Stereoselective synthesis of (+)-flutriafol

Article abstract of DOI:10.1016/j.tetasy.2008.06.007

The stereoselective synthesis of (+)-flutriafol, a triazole fungicide, has been accomplished in seven linear steps from (1S)-[(4R)-2,2-dimethyl-[1,3]-dioxolan-4-yl]-(4-methoxyphenyl)methanol in 15% overall yield. Diastereoselective nucleophilic 1,2-addition was employed as a key step for constructing the requisite chiral 1,2-diol for flutriafol. A high degree of 1,4-asymmetric induction could be realized via a chelation-controlled mechanism during the key alkylation step.

Full text of DOI:10.1016/j.tetasy.2008.06.007

Tetrahedron: Asymmetry 19 (2008) 1504–1508
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of (+)-flutriafol
Minsun Chang a, Tae Hyun Kim b, Hee-Doo Kim b,
*
a Department of Biological Science, Sookmyung Women’s University, Seoul 140-742, Republic of Korea
b College of Pharmacy, Sookmyung Women’s University, Yongsan-ku, Seoul 140-742, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The stereoselective synthesis of (+)-flutriafol, a triazole fungicide, has been accomplished in seven linear
steps from (1S)-[(4R)-2,2-dimethyl-[1,3]-dioxolan-4-yl]-(4-methoxyphenyl)methanol in 15% overall
yield. Diastereoselective nucleophilic 1,2-addition was employed as a key step for constructing the req-
uisite chiral 1,2-diol for flutriafol. A high degree of 1,4-asymmetric induction could be realized via a che-
lation-controlled mechanism during the key alkylation step.
Received 13 May 2008
Accepted 4 June 2008
Available online 2 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
(+)-isomer of flutriafol was more active than the (ꢀ)-isomer
against both Alternaria solani and Alternaria mali.4 Its absolute con-
Flutriafol is a broad-spectrum triazole fungicide used for the
control of important cereal diseases including powdery mildews,
rusts, Septoria spp., and Rhynchosporium secalis.1 It shares a com-
mon mode of action with other triazole fungicides by inhibiting
figuration has not yet been determined. However, optically active
flutriafol has been separated only by a chromatographic method
through enantiomeric or diastereomeric chiral separation.5 The
asymmetric synthesis of flutriafol has not yet been reported; there-
fore, the synthesis of flutriafol in enantiopure form is of interest.
Our recent development of the chelation-controlled asymmetric
the C-14a-demethylase enzyme involved in the biosynthesis of
fungal sterols.2 A characteristic structural feature of flutriafol is
the tertiary alcohol with a 1,2,4-triazolylmethyl group and two dif-
ferently substituted fluorophenyl groups. As shown in Scheme 1,
flutriafol has one stereogenic center, but is marketed in the race-
mic form. Considering that the stereogenic center of flutriafol is
located close to the 1,2,4-triazole ring, a key template in the bind-
ing of flutriafol to their target sites, chirality is expected to play a
crucial role in the bioactivities of flutriafol. This has actually been
proven by some bioassay results.3 It was also reported that the
alkylation process permitting efficient syntheses of chiral a-hydro-
xy esters prompted us to see if this process would be readily adapt-
able to the synthesis of chiral 1,2-diols.6 If so, an efficient synthesis
of (+)-flutriafol via chiral diol 5 would be feasible. Our synthetic
strategy for (+)-flutriafol was based on the approach outlined in
Scheme 1. A retrosynthetic analysis of (+)-flutriafol reveals the reg-
ioselective ring opening of epoxide 7 as a possible key step. As
epoxide 7 shall be accessible from the corresponding diol 5, we
F
F
F
F
O
O
N
N
HO
HO
HO
chiral
auxiliary
N
O
HO
O
chiral
auxiliary
(S)
F
F
F
F
F
α-Alkoxy
Ketone
7
5
(+)-Flutriafol
Asymmetric
nucleophilic 1,2-addition
Scheme 1. Retrosynthetic analysis of (+)-flutriafol.
* Corresponding author. Tel.: +82 2 710 9567; fax: +82 2 703 0736.
E-mail address: hdkim@sm.ac.kr (H.-D. Kim).
