N-benzoyl-L-threonine-isopropyl-ester-mediated crystallization-induced dynamic resolution of α-bromo arylacetates for the asymmetric synthesis of α-thio and α-oxy arylacetates

Article abstract of DOI:10.1002/ejoc.201301539

N-Benzoyl-L-threonine-isopropyl-ester-mediated crystallization-induced dynamic resolution (CIDR) of configurationally labile α-bromo arylacetates has been investigated. The CIDR was successfully used for the asymmetric preparation of these compounds with

Full text of DOI:10.1002/ejoc.201301539

FULL PAPER
DOI: 10.1002/ejoc.201301539
N-Benzoyl-
L
-Threonine-Isopropyl-Ester-Mediated Crystallization-Induced
Dynamic Resolution of α-Bromo Arylacetates for the Asymmetric Synthesis of
α-Thio and α-Oxy Arylacetates
Kon Ji Park,[a] Yelim Kim,[a] Myung-su Lee,[a] and Yong Sun Park*[a]
Keywords: Synthetic methods / Asymmetric synthesis / Nucleophilic substitution / Chiral auxiliaries / Chiral resolution
N-Benzoyl-
L
-threonine-isopropyl-ester-mediated
crystalli-
reactions with sulfur and oxygen nulceophiles gave α-thio
and α-oxy arylacetates with up to 98:2 dr. The method was
further developed for the preparation of highly enantioen-
riched 2-phenylthio-2-arylethanols with up to 97:3 er, and
1,4-benzoxazin-3-ones with up to 94:6 er.
zation-induced dynamic resolution (CIDR) of configuration-
ally labile α-bromo arylacetates has been investigated. The
CIDR was successfully used for the asymmetric preparation
of these compounds with up to 98:2 dr, under solution and
solvent-free conditions. Subsequent nucleophilic substitution
In an earlier study, we presented a CIDR method for the
resolution of N-(S)-(1-phenylethyl)-α-chloro-α-aryl acet-
amide (1), in which (αS)-1 selectively crystallizes from aque-
ous ammonia solution in a process controlled by the ther-
modynamics of the phase equilibrium, as shown in Fig-
ure 1. Chloride 1 has, however, limited synthetic utility for
asymmetric synthesis, due to its low reactivity towards nu-
cleophiles and the harsh conditions required for the re-
moval of the chiral auxiliary.[4b,4c] In a continuation of our
work on the asymmetric synthesis of α-heteroatom-substi-
tuted carboxylic acid derivatives, in this paper, we report a
new CIDR method for the resolution of l-threonine-de-
rived α-bromo arylacetates, and an efficient nucleophilic
substitution with sulfur and oxygen nucleophiles for the
asymmetric synthesis of α-thio and α-oxy arylacetate deriv-
atives.
Introduction
Chiral α-thio and α-oxy acid derivatives are ubiquitous
structural subunits in biologically active compounds, and
the nucleophilic substitution of α-halo acid derivatives with
sulfur and oxygen nucleophiles provides an efficient ap-
proach for their synthesis.[1] However, the stereospecific nu-
cleophilic substitution (SN2) approach seems to lack gener-
ality for asymmetric synthesis, since the optically pure α-
halo acids are generally obtained from a limited number
of natural α-amino acids.[2] In an alternative approach, the
dynamic resolution of chiral α-halo acid derivatives in nu-
cleophilic substitutions can allow easy access to a wide
range of enantioenriched α-heteroatom-substituted acid de-
rivatives. Many successful results on the chiral-auxiliary-
mediated dynamic resolution of α-halo acid derivatives in
nucleophilic substitution reactions have recently been re-
ported.[3]
The dynamic resolution of α-halo acid derivatives is not
limited to soluble diastereomeric species. The dynamic pro-
cess can be controlled by the thermodynamics of phase
changes, such as crystallization. When two diastereomeric
α-halo acid derivatives have different solubilities, the selec-
tive precipitation of one diastereomer facilitates the conver-
sion of the more soluble diastereomer into the less soluble
diastereomer, which is then isolated in high yield and dia-
stereomeric purity. The crystallization-induced dynamic res-
olution (CIDR) of α-halo amides, imides, and carboxylic
acid salts has previously been reported by us and other re-
search groups.[4]
[a] Department of Chemistry, Konkuk University
120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, Korea
E-mail: parkyong@konkuk.ac.kr
http://konkuk.ac.kr/~parkyong/lab.htm
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301539.
Figure 1. CIDR of α-halo phenylacetic acid derivatives.
Eur. J. Org. Chem. 2014, 1645–1652
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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K. J. Park, Y. Kim, M.-s. Lee, Y. S. Park
FULL PAPER
Results and Discussion
In our most recent study on the dynamic resolution of
α-bromo phenylacetate 2 using N-benzoyl-l-threonine iso-
propyl ester, we observed that a diastereomer of 2 showed
interesting crystallization behavior. Highly diastereoen-
riched (αR)-2 was obtained as a solid by selective crystalli-
zation in 23–30% yields with up to 97:3 diastereomeric ratio
(dr).[5,6] We reasoned that this finding could be used for
the dynamic resolution of 2 by removing (αR)-2 from the
equilibrium mixture of diastereomers by selective crystalli-
zation, as shown in Figure 1.[7] Initial studies were con-
ducted to find an appropriate solvent system in which (αR)-
2 could be selectively precipitated while the two dia-
stereomers of 2 equilibrate in solution simultaneously. Sev-
eral solvents were screened on the basis of the dr of 2 ob-
tained after complete evaporation to dryness. The best sol-
vent proved to be a mixed solvent system of n-hexane/ethyl
acetate, and the optimum ratio was found to be 5:1 (n-hex-
ane/EtOAc). The best CIDR was performed at a 0.2 m con-
centration of 2 (50:50 dr) at room temperature with the
gradual evaporation of solvent to promote the generation
of crystal. After the solvent was allowed to evaporate over
7 d, (αR)-2 was quantitatively recovered with 90:10 dr. Al-
though the CIDR of (αR)-2 occurred efficiently, this ratio
is not high enough for use in further synthetic transforma-
tions. More effort was put into improving the dr of 2 by
recrystallization. When the product with 90:10 dr was dis-
solved in a minimum amount of n-hexane/EtOAc (5:1), the
Figure 2. (a) Solvent-free CIDR of α-bromo phenylacetate
2
(50 mg, spread over the bottom of a 15 mm-diameter vial). (b) Epi-
merization of (αR)-2 in solution with and without DIEA (20 mg in
2.0 mL of solvent).
recrystallization started within 4–5 h at room temperature. amine), 1.0 equiv.] accelerates the epimerization in all the
The mixture was allowed to stand overnight at room temp., solvents. After 6 d in chloroform, the dr of 2 was 98:2 with-
and then it was filtered to give a 70% crystallization yield out DIEA and 67:33 with DIEA.
with a dr of Ͼ98:2.
