Kinetic resolution of secondary alcohols by chiral dmap derivatives prepared by the Ugi multicomponent reaction

Article abstract of DOI:10.3987/COM-12-12624

The kinetic resolution of secondary alcohols was examined by new chiral DMAP derivatives, which can readily be prepared by the Ugi multicomponent reaction in a one-pot operation. The initial screening of DMAP derivatives indicated that the catalyst bearing L-valine with an S configuration at the a-position of amide showed the best stereoselectivity factor. After the reaction conditions were optimized with (S,S)-4a in the kinetic resolution of secondary alcohols, various acyclic and cyclic secondary alcohols could be resolved with an s -factor of up to 12.

Full text of DOI:10.3987/COM-12-12624

HETEROCYCLES, Vol. 87, No. 2, 2013
329
HETEROCYCLES, Vol. 87, No. 2, 2013, pp. 329 - 340. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 12th November, 2012, Accepted, 30th November, 2012, Published online, 6th December, 2012
DOI: 10.3987/COM-12-12624
KINETIC RESOLUTION OF SECONDARY ALCOHOLS BY CHIRAL
DMAP DERIVATIVES PREPARED BY THE UGI MULTICOMPONENT
REACTION
Hiroki Mandai,* Shunsuke Irie, Masaru Akehi, Kazunobu Yuri, Masaaki
Yoden, Koichi Mitsudo, and Seiji Suga*
Division of Chemistry and Biotechnology, Graduate School of Natural Science
and Technology, Okayama University, 3-1-1 Tsushima-naka, Kita-ku, Okayama
700-8530, Japan; E-mail: mandai@cc.okayama-u.ac.jp, suga@cc.okayama-u.ac.jp
Abstract – The kinetic resolution of secondary alcohols was examined by new
chiral DMAP derivatives, which can readily be prepared by the Ugi
multicomponent reaction in a one-pot operation. The initial screening of DMAP
derivatives indicated that the catalyst bearing -valine with an S configuration at
L
the -position of amide showed the best stereoselectivity factor. After the reaction
conditions were optimized with (S,S)-4a in the kinetic resolution of secondary
alcohols, various acyclic and cyclic secondary alcohols could be resolved with an
s-factor of up to 12.
INTRODUCTION
The development of chiral nucleophilic catalysts is an important field of study in synthetic organic
chemistry. Various catalysts have been developed to date and used in various asymmetric transformations,
such as the kinetic resolution of racemic alcohols or amine, desymmetrization of meso-anhydrides, and
carbon-carbon bond-forming reactions.1 In kinetic resolution, the catalyst is evaluated in terms of Kagan's
equation, which gives the stereoselectivity factor (s).2 In general, a catalyst with an s-factor of greater
than 20 is considered to be synthetically useful.3 However, such chiral catalysts sometimes require a
multistep synthesis and/or cumbersome resolution of the racemate of the catalyst (optical resolution or
chiral HPLC separation). Furthermore, in most cases, precise modification of the catalysts is not easy.
Therefore, a short and practical synthesis of chiral DMAP derivatives, which can efficiently promote
asymmetric transformations, is highly desirable.
Recently, we developed a diastereoselective Ugi reaction4 of a 4-(N,N-dimethylamino)pyridine
(DMAP)-based aldehyde with various -amino acids and tert-butyl isocyanide (Eq. 1).5

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The reactions of 4-(dimethylamino)-3-pyridinecarboxaldehyde (1) with various -amino acids gave the
3-substituted chiral DMAP derivatives in moderate yield (18%–63%) with good to high
diastereoselectivity (up to 92:8 d.r.). This new synthetic method for accessing 3-substituted chiral DMAP
derivatives6 offers several advantages: (1) highly functionalized chiral DMAP derivatives can be easily
prepared by a one-pot operation; (2) each component (aldehyde, -amino acid, and isocyanide) is readily
available; and (3) diastereomerically pure DMAP derivatives can be potentially obtained by traditional
purification techniques. Our preliminary studies showed that the major diastereomer of the Ugi product7
had a moderate s-factor (s = 2.3) in the kinetic resolution of 1-phenylethyl alcohol under unoptimized
reaction conditions.
