A new method for production of chiral 2-aryloxypropanoic acids using effective kinetic resolution of racemic 2-aryloxycarboxylic acids

Article abstract of DOI:10.3987/COM-12-S(N)79

We report a novel method for the preparation of 2-aryloxypropanoic acids by kinetic resolution of racemic 2-aryloxypropanoic acids using enantioselective esterification. The usage of pivalic anhydride (Piv₂O) as an activating agent, bis(a-naphthyl)methanol ((α-Np)₂CHOH) as an achiral alcohol, and (+)-benzotetramisole ((+)-BTM) as a chiral acyl-transfer catalyst enables the effective separation of various racemic 2-aryloxypropanoic acids to afford optically active carboxylic acids and the corresponding esters with high enantioselectivities. Furthermore, theoretical calculations of the transition states required to form the chiral esters successfully proved the enantiomer recognition mechanism of the asymmetric esterification.

Full text of DOI:10.3987/COM-12-S(N)79

HETEROCYCLES, Vol. 86, No. 2, 2012
1227
HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1227 - 1252. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 30th June, 2012, Accepted, 30th August, 2012, Published online, 10th September, 2012
DOI: 10.3987/COM-12-S(N)79
A
NEW
METHOD
FOR
PRODUCTION
OF
CHIRAL
2-ARYLOXYPROPANOIC ACIDS USING EFFECTIVE KINETIC
RESOLUTION OF RACEMIC 2-ARYLOXYCARBOXYLIC ACIDS
Atsushi Tengeiji, Kenya Nakata, Keisuke Ono, and Isamu Shiina*
Department of Applied Chemistry, Faculty of Science, Tokyo University of
Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan; E-mail:
shiina@rs.kagu.tus.ac.jp
Abstract – We report a novel method for the preparation of 2-aryloxypropanoic
acids by kinetic resolution of racemic 2-aryloxypropanoic acids using
enantioselective esterification. The usage of pivalic anhydride (Piv2O) as an
activating agent, bis(!-naphthyl)methanol ((!-Np)2CHOH) as an achiral alcohol,
and (+)-benzotetramisole ((+)-BTM) as a chiral acyl-transfer catalyst enables the
effective separation of various racemic 2-aryloxypropanoic acids to afford
optically active carboxylic acids and the corresponding esters with high
enantioselectivities. Furthermore, theoretical calculations of the transition states
required to form the chiral esters successfully proved the enantiomer recognition
mechanism of the asymmetric esterification.
INTRODUCTION
Optically pure 2-aryloxypropanoic acids and their derivatives are important moieties that are widely used
in the agrochemical and pharmaceutical industries (Scheme 1). In the case of the herbicide Mecoprop®,
2-(4-chloro-2-methylphenoxy)propanoic acid, only the (R)-(+)-enantiomer exhibits herbicidal activity and
is manufactured in the optically pure form, Mecoprop-P® (MCPP-P).1 In addition, although the
!
2-adrenergic receptor agonist Lofexidine, which can be derived from 2-aryloxypropanoic acids, is on the
market as a racemic mixture, it was reported that the (S)-(–)-enantiomer has 10-fold more potency than
the (R)-(+)-enantiomer.2 Therefore, synthetic strategies to afford chiral 2-aryloxypropanoic acids or their
derivatives are essential to afford beneficial enantiomers, and have attracted the interest of many research
groups.
The authors dedicate this paper to Professor Dr. Ei-ichi Negishi on the celebration of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
Cl
Me
O
Cl
O
H
Cl
N
Me
CO2H
Me
N
Mecoprop-P®
(MCPP-P)
Lofexidine
Scheme 1. Related bioactive compounds of 2-aryloxypropanoic acids
Chiral 2-aryloxypropanoic acid derivatives can be obtained by SN2 reaction at the 2-positon of the
corresponding chiral lactic acid derivatives produced by fermentation.3 However, because of concerns
about the loss of precious chiral substrates4 and unexpected racemization in the 2-substitution step, it may
be an effective approach to configure directly the chiral center of 2-aryloxypropanoic acids after
introducing the 2-aryloxy groups.
There are several straightforward routes to the preparation of optically active 2-aryloxypropanoic acids
from prochiral or racemic aryloxy compounds, such as asymmetric hydrogenation of 2-aryloxypropenoic
acids,5 microbial deracemization,6 and optical resolution.7 Of these, the optical resolution system is
thought to be the most valuable in terms of usability for the enhancement of enantiomeric excess in the
synthesized products. However, to the best of our knowledge, reported optical resolutions to date have
been limited to those involving enzymatic hydrolysis. As the enzymatic approach requires strict
validation, development of an effective and non-enzymatic optical resolution of racemic 2-aryloxy
carboxylic acids would be highly beneficial in process chemistry.
Several non-enzymatic kinetic resolution systems of racemic 2-arylpropanoic acids have been developed
in recent years (Scheme 2). Initially, we introduced an effective system of kinetic resolution by applying
asymmetric esterification of racemic carboxylic acids, and demonstrated that various racemic
2-arylpropanoic acids could be kinetically separated to afford the optically active carboxylic acids and
corresponding esters.8 This kinetic resolution system consists of carboxylic acid anhydride as an
activating agent, bis(!-naphthyl)methanol ((!-Np)2CHOH) as an achiral nucleophile, and commercially
available (+)-benzotetramisole ((+)-BTM)9 as a chiral acyl-transfer catalyst. Simply by mixing racemic
carboxylic acids with these reagents and chiral BTM, the corresponding chiral carboxylic esters and
unreacted chiral carboxylic acids could be obtained in high enantiomeric excesses. Moreover, based on
our knowledge of activating carboxylic acids in macrolactonization using 2-methyl-6-nitrobenzoic
anhydride (MNBA),10 we have developed activating agents using suitable carboxylic acid anhydrides
such as p-methoxybenzoic anhydride (PMBA),8 followed by pivalic anhydride (Piv2O).11 Furthermore, in
a mechanistic study, it was revealed that this enantioselective esterification proceeds through a mixed

HETEROCYCLES, Vol. 86, No. 2, 2012
1229
anhydride (MA), a reactive intermediate formed in situ from the substrate and the activating reagent,
followed by formation of a transition state with the achiral alcohol and the chiral BTM.11
Shiina (2008)
(!-Np)2CHOH (0.5 equiv.)
PMBA (1.2 equiv.)
i-Pr2NEt (1.8 equiv.)
CO2H
Me
CO2CH(!-Np)2
(+)-BTM (5 mol%)
CO2H
Me
+
Me
(R)-Ester
CH2Cl2 (0.2 M); rt, 4 h
rac-CO2H
(S)-CO2H
(39% yield, 52% ee)
(36% yield, 91% ee)
PMBA = p-Methoxybenzoic anhydride
Birman (2009)
S
N
S
N
DCC (0.53 equiv.),
toluene
; rt, 15 min
N
N
OPh
Ph
O
Ph
Me
CO O
2
Me
CO2H
(+)-BTM
(+)-HBTM
rac-CO2H
(!-Np)2CHOH (0.5 equiv.)
i-Pr2NEt (1.0 equiv.)
(+)-HBTM (5 mol%)
O
+
O
Me
CO2H
Me
CO2CH(!-Np)2
toluene; rt, 10 h
(S)-Ester
(45% yield, 90% ee)
(R)-CO2H
(76% ee)
Scheme 2. Previously reported kinetic resolution of racemic carboxylic acids by asymmetric
esterification
Subsequently, Birman et al. disclosed a novel procedure of high-enantioselective esterification by
switching from the carboxylic acid anhydride to DCC and from BTM to homobenzotetramisole (HBTM),
respectively.12 They also showed that this kinetic resolution system is applicable to a variety of racemic
2-substituted propanoic acids including 2-aryl, 2-aryloxy, and 2-arylthiopropanoic acids. However, as this
procedure is a two-stage treatment, involving generation of the symmetrical carboxylic acid anhydride
(SA) by DCC followed by completion of esterification by adding nucleophile, base, and catalyst, it can
still be further improved.
In this study, a one-stage treatment based on in situ MA-formation was applied to the kinetic resolution of
2-aryloxypropanoic acids using Piv2O. We aimed to investigate further the substrate scope and elucidate
its transition state and chiral recognition mechanism.
RESULTS AND DISCUSSION
In our previous study on the kinetic resolution of racemic 2-arylpropionic acids, we were able to identify
the equivalent amounts of each reagent required as 0.5 equiv. of (!-Np)2CHOH, 1.2 equiv. of Piv2O, 1.8

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HETEROCYCLES, Vol. 86, No. 2, 2012
equiv. of i-Pr2NEt, and 5 mol% of (+)-BTM. Therefore, in the current study, we used these optimized
conditions as the initial reaction conditions for the screening of suitable solvents.
2-Phenoxypropanoic acid (1a), a simple 2-aryloxypropanoic acid, was selected as the model substrate,
and six commonly-used solvents were employed in our initial screening (Table 1).
Table 1. Screening of solvents to optimize reaction conditions for the kinetic resolution of
2-aryloxypropanoic acids
(!-Np)2CHOH (0.5 equiv.)
Piv2O (1.2 equiv.)
i-Pr2NEt (1.8 equiv.)
(+)-BTM (5 mol%)
+
O
O
O
Me
CO2CH(!-Np)2
Me
CO2H
Me
CO2H
solvent (0.2 M); rt, 24 h
(R)-1a
rac-1a
(S)-2a
Yielda of
ee of
(S)-2a/(R)-1a (%)
75/54
Entry
Solvent
s
(S)-2a/(R)-1a (%)
42/46
1
2
3
4
5
6
CH2Cl2
THF
12
16
12
49/43
75/76
DMF
47/46
74/63
Et2O
47/41
59/61
7.1
6.8
6.0
toluene
MeCN
50/43
58/61
46/50
58/49
aisolated yield.
To evaluate the effectiveness of the kinetic resolution, we used a selectivity factor (s-value), which
indicates the ratio of reactivities of the (R)- and (S)-carboxylic acids.13 In all entries except CH2Cl2 (Entry
1, 42% yield), 0.5 equiv. of (!-Np)2CHOH was converted to the ester almost quantitatively, while the
enantiomeric excesses of the esters produced and s-values greatly depended on the solvent used. Diethyl
ether (Entry 4), toluene (Entry 5), and MeCN (Entry 6) gave diminished enantiomeric excesses of esters
below 60% ee. Tetrahydrofuran (THF) gave the best enantiomeric excess and s-value, as shown in Entry
2 (75% ee, s = 16).
Having optimized the reaction conditions, a variety of 2-aryloxypropanoic acids bearing various
substituted phenyls or bicyclic aromatic rings were applied to the investigation of the substrate scope
(Table 2).

