Asymmetric zinc-Reformatsky reaction of Evans chiral imide with acetophenones and its application to the stereoselective synthesis of triazole antifungal agents

Article abstract of DOI:10.1016/j.tetasy.2007.03.015

The Ni(acac)₂ catalytic ZnEt₂-mediated asymmetric Reformatsky-type reaction of Evans chiral imide with various acetophenones was studied. The chiral imido zinc enolate, which was formed through the metal-halogen exchange reaction of

Full text of DOI:10.1016/j.tetasy.2007.03.015

Tetrahedron: Asymmetry 18 (2007) 949–962
Asymmetric zinc-Reformatsky reaction of Evans chiral imide
with acetophenones and its application to the stereoselective
synthesis of triazole antifungal agents
Luo-Ting Yu,a,b,c Meng-Tsung Ho,d Ching-Yao Change and Teng-Kuei Yangc,d,
*
aLaboratory of Organo-metallic Chemistry, East China University of Science and Technology, Shanghai 200237, China
bDepartment of Pharmaceutical and Biochemical Engineering, Sichuan University, Sichuan 610065, China
cWisdom Pharmaceutical Co. Ltd, Haimen, Jiangsu 226100, China
dDepartment of Chemistry, National Chung-Hsing University, Taichung 402, Taiwan, ROC
eDepartment of Biotechnology and Bioinformatics, Asia University, Wufeng, Taichung 413, Taiwan, ROC
Received 10 February 2007; accepted 12 March 2007
Abstract—The Ni(acac)2 catalytic ZnEt2-mediated asymmetric Reformatsky-type reaction of Evans chiral imide with various aceto-
phenones was studied. The chiral imido zinc enolate, which was formed through the metal–halogen exchange reaction of chiral a-bromo-
propionyl-2-oxazolidinones 2 with diethyl zinc under the catalysis of Ni(acac)2, performed the asymmetric zinc-Reformatsky reaction
with activated a-haloacetophenones 3 to give the chiral b-hydroxyamide 4 in good yields and high ratios of syn-(2R,3R)-isomers (up
to >97%). This new asymmetric synthesis technology affords a practical method to synthesize the versatile chiral building block 5 for
triazole antifungal agents, such as Voriconazole, Ravuconazole, TAK-187, and RO-0094815.
ꢀ 2007 Published by Elsevier Ltd.
1. Introduction
Reformatsky reaction, but are rarely used in the asymmet-
ric-type reaction.3 In 1998, Saigo reported using Ge(0) to
prepare a chiral imido auxiliary Ge enolate and performed
the asymmetric Ge-Reformatsky reaction with aldehydes
to give the chiral b-hydroxyesters in good diastereoselectiv-
ities.4 In 2000, Fukuzawa employed chiral 2-oxazolidinones
and ‘SuperQuat’ oxazolidinones as chiral auxiliaries to
proceed in the asymmetric Sm-Reformatsky reaction with
aldehydes in which high diastereoselectivities were ob-
tained.5 However, these metals are too expensive to use
for practical purpose and these literatures report only using
aldehydes as the electrophiles. For ketones as the substrate,
the asymmetric Reformatsky reaction generally leads to
lower diastereoselectivity, because it is more difficult to
distinguish between two substitutive carbon-atoms of a
ketone than between one substitutive carbon-atom and one
hydrogen-atom of an aldehyde. For the purpose of directly
and conveniently preparing b-hydroxyesters with a quater-
nary b-carbon, the asymmetric Reformatsky reaction of
ketones has been a challenging issue. In 2002, Yamano
reported an asymmetric Reformatsky reaction of ketones
with excellent stereoselectivities by using a cinchona
alkaloid as the chiral ligand, but the carbonyl substrate is
Reformatsky reaction was first discovered in the late 19th
century and involves a reaction between an aldehyde (or
ketone) and an a-haloester in the presence of metallic zinc.1
This long historical reaction has the advantage of forming
a carbon–carbon bond under mild and neutral conditions.
For the asymmetric-type reaction of a prochiral ketone and
a chiral metallic enolate, a Reformatsky reaction mediated
by a chiral halo-organozinc reagent could afford a chiral b-
hydroxyester with better results, compared to the corre-
sponding aldol reaction, which generally requires ultra
low temperature and strongly basic conditions.2 However,
a common problem for the traditional Reformatsky reac-
tion is the lack of reactivity for the insertion of zinc into
the halogen–carbon bond, so it is necessary to activate
the zinc reagent and one often needs to raise reaction tem-
peratures, which generally results in a poor stereoselectiv-
ity. A series of metals were used to perform the
*
Corresponding author. Tel.: +86 513 82263281; fax: +86 513 8227902;
e-mail addresses: tk@wisdompharma.com; tkyang@mail.nchu.edu.tw
0957-4166/$ - see front matter ꢀ 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetasy.2007.03.015

950
L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
limited to the ketones possessing an adjacent sp2-nitrogen.6
On the other hand, Cozzi in 2006 also reported a catalytical
asymmetric Reformatsky reaction of ketones with iodo
esters by using [ClMn(salen)] as the chiral catalyst to
obtain moderate enantioselectivities.7 Herein, we employ
Evans chiral imido zinc enolates and a series of acetophe-
nones to perform the asymmetric Reformatsky reaction.
Target compound 5 is a key intermediate in the syntheses
of a series of optically active triazole antifungal agents,
such as Voriconazole, Ravuconazole, TAK-187, and RO-
0094815 (Scheme 1).8
In these syntheses, Evans chiral auxiliaries (2-oxazolidi-
nones) 1 served as a useful tool for constructing the vicinal
syn-stereogenic centers, as required in compound 5 and all
of the chiral triazole antifungal drugs. The retrosynthetic
analysis in Scheme 2 indicated an asymmetric Reformatsky
reaction between acetophenones and a a-halo-organozinc
reagent coupled with 2-oxazolidinones, which would give
chiral b-hydroxyamide 4 diastereoselectively.
Our investigation covered a detailed study on the asymmet-
ric Reformatsky reaction of various zinc enolates with
F
HO
HO
N
N
N
N
N
N
CN
N
S
N
F
N
F
HO
R
N
F
F
N
CO2H
R
Voriconazole
Ravuconazole
N
Fn
O
5
HO
HO
N
N
N
N
N
CN
N
OCH2CF2CF2H
N
N
N
S
N
F
F
F
F
TAK-187
RO-0094815
Scheme 1.
R2
N
O
R2
R1
H
OH
O
O
Cl
R
O
N
OH
O
N
N
Ar
N
O
R
Cl
R
Br
Zn
Ar
OH
Me
O
R
R2
H
R1
O
Me
R2
Ar
Me
4
5
O
O
O
O
[Zn]
HN
R1
O
N
O
Cl
+
Ar
Br
R2
R2
R1
R2
R2
1
3
2
2a R1 = Bn ; R2 = H
2b R1 = i-Pr; R2 =Ph
3a Ar = 2,4-difluorophenyl
3b Ar = 2,5-difluorophenyl
1a R1 = Bn ; R2 = H
1b R1 = i-Pr; R2 =Ph
4a R1 = Bn, R2 = H, Ar = 2,4-difluorophenyl
4b R1 = Bn, R2 = H, Ar = 2,5-difluorophenyl
4c R1 = i-Pr, R2 = Ph, Ar = 2,4-difluorophenyl
4d R1 = i-Pr, R2 = Ph, Ar = 2,5-difluorophenyl
4e R1 = i-Pr, R2 = Ph, Ar = Ph
5a Ar = 2,4-difluorophenyl
5b Ar = 2,5-difluorophenyl
Scheme 2.