In this paper, we report the details of the kinetic resolution of various secondary alcohols using
diastereomerically pure chiral DMAP derivatives.
RESULTS AND DISCUSSION
We began by examining the kinetic resolution of racemic 1-phenylethyl alcohol (2a) with an array of
single diastereomers of DMAP derivatives possessing a chiral side chain at the C-3 position of the DMAP
moiety, which could be obtained through a diastereoselective Ugi reaction, followed by a traditional
purification technique (flash chromatography on SiO2).5 As illustrated in Table 1, the kinetic resolution of
rac-2a was carried out with 0.75 equivalents of acetic anhydride and triethylamine in the presence of 5
mol % catalyst in toluene at 0 °C for 15 h. Catalysts 4ad having an R configuration at the -position of
the amide with an alkyl-substituted -amino acid (e.g., L-valine) showed s-factors of 1.92.2 (entries 14).
Catalysts with a heteroatom-substituted -amino acid resulted in similar s-factors (s = 2.22.4, entries 5
and 6). However, a minor diastereomer of the Ugi product,8 which has an S configuration at the
-position of the amide bearing L-valine or L-methionine [(S,S)-catalyst 4a and 4e], showed a slightly
better s-factor (s = 3.4) than those obtained with the corresponding (S,R)-catalysts 4a and 4e (s = 2.1 and
2.2). Amide-modified catalysts (S,R)-4g and (S,R)-4h were ineffective (s = 1.8 and 1.0) in the current
reaction (entries 9 and 10 vs 1). DMAP derivatives possessing a chiral side chain at the C-2 position of
the DMAP moiety, (S,RS)-4i9 did not catalyze the reaction, probably due to the steric hindrance around

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331
the nucleophilic site. According to these results, (S,S)-4a was thought to be the best catalyst among those
tested, and we decided to use (S,S)-4a for further optimization of the reaction conditions.
Table 1. Catalyst screening for the kinetic resolution of rac-2a
er of 2a er of 3a
(R:S)b (S:R)b
Entry Catalyst Conv. (%)a
sc
1
(S,R)-4a 66
(S,R)-4b 65
(S,R)-4c 70
(S,R)-4d 65
(S,R)-4e 70
69:31
60:40
59:41
59:41
61:39
60:40
61:39
37:63
36:64
59:41
52:48
-
2.1
1.9
2.1
2.2
2.2
2.4
3.4
3.4
1.8
1.0
-
2
66:34
71:29
70:30
73:27
74:26
14:86
14:86
64:36
50:50
-
3
4
5
6
(S,R)-4f
(S,S)-4a 72
(S,S)-4e
72
69
7
8
9
(S,R)-4g 62
(S,R)-4h 64
(S,RS)-4i <2
10
11
aConversions were determined by HPLC analysis, using the following equation [conversion = ee2a/(ee2a + ee3a)]. bDetermined by
HPLC analysis (CHIRALCEL OD-H). cs = ln(1-conversion)(1-ee2a)/ln(1-conversion)(1+ee2a).

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To increase the efficiency of resolution, we next examined the solvent effect with (S,S)-4a (Table 2).
Solvents such as dichloromethane and diethyl ether decreased the s-factor to 2.0 and 3.1, respectively,
compared to that with toluene (entries 2 and 3 vs 1). Polar solvents, such as acetonitrile, t-amyl alcohol,
and ethyl acetate, resulted in low s-factors of 1.72.7 (entries 46). Although we did not find any
correlation between the s-factor and the nature of solvent, toluene was selected as the optimal solvent in
view of the s-factor.
Table 2. Solvent effect in the kinetic resolution of rac-2a
er of 2a er of 3a
Entry
Solvent
Conv. (%)a
sc
(R:S)b
14:86
31:69
16:84
31:69
29:71
15:85
(S:R)b
1
2
3
4
5
6
toluene
CH2Cl2
72
66
73
77
64
79
37:63 3.4
41:59 2.0
37:63 3.1
44:56 1.7
38:62 2.3
41:59 2.7
Et2O
MeCN
t-amyl alcohol
EtOAc
aConversions were determined by HPLC analysis, using the following equation [conversion = ee2a/(ee2a + ee3a)]. bDetermined by
HPLC analysis (CHIRALCEL OD-H). cs = ln(1-conversion)(1-ee2a)/ln(1-conversion)(1+ee2a).