HETEROCYCLES, Vol. 86, No. 2, 2012
1231
Table 2. Kinetic resolution of racemic 2-aryloxypropanoic acids
(!-Np)2CHOH (0.5 equiv.)
Piv2O (1.2 equiv.)
i-Pr2NEt (1.8 equiv.)
(+)-BTM (5 mol%)
Ar
Ar
Ar
+
O
O
O
Me
CO2CH(!-Np)2
Me
CO2H
Me
CO2H
THF (0.2 M); rt, 24 h
(R)-1a–q
rac-1a–q
(S)-2a–q
Yielda of
ee of
Entry
Ar
s
(S)-2/(R)-1 (%)
49/43
46/45
49/43
49/50
46/45
46/39
50/45
49/46
50/47
50/49
46/51
47/44
48/45
48/49
49/43
47/53
47/50
(S)-2/(R)-1 (%)
75/76
93/90
75/78
72/68
88/86
76/77
73/76
84/88
87/83
75/73
78/69
90/90
86/85
95/88
88/76
92/79
96/89
1b
2
C6H5 (a)
o-Cl-C6H4 (b)
m-Cl-C6H4 (c)
p-Cl-C6H4 (d)
o-Me-C6H4 (e)
m-Me-C6H4 (f)
p-Me-C6H4 (g)
p-Cl-o-Me-C6H3 (h)
!-Naphthyl (i)
"-Naphthyl (j)
2,6-Cl2-C6H3 (k)
2,4-Cl2-C6H3 (l)
o-F-C6H4 (m)
16
82
16
12
45
17
14
34
36
15
16
60
35
110
38
58
131
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
o-Br-C6H4 (n)
o-MeO-C6H4 (o)
o-NO2-C6H4 (p)
o-Ph-C6H4 (q)
aisolated yield, bTable 1, Entry 2.
In all entries, the yields of the corresponding esters were almost quantitative. In Entries 2–7, carboxylic
acids incorporating an Me or Cl substituent at the ortho-, meta-, or para-position of the 2-phenoxy group
were investigated. The substituent of the phenoxy group was found to affect the stereochemistry, with
carboxylic acids bearing the ortho-substituted phenoxy group giving good enantiomeric excesses and
high s-values, while substituents at the meta- (Entry 3, s = 16 and Entry 6, s = 17) or para- (Entry 4, s =
12 and Entry 7, s = 14) positions having little effect relative to unsubstituted 2-phenoxypropanoic acid
(1a) (Entry 1, s = 16). By exploiting this tendency, racemic 2-(p-chloro-o-methylphenoxy)propanoic acid
(rac-1h), MCPP, was successfully separated to provide the potent (R)-(+)-carboxylic acid ((R)-1h),
MCPP-P (Entry 8, 46% yield, 88% ee). A similar tendency was also observed in carboxylic acids
incorporating a naphthoxy group. For example, 2-(!-naphthoxy)propanoic acid (1i) (Entry 9, s = 36) gave
a good s-value compared with 2-("-naphthoxy)propanoic acid (1j) (Entry 10, s = 15).

1232
HETEROCYCLES, Vol. 86, No. 2, 2012
In addition, the carboxylic acid bearing substituents at both ortho-positions of the phenoxy group,
2-(2,6-dichlorophenoxy)propanoic acid (1k) (Entry 11, s = 16), gave diminished selectivity compared
with an ortho-monosubstituted (Entry 2, s = 82) or ortho, para-disubstituted phenoxy group on the
carboxylic acid (Entry 12, s = 60).
Furthermore, a series of carboxylic acids incorporating an ortho-substituent such as a halogen (Entries 2,
13, and 14), methoxy (Entry 15), nitro (Entry 16), or phenyl (Entry 17) substituent in the phenoxy group
were examined. Therefore, irrespective of the electric properties of the substituents, bulky
ortho-substituents in the phenoxy group have a tendency to enhance the enantioselectivity as represented
by the o-bromophenoxy group (Entry 14, s = 110) and o-phenylphenoxy group (Entry 17, s = 131).
Regarding the absolute configuration of these products, it was experimentally confirmed that the obtained
esters (2) take S configuration in entries 1, 2, and 12 (see experimental section). In a similar fashion, it is
easy to consider that the other produced chiral esters take S configuration.
We then considered whether other extended 2-aryloxyalkanoic acids are applicable to our procedure. The
o-phenylphenoxy group that showed the best selectivity in Table 2 was applied to the screening of
alkanoic acids (Table 3). Contrary to our expectations, conversion yields of 2-aryloxybutanoic acid (1r)
(Entry 2) and 2-aryloxypentanoic acid (1s) (Entry 3) into the corresponding esters were dramatically
reduced to approximately 20%. Doubling of the catalyst loading led to some improvement in the yield of
the corresponding ester (R)-2s, but only up to 34% (Entry 4). As shown in Entry 5, it is clear that
2-aryloxyalkanoic acids that branch at the 3-position are not suitable for this kinetic resolution system.
Table 3. Kinetic resolution of racemic 2-(o-phenylphenoxy)alkanoic acids
(!-Np)2CHOH (0.5 equiv.)
Ph
O
Ph
O
Ph
O
Piv2O (1.2 equiv.)
i-Pr2NEt (1.8 equiv.)
(+)-BTM (5 mol%)
+
R
CO2CH(!-Np)2
R
CO2H
R
CO2H
THF (0.2 M); rt, 24 h
(R)-1q–t
rac-1q–t
(S)-2q–t
Yielda of
ee of
(S)-2/(R)-1 (%)
96/89
Entry
R
s
(S)-2/(R)-1 (%)
47/50
1b
2
Me (q)
Et (r)
131
45
33
36
-
22/76
94/30
3
4c
n-Pr (s)
n-Pr (s)
i-Pr (t)
18/80
93/21
34/53
91/51
5
0/68
-/-
aisolated yield, bTable 2, Entry 17, c(+)-BTM (10 mol%).

HETEROCYCLES, Vol. 86, No. 2, 2012
1233
Subsequently, we anticipated that removing the aryl group of the separated chiral 2-aryloxypropionic acid
esters would offer a novel approach to provide optically active 2-hydroxypropanoic acid esters, applicable
for further syntheses. Specifically, based on the preference of substituents in the phenoxy group as
described above, an o-tert-butyl-p-methoxyphenoxy group was selected as the aryloxy group
incorporating both a bulky substituent in the ortho-position and a p-methoxy substituent that are
oxidatively removable by cerium ammonium nitrate (CAN).14 As shown in Scheme 3, racemic
2-(o-tert-butyl-p-methoxyphenoxy)propanoic acid (rac-1u) was readily prepared from racemic ethyl
2-bromopropanoate and an inexpensive antioxidant, butylated hydroxy anisole (BHA), and then kinetic
resolution of rac-1u was successfully accomplished to provide the desired optically active ester (S)-2u in
48% yield with an excellent selectivity (96% ee, s = 158). Finally, the oxidative deprotection of the
p-methoxy aryl group in (S)-2u afforded the corresponding 2-hydroxypropanoic acid ester ((S)-3) in 62%
yield with maintenance of optical purity (96% ee).
MeO
tBu
O
1) NaH, DMF
2) NaOH aq., EtOH,
then HCl aq.
MeO
tBu
OH
Br
+
Me
CO2Et
84%
Me
rac-1u
CO2H
BHA
(antioxidant)
(!-Np)2CHOH (0.5 equiv.)
Piv2O (1.2 equiv.)
i-Pr2NEt (1.8 equiv.)
(+)-BTM (5 mol%)
tBu
O
MeO
tBu
O
MeO
+
THF (0.2 M); rt, 24 h
s = 158
Me
CO2CH(!-Np)2
Me
CO2H
(S)-2u
48% yield, 96% ee
(R)-1u
43% yield, 93% ee
CAN (5 equiv.)
DMF-H2O (8 : 1, v/v); rt
(S)-3
62% yield
96% ee
OH
CO2CH(!-Np)2
Me
Scheme 3. Kinetic resolution of racemic 2-(o-tert-butyl-p-methoxyphenoxy)propanoic acid (rac-1u) and
deprotection of the aryloxy group
To explain these experimental findings, theoretical aspects including the transition state and the chiral
recognition mechanism of the asymmetric esterification were considered next. Given the perspectives
described in our previous work,11 we propose a catalytic cycle for this reaction as depicted in Scheme 4.

1234
HETEROCYCLES, Vol. 86, No. 2, 2012
O
O
(S)
O
O
O
+
t-Bu
(!-Np)2HCO
HO
Me
(S)-2a
t-Bu
O
t-Bu
S
N
Ph
N
symmetrical
anhydride
(SA)
(+)-BTM
Catalyst
step D
step A
HO
1/2
(!-Np)2CHOH
O
N
O
O
t-Bu
Ph
S
Me
S
N
O
N
O
Ph
N
O
t-Bu
O
t-Bu
second intermediate (int-II)
first intermediate (int-I)
mixed anhydride (MA)
O
O
(S)
O
step C
step B
t-Bu
O
O
Me
O
(S)-MA
HO
+
Me
rac-1a
O
O
Catalyst
Catalyst
(R)
O
t-Bu
O
O
Me
+
O
(R)-MA
HO
t-Bu
(R)
H3O+
O
HO
Me
quenching
(R)-1a
Scheme 4. Proposed reaction pathway for the kinetic resolution of rac-1a
First, a MA forms as the key intermediate in situ from Piv2O with racemic 2-phenoxypropanoic acid
(rac-1a) via generation of a zwitterion (int-I) through steps A and B by promotion of the acyl-transfer
catalyst, (+)-BTM. In the next step C, (S)-, and (R)-MA would be activated again by (+)-BTM to form the
corresponding zwitterionic species (int-II), and half the amount of int-II generated from (S)-MA would
selectively react with (!-Np)2CHOH to afford the desired (S)-2a with high enantiomeric excess through
step D. The remaining mixed anhydride ((R)-MA) would be hydrolyzed to produce unreacted (R)-1a as a
recovered optically active starting material with good enantiopurity. It is anticipated step D would be the
key enantio-determining step during this multiple transacylation process.
Based on these considerations, determination of the transition state forming the optically active (S)-2a
from (S)-1a with (!-Np)2CHOH, (+)-BTM, and Piv2O via the dihydroimidazolium salt (Int-II) was
carried out using density functional theory (DFT) calculations at the B3LYP/6-31G*//B3LYP/6-31G*
level of theory according to the method previously reported.11,15

HETEROCYCLES, Vol. 86, No. 2, 2012
1235
We successfully obtained two predominant transition states ((S)-ts1 and (S)-ts2) to produce the desired
ester (S)-2a as depicted in Scheme 5. These transition states differed in orientation of the 2-phenoxy
groups of (S)-1a, with the 2-phenoxy group of the (S)-ts1 overlapping the phenyl ring at the C-2 position
of the dihydroimidazolium salt, while the 2-phenoxy group of (S)-ts2 faces the opposite side. (S)-ts1 is
lower in energy than (S)-ts2 by 1.66 kcal/mol owing to the stable stacking structure of aromatic rings as
illustrated in Scheme 5 and Figure 1. Consequently, it was supposed that esterification of (S)-1a proceeds
through (S)-ts1.
The high selectivity in the present kinetic resolution could be explained by the rapid transformation of
(S)-1a into (S)-2a via this stabilized transition structure consisting of the (!-Np)2CHOH and the
dihydroimidazolium salt (int-II) derived from the mixed anhydride (S)-MA and (+)-BTM. In the case of
the preferred (S)-ts1, the distance of the forming carbon–oxygen bond (between the carbonyl carbon of
the acid component and oxygen of the hydroxyl group) is 2.169 Å, accompanied by the coordination of
oxygen in the carbonyl moiety onto the hydrogen at the C-1 position of alcohol at a distance of 2.401 Å,
as shown in Figure 1. It is further observed that the distance of the cleaving oxygen–hydrogen bond
(between oxygen and hydrogen in the hydroxyl group) is 1.277 Å.
O
O
N
S
Me
O
Ph
N
O
t-Bu
second intermediate (int-II)
generated from (±)-1a
step D
OH
(S)-ts1
(S)-ts2
(R)-ts1
(R)-ts2
H
H
O
H
O
H
Me
O
Me
O
H O
O
H O
O
H
O
H
H
O
H
O
H
H O
O
O
S
N
S
N
S
N
S
N
t-Bu
t-Bu
t-Bu
t-Bu
N
N
N
N
O
O
O
O
O
O
Me
Me
preferable transition state;
rel = 0 kcal/mol
unpreferable transition state; unfavorable transition state; unfavorable transition state;
E
E
rel = +1.66 kcal/mol
Erel = +3.90 kcal/mol
E
rel = +7.30 kcal/mol
O
O
(S)
O
(R)
O
O
O
(!-Np)2HCO
+
+
(!-Np)2HCO
t-Bu
HO
t-Bu
HO
Me
Me
(S)-2a
(R)-2a
Scheme 5. Calculated transition state of the kinetic resolution of rac-1a
A frequency analysis of (S)-ts1 revealed that the nucleophilic attack of the alcohol to the carbonyl group
and the deprotonation of the hydroxyl group with the pivalate anion proceeded under a concerted reaction