The CIDR method for the asymmetric preparation of α-
In addition, we observed an unusual solvent-free CIDR bromo phenylacetate 2 has been applied to the preparation
of (αR)-2, as shown in the plot of Figure 2 (a). The sponta- of optically active α-thio-substituted acetates, as shown in
neous dynamic resolution was monitored in terms of % de Table 1. For the asymmetric nucleophilic substitution of
1
(diastereomeric excess) by H NMR spectroscopic analysis (αR)-2, it is important to carry out the nucleophilic substi-
of 2. When completely solvent-free 2 (colorless oil; 50:50 tution in an efficient and stereocontrolled manner, and to
dr) was stored in a capped vial at room temp., a slow minimize the epimerization of (αR)-2 upon exposure to the
crystallization took place, and the dr of 2 gradually in- basic conditions. The high reactivity of the sulfur nucleo-
creased until 98:2 dr was obtained after 30 d. The solvent- philes may result in the nucleophilic substitution being suf-
free crystallization appears to depend on the temperature. ficiently fast relative to the epimerization process, thereby
The crystallization was faster at higher temperatures giving the substitution product with high dr values. When
(40 °C), but the final dr after 30 days was much lower (90:10 (αR)-2 (98:2 dr) was treated with potassium thioacetate
dr).
(AcS–K+) in MeOH (0.02 m) at room temp. for 10 min, the
The configurational stability of α-bromo phenylacetate substitution successfully gave α-acetylthio-substituted prod-
(αR)-2 in solution determines whether the bromide can be uct (αR)-3 with 98:2 dr in 99% yield (Table 1, entry 1).
advantageously utilized in asymmetric synthesis. To test the However, when thiophenol (PhSH) was used as the nucleo-
configurational stability of (αR)-2 in solution, the progress phile in the presence of DIEA, the slower substitution in
of the epimerization was monitored in terms of % de by MeOH produced α-phenylthio-substituted product (αR)-4
1H NMR spectroscopic analysis of (αR)-2 (98:2 dr) in three with 87:13 dr in 88% yield (Table 1, entry 2). The result
selected solvents (deuterated CHCl3, CH3CN, and DMF), indicates that the substitution with PhSH is not fast enough
as shown in Figure 2 (b). Samples of lower concentration relative to the rate of epimerization of 2, and therefore (αR)-
(0.02 m) were prepared for the epimerization studies so that 2 undergoes epimerization under the basic conditions in
the compounds would stay in solution. The results clearly MeOH. As expected from the results shown in Figure 2 (b),
indicate that (αR)-2 is configurationally stable in CHCl3, the substitutions with PhSH in less polar solvents such as
but labile in polar solvents such as CH3CN and DMF. The CH2Cl2, diethyl ether, CHCl3, and toluene gave α-phen-
plots also show that the base [DIEA (diisopropylethyl- ylthio-substituted product (αR)-4 with significantly im-
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Eur. J. Org. Chem. 2014, 1645–1652

Crystallization-Induced Dynamic Resolution
proved dr values (Table 1, entries 3–6). No substantial dif- n-octanethiol gave α-alkylthio-substituted products 14 and
ference in dr was observed when Et3N was used as the base, 15 with 98:2 and 92:8 dr values, respectively. These substitu-
but a slightly lower dr was observed with DABCO (1,4- tion reactions, though, gave mixtures of products, and the
diazabicyclo[2.2.2]octane; Table 1, entries 7 and 8). Gratify- desired products were isolated in low yields of 64 and 32%,
ingly, a high dr of 98:2 was observed with K2CO3 in toluene, respectively, as shown in Table 2, entries 10 and 11. The use
but only a lower 63% yield was observed (Table 1, entry 9). of other bases, including Et3N, DIEA, and pyridine, led to
In the reactions of 2 (53:47 dr), nucleophilic substitutions less satisfactory dr values ranging from 88:12 to 80:20 with
with AcS–K+ and PhSH produced the corresponding prod- the aliphatic thiol nucleophiles. When the sterically de-
ucts (i.e., 3 and 4) with 51:49 and 52:48 dr values, respec- manding triphenylmethanethiol was tested, however, the re-
tively (Table 1, entries 10 and 11). This result implies that action with K2CO3 gave no detectable amount of product
no dynamic kinetic resolution of α-bromo phenylacetate 2 after 4 h (Table 2, entry 12). Increasing the reaction tem-
is operating in the nucleophilic substitution with the thio perature to 40 °C did not result in any significant change in
nucleophiles.[3]
either the yield or the dr in the reactions with the aliphatic
thiols.
Table 1. Nucleophilic substitution with sulfur nucleophiles.
Table 2. Nucleophilic substitution with various thiol nucleophiles.
Entry dr
of 2
Conditions
Time dr[a]
[h]
Yield[b]
[%]
1
2
3
4
5
6
7
8
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
98:2
AcS–K+, MeOH
0.2
4
4
4
4
4
4
4
4
98:2
87:13 93
99
PhSH, DIEA, MeOH
PhSH, DIEA, CH2Cl2
PhSH, DIEA, ether
PhSH, DIEA, CHCl3
PhSH, DIEA, toluene
PhSH, Et3N, toluene
PhSH, DABCO, toluene
PhSH, K2CO3, toluene
95:5
95:5
96:4
97:3
97:3
95:5
98:2
60
96
64
94
90
81
63
9
10
11
53:47 AcS–K+, MeOH
0.2
4
51:49 99
52:48 67
53:47 PhSH, K2CO3, toluene
[a] The dr values were determined from the 1H NMR spectra of
the reaction mixtures. [b] Isolated yields.
Next, the scope of the efficient nucleophilic substitution
reaction was examined by testing a series of substituted thio-
phenols with electron-donating and electron-withdrawing
groups at the para and ortho positions, as shown in Table 2.
When α-bromo phenylacetate (αR)-2 with 98:2 dr was
treated with five different para-substituted arenethiols, the
substitution reaction run in the presence of K2CO3 for 4 h
gave α-arylthio-substituted products 5–9 with comparably
high dr values in 81–97% yields (Table 2, entries 1–5). Also,
different ortho substituents such as amino, methoxy, meth-
oxycarbonyl, and methyl groups have only a minor influ-
ence on the dr of the products (i.e., 10–13), as shown in
Table 2, entries 6–9. The results indicate that the stereose-
lectivity of the reaction is independent of the electronic na-
ture of both the para and the ortho substituents of the ar-
enethiol nucleophiles. However, the substituents in the ortho
positions seem to influence the rate of substitution. The re-
actions of ortho-substituted arenethiols gave lower yields Ϫ
ranging from 53 to 73% after 4 h Ϫ than those with the
corresponding para-substituted derivatives. It follows that
all differences in rate between the para- and ortho-substi-
tuted compounds arise from steric effects. Moreover, the
[a] All reactions were carried out for 4 h. [b] The dr values were
determined from the 1H NMR spectra of the reaction mixtures.
same reaction of 2 with the aliphatic thiols benzyl thiol and [c] Isolated yield.