To clarify the effect of the acylating reagent, sterically hindered anhydrides were used in the kinetic
resolution (Table 3). Propionic anhydride and isobutyric anhydride did not improve the s-factor compared
to that with acetic anhydride, while showing almost the same reactivity as acetic anhydride (entries 2 and
3 vs 1). Based on these results, acetic anhydride was thought to be the best acylating reagent in the current
reaction.
Table 3. The kinetic resolution of rac-2a using other acylating agents
er of 2a er of 3a
Entry
R
Conv. (%)a
sc
(R:S)b
15:85
24:76
24:76
(S:R)b
34:66
36:64
34:66
1
2
3
Me 69
Et 65
i-Pr 62
3.7
2.8
3.1
aConversions were determined by HPLC analysis, using the following equation [conversion = ee2a/(ee2a + ee3a)]. bDetermined by
HPLC analysis (CHIRALCEL OD-H). cs = ln(1-conversion)(1-ee2a)/ln(1-conversion)(1+ee2a).

HETEROCYCLES, Vol. 87, No. 2, 2013
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Next, the effect of auxiliary base was investigated to improve the s-factor. The use of Hünig's base
(DIPEA) decreased the s-factor (s = 3.5). Cyclic bases including DBU, N-methylmorpholine (NMM), and
N-methylpiperidine (NMP) were found to be slightly inferior to Et3N with respect to the s-factor.
Table 4. Effect of auxiliary base in the kinetic resolution of rac-2a
er of 2a er of 3a
Entry Base
Conv.(%)b
61
sc
(R:S)b (S:R)b
1
2
3
4
5
Et3N
22:78
32:68
32:68
36:64
37:63
35:65
3.7
3.5
2.3
3.2
3.5
(i-Pr)2EtN 62
22:78
36:64
15:85
16:86
DBU
NMM
NMP
49
73
70
aConversions were determined by HPLC analysis, using the following equation [conversion = ee2a/(ee2a + ee3a)]. bDetermined by
HPLC analysis (CHIRALCEL OD-H). cs = ln(1-conversion)(1-ee2a)/ln(1-conversion)(1+ee2a).
We next examined the concentration of substrate and the reaction temperature, since these might be
important for achieving high enantioselectivity (Tables 5 and 6). As shown in Table 5, various concentrations
Table 5. Effect of substrate concentration in the kinetic resolution of rac-2a
er of 2a er of 3a
Entry Concn (M) Conv. (%)b
sc
(R:S)b
(S:R)b
39:61
37:63
35:65
32:68
29:71
24:76
1
2
3
4
5
6
0.50
0.33
0.10
0.05
0.03
0.01
79
75
71
64
53
25
8:92
3.6
3.6
3.8
3.8
3.8
3.7
11:89
13:87
18:82
26:74
41:59
aConversions were determined by HPLC analysis, using the following equation [conversion = ee2a/(ee2a + ee3a)]. bDetermined by
HPLC analysis (CHIRALCEL OD-H). cs = ln(1-conversion)(1-ee2a)/ln(1-conversion)(1+ee2a).

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Table 6. Effect of reaction temperature in the kinetic resolution of rac-2a
er of 2a er of 3a
Entry Temp (°C) Conv. (%)b
sc
(R:S)b
18:82
19:81
22:78
33:67
42:58
(S:R)b
32:68
28:72
23:77
17:83
13:87
1
2
3
4
5
0
64
59
51
34
17
3.8
4.7
5.8
7.0
8.1
-20
-40
-60
-78
aConversions were determined by HPLC analysis, using the following equation [conversion = ee2a/(ee2a + ee3a)]. bDetermined by
HPLC analysis (CHIRALCEL OD-H). cs = ln(1-conversion)(1-ee2a)/ln(1-conversion)(1+ee2a).