L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
951
Evans chiral imido auxiliaries and a series of aceto-
phenones, such as a-chloro-2,4-difluoroacetophenone, a-
chloro-2,5-difluoroacetophenone, a-chloroacetophenone,
acetophenone, 4-methoxyacetophenone, and 4-nitroace-
tophenone. We found that the chiral a-bromopropionyl-
2-oxazolidinones 2 with diethyl zinc under catalysis of
Ni(acac)2 performed the asymmetric zinc-Reformatsky
reaction with a-chloroacetophenones 3 to give chiral b-
hydroxyamides 4 in good yields and high ratios of syn-
(2R,3R)-isomers (up to >97%). After the dissociation of
the chiral b-hydroxyamides 4 followed by triazole substitu-
tion, compounds 5 were obtained in good yields, which
provided a practical route to the new triazole antifungal
agents, and chiral imido auxiliaries 1 were recycled in high
yields.
carbon bond. Recently, we noticed that Adrian used a cat-
alytic amount of Ni(acac)2 to make diethyl zinc generate a
zinc enolate through a metal–halogen exchange process
with a good reactivity at room temperature.13 In the hope
of obtaining a good stereoselectivity under a lower reaction
temperature, we employed diethyl zinc and a catalytic
amount of Ni(acac)2 to generate zinc enolates with 2-oxa-
zolidinone type chiral auxiliaries to perform the asymmet-
ric Reformatsky reaction with acetophenones. We found
that the use of Evans chiral auxiliaries in such asymmetric
Reformatsky reaction would induce a vicinal syn stereo-
genic center in the resulting b-hydroxyamides. Table 1
shows a typical Ni(acac)2 catalytic, ZnEt2-mediated asym-
metric Reformatsky reaction of chiral a-bromoamide 2a
with a-chloro-2,4-difluoroacetophenone 3a under a wide
range of reaction conditions. HPLC analysis of the unpuri-
fied reaction mixtures indicates that the syn-isomer, S2, is
clearly the major product among the four possible isomers.
2. Results and discussion
The results in Table 1 indicate that side product 7, gener-
ated from the self-addition of 3a, could be reduced from
25.7% to 6.1%, by decreasing the reaction temperature
from 30 to ꢀ30 ꢁC (entry 1 vs entry 7). We also found quite
good Si diastereofacial bias (S2:S1 = 41.2:1) and moderate
anti:syn selectivity (3.2:1) under the reaction condition
shown in entry 7.
The traditional zinc dust used in a Reformatsky reaction
generally needs to be activated under a higher temperature,
which would result in lower stereoselectivity in an asym-
metric-type reaction. The idea of a ‘catalytic’ Reformatsky
reaction has been reported on some metals, such as magne-
sium,9 cerium,10 titanium,11 and nickel,12 which were em-
ployed to facilitate the insertion of zinc into the halogen–
Table 1.
O
O
O
O
OH
S
O
O
OH
R
O
Cl
Cl
Cl
Cl
R
S
N
N
O
O
O
O
1) 5 mol % Ni(acac)2
1.5eq Et2Zn (1M Hex)
0
Me
Me
O
O
oC, CH2Cl2 , 30 min
F
F
F
F
F
Bn
Bn
4a(S1)
4a S
(
)
2
N
O
2) CH2Cl2
1.0 eq
O
F
Br
OH
O
OH
Cl
3a
Bn
2a
R
S
R
S
N
N
F
Me
Me
F
F
F
Bn
Bn
Temperature:
T (o C)
4a A
(
)
2
4a(A1)
time of dropping 3a: t1 (min)
Reaction time :
t2 (hr)
O
O
O
OH
O
Cl
N
O
Me
F
F
F
F
F
F
Bn
6
7
Entry
T (ꢁC)
t1 (min)
t2 (h)
Product ratio (HPLC)a
S2:S1
syn:anti
Isolatedb yield (%)
4a(S1)
4a(S2)
4a(A1)
4a(A2)
7
1
2
3
4
5
6
7
8
9
30
0
0
60
1
60
1
60
1
60
60
60
60
3
3
3
3
3
4
4
0.5
11.8
2.8
1.9
1.9
1.8
1.9
1.7
1.8
1.5
1.5
18.1
36.5
51.3
55.2
65.1
63.0
70.0
68.8
65.2
66.1
39.6
34.5
25.5
18.3
19.5
15.6
17.6
16.1
16.1
15.9
4.8
4.9
4.5
5.2
4.8
4.7
4.6
5.5
4.4
4.3
25.7
21.3
16.8
19.4
8.8
14.8
6.1
7.8
1.5:1
13.0:1
27.0:1
29.1:1
36.2:1
33.2:1
41.2:1
38.2:1
43.5:1
44.1:1
0.7:1
1.0:1
1.8:1
2.4:1
2.8:1
3.2:1
3.2:1
3.3:1
3.3:1
3.3:1
10.1
31.3
46.5
48.7
54.5
55.2
63.6
48.9
60.3
30.8
ꢀ15
ꢀ15
ꢀ30
ꢀ30
ꢀ30
ꢀ40
ꢀ60
12
12
12.8
12.2
10
a All the products were not purified and the ratios were taken directly from the UV response of the HPLC under the conditions: [column: Lichrospher
100RP18; mobile phase: CH3CN/H2O = 64:36; UV: 220 nm; retention time (min): 4a(A1) (7.6); 4a(A2) (8.0); 4a(S2) (11.3); 4a(S1) (12.5); 7 (10.1)].
b The yields of pure compound 4a(S2) were obtained through flash chromatography.

952
L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
In Table 1, we used dichloromethane as the reaction solvent
because it was reported that dichloromethane could provide
good reactivity in the exchange between zinc and nickel
complex.13,14 However, the nature of the solvent would
exert a great influence on the transition state (TS) of the
asymmetric Reformatsky reaction, which has a tight rela-
tionship with the stereoselectivity. Therefore, we checked
the solvent effect with two types of ZnEt2 solutions. In order
to diminish the reaction complexity, we chose acetophenone
8 as a substrate to perform the asymmetric Reformatsky
reaction, with the results shown in Table 2.
Ph
O
O
Ph
O
O
N
O
O
N
N
O
Ph
O
O
Ph
Ph
Ph
10
11
Scheme 3.
Br
Br
Re-face
Me
Si-face
H
Zn
Zn
The results in Table 2 display a quite significant solvent
effect, in which we can find that polar solvents give better
stereoselectivities (entries 1 and 2). Conversely, those
solvents, such as THF and CH3CN, which can act as good
ligands to the metal, might interfere with the coordination
structure of the transition state of the asymmetric Refor-
matsky reaction, thus leading to poor stereoselectivities
(entries 6 and 7). Furthermore, the major product was
the self-addition product 10 in THF or the dehydrohalo-
genation product 11 in CH3CN, respectively (Scheme 3).
On the other hand, non-polar solvents, such as benzene
and toluene, give moderate stereoselectivities (entries 3–
5). Nevertheless, all reactions give very good yields if the
non-coordinating solvents are used.
O
O
O
O
N
O
N
O
H
Me
Ph
Ph
Ph
Ph
Si-face
Re-face
Z
-form
E-form
O
O
OH
Ph
O
N
OH
O
R
S
O
Ph
N
O
Me
Me
Ph
Ph
Ph
Ph
From a mechanistic view, we propose that the zinc enolate has
both an E-form and a Z-form configuration in which the
Z-form enolate is more preferred and produces the (R)-con-
figuration at the b-carbon of the adduct (Scheme 4). As the
S2 + A1
A2 + S1
Scheme 4.
Table 2.
O
OH
O
O
OH
O
R
S
R
Ph
N
S
O
N
O
Ph
Me
Ph
Ph
Ph
Ph
Me
1) 5 mol % Ni(acac)2
H
O
O
1.5eq Et2Zn (solvent)
solvent , 0oC , 30 min
11 (S1)
1H NMR, δ
5.38 ppm
11 (S2)
OH
N
O
Br
Ph
O
O
O
OH
O
O
2) 1.0 eq
Ph
8
R
S
Ph
S
R
N
O
Ph
Ph
N
O
2b
Ph
Ph
Me
Me
Ph
Ph
solvent , -30oC
11 (A1)
11 (A2)
Entry
Et2Zn solvent
Reaction solvent
1H NMRa
Isolatedb yield (%)
9(S1)
9(S2)
9(A1)
9(A2)
S2:S1
syn:anti
(S2+A1):(S1+A2)
1
2
3
4
5
6
7
n-Hexane
Toluene
n-Hexane
Toluene
n-Hexane
n-Hexane
n-Hexane
CH2Cl2
CH2Cl2
Benzene
Toluene
Toluene
THF
2.0
2.1
4.2
3.3
3.0
11.3
—
95.5
95.3
85.2
89.1
90.5
45.6
—
2.3
2.3
9.5
7.1
6.2
37.3
—
0.2
0.3
1.1
0.5
0.3
5.8
—
47.8:1
45.4:1
20.3:1
27.0:1
30.2:1
4.0:1
39.0:1
37.5:1
8.4:1
12.2:1
14.4:1
1.3:1
—
40.7:1
40.7:1
17.9:1
25.3:1
29.3:1
4.8:1
83.7
83.1
78.4
84.3
82.7
25.5c
d
CH3CN
—
—
a The ratios were taken directly from the characteristic 1H NMR peaks of the four diastereomers for [d (ppm): 9(S1) (5.35); 9(S2) (5.38); 9(A1) (5.50); 9(A2)
(5.15)].
b The yields of the mixture, which consisted of all the four diastereomers were obtained through simple purification by flash chromatography.
c The main product was compound 10 (see Scheme 3).
d The main product was compound 11.

