8, v/v, flow
rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 17.5 min
(minor) and tR = 20.3 min (major), 57:43 er; 1H NMR (400
MHz, CDCl3, 50 °C) ¤ 7.93-7.70 (m, 5H), 7.52-7.10 (m, 7H),
6.02 (s, 1H), 2.23 (bs, 0.8H); 13C NMR (100 MHz, CDCl3) ¤
143.8, 141.2, 133.4, 133.0, 128.7, 128.5, 128.2, 127.8, 126.8,
126.3, 126.1, 125.1, 124.9, 76.5; IR (KBr) 3227, 3057, 1454,
75.7; IR (KBr) 3329, 1497, 1327, 1171, 1111, 731 cm¹1; ½ꢀꢁD
20
¹9.9 (c 0.42, CHCl3, 61:39 er) [lit.84 ½ꢀꢁD = ¹19.4 (c 1.05,
CHCl3, 51% ee, (R) form)].
(S)-Phenyl(4-(trifluoromethyl)phenyl)methyl Isobutyrate
(4p): Colorless liquid. Enantiomeric ratio was determined by
HPLC with DICEL CHIRALPAKμ AD-H (hexane/i-PrOH =
99.5/0.5, v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254
nm), tR = 9.3 min (minor) and tR = 10.2 min (major), 64:36 er;
1H NMR (400 MHz, CDCl3) ¤ 7.59 (d, J = 8.4 Hz, 2H), 7.46
(d, J = 8.4 Hz, 2H), 7.40-7.24 (m, 5H), 6.88 (s, 1H), 2.69 (sep,
J = 7.0 Hz, 1H), 1.22 (d, J = 7.0 Hz, 3H), 1.22 (d, J = 7.0 Hz,
3H); 13C NMR (100 MHz, CDCl3) ¤ 175.9, 144.6, 139.7, 130.1
(q, J = 32.6 Hz), 128.8, 128.3, 127.3, 127.1, 125.6 (q, J = 3.8
Hz), 124.1 (q, J = 272.2 Hz), 76.0, 34.3, 19.0, 18.9; IR (KBr)
2976, 1738, 1470, 1327, 1150, 1126, 1113, 1067, 839, 698
cm¹1; HRMS (FAB+) calculated for C18H17F3O2Na [M + Na]+
23
1034, 1024, 816, 739, 700 cm¹1; ½ꢀꢁD ¹2.9 (c 0.62, CHCl3,
24
76.5:23.5 er) [lit.83 ½ꢀꢁD +8.6 (c 0.50, CHCl3, 92% ee, (S)
form)].
(S)-(2-Naphthyl)phenylmethyl Isobutyrate (4n): Color-
less solid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OD-H (hexane/i-PrOH = 99.5/0.5,
v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR =
1
23
9.0 min (minor) and tR = 12.1 min (major), 83:17 er; H NMR
345.1072, found 345.1054; ½ꢀꢁD +9.44 (c 0.54, CHCl3, 64:36
(400 MHz, CDCl3) ¤ 7.89-7.78 (m, 4H), 7.55-7.22 (m, 8H),
7.03 (s, 1H), 2.71 (sep, J = 7.2 Hz, 1H), 1.30-1.19 (m, 6H);
13C NMR (100 MHz, CDCl3) ¤ 176.1, 140.4, 137.9, 133.2,
133.0, 128.6, 128.5, 128.3, 128.0, 127.8, 127.2, 126.4, 126.2,
125.0, 76.8, 34.4, 19.1; IR (KBr) 176.1, 140.4, 137.9, 133.2,
133.0, 128.6, 128.5, 128.3, 128.0, 127.8, 127.2, 126.4, 126.2,
125.0, 76.8, 34.4, 19.1 cm¹1; HRMS (ESI+) calculated for
C21H20O2 [M+H]+ 305.1536, found 305.1560; mp 63.0-
er).
(4-Methoxyphenyl)(4-(trifluoromethyl)phenyl)methanol
(2q):85 Colorless solid. Enantiomeric ratio was determined by
HPLC with DICEL CHIRALPAKμ IA-3 (hexane/i-PrOH =
93/7, v/v, flow rate = 0.500 mL min¹1, 30 °C, UV = 254 nm),
tR = 15.1 min (minor) and tR = 16.0 min (major), 61:39 er;
1H NMR (400 MHz, CDCl3) ¤ 7.59 (d, J = 8.4 Hz, 2H), 7.51
(d, J = 8.4 Hz, 2H), 7.31-7.22 (m, 2H), 6.95-6.85 (m, 2H),
5.85 (s, 1H), 3.80 (s, 3H), 2.18 (bs, 1H); 13C NMR (100 MHz,
CDCl3) ¤ 159.2, 148.0, 135.4, 129.3 (q, J = 32.3 Hz), 128.1,
126.6, 125.2 (q, J = 3.8 Hz), 124.3 (q, J = 271.9 Hz), 114.0,
75.1, 55.0; IR (KBr) 3300, 2959, 2897, 2845, 1614, 1585,
23
63.7 °C; ½ꢀꢁD ¹5.9 (c 0.79, CHCl3, 76:24 er).