Eur. J. Org. Chem. 2014, 1645–1652
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1647

K. J. Park, Y. Kim, M.-s. Lee, Y. S. Park
FULL PAPER
Having successfully developed a method for the asym-
To demonstrate the further synthetic utility of this meth-
metric synthesis of α-thio phenylacetates, we directed our odology, the CIDR process used for the preparation of
efforts to the asymmetric preparation of α-oxy phenylacet- (αR)-2 was applied to two different α-bromo arylacetates 23
ates. The nucleophilic substitution of (αR)-2 with a phenox- and 24, as shown in Scheme 1. The variation in the aryl
ide anion was examined in the presence of a base, as shown group of the α-bromo arylacetate influenced neither the
in Table 3. The reaction of (αR)-2 with p-methoxyphenol yield nor the dr, and gave both the p-chloro-substituted [i.e.,
and K2CO3 in toluene did not give α-aryloxy-substituted (αR)-23] and p-bromo-substituted [i.e., (αR)-24] derivatives
product 17 (Table 3, entry 1). When DMF was used as a with 98:2 dr. When the highly diastereoenriched (αR)-23
solvent with K2CO3, the substitution product 17 was pro- and (αR)-24 were treated with PhSH and K2CO3 in toluene,
duced with 85:15 dr in 71% yield after 0.5 h. The low dr after 4 h, α-phenylthio-substituted products 25 and 26 were
may be attributed to the epimerization promoted by the po- formed with 97:3 dr. α-Phenylthio-substituted products 4
lar solvent. Pleasingly, the use of tBuO–Na+ improved the and 25 were reduced with LiAlH4 to give 2-phenylthio eth-
dr of 17 to 92:8 dr.[8] No further improvement in the dr of anols 27 and 28 with 97:3 and 95:5 enantiomeric ratios (er
17 could be achieved by varying the reaction parameters values), respectively. These compounds are known to be
such as base, solvent, and reaction temperature (Table 3, versatile synthetic intermediates.[9,10] Furthermore, the reac-
entries 4–6). The same reaction of 2 with 51:49 dr gave 17 tions of (αR)-2, (αR)-23, and (αR)-24 with o-aminophenol
with 74:26 dr. This result indicates that a minor dynamic produced 1,4-benzoxazin-3-ones under the optimized reac-
kinetic resolution of α-bromo phenylacetate 2 occurs during tion conditions listed in Table 3. After 0.5 h, the one-pot
the nucleophilic substitution reaction with the phenoxide to substitution–cyclization reaction gave 29–31 in 68–76%
favor the (αS)-product.[3] The reactions with p-benzoxy, p- yields, with 94:6, 93:7, and 93:7 er values, respectively. The
nitro, o-methoxy, o-chloro, and o-nitrophenol nucleophiles o-amino group underwent a spontaneous intramolecular
gave α-aryloxy phenylacetates 18–22 with somewhat lower amide formation to remove chiral auxiliary and give the
dr values in 56–67% yields under the same conditions. No 1,4-benzoxazin-3-ones. Despite the significance of optically
clear trends can be seen that relate the electronic and steric active 1,4-benzoxazin-3-ones in biological and medicinal
properties of the substituents to the dr of the product and chemistry,[11] the asymmetric synthesis of these compounds
the rate of the reaction. (Table 3, entries 7–11).
has rarely been reported.[12]
Table 3. Nucleophilic substitution with a p-methoxyphenoxide nu-
cleophile.
Entry[a]
1
Y
Conditions
dr[b]
Product Yield
[%][c]
p-MeO K2CO3, toluene,
–
17
n.r.
r.t.
2
3
p-MeO K2CO3, DMF, r.t.
85:15
92:8
17
17
71
87
p-MeO tBuO–Na+, DMF,
r.t.
4
p-MeO tBuO–K+, DMF,
89:11
86:14
89:11
85:15
87:13
89:11
88:12
86:14
17
17
17
18
19
20
21
22
53
78
82
62
59
64
67
56
Scheme 1. Asymmetric synthesis of 2-phenylthio-2-arylethanols
and 1,4-benzoxazin-3-ones.
r.t.
5
p-MeO tBuO–Na+,
CH3CN, r.t.
6
p-MeO tBuO–Na+, DMF,
0 °C
Conclusions
7
p-BnO tBuO–Na+, DMF,
r.t.
We discovered that N-benzoyl-l-threonine isopropyl es-
ter is an efficient chiral auxiliary for the CIDR of α-bromo
arylacetates. The new and practical CIDR method coupled
with a subsequent nucleophilic substitution represents an
efficient and direct approach to the asymmetric synthesis of
thio- or oxy-substituted arylacetates, 2-arylethanols, and
1,4-benzoxazin-3-ones. The simplicity of the protocol, with
its mild reaction conditions and easy removal of the chiral
auxiliary, gives impetus to develop this methodology fur-
ther. Studies on the potential application of this methodol-
8
p-NO2 tBuO–Na+, DMF,
r.t.
9
o-MeO tBuO–Na+, DMF,
r.t.
10
11
o-Cl
tBuO–Na+, DMF,
r.t.
o-NO2 tBuO–Na+, DMF,
r.t.
[a] All reactions were carried out for 0.5 h. [b] The dr values were
determined from the 1H NMR spectra of the reaction mixtures.
[c] Isolated yield.
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Crystallization-Induced Dynamic Resolution
134.5, 133.5, 132.1, 132.0, 130.3, 128.8, 127.1, 123.7, 73.6, 70.3,
55.8, 45.5, 21.7, 21.5, 16.9 ppm. HRMS calcd. for C22H24Br2NO5
[M + H]+ 540.0021; found 540.0023.
ogy to the asymmetric synthesis of various types of α-sub-
stituted carboxylic acid derivatives are currently underway.
Crystallization-Induced Dynamic Resolution of 2: n-Hexane (10 mL)
was carefully added to a solution of 2 (1.0 g, 2.2 mmol) in EtOAc
(2 mL). The mixture was allowed to evaporate at room temp. over
7 d. The resulting solid 2 (ca. 90:10 dr) was dissolved in n-hexane/
EtOAc (5:1; 4 mL). The mixture was allowed to stand overnight at
room temp., and the resulting precipitate was filtered and washed
with cold n-hexane to give 2 (711 mg, 70% crystallization yield,
Ͼ 98:2 dr).