L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
953
isopropyl group of the chiral auxiliary moiety blocks the Re-
face of the zinc enolate, the carbonyl molecule preferably
approaches the Si-face of the zinc enolate, which gives the
diastereoselectivities appeared as (S2+A1):(S1+A2) = 40.7:1
in the best cases (entries 1 and 2).
reaction. However, too low a temperature (ꢀ60 ꢁC) would
not only greatly reduce the reactivity but also make the
reaction sluggish enough to lower the reaction yield. The
optimal reaction temperature was ꢀ30 ꢁC in our study,
which gave the best diastereoselectivities with the highest
isolated yields.
After the study of Table 2, we decided to broaden our
investigations on the asymmetric Reformatsky reaction
with various Evans chiral auxiliaries and acetophenones
at different temperatures, as shown in Table 3.
On the other hand, we also studied the effect of various
Evans chiral auxiliaries and acetophenones on the asym-
metric Reformatsky reaction. As described in Table 3
(entries 12 and 16), a sterically more crowded chiral auxil-
iary 1b (R1 = i-Pr, R2 = Ph) displays a better diastereo-
selectivity with the best ratio of S2 up to 97.2%. The
variation of acetophenones was also investigated. From
the results given in Table 3, we observed that the electron
withdrawing substitution of acetophenones would increase
the reactivity of the carbonyl group, which gave better
Our observations indicate that the reaction temperature is
an important factor in the stereoselectivity and chemical
yield of the asymmetric Reformatsky reaction. In general,
lowering the reaction temperature would make the coordi-
nation structure of the transition state more stable, which
benefits the favorable space tropism in the asymmetric
Table 3.
OH
O
O
O
OH
O
O
O
O
R4
R4
S
R
S
R
Ar
N
O
Ar
Ar
N
O
1) 5 mol % Ni(acac)2
R3
R3
S2
1.5eq Et2Zn (1M n-Hex)
R2
O
R2
O
CH2Cl2, 0 oC, 30 min
R1
R1
R2
R2
R3
S1
N
O
O
Br
2) 1.0 eq
R2
R4
R1
R2
OH
O
OH
Ar
R4
R4
R
S
S
R
Ar
N
O
CH2Cl2 , T oC
N
O
R3
R3
R2
R2
R1
R1
R2
R2
A2
A1
Entry
S2
T (ꢁC)
Ar
R1
R2
R3
R4
1H NMRa and HPLCb
Isolatedc yield (%)
S1
S2
A1
A2
S2:S1
syn:anti
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
9
30
0
Ph
Ph
Ph
Ph
Ph
Ph
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Bn
Bn
Bn
Bn
Bn
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
H
H
20.3
5.2
2.0
8.1
4.2
2.0
16.1
2.3
1.8
1.7
1.7
2.0
2.4
1.2
2.9
1.1
4.4
3.5
1.8
1.8
31.5
84.8
95.5
72.3
88.1
95.9
24.2
62.1
74.2
75.0
49.6
74.2
92.9
97.1
91.2
97.2
42.5
92.3
97.1
88.9
39.2
7.9
2.3
13.3
5.7
1.9
50.6
29.5
18.8
18.3
43.9
18.6
3.4
9.0
2.1
0.2
6.3
2.0
0.2
9.1
6.1
5.2
5.0
4.8
5.2
1.3
0.3
2.0
0.5
1.6
0.1
0.2
1.5
1.6:1
11.5:1
47.8:1
8.9:1
21.0:1
48.0:1
1.5:1
27.0:1
41.2:1
44.1:1
29.2:1
37.1:1
38.7:1
80.9:1
31.4:1
88.4:1
9.4:1
1.1:1
9.0:1
39.0:1
4.1:1
12.0:1
46.6:1
0.7:1
1.8:1
3.2:1
3.3:1
1.1:1
48.2
76.8
83.7
68.9
77.9
82.2
10.1
54.2
63.6
23.3
44.5
64.9
72.1
78.6
76.5
76.7
65.7
74.8
72.6
71.2
9
9
ꢀ30
4e
4e
4e
4a
4a
4a
4a
4b
4b
4c
4c
4d
4d
12
13
14
15
30
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
0
ꢀ30
30
2,4-Difluorophenyl
2,4-Difluorophenyl
2,4-Difluorophenyl
2,4-Difluorophenyl
2,5-Difluorophenyl
2,5-Difluorophenyl
2,4-Difluorophenyl
2,4-Difluorophenyl
2,5-Difluorophenyl
2,5-Difluorophenyl
Ph
0
ꢀ30
ꢀ60
0
ꢀ30
Bn
H
3.2:1
0
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
20.3:1
57.8:1
15.9:1
57.8:1
0.9:1
22.3:1
89.9:1
9.6:1
ꢀ30
0
1.4
3.9
1.2
51.4
4.2
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
Cl
d
4-Methoxyphenyl
4-Nitrophenyl
2,4-Difluorophenyl
H
H
Cl
25.6:1
53.9:1
49.3:1
0.9
7.9
a Product ratios were taken directly from the 1H NMR characteristic peaks of the four diastereomers for: 9 [d (ppm): S1 (5.35); S2 (5.38); A1 (5.50); A2
(5.15)]; 4e [d (ppm): S1 (5.30); S2 (5.35); A1 (5.50); A2 (5.24)]; 4c [d (ppm): S1 (5.40); S2 (5.33); A1 (5.44); A2 (5.24)]; 4d [d (ppm): S1 (5.38); S2 (5.33); A1
(5.46); A2 (5.28)]; 12 [d (ppm): S1 (5.39); S2 (5.42); A1 (5.57); A2 (5.55)]; 13 [d (ppm): S1 (5.32); S2 (5.37); A1 (5.49); A2 (5.19)]; 14 [d (ppm): S1 (5.32); S2
(5.37); A1 (5.50); A2 (5.19)]; 15 [d (ppm): S1 (5.34); S2 (5.38); A1 (5.23); A2 (5.20)].
b The ratios of the four diastereomers for 4a and 4b were taken directly from the UV response of the HPLC detector. See Table 1.
c The enantiomerically pure compounds 4a(S2) and 4b(S2) were obtained through chromatography. The mixtures containing all the four diastereomers for
9, 4e, 4c, 4d, 12, 13, 14, 15 were obtained, respectively, by purification through flash chromatography.
d Triazole group.

954
L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
stereoselectivities. On the other hand, the electron donating
or sterically bulky substitution of acetophenones would
reduce the reactivity of the carbonyl group, which resulted
in poor stereoselectivity. The results obtaind from our
studies are shown in Table 4.
duced, which could be rationalized due to the interference
of excess Ni2+ in the complexation of Zn2+ and chiral
imide 2b. The mechanism can be interpreted in a catalytic
cycle described in Scheme 5.13 The Ni2+ is reduced into
Ni(0) by diethyl zinc and then the Ni(0) reacts with chiral
imide 2b to form the imido nickel enolate at room temper-
ature. The exchange between Ni2+ and Zn2+ generates the
imido zinc enolate, which performs the asymmetric Refor-
matsky reaction with acetophenone 8. We believed that the
differences amongst the various nickel ligands resulted
from the different solubilities of these nickel complexes in
dichloromethane, which influenced the exchange rates of
zinc and nickel complexes (Table 5, entries 1 and 7–9).
Other metal complex catalysts gave poor results in both
reactivity and stereoselectivity, compared to the nickel
Attention was then focused on the effect of the catalysis.
Although nickel complexes have been reported to have
good effect on activating diethyl zinc in the Reformatsky
reaction, it was necessary for further investigations on the
stoichiometry of the catalyst, different kinds of metals
and Lewis acid effects, as shown in Table 5.
As the amount of catalyst Ni(acac)2 was increased from 5
to 50 mol %, the diastereoselectivity was significantly re-
Table 4.
Entrya
Changesb
Stereoselectivity
Reasons
14, 16, 19
18
3, 6
6, 17
16, 20
Electron withdrawing groups on Ar
Electron donating groups on Ar
R4 changed from H to Cl
R4 changed from Cl to triazole
R3 changed from Me to Et
"
#
"
#
#
Electronic effect
Electronic effect
Electronic effect
Steric effect
Steric effect
a See Table 3.
b See the formula of Table 3.
Table 5.
O
O
OH
O
OH
S
O
R
S
R
Ph
N
O
N
O
Ph
1) x mol % Ni(acac)2
1.0 eq Lewis acid
1.5 eq Et2Zn (1M n-Hex)
CH2Cl2, 0 oC, 30 min
Me
Ph
Ph
Ph
Ph
Me
H
O
O
9(S2)
9(S1)
N
O
Br
O
Ph
2) 1.0 eq
8
Ph
O
O
OH
S
R
O
OH
O
Ph
CH2Cl2, -30 o
R
2b
Ph
N
O
S
N
O
Ph
C
Me
Ph
Ph
Ph
Ph
Me
9 A
9 A
( )
2
(
)
1
Entry
X (mol %)
Catalyst
Lewis acid 1.0 equiv
1H NMRa
Isolatedb yield (%)
9(S1)
9(S2)
9(A1)
9(A2)
S2:S1
syn:anti
1
2
3
4
5
6
7
8
9
5
10
50
5
5
5
5
5
5
5
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2(PPh3)2
NiCl2
NiCl2(PPh3)2
Cu(OTf)2
2.0
3.5
8.7
2.8
—
3.1
3.4
4.9
3.0
24.3
13.8
95.5
92.0
81.3
87.1
—
95.5
90.9
80.6
93.4
35.2
25.3
2.3
4.2
9.1
9.7
—
1.1
5.4
12.5
3.4
29.7
53.8
0.2
0.3
0.9
0.4
—
0.3
0.3
2.0
0.2
10.8
7.1
47.8:1
26.3:1
9.3:1
31.1:1
—
30.8:1
26.7:1
16.4:1
31.1:1
1.4:1
39.0:1
21.2:1
9.0:1
8.9:1
—
70.4:1
16.5:1
5.9:1
26.8:1
1.5:1
0.6:1
83.7
81.4
66.7
32.7
c
LiBr
MgBr2
ZnBr2
70.1
68.3
43.6
81.9
10.5
36.2
d
10
11
5
PdCl2(CH3CN)2
1.8:1
a Product ratios were taken directly from the 1HNMR characteristic peaks of the four diastereomers for: [d (ppm): 9(S1) (5.35); 9(S2) (5.38); 9(A1) (5.50);
9(A2) (5.15)].
b The yields of the mixture, which consisted of all the four diastereomers were obtained through purification by flash chromatography.
c The main product was compound 10.
d 10 mol % PPh3 was added in the reaction.

