Synthesis and fungicidal activity of enantiomerically pure (R)- and (S)-silicon-containing azole fungicides

Article abstract of DOI:10.1016/j.bmc.2004.04.027

Enantiomerically pure (R)- and (S)-1-(1H-1,2,4-triazol-1-yl)-2-(4- fluorophenyl)-3-trimethylsilylpropan-2-ol 1 were prepared via an enantioselective Grignard reaction. The absolute stereochemistry of 1 was determined by X-ray analysis. In a comparison of in vitro antifungal activities of the enantiomers, the (-)-enantiomer with the R-absolute configuration was far more potent than the (+)-enantiomer.

Full text of DOI:10.1016/j.bmc.2004.04.027

Bioorganic & Medicinal Chemistry 12 (2004) 3561–3567
Synthesis and fungicidal activity of enantiomerically pure
(R)- and (S)-silicon-containing azole fungicides
Hiroyuki Itoh,a,* Youji Furukawa,b Mikio Tsudaa and Hideo Takeshibac
aAgroscience Research Laboratories, Sankyo Agro Co., Ltd, 894, Yasu, Yasu-cho, Yasu-gun, Shiga-ken 520-2342, Japan
bBiomedical Research Laboratories, Sankyo Co., Ltd, 2-58, Hiromachi, 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan
cChemtech Labo Inc. 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140-8710, Japan
Received 31 March 2004; revised 22 April 2004; accepted 22 April 2004
Available online 18 May 2004
Abstract—Enantiomerically pure (R)- and (S)-1-(1H-1,2,4-triazol-1-yl)-2-(4-fluorophenyl)-3-trimethylsilylpropan-2-ol 1 were pre-
pared via an enantioselective Grignard reaction. The absolute stereochemistry of 1 was determined by X-ray analysis. In a com-
parison of in vitro antifungal activities of the enantiomers, the ())-enantiomer with the R-absolute configuration was far more
potent than the (+)-enantiomer.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Chemistry
In our search for azole fungicides, we found that 1-
(1H-1,2,4-triazol-1-yl)-2-(4-fluorophenyl)-3-trimethylsilyl-
propan-2-ol 1 had excellent fungicidal activities for
various crops. In a previous paper, we reported our
experience in synthesizing racemic 1 and evaluating its
fungicidal activities as a racemic compound.1–3 Enantio-
mers are well known to exhibit frequent and diverse
biological activities. In one study by Carelli et al., for
example, cytochrome P450 from phytophathogen was
found to interact in interesting ways with azole fungicide
in enantiomerically pure form.4 To follow along in a
similar vein, other groups went on to study the synthesis
of optical active azole fungicides.5–7
Earlier we reported the two procedures for the synthesis
of 1 as shown in Scheme 1. Method A involves the
Grignard reaction to a triazolylacetophenone 4 in the
last step.1;2 Method B, the turn of a reaction process was
replaced, involves the reaction of 1H-1,2,4-triazole
sodium salt 3 with 1-chloro-2-(4-fluorophenyl)-3-tri-
methylsilylpropan-2-ol 6 obtained by the Grignard
reaction to a phenacyl chloride 2.3 Since the Grignard
reaction was used to generate the chiral carbon in both
routes, we decided to make the Grignard reaction
enantioselective.
NNa
N
Both (R)-and (S)-1 must be available in enantiomeri-
cally pure forms in order to properly evaluate the
effectiveness of 1. In this paper we report an efficient
synthesis of both enantiomers of 1 in enantiomerically
pure forms using (1R,2S)- or (1S,2R)-phenylcyclohexa-
nol as a chiral auxiliary.
Si
N
MgCl
OH
O
O
Cl
N
N
N
N
Si
3
5
N
N
F
F
F
2
4
1
OH
OH
O
Cl
Cl
Si
N
N
Si
5
3
N
F
F
F
Keywords: Fungicidal activities; Enantiomer; Synthesis; X-ray analysis.
* Corresponding author. Tel.: +81-77-586-1223; fax: +81-77-586-2538;
e-mail: hiroit@yasu.sankyo.co.jp
2
6
1
Scheme 1. Our previous method for the preparation of 1.