Experimental Section
General Methods: All reactions were performed in oven-dried glass-
ware under a nitrogen atmosphere. All chemicals were obtained
from commercial sources, and were used as received. Analytical
thin-layer chromatography (TLC) was performed on silica gel
plates with QF-254 indicator, and TLC visualization was carried
out with UV light. Flash column chromatography was performed
with 230–400 mesh silica gel. Analytical chiral stationary phase
HPLC was performed using a pump system coupled to an ab-
sorbance detector (217 nm). Chiralcel OD (25 cmϫ4.6 mm i.d.)
and Chiralcel OJ-H (25 cmϫ4.6 mm i.d.) columns were used with
a 2-propanol/hexane mobile phase to determine enantiomeric ra-
tios. 1H and 13C NMR spectra were acquired with a Bruker
Preparation of N-Benzoyl-O-(α-acetylthio-α-phenylacetyl)-l-threo-
nine Isopropyl Ester [(αS)-3]: Potassium thioacetate (1.0 equiv.) was
added to a solution of α-bromophenylacetate 2 (98:2 dr) in meth-
anol (ca. 0.02 m) at room temperature. The reaction mixture was
stirred at room temperature for 0.2 h, then the solvent was evapo-
rated. The crude material was purified by column chromatography
to give 3 (99%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3,
major diastereomer): δ = 7.89–7.31 (m, 10 H), 6.88 (d, J = 9.2 Hz,
1 H), 5.54 (m, 1 H), 5.28 (s, 1 H), 5.05 (m, 1 H), 4.97 (m, 1 H),
2.36 (s, 3 H), 1.27 (m, 6 H), 1.23 (d, J = 6.0 Hz, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, major diastereomer): δ = 194.0, 169.0,
168.9, 167.6, 134.1, 133.7, 131.9, 128.9, 128.6, 128.5, 127.3, 72.6,
70.0, 55.9, 50.3, 30.0, 21.8, 21.6, 17.1 ppm. C24H27NO6S (457.54):
calcd. C 63.00, H 5.95, N 3.06; found C 63.18, H 6.03, N 3.21.
1
(400 MHz, H; 100.6 MHz, 13C) spectrometer. Chemical shifts (δ)
are reported in ppm, and [D]chloroform (CDCl3) was used as an
internal standard (δ = 7.26 ppm, H; δ = 77.07 ppm, 13C). Multi-
1
plicities are indicated by: s (singlet), d (doublet), t (triplet), q (quar-
tet), m (multiplet), and br. (broad). Coupling constants (J) are re-
ported in Hz. HRMS spectra were measured with a JEOL JMS-
700 instrument using the FAB method. Optical rotations were re-
corded with a JASCO P-2000 digital polarimeter.
General Procedure for the Preparation of α-Thio-Substituted Aryl-
General Procedure for the Preparation of α-Bromo Arylacetates 2,
23, and 24: N-Benzoyl-l-threonine isopropyl ester (10.0 mmol) was
treated with racemic α-bromo arylcarboxylic acid (1.0 equiv.), DCC
(1.0 equiv.), and DMAP (0.05 equiv.) in CH2Cl2 (50 mL), and the
mixture was stirred at room temperature for 7–10 h. The precipitate
was removed by filtration, and the filtrate was washed with water.
The organic phase was dried with MgSO4, filtered, and concen-
trated. The crude product was purified by column chromatography
on silica gel.
acetates 4–15, 25, and 26:
A thiol (1.2 equiv.) and K2CO3
(1.0 equiv.) were added to a solution of α-bromo arylacetates
(1.0 mmol) in toluene (ca. 0.02 m) at room temperature. The re-
sulting reaction mixture was stirred at room temperature for 4 h,
then the solvent was evaporated. The crude material was purified
by column chromatography to give the α-thio-substituted arylacet-
ate.
N-Benzoyl-O-(α-phenylthio-α-phenylacetyl)-
L-threonine
Isopropyl
Ester [(αS)-4]: A colorless oil was obtained in 96% yield. 1H NMR
(400 MHz, CDCl3, major diastereomer): δ = 7.78–7.20 (m, 15 H),
6.68 (d, J = 8.8 Hz, 1 H), 5.51 (m, 1 H), 4.96 (m, 2 H), 4.92 (s, 1
H), 1.25 (m, 6 H), 1.07 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 169.0, 168.9, 167.7,
135.4, 133.7, 132.0, 131.9, 129.1, 128.8, 128.7, 128.5, 127.9, 127.2,
72.7, 70.1, 56.4, 55.9, 21.7, 21.5, 16.8 ppm. C28H29NO5S (491.60):
calcd. C 68.41, H 5.95, N 2.85; found C 68.19, H 5.90, N 3.07.
N-Benzoyl-O-(α-bromo-α-phenylacetyl)-L-threonine Isopropyl Ester
[(αR)-2]: A white solid was obtained in 70% yield. 1H NMR
(400 MHz, CDCl3, major diastereomer): δ = 7.76–7.32 (m, 10 H),
6.70 (d, J = 9.2 Hz, 1 H), 5.56 (m, 1 H), 5.34 (s, 1 H), 4.99 (m, 1
H), 4.86 (m, 1 H), 1.36 (d, J = 6.4 Hz, 3 H), 1.20 (d, J = 6.0 Hz, 3
H), 1.09 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
major diastereomer): δ = 168.8, 167.5, 167.0, 135.4, 133.5, 132.0,
129.4, 128.9, 128.8, 128.6,127.1, 73.3, 70.1, 55.7, 46.7, 21.7, 21.4,
16.9 ppm. C22H24BrNO5 (462.34): calcd. C 57.15, H 5.23, N 3.03;
found C 57.28, H 5.43, N 3.01.
N-Benzoyl-O-[α-(p-methoxyphenylthio)-α-phenylacetyl]-L-threonine
Isopropyl Ester [(αS)-5]: A colorless oil was obtained in 88% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.49–7.25
(m, 12 H), 6.77–6.69 (m, 3 H), 5.52 (m, 1 H), 4.94 (m, 2 H), 4.74
(s, 1 H), 3.75 (s, 3 H), 1.25 (m, 6 H), 1.10 (d, J = 6.4 Hz, 3 H)
ppm. 13C NMR (100 MHz, CDCl3, major diastereomer): δ = 169.1,
169.0, 167.7, 160.2, 135.8, 135.7, 133.7, 132.0, 128.7, 128.6, 128.5,
128.3, 127.2, 123.5, 114.5, 72.5, 70.1, 57.5, 55.9, 55.3, 21.7, 21.5,
17.0 ppm. HRMS calcd. for C29H32NO6S [M + H]+ 522.1950;
found 522.1951.
N-Benzoyl-O-[α-bromo-α-(p-chlorophenyl)acetyl]-
L-threonine
Iso-
propyl Ester [(αR)-23]: A white solid was obtained in 65% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.73–7.27
(m, 9 H), 6.66 (d, J = 8.8 Hz, 1 H), 5.53 (m, 1 H), 5.29 (s, 1 H),
4.98 (m, 1 H), 4.91 (m, 1 H), 1.37 (d, J = 6.4 Hz, 3 H), 1.22 (d, J
= 6.4 Hz, 3 H), 1.10 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 168.9, 167.5, 166.8,
135.5, 134.0, 133.5, 132.1, 130.1, 129.1, 128.7, 127.1, 73.5, 70.2,
55.7, 45.5, 21.7, 21.5, 16.9 ppm. HRMS calcd. for C22H24BrClNO5
[M + H]+ 496.0526; found 496.0527.