URL: http://sdic.sookmyung.ac.kr/~hdkim (H.-D. Kim).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.06.007

M. Chang et al. / Tetrahedron: Asymmetry 19 (2008) 1504–1508
1505
envisioned that the chelation-controlled asymmetric nucleophilic
1,2-addition to
-alkoxy ketone,7 followed by removal of the chiral
auxiliary would provide the requisite chiral diol 5.
best additive for the reaction. Thus, the optimum conditions in-
volved performing the reaction in the presence of MgBr2-etherate
in dichloromethane (DCM) at ꢀ78 °C, to give the desired major
product 4a and its diastereomer 4b in 95% chemical yield, in a
51:1 ratio of diastereomers. The absolute configuration of the new-
ly created stereogenic center of 4a could not be rigorously estab-
lished at the present stage, but was assigned tentatively as (S) on
the basis of our proposed chelation model as shown in Figure
1.6a The subsequent transformation of 4a to (+)-flutriafol is
outlined in Scheme 3. Alcohol 4a was then converted to the
corresponding diol 5 by treating with trimethylsilyl chloride
a
2. Results and discussion
Our synthesis began with the preparation of chiral auxiliary-
conjugated
a-alkoxy ketone as a substrate for the diastereoselec-
tive nucleophilic 1,2-addition reaction (Scheme 2). Chiral auxiliary
1, readily prepared from (R)-glyceraldehyde diacetonide, was
linked to the reaction template as its ether form, simply by an O-
alkylative epoxide ring opening reaction.6a,8 Alcohol 1 was con-
verted to the corresponding alkoxide with KH in tetrahydrofuran
(THF), followed by O-alkylation with 2-(2-fluorophenyl)oxirane
in the presence of 18-crown-6 to afford ether 2 in 53% yield.
Oxidation of the resulting alcohol was carried out with tetrapropyl-
ammonium perruthenate (TPAP) in the presence of N-methylmor-
pholine-N-oxide (NMO) to give ketone 3 in 65% yield. With key
substrate 3 in hand, we undertook a short study to determine
the optimum conditions for the asymmetric nucleophilic 1,2-addi-
tion reaction. As shown in Table 1, performing the reaction at a
lower temperature in a less basic solvent led to better results.
The addition of an additive to the reaction led to a dramatic break-
through in stereoselectivity, with MgBr2-etherate proving to be the
Ar
O
H
O
Nu-
M+
O
O
Nucleophile approaches
from the convex side
of the complex
OCH3
Figure 1. Possible chelation model for asymmetric nucleophilic 1,2-addition.
F
O
O
O
O
F
O
OH
F
O
OH
O
O
O
O
TPAP, NMO
DCM, 65%
KH, 18-crown-6
THF, 53%
OCH3
OCH3
OCH3
1
2
3
Scheme 2. Preparation of chiral auxiliary-conjugated a-alkoxy ketone.
Table 1
Asymmetric nucleophilic 1,2-addition
F
F
F
O
O
F
O
O
HO
OH
O
O
O
O
O
O
MgBr
+
additive, solvent
)))
F
F
OCH3
3
OCH3
4a
OCH3
4b
Entry
Solvent
Temperature (°C)
Additive
Yield (%)
Ratioa (4a:4b)
1
2
3
4
5
6
7
8
9
10
THF
THF
rt
None
None
None
None
None
LiBr
LiOCl4
Ph2Zn
MgCl2
93
98
95
94
97
90
96
80
93
95
2:1
3:1
4:1
1:1
7:1
5:1
6:1
4:1
15:1
51:1
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
Ether
DME
DCM
DCM
DCM
DCM
DCM
DCM
MgBr2ꢁOEt2
a
The ratio (R/S) was determined by HPLC analysis (Chiralcel OD column).

1506
M. Chang et al. / Tetrahedron: Asymmetry 19 (2008) 1504–1508
F
F
F
O
HO
O
(DHQD)2PHAL, K2Os4(H2O)2
K3Fe(CN)6, -BuOH-H2O
TMSCl, NaI, SnCl2
HO
O
HO
CH3CN
75%
t
F
86%, 69% ee
F
F
4a
5
8
(96% de)
TsCl
OCH3
99%
F
F
F
N
HO
HO
F
DBU
t-BuOK
DMF, 100 oC
O
N
N
TsO
THF
77%
77%
F
F
(+)-Flutriafol
6
7
Scheme 3. Synthesis of (+)-flutriafol.