0968-0896/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2004.04.027

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H. Itoh et al. / Bioorg. Med. Chem. 12 (2004) 3561–3567
In their subsequent study, Whitesell et al. also reported
Si
that trans-2-phenylcyclohexanol can be used in place of
8-phenylmenthol for asymmetric reactions of a-keto
esters.10 Thereafter, Peter and Helmut compared the
diastereoselectivity between 8-phenylmenthyl phenyl-
glyoxylate and trans-2-phenylcyclohexyl phenylglyoxyl-
ate in several kinds of reactions.11 While the commercial
availability of the (1R,2S)- and (1S,2R)-trans-2-phenyl-
cyclohexanols and their ability to synthesize both
enantiomers makes them attractive, the de value in the
methyl Grignard reaction was unsatisfactory in Peter
and Helmut’s results. Predictably, the addition of 5 to
racemic trans-2-phenylcyclohexyl 2-(4-fluorophenyl)gly-
oxylate 9 resulted in the generation of diastereomixture
10 of 50% de. Since the diastereomixture was solidified,
we attempted to recrystallize from ethanol. This strategy
proved successful, and diastereomixture 10 could be
converged on a single diastereomer of >99% de by
HPLC.
5
O
OH
O
F
F
O
O
O
8
7
Si
5
O
OH
O
F
F
O
O
O
10
9
Scheme 2. The Grignard reaction of 5 with phenylglyoxylates.
Whitesell et al. reported the use of 8-phenylmenthyl
esters to allow the enantioselective addition of a Grig-
nard reagent to a-keto esters.8;9 The enantioselectivity
of the addition to phenylglyoxylates is quite high
when conducted at dry ice/acetone bath temperature.
This method was adapted for the reaction of ())-8-
Next, we carried out the addition reaction with (1R,2S)-
and (1S,2R)-trans-2-phenylcyclohexanols to provide the
corresponding diastereomixture in the same diastereo-
selectivity and then recrystallized them from ethanol to
give the single diastereomers 10()) and 10(+) of >99%
de by HPLC.
phenylmenthyl 2-(4-fluorophenyl)glyoxylate
7
with
trimethylsilylmethyl Grignard reagent 5 as shown in
Scheme 2. An analysis of the diastereomixture 8, ob-
tained as an oily product, by reverse phase HPLC
(Shiseido Capcellpak C18 (4.6 · 150 mm), 80% aceto-
nitrile–water used as eluent, 3 mL/min) showed only
50% de.
Next, we used X-ray diffraction to verify that the
absolute configuration of the generated chiral carbon of
the product from (1R,2S)-trans-2-phenylcyclohexyl 2-(4-
fluorophenyl)glyoxylate 10()) was R (Fig. 1).
Figure 1. (a) Molecular structure of 10()) with atomic numbering and (b) stereoscopic view of 10()).

H. Itoh et al. / Bioorg. Med. Chem. 12 (2004) 3561–3567
3563
Once a novel method for the preparation of racemic 1
was developed, the single diastereomers 10()) and 10(+)
were treated in the same manner to obtain 1()) and
1(+).
OH
Si
LAH
HO
Si
OH
O
F
O
F
10
11
Analysis of 1()) and 1(+) by chiral HPLC (Chiralcell OJ
(4.6 · 250 mm), 3% ethanol–hexane used as eluent,
1.2 mL/min) showed >99% ee. We verified that the
absolute configuration of 1(+) was S by X-ray diffrac-
tion (Fig. 2).
OH
F
OH
MsCl
MsO
Si
N
N
Si
3
N
Pyridine
F
12
1
3. X-ray crystal structure
Scheme 3. Novel method for the preparation of 1.
The atom labeling and thermal ellipsoids of 10()) are
shown in Figure 1. The absolute configuration of C1 and
C2 atoms of the cyclohexane ring in 10()) were deter-
mined R and S, respectively, by starting material. As the
atomic configurations were standard, the configuration
at the C9 atom was determined to be R as shown in
Figure 1. The cyclohexane ring of 10()) takes the chair
conformation. The crystal was stabilized by intramo-
lecular hydrogen bonding between O19 and O20 to
enable the fractional crystallization of 10()).