of substrate were tested. The reactions at lower concentrations were slightly better than the control
reaction (0.5 M) while retaining satisfactory conversions of 2a (entries 35 vs 1). At a lower
concentration (0.05 M), the reaction at -78 °C gave the highest s-factor (s =8.1; Table 6; entry 5).10
With the optimal conditions in hand, we then subjected various secondary alcohols to kinetic resolution
with (S,S)-4a, as shown in Figure 1. Naphthyl-based carbinols 2b and 2c could be resolved with s = 9.3
and 9.1, respectively. Phenyl-based carbinol 2d possessing a sterically hindered substituent (t-Bu) could
also be used in the kinetic resolution with s =12.4, indicating that the steric environment of the substrate
affected on the s-factor. On the other hand, propargylic alcohols 2e and 2f resulted in low s-factors (s =
2.8 and 3.8) compared to 2ad, and were considered to be unsuitable substrates in the kinetic resolution
with (S,S)-4a. The cyclic alcohol 2g with a phenyl substituent at the -position gave s = 10.4, whereas the
reaction of mono-protected cis-1,2-cyclohexanediol 2h proceeded with s = 2.6. Based on these results,
aryl-substituted carbinols 2ad and 2g could be resolved by the new catalyst (S,S)-4a with a satisfactory
s-factor. Although we only confirmed the reaction kinetics (s-factor) for various alcohols with (S,S)-4a at
a certain reaction time (15 h), for obtaining high enantiopurity of the recovering alcohols, longer reaction
time (higher conversion) should be required according to the corresponding s-factor.2

HETEROCYCLES, Vol. 87, No. 2, 2013
335
(S,S)-4a (5 mol %)
OH
R2
OH
R2
OAc
R2
Ac2O (0.75 equiv)
R1
rac-2
R1
R1
+
Et3N (0.75 equiv)
toluene (0.05 M)
-78 °C, 15 h
R1 R2
2
3
OAc
Me
OAc
OAc
Me
OAc
Ph t-Bu
Me
Ph
3a
3b
17% conv
s = 9.3
3c
3d
17% conv
14% conv
8% conv
s = 8.1
s = 9.1
s = 12.4
OAc
Me
OAc
Ph
OAc
OBz
OAc
Ph
Ph
3g
3e
18% conv
s = 2.8
3f
3h
14% conv
19% conv
s = 3.8
34% conv
s = 2.6
s = 10.4
Figure 1. Substrate scope for the kinetic resolution of rac-alcohols.
In conclusion, we found that a minor diastereomer of the Ugi product, (S,S)-4a, can catalyze the kinetic
resolution of secondary alcohols with s-factors of up to 12. To the best of our knowledge, this is the first
example of the kinetic resolution of secondary alcohols with a chiral DMAP derivative that was prepared
by the diastereoselective Ugi multicomponent reaction.11 This new approach for accessing chiral DMAP
derivatives in a one-pot operation may become an attractive tool for constructing nucleophilic catalyst
libraries. Studies on the further optimization of the catalyst structure and the use of a major diastereomer
of the Ugi product [(S,R)-catalyst] in other important classes of asymmetric transformations are currently
in progress.
EXPERIMENTAL
All melting points were determined using a Yanaco micro melting point apparatus MP-S3 and are
uncorrected. Solvents were generally distilled and dried by standard procedures prior to use.12 The IR
spectra were recorded on a JASCO FT/IR-4100 spectrometer. NMR spectra were recorded on a Varian
VNMRS-400 spectrometer at the SC-NMR Laboratory (Okayama University), operating at 400 MHz for
13
1H NMR and 100 MHz for C NMR. Chemical shifts in CDCl3 are reported on the  scale relative to
CHCl3 (7.26 ppm) as an internal reference for 1H NMR. For 13C NMR, chemical shifts are reported on the
scale relative to CHCl3 (77.0 ppm) as an internal reference. Column chromatography was performed
with silica gel 60N (spherical, neutral, 40–50 m) purchased from KANTO CHEMICAL. Optical

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rotations were measured on a HORIBA Model SEPA-300 High-sensitive polarimeter. High-resolution
FAB mass spectra (HRMS) were measured on a JEOL JMS-700 MStation at the Mass Spectrometry
Facility (Okayama University). The enantiomeric ratio (er) (= enantiomeric composition) and
enantiomeric excess (ee) were determined by HPLC or GC analysis. HPLC was performed on Shimazu
HPLC systems consisting of the following: pump, LC-10AD; detector, SPD-10A, 254 nm; column,
DAICEL CHIRALCEL OD-H; mobile phase, hexane/i-PrOH. GC was performed on Shimazu
chromatograph GC-14B (CP-Cyclodextrin-B-2,3,6-M-19 (0.25 mm, 0.25 µm, 25 m) in comparison with
authentic racemic materials.