(R)-(4-Methoxyphenyl)phenylmethanol (2o):82 Colorless
solid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OJ-H (hexane/i-PrOH = 90/10, v/v,
flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 29.6
min (major) and tR = 34.7 min (minor), 70:30 er; 1H NMR (400
MHz, CDCl3) ¤ 7.45-7.21 (m, 7H), 6.87 (d, J = 8.4 Hz, 2H),
5.82 (d, J = 2.8 Hz, 1H), 3.79 (s, 3H), 2.14 (d, J = 2.8 Hz,
0.9H); 13C NMR (100 MHz, CDCl3) ¤ 159.1, 144.1, 136.3,
128.5, 128.0, 127.5, 126.5, 114.0, 75.9, 55.4; IR (KBr) 3395,
23
1514, 1325, 1067, 812, 779 cm¹1; ½ꢀꢁD +10.0 (c 1.03, CHCl3,
61:39 er, unknown absolute configuration).
(4-Methoxyphenyl)(4-(trifluoromethyl)phenyl)methyl
Isobutyrate (4q):
Colorless liquid. Enantiomeric ratio
was determined by HPLC with DICEL CHIRALPAKμ AS-3
¹1
(hexane/i-PrOH = 98/2, v/v, flow rate = 1.00 mL min
,
21
2951, 2837, 1611, 1518, 1252, 1034, 810, 717, 696 cm¹1; ½ꢀꢁD
30 °C, UV = 254 nm), tR = 3.6 min (major) and tR = 4.1 min
(minor), 60:40 er; H NMR (400 MHz, CDCl3) ¤ 7.59 (d, J =
24
+1.2 (c 0.98, CHCl3, 61:39 er) [lit.83 ½ꢀꢁD +12.7 (c 0.50,
1
CHCl3, 93% ee, (R) form)].
8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.27-7.17 (m, 2H), 6.90-
6.80 (m, 3H), 3.79 (s, 3H), 2.67 (sep, J = 7.0 Hz, 1H), 1.22 (d,
J = 7.0 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) ¤ 175.8, 159.8, 144.9, 132.0, 130.0 (q, J = 32.6 Hz),
128.8, 127.2, 125.5 (q, J = 3.8 Hz), 124.2 (q, J = 272.2 Hz,
overap several pearks), 114.2, 75.8, 55.3, 34.3, 18.9 (2); IR
(KBr) 2976, 2938, 2839, 1736, 1585, 1329, 1252, 1125, 1067,
1018, 829, 766, 603 cm¹1; HRMS (FAB+) calculated for
(S)-(4-Methoxyphenyl)phenylmethyl Isobutyrate (4o):
Colorless liquid. Enantiomeric ratio was determined by HPLC
with DICEL CHIRALPAKμ AD-H (hexane/i-PrOH = 99.5/
0.5, v/v, flow rate = 1.00 mL min¹1, 30 °C, UV = 254 nm),
tR = 22.0 min (major) and tR = 25.3 min (minor), 74:26 er;
1H NMR (400 MHz, CDCl3) ¤ 7.38-7.22 (m, 7H), 6.90-6.81
(m, 3H), 3.79 (s, 3H), 2.65 (sep, J = 7.2 Hz, 1H), 1.26-1.16
(m, 6H); 13C NMR (100 MHz, CDCl3) ¤ 176.1, 159.3, 140.8,
132.8, 128.7, 128.6, 127.8, 126.9, 114.0, 76.3, 55.4, 34.3, 19.1;
23
C19H20F3O3 [M+H]+ 353.1359, found 353.1374; ½ꢀꢁD +10.0
(c 1.03, CHCl3, 60:40 er, unknown absolute configuration).
Bull. Chem. Soc. Jpn. 2016, 89, 1081–1092 | doi:10.1246/bcsj.20160135
© 2016 The Chemical Society of Japan | 1089

(R)-4-Phenyl-3-butyn-2-ol (2r):
Yellow liquid.