As outlined in Scheme 3, the racemic 1 was produced by
reducing the ester 10 with lithium aluminum hydride in
tetrahydrofuran to give diol 11 in 70% yield, treating
diol 11 with methanesulfonyl chloride in pyridine to give
mesylate 12 in 90% yield, and reacting mesylate 12 with
1H-1,2,4-triazole sodium salt in N,N-dimethylforma-
mide. The resulting to afford racemic 1 was provided in
40% yield.
Figure 2. (a) Molecular structure of 1(+) with atomic numbering and (b) stereoscopic view of 1(+).

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H. Itoh et al. / Bioorg. Med. Chem. 12 (2004) 3561–3567
Table 1. Fungicidal activities of enantiomers
Compd no
Rhizoctonia solani
Sheath blight
(g/10a)
Pyricularia oryzae
Rice blast
(g/10a)
IC50 (ppm)
IC50 (ppm)
1())
1
0.016
0.042
0.54
25
25
0.95
1.25
33.5
100
100
1(+)
>100
>100
The atomic labeling and thermal ellipsoids of 1(+) are
shown in Figure 2. The configuration of 1(+) was
determined by observing and calculating the F (+)/F ())
ratios of Bijvoet pairs with the mean F value of each
independent reflection. The data are available as sup-
porting information. Based on the results, the stereo-
chemistry of 1(+) was determined to be S as that shown
in Figure 2. The crystal was stabilized by intramolecular
hydrogen bonding between O15 and N4.
6. Experimental
All melting points (mp) were uncorrected. IR was re-
1
corded on a Perkin Elmer 1600 spectrometer and H
NMR spectra were recorded on a Varian Gemini 200
spectrometer using tetramethylsilane as an internal
standard. MS were obtained on a JEOL JMS-D300
spectrometer and a VG Auto Spec M mass spectrome-
ter. TLC was performed on a plate precoated with a
0.25 mm-thick layer of silica gel (E. Merck), and the
spots were made visible by ultraviolet (UV) irradiation
or by spraying with a solution made of 25 g ammonium
molybdate and 1 g ceric sulfate in 500 mL of 10% sul-
furic acid followed by heating. Silica gel (350–250 mesh,
Yamamura Chemical Laboratories Co., Ltd) was used
for column chromatography and preparative TLC was
carried out on a plate precoated with a 2 mm-thick layer
of silica gel (E. Merck). The following abbreviations are
used hereafter: s, singlet; d, doublet; dd, doublet of
doublet; t, triplet; dt, doublet of triplet; q, quartet;
m, multiplet. Optical rotations were determined on a
JASCO DIP-370 digital polarimeter at 27 ꢁC at
the sodium D-line; the concentrations are reported
g/100 mL.
4. Fungicidal activities and discussion
The in vitro and in vivo antifungal activities of 1()),
1(+) and racemic 1 are shown in Table 1. The enantio-
mer 1()) was more potent than racemic 1 against both
Pyricularia oryzae and Rhizoctonia solani in vitro. In
contrast, the other enantiomer 1(+) showed over 10-fold
less activity than 1()) against both pathogens in vivo.
In the test of the fungicidal activity for rice blast and
sheath blight by submerged application, 1()) showed
almost the same efficacy as 1. On the other hand, 1(+)
showed no efficacy at the same treatment dose.
6.1. 2-Phenylcyclohexyl 2-(4-fluorophenyl)glyoxylate (9)