(TMSCl) and NaI.9 At this stage, the enantiomeric purity of the 4a
was reconfirmed by analyzing diol 5 by chiral HPLC (Chiralcel OD
column). When treating 4a with ceric ammonium nitrate; how-
ever, racemization occurred extensively, providing the diol with
low enantiomeric purity. As chiral diols are generally readily avail-
able from the corresponding alkenes by Sharpless asymmetric
dihydroxylation, we also prepared this chiral diol 5 from alkene
sured on a JASCO DIP 1000 digital polarimeter. 1H NMR and 13C
NMR spectra were obtained on a Varian Inova 400 spectrometer
and the chemical shifts are reported as values in parts per million
(d) relative to tetramethylsilane (TMS) as an internal standard. The
infrared spectra (IR) were recorded on a JASCO FT/IR-430 spectro-
photometer. Thin layer chromatography (TLC) was carried out on
0.25 mm E. Merck precoated silica gel glass plates (60F254). Column
chromatography was performed using the forced flow of indicated
solvent on Merck Kieselgel 60 (230–400 mesh). Chiral HPLC was
performed using a Shimadzu LC-10AS pumping system and Shima-
dzu SPD-10A UV detector with a chiral column (Chiralcel OD,
8
by Sharpless asymmetric dihydroxylation.10 However, the
enantioselectivity is not high enough (69% ee) due to the structural
similarity between the two substituents around the double bond.
Thus, diol 5 with high enantiomeric purity is needed for the asym-
metric synthesis of flutriafol. In this sense, the asymmetric nucleo-
0.46 cm (
U
) ꢂ 25 cm, Daicel Chemical Ind., Ltd). ( )-Flutriafol was
philic 1,2-addition to an
a-alkoxy ketone can provide an
purchased from Fluka. Unless otherwise noted, the materials were
obtained from commercially available sources and were used with-
out further purification. THF was freshly distilled from sodium
benzophenone ketyl under an argon atmosphere. Benzene, DCM,
DMF, triethylamine (TEA) and toluene were freshly distilled under
a nitrogen atmosphere with calcium hydride.
alternative way to chiral diols not easily accessible by the Sharp-
less asymmetric dihydroxylation method. Selective tosylation of
diol 5 with p-toluenesulfonyl chloride (TsCl) followed by treatment
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) afforded epoxide 7
in 76% yield over two steps. Finally, treatment of 1,2,4-triazole
with t-BuOK followed by a ring opening reaction with epoxide 7
at 100 °C in N,N-dimethylformamide (DMF) provided (+)-flutriafol
in 77% yield. Spectral analyses of the synthetic (+)-flutriafol were
found to be identical with those of commercially available ( )-flu-
triafol. The observed optical rotation of synthetic flutriafol was
4.2. 2-{[(R)-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl](4-
methoxyphenyl)methyl]oxy}-1-(2-fluorophenyl) ethanol 2
A solution of alcohol 1 (273 mg, 1.15 mmol) in THF (3 mL) was
added to a suspension of KH (651 mg, 35% in oil, 5.75 mmol) in THF
(7 mL). After being stirred at 55 °C for 30 min, 2-(2-fluoro-
phenyl)oxirane (285 mg, 2.60 mmol) and 18-crown-6 (10 mg)
were added at 0 °C and the mixture was gradually heated to reflux-
ing temperature for 3 h. The reaction mixture was quenched with
aq NH4Cl (10 mL) and diluted with ethyl acetate (30 mL). The
organic layers were washed with brine, dried over anhydrous
Na2SO4, filtered, and then concentrated. The resulting crude resi-
due was purified by column chromatography on silica gel (17%
ethyl acetate in hexane) to give the title compound 2 as an oil
[a]D = +21.8 (c 0.2, CHCl3), in 96% ee by chiral HPLC analysis.
3. Conclusion
In conclusion, we have shown that (+)-flutriafol can be prepared
efficiently from our chiral auxiliary via chelation-controlled diaste-
reoselective nucleophilic 1,2-addition and an epoxide ring opening
reaction. A high degree of 1,4-asymmetric induction has been real-
ized during the key alkylation step via the chelation-controlled
mechanism. Our synthetic method offers an alternative way to chi-
ral diols not easily accessible from the Sharpless asymmetric
dihydroxylation.