5H); 13C NMR (100 MHz, CDCl3) ¤ 166.2, 133.0, 130.3,
129.7, 128.4, 74.4, 30.4, 23.6; IR (KBr) 3526, 3065, 3032,
1699, 1450, 1277, 1111, 714.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 80/20, v/v, flow
rate = 0.800 mL min¹1, 30 °C, UV = 254 nm), tR = 8.3 min
(major) and tR = 17.4 min (minor), 52:48 er; 1H NMR (400
MHz, CDCl3) ¤ 7.49-7.39 (m, 2H), 7.32-7.26 (m, 3H), 4.76
(q, J = 7.0 Hz, 1H), 1.74 (bs, 1H), 1.56 (d, J = 7.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) ¤ 131.7, 128.4, 128.3, 122.7,
91.1, 84.0, 58.8, 24.4; IR (KBr) 3354, 2982, 2232, 1489, 1107,
trans-2-(Isobutyryloxy)cyclohexyl Benzoate (4t): Color-
less liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALPAKμ AS-3 (hexane/i-PrOH = 81.7/18.3,
v/v, flow rate = 0.300 mL min¹1, 30 °C, UV = 254 nm), tR =
17.9 min and tR = 20.7 min, 50:50 er; 1H NMR (400 MHz,
CDCl3) ¤ 8.00 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.7 Hz, 1H),
7.42 (t, J = 7.7 Hz, 2H), 5.10-4.99 (m, 2H), 2.44 (sep, J =
7.0 Hz, 1H), 2.23-2.15 (m, 1H), 2.10-2.01 (m, 1H), 1.85-1.71
(m, 2H), 1.61-1.31 (m, 4H), 1.04 (d, J = 7.0 Hz, 3H), 0.97 (d,
J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) ¤ 176.6, 165.9,
133.0, 130.2, 129.7, 128.4, 77.4, 74.7, 73.1, 34.1, 30.3, 23.6,
19.0, 18.8; IR (KBr) 2972, 2864, 2349, 1732, 1714, 1454, 845,
711; HRMS (FAB+) calculated for C17H23O4 [M+H]+
291.1590, found 291.1600.
21
25
934, 751; ½ꢀꢁD = +2.78 (c 0.55, Et2O, 52:48 er) [lit.86 ½ꢀꢁD
¹50.6 (c 1.475, Et2O, >95% ee, (S) form)].
(S)-4-Phenylbut-3-yn-2-yl Isobutyrate (4r):
Yellow
liquid. Enantiomeric ratio was determined by HPLC with
DICEL CHIRALCELμ OD-H (hexane/i-PrOH = 99/1, v/v,
flow rate = 0.500 mL min¹1, 30 °C, UV = 254 nm), tR = 9.6
min (minor) and tR = 11.5 min (major), 67:33 er; 1H NMR (400
MHz, CDCl3) ¤ 7.48-7.38 (m, 2H), 7.32-7.26 (m, 3H), 5.69
(q, J = 6.5 Hz, 1H), 2.59 (sep, J = 7.1 Hz, 1H), 1.57 (d, J =
6.5 Hz, 3H), 1.20 (d, J = 7.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) ¤ 176.2, 132.0, 128.7, 128.4, 122.5, 87.7, 84.5, 60.7,
34.1, 21.6, 19.1, 18.9; IR (KBr) 3051, 2976, 2936, 1732, 1470,
1069, 800, 777; HRMS (FAB+) calculated for C14H16O2
This research was partially supported by the Naito Founda-
tion and a Grant-in-Aid for Scientific Research on Innovative
Areas “Advanced Molecular Transformations by Organocata-
lysts” from MEXT (Japan). The authors thank the Division of
Instrumental Analysis, Department of Instrumental Analysis &
Cryogenics, Advanced Science Research Center, Okayama
University for the NMR and high-resolution mass spectrometry
measurements (FAB, EI, and ESI).
24
[M+H]+ 216.1144, found 216.1154; ½ꢀꢁD = ¹1.91 (c 0.338,
Et2O, 67:33 er).
(1R,2S)-2-Phenylcyclohexan-1-ol (2s):
Colorless solid.
Enantiomeric ratio was determined by HPLC with DICEL
CHIRALCELμ OD-H (hexane/i-PrOH = 99.5/0.5, v/v, flow
rate = 1.00 mL min¹1, 30 °C, UV = 254 nm), tR = 22.2 min
(minor) and tR = 22.5 min (major), 55:45 er; 1H NMR (400
MHz, CDCl3) ¤ 7.36-7.29 (m, 2H), 7.29-7.20 (m, 3H), 3.67
(td, J = 11.5, 4.4 Hz, 1H), 2.43 (ddd, J = 11.5, 9.7, 3.3 Hz,
1H), 2.17 (s, 0.13H), 2.15-2.06 (m, 1H), 1.92-1.80 (m, 2H),
1.80-1.61 (m, 1H), 1.61-1.25 (m, 4H); 13C NMR (100 MHz,
CDCl3) ¤ 143.4, 128.9, 128.0, 126.9, 74.5, 53.3, 34.5, 33.4,
26.2, 25.2; IR (KBr) 3298, 2932, 2855, 1447, 1051, 746, 696;
Supporting Information
Experimental procedures, spectral and analytical data for all
substrates and products. This material is available on http://
dx.doi.org/10.1246/bcsj.20160135.
References
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