Azole fungicides such as imidazole and triazole have
been shown to inhibit the fungal biosynthesis of ergos-
terol, an important constituent of the fungal cell mem-
brane. A crucial step in ergosterol biosynthesis is the
14C-demethylation of lanosterol, mediated by the
cytochrome P450 monooxygenase enzyme.12
Oxalyl chloride (40.0 g, 0.31 mol) was added to a solu-
tion of 2-(4-fluorophenyl)glyoxylic acid (13.1 g,
78.0 mmol) in dichloromethane (100 mL) and stirred at
room temperature for 3 h. After evaporation the solvent
and dissolving the residue with acetonitrile (100 mL), the
solution was added to a solution of trans-2-phenylcy-
clohexanol (3.1 g, 17.6 mmol) in acetonitrile (50 mL),
stirred for 3 h at room temperature, poured into ice, and
extracted with ethyl acetate. The organic layer was wa-
shed with diluted hydrochloric acid, aqueous solution of
sodium hydrogencarbonate, and water, and dried over
magnesium sulfate. The solvent was evaporated to give
an oily residue, which was purified by column chroma-
tography (ethyl acetate–hexane, 1:10, v/v) to afford 3
(4.4 g, 77%) as colorless crystals (recrystallized from
diisopropyl ether), mp 66 ꢁC. IR (KBr) cmꢀ1: 3007,
2858, 1961, 1919, 1750, 1681, 1593, 1494, 1448, 1300,
1225. 1H NMR (200 MHz, CDCl3): d 1.30–2.31 (8H, m),
2.76 (1H, dt, J ¼ 3:9, 10.7 Hz), 5.41 (1H, dt, J ¼ 4:6,
10.7 Hz), 6.90 (2H, t, J ¼ 8:5 Hz), 7.16–7.40 (7H, m).
MS m=z: 326 (Mþ), 214, 160. Anal. Calcd for
C20H19FO3: C, 73.60; H, 5.87; F, 5.82. Found: C, 73.64;
H, 5.94; F, 5.74.
These results agree with the earlier contention that the
R-absolute configuration is the only enantiomer that can
fit sterically over the lanosterol skeleton and effectively
inhibit cytochrome P450 14C-demethylase.
5. Conclusion
We found a novel and efficient method to prepare sili-
con-containing triazolyl derivatives 1 via a Grignard
reaction with phenylglyoxylate. The optically active
enantiomers 1()) and 1(+) were synthesized by follow-
ing exactly the same procedure used to prepare the
racemic 1 with the use of (1R,2S)- and (1S,2R)-trans-2-
phenylcyclohexanols as a chiral auxiliary. The absolute
configuration of enantiomer 1(+) was determined by
X-ray crystallographic analysis. Comparison of the
antifungal activity of the enantiomers revealed that the
())-enantiomer with the R-absolute configuration was
far more potent than the (+)-enantiomer.
The same procedure was used to prepare optically active
enantiomers 9()) and 9(+) with NMR and MS spectra
identical to those of 9.

H. Itoh et al. / Bioorg. Med. Chem. 12 (2004) 3561–3567
3565
27
D
27
D
9()) 91%, ½aꢁ )9.3 (c 3.75, CHCl3); 9(+) 88%, ½aꢁ
single diastereomer 10 (531 mg, 1.3 mmol) in 46%. Mp
101 ꢁC. IR (KBr) cmꢀ1: 3477, 2950, 2862, 1713, 1602,
1506, 1450, 1381, 1250, 1197, 1113, 1092, 1016. 1H
NMR (200 MHz, CDCl3): d )0.13 (9H, s), 1.20–1.60
(7H, m), 1.70–1.95 (3H, m), 2.20–2.35 (1H, m), 2.69 (1H,
dt, J ¼ 3:7, 10.9 Hz), 3.67 (1H, s), 4.96 (1H, dt, J ¼ 4:4,
10.9 Hz), 6.68 (2H, t, J ¼ 8:6 Hz), 6.95–7.14 (7H, m).
MS m=z: 414 (Mþ), 211, 195, 121. Anal. Calcd for
C24H31FO3Si: C, 69.53; H, 7.54. Found: C, 69.82; H,
7.41.
+12.0ꢁ (c 2.75, CHCl3).
The following compound 7 was prepared similarly.
6.2. ())-8-Phenylmenthyl 2-(4-fluorophenyl)glyoxylate (7)
82%, mp 121–122 ꢁC. IR (KBr) cmꢀ1: 2900, 2853, 1954,
1898, 1700, 1678, 1597, 1500, 1445, 1416, 1330, 1225. 1H
NMR (200 MHz, CDCl3): d 0.93 (3H, d, J ¼ 8:6 Hz),
0.85–1.72 (7H, m), 1.30 (3H, s), 1.37 (3H, s), 2.08 (1H,
dt, J ¼ 4:8, 12.0 Hz), 5.01 (1H, dt, J ¼ 4:8, 12.0 Hz),
6.84–7.28 (7H, m), 8.01 (2H, dd, J ¼ 5:7, 10.0 Hz). MS
m=z: 382 (Mþ), 330, 193, 165. Anal. Calcd for
C24H27FO3: C, 75.37; H, 7.12; F, 4.97. Found: C, 75.51;
H, 7.21; F, 4.98.