Preparation of chiral DMAP derivatives
The preparation of and analytical data for the catalysts (S,R)-4af and (S,RS)-4j were reported
previously.5
(S)-N-(1-(tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridin-3-yl)methyl)-L-valine methyl ester
1
((S,S)-4a). colorless solid; mp 135-136 °C; H NMR (400 MHz, CDCl3)  8.36 (s, 1H), 8.32 (d, J = 5.6
Hz, 1H), 7.74 (br, 1H), 6.86 (d, J = 5.6 Hz, 1H), 4.41 (s, 1H), 3.58 (s, 3H), 3.01 (br, 1H), 2.88 (s, 6H),
13
2.11 (br, 1H), 1.931.85 (m, 1H), 1.39 (s, 9H), 0.98 (d, J = 6.8 Hz, 6H); C NMR (100 MHz, CDCl3)
174.6, 171.0, 159.1, 149.6, 149.3, 113.9, 67.5, 59.7, 51.6, 50.8, 44.5, 31.6, 28.7, 19.8, 18.6; IR (KBr)
= 3194, 2963, 1732, 1671 cm1; HRMS-FAB (m/z): [M+H]+ calcd. for C19H33N4O3 365.2553, found
365.2548; []D25  (c 0.145, MeOH).
(S)-N-(1-(tert-Butylcarbamoyl)-1-(4-(dimethylamino)pyridyn-3-yl)methyl)-L-methionine
methyl
ester ((S,S)-4e). colorless solid; mp 99-100 °C; 1H NMR (400 MHz, CDCl3)  8.36 (s, 1H), 8.33 (d, J =
5.6 Hz, 1H), 7.60 (br, 1H), 6.88 (d, J = 5.6 Hz, 1H), 4.47 (s, 1H), 3.60 (s, 3H), 3.43 (br, 1H), 2.87 (s, 6H),
2.63 (d, J = 7.1 Hz, 1H), 2.61 (d, J = 7.1 Hz, 1H), 2.28 (br, 1H), 2.11 (s, 3H), 2.011.92 (m, 1H),
1.881.79 (m, 1H), 1.40 (s, 9H); 13C NMR (100 MHz, CDCl3)  174.4, 170.8, 159.1, 149.8, 149.6, 129.0,
114.0, 59.9, 59.7, 52.0, 50.9, 44.5, 32.7, 30.6, 28.7, 15.5; IR (KBr)  = 3309, 2991, 2960, 2382, 1727,
25
1673 cm1; HRMS-FAB (m/z): [M+H]+ calcd. for C19H33N4O3S 397.2273, found 397.2279; []D 
(c 0.125, MeOH).