N-Benzoyl-O-[α-(p-methylphenylthio)-α-phenylacetyl]-L-threonine
Isopropyl Ester [(αS)-6]: A pale yellow oil was obtained in 97%
yield. 1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.79–
7.01 (m, 14 H), 6.69 (d, J = 9.2 Hz, 1 H), 5.50 (m, 1 H), 4.94 (m,
2 H), 4.84 (s, 1 H), 2.28 (s, 3 H), 1.22 (m, 6 H), 1.08 (d, J = 6.4 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3, major diastereomer): δ =
169.0, 168.9, 167.7, 138.3, 135.6, 133.8, 132.8, 132.0, 129.9, 129.8,
128.7, 128.6, 128.5, 128.3, 127.2, 72.5, 70.0, 56.9, 55.9, 21.7, 21.5,
21.1, 16.9 ppm. C29H31NO5S (505.63): calcd. C 68.89, H 6.18, N
2.77; found C 69.90, H 6.05, N 2.61.
N-Benzoyl-O-[α-bromo-α-(p-bromophenyl)acetyl]-L-threonine Iso-
propyl Ester [(αR)-24]: A white solid was obtained in 69% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.75–7.27
(m, 9 H), 6.66 (d, J = 8.8 Hz, 1 H), 5.53 (m, 1 H), 5.27 (s, 1 H),
4.98 (m, 1 H), 4.92 (m, 1 H), 1.37 (d, J = 6.8 Hz, 3 H), 1.22 (d, J
= 6.0 Hz, 3 H), 1.11 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 168.9, 167.5, 166.8,
Eur. J. Org. Chem. 2014, 1645–1652
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1649

K. J. Park, Y. Kim, M.-s. Lee, Y. S. Park
FULL PAPER
N-Benzoyl-O-[α-(p-chlorophenylthio)-α-phenylacetyl]-
L
-threonine
N-Benzoyl-O-[α-(2,6-dimethylphenylthio)-α-phenylacetyl]-
L-
Isopropyl Ester [(αS)-7]: A pale yellow oil was obtained in 97%
threonine Isopropyl Ester [(αS)-13]: A yellow oil was obtained in
1
yield. 1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.37– 53% yield. H NMR (400 MHz, CDCl3, major diastereomer): δ =
7.17 (m, 14 H), 6.67 (d, J = 8.8 Hz, 1 H), 5.51 (m, 1 H), 4.95 (m,
2 H), 4.85 (s, 1 H), 1.22 (d, J = 6.4 Hz, 6 H), 1.08 (d, J = 6.0 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3, major diastereomer): δ =
169.0, 168.7, 167.6, 135.1, 134.3, 133.8, 133.7, 132.0, 131.9, 129.2,
128.8, 128.7, 128.5, 128.4, 127.2, 72.7, 70.1, 56.5, 55.9, 21.7, 21.5,
16.9 ppm. C28H28ClNO5S (526.05): calcd. C 63.93, H 5.37, N 2.66;
found C 63.78, H 5.50, N 2.61.
7.76–7.02 (m, 13 H), 6.65 (d, J = 9.2 Hz, 1 H), 5.52 (m, 1 H), 4.92
(m, 2 H), 4.52 (s, 1 H), 2.35 (s, 6 H), 1.26 (d, J = 6.4 Hz, 3 H),
1.22 (d, J = 6.4 Hz, 3 H), 1.09 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 169.0, 168.9, 167.6,
143.7, 136.3, 133.7, 132.0, 131.3, 129.1, 128.7, 128.5, 128.4, 128.3,
128.2, 127.2, 72.4, 70.1, 56.0, 55.9, 21.9, 21.7, 21.5, 16.8 ppm.
HRMS calcd. for C30H34NO5S [M + H]+ 520.2158; found
520.2159.
N-Benzoyl-O-[α-(p-methoxycarbonylphenylthio)-α-phenylacetyl]-
L
-threonine Isopropyl Ester [(αS)-8]: A yellow oil was obtained in
N-Benzoyl-O-(α-benzylthio-α-phenylacetyl)-L-threonine Isopropyl
1
Ester [(αS)-14]: A pale yellow oil was obtained in 64% yield. 1H
NMR (400 MHz, CDCl3, major diastereomer): δ = 7.53–7.26 (m,
15 H), 6.66 (d, J = 9.2 Hz, 1 H), 5.53 (m, 1 H), 4.96 (m, 2 H), 4.39
(s, 1 H), 3.75 (d, J = 13.6 Hz, 2 H), 3.59 (d, J = 13.0 Hz, 2 H),
1.29 (d, J = 6.4 Hz, 3 H), 1.25 (d, J = 6.8 Hz, 3 H), 1.14 (d, J =
6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major dia-
stereomer): δ = 169.3, 169.0, 167.6, 136.9, 135.6, 133.6, 132.0,
129.1, 128.7, 128.6, 128.5, 128.3, 128.2, 127.4, 127.2, 72.4, 70.1,
55.9, 51.6, 36.1, 21.7, 21.5, 17.0 ppm. C29H31NO5S (505.63): calcd.
C 68.89, H 6.18, N 2.77; found C 69.78, H 6.02, N 2.88.
86% yield. H NMR (400 MHz, CDCl3, major diastereomer): δ =
7.75–7.26 (m, 14 H), 6.67 (d, J = 9.2 Hz, 1 H), 5.51 (m, 1 H), 5.06
(s, 1 H), 4.94 (m, 2 H), 3.88 (s, 3 H), 1.23 (d, J = 6.4 Hz, 3 H),
1.20 (d, J = 6.4 Hz, 3 H), 1.07 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 169.0, 168.5, 167.6,
166.4, 140.7, 134.6, 133.7, 132.0, 130.1, 129.2, 129.0, 128.8, 128.7,
128.6, 128.4, 127.2, 72.9, 70.1, 55.8, 55.0, 52.2, 21.7, 21.5,
16.8 ppm. HRMS calcd. for C30H32NO7S [M + H]+ 550.1899;
found 550.1899.