The same procedure was used to prepare optically active
diastereomers 10()) and 10(+) with NMR and MS
spectra identical to those of 10.
6.6. (10R,20S,2R)-2-Phenylcyclohexyl 2-(4-fluorophenyl)-
2-hydroxy-3-trimethylsilylpropionate 10())
27
D
6.3. 2-Phenylcyclohexyl 2-(4-fluorophenyl)-2-hydroxy-3-
trimethylsilylpropionate (10)
50%, ½aꢁ )61.3 (c 3.15, CHCl3). Recrystallization from
ethanol solution gave colorless plates. The crystal used
has approximate dimensions of 0.5 · 0.2 · 0.2 mm. Data
were collected on a diffractometer, Rigaku AFC7R, and
corrected for Lorentz and polarization factors.
Absorption correction was not applied. The structure
was determined by a direct method with the program
SIR 92.13 The parameters refined include the coordinates
and anisotropic thermal parameters for all nonhydrogen
atoms. Most of the hydrogen atoms were found in the
difference map and the remaining hydrogen atoms were
calculated at ideal positions and refined in terms of
isotropic temperature factors. The final cycle of full-
matrix least-squares refinement was based on 1921
observed reflections ðF P 2rðF ÞÞ and converged with
R ¼ 0:035 and Rw ¼ 0:043. A Chebychev weighting
scheme was used.14 Crystal data and conditions of data
collection are summarized in Table 2. Tables of atomic
coordinates, thermal parameters, bond distances, bond
angles, and torsion angles are available as supporting
information.
A solution of trimethylsilylmethylmagnesium chloride in
diethyl ether (4.1 mL, 4.1 mmol) was added dropwise to
a solution of 9 (890 mg, 2.7 mmol) in diethyl ether
(5 mL) at )70 ꢁC and stirred for 1 h at the same tem-
perature. The reaction mixture was poured into ice and
extracted with ethyl acetate. The organic layer was wa-
shed with aqueous solution of ammonium chloride and
dried over magnesium sulfate. The solvent was evapo-
rated to give 10 (1.1 g, 98%) as diastereomixture (4:1).
The same procedure was used to prepare diastereomix-
tures of 10()) and 10(+) with NMR and MS spectra
identical to those of 10. Diastereomixture 10()) (3.5:1)
was obtained in 90% yield and diastereomixture 10(+)
(3.4:1) was obtained in 97% yield.
The following compound 8 was prepared similarly.
6.4. ())-8-Phenylmenthyl 2-(4-fluorophenyl)-2-hydroxy-3-
trimethylsilylpropionate (8)
6.7. (10S,20R,2S)-2-Phenylcyclohexyl 2-(4-fluorophenyl)-
2-hydroxy-3-trimethylsilylpropionate 10(+)
70%, oil. IR (neat) cmꢀ1: 3564, 3501, 2950, 2872, 1715,
1603, 1504, 1445, 1371, 1248, 1207, 1159, 1086, 1009. 1H
NMR (200 MHz, CDCl3): d )0.10 (9H, s), 0.82 (3H, d,
J ¼ 7:1 Hz), 0.70–2.15 (7H, m), 0.97 (3H, s), 1.06 (3H,
s), 4.79 (1H, dt, J ¼ 4:7, 11.8 Hz), 6.95 (2H, t,
J ¼ 8:5 Hz), 7.20–7.54 (7H, m). MS m=z: 470 (Mþ), 211,
121. Anal. Calcd for C28H39FO3Si: C, 71.45; H, 8.35; F,
4.04. Found: C, 71.12; H, 8.37; F, 4.13.
27
63%, ½aꢁ +64.4 (c 2.05, CHCl3).