(R)-N-(1-(1,1,3,3-Tetramethylbutylcarbamoyl)-1-(4-(dimethylamino)pyridin-3-yl)methyl)-L-valine
methyl ester ((S,R)-4g). To a suspension of 4-(dimethylamino)-3-pyridinecarboxaldehyde (30.8 mg, 0.21
mmol) and L-valine (26.7 mg, 0.23 mmol) in dry MeOH (0.4 mL) in a screw-cap test tube was added
1,1,3,3-tetramethylbutyl isocyanide (39.6 L, 0.23 mmol), and the reaction mixture was stirred for 36 h at
50 °C. The solvent was evaporated in vacuo and the resulting residue was purified by column
chromatography on SiO2 (EtOAc only) to give (S,R)-4g as a colorless solid (37.8 mg, 45% yield as a

HETEROCYCLES, Vol. 87, No. 2, 2013
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1
single diastereomer); mp 113-114 °C; H NMR (400 MHz, CDCl3)  8.52 (s, 1H), 8.36 (d, J = 5.6 Hz,
1H), 7.24 (br, 1H), 6.88 (d, J = 5.6 Hz, 1H), 4.57 (s, 1H), 3.69 (s, 3H), 2.83 (s, 6H), 2.782.74 (m, 1H),
2.47 (br, 1H), 1.951.87 (m, 1H), 1.75 (d, J = 15 Hz, 1H), 1.62 (d, J = 15 Hz, 1H), 1.39 (s, 3H), 1.38 (s,
3H), 0.96 (s, 9H), 0.90 (d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3)  174.6,
170.3, 159.5, 150.5, 149.9, 127.9, 113.7, 64.6, 58.6, 54.8, 52.4, 51.5, 44.3, 31.5, 31.4, 31.3, 28.9, 28.6,
19.2, 18.4; IR (KBr)  = 3207, 3043, 2966, 1732, 1666 cm1; HRMS-FAB (m/z): [M+H]+ calcd. for
C23H40N4O3 421.3179, found 421.3173; []D25 137 (c 0.735, MeOH).
(R)-N-(1-(Benzylcarbamoyl)-1-(4-(dimethylamino)pyridin-3-yl)methyl)-L-valine
methyl
ester
((S,R)-4h). To a suspension of 4-(dimethylamino)-3-pyridinecarboxaldehyde (30.3 mg, 0.20 mmol) and
L-valine (26.2 mg, 0.22 mmol) in dry MeOH (0.4 mL) in a screw-cap test tube was added benzyl
isocyanide (26.8 L, 0.22 mmol), and the reaction mixture was stirred for 16 h at 50 °C. The solvent was
evaporated in vacuo and the resulting residue was purified by column chromatography on SiO2 (EtOAc
1
only) to give (S,R)-4h as a yellowish oil (18.6 mg, 23% yield as a single diastereomer); H NMR (400
MHz, CDCl3)  8.54 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 7.62 (br, 1H), 7.337.20 (m, 5H), 6.87 (d, J = 5.6
Hz, 1H), 4.71 (s, 1H), 4.47 (dd, J = 15, 6.0 Hz, 1H), 4.42 (dd, J = 15, 6.0 Hz, 1H), 3.65 (s, 3H), 2.852.79
(m, 1H), 2.75 (s, 6H), 2.50 (br, 1H), 1.971.89 (m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3)  174.6, 171.7, 159.5, 150.5, 150.0, 138.1, 128.7, 127.7, 127.6, 127.5,
113.8, 64.9, 58.5, 51.6, 44.2, 43.5, 31.3, 19.2, 18.5; IR (KBr)  = 3339, 3171, 2955, 1738, 1666 cm1;
25
HRMS-FAB (m/z): [M+H]+ calcd. for C22H31N4O3 399.2396, found 399.2383; []D  (c 0.465,
MeOH).
4.3. Kinetic Resolution of Racemic Secondary Alcohols
General Method: To a solution of chiral DMAP derivative (0.010 mmol), racemic secondary alcohol 2
(0.20 mmol) and triethylamine (21 L, 0.15 mmol) in toluene (4.0 mL) at – 78 °C was added acetic
anhydride (14 L, 0.15 mmol), and the reaction mixture was stirred at the same temperature for 15 h. The
reaction was quenched with MeOH and concentrated in vacuo. The resulting residue was filtered through
a short plug of SiO2 (hexane/Et2O = 3:1, v/v) to give the acetate and the unreacted alcohol, which were
subjected to HPLC analysis.