1236
HETEROCYCLES, Vol. 86, No. 2, 2012
mechanism because the carbon–oxygen bond-forming step and the oxygen–hydrogen bond-cleaving
process occurred synchronously. The diarylalcohol moiety of (!-Np)2CHOH in (S)-ts1 has a rigid
structure, in which the conformation is restricted by the attractive interaction between one of the
naphthalene rings and the positive electronic charge on the face of the dihydroimidazolium salt as well as
coordination of the oxygen atoms in the pivalate anion onto the hydrogen atom in the hydroxyl group
(1.151 Å) and the hydrogen atom at the C-2 position of the dihydroimidazolium salt (2.100 Å).
1.277 Å
1.235 Å
1.151 Å
1.184 Å
2.360 Å
2.401 Å
2.155 Å
2.169 Å
2.100 Å
2.079 Å
transition state ((S)-ts1)
transition state ((S)-ts2)
1.185 Å
1.233 Å
1.229 Å
1.189 Å
2.401 Å
2.298 Å
2.107 Å
2.134 Å
2.063 Å
2.045 Å
transition state ((R)-ts1)
transition state ((R)-ts2)
Figure 1. Structure of calculated transition state ((S)-ts1, (S)-ts2, (R)-ts1, and (R)-ts2)
Conversely, complexation of (!-Np)2CHOH with the dihydroimidazolium salt (int-II) including (R)-MA
and (+)-BTM, an enantiomer of (S)-MA, produced two transition states, (R)-ts1 and (R)-ts2, with a high
energy relative to (S)-ts1, Erel = +3.90 kcal/mol and +7.30 kcal/mol, respectively (Scheme 5). Thus, it is
supposed that transformation of (R)-1a into (R)-2a proceeds mainly through the former transition state,
(R)-ts1. These high-energy transition states derived from the steric repulsion between the methyl
substituent at the 2-position of (R)-1a and the phenyl group at the C-2 position of the dihydroimidazolium

HETEROCYCLES, Vol. 86, No. 2, 2012
1237
salt to afford the corresponding (R)-2a. In addition, it is considered that the strained conformation of the
2-phenoxy group necessary to avoid the steric hindrance of (!-Np)2CHOH destabilizes its transition state.
On the basis of theoretical calculations, it is certain that the desired chiral (S)-2a was selectively obtained
by the rapid transformation of (S)-MA through the most stable transition state (S)-ts1, while the
esterification of (R)-1a via (R)-ts1 proceeded very slowly according to the energy gap of 3.90 kcal/mol.
Using this established protocol for proving transition states, we then tried to account theoretically for the
enhanced selectivity by substitution at the ortho-position in the phenoxy group, as depicted in Table 2.
2-(o-Chlorophenoxy)propanoic acid (1b) (Table 2, Entry 2, s = 82) was selected as a model substrate for
further computational calculations to determine the transition states and their energies. Successful
calculations of 1b disclosed four possible transition states that afford the corresponding esters;
(S)-o-Cl-ts1 and (S)-o-Cl-ts2 derived from (S)-1b, and (R)-o-Cl-ts1 and (R)-o-Cl-ts2 derived from (R)-1b,
respectively (Scheme 6).
Cl
O
O
N
S
Me
O
Ph
N
O
t-Bu
second intermediate (int-II)
generated from (±)-1b
step D
OH
(S)-o-Cl-ts1
(S)-o-Cl-ts2
(R)-o-Cl-ts2
(R)-o-Cl-ts1
H
H
H
H
Cl
O
Me
O
Me
O
O
O
H
H
O
H
H O
O
H
H
O
H
H
O
O
O
O
O
O
S
N
N
Cl
t-Bu
S
N
S
N
S
N
t-Bu
t-Bu
t-Bu
Cl
N
N
N
O
O
O
O
O
Me
Me
Cl
preferable transition state;
unpreferable transition state; unfavorable transition state; unfavorable transition state;
Erel = 0 kcal/mol
Erel = +3.31 kcal/mol
Erel = +5.93 kcal/mol
Erel = +4.01 kcal/mol
O
(S)
Cl
O
Cl
O
+
(R)
O
O
O
(!-Np)2HCO
(!-Np)2HCO
+
t-Bu
HO
t-Bu
HO
Me
Me
(S)-2b
(R)-2b
Scheme 6. Calculated transition state of the kinetic resolution of rac-1b
Calculations of the energy of each transition state revealed the enhancement of the relative energy of the
unfavorable (R)-o-Cl-ts2 (Erel(o-Cl) = +4.01 kcal/mol, Scheme 6) compared with the corresponding relative
energy of (R)-ts1 derived from (R)-1a (Erel = +3.90 kcal/mol, Scheme 5). Therefore, it is considered that

1238
HETEROCYCLES, Vol. 86, No. 2, 2012
the large energy gap because of the increased strain at the 2-phenoxy group by ortho-substitution causes
the observed high ee shown in Table 2.
CONCLUTIONS
In summary, we have developed an effective kinetic resolution system to provide optically active
2-aryloxypropanoic acids and the corresponding esters. By screening the reaction media, it was found that
THF was the most suitable solvent to achieve high enantiomeric excesses of the recovered carboxylic
acids and the formed esters. Investigation of a series of substituents on the 2-phenoxy groups showed the
preference of ortho-substituted bulky groups. This perception was also utilized for the production of the
optically pure 2-hydroxypropanoic acid ester using the o-tert-butyl-p-methoxyphenyl group as a
functional protecting group.
In addition, we succeeded in disclosing the reaction mechanism to afford high enantioselectivity using
theoretical calculations, and expounded on the substituent effect in the 2-phenoxy group. Further
investigation will be focused on different racemic carboxylic acids bearing other hetero atoms at the
2-position.
EXPERIMENTAL
1
All melting points were uncorrected. IR spectra were taken on a JASCO FT/IR-6100 spectrometer. H
and 13C NMR spectra were measured in CDCl3 with a Bruker AM400 (400 MHz for 1H NMR, 100 MHz
for 13C NMR) instrument, and the chemical shifts were reported in ppm from tetramethylsilane (0.00
ppm) for 1H NMR and CDCl3 (77.0 ppm) for 13C NMR as an internal standard, respectively. HRMS were
recorded by Bruker ESI-TOF MS. Column chromatography was performed on Silica gel 60 (Merck) or
Wakogel B5F. Thin layer chromatography was performed on Wakogel B5F. All reactions were carried
out under argon atmosphere in dried glassware, unless otherwise noted. Diethyl ether was distilled from
sodium and benzophenone, dichloromethane was distilled from diphosphorus pentoxide, then calcium
hydride, and dried over MS 4A, and THF and DMF were distilled from calcium hydride, and dried over
MS 4A.
Racemic 2-aryloxypropanoic acids, rac-1a–c and rac-1l, were purchased from Tokyo Kasei Kogyo Co.,
Ltd (TCI). Rac-1d–k, rac-1m–r, and rac-1u were prepared from racemic ethyl 2-bromopropanoate or
methyl 2-bromobutanoate and the corresponding hydroxyaryl compounds according to literature method.6
Methyl (R)-lactate that was used for the preparation of the authentic (S)-2b was also purchased from TCI.
Racemic ethyl 2-([1,1'-biphenyl]-2-yloxy)pentanoate (rac-4s).
To a mixture of racemic ethyl 2-hydroxypentanoate (1.46 g, 10.0 mmol), 2-phenylphenol (1.70 g, 10.0
mmol), and triphenylphosphine (3.15 g, 12.0 mmol) in THF (35 mL) at 0 °C was added 40% diisopropyl

HETEROCYCLES, Vol. 86, No. 2, 2012
1239
azodicarboxylate in toluene (7.37 mL, 14.0 mmol). After the reaction mixture had been stirred for 2 h at
room temperature, 40% diisopropyl azodicarboxylate in toluene (2.11 mL, 4.00 mmol) was added. The
reaction mixture was stirred for 14 h at room temperature, and then diluted with hexane. After filtration of
the slurry mixture and evaporation of the solvent, the crude product was purified by silica gel column
chromatography (EtOAc/hexane = 1/40) to afford rac-4s (1.12 g, 38% yield) as a colorless oil: IR (neat):
-1
1
2961, 1732, 1598, 1584, 1503, 1480, 770, 751, 732, 698 cm ; H NMR (CDCl ): " 7.63-7.56 (m, 2H, Ar),
3
7.42-7.20 (m, 5H, Ar), 7.07-7.00 (m, 1H, Ar), 6.86-6.80 (m, 1H, Ar), 4.60 (t, J = 6.2 Hz, 1H, 2-H), 4.18
(q, J = 7.2 Hz, 2H, OEt), 1.82 (dt, J = 6.2, 7.6 Hz, 2H, 3-H), 1.37 (qt, J = 7.2, 7.6 Hz, 2H, 4-H), 1.22 (t, J
13
= 7.2 Hz, 3H, OEt), 0.85 (t, J = 7.2 Hz, 3H, 5-CH3); C NMR (CDCl ): " 171.9 (1), 154.8, 138.4, 131.5,
3
131.2, 129.7, 128.4, 127.8, 126.8, 121.7, 113.1, 76.7 (2), 61.0 (Et), 34.7 (3), 18.3 (4), 14.1 (Et), 13.7 (5);
+
HR MS: calcd for C H O Na (M + Na )ꢀ321.1461, found 321.1468.
19 22
3
Racemic 2-((1,1'-biphenyl)-2-yloxy)pentanoic acid (rac-1s).
To a solution of rac-4s (1.08 g, 3.62 mmol) in ethanol (20 mL) at 0 °C was added aqueous sodium
hydroxide (4.2 M, 5.0 mL, 21 mmol). The reaction mixture was stirred at room temperature for 4 h, and
then it was acidified with 1 M hydrochloric acid (50 mL). The mixture was extracted with EtOAc, and the
organic layer was dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent,
the crude product was crystallized from CH2Cl2 and hexane to afford rac-1s (879 mg, 90% yield) as a
white solid: Mp 131-133 °C (CH2Cl2/hexane); IR (KBr): 2972, 1704, 1599, 1583, 1502, 1479, 772, 748,
-1
728, 701 cm ; H NMR (CDCl ): " 9.42 (br s, 1H, CO H), 7.59-7.50 (m, 2H, Ar), 7.45-7.23 (m, 5H, Ar),
1
3
2
7.12-7.05 (m, 1H, Ar), 6.93-6.86 (m, 1H, Ar), 4.65 (t, J = 6.0 Hz, 1H, 2-H), 1.94-1.78 (m, 2H, 3-H),
13
1.46-1.31 (m, 2H, 4-H), 0.86 (t, J = 7.2 Hz, 3H, 5-CH3); C NMR (CDCl ): " 175.2 (1), 154.2, 138.1,
3
131.9, 131.3, 129.5, 128.6, 128.0, 127.1, 122.4, 113.5, 76.7 (2), 34.4 (3), 18.1 (4), 13.6 (5); HR MS: calcd
+
for C H O Na (M + Na )ꢀ293.1148, found 293.1152.
17 18
3
Racemic ethyl 2-[(1,1'-biphenyl)-2-yloxy]-3-methylbutanoate (rac-4t).
To a solution of ethyl 3-methyl-2-oxobutanoate (290 mg, 2.0 mmol) in Et2O (4 mL) at 0 °C was added
sodium borohydride (150 mg, 4.0 mmol) in water (2 mL). After the reaction mixture had been stirred for
1 h at 0 °C, sodium borohydride (38 mg, 1.0 mmol) was added. The reaction mixture was stirred for 2 h at
0 °C, and then diluted with water. The mixture was extracted with CH2Cl2, and the organic layer was
dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, ethyl
2-hydroxy-3-methylbutanoate was obtained as a colorless oil. This crude product was used in the next
reaction without further purification.
To a solution of ethyl 2-hydroxy-3-methylbutanoate (2.0 mmol) and 2,6-lutidine (290 µL, 2.5 mmol) in
CH2Cl2 (6 mL) at –78 °C was added trifluoromethanesulfonic anhydride (420 µL, 2.5 mmol). The