D
6.8. 2-(4-Fluorophenyl)-3-trimethylsilylpropan-1,2-diol
(11)
Lithium aluminum hydride (75 mg, 2.0 mmol) was ad-
ded to a solution of 10 (414 mg, 1.0 mmol) in tetrahy-
drofuran (40 mL). After stirring for 1 h at 0 ꢁC, the
mixture was diluted with ethyl acetate (10 mL), metha-
nol (10 mL), and water (1 mL) in succession and filtered
through celite. The filtrate was concentrated to give a
solid and purified by column chromatography (ethyl
acetate–hexane, 1:4, v/v) to afford 11 (170 mg, 70%) as
colorless crystals (recrystallized from diisopropyl ether),
mp 50 ꢁC. IR (KBr) cmꢀ1: 3306, 2950, 2897, 2360, 1894,
1722, 1604, 1504, 1425, 1228, 1161, 1075, 1015. 1H
NMR (200 MHz, CDCl3): d )0.17 (9H, s), 1.14 (1H, d,
6.5. Resolution of (10R*,20S*,2R*)-2-phenylcyclohexyl
2-(4-fluorophenyl)-2-hydroxy-3-trimethylsilylpropionate
(10)
Diastereomixture 10 (1.18 g, 2.8 mmol) was dissolved in
hot ethanol (10 mL). After cooling, the resulting pre-
cipitates were collected by filtration to give a solid
(765 mg, 1.8 mmol). This solid was dissolved in ethanol
(7 mL) and recrystallized from the solution to afford a

3566
H. Itoh et al. / Bioorg. Med. Chem. 12 (2004) 3561–3567
Table 2. Summary of crystal data and intensity collections for 10())
The same procedure was used to prepare optically active
enantiomers 12()) and 12(+) with NMR and MS spec-
tra identical to those of 12. Enantiomers 12()) and 12(+)
were obtained in 90% and 84% yields, respectively.
Formula
C24H31O3FSi
414.6
Formula weight
Crystal color
Crystal description
Crystal system
Space group
Colorless
Prismatic
Monoclinic
C2
6.10. (RS)-2-(4-Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-
3-trimethylsilylpropan-2-ol (1)
ꢀ
a (A)
24.589(3)
6.934(1)
17.211(2)
126.394(8)
2362.3(6)
4
ꢀ
b (A)
ꢀ
c (A)
A mixture of 12 (1.43 g, 4.46 mmol) and 1H-1,2,4-
triazole sodium salt (900 mg, 8.9 mmol) in N,N-dimeth-
ylformamide (20 mL) was heated to 80 ꢁC for 2 h. The
reaction mixture was poured into ice and extracted with
ethyl acetate. The organic layer was washed with water
and dried over magnesium sulfate. The solvent was
evaporated to give a solid, which was purified by column
chromatography (ethyl acetate–hexane, 1:1, v/v) to af-
ford 1 (529 mg, 40%) as colorless crystals. The NMR
and MS spectra of 1 were identical to these reported in
the literature.1
b (deg)
3
ꢀ
V (A )
Z
Dc (g/cm3)
Absorption coef (cmꢀ1
Temperature (ꢁC)
Radiation
1.166
1.112
)
25
Cu Ka
(k ¼ 1:5418)
2h range of reflections for cell
determination (deg)
Scan mode
50–59
x–2h
2–136
2345
1921
26 range of data collection (deg)
No of unique reflections
No of reflections used for refinement
(F P 2rðF ÞÞ
The same procedure was used to prepare optically active
enantiomers 1()) and 1(+) with NMR and MS spectra
identical to those of 1.
R
Rw
0.035
0.043
6.11. (R)-2-(4-Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-
trimethylsilylpropan-2-ol 1())
J ¼ 14:7 Hz), 1.27 (1H, d, J ¼ 14:7 Hz), 1.85 (1H, b s),
2.70 (1H, b s), 2.58 (1H, d, J ¼ 11 Hz), 3.73 (1H, d,
J ¼ 11:0 Hz), 7.03 (2H, t, J ¼ 8:9 Hz), 7.39 (2H, dd,
J ¼ 5:5, 8.9 Hz). MS m=z: 224 (Mþ)18), 211, 195, 121.
Anal. Calcd for C12H19FO2Si: C, 59.47; H, 7.90. Found:
C, 59.24; H, 7.73.
27
40%, ½aꢁ )70.5 (c 3.75, CHCl3).