N-Benzoyl-O-[α-(2-naphtylthio)-α-phenylacetyl]-L-threonine Iso-
propyl Ester [(αS)-9]: A pale yellow oil was obtained in 81% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.45–7.26
(m, 17 H), 6.70 (d, J = 8.8 Hz, 1 H), 5.51 (m, 1 H), 5.03 (s, 1 H),
4.93 (m, 1 H), 4.35 (m, 1 H), 1.19 (d, J = 6.4 Hz, 6 H), 1.01 (d, J
= 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major dia-
stereomer): δ = 169.0, 168.9, 167.6, 135.4, 133.7, 133.5, 132.6,
132.0, 131.1, 129.1, 128.8, 128.7, 128.5, 127.7, 127.5, 127.2, 126.6,
126.5, 72.7, 70.1, 56.4, 55.9, 21.7, 21.4, 16.8 ppm. C32H31NO5S
(541.66): calcd. C 70.96, H 5.77, N 2.59; found C 71.19, H 5.91, N
2.61.
N-Benzoyl-O-[α-(n-octylthio)-α-phenylacetyl]-L-threonine Isopropyl
Ester [(αS)-15]: A pale yellow oil was obtained in 32% yield. 1H
NMR (400 MHz, CDCl3, major diastereomer): δ = 7.79–7.27 (m,
10 H), 6.70 (d, J = 9.2 Hz, 1 H), 5.54 (m, 1 H), 4.95 (m, 2 H), 4.55
(s, 1 H), 2.47 (m, 2 H), 1.51 (m, 2 H), 1.35–1.25 (m, 16 H), 1.15
(d, J = 6.4 Hz, 3 H), 0.87 (t, J = 6.8 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 169.5, 169.0, 167.6,
136.0, 135.7, 132.0, 128.7, 128.6, 128.4, 128.2, 127.2, 72.2, 70.1,
56.0, 52.4, 32.0, 31.8, 29.1, 28.9, 28.8, 22.6, 21.7, 21.5, 21.5, 17.0,
14.1 ppm. C30H41NO5S (527.72): calcd. C 68.28, H 7.83, N 2.65;
found C 68.40, H 7.99, N 2.61.
N-Benzoyl-O-[α-(o-aminophenylthio)-α-phenylacetyl]-L-threonine
Isopropyl Ester [(αS)-10]: A pale yellow oil was obtained in 56%
yield. 1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.34–
6.88 (m, 13 H), 6.65 (d, J = 8.0 Hz, 1 H), 6.58 (m, 1 H), 5.52 (m,
1 H), 4.98 (m, 2 H), 4.71 (s, 1 H), 1.25 (m, 6 H), 1.14 (d, J = 6.0 Hz,
3 H) ppm. 13C NMR (100 MHz, CDCl3, major diastereomer): δ
= 169.3, 169.2, 167.7, 148.9, 137.1, 136.1, 133.8, 132.0, 131.0, 128.7,
128.6, 128.4, 128.2, 127.3, 118.6, 115.8, 115.3, 72.4, 70.1, 56.0, 55.5,
21.8, 21.6, 16.9 ppm. C28H30N2O5S (506.62): calcd. C 66.38, H
5.97, N 5.53; found C 66.51, H 5.80, N 5.40.
N-Benzoyl-O-[α-phenylthio-α-(p-chlorophenyl)acetyl]-L-threonine
Isopropyl Ester [(αS)-25]: A pale yellow oil was obtained in 86%
yield. 1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.78–
7.22 (m, 14 H), 6.67 (d, J = 8.8 Hz, 1 H), 5.49 (m, 1 H), 4.95 (m,
2 H), 4.85 (s, 1 H), 1.20 (m, 6 H), 1.03 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3, major diastereomer): δ = 169.0,
168.6, 167.6, 134.4, 134.1, 133.7, 133.1, 132.5, 132.0, 129.8, 129.1,
128.9, 128.7, 128.2, 127.2, 72.8, 70.2, 55.9, 55.8, 21.7, 21.5,
16.9 ppm. HRMS calcd. for C28H29ClNO5S [M + H]+ 526.1455;
found 526.1454.
N-Benzoyl-O-[α-(o-methoxyphenylthio)-α-phenylacetyl]-L-threonine
Isopropyl Ester [(αS)-11]: A yellow oil was obtained in 73% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.53–7.20
(m, 12 H), 6.84–6.76 (m, 2 H), 6.71 (d, J = 9.2 Hz, 1 H), 5.49 (m,
1 H), 5.12 (s, 1 H), 4.92 (m, 2 H), 3.85 (s, 3 H), 1.20 (m, 6 H), 1.04
(d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major
diastereomer): δ = 169.1, 169.0, 167.7, 158.7, 135.6, 133.7, 133.6,
132.0, 129.6, 128.7, 128.6, 128.5, 128.3, 127.2, 121.4, 121.0, 110.9,
72.4, 70.0, 56.0, 55.8, 54.0, 21.7, 21.4, 16.8 ppm. HRMS calcd. for
C29H32NO6S [M + H]+ 522.1950; found 522.1950.
N-Benzoyl-O-[α-phenylthio-α-(p-bromophenyl)acetyl]-L-threonine
Isopropyl Ester [(αS)-26]: A pale yellow oil was obtained in 79%
yield. 1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.71–
7.22 (m, 14 H), 6.66 (d, J = 8.8 Hz, 1 H), 5.50 (m, 1 H), 4.95 (m,
2 H), 4.83 (s, 1 H), 1.23 (m, 6 H), 1.12 (d, J = 6.4 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3, major diastereomer): δ = 169.0,
168.5, 167.6, 134.6, 133.7, 133.1, 132.5, 132.0, 131.9, 130.1, 129.1,
128.7, 128.2, 127.2, 122.5, 72.8, 70.2, 55.9, 21.7, 21.5, 16.9 ppm.
HRMS calcd. for C28H29BrNO5S [M + H]+ 572.0929; found
572.0930.
N-Benzoyl-O-[α-(o-methoxycarbonylphenylthio)-α-phenylacetyl]-
L
-threonine Isopropyl Ester [(αS)-12]: A yellow oil was obtained in
1
68% yield. H NMR (400 MHz, CDCl3, major diastereomer): δ =
7.51–7.16 (m, 14 H), 6.76 (d, J = 9.2 Hz, 1 H), 5.53 (m, 1 H), 5.13
(s, 1 H), 4.92 (m, 2 H), 3.87 (s, 3 H), 1.22 (d, J = 6.4 Hz, 6 H),
General Procedure for the Preparation of α-Oxy Arylacetate Deriva-
tives 17–22 and 29–31: α-Bromoarylacetate (0.9 equiv.) was added
to a solution of a phenol nucleophile (1.0 equiv.) and tBuO–Na+
1.19 (d, J = 6.4 Hz, 3 H), 1.02 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (0.9 equiv.) in DMF (ca. 0.1 m) at room temperature. The mixture
(100 MHz, CDCl3, major diastereomer): δ = 169.1, 169.0, 167.7,
166.8, 139.1, 134.5, 133.6, 132.6, 132.0, 131.2, 129.0, 128.7, 128.6,
127.5, 127.3, 125.4 ppm. HRMS calcd. for C30H32NO7S [M + H]+
550.1899; found 550.1898.
was stirred for 0.5 h under a nitrogen atmosphere, then it was sub-
jected to an extractive work-up, and the organic phase was concen-
trated. The crude mixture was purified by column chromatography
to give the α-phenoxy arylacetate.