1240
HETEROCYCLES, Vol. 86, No. 2, 2012
reaction mixture had been stirred for 5 min at –78 °C, and then gradually raised to room temperature for 2
h. After cooling to 0 °C, the reaction mixture was diluted with water. The mixture was extracted with
CH2Cl2, and the organic layer was dried over sodium sulfate. After filtration of the mixture and
evaporation of the solvent, the crude product was diluted with CH2Cl2-hexane (1:1, v/v) and filtered
through
silica
gel.
The
filtrate
was
concentrated
to
afford
ethyl
3-methyl-2-{[(trifluoromethyl)sulfonyl]oxy}butanoate (470 mg, 84% yield) as a pale yellow oil. This
crude product was used in the next reaction without further purification.
To a solution of 3-methyl-2-{[(trifluoromethyl)sulfonyl]oxy}butanoate (284 mg, 1.67 mmol) and
2-phenylphenol (464 mg, 1.67 mol) in DMF (4 mL) at 0 °C was added sodium hydride (55% in paraffin
liquid, 87 mg, 2.0 mmol). After the reaction mixture had been stirred for 25 min at room temperature,
water was added. The mixture was extracted with hexane-EtOAc (1:1, v/v), and the organic layer was
dried over sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product
was purified by preparative thin layer chromatography on silica (EtOAc/hexane = 1/3) to afford rac-4t
(411 mg, 82% yield) as a colorless oil: IR (neat): 2961, 1732, 1598, 1584, 1503, 1480, 770, 751, 732, 698
-1
1
cm ; H NMR (CDCl ): " 7.64-7.58 (m, 2H, Ar), 7.43-7.19 (m, 5H, Ar), 7.12-7.05 (m, 1H, Ar),
3
6.93-6.86 (m, 1H, Ar), 4.43 (d, J = 4.8 Hz, 1H, 2-H), 4.19 (q, J = 7.2 Hz, 2H, OEt), 2.19 (dqq, J = 4.8, 6.8,
6.8 Hz, 1H, 3-H), 1.22 (t, J = 7.2 Hz, 3H, OEt), 0.92 (d, J = 6.8 Hz, 3H, 4-CH3), 0.91 (d, J = 6.8 Hz, 3H,
13
4-CH3); C NMR (CDCl ): " 171.1 (1), 154.9, 138.5, 131.5, 131.1, 129.8, 128.3, 127.7, 126.7, 121.4,
3
112.3, 81.3 (2), 60.9 (Et), 31.7 (3), 18.7 (4), 17.5 (4), 14.2 (Et); HR MS: calcd for C H O Na (M +
19 22
3
+
Na )ꢀ321.1461, found 321.1452.
Racemic (R)-2-[(1,1'-biphenyl)-2-yloxy]-3-methylbutanoic acid (rac-1t).
Rac-4t (377 mg, 1.26 mmol) was hydrolyzed in accordance with the preparation of rac-3s, and then
crystallized from CH2Cl2 and hexane to afford rac-1t (257 mg, 75% yield) as a white solid: Mp 82-84 °C
-1
1
(CH2Cl2/hexane); IR (KBr): 2967, 1702, 1601, 1585, 1503, 1479, 766, 748, 727, 697 cm ; H NMR
(CDCl ): " 8.58 (br s, 1H, CO H), 7.59-7.51 (m, 2H, Ar), 7.46-7.18 (m, 5H, Ar), 7.11-7.03 (m, 1H, Ar),
3
2
6.89-6.80 (m, 1H, Ar), 4.43 (d, J = 4.0 Hz, 1H, 2-H), 2.31-2.18 (m, 1H, 3-H), 0.95 (d, J = 6.8 Hz, 3H,
13
4-CH3), 0.94 (d, J = 6.8 Hz, 3H, 4-CH3); C NMR (CDCl ): " 174.6 (1), 154.5, 138.1, 131.8, 131.3,
3
129.7, 128.6, 127.9, 127.1, 122.1, 112.8, 81.3 (2), 31.6 (3), 18.6 (4), 17.2 (4); HR MS: calcd for
+
C H O Na (M + Na )ꢀ293.1148, found 293.1158.
17 18
3
General procedure for kinetic resolution of racemic 2-aryloxypropanoic acid (Tables 1–3, Scheme
3).
To a mixture of racemic 2-aryloxypropanoic acid (rac-1) (0.200 mmol), pivalic anhydride (48.7 µL,
0.240 mmol), and bis(!-naphthyl)methanol (28.4 mg, 0.100 mmol) in solvent (1.0 mL) at room

HETEROCYCLES, Vol. 86, No. 2, 2012
1241
temperature were successively added diisopropylethylamine (62.7 µL, 0.360 mmol) and (+)-BTM (2.5
mg, 10 µmol). The reaction mixture was stirred for 24 h at room temperature, and then quenched with 1
M hydrochloric acid. The mixture was extracted with EtOAc, and the organic layer was dried over
sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was
purified by preparative thin layer chromatography on silica (toluene/hexane = 90/10) to afford the
corresponding (S)-2. The polar fraction including carboxylic acid was further purified by preparative thin
layer chromatography on silica (EtOAc/hexane/formic acid = 10/40/1) to afford the recovered optically
active (R)-1.
(R)-2-Phenoxypropanoic acid ((R)-1a). [Table 1, Entry 2 (Table 2, Entry 1), 43% yield, 76% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min): tR = 16.3 min (12.0%),
tR = 22.0 min (88.0%); The absolute configuration was determined as R by the comparison of the
retention time with the literature data.12a
Di(1-naphthyl)methyl (S)-2-phenoxypropanoate ((S)-2a). [Table 1, Entry 2 (Table 2, Entry 1), 49%
yield, 75% ee] Spectroscopic data were previously reported.12a HPLC (CHIRALCEL OD-H,
i-PrOH/hexane = 1/9, flow rate = 0.5 mL/min): tR = 12.2 min (12.4%), tR = 27.0 min (87.6%).
(R)-2-(2-Chlorophenoxy)propanoic acid ((R)-1b). [Table 2, Entry 2, 45% yield, 90% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 20.5 min (4.9%),
tR = 25.7 min (95.1%). The absolute configuration was determined as R by the comparison of the
retention time with that of the authentic sample (S)-1b derived from methyl (R)-lactate (vide infra).
Di(1-naphthyl)methyl (S)-2-(2-chlorophenoxy)propanoate ((S)-2b). [Table 2, Entry 2, 46% yield, 93%
ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 19.3 min (96.4%),
1
t = 24.0 min (3.6%); H NMR (CDCl ): " 8.47 (s, 1H, 1’-H), 8.10-7.75 (m, 6H, Ar), 7.57-7.17 (m, 9H,
3
R
Ar), 6.96-6.78 (m, 2H, Ar), 6.75-6.62 (m, 1H, Ar), 4.86 (q, J = 6.8 Hz, 1H, 2-H), 1.68 (d, J = 6.8 Hz, 3H,
13
3-CH3); C NMR (CDCl ): " 170.8 (1), 153.2, 134.2, 134.1, 133.9, 133.8, 131.1, 130.9, 130.5, 129.3,
3
129.1, 129.0, 128.8, 127.4, 126.8, 126.6, 126.2, 125.93, 125.85, 125.8, 125.2, 125.1, 123.7, 123.30,
+
123.28, 122.5, 115.0, 74.0 (2), 71.9 (1’), 18.4 (3); HR MS: calcd for C H ClO Na (M + Na ) 489.1228,
30 23
3
found 489.1210; Analytical data on racemic compound: Mp 163-164 °C (hexane); IR (KBr): 3064, 1749,
1589, 1510, 1481, 1185, 1122, 803, 786, 780, 758 cm-1. The absolute configuration was determined as S
by the comparison of the retention time with that of the authentic sample (R)-2b derived from methyl
(R)-lactate (vide infra).
(R)-2-(3-Chlorophenoxy)propanoic acid ((R)-1c). [Table 2, Entry 3, 43% yield, 78% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min): tR = 14.4 min (10.8%),
tR = 17.8 min (89.2%).
Di(1-naphthyl)methyl (S)-2-(3-chlorophenoxy)propanoate ((S)-2c). [Table 2, Entry 3, 49% yield, 75%

1242
HETEROCYCLES, Vol. 86, No. 2, 2012
ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 1.0 mL/min): tR = 17.5 min (87.3%),
1
t = 21.9 min (12.7%); H NMR (CDCl ): " 8.45 (s, 1H, 1’-H), 8.06-7.73 (m, 6H, Ar), 7.58-7.18 (m, 8H,
3
R
Ar), 7.06-6.95 (m, 1H, Ar), 6.94-6.81 (m, 2H, Ar), 6.69-6.61 (m, 1H, Ar), 4.83 (q, J = 6.8 Hz, 1H, 2-H),
13
1.61 (d, J = 6.8 Hz, 3H, 3-CH3); C NMR (CDCl ): " 171.0 (1), 158.2, 134.9, 134.1, 134.0, 133.9, 133.8,
3
131.1, 130.9, 130.2, 129.4, 129.2, 129.0, 128.8, 126.9, 126.6, 126.2, 126.0, 125.9, 125.7, 125.2, 125.1,
123.3, 123.2, 121.8, 115.7, 113.3, 72.8 (2), 72.1 (1’), 18.5 (3); HR MS: calcd for C H ClO Na (M +
30 23
3
+
Na ) 489.1228, found 489.1213; Analytical data on racemic compound: Mp 127-128 °C (hexane); IR
(KBr): 3060, 1743, 1625, 1595, 1580, 1510, 1476, 1183, 1131, 800, 783 cm-1.
(R)-2-(4-Chlorophenoxy)propanoic acid ((R)-1d). [Table 2, Entry 4, 50% yield, 68% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min): tR = 19.8 min (15.9%),
-1
1
t = 25.9 min (84.1%); IR (KBr): 2995, 1717, 1595, 1490, 825 cm ; H NMR (CDCl ): " 7.27-7.15 (m,
3
R
13
2H, Ar), 6.85-6.75 (m, 2H, Ar), 4.74 (q, J = 7.5 Hz, 1H, 2-H), 1.64 (d, J = 7.5 Hz, 3H, 3-CH3); C NMR
(CDCl ): " 177.0 (1), 155.8, 129.6, 127.0, 116.6, 72.4 (2), 18.3 (3); HR MS: calcd for C H ClO Na (M +
3
9
9
3
+
Na ) 223.0132, found 223.0143; Analytical data on racemic compound: Mp 115-116 °C
(CH2Cl2/hexane); IR (KBr): 3065, 1717, 1600, 1510, 1123, 777, 698 cm-1.
Di(1-naphthyl)methyl (S)-2-(4-chlorophenoxy)propanoate ((S)-2d). [Table 2, Entry 4, 49% yield, 72%
ee] HPLC (CHIRALCEL OD-H, i-PrOH/hexane = 1/300, flow rate = 1.0 mL/min): tR = 33.6 min (14.2%),
1
t = 38.1 min (85.8%); H NMR (CDCl ): " 8.45 (s, 1H, 1’-H), 8.03-7.75 (m, 1H, Ar), 7.93-7.75 (m, 5H,
3
R
Ar), 7.56-7.41 (m, 3H, Ar), 7.38-7.19 (m, 5H, Ar), 7.07-7.00 (m, 2H, Ar), 6.73-6.64 (m, 2H, Ar), 4.79 (q,
13
J = 6.8 Hz, 1H, 2-H), 1.61 (d, J = 6.8 Hz, 3H, 3-CH3); C NMR (CDCl ): " 171.1 (1), 156.0, 134.2,
3
133.93, 133.92, 133.8, 131.1, 130.8, 129.4, 129.3, 129.3, 129.2, 129.0, 128.8, 126.8, 126.6, 126.5, 126.3,
126.0, 125.9, 125.6, 125.2, 125.0, 123.3, 123.2, 116.4, 116.4, 73.0 (2), 72.0 (1’), 18.5 (3); HR MS: calcd
+
for C H ClO Na (M + Na ) 489.1228, found 489.1223; Analytical data on racemic compound: Mp
30 23
3
123-125 °C (hexane); IR (KBr): 3063, 1746, 1598, 1511, 1490, 1186, 1133, 825, 783, 775 cm-1.
(R)-2-(o-Tolyloxy)propanoic acid ((R)-1e). [Table 2, Entry 5, 45% yield, 86% ee] HPLC (CHIRALPAK
AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 15.5 min (6.9%), tR = 14.3 min
1
(93.1%); H NMR (CDCl ): " 7.17-7.08 (m, 2H, Ar), 6.92-6.87 (m, 1H, Ar), 6.74-6.68 (m, 1H, Ar), 4.78
3
13
(q, J = 6.8 Hz, 1H, 2-H), 2.26 (s, 3H, ArCH ), 1.65 (d, 3H, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): "
3
3
3
177.8 (1), 155.4, 131.2, 127.5, 126.8, 121.7, 112.0, 72.4 (2), 18.5 (3), 16.2 (ArCH3); HR MS: calcd for
+
C H O Na (M + Na )ꢀ203.0679, found 203.0670; Analytical data on racemic compound: Mp 92-94 °C
10 12 3
(CH2Cl2/hexane); IR (KBr): 2990, 1713, 1601, 1591, 1494, 759 cm-1.
Di(1-naphthyl)methyl (S)-2-(o-tolyloxy)propanoate ((S)-2e). [Table 2, Entry 5, 46% yield, 88% ee]
HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 14.8 min (94.2%), tR