L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
955
O
O
ONiBr
Aux
Aux
Aux
Zn+2
Br
NiBr
Ni0
OZnBr
Aux
Ni+2
C4H10, Zn+2
Et2Zn
Scheme 5.
complex (Table 5, entries 10 and 11). The addition of Lewis
acids does not have much positive effect on this reaction
with the exception of ZnBr2, which improved the syn:anti
selectivity due to facilitation of the Ni2+–Zn2+ exchange
of the enolates at lower temperatures.
cyclic transition state model15 as shown in Scheme 6. As we
mentioned before, the predominated (Z)-form zinc enolate
preferably attacked the acetophenone from its Si-face in
order to avoid the steric congestion of the isopropyl group
of the 2-oxazolidinone moiety. This proposal is proven by
the constant high ratios of (S2+A1):(S1+A2). In addition,
S2 is more preferred than A1 because the axial aryl group
of transition state Aꢁ1 is more sterically crowded than that
of Sꢁ2. Some of the absolute structures of the asymmetric
On the basis of the results obtained above, the S2-predom-
inated trends of the asymmetric Reformatsky reaction can
now be rationalized by the Zimmerman–Traxler chair peri-
Br
Br
Zn
Zn
O
O
O
O
O
O
R3
R3
N
O
N
O
N
O
R3
Br
R2
R2
R2
R1
R1
R1
R2
R2
R2
E
-form
Z
-form
2b
Si
Re face attack
Re
O
Si
R2
R2
R2
R2
R2
R1
R2
R1
R2
R1
R2
R1
O
O
O
O
O
O
O
O
N
H
N
N
H
H
N
H
R4
Ar
R4
Ar
Br Zn
Br Zn
Br Zn
Br Zn
O
O
O
H
H
R3
R3
O
O
O
O
Ar
Ar
R3
R4
R3
H
H
R4
*
*
*
*
S2
A2
S1
A1
OH
R
O
O
OH
S
O
O
OH
S
O
O
OH
R
O
O
R4
Ar
R4
Ar
R4
R4
S
S
R
R
N
O
N
O
Ar
N
O
Ar
N
O
R3
R3
R3
R3
R2
R2
R2
R2
R1
R1
R1
A1
R1
R2
R2
R2
R2
A2
S1
S2
( R1, R2, R3, R4, Ar: see Table 3 )
Scheme 6.

956
L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
OH
R
O
R
O
O
Cl
LiOH ; H2O2
THF ; H2O
R
R
+
Auxiliary
Ar
Aux
Ar
OH
Me
Me
4c (see Table 3)
4d
71.6%
16
17 73.8%
1b 74.1%
1b
79.6%
sodium triazolate
DMF, 60 oC, 3 h.
N
N
OH
5a
O
89.3%
N
5b 87.9%
R
R
Ar
OH
Me
Scheme 7.
Reformatsky reaction adducts, 4a(S2), 9(S2) and 4b(A1),
have been confirmed by X-ray single-crystal diffractometry
analysis (see Section 4).
dried by distillation under nitrogen from sodium metal,
and dichloromethane was distilled under nitrogen from cal-
cium hydride. Flash chromatography was carried out using
Merck silica gel 60 (230–400 mesh). Melting points were
recorded on a Fargo Mp-1D. Optical rotations were
measured on a Perkin Elmer 241 polarimeter. Infrared
spectra were recorded on a Bruker FT-IR Equinox 55
Infrared Spectrophotometer. NMR spectra were recorded
on a Varian Mercury 400 or Varian Inova 600, and the
chemical shifts were reported as d value in parts per million
relative to TMS in CDCl3 (d = 0), used as internal standard
for 1H NMR spectra, and the center peak of CDCl3
(d = 77.0 ppm) used as the internal standard in the 13C
NMR spectra. Analytical HPLC was performed on Varian
Star (UV detector 310) chromatograph equipped with a
4 mm · 25 cm Lichrospher 100RP18 5 lm column coupled
to a UV detector (210 nm) using an acetonitrile/water mix-
ture of 64:36 as the eluent or a 4.6 mm · 25 cm Chiralcel
OD-H column (UV 210 nm, eluent IPA/n-Hex mixture of
10:90). HRMS-FAB mass were collected on Finnigan,
Thermo Quest MAT 95XL. X-ray single-crystal diffrac-
tometer analysis was performed on a Bruker AXS
SMART-1000.
After our successful studies on finding the best way to
create the correct vicinal syn-stereogenic centers, the
subsequent process toward target compound 5 was the
removal of the Evans chiral auxiliary moiety of b-hydroxy-
amide 4 under the reported condition (LiOH, H2O2, THF,
then Na2SO3 and HCl)16 to obtain the epoxy acid and then
treatment with excess sodium triazolate (Scheme 7). The
Evans chiral auxiliaries were recovered in yields of 74–80%.
3. Conclusion
In conclusion, we have reported a new asymmetric synthe-
sis of chiral b-hydroxyamide 4 through an asymmetric zinc-
Reformatsky reaction. Our study demonstrated that the
zinc enolates of Evans chiral imides, which formed through
the metal–halogen exchange reaction of chiral a-bromo-
amide 2 and diethyl zinc in the presence of Ni(acac)2 cata-
lyst, reacted with acetophenones with good facial
diastereoselectivity and syn:anti selectivity. Under the
optimized condition, the desired S2 diastereoisomer was
obtained in a ratio of >97%, which was transformed into
target compound 5 efficiently in a high yield with a good
recovery of the chiral auxiliary. These results have offered
a very prominent route to the industrial by useful chirally
building block 5, which is known as a key intermediate
to several triazole antifungal drugs.
4.1. (S)-4-Isopropyl-5,5-diphenyl-2-oxazolidinone, 1b
To a cold solution (0 ꢁC) of L-valine (25.00 g, 0.21 mol),
H2O (200 mL), and 1 M NaOH (200 mL) in an ice bath
was slowly added ethyl chloroformate (20.5 mL,
0.21 mol) within pH 9–10 and then stirred for 1 h at room
temperature. After the reaction mixture was extracted with
ethyl acetate (3 · 100 mL), the aqueous phases were ad-
justed to pH 3–4 with 1 M HCl at 0 ꢁC in an ice bath
and then extracted again with ethyl acetate (3 · 100 mL).
The combined organic phases were washed with H2O
(100 mL), brine (200 mL), dried over anhydrous MgSO4,
and concentrated to give (S)-2-(ethoxycarbonyl)-3-meth-
ylbutanoic acid as a white solid (39.77 g). To the solution
of (S)-2-(ethoxycarbonyl)-3-methylbutanoic acid (39.77 g,
0.23 mol) and MeOH (400 mL) was slowly added dropwise
SOCl2 (30.14 g, 0.25 mol) at 0 ꢁC in an ice bath and stirred
for 3 h at room temperature. Having been concentrated,
4. Experimental
Acetophenone 8, a-chloroacetophenone, 4-methoxyace-
tophenone, 4-nitro-acetophenone, a-chloro-2,4-difluoro-
acetophenone 3a, (S)-4-benzyl-2-oxazolidinone 1a, and
other starting materials were obtained from commercial
suppliers and used without further purification unless
otherwise stated. Diethyl zinc (1.0 M in n-hexane and
1.2 M in toluene) was purchased from Aldrich Chemical
Co. and used as received. THF, benzene and toluene were