1650
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 1645–1652

Crystallization-Induced Dynamic Resolution
N-Benzoyl-O-[α-(p-methoxyphenoxy)-α-phenylacetyl]-
L
-threonine
72.3, 70.0, 56.3, 55.9, 21.7, 21.3, 16.6 ppm. HRMS calcd. for
C28H29ClNO6 [M + H]+ 510.1683; found 510.1683.
Isopropyl Ester [(αS)-17]: A colorless oil was obtained in 87% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.73–6.74
(m, 14 H), 6.68 (d, J = 9.2 Hz, 1 H), 5.55 (s, 1 H), 5.50 (m, 1 H),
4.93 (m, 2 H), 3.70 (s, 3 H), 1.21 (d, J = 6.0 Hz, 3 H), 1.15 (d, J =
6.4 Hz, 3 H), 0.98 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3, major diastereomer): δ = 169.2, 169.0, 167.7, 154.7, 151.3,
135.3, 133.7, 132.0, 129.1, 128.8, 128.7, 127.2, 127.0, 116.5, 114.7,
79.4, 72.5, 70.1, 56.0, 55.6, 21.7, 21.4, 16.6 ppm. C29H31NO7
(505.57): calcd. C 68.90, H 6.18, N 2.77; found C 68.71, H 6.15, N
2.69.
N-Benzoyl-O-[α-(o-nitrophenoxy)-α-phenylacetyl]-L-threonine Iso-
propyl Ester [(αS)-22]: A colorless oil was obtained in 59% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.57–6.94
(m, 15 H), 5.81 (s, 1 H), 5.50 (m, 1 H), 4.99 (m, 1 H), 4.76 (m, 1
H), 3.82 (s, 3 H), 1.17 (d, J = 6.4 Hz, 3 H), 1.10 (d, J = 6.4 Hz, 3
H), 0.77 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3,
major diastereomer): δ = 168.5, 167.9, 167.7, 150.0, 140.5, 134.0,
133.7, 133.5, 132.0, 129.5, 129.0, 128.7, 127.3, 126.9, 125.7, 121.7,
115.3, 79.4, 73.2, 70.0, 55.7, 21.7, 21.1, 16.4 ppm. HRMS calcd. for
C28H29N2O8 [M + H]+ 521.1924; found 521.1925.
For the removal of the chiral auxiliary, a mixture of 17 and excess
acetyl chloride in methanol (5 mL) was stirred for 12 h. The solvent
was evaporated, and the crude material was purified by column
chromatography to give methyl 2-(p-methoxyphenoxy)phenylacet-
(S)-2-Phenyl-2H-1,4-benzoxazin-3(4H)-one (29): A colorless oil was
obtained in 76% yield. 1H NMR (CDCl3, 400 MHz): δ = 9.67 (br.,
1 H), 7.47–6.81 (m, 9 H), 5.70 (s, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 166.6, 142.9, 135.2, 128.9, 128.7, 125.9, 124.4, 122.7,
117.2, 116.1, 78.5 ppm. The spectroscopic data of 29 were identical
to those of the authentic material reported previously.[11a] Chiral
HPLC: 94:6 er; tR (S; major enantiomer): 35.5 min; tR (R; minor
enantiomer): 29.1 min; (Chiralcel OJ-H column; 20% 2-propanol
in hexane; 0.5 mL/min). [α]2D0 = +52.1 (c = 0.07, CHCl3).
1
ate (66%). H NMR (CDCl3, 400 MHz): δ = 7.61–7.33 (m, 5 H),
6.87 (d, J = 9.6 Hz, 2 H), 6.78 (d, J = 9.6 Hz, 2 H), 5.55 (s, 1 H),
3.71 (s, 3 H), 3.70 (s, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ
= 170.6, 154.7, 151.4, 135.7, 129.0, 128.8, 127.1, 116.9, 114.7, 79.7,
55.6, 52.5 ppm. Chiral HPLC: 92:8 er; tR (S; major enantiomer):
15.7 min; tR (R; minor enantiomer): 25.7 min; (Chiralcel OD col-
umn; 5% 2-propanol in hexane; 0.5 mL/min).
(S)-2-(p-Chlorophenyl)-2H-1,4-benzoxazin-3(4H)-one (30): A color-
1
N-Benzoyl-O-[α-(p-benzoxyphenoxy)-α-phenylacetyl]-L-threonine
less oil was obtained in 73% yield. H NMR (CDCl3, 400 MHz):
δ = 9.35 (br., 1 H), 7.41–6.80 (m, 8 H), 5.65 (s, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 166.0, 142.7, 134.9, 133.6, 128.9,
128.4, 125.8, 124.6, 122.9, 117.3, 116.1, 77.9 ppm. HRMS calcd.
for C14H11ClNO2 [M + H]+ 260.0478; found 260.0479. Chiral
HPLC: 93:7 er; tR (S; major enantiomer): 19.5 min; tR (R; minor
enantiomer): 16.7 min; (Chiralcel OJ-H column; 20% 2-propanol
in hexane; 0.5 mL/min). [α]2D0 = +13.5 (c = 0.07, CHCl3).
Isopropyl Ester [(αS)-18]: A colorless oil was obtained in 62% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.48–7.37
(m, 15 H), 6.87–6.74 (m, 4 H), 6.67 (d, J = 8.8 Hz, 1 H), 5.55 (s, 1
H), 5.48 (m, 1 H), 4.99–4.88 (m, 4 H), 1.20 (d, J = 6.4 Hz, 3 H),
1.13 (d, J = 6.4 Hz, 3 H), 0.98 (d, J = 6.0 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3, major diastereomer): δ = 169.2, 168.9, 167.6,
153.8, 151.5, 137.0, 135.3, 133.7, 132.0, 129.1, 128.8, 128.7, 128.6,
128.0, 127.5, 127.2, 127.0, 116.4, 115.8, 79.3, 72.5, 70.5, 70.1, 55.9,
21.7, 21.4, 16.6 ppm. HRMS calcd. for C35H36NO7 [M + H]+
582.2492; found 582.2491.
(S)-2-(p-Bromophenyl)-2H-1,4-benzoxazin-3(4H)-one (31): A color-
1
less oil was obtained in 68% yield. H NMR (CDCl3, 400 MHz):
δ = 9.12 (br., 1 H), 7.35–6.80 (m, 8 H), 5.64 (s, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 165.7, 142.7, 134.1, 131.9, 128.7,
125.7, 124.6, 123.1, 122.9, 117.3, 116.0, 77.9 ppm. HRMS calcd.
for C14H11BrNO2 [M + H]+ 303.9973; found 303.9974. Chiral
HPLC: 93:7 er; tR (S; major enantiomer): 20.4 min; tR (R; minor
enantiomer): 16.4 min; (Chiralcel OJ-H column; 20% 2-propanol
in hexane; 0.5 mL/min). [α]2D0 = +17.9 (c = 0.04, CHCl3).