HETEROCYCLES, Vol. 86, No. 2, 2012
1243
1
= 18.5 min (5.8%); H NMR (CDCl ): " 8.52 (s, 1H, 1’-H), 8.05-7.97 (m, 1H, Ar), 7.93-7.77 (m, 5H, Ar),
3
7.55-7.19 (m, 8H, Ar), 7.13-7.05 (m, 1H, Ar), 6.96-6.80 (m, 2H, Ar), 6.66-6.58 (m, 1H, Ar), 4.88 (q, J =
13
6.8 Hz, 1H, 2-H), 2.19 (s, 3H, ArCH ), 1.63 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 171.6 (1),
3
3
3
155.7, 134.4, 134.2, 133.9, 133.8, 131.2, 131.0, 130.9, 129.3, 129.0, 128.9, 128.8, 127.4, 126.8, 126.60,
126.57, 126.3, 125.9, 125.8, 125.6, 125.2, 125.1, 123.4, 123.3, 121.3, 111.9, 72.7 (2), 71.7 (1’), 18.6 (3),
+
16.2 (ArCH ); HR MS: calcd for C H O Na (M + Na )ꢀ469.1774, found 469.1758; Analytical data on
31 26
3
3
racemic compound: Mp: 142-144 °C (hexane); IR (KBr): 3062, 1749, 1601, 1592, 1510, 1494, 1179,
1135, 803, 785, 756 cm-1.
(R)-2-(m-Tolyloxy)propanoic acid ((R)-1f). [Table 2, Entry 6, 39% yield, 77% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 19.2 min (11.4%),
1
t = 24.9 min (88.6%); H NMR (CDCl ): " 7.18-7.08 (m, 1H, Ar), 6.84-6.75 (m, 1H, Ar), 6.75-6.61 (m,
3
R
13
2H, Ar). 4.78 (q, J = 6.8 Hz, 1H, 2-H), 2.30 (s, 3H, ArCH3), 1.63 (d, J = 6.8 Hz, 3H, 3-CH3); C NMR
(CDCl ): " 176.8 (1), 157.1, 139.9, 129.4, 122.9, 116.2, 111.9, 72.1 (2), 21.5 (ArCH ), 18.4 (3); HR MS:
3
3
+
calcd for C H O Na (M + Na )ꢀ203.0679, found 203.0681; Analytical data on racemic compound: Mp
10 12 3
106-108 °C (CH2Cl2/hexane); IR (KBr): 2993, 1709, 1610, 1585, 1488, 770 cm-1.
Di(1-naphthyl)methyl (S)-2-(m-tolyloxy)propanoate ((S)-2f). [Table 2, Entry 6, 46% yield, 76% ee]
HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 22.3 min (87.9%), tR
1
= 31.8 min (12.1%); H NMR (CDCl ): " 8.47 (s, 1H, 1’-H), 8.06-7.97 (m, 1H, Ar), 7.93-7.75 (m, 5H,
3
Ar), 7.56-7.18 (m, 8H, Ar), 7.08-6.90 (m, 1H, Ar), 6.77-6.70 (m, 1H, Ar), 6.65-6.58 (m, 2H, Ar), 4.85 (q,
13
J = 6.8 Hz, 1H, 2-H), 2.17 (s, 3H, ArCH ), 1.61 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 171.6
3
3
3
(1), 157.5, 139.6, 134.4, 134.1, 133.9, 133.8, 131.2, 130.9, 129.3, 129.2, 129.0, 128.9, 128.8, 126.8, 126.6,
126.3, 125.9, 125.8, 125.7, 125.2, 125.1, 123.35, 123.28, 122.4, 115.8, 112.0, 72.5 (2), 71.7 (1’), 21.4
+
(ArCH ), 18.6 (3); HR MS: calcd for C H O Na (M + Na )ꢀ469.1774, found 469.1760; Analytical data
31 26
3
3
on racemic compound: Mp 147-149 °C (hexane); IR (KBr): 3059, 1745, 1699, 1591, 1510, 1489, 1170,
1131, 801, 784 cm-1.
(R)-2-(p-Tolyloxy)propanoic acid ((R)-1g). [Table 2, Entry 7, 45% yield, 76% ee] HPLC (CHIRALPAK
AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 26.7 min (12.0%), tR = 34.6 min
1
(88.0%); H NMR (CDCl ): " 7.10-7.04 (m, 2H, Ar), 6.82-6.77 (m, 2H, Ar), 4.74 (q, J = 6.8 Hz, 1H,
3
13
2-H), 2.27 (s, 3H, ArCH3), 1.62 (d, J = 6.8 Hz, 3H, 3-CH3); C NMR (CDCl ): " 177.0 (1), 155.0, 131.5,
3
+
130.1, 115.2, 72.5 (2), 20.5 (ArCH ), 18.4 (3); HR MS: calcd for C H O Na (M + Na )ꢀ203.0679,
10 12
3
3
found 203.0669; Analytical data on racemic compound: Mp 101-102 °C (CH2Cl2/hexane); IR (KBr):
2997, 1715, 1613, 1584, 1509, 808 cm-1.
Di(1-naphthyl)methyl (S)-2-(p-tolyloxy)propanoate ((S)-2g). [Table 2, Entry 7, 50% yield, 73% ee]

1244
HETEROCYCLES, Vol. 86, No. 2, 2012
HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 26.5 min (86.5%), tR
1
= 31.2 min (13.5%); H NMR (CDCl ): " 8.45 (s, 1H, 1’-H), 8.03-7.97 (m, 1H, Ar), 7.93-7.77 (m, 5H,
3
Ar), 7.56-7.40 (m, 3H, Ar), 7.39-7.18 (m, 5H, Ar), 6.97-6.90 (m, 2H, Ar), 6.74-6.67 (m, 2H, Ar), 4.83 (q,
13
J = 6.8 Hz, 1H, 2-H), 2.26 (s, 3H, ArCH ), 1.61 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 171.6
3
3
3
(1), 155.3, 134.3, 134.1, 133.9, 133.7, 131.2, 130.8, 130.7, 129.9, 129.9, 129.3, 129.0, 128.9, 128.77,
126.79, 126.5, 126.3, 125.9, 125.8, 125.6, 125.2, 125.1, 123.4, 123.3, 114.9, 114.9, 72.7 (2), 71.7 (1’),
+
20.5 (ArCH ), 18.6 (3); HR MS: calcd for C H O Na (M + Na )ꢀ469.1774, found 469.1764; Analytical
31 26 3
3
data on racemic compound: Mp 133-136 °C (hexane); IR (KBr): 3064, 1746, 1600, 1510, 1181, 1132,
822, 799, 784, 775 cm-1.
(R)-2-(4-Chloro-2-methylphenoxy)propanoic acid ((R)-1h). 16 [Table 2, Entry 8, 46% yield, 88% ee]
HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 18.2 min
1
(6.1%), t = 26.2 min (93.9%); H NMR (CDCl ): " 7.13 (d, J = 2.6 Hz, 1H, Ar), 7.06 (dd, J = 8.8, 2.6 Hz,
3
R
1H, Ar), 6.64 (d, J = 8.8 Hz, 1H, Ar), 4.74 (q, J = 6.8 Hz, 1H, 2-H), 2.23 (s, 3H, ArCH3), 1.65 (d, J = 6.8
13
Hz, 3H, 3-CH ); C NMR (CDCl ): " 177.1 (1), 154.1, 130.9, 129.6, 126.5, 126.4, 113.2, 72.7 (2), 18.4
3
3
+
(3), 16.1 (ArCH ); HR MS: calcd for C H ClO Na (M + Na )ꢀ237.0289, found 237.0289; Analytical
10 11
3
3
data on racemic compound: Mp 92-94 °C (CH2Cl2/hexane); IR (KBr): 2988, 1705, 1601, 1493, 880, 793,
662 cm-1.
Di(1-naphthyl)methyl (S)-2-(4-chloro-2-methylphenoxy)propanoate ((S)-2h). [Table 2, Entry 8, 49%
yield, 84% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 17.0
1
min (92.2%), t = 19.8 min (7.8%); H NMR (CDCl ): " 8.43 (s, 1H, 1’-H), 7.99-7.77 (m, 6H, Ar),
3
R
7.55-7.42 (m, 3H, Ar), 7.39-7.26 (m, 4H, Ar), 7.23-7.17 (m, 1H, Ar), 7.01 (d, J = 2.6 Hz, 1H, Ar), 6.81
(dd, J = 8.8, 2.6 Hz, 1H, Ar), 6.49 (d, J = 8.8 Hz, 1H, Ar), 4.83 (q, J = 6.8 Hz, 1H, 2-H), 2.11 (s, 3H,
13
ArCH3), 1.64 (d, J = 6.8 Hz, 3H, 3-CH3); C NMR (CDCl ): " 171.2 (1), 154.2, 134.2, 134.0, 133.9,
3
133.7, 131.1, 130.8, 130.7, 129.41, 129.40, 129.1, 129.0, 128.83, 126.84, 126.6, 126.14, 126.13, 126.00,
125.96, 125.9, 125.6, 125.1, 125.0, 123.22, 123.18, 113.0, 73.0 (2), 71.8 (1’), 18.5 (3), 16.1 (ArCH3); HR
+
MS: calcd for C H ClO Na (M + Na )ꢀ 503.1384, found 503.1377; Analytical data on racemic
31 25
3
amorphous compound: IR (KBr): 3062, 1740, 1597, 1510, 1489, 1180, 1127, 800, 781, 767, 755, 738
cm-1.
(R)-2-(1-Naphthoxy)propanoic acid ((R)-1i). [Table 2, Entry 9, 47% yield, 83% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 29.5 min (8.5%),
1
t = 32.9 min (91.5%); H NMR (CDCl ): " 10.81 (br s, 1H, CO H), 8.36-8.27 (m, 1H, Ar), 7.83-7.75 (m,
3
R
2
1H, Ar), 7.53-7.42 (m, 3H, Ar), 7.36-7.29 (m, 1H, Ar), 6.77-6.69 (m, 1H, Ar), 4.98 (q, J = 6.8 Hz, 1H,
13
2-H), 1.78 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 177.6 (1), 153.1, 134.7, 127.5, 126.6, 125.7,
3
3