L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
957
the resulting mixture was extracted with ethyl acetate
(3 · 200 mL) and the combined organic phases were
washed, respectively, with H2O (100 mL), saturated
aqueous NaHCO3 (100 mL), brine (200 mL), dried over
anhydrous MgSO4, and concentrated to give (S)-methyl
2-(ethoxycarbonyl)-3-methylbutanoate as a white solid
(41.91 g). To a solution of (S)-methyl 2-(ethoxycarbonyl)-
3-methylbutanoate (41.91 g, 0.22 mol) and THF (600 mL)
was slowly added dropwise PhMgBr (0.66 mol, freshly pre-
pared from Mg and PhBr) at 0 ꢁC in an ice bath and then
stirred for 2 h at room temperature. To the resulting mix-
ture was slowly added dropwise 1 M NaOH (200 mL) at
0 ꢁC and stirred for 3 h in an ice bath and then concen-
trated. The resulting mixture was filtered to give a white so-
lid and the filtrate extracted with CHCl3 (3 · 100 mL). The
filtered solid was dissolved again into the combined organic
phases and recrystallization (ethyl acetate/hexane) was car-
ried out to give Evans auxiliary 1b as a white solid (53.35 g,
90.3% yield): [a]D = ꢀ255.2 (c 0.20, CHCl3); mp 252–
(4 · 100 mL) and the combined organic phases were
washed, respectively, with saturated aqueous NaHCO3
(100 mL) and brine (100 mL), dried over anhydrous
MgSO4, and concentrated. The crude product was purified
by flash chromatography (hexane/ethyl acetate = 10:1) to
1
give target compound 2a (14.70 g, 83.6% yield): H NMR
(400 MHz, CDCl3)
d 7.37–7.25 (m, 5H), 5.73 (q,
J = 6.4 Hz, 1H), 4.75–4.71 (m, 1H), 4.27–4.21 (m, 2H),
3.22 (dd, J = 13.2, 3.2 Hz, 1H), 2.80 (dd, J = 13.2,
9.6 Hz, 1H), 1.88 (d, J = 6.4 Hz, 3H).
4.4. (4S)-3-(2-Bromopropanoyl)-4-isopropyl-5,5-diphenyl-2-
oxazolidinone, 2b
Following the procedure described above, but using
another Evans auxiliary (S)-4-(1-methylethyl)-5,5-diphe-
nyl-2-oxazolidinone 1b as the reactant, product 2b was
obtained (racemic mixtures, 88.5% yield): 1H NMR
(400 MHz, CDCl3) d 7.50–7.26 (m, 10H), 5.64–5.58 (m,
1H), 5.50 (d, J = 2.4 Hz, 1H), 5.35 (d, J = 3.6 Hz, 1H),
2.05–1.99 (m, 1H), 1.82 (d, J = 6.8 Hz, 3H), 1.72 (d, J =
6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.8 Hz,
3H), 0.84 (d, J = 6.8 Hz, 3H), 0.77 (d, J = 6.8 Hz, 3H).
1
253 ꢁC; IR (neat): 3456, 2976, 1757, 1501, 1450 cmꢀ1; H
NMR (400 MHz, CDCl3) d 7.55–7.53 (m, 2H), 7.43–7.22
(m, 8H), 6.44 (s, 1H), 4.36 (d, J = 3.6 Hz, 1H), 1.91–1.83
(m, 1H), 0.90 (d, J = 6.8 Hz, 3H), 0.69 (d, J = 6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) d 158.77, 143.92,
139.26, 128.53, 128.21, 128.07, 127.68, 126.30, 125.68,
89.41, 65.81, 29.59, 20.86, 15.62; MS (EI): 281, 238, 194,
183, 165, 77; HRMS (EI): calcd for C11H9NO5 MH+
281.1416, found MH+ 281.1413; The enantiomer ratio
was determined by anal. HPLC (Chiralcel OD-H column)
to be >99% ee.
4.5. Asymmetric Reformatsky reactions
All reactions were carried out under a nitrogen atmosphere
using a Schlenk tube with standard techniques for air-sen-
sitive materials. The following description provides a typi-
cal experimental procedure for the Reformatsky reaction of
Evans chiral imide zinc enolates with a series of acetophe-
nones. Ni(acac)2 (0.05 mmol) and an Evans chiral imide
(1.00 mmol) were placed in a 20-mL Schlenk tube equipped
with a magnetic stirring bar and dried in vacuo. Under the
nitrogen atmosphere, dry CH2Cl2 (2.0 mL) was added to
the Schlenk tube to dissolve the mixture and the resulting
solution was adjusted to 0 ꢁC in an ice bath. ZnEt2
(1.0 M in n-Hex, 1.50 mL) was added dropwise to the
Schlenk tube at 0 ꢁC and the resulting solution was stirred
for 30 min. Then the Schlenk tube was adjusted to a de-
signed temperature in a constant temperature regulator
and a solution of an acetophenones-type compound
(1.00 mmol) in dry CH2Cl2 (2.0 mL) was slowly dropwise
injected over a designed time. The resulting solution was
stirred for several hours, monitored by anal. HPLC (UV
210 nm). The resulting solution was hydrolyzed with satu-
rated aqueous KH2PO4 (2.0 mL) and extracted with
CH2Cl2 (3 · 10 mL). The combined organic phases were
washed with H2O (5 mL) and brine (5 mL), dried over
anhydrous MgSO4, and concentrated in vacuo. The crude
product was measured and analyzed. Simple purification
was done by flash chromatography to afford a mixture con-
sisting of all the four diastereomers. Optical pure diastereo-
mers were, respectively, isolated by recrystallization (ether/
hexane) or by flash chromatography (ethyl acetate/hex-
ane). The yields and the ratios of the diastereomers of each
experiments are listed in the tables above.
4.2. a-Chloro-2,5-difluoroacetophenone, 3b
To a cooled (0 ꢁC) mixture of 1,4-difluorobenzene (35.00 g,
0.31 mol) and AlCl3 (62.00 g, 0.46 mol) was added drop-
wise chloroacetyl chloride (27.0 mL, 0.34 mol), and the
resulting mixture stirred at 0 ꢁC for 1 h and at 60 ꢁC for
1 h. The resulting mixture was added carefully to concen-
trated HC1 (70 mL) and ice water (200 mL) and stirred
for a few minutes, after which it was extracted by CH2Cl2
(3 · 100 mL). The organic phase was washed with water
(50 mL) and brine (100 mL), dried over anhydrous MgSO4,
and concentrated. The residual oil was evaporated under
reduced pressure to get the product as a white solid
(49.28 g, 84.3% yield): mp 48–49 ꢁC; IR (neat): 1696,
1
1601, 538 cmꢀ1; H NMR (300 MHz, CDCl3) d 7.67–7.62
(m, 1H), 7.33–7.27 (m, 1H), 7.19 (dt, J = 10.0, 4.0 Hz,
1H), 4.73 (d, J = 3.2 Hz, 2H).
4.3. (4S)-4-Benzyl-3-(2-bromopropanoyl)-2-oxazolidinone,
2a
To a solution of (S)-4-benzyl-2-oxazolidinone 1a (10.00 g,
56.43 mmol) in THF (50 mL) was added 60% NaH
(3.4 g, 85.00 mmol) at room temperature and the reaction
mixture stirred for 1 h. After the resulting mixture was
cooled to ꢀ30 ꢁC, the solution of 2-bromopropionyl bro-
mide (41.6 mL, 85.0 mmol) in THF (250 mL) was added
dropwise, and then stirred for 1 h at ꢀ30 ꢁC and 1 h at
0 ꢁC. The reaction was quenched with saturated aqueous
NaH2PO4 (200 mL) and the mixture was concentrated.
The resulting mixture was extracted with ethyl acetate
4.5.1.
[3(2R,3R),4S]-4-Benzyl-3-[4-chloro-3-(2,4-difluoro-
phenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxazolidinone,
4a(S2). The product was obtained by using 2a and 3a
to perform the asymmetric Reformatsky reaction and