(227 mg, 53%); ½a D23
¼ ꢀ61:2 (c 0.16, CHCl3); IR (NaCl, neat):
ꢃ
cmꢀ1 3444, 3069, 2986, 2934, 1512, 1455, 1244; 1H NMR
(400 MHz, CDCl3): d 7.49 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.16–7.12
(m, 1H), 7.16 (d, J = 8.8 Hz, 2H), 7.06 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H),
6.88 (ddd, J = 10.8, 7.6, 1.2 Hz, 1H), 6.80 (d, J = 8.8 Hz, 2H), 5.12
(dd, J = 9.6, 3.2 Hz, 1H), 4.30–4.20 (m, 1H), 4.12 (d, J = 8.0 Hz, 1H),
3.73 (s, 3H), 3.66 (ddd, J = 11.2, 3.2, 1.2 Hz, 1H), 3.59 (dd, J = 8.8,
6.8 Hz, 1H), 3.48 (dd, J = 8.8, 6.8 Hz, 1H), 3.22 (dd, J = 11.2, 9.6 Hz,
1H), 2.60–2.50 (br s, 1H), 1.42(s, 3H), 1.33(s, 3H); 13C NMR
4. Experimental
4.1. General
The melting points were obtained using Büchi 535 melting
point apparatus and are uncorrected. Optical rotations were mea-

M. Chang et al. / Tetrahedron: Asymmetry 19 (2008) 1504–1508
1507
(100 MHz, CDCl3):
d
159.69, 159.41, 131.64, 128.74, 128.60,
(15), 181 (18), 221 (14), 493 [100, (M+Na)]; HRMS (FAB+) calcd
for C27H28F2O5Na (M+Na) 493.1803, found 493.1805; HPLC (Chiral-
cel OD column, eluent = 0.5% isopropanol in hexane, flow
rate = 0.5 mL/min) tR of major (S) = 43.9 min; tR of minor
(R) = 50.2 min (S:R = 51:1). Minor (4b): Rf = 0.37 (n-hexane–
128.06, 127.59, 124.15, 114.90, 114.68, 113.99, 113.88, 110.15,
82.98, 80.25, 79.05, 72.33, 66.02, 55.24, 27.02, 25.45; LRMS (FAB)
m/z (rel intensity) 133 (7), 163 (86), 180 (100), 221 (15), 399 [69,
(M+Na)]; HRMS (FAB+) calcd for C21H25FO5Na (M+Na) 399.1584,
found 399.1581.
EtOAc = 3:1); ½a 2D3
ꢃ
¼ ꢀ28:17 (c 0.66, CHCl3); 1H NMR (400 MHz,
CDCl3) d 7.64 (t, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.8, 6.4 Hz, 2H),
7.19–7.14 (m, 1H), 7.07 (d, J = 6.4 Hz, 1H), 7.04 (d, J = 6.4 Hz, 2H),
6.87–6.82 (m, 3H), 6.76 (d, J = 8.0 Hz, 2H), 4.28 (br s, 1H), 4.17–
4.13 (m, 3H), 3.72–3.70 (m, 4H), 3.58–3.53 (m, 1H), 3.49–3.44
(m, 1H), 1.36 (s, 3H), 1.26 (s, 3H).