HETEROCYCLES, Vol. 86, No. 2, 2012
1245
+
125.55, 125.49, 122.1, 121.6, 105.8, 72.5 (2), 18.5 (3); HR MS: calcd for C H O Na (M + Na )ꢀ
13 12
3
239.0679, found 239.0681; Analytical data on racemic compound: Mp: 158-160 °C (CH2Cl2/hexane); IR
(KBr): 2959, 1706, 1628, 1596, 1580, 1506, 794, 769 cm-1.
Di(1-naphthyl)methyl (S)-2-(1-naphthoxy)propanoate ((S)-2i). [Table 2, Entry 9, 50% yield, 87% ee]
HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min): tR = 13.2 min (93.3%), tR =
1
16.8 min (6.7%); H NMR (CDCl ): " 8.48 (s, 1H, 1’-H), 8.33-8.01 (m, 2H, Ar), 7.93-7.71 (m, 6H, Ar),
3
7.57-7.05 (m, 12H, Ar), 6.63-6.56 (m, 1H, Ar), 5.04 (q, J = 6.8 Hz, 1H, 2-H), 1.74 (d, J = 6.8 Hz, 3H,
13
3-CH3); C NMR (CDCl ): " 171.4 (1), 153.3, 134.6, 134.3, 134.0, 133.9, 133.7, 131.2, 130.8, 129.4,
3
128.98, 128.96, 128.8, 127.3, 126.9, 126.51, 126.51, 126.47, 126.0, 125.8, 125.7, 125.5, 125.4, 125.3,
125.2, 125.1, 123.4, 123.3, 122.3, 121.2, 105.8, 73.0 (2), 71.8 (1’), 18.5 (3); HR MS: calcd for
+
C H O Na (M + Na )ꢀ 505.1774, found 505.1789; Analytical data on racemic compound: Mp
34 26
3
169-172 °C (hexane); IR (KBr): 3060, 1745, 1628, 1598, 1579, 1508, 1177, 1132, 801, 792, 775, 730
cm-1.
(R)-2-(2-Naphthoxy)propanoic acid ((R)-1j). [Table 2, Entry 10, 49% yield, 73% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 40.3 min (13.6%),
1
t = 54.1 min (86.4%); H NMR (CDCl ): " 9.24 (br s, 1H, CO H), 7.80-7.61 (m, 3H, Ar), 7.49-7.38 (m,
3
R
2
1H, Ar), 7.38-7.29 (m, 1H, Ar), 7.22-7.14 (m, 1H, Ar), 7.10-7.04 (m, 1H, Ar), 4.94 (q, J = 6.8 Hz, 1H,
13
2-H), 1.71 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 177.0 (1), 155.1, 134.2, 129.9, 129.5, 127.6,
3
3
+
126.9, 126.6, 124.2, 118.7, 108.0, 72.1 (2), 18.4 (3); HR MS: calcd for C H O Na (M + Na )ꢀ239.0679,
13 12 3
found 239.0676; Analytical data on racemic compound: Mp 107-108 °C (CH2Cl2/hexane); IR (KBr):
2986, 1713, 1630, 1601, 1513, 838, 807, 743 cm-1.
Di(1-naphthyl)methyl (S)-2-(2-naphthoxy)propanoate ((S)-2j). [Table 2, Entry 10, 50% yield, 75% ee]
HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min): tR = 16.7 min (87.3%), tR =
1
23.6 min (12.7%); H NMR (CDCl ): " 8.47 (s, 1H, 1’-H), 8.07-7.60 (m, 8H, Ar), 7.55-7.00 (m, 12H, Ar),
3
13
6.97-6.90 (m, 1H, Ar), 5.00 (q, J = 6.8 Hz, 1H, 2-H), 1.65 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ):
3
3
" 171.5 (1), 155.4, 134.3, 134.2, 134.0, 133.9, 133.7, 131.2, 130.8, 129.6, 129.38, 129.36, 129.0, 128.9,
128.7, 127.5, 127.03, 126.97, 126.5, 126.3, 126.2, 126.0, 125.7, 125.6, 125.2, 125.0, 124.0, 123.24,
+
123.16, 118.9, 107.8, 72.7 (2), 71.9 (1’), 18.6 (3); HR MS: calcd for C H O Na (M + Na )ꢀ505.1774,
34 26
3
found 505.1754; Analytical data on racemic compound: Mp 184-186 °C (hexane); IR (KBr): 3060, 1751,
1629, 1600, 1579, 1511, 1177, 1132, 832, 801, 780, 756 cm-1.
(R)-2-(2,6-Dichlorophenoxy)propanoic acid ((R)-1k). [Table 2, Entry 11, 51% yield, 69% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min): tR = 17.2 min (84.4%),
1
t = 19.1 min (15.6%); H NMR (CDCl ): " 8.24 (br s, 1H, CO H), 7.36-7.26 (m, 2H, Ar), 7.06-6.98 (m,
3
R
2

1246
HETEROCYCLES, Vol. 86, No. 2, 2012
13
1H, Ar), 4.95 (q, J = 6.8 Hz, 1H, 2-H), 1.61 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 174.6 (1),
3
3
+
149.2, 129.4, 129.2, 125.7, 77.4 (2), 17.9 (3); HR MS: calcd for C H Cl O Na (M + Na ) 256.9743,
9
8
2 3
found 256.9733. Analytical data on racemic compound: Mp 108-110 °C (CH2Cl2/hexane); IR (KBr): 2932,
1710, 1567, 1460, 1450, 1441, 786, 773 cm-1.
Di(1-naphthyl)methyl (S)-2-(2,6-dichlorophenoxy)propanoate ((S)-2k). [Table 2, Entry 11, 46% yield,
78% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 18.6 min
1
(88.8%), t = 22.5 min (11.2%); H NMR (CDCl ): " 8.52 (s, 1H, 1’-H), 8.00-7.94 (m, 2H, Ar), 7.92-7.80
3
R
(m, 4H, Ar), 7.52-7.33 (m, 8H, Ar), 7.19-7.11 (m, 2H, Ar), 6.89-6.81 (m, 1H, Ar), 5.04 (q, J = 6.4 Hz, 1H,
13
2-H), 1.63 (d, J = 6.4 Hz, 3H, 3-CH3); C NMR (CDCl ): " 170.1 (1), 150.1, 134.32, 134.30, 133.81,
3
133.79, 131.0, 129.2, 129.2, 128.9, 128.9, 128.9, 128.8, 128.8, 126.7, 126.7, 126.0, 125.9, 125.9, 125.9,
125.2, 125.2, 125.0, 123.45, 123.36, 77.9 (2), 71.7 (1’), 18.7 (3); HR MS: calcd for C H Cl O Na (M +
30 22
2 3
+
Na ) 523.0838, found 523.0849; Analytical data on racemic amorphous compound: IR (KBr): 3061, 1731,
1599, 1565, 1510, 1163, 1107, 800, 775, 729 cm-1.
(R)-2-(2,4-Dichlorophenoxy)propanoic acid ((R)-1l). [Table 2, Entry 12, 44% yield, 90% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 19.9 min (5.2%),
tR = 28.6 min (94.8%); The absolute configuration was determined as R by the comparison of the retention
time with the literature data.12a
Di(1-naphthyl)methyl (S)-2-(2,4-dichlorophenoxy)propanoate ((S)-2l). [Table 2, Entry 12, 47% yield,
90% ee] Spectroscopic data were previously reported.12a HPLC (CHIRALPAK AD-H, i-PrOH/hexane =
1/50, flow rate = 0.5 mL/min): tR = 27.4 min (95.2%), tR = 33.8 min (4.8%); The absolute configuration
was determined as S by the comparison of the retention time with the literature data.12a.
(R)-2-(2-Fluorophenoxy)propanoic acid ((R)-1m). [Table 2, Entry 13, 45% yield, 85% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 22.1 min (7.7%),
1
t = 27.0 min (92.3%); H NMR (CDCl ): " 9.99 (br s, 1H, CO H), 7.13-6.91 (m, 4H, Ar), 4.79 (q, J = 6.8
3
R
2
13
Hz, 1H, 2-H), 1.67 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 176.6 (1), 153.3 (d, J = 245.0 Hz),
3
3
145.1 (d, J = 10.2 Hz), 124.4 (d, J = 4.4 Hz), 123.2 (d, J = 6.5 Hz), 117.9 (d, J = 1.4 Hz), 116.8 (d, J =
+
18.9 Hz), 74.3 (2), 18.3 (3); HR MS: calcd for C H FO Na (M + Na )ꢀ207.0428, found 207.0437;
9
9
3
Analytical data on racemic compound: Mp 85-87 °C (CH2Cl2/hexane); IR (KBr): 2998, 1721, 1614, 1591,
1503, 754 cm-1.
Di(1-naphthyl)methyl (S)-2-(2-fluorophenoxy)propanoate ((S)-2m). [Table 2, Entry 13, 48% yield,
86% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 19.9 min
1
(93.0%), t = 25.4 min (7.0%); H NMR (CDCl ): " 8.46 (s, 1H, 1’-H), 7.99-7.79 (m, 6H, Ar), 7.56-7.22
3
R
(m, 8H, Ar), 7.07-6.97 (m, 1H, Ar), 6.90-6.72 (m, 3H, Ar), 4.88 (q, J = 6.8 Hz, 1H, 2-H), 1.67 (d, J = 6.8