958
L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
purification by flash chromatography (ethyl acetate/
(100 MHz, CDCl3) d 177.59, 159.70, 158.10, 155.37,
153.77, 152.75, 135.00, 129.78, 129.73, 129.69, 129.64,
129.35, 129.10, 127.53, 117.09, 117.04, 116.92, 116.86,
116.67, 116.50, 116.47, 116.26, 116.20, 116.10, 116.04,
66.20, 55.69, 51.50, 51.46, 40.69, 40.66, 37.70, 14.71; MS
(FAB): 406, 370, 191, 136, 91, 77; HRMS (FAB): calcd
for C21H20ClF2NO4 MH+ 424.1127, found MH+ 424.1133.
hexane 1:5). Mp 108–110 ꢁC; [a]D = +9.9 (c 1.0, CH2Cl2);
1
IR (neat): 3466, 1786, 1669, 1501, 1387 cmꢀ1; H NMR
(400 MHz, CDCl3) d 7.79 (dt, J = 8.8, 6.4 Hz, 1H),
7.39–7.25 (m, 5H), 6.96–6.71 (m, 2H), 5.01 (s, 1H), 4.77
(q, J = 6.8 Hz, 1H), 4.73–4.67 (m, 1H), 4,21 (d, J =
4.8 Hz, 1H), 4.05 (d, J = 11.2 Hz, 1H), 3.96 (dd, J =
11.2, 0.8 Hz, 1H), 3.48 (dd, J = 13.6, 3.6 Hz, 1H), 2.74
(dd, J = 13.2, 10.4 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 177.60, 163.59, 163.51,
161.94, 161.86, 159.53, 159.45, 157.88, 157.80, 152.80,
135.02, 130.86, 130.82, 130.80, 130.76, 129.35, 129.01,
127.52, 123.62, 123.60, 123.54, 123.52, 111.36, 111.24,
104.38, 104.20, 104.03, 77.38, 77.34, 66.17, 55.69, 51.80,
51.76, 40.89, 40.86, 37.69, 14.66; MS (FAB): 406, 370,
191, 136, 91, 77; HRMS (FAB): calcd for C21H20ClF2-
NO4 MH+ 424.1127, found MH+ 424.1133. The absolute
configuration was determined using single crystal X-ray
crystallography diffractometer, as shown below.
4.5.3. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-(3-phenyl-
3-hydroxy-2-methyl-1-oxobutyl)-2-oxazolidinone,
9(S2).
The product was obtained by using 2b and 8 to perform
the asymmetric Reformatsky reaction and purification by
flash chromatography (ethyl acetate/hexane 1:6). Mp
192–194 ꢁC; [a]D = ꢀ127.3 (c 1.0, CH2Cl2); IR (neat):
1
3450, 1781, 1669, 1476, 1385 cmꢀ1; H NMR (400 MHz,
CDCl3) d 7.48–7.20 (m, 15H), 5.38 (d, J = 3.2 Hz, 1H),
4.26 (s, 1H), 4.22 (q, J = 6.8 Hz, 1H), 2.06–2.02 (m, 1H),
0.95 (d, J = 6.8 Hz, 3H), 0.86 (d, J = 6.8 Hz, 3H), 0.48
(d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
178.31, 152.90, 145.14, 141.92, 137.59, 128.84, 128.69,
128.46, 128.10, 12800, 126.54, 125.78, 125.45, 124.90,
89.73, 74.77, 65.26, 45.38, 30.24, 29.52, 21.79, 16.63,
12.66; MS (FAB): 458, 440, 238, 121, 77; HRMS (FAB):
calcd for C29H31NO4 MH+ 458.2331, found MH+
458.2341. The absolute configuration was determined using
single crystal X-ray crystallography diffractometer, as
shown below.
X-ray crystal data for 4a(S2): C21H20ClF2NO4, MW =
˚
423.83, Monoclinic, Space group: P2(1), a = 14.486(3) A,
˚
a = 90ꢁ,
b = 7.0875(13) A,
b = 97.275(4)ꢁ,
c =
3
˚
˚
20.257(4) A, c = 90ꢁ, Volume 2063.0(6) A , T = 293(2) K,
Z = 4, Dc = 1.203 mg mꢀ3, Absorption coefficient: 0.230
mmꢀ1, Wavelength: 0.71073 A, F(000): 880, Crystal size:
˚
0.32 · 0.28 · 0.14 mm3, Independent reflections: 7726
[R(int) = 0.0480], Reflections collected: 11,768; Refinement
method: Full-matrix least-squares on F2, Goodness-of-fit
on F2: 1.008, Final R indices [I > 2r(I)]: R1 = 0.0529,
wR2 = 0.1090, SADABS. CCDC No. 642377.
X-ray crystal data for 9(S2): C29H31NO4, MW = 457.55,
˚
Orthorhombic, Space group: P2(1)2(1)2, a = 8.2983(7) A,
˚
˚
a = 90ꢁ, b = 23.271(2) A, b = 90ꢁ, c = 6.4644(7) A,
3
˚
4.5.2.
[3(2R,3S),4S]-4-Benzyl-3-[4-chloro-3-(2,4-difluoro-
c = 90ꢁ, Volume 2525.6(5) A , T = 293(2) K, Z = 4,
phenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxazolidinone,
4a(A1). The product was obtained by using 2a and 3a to
perform the asymmetric Reformatsky reaction and purifi-
cation by flash chromatography (ethyl acetate/hexane
1:5). Oil; [a]D = +32.8 (c 1.0, CH2Cl2); IR (neat): 3460,
1789, 1673, 1498, 1385 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.67 (dt, J = 6.8, 2.0 Hz, 1H), 7.30–7.25 (m, 5H), 6.97–
6.82 (m, 2H), 5.00 (d, J = 6.8 Hz, 1H), 4.85 (q,
J = 6.8 Hz, 1H), 4.53–4.49 (m, 1H), 4.14–3.96 (m, 4H),
2.64 (dd, J = 13.2, 3.2 Hz, 1H), 2.09 (dd, J = 13.6,
9.6 Hz, 1H), 1.42 (d, J = 4.4 Hz, 3H); 13C NMR
Dc = 1.365 mg mꢀ3, absorption coefficient: 0.080 mmꢀ1
,
˚
Wavelength: 0.71073 A, F(000): 976, Crystal size:
0.55 · 0.52 · 0.47 mm3, Independent reflections: 4947
[R(int) = 0.0696], Reflections collected: 14314; Refinement
method: Full-matrix least-squares on F2, Goodness-of-fit
on F2: 1.184, Final R indices [I > 2r(I)]: R1 = 0.0660,
wR2 = 0.1781, SADABS. CCDC No. 642379.
4.5.4. [3(2R,3R),4S]-4-Benzyl-3-[4-chloro-3-(2,5-difluoro-
phenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxazolidinone,
4b(S2). The product was obtained by using 2a and 3b to

L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
959
perform the asymmetric Reformatsky reaction and purifi-
cation by flash chromatography (ethyl acetate/hexane
1:5). Oil; [a]D = +7.7 (c 1.0, CH2Cl2); IR (neat): 3457,
4.5.5.
[3(2R,3S),4S]-4-Benzyl-3-[4-chloro-3-(2,5-difluoro-
phenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxazolidinone,
4b(A1). The product was obtained by using 2a and 3b to
perform the asymmetric Reformatsky reaction and purifi-
cation by flash chromatography (ethyl acetate/hexane
1:5). Mp 109–111 ꢁC; [a]D = +41.4 (c 1.0, CH2Cl2); IR
1
1784, 1669, 1488, 1388 cmꢀ1; H NMR (400 MHz, CDCl3)
d 7.56–6.99 (m, 8H), 5.06 (s, 1H), 4.79 (q, J = 7.2 Hz, 1H),
4.73–4.62 (m, 1H), 4.22 (d, J = 4.8 Hz, 2H), 4.06 (d,
J = 11.2 Hz, 1H), 3.96 (d, J = 11.2 Hz, 1H), 3.48 (dd,
J = 13.2, 4.0 Hz, 1H), 2.74 (dd, J = 13.2, 10.0 Hz, 1H),
1.05 (d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) d
177.59, 159.70, 158.10, 155.37, 153.77, 152.75, 135.00,
129.78, 129.73, 129.69, 129.64, 129.35, 129.10, 127.53,
117.09, 117.04, 116.92, 116.86, 116.67, 116.50, 116.47,
116.26, 116.20, 116.10, 116.04, 66.20, 55.69, 51.50, 51.46,
40.69, 40.66, 37.70, 14.71; MS (FAB): m/z 424 (MH+),
406, 374, 229, 178, 91, 77; HRMS (FAB): calcd for
C21H20ClF2NO4 MH+ 424.1127, found MH+ 424.1116.
(neat): 3460, 1790, 1669, 1486, 1386 cmꢀ1 1H NMR
;
(400 MHz, CDCl3) d 7.45–7.40 (m, 1H), 7.28–7.21 (m,
3H), 7.06–6.92 (m, 4H), 5.03 (s, 1H), 4.87 (q, J = 6.8 Hz,
1H), 4.54–4.50 (m, 1H), 4.12–3.94 (m, 4H), 2.64 (dd,
J = 13.6, 3.2 Hz, 1H), 2.13 (dd, J = 13.2, 9.6 Hz 1H),
1.41 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
176.80, 159.78, 157.36, 155.86, 153.46, 152.17, 134.48,
131.86, 131.78, 131.71, 128.92, 128.77, 127.22, 117.05,
116.97, 116.78, 116.73, 116.70, 116.52, 116.47, 116.14,
116.05, 115.90, 115.81, 76.55, 76.50, 65.67, 54.41, 49.08,