(R)-1-Phenylethyl acetate (3a). a colorless oil (17% conversion, 87:13 er); HPLC (DAICEL
CHIRALCEL OD-H, hexane/i-PrOH = 19:1, 0.300 mL/min, 30 °C, 254 nm): Rt 15.1 min (major ester),
15.8 min (minor ester); 1H NMR (400 MHz, CDCl3)  7.417.29 (m, 5H), 5.94 (q, J = 6.6 Hz, 1H), 2.08
(s, 3H), 1.57 (d, J = 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3)  169.9, 141.5, 128,2, 127.6, 125.8, 72.0,
20
22.0, 21.0; IR (neat)  = 3064, 3033, 2982, 2934, 1744 cm1; []D  (c 0.105, CHCl3, 89:11 er);
lit.,13 [α]D21 +43 (c 2.10, CHCl3 (er >99:<1)).

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(R)-1-(2-Naphthyl)ethyl acetate (3b). a colorless oil (17% conversion, 89:11 er); HPLC (DAICEL
CHIRALCEL OJ-H, hexane/i-PrOH = 19:1, 0.300 mL/min, 30 °C, 254 nm): Rt 24.3 min (major ester),
30.0 min (minor ester); 1H NMR (400 MHz, CDCl3)  7.907.86 (m, 4H), 7.557.49 (m, 3H), 6.13 (q, J =
13
6.6 Hz, 1H), 2.15 (s, 3H), 1.68 (d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl3)  170.2, 138.9, 133.1,
132.9, 128.2, 127.9, 127.5, 126.1, 125.9, 124.9, 124.0, 72.3, 22.1, 21.2; IR (neat)  = 3057, 3024, 2980,
20
22
2933, 1738 cm1; []D  (c 0.400, CHCl3, 86:14 er); lit.,14 [α]D +122 (c 1.00, CHCl3 (er
>99.5:<0.5)).
(R)-1-(1-Naphtyl)ethyl acetate (3c). a colorless oil (14% conversion, 89:11 er); HPLC (DAICEL
CHIRALCEL OD-H, hexane/i-PrOH = 9:1, 0.300 mL/min, 30 °C, 254 nm): Rt 17.0 min (major ester),
20.7 min (minor ester); 1H NMR (400 MHz, CDCl3)  8.14 (d, J = 7.9 Hz, 1H), 7.91 (bd, J = 7.9 Hz, 1H),
7.84 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.60-7.49 (m, 3H), 6.71 (q, J = 6.6 Hz, 1H), 2.16 (s,
13
3H), 1.75 (d, J = 6.6 Hz, 3H); C NMR (100 MHz, CDCl3)  170.3, 137.3, 133.7, 130.2, 128.8, 128.4,
20
126.2, 125.6, 125.3, 123.1, 123.1, 69.3, 21.6, 21.3; IR (neat)  = 3051, 2982, 2933, 1739 cm1; []D
 (c 0.375, CHCl3, 86:14 er); lit.,14 [α]D22 +52 (c 1.00, CHCl3 (er >99.5:<0.5)).
(R)-2,2-Dimethyl-1-phenylpropyl acetate (3d). a colorless oil (8% conversion, 92:8 er); GC (chiral
capillary column CP-CYCLODEX -236M, 100 °C for 5 min, rate of temperature increase 1.0 °C/min):
Rt 26.2 min (minor ester), 26.7 min (major ester) ; 1H NMR (400 MHz, CDCl3)  7.347.24 (m, 5H), 5.51
(s, 1H), 2.10 (s, 3H), 0.95 (s, 9H); 13C NMR (100 MHz, CDCl3)  170.1, 138.4, 127.7, 127.5, 127.4, 82.7,
19
34.9, 26.0, 21.1; IR (neat)  = 3033, 2971, 2907, 2871, 1742 cm1; []D  (c 1.00×10-2, CHCl3,
93:7 er).
(S)-1-Phenyl-2-propyn-1-yl acetate (3e). a colorless oil (18% conversion, 72:28 er); GC (chiral capillary
column CP-CYCLODEX -236M, 100 °C for 5 min, rate of temperature increase 1.0 °C/min): Rt 24.1
1
min (major ester), 25.3 min (minor ester); H NMR (400 MHz, CDCl3)  7.567.53 (m, 2H), 7.437.35
(m, 3H), 6.46 (d, J = 2.3 Hz, 1H), 2.67 (d, J = 2.3 Hz, 1H), 2.12 (s, 1H); 13C NMR (100 MHz, CDCl3) 
169.6, 136.4, 129.0, 128.6, 127.6, 80.2, 75.4, 65.2, 21.0; IR (neat)  = 3288, 3066, 3035, 2937, 2126,
1742 cm1; []D19  (c 0.04, CHCl3, 62:38 er); lit.,15 [α]D25 -4.8 (c 0.25, CHCl3 (er >99.5:<0.5)).