4.3. 2-{[(R)-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl](4-
methoxyphenyl)methyl]oxy}-1-(2-fluorophenyl)ethan-1-one 3
TPAP (16 mg, 0.046 mmol) was added to a mixture of alcohol 2
(172 mg, 0.46 mmol) and NMO (107 mg, 0.92 mmol) in dichloro-
methane (9 mL). After being stirred for 1 h at room temperature,
the reaction mixture was quenched by the addition of saturated
aqueous sodium sulfite solution (1 mL). The resulting mixture
was diluted with dichloromethane. The organic layer was washed
successively with brine, aqueous copper sulfate solution, water and
brine, dried over anhydrous Na2SO4, filtered, and then concen-
trated. The resulting crude residue was purified by column chro-
matography on silica gel (17% ethyl acetate in hexane) to give
the title compound 3 as a white solid (111 mg, 65%); mp: 66–
4.5. (S)-1-(2-Fluorophenyl)-1-(4-fluorophenyl)ethane-1,2-diol 5
Tin(II) chloride (1.9 mg, 0.01 mmol), chlorotrimethylsilane
(37.8 lL, 0.30 mmol), and sodium iodide (44.7 mg, 0.30 mmol)
were sequentially added to a stirred solution of 4a (46.7 mg,
0.10 mmol) in acetonitrile (3 mL) at 0 °C. After being stirred for
1 h at 0 °C, the reaction mixture was quenched by the addition of
saturated aqueous sodium bicarbonate solution (1 mL). The result-
ing mixture was diluted with ethyl acetate (30 mL). The organic
layer was washed successively with water and brine, dried over
anhydrous Na2SO4, filtered, and then concentrated. The resulting
crude residue was purified by column chromatography on silica
gel (17% ethyl acetate in hexane) to give the title compound 5 as
68 °C; ½a 2D4
ꢃ
¼ ꢀ68:6 (c 0.11, CHCl3); 1H NMR (400 MHz, CDCl3) d
7.82 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 7.43 (m, 1H), 7.19 (d, J = 8.0 Hz,
2H), 7.15 (dd, J = 7.6, 7.6 Hz, 1H), 6.99 (dd, J = 11.0, 7.6 Hz, 1H),
6.80 (d, J = 8.0 Hz, 2H), 4.59 (dd, J = 18.4, 3.2 Hz, 1H), 4.45 (d,
J = 7.2 Hz, 1H), 4.38 (m, 1H), 4.06 (dd, J = 18.0, 3.2 Hz, 1H), 3.73
(s, 3H), 3.60 (dd, J = 8.4, 6.4 Hz, 1H), 3.52 (dd, J = 8.4, 7.2 Hz, 1H),
1.36 (s, 3H), 1.30 (s, 3H); 13C NMR (100 MHz, CDCl3) d 194.37,
161.70, 159.67, 134.65, 130.43, 128.92 (2C), 128.76, 124.44,
116.38, 116.15, 113.90 (2C), 110.03, 83.12, 78.94, 73.92, 66.01,
55.18, 26.60, 25.62; IR (KBr) cmꢀ1 2985, 2932, 1699, 1610, 1512,
1247; LRMS (FAB) m/z (rel intensity) 397 [100, (M+Na)], 398
(18), 399 (5); HRMS (FAB+) calcd for C21H23FO5Na (M+Na)
397.1427, found 397.1428.
a white solid (18.7 mg, 75%); mp: 66–67 °C; ½a D22
¼ ꢀ25:6 (c 0.8,
ꢃ
CHCl3); 1H NMR (400 MHz, CDCl3): d 7.62 (ddd, J = 8.0, 8.0,
1.6 Hz, 1H), 7.30–7.10 (m, 3H), 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 6.97–
6.80 (m, 3H), 4.18 (d, J = 11.2 Hz, 1H), 4.04 (d, J = 11.2Hz, 1H),
3.37 (br s, 1H), 2.09 (br s, 1H); 13C NMR (100 MHz, CDCl3):
163.20, 160.75, 138.97, 129.74, 129.69, 128.70, 127.71, 124.26,
116.37, 116.14, 115.15, 114.94, 68.52, 68.48; IR (KBr pellet,
cmꢀ1): 3425, 2955, 2925,1604, 1486, 1225, 1160; HPLC (Chiralcel
OD column) eluent = 5% isopropanol in hexane, flow rate =
0.5 mL/min; detection 254 nm light, tR of (S)-major 38.6 min;
tR of (R)-minor 34.9 min (S:R = 51:1); MS (FAB+) m/z (rel inten-
sity) 227 (75), 233 (50), 260 (100), 273 [14, (M+Na)]; HRMS
(FAB+) calcd for C14H12F2O2Na (M+Na) 273.0703, found
273.0696.