N-Benzoyl-O-[α-(p-nitrophenoxy)-α-phenylacetyl]-L-threonine Iso-
propyl Ester [(αS)-19]: A pale yellow oil was obtained in 56% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.55–6.94
(m, 15 H), 5.81 (s, 1 H), 5.49 (m, 1 H), 4.99 (m, 1 H), 4.76 (m, 1
H), 1.17 (d, J = 6.0 Hz, 3 H), 1.10 (d, J = 6.4 Hz, 3 H), 0.77 (d, J
= 6.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major dia-
stereomer): δ = 168.5, 167.9, 167.7, 150.0, 140.5, 134.0, 133.7,
133.5, 132.0, 129.5, 129.0, 128.7, 127.3, 126.9, 125.7, 121.7, 115.1,
79.4, 73.2, 70.0, 55.7, 21.7, 21.1, 16.4 ppm. HRMS calcd. for
C28H29N2O8 [M + H]+ 521.1924; found 521.1924.
General Procedure for the Preparation of 2-Arylethanols 27 and 28:
A solution of α-thio arylacetate (1.0 mmol) in diethyl ether (5 mL)
was added dropwise to a suspension of lithium aluminum hydride
(4.0 equiv.) in diethyl ether (5 mL), and the mixture was stirred at
room temp. for 3 h. The excess lithium aluminum hydride was de-
stroyed with water and EtOAc. The resulting mixture was washed
with NH4Cl (sat. aq.), dried with MgSO4, and concentrated in
vacuo. The residue was purified by chromatography on silica gel
(EtOAc/hexanes) to give the 2-arylethanol.
N-Benzoyl-O-[α-(o-methoxyphenoxy)-α-phenylacetyl]-L-threonine
Isopropyl Ester ((αS)-20): A colorless oil was obtained in 64% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.38–6.77
(m, 15 H), 5.68 (s, 1 H), 5.51 (m, 1 H), 4.95–4.84 (m, 2 H), 3.82 (s,
3 H), 1.20 (d, J = 6.0 Hz, 3 H), 1.14 (d, J = 6.4 Hz, 3 H), 0.94
(d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major
diastereomer): δ = 169.1, 168.9, 167.8, 150.4, 146.8, 135.5, 133.8,
131.9, 128.7, 128.6, 127.2, 127.1, 123.2, 121.0, 117.2, 113.2, 80.0,
72.3, 70.0, 56.3, 55.9, 21.7, 21.3, 16.6 ppm. HRMS calcd. for
C29H32NO7 [M + H]+ 506.2179; found 506.2178.
(S)-2-Phenyl-2-(phenylthio)ethanol (27): A pale yellow oil was ob-
tained in 76% yield. 1H NMR (CDCl3, 400 MHz): δ = 7.38–7.24
(m, 10 H), 4.32 (t, J = 6.8 Hz, 1 H), 3.92 (m, 2 H), 2.04 (br., 1 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 138.9, 133.8, 132.6, 129.0,
128.7, 128.1, 127.8, 127.6, 65.3, 56.1 ppm. The spectroscopic data
of 27 were identical to those of the authentic material reported
previously.[10a] Chiral HPLC: 97:3 er; tR (S; major enantiomer):
35.1 min; tR (R; minor enantiomer): 27.7 min; (Chiralcel OD col-
umn; 5% 2-propanol in hexane; 0.5 mL/min); [α]2D0 = +176.6 (c =
0.03, CHCl3).
N-Benzoyl-O-[α-(o-chlorophenoxy)-α-phenylacetyl]-L-threonine Iso-
propyl Ester [(αS)-21]: A pale yellow oil was obtained in 67% yield.
1H NMR (400 MHz, CDCl3, major diastereomer): δ = 7.81–6.74
(m, 15 H), 5.68 (s, 1 H), 5.51 (m, 1 H), 4.96–4.85 (m, 2 H), 3.82 (s,
3 H), 1.19 (d, J = 6.0 Hz, 3 H), 1.14 (d, J = 6.4 Hz, 3 H), 0.94
(d, J = 6.4 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3, major (S)-2-(p-Chlorophenyl)-2-(phenylthio)ethanol (28): A pale yellow oil
diastereomer): δ = 169.1, 168.9, 167.8, 150.4, 146.8, 135.5, 133.8,
131.9, 128.7, 128.6, 127.2, 127.1, 123.2, 121.0, 117.2, 113.2, 80.0,
was obtained in 78% yield. 1H NMR (CDCl3, 400 MHz): δ = 7.32–
7.21 (m, 9 H), 4.27 (t, J = 6.8 Hz, 1 H), 3.89 (m, 2 H), 2.10 (t, J =
Eur. J. Org. Chem. 2014, 1645–1652
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1651

K. J. Park, Y. Kim, M.-s. Lee, Y. S. Park
FULL PAPER
6.4 Hz, 1 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 137.6, 133.5,
133.2, 132.8, 129.5, 129.1, 128.9, 127.9, 65.0, 55.6 ppm. The spec-
troscopic data of 28 were identical to those of the authentic mate-
rial reported previously.[13] Chiral HPLC: 95:5 er; tR (S; major
enantiomer): 32.1 min; tR (R; minor enantiomer): 26.3 min; (Chi-
[5]
[6]
The absolute configuration of (αR)-2 was determined after
methanolysis to remove the chiral auxiliary, by comparison of
the order of elution from a chiral stationary phase (CSP)-
HPLC with that reported in the literature. M. M. Jones, J. M. J.
Williams, Chem. Commun. 1998, 2519–2520.
When we carried out the methanolysis of 2 (97:3 dr) under
acidic conditions with AcCl in MeOH at room temp., methyl
α-bromo phenylacetate was obtained with 95:5 er and 27%
conversion after 6 h, 91:9 er and 61% conversion after 12 h,
and 80:20 er and 84% conversion after 24 h.
ralcel OD column; 5% 2-propanol in hexane; 0.5 mL/min). [α]2D0
+134.1 (c = 0.04, CHCl3).
=
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures and characterization data,
including NMR spectra and HPLC chromatograms.
[7]
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Acknowledgments
When 17 (92:8 dr) was treated with AcCl in MeOH for 12 h,
the chiral auxiliary was removed, and methyl 2-(p-meth-
oxyphenoxy)phenylacetate was produced with 92:8 er. The (S)-
configuration of the major enantiomer was confirmed by com-
This work was supported by Konkuk University in 2013.
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Received: October 10, 2013
Published Online: January 8, 2014
1652
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Eur. J. Org. Chem. 2014, 1645–1652