(R)-4-Phenyl-3-butyn-2-yl acetate (3f). a colorless oil (19% conversion, 77:23 er); GC (chiral capillary
column CP-CYCLODEX -236M, 100 °C for 5 min, rate of temperature increase 1.0 °C/min): Rt 38.8
1
min (minor ester), 39.2 min (major ester); H NMR (400 MHz, CDCl3)  7.477.41 (m, 2H), 7.357.27
(m, 3H), 5.69 (q, J = 6.7 Hz, 1H), 2.11 (s, 3H), 1.58 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) 
170.0, 131.9, 128.6, 128.2, 122.2, 87.4, 84.5, 60.8, 21.5, 21.1; IR (neat)  = 3058, 2989, 2936, 1743 cm1;
[]D20  (c 0.455, CHCl3, 77:23 er); lit.,16 [α]D20 +188 (c 1.10, CHCl3 (er 99.5:0.5)).

HETEROCYCLES, Vol. 87, No. 2, 2013
339
(1R, 2S)-trans-2-Phenylcyclohexyl acetate (3g). a colorless oil (14% conversion, 91:9 er); The product
was hydrolyzed and the enantiomeric ratio was determined by HPLC analysis of alcohol 2g. (DAICEL
CHIRALCEL OD-H, 0.46 cm  × 25 cm, hexane/i-PrOH = 199:1, 1.00 mL/min, 30 °C, 220 nm): Rt 16.2
1
min (minor alcohol), 17.9 min (major alcohol); H NMR (400 MHz, CDCl3)  7.387.34 (m, 2H),
7.297.24 (m, 3H), 5.07 (ddd, J = 4.5, 4.5, 4.5 Hz, 1H), 2.782.71 (m, 1H), 2.232.20 (m, 1H), 2.051.85
13
(m, 3H), 1.84 (s, 3H), 1.711.36 (m, 4H); C NMR (100 MHz, CDCl3)  170.2, 143.0, 128.1, 127.4,
20
126.3, 75.7, 49.6, 33.7, 32.2, 25.7, 24.6, 20.8; IR (neat)  = 3062, 3029, 2935, 2859, 1738 cm1; []D
 (c 0.270, CHCl3, 90:10 er).
(1S, 2R)-cis-2-Acetoxycyclohexyl benzoate (3h). a colorless oil (34% conversion, 68:32 er); GC (chiral
capillary column CP-CYCLODEX -236M, 100 °C for 5 min, rate of temperature increase 1.0 °C/min):
1
Rt 89.2 min (minor ester), 89.8 min (major ester); H NMR (400 MHz, CDCl3)  8.068.03 (m, 2H),
7.587.54 (m, 1H), 7.477.43 (m, 2H), 5.345.32 (m, 1H), 5.10-5.06 (m, 1H), 2.03 (s, 3H), 2.011.90 (m,
13
2H), 1.781.65 (m, 4H), 1.571.43 (m, 2H); C NMR (100 MHz, CDCl3)  170.4, 165.7, 132.9, 130.5,
19
129.6, 128.3, 71.5, 71.2, 28.1, 27.4, 22.2, 21.2, 21.1; IR (neat)  = 2942, 2865, 1719, 1602 cm1; []D
 (c 0.31, CHCl3, 68:32 er).
ACKNOWLEDGEMENTS
Financial support was provided by Grant-in-Aid for Young Scientists (Start-up, No. 21850020) from the
Japan Society for the Promotion of Science (JSPS), Okayama Foundation for Science and Technology,
Wesco Scientific Promotion, and Okayama University. We are grateful to the SC-NMR Laboratory of
Okayama University for the NMR spectra.
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12.
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