4.4. 2-{[(R)-[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl](4-
methoxyphenyl)methyl]oxy}-(1S)-1-(2-fluorophenyl)-1-(4-
fluorophenyl)ethanol 4a
A mixture of ketone 3 (78.3 mg, 0.21 mmol) and MgBr2ꢁOEt2
(216 mg, 0.84 mmol) in CH2Cl2 (5 mL) was sonicated in ultrasonic
cleaning water bath (BransonicÒ 1210R-DTH) for 10 min, and then
cooled to ꢀ78 °C. To the reaction mixture was added dropwise
4.6. (S)-Toluene-4-sulfonic acid 2-(4-fluorophenyl)-2-(2-fluoro-
phenyl)-2-hydroxy ethyl ester 6
4-fluorophenylmagnesium bromide (418
l
L, 1.0 M solution in
To a solution of the diol 5 (29.5 mg, 0.12 mmol, 96% ee) in
THF, 0.42 mmol) via syringe. The whole was stirred at ꢀ78 °C for
2 h and allowed to warm to room temperature. The reaction mix-
ture was quenched with aqueous NaHCO3 (1 mL) and diluted with
dichloromethane (30 mL). The organic layer was stirred with aque-
ous NH4Cl (10 mL) for 10 min. The layers were separated, and the
aqueous layer was extracted twice with dichloromethane
(15 mL). The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and then concentrated in
vacuo. The resulting crude residue was purified by column chro-
matography on silica gel (15% ethyl acetate in hexane) to give
the title compound 4a as pale yellow oil (70 mg, 97%): major
dichloromethane (3 mL) was added triethylamine (41 lL,
0.30 mmol) followed by 4-dimethylaminopyridine (2 mg). The
solution was cooled to 0 °C and p-toluenesulfonyl chloride
(33.7 mg, 0.12 mmol) was added, and then the mixture was
allowed to warm to room temperature. After being stirred for
24 h, the reaction mixture was diluted with dichloromethane
(30 mL). The organic layer was washed successively with water
and brine, dried over anhydrous Na2SO4, filtered, and then concen-
trated. The resulting crude residue was purified by column chro-
matography on silica gel (12% ethyl acetate in hexane) to give
the title compound 6 as a white solid (46.7 mg, 98%); mp: 134–
(4a): Rf = 0.39 (n-hexane–EtOAc = 3:1);
½
a 2D3
ꢃ
¼ ꢀ32:9 (c 0.95,
135 °C; [
a]
D = ꢀ 26.7 (c 0.12, CHCl3); 1H NMR (400 MHz, CDCl3):
CHCl3); 1H NMR (400 MHz, CDCl3) d 7.74 (ddd, J = 8.0, 8.0, 1.6 Hz,
1H), 7.30 (dd, J = 8.8, 6.0 Hz, 2H), 7.19–7.05 (m, 4H), 6.90–6.78
(m, 5H), 4.22 (dd, J = 10.0, 2.4 Hz, 1H), 4.2–4.1 (m, 3H), 3.75 (d,
J = 10.0 Hz, 1H), 3.72 (s, 3H), 3.66 (dd, J = 8.8, 6.0 Hz, 1H), 3.43
(dd, J = 8.8, 6.0 Hz, 1H), 1.31 (s, 3H), 1.24 (s, 3H); 13C NMR
(100 MHz, CDCl3) 162.83, 160.39, 158.21, 139.83, 131.43, 131.32,
129.54, 129.19, 129.11, 128.50, 128.16, 128.07, 123.96, 115.97,
115.74, 114.60, 114.40, 113.96, 109.98, 85.39, 79.09, 76.11, 74.37,
65.89, 55.20, 22.66, 25.51; IR (NaCl, neat) cmꢀ1 3446, 3032, 2986,
1512, 1490, 1448, 1243; LRMS (FAB+) m/z (rel intensity) 163
d 7.63 (dd, J = 6.8, 2.0 Hz, 2H), 7.55 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H),
7.26–7.19 (m, 5H), 7.10 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.91–6.84
(m, 3H), 4.57 (dd, J = 10.0, 1.2 Hz, 1H), 4.52 (d, J = 10.0 Hz, 1H),
3.13 (d, J = 2.4 Hz, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3)
160.51, 158.07, 145.05, 137.13, 132.07, 130.08, 129.99, 129.80
(2C), 128.13, 127.94, 127.88 (2C), 124.38, 116.26, 116.04, 115.18,
114.97, 75.53, 73.90, 21.71; IR (KBr pellet, cmꢀ1): 3530, 3434,
3069, 2932, 1373, 1164; LRMS (FAB+) (rel intensity) 233 (39),
264 (21), 427 [34, (M+Na)], 460 (100); HRMS (FAB+) calcd for
C21H18F2O4SNa (M+Na) 427.0792, found 427.0796.