960
L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
49.04, 42.21, 42.16, 36.95, 11.97; MS (FAB): m/z 424
(MH+), 406, 370, 229, 178, 91, 77; HRMS (FAB): calcd
for C21H20ClF2NO4 MH+ 424.1127, found MH+
424.1123. The absolute configuration was determined using
a single crystal X-ray crystallography diffractometer, as
shown below.
4.5.8. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-(4-chloro-
3-phenyl-3-hydroxy-2-methyl-1-oxobutyl)-2-oxazolidinone,
4e(S2). The product was obtained by using 2b and a-
chloro-acetophenone to perform the asymmetric Refor-
matsky reaction and purification by flash chromatography
(ethyl acetate/hexane 1:6). Mp 216–217 ꢁC; [a]D = ꢀ112.5
(c 1.0, CH2Cl2); IR (neat): 3471, 1792, 1677, 1498,
1
X-ray crystal data for 4b(A1): C21H20ClF2NO4, MW =
423.83, Orthorhombic, Space group: P2(1)2(1)2, a =
1384 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.53–7.25 (m,
15H), 5.35 (d, J = 3.2 Hz, 1H), 4.71 (s, 1H), 4.54 (q,
J = 7.2 Hz, 1H), 3.91 (d, J = 11.2 Hz, 1H), 3.76 (d, J =
10.8 Hz, 1H), 2.06–2.02 (m, 1H), 0.95 (d, J = 6.8 Hz,
3H), 0.85 (d, J = 6.8 Hz, 3H), 0.54 (d, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) d 177.59, 152.74, 141.97,
140.91, 137.52, 128.92, 128.78, 128.52, 128.16, 127.51,
125.77, 125.53, 125.44, 89.84, 77.31, 65.33, 52.38, 41.66,
29.74, 21.76, 16.38, 13.04; MS (FAB): m/z 492 (MH+),
474, 282, 256, 91, 77; HRMS (FAB): calcd for
C29H30ClNO4 MH+ 492.1941, found MH+ 492.1948.
˚
˚
˚
16.7882(18) A, a = 90ꢁ, b = 11.1748(9) A, b = 90ꢁ, c =
3
˚
21.3114(17) A, c = 90ꢁ, Volume 1976.2(3) A , T =
293(2) K, Z = 4, Dc = 1.424 mg mꢀ3, Absorption coeffi-
cient: 0.240 mmꢀ1, Wavelength: 0.71073 A, F(000): 880,
˚
Crystal size: 0.49 · 0.36 · 0.27 mm3, Independent reflec-
tions: 3872 [R(int) = 0.0412], Reflections collected: 11,259;
Refinement method: Full-matrix least-squares on F2, Good-
ness-of-fit on F2: 1.046, Final R indices [I > 2r(I)]:
R1 = 0.0401, wR2 = 0.0911, SADABS. CCDC No. 642378.
4.5.6. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-[4-chloro-3-
(2,4-difluorophenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxa-
zolidinone, 4c(S2). The product was obtained by using 2b
and 3a to perform the asymmetric Reformatsky reaction
and purification by flash chromatography (ethyl acetate/
hexane 1:5). Oil; [a]D = ꢀ110.7 (c 1.0, CH2Cl2); IR (neat):
4.5.9. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-[3-(4-meth-
oxyphenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxazolidinone,
13(S2). The product was obtained by using 2b and
4-methoxyl-acetophenone to perform the asymmetric
Reformatsky reaction and purification by flash chromato-
graphy (ethyl acetate/hexane 1:6). Oil; [a]D = ꢀ124.2 (c
1.0, CH2Cl2); IR (neat): 3499, 1784, 1677, 1512, 1451,
3455, 1787, 1673, 1490, 1451, 1391 cmꢀ1
;
1H NMR
1
(600 MHz, CDCl3) d 7.71 (dt, J = 6.0, 4.4 Hz, 1H), 7.46–
7.25 (m, 10H), 6.90–6.87 (m, 1H), 6.79–6.76 (m, 1H),
5.33 (d, J = 2.0 Hz, 1H), 5.09 (s, 1H), 4.77 (q,
J = 4.8 Hz, 1H), 4.14 (d, J = 7.2 Hz, 1H), 3.89 (d,
J = 11.2, 0.8 Hz, 1H), 2.06–2.03 (m, 1H), 0.94 (d,
J = 4.8 Hz, 3H), 0.85 (d, J = 4.4 Hz, 3H), 0.49 (d,
J = 4.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) d 177.55,
163.47, 163.39, 161.82, 161.73, 159.42, 159.34, 157.77,
157.69, 152.57, 141.83, 137.29, 130.99, 130.95, 130.93,
130.89, 128.91, 128.79, 128.53, 128.21, 125.68, 125.36,
123.42, 123.37, 111.19, 111.05, 111.03, 104.23, 104.05,
103.88, 89.96, 77.07, 77.04, 65.55, 51.49, 51.45, 40.57,
40.54, 29.53, 21.80, 16.63, 13.87; MS (FAB): m/z 528
(MH+), 510, 238, 154, 77; HRMS (FAB): calcd for
C29H28ClF2NO4 MH+ 528.1753, found MH+ 528.1758.
1366 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.45–7.25 (m,
12H), 6.85 (d, J = 8.8 Hz, 2H), 5.37 (d, J = 3.6 Hz, 1H),
4.20 (s, 1H), 4.16 (q, J = 7.2 Hz, 1H), 3.79 (s, 3H), 2.05–
2.01 (m, 1H), 1.61 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H), 0.85
(d, J = 7.2 Hz, 3H), 0.49 (d, J = 6.8 Hz, 3H); 13C NMR
(150 MHz, CDCl3) d 178.39, 158.21, 152.96, 141.93,
137.64, 137.37, 128.87, 128.72, 128.48, 128.12, 126.11,
125.81, 125.49, 113.33, 89.74, 74.60, 65.24, 55.19, 45.51,
30.31, 29.56, 21.82, 16.64, 12.70; MS (FAB): m/z 488
(MH+), 470, 426, 256, 121, 77; HRMS (FAB): calcd for
C30H33NO5 MH+ 488.2437, found MH+ 488.2444.
4.5.10. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-[3-(4-nitro-
phenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxazolidinone,
14(S2). The product was obtained by using 2b and 4-ni-
tro-acetophenone to perform the asymmetric Reformat-
sky reaction and purification by flash chromatography
(ethyl acetate/hexane 1:6). Oil; [a]D = ꢀ101.4 (c 1.0,
CH2Cl2); IR (neat): 3503, 1753, 1669, 1505, 1350,
4.5.7. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-[4-chloro-3-
(2,5-difluorophenyl)-3-hydroxy-2-methyl-1-oxobutyl]-2-oxa-
zolidinone, 4d(S2). The product was obtained by using 2b
and 3b to perform the asymmetric Reformatsky reaction
and purification by flash chromatography (ethyl acetate/
hexane 1:5). Oil; [a]D = ꢀ109.1 (c 1.0, CH2Cl2); IR (neat):
1324 cmꢀ1 1H NMR (400 MHz, CDCl3) d 8.18 (d,
;
J = 9.2 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.45–7.26
(m, 10H), 5.37 (d, J = 3.2 Hz, 1H), 4.44 (s, 1H), 4.24
(q, J = 7.2 Hz, 1H), 2.08–2.04 (m, 1H), 1.63 (s, 3H),
0.96 (d, J = 7.2 Hz, 3H), 0.86 (d, J = 6.4 Hz, 3H), 0.45
(d, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3) d
177.68, 152.99, 152.62, 146.85, 141.80, 137.42, 128.95,
128.85, 128.56, 128.26, 126.11, 125.78, 125.44, 123.36,
90.04, 74.88, 65.49, 45.02, 30.08, 29.52, 21.86, 16.70,
12.59; MS (FAB): m/z 502 (MH+), 484, 282, 91, 77;
HRMS (FAB): calcd for C29H30N2O6 MH+ 502.2182,
found MH+ 502.2184.
1
3456, 1790, 1672, 1500, 1391 cmꢀ1; H NMR (400 MHz,
CDCl3) d 7.48–6.94 (m, 13H), 5.33 (d, J = 3.2 Hz, 1H),
5.12 (s, 1H), 4.57 (q, J = 6.8 Hz, 1H), 4.15 (d,
J = 11.2 Hz, 1H), 3.89 (dd, J = 11.6, 1.2 Hz, 1H), 2.07–
2.03 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.85 (d,
J = 6.8 Hz, 3H), 0.50 (d, J = 7.2 Hz, 3H); 13C NMR
(150 MHz, CDCl3) d 177.54, 159.71, 156.38, 155.98,
154.96, 159.34, 157.77, 157.69, 152.57, 141.83, 137.29,
130.99, 130.95, 130.93, 130.89, 128.91, 128.79, 128.53,
128.21, 125.68, 125.36, 123.42, 123.37, 111.19, 111.05,
111.03, 104.23, 104.05, 103.88, 89.96, 65.58, 51.79, 51.75,
40.76, 40.73, 29.57, 21.83, 16.65, 13.92; MS (FAB): m/z
528 (MH+), 510, 238, 154, 77; HRMS (FAB): calcd for
C29H28ClF2NO4 MH+ 528.1753, found MH+ 528.1758.
4.5.11. [3(2R,3R),4S]-5,5-Diphenyl-4-isopropyl-3-[4-chloro-
3-(2,4-difluorophenyl)-3-hydroxy-2-ethyl-1-oxobutyl]-2-oxa-
zolidinone, 15(S2). The product was obtained by using
(4S)-3-(2-bromobutanoyl)-4-isopropyl-5,5-diphenyl-2-oxa-