HETEROCYCLES, Vol. 86, No. 2, 2012
1247
13
Hz, 3H, 3-CH ); C NMR (CDCl ): " 171.0 (1), 152.9 (d, J = 245.7 Hz), 145.4 (d, J = 10.3 Hz), 134.2,
3
3
134.1, 133.9, 133.8, 131.1, 130.9, 129.3, 129.1, 128.9, 128.8, 126.8, 126.6, 126.1, 125.93, 125.86, 125.7,
125.2, 125.1, 124.1 (d, J = 3.7 Hz), 123.29, 123.27, 122.3 (d, J = 7.4 Hz), 116.8 (d, J = 1.5 Hz), 116.5 (d,
+
J = 18.3 Hz), 74.2 (2), 71.9 (1’), 18.5 (3); HR MS: calcd for C H FO Na (M + Na )ꢀ473.1523, found
30 23
3
473.1536; Analytical data on racemic compound: Mp 139-143 °C (hexane); IR (KBr): 3071, 1733, 1612,
1504, 1180, 1131, 803, 788, 780, 747 cm-1.
(R)-2-(2-Bromophenoxy)propanoic acid ((R)-1n). [Table 2, Entry 14, 49% yield, 88% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 20.8 min (5.9%),
1
t = 25.8 min (94.1%); H NMR (CDCl ): " 7.60-7.54 (m, 1H, Ar), 7.28-7.22 (m, 1H, Ar), 6.95-6.85 (m,
3
R
13
1H, Ar), 4.81 (q, J = 6.8 Hz, 1H, 2-H), 1.72 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 174.9 (1),
3
3
+
153.6, 133.8, 128.6, 123.7, 115.4, 113.3, 74.0 (2), 18.2 (3); HR MS: calcd for C H BrO Na (M + Na )ꢀ
9
9
3
266.9933, found 266.9621; Analytical data on racemic compound: Mp 139-142 °C (CH2Cl2/hexane); IR
(KBr): 2870, 1709, 1589, 1573, 1478, 749, 666 cm-1.
Di(1-naphthyl)methyl (S)-2-(2-bromophenoxy)propanoate ((S)-2n). [Table 2, Entry 14, 48% yield,
95% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 20.8 min
1
(2.6%), t = 25.9 min (97.4%); H NMR (CDCl ): " 8.47 (s, 1H, 1’-H), 8.03-7.78 (m, 6H, Ar), 7.57-7.22
3
R
(m, 9H, Ar), 6.99-6.90 (m, 1H, Ar), 6.82-6.74 (m, 1H, Ar), 6.70-6.62 (m, 1H, Ar), 4.88 (q, J = 6.8 Hz, 1H,
13
2-H), 1.70 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 170.8 (1), 154.1, 134.2, 134.0, 133.9, 133.8,
3
3
133.6, 131.1, 130.8, 129.4, 129.1, 129.0, 128.8, 128.2, 126.8, 126.6, 126.3, 125.95, 125.85, 125.76, 125.2,
125.1, 123.29, 123.28, 122.9, 114.7, 112.8, 74.0 (2), 71.9 (1’), 18.4 (3); HR MS: calcd for
+
C H BrO Na (M + Na )ꢀ 533.0723, found 533.0733; Analytical data on racemic compound: Mp:
30 23
3
165-168 °C (hexane); IR (KBr): 3061, 1745, 1626, 1599, 1587, 1510, 1180, 1138, 803, 784, 780, 749
cm-1.
(R)-2-(2-Methoxyphenoxy)propanoic acid ((R)-1o). [Table 2, Entry 15, 43% yield, 76% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 1.0 mL/min): tR = 29.5 min (11.8%),
1
t = 33.1 min (88.2%); H NMR (CDCl ): " 7.10-7.01 (m, 1H, Ar), 7.00-6.85 (m, 3H, Ar), 4.63 (q, J = 6.8
3
R
13
Hz, 1H, 2-H), 3.87 (s, 3H, OCH ), 1.66 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 174.1 (1), 150.4,
3
3
3
146.7, 124.4, 121.4, 119.0, 112.3, 76.9 (2), 55.9 (OCH ), 18.5 (3); HR MS: calcd for C H O Na (M +
10 12
4
3
+
Na )ꢀ219.0628, found 219.0620; Analytical data on racemic compound: Mp 79-80 °C (CH2Cl2/hexane);
IR (KBr): 2953, 1719, 1592, 1505, 753, 740 cm-1.
Di(1-naphthyl)methyl (S)-2-(2-methoxyphenoxy)propanoate ((S)-2o). [Table 2, Entry 15, 49% yield,
88% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min): tR = 13.8 min
1
(94.2%), t = 19.3 min (5.8%); H NMR (CDCl ): " 8.46 (s, 1H, 1’-H), 8.01-7.79 (m, 6H, Ar), 7.55-7.23
3
R

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HETEROCYCLES, Vol. 86, No. 2, 2012
(m, 8H, Ar), 6.96-6.82 (m, 2H, Ar), 6.77-6.64 (m, 2H, Ar), 4.88 (q, 1H, J = 6.8 Hz, 2-H), 3.74 (s, 3H,
13
OCH3), 1.66 (d, 3H, J = 6.8 Hz, 3-CH3); C NMR (CDCl ): " 171.5 (1), 149.9, 147.0, 134.3, 134.2,
3
133.84, 133.76, 131.1, 130.9, 129.3, 129.0, 128.9, 128.8, 126.8, 126.6, 126.2, 125.9, 125.8, 125.7, 125.2,
125.1, 123.4, 123.3, 122.5, 120.7, 116.0, 112.4, 74.0 (2), 71.6 (1’), 55.9 (OCH3), 18.7 (3); HR MS: calcd
+
for C H O Na (M + Na )ꢀ 485.1723, found 485.1723; Analytical data on racemic compound: Mp
31 26
4
164-165 °C (hexane); IR (KBr): 3061, 1745, 1592, 1502, 1180, 1135, 800, 780, 741 cm-1.
(R)-2-(2-Nitrophenoxy)propanoic acid ((R)-1p). [Table 2, Entry 16, 53% yield, 79% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/10/0.01, flow rate = 0.75 mL/min): tR = 11.1 min (10.4%),
1
t = 15.3 min (89.6%); H NMR (CDCl ): " 8.57 (br s, 1H, CO H), 7.96-7.89 (m, 1H, Ar), 7.62-7.52 (m,
3
R
2
1H, Ar), 7.19-7.11s (m, 1H, Ar), 7.09-7.02 (m, 1H, Ar), 4.97 (q, J = 6.8 Hz, 1H, 2-H), 1.76 (d, J = 6.8 Hz,
13
3H, 3-CH3); C NMR (CDCl ): " 172.9 (1), 150.4, 134.6, 126.29, 126.28, 122.3, 115.8, 74.6 (2), 18.1
3
+
(3); HR MS: calcd for C H NO Na (M + Na )ꢀ234.0373, found 234.0385; Analytical data on racemic
9
9
5
compound: Mp 157-159 °C (CH2Cl2/hexane); IR (KBr): 2870, 1736, 1605, 1585, 1524, 1486, 1358, 741
cm-1.
Di(1-naphthyl)methyl (S)-2-(2-nitrophenoxy)propanoate ((S)-2p). [Table 2, Entry 16, 47% yield, 92%
ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min): tR = 16.6 min (96.0%),
1
t = 18.5 min (4.0%); H NMR (CDCl ): " 8.47 (s, 1H, 1’-H), 7.99-7.78 (m, 6H, Ar), 7.74-7.66 (m, 1H,
3
R
Ar), 7.55-7.23 (m, 8H, Ar), 7.13-7.04 (m, 1H, Ar), 6.95-6.86 (m, 1H, Ar), 6.77-6.70 (m, 1H, Ar), 4.94 (q,
13
J = 6.8 Hz, 1H, 2-H), 1.70 (d, J = 6.8 Hz, 3H, 3-CH3); C NMR (CDCl ): " 170.2 (1), 150.6, 134.0,
3
133.9, 133.8, 133.7, 133.5, 133.5, 130.9, 130.8, 129.4, 129.3, 129.0, 128.9, 126.8, 126.7, 126.1, 126.0,
125.91, 125.88, 125.5, 125.3, 125.1, 123.18, 123.17, 121.3, 115.3, 74.2 (2), 72.2 (1’), 18.3 (3); HR MS:
+
calcd for C H NO Na (M + Na )ꢀ500.1468 found 500.1467; Analytical data on racemic compound:
30 23
5
Mp 156-160 °C (hexane); IR (KBr): 3062, 1736, 1607, 1586, 1521, 1483, 1346, 1168, 1103, 801, 787,
773, 744 cm-1.
(R)-2-[(1,1'-Biphenyl)-2-yloxy]propanoic acid ((R)-1q). [Table 2, Entry 17 (Table 3, Entry 1), 50%
yield, 89% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min):
1
t = 20.3 min (5.5%), t = 26.5 min (94.5%); H NMR (CDCl ): " 7.58-7.52 (m, 2H, Ar), 7.45-7.38 (m,
3
R
R
2H, Ar), 7.38-7.26 (m, 3H, Ar), 7.14-7.08 (m, 1H, Ar), 6.97-6.92 (m, 1H, Ar), 4.70 (q, J = 6.8 Hz, 1H,
13
2-H), 1.53 (d, J = 6.8 Hz, 3H, 3-CH ); C NMR (CDCl ): " 175.4 (1), 153.8, 138.0, 132.1, 131.4, 129.4,
3
3
+
128.7, 128.2, 127.2, 122.7, 114.4, 73.3 (2), 18.2 (3); HR MS: calcd for C H O Na (M + Na )ꢀ265.0602,
15 14 3
found 265.0607; Analytical data on racemic compound: Mp 138-141 °C (CH2Cl2/hexane); IR (KBr):
2986, 1706, 1601, 1587, 1504, 1481, 754, 725, 700 cm-1.
Di(1-naphthyl)methyl (S)-2-[(1,1'-biphenyl)-2-yloxy]propanoate ((S)-2q). [Table 2, Entry 17 (Table 3,

HETEROCYCLES, Vol. 86, No. 2, 2012
1249
Entry 1), 47% yield, 96% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75
1
mL/min): t = 20.2 min (97.8%), t = 26.7 min (2.2%); H NMR (CDCl ): " 8.45 (s, 1H, 1’-H), 8.07-7.73
3
R
R
(m, 6H, Ar), 7.61-6.95 (m, 16H, Ar), 6.85-6.70 (m, 1H, Ar), 4.85 (q, J = 6.8 Hz, 1H, 2-H), 1.49 (d, J =
13
6.8 Hz, 3H, 3-CH3); C NMR (CDCl ): " 171.5 (1), 154.2, 138.3, 134.3, 134.1, 133.9, 133.8, 131.5,
3
131.3, 131.2, 130.8, 129.5, 129.5, 129.3, 129.02, 128.95, 128.8, 128.4, 127.8, 127.8, 126.8, 126.7, 126.6,
126.4, 126.0, 125.8, 125.6, 125.2, 125.1, 123.31, 123.29, 121.9, 113.4, 72.9 (2), 71.8 (1’), 18.4 (3); HR
+
MS: calcd for C H O Na (M + Na )ꢀ531.1931, found 531.1955; Analytical data on racemic amorphous
36 28 3
compound: IR (KBr): 3059, 1737, 1599, 1584, 1509, 1480, 1180, 1135, 801, 778, 754, 734, 699 cm-1.
(R)-2-[(1,1'-Biphenyl)-2-yloxy]butanoic acid ((R)-1r). [Table 3, Entry 2, 76% yield, 30% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 18.3 min (35.2%),
1
t = 23.2 min (64.8%); H NMR (CDCl ): " 9.33 (br s, 1H, CO H), 7.58-7.51 (m, 2H, Ar), 7.45-7.23 (m,
3
R
2
5H, Ar), 7.13-7.04 (m, 1H, Ar), 6.92-6.85 (m, 1H, Ar), 4.62 (t, J = 5.6 Hz, 1H, 2-H), 1.93 (dq, J = 5.6, 7.6
13
Hz, 2H, 3-H), 0.94 (t, J = 7.6 Hz, 3H, 4-CH ); C NMR (CDCl ): " 175.5 (1), 154.2, 138.1, 131.8, 131.3,
3
3
129.6, 128.6, 128.0, 127.1, 122.3, 113.5, 77.6 (2), 25.7 (3), 9.1 (4); HR MS: calcd for C H O Na (M +
16 16
3
+
Na )ꢀ 279.0992, found 279.0992; Analytical data on racemic compound: Mp 150-152 °C
(CH2Cl2/hexane); IR (KBr): 2972, 1704, 1597, 1584, 1503, 1480, 773, 751, 738, 701 cm-1.
Di(1-naphthyl)methyl (S)-2-[(1,1'-biphenyl)-2-yloxy]butanoate ((S)-2r). [Table 3, Entry 2, 22% yield,
94% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 20.4 min
1
(97.1%), t = 22.1 min (2.9%); H NMR (CDCl ): " 8.48 (s, 1H, 1’-H), 7.96-7.75 (m, 5H, Ar), 7.57-7.39
3
R
(m, 5H, Ar), 7.37-7.16 (m, 9H, Ar), 7.10-6.97 (m, 2H, Ar), 6.78-6.72 (m, 2H, Ar), 4.75 (t, J = 5.6 Hz, 1H,
13
2-H), 1.89 (dq, J = 5.6, 7.6 Hz, 2H, 3-H), 0.84 (t, J = 7.6 Hz, 3H, 4-CH ); C NMR (CDCl ): " 170.8 (1),
3
3
154.4, 138.3, 134.4, 134.1, 133.9, 133.7, 131.4, 131.21, 131.16, 130.8, 129.6, 129.6, 129.3, 129.0, 129.0,
128.8, 128.4, 127.7, 127.7, 126.8, 126.7, 126.54, 126.47, 126.0, 125.8, 125.5, 125.2, 125.1, 123.3, 123.3,
+
121.6, 112.6, 77.2 (2), 71.6 (1’), 26.0 (3), 9.3 (4); HR MS: calcd for C H O Na (M + Na )ꢀ545.2087,
37 30
3
found 545.2080; Analytical data on racemic amorphous compound: IR (KBr): 3059, 1734, 1599, 1583,
1509, 1480, 1177, 1134, 800, 794, 778, 753, 734, 700 cm-1.
(R)-2-[(1,1'-Biphenyl)-2-yloxy]pentanoic acid ((R)-1s). [Table 3, Entry 3, 80% yield, 21% ee] HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 17.4 min (39.7%),
tR = 21.5 min (60.3%).
Di(1-naphthyl)methyl (S)-2-[(1,1'-biphenyl)-2-yloxy]pentanoate ((S)-2s). [Table 3, Entry 3, 18% yield,
93% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 17.7 min
1
(96.4%), t = 20.6 min (3.6%); H NMR (CDCl ): " 8.46 (s, 1H, 1’-H), 8.09-8.02 (m, 1H, Ar), 7.97-7.76
3
R
(m, 5H, Ar), 7.59-7.40 (m, 5H, Ar), 7.39-7.16 (m, 9H, Ar), 7.11-6.96 (m, 2H, Ar), 6.80-6.73 (m, 1H, Ar),