1508
M. Chang et al. / Tetrahedron: Asymmetry 19 (2008) 1504–1508
4.7. (S)-2-(2-Fluorophenyl)-2-(4-fluorophenyl)oxirane 7
AD-H column) eluent = 7% isopropanol in hexane, flow rate =
0.5 mL/min; detection 254 nm light, tR of (S)-major 29.5 min; tR
of (R)-minor 31.9 min (S:R = 51:1); LRMS (FAB+) m/z (rel intensity)
233 (54), 302 [100, (M+H)]; HRMS (FAB+) calcd for C16H14F2N3O
(M+H) 302.1105, found 302.1106.
To a solution of the tosylate 6 (35.7 mg, 0.10 mmol) in tetrahy-
drofuran (3 mL) was added 1,8-diazabicyclo[5,4,0]undec-7-ene
(36.2
lL, 0.24 mmol). After the resulting mixture was stirred for
30 min at room temperature, the reaction mixture was diluted
with ethyl acetate (30 mL). The organic layer was washed succes-
sively with water and brine, dried over anhydrous Na2SO4, filtered,
and then concentrated. The resulting crude residue was purified by
column chromatography on silica gel (3% ethyl acetate in hexane)
to give the title compound 7 as a white solid (14.7 mg, 77%); 1H
NMR (400 MHz, CDCl3) d 7.41 (ddd, J = 7.6, 7.6, 2.0 Hz, 1H), 7.31–
7.25 (m, 1H), 7.19–7.16 (m, 2H), 7.10 (ddd, J = 7.6, 7.6, 1.2 Hz,
1H), 7.04–6.99 (m, 1H), 6.94–6.88 (m, 2H), 3.24 (dd, J = 5.2,
0.8 Hz, 1H), 3.13 (d, J = 5.2 Hz, 1H); IR (NaCl neat, cmꢀ1) 3050,
2986, 1606, 1509, 1453, 1220, 1159.
Acknowledgment
This work was supported by the Korea Research Foundation
Grant funded by the Korean Government (MOEHRD) (KRF-2005-
041-E00490) and the SRC program of KOSEF (Research Center for
Women’s Diseases).
References
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4.8. (S)-(+)-Flutriafol
To a solution of 1,2,4-triazole (8.3 mg, 0.12 mmol) in dimethyl-
formamide (3 mL) was added potassium tert-butoxide (128.5 mg,
0.12 mmol). The reaction mixture was heated to 50 °C for 30 min,
and then cooled to room temperature. The epoxide 7 (25.5 mg,
0.11 mmol) was then added and the mixture stirred for 24 h at
100 °C. The reaction mixture was cooled to room temperature,
and diluted with ethyl acetate (15 mL) and water (15 mL). The
aqueous layer was extracted with ethyl acetate (3 ꢂ 15 mL) and
the combined organic layers were washed with brine. The solution
was dried over Na2SO4 and the solvent removed under reduced
pressure. The residue was purified over silica gel (50% ethyl acetate
in hexane) to yield (+)-flutriafol as a syrup (24.7 mg, 77%);
½
a 2D3
ꢃ
¼ þ21:8 (c 0.2, CHCl3); 1H NMR (400 MHz, CDCl3) d 7.91 (s,
1H), 7.69 (s, 1H), 7.56 (ddd, J = 8.0, 8.0, 1.6 Hz, 1H), 7.35 (m, 2H),
7.16 (m, 1H), 7.02 (ddd, J = 7.6, 7.6, 1.2 Hz, 1H), 6.97–6.89 (m,
3H), 5.36 (bs, 1H), 5.14 (dd, J = 14.0, 0.8 Hz, 1H), 4.72 (dd,
J = 14.0, 1.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) 163.37, 160.91,
159.68, 157.27, 137.83, 130.09, 128.71, 127.71, 127.63, 124.72,
115.94, 115.70, 115.37, 115.16, 57.47, 57.41; IR (KBr pellet,
cmꢀ1) 3423, 2925, 1604, 1509, 1483, 1226, 1162; HPLC (Chiralcel
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