L.-T. Yu et al. / Tetrahedron: Asymmetry 18 (2007) 949–962
961
zolidinone and 3a to perform the asymmetric Reformatsky
reaction and purification by flash chromatography (ethyl
acetate/hexane 1:5). Oil; [a]D = ꢀ148.6 (c 1.0, CH2Cl2);
116.74, 116.67, 116.61, 116.58, 116.51, 116.45, 116.37,
116.34, 57.50, 51.85, 44.56, 12.33.
1
IR (neat): 3454, 1779, 1671, 1503, 1390 cmꢀ1; H NMR
4.7. (2R,3R)-3-[3-(2,4-Difluorophenyl)-3-hydroxy-2-methyl-
3-(1H-1,2,4-triazol-1-yl)]butanoic acid, 5a
(400 MHz, CDCl3) d 7.70 (dt, J = 8.8, 6.8 Hz, 1H), 7.54
(d, J = 7.2 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.38–7.22
(m, 6H), 6.91–6.76 (m, 2H), 5.39 (d, J = 2.8 Hz, 1H),
4.71 (s, 1H), 4.56 (dd, J = 10.8, 3.6 Hz, 1H), 4.24 (d,
J = 11.2 Hz, 1H), 3.80 (dd, J = 11.6, 1.2 Hz, 1H), 2.12–
2.08 (m, 1H), 1.46–1.25 (m, 2H), 1.02 (d, J = 6.8 Hz,
3H), 0.84 (d, J = 6.4 Hz, 3H), ꢀ0.11 (t, J = 7.6 Hz, 3H);
13C NMR (150 MHz, CDCl3) d 176.35, 163.51, 163.44,
161.86, 161.77, 159.52, 159.44, 157.87, 157.80, 152.99,
142.27, 137.33, 131.15, 131.11, 131.08, 131.05, 128.98,
128.72, 128.58, 128.12, 125.48, 125.07, 123.56, 123.54,
123.48, 123.46, 111.12, 110.98, 104.2, 104.10, 103.93,
89.64, 66.61, 51.78, 51.74, 47.88, 29.90, 29.69, 22.76,
22.02, 16.51, 9.72.
To a cooled (0 ꢁC) solution of sodium triazole (1.00 g,
10.98 mmol) in DMF (30 mL) was slowly added dropwise
a solution of epoxy acid 16 obtained above (0.94 g,
4.12 mmol) in DMF (5 mL), and the mixture was heated
to 60 ꢁC for 3 h. The mixture was cooled to 0 ꢁC, and
1 M HCl was then added until pH 3–4. The resulting mix-
ture was extracted with ethyl acetate (5 · 20 mL) and the
combined organic phases were washed with brine
(30 mL), dried over anhydrous MgSO4, and then concen-
trated. Recrystallization (methanol) gave product 5a as a
white solid (1.09 g, 89.3% yield): mp 212–213 ꢁC;
[a]D = ꢀ52.4 (c 1.0, MeOH); IR (neat): 3350, 3107, 3000–
2200, 1669, 1498, 1130 cmꢀ1; 1H NMR (300 MHz, CDCl3)
d 8.29 (s, 1H), 7.58 (s, 1H), 7.21–7.12 (m, 2H), 6.88–6.83
(m, 1H), 4.75 (d, J = 14.4 Hz, 1H), 4.68 (d, J = 14.4 Hz,
1H), 3.10 (q, J = 7.2 Hz, 1H), 0.84 (d, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 175.32, 163.92, 163.76,
160.67, 160.62, 160.50, 160.46, 157.35, 157.19, 150.67,
145.19, 130.51, 130.43, 130.39, 130.31, 125.06, 125.01,
124.89, 124.84, 111.28, 111.24, 111.01, 110.97, 104.57,
104.20, 103.86, 76.04, 75.97, 56.41, 56.35, 45.46, 45.40,
12.97. Anal. Calcd for C13H13F2N3O3: C, 52.53; H, 4.41;
N, 14.14. Found: C, 52.69; H, 4.58; N, 14.11.
4.6. (2R,3R)-3-[3-(2,4-Difluorophenyl)-3,4-epoxy-2-methyl]-
butanoic acid, 16
To a cooled (ꢀ10 ꢁC) solution of chlorohydrin imide 4c
(3.00 g, 5.69 mmol) in THF (40 mL) and H2O (10 mL)
was slowly added dropwise a 30% aqueous solution of
H2O2 (3.5 mL, 34.14 mmol). To the resulting mixture was
slowly added LiOHÆH2O (0.72 g, 17.07 mmol) in small por-
tions at ꢀ10 to ꢀ5 ꢁC. Once the addition was finished, the
reaction was stirred at ꢀ5 ꢁC for 1 h and 0 ꢁC for 0.5 h.
Two molars of aqueous Na2SO3 (18 mL) was then added
dropwise slowly at 0–5 ꢁC, and the mixture was stirred
for 30 min. The alkaline mixture was extracted with chloro-
form (3 · 30 mL). The combined organic phases were con-
centrated and the residue was purified by flash
chromatography (hexane/ethyl acetate = 1:1) to give Evans
chiral auxiliary 1b (1.19 g, recovery 74.1%). The aqueous
phase (pH 11) was acidified to pH 2 with saturated aqueous
NaHSO4 before it was extracted with chloroform
(3 · 30 mL). The combined organic phases were washed
with brine (20 mL), dried over anhydrous MgSO4 and con-
centrated to give epoxy acid 16 as a colorless oil, which
could be used directly in the next step without further
purification. The pure product (2.15 g, 71.6% yield) was
obtained by flash chromatography (ethyl acetate): oil;
[a]D = ꢀ42.7 (c 1.0, CH2Cl2); IR (neat): 3300–2800, 1705,
4.7.1.
(2R,3R)-3-[3-(2,5-Difluorophenyl)-3-hydroxy-2-
methyl-3-(1H-1,2,4-triazol-1-yl)]butanoic acid, 5b. Fol-
lowing the procedure described above, but using epoxy
acid 17 as the reactant, 5b was obtained as a white solid
(1.08 g, 87.9% yield): mp 191–193 ꢁC; [a]D = ꢀ43.1 (c 1.0,
MeOH); IR (neat): 3416, 3200–2200, 1678, 1615, 1491,
1
1127 cmꢀ1; H NMR (400 MHz, CDCl3) d 8.31 (s, 1H),
7.61 (s, 1H), 7.19–7.14 (m, 1H), 7.05–6.88 (m, 3H), 4.81
(d, J = 14.4 Hz, 1H), 4.73 (d, J = 14.4 Hz, 1H), 3.13 (q,
J = 7.2 Hz, 1H), 0.84 (d, J = 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 174.78, 158.75, 157.17, 155.49,
153.9, 150.35, 144.90, 130.80, 130.75, 130.70, 130.65,
117.19, 117.13, 117.01, 116.95, 116.05, 115.99, 115.89,
115.83, 115.40, 115.37, 115.22, 115.20, 75.71, 75.67,
55.86, 55.84, 44.89, 44.87. Anal. Calcd for C13H13F2N3O3:
C, 52.53; H, 4.41; N, 14.14. Found: C, 52.62; H, 4.63; N,
14.07.
1
1503, 1265 cmꢀ1; H NMR (400 MHz, CDCl3) d 7.40 (dt,
Jd = 6.8, Jt = 8.8 Hz, 1H), 6.89–6.78 (m, 2H), 3.16 (d,
J = 4.8 Hz, 1H), 3.02 (q, J = 7.2 Hz, 1H), 2.91 (d,
J = 4.8 Hz, 1H), 1.19 (dd, J = 7.2, 0.8 Hz, 3H).
References
4.6.1. (2R,3R)-3-[3-(2,5-Difluorophenyl)-3,4-epoxy-2-methyl]-
butanoic acid, 17. Following the previous procedure, the
removal of Evans chiral auxiliary section from chloro-
hydrin imide 4d was carried out with a 79.6% recovery of
Evans auxiliary 1b and epoxy acid 17 was obtained
(73.8% yield): oil; [a]D = ꢀ41.5 (c 1.0, CH2Cl2); IR (neat):
1. (a) Reformatskii, S. N. Ber. Dtsch. Chem. Ges. 1887, 20, 1201;
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