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HETEROCYCLES, Vol. 86, No. 2, 2012
4.80 (t, J = 6.0 Hz, 1H, 2-H), 1.89-1.76 (m, 2H, 3-H), 1.39-1.24 (m, 2H, 4-H), 0.75 (t, J = 7.2 Hz, 3H,
13
5-CH ); C NMR (CDCl ): " 171.0 (1), 154.5, 138.3, 134.4, 134.1, 133.9, 133.8, 131.4, 131.23, 131.19,
3
3
130.8, 129.6, 129.6, 129.4, 128.98, 128.96, 128.8, 128.4, 127.7, 127.7, 126.8, 126.7, 126.53, 126.51,
126.0, 125.8, 125.6, 125.2, 125.1, 123.4, 123.3, 121.6, 112.6, 76.1 (2), 71.7 (1’), 34.5 (3), 18.2 (4), 13.5
+
(5); HR MS: calcd for C H O Na (M + Na )ꢀ559.2244, found 559.2245; Analytical data on racemic
38 32
3
amorphous compound: IR (KBr): 3060, 1748, 1599, 1583, 1505, 1481, 1176, 1138, 797, 779, 751, 736,
697 cm-1.
(R)-2-(2-(tert-Butyl)-4-methoxyphenoxy)propanoic acid ((R)-1u). [Scheme 3, 43% yield, 93% ee]
HPLC (CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 12.5 min
1
(3.7%), t = 15.8 min (96.3%); H NMR (CDCl ): " 9.95 (br s, 1H, CO H), 6.94-6.89 (m, 1H, Ar),
3
R
2
6.66-6.56 (m, 2H, Ar), 4.79 (d, J = 6.8 Hz, 1H, 2-H), 3.75 (s, 3H, OCH3), 1.69 (d, J = 6.8 Hz, 3H, 3-CH3),
13
1.40 (s, 9H, t-Bu); C NMR (CDCl ): " 177.5 (1), 153.7, 149.9, 139.8, 115.0, 111.6, 109.7, 71.6 (2),
3
+
55.6 (OCH ), 35.0 (t-Bu), 29.8 (t-Bu), 18.5 (3); HR MS: calcd for C H O Na (M + Na )ꢀ275.1254,
14 20
4
3
found 275.1263; Analytical data on racemic compound: Mp 108-110 °C (CH2Cl2/hexane); IR (KBr):
2953, 1712, 1603, 1499, 803, 767 cm-1.
Di(1-naphthyl)methyl (S)-2-(2-tert-butyl-4-methoxyphenoxy)propanoate ((S)-2u). [Scheme 3, 48%
yield, 96% ee] HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50, flow rate = 0.75 mL/min): tR = 12.0
1
min (2.1%), t = 14.1 min (97.9%); H NMR (CDCl ): " 8.44 (s, 1H, 1’-H), 8.14-7.72 (m, 6H, Ar),
3
R
7.58-7.22 (m, 7H, Ar), 7.19-7.12 (m, 1H, Ar), 6.86 (d, J = 3.2 Hz, 1H, Ar), 6.52 (d, J = 8.8 Hz, 1H, Ar),
6.41 (dd, J = 8.8, 3.2 Hz, 1H, Ar), 4.90 (d, J = 6.8 Hz, 1H, 2-H), 3.75 (s, 3H, OCH3), 1.65 (d, J = 6.8 Hz,
13
3H, 3-CH ), 1.30 (s, 9H, t-Bu); C NMR (CDCl ): " 171.8 (1), 153.5, 150.1, 139.5, 134.4, 134.1, 133.9,
3
3
133.8, 131.2, 130.8, 129.3, 128.9, 128.9, 128.8, 126.8, 126.5, 126.4, 125.9, 125.7, 125.5, 125.2, 125.1,
123.34, 123.32, 114.7, 111.6, 109.6, 72.1 (1’), 71.6 (2), 55.6 (OCH3), 34.9 (t-Bu), 29.6 (t-Bu), 18.6 (3);
+
HR MS: calcd for C H O Na (M + Na )ꢀ 541.2349, found 541.2324; Analytical data on racemic
35 34
4
amorphous compound: IR (KBr): 3053, 2952, 1735, 1599, 1585, 1510, 1498, 1485, 1179, 1127, 799, 793,
778 cm-1.
Removal of 2-tert-butyl-4-methoxyphenoxy group of (S)-2u (Scheme 3). 14
To a stirred solution of (S)-di(naphthalen-1-yl)methyl 2-(2-(tert-butyl)-4-methoxyphenoxy)propanoate
((S)-2u) (50.0 mg, 96.4 µmol, 96% ee) in DMF-H2O (8:1, v/v) (1.8 mL) at room temperature was added
cerium ammonium nitrate (264 mg, 0.48 mmol) in one portion, and then the reaction mixture was stirred
for 50 min. After cooling at 0 °C, the reaction mixture was diluted with water (4 mL) and extracted with
EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, and then dried over
sodium sulfate. After filtration of the mixture and evaporation of the solvent, the crude product was

HETEROCYCLES, Vol. 86, No. 2, 2012
1251
purified by preparative thin layer chromatography on silica (EtOAc/hexane = 3/2) to afford (S)-3 (21.1
mg, 62% yield, 96% ee) as a white solid.
Di(1-naphthyl)methyl (S)-2-hydroxypropanoate ((S)-3). [Scheme 3, 96% ee] Mp 142-148 °C
(AcOEt/hexane); IR (KBr): 3363, 3062, 1743, 1597, 1512, 1188, 1126, 787, 741 cm-1; HPLC
(CHIRALPAK AD-H, i-PrOH/hexane = 1/9, flow rate = 0.75 mL/min): tR = 29.5 min (1.9%), tR = 39.1
1
min (98.1%); H NMR (CDCl ): " 8.46 (s, 1H, 1’-H), 8.03-7.78 (m, 6H, Ar), 7.56-7.32 (m, 8H, Ar),
3
13
4.48-4.34 (m, 1H, 2-H), 2.82 (br s, 1H, OH), 1.44 (d, J = 7.2 Hz, 3H, 3-CH ); C NMR (CDCl ): " 174.9
3
3
(1), 134.2, 134.1, 133.9, 133.9, 131.0, 130.9, 129.4, 129.3, 129.0, 128.9, 126.9, 126.8, 126.0, 126.0, 125.9,
125.7, 125.22, 125.18, 123.2, 123.2, 72.4 (1’), 67.0 (2), 20.5 (3); HR MS: calcd for C H O Na (M +
24 20
3
+
Na )ꢀ379.1305, found 379.1322.
Preparation of the authentic sample of (S)-2b from Methyl (R)-lactate
Methyl (S)-2-(2-chlorophenoxy)propanoate ((S)-5b).
To a mixture of methyl (R)-lactate (191 µL, 2.00 mmol), 2-chlorophenol (207 µL, 2.00 mmol), and
triphenylphosphine (577 mg, 2.20 mmol) in Et2O (8 mL) at 0 °C was added 40% diisopropyl
azodicarboxylate in toluene (1.58 mL, 3.00 mmol). After the reaction mixture had been stirred for 30 min
at 0 °C followed by 2 h at room temperature, and then diluted with hexane. After filtration of the slurry
mixture and evaporation of the solvent, the crude product was purified by silica gel column
chromatography (EtOAc/hexane = 1/40) to afford (S)-5b (334 mg, 78% yield) as a colorless oil: IR
-1
1
(neat): 2954, 1751, 1589, 1481, 1450, 748 cm ; H NMR (CDCl ): " 7.40-7.34 (m, 1H, Ar), 7.20-7.12 (m,
3
1H, Ar), 6.97-6.90 (m, 1H, Ar), 6.87-6.81 (m, 1H, Ar), 4.77 (q, J = 6.8 Hz, 1H, 2-H), 3.76 (s, 3H, OMe),
13
1.67 (d, J = 6.8 Hz, 3H, 3-H); C NMR (CDCl ): " 172.1 (1), 153.4, 130.6, 127.6, 123.9, 122.7, 115.4,
3
+
74.2 (2), 52.3 (Me), 18.5 (3); HR MS: calcd for C H ClO Na (M + Na ) 237.0289, found 237.0292.
10 11
3
(S)-2-(2-Chlorophenoxy)propanoic acid ((S)-1b).
(S)-5b (298 mg, 1.39 mmol) was hydrolyzed in accordance with the preparation of rac-3s, and then
crystallized from CH2Cl2 and hexane to afford (S)-1b (202 mg, 73% yield) as a white solid: HPLC
(CHIRALPAK AD-H, i-PrOH/hexane/TFA = 1/50/0.05, flow rate = 0.75 mL/min): tR = 21.7 min (99.3%),
tR = 26.8 min (0.7%).
Di(1-naphthyl)methyl (S)-2-(2-chlorophenoxy)propanoate ((S)-2b).
To a mixture of (S)-1b (10.0 mg, 50.0 µmol), 2-methyl-6-nitrobenzoic anhydride (MNBA) (20.7 mg, 60.0
µmol), and bis(!-naphthyl)methanol (14.2 mg, 50.0 µmol) in CH2Cl2 (1.0 mL) at room temperature were
successively added triethylamine (16.6 µL, 0.120 mmol) and DMAP (1.2 mg, 10 µmol). The reaction
mixture was directly purified by preparative thin layer chromatography on silica (CH2Cl2/hexane = 1/1) to
afford (S)-2b (22.4 mg, 96% yield) as a white solid: HPLC (CHIRALPAK AD-H, i-PrOH/hexane = 1/50,

1252
HETEROCYCLES, Vol. 86, No. 2, 2012
flow rate = 0.75 mL/min): tR = 20.0 min (99.6%), tR = 24.7 min (0.4%).
ACKNOWLEDGEMENTS
This study was partially supported by a Research Grant from the Center for Chirality, and Grants-in-Aid
for Scientific Research from the Ministry of Education, Science, Sports and Culture, Japan.
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