D
6.12. (S)-2-(4-Fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-
trimethylsilylpropan-2-ol 1(+)
27
D
The same procedure was used to prepare optically active
enantiomers 11()) and 11(+) with NMR and MS spec-
27%, ½aꢁ +70.1 (c 3.62, CHCl3). Recrystallization from
diisopropyl ether solution gave colorless plates. The
crystal used has approximate dimensions of
0.3 · 0.3 · 0.2 mm. Diffraction experiments and structure
determination were carried out using the method and
procedures described for 10()). The absolute configu-
ration of 1(+) was determined based on anomalous
scattering effects of the silicon atom. The final refine-
ment converged at R ¼ 0:050 and Rw ¼ 0:063. Crystal
data and conditions of data collection are summarized
in Table 3. Tables of atomic coordinates, thermal
parameters, bond distances, bond angles, and torsion
angles are available as supporting information.
tra identical to those of 11. Enantiomers 11()) and 11(+)
27
were obtained in 43%, ½aꢁ +4.7 (c 4.05, CHCl3) and
D
27
D
45%, ½aꢁ )3.2 (c 3.10, CHCl3) yields, respectively.
6.9. 2-(4-Fluorophenyl)-1-methanesulfonyloxy-3-trimeth-
ylsilylpropan-2-ol (12)
Methanesulfonyloxy chloride (720 mg, 6.3 mmol) was
added to a solution of 11 (1.26 g, 5.2 mmol) in pyridine
(15 mL) at 0 ꢁC. After stirring for 2 h at the same tem-
perature, the reaction mixture was poured into ice and
extracted with ethyl acetate. The organic layer was wa-
shed with aqueous solution of ammonium chloride and
dried over magnesium sulfate. The solvent was evapo-
rated to give a solid, which was purified by column
chromatography (ethyl acetate–hexane, 1:4, v/v) to af-
ford 12 (1.5 g, 90%) as colorless crystals (recrystallized
6.13. Antifungal activity
IC50s (50% inhibitory concentration) of the compounds
were determined by an agar dilution method using po-
tato dextrose agar medium (PDA). The agar medium
(10 mL) was poured into petri dishes containing 0.1 mL
of serial dilutions of the test compounds dissolved in
dimethyl sulfoxide containing 10% Tween 20 and was
solidified.
from diisopropyl ether), mp 115–116 ꢁC. IR (KBr) cmꢀ1
:
3493, 2950, 2895, 1908, 1722, 1736, 1605, 1510, 1425,
1340, 1248, 1159, 1097, 1064. 1H NMR (200 MHz,
CDCl3): d )0.17 (9H, s), 1.24 (1H, d, J ¼ 14:8 Hz), 1.38
(1H, d, J ¼ 14:8 Hz), 2.47 (1H, s), 2.91 (3H, s), 4.27 (2H,
s), 7.05 (2H, t, J ¼ 8:8 Hz), 7.41 (2H, dd, J ¼ 5:2,
8.8 Hz). MS m=z: 320 (Mþ), 211, 195, 121. Anal. Calcd
for C13H21FO4SSi: C, 48.73; H, 6.61; F, 5.93; S, 10.01.
Found: C, 48.58; H, 6.53; F, 5.86; S, 9.86.
The 4 mm mycelial disks of P. oryzae or R. solani were
then placed in center of the PDA plates, and measured
the mycelial growth rate between 24 and 48 h at 25 ꢁC to
determine the IC50s for these fungi.

H. Itoh et al. / Bioorg. Med. Chem. 12 (2004) 3561–3567
Table 3. Summary of crystal data and intensity collections for 1(+)
3567
placed around the base of each seedling. The seedlings
were then kept in a moist chamber (relative humidity:
100%) for 7 days at 25–27 ꢁC. The number of grams per
10 acres required to eradicate rice sheath blight
was determined after 7 days. The results are shown in
Table 1.
Formula
C14H20N3FOSi
293.4
Formula weight
Crystal color
Crystal description
Crystal system
Space group
Colorless
Prismatic
Orthorhombic
P21P21
11.666(2)
12.784(1)
10.933(1)
1630.5(3)
4
ꢀ
a (A)
ꢀ
b (A)
ꢀ
c (A)
3
ꢀ
Acknowledgements
V (A )
Z
Dc (g/cm3)
Absorption coef (cmꢀ1
Temperature (ꢁC)
Radiation
1.195
1.365
We are grateful to Dr. S. Sugai and Dr. T. Jojima, the
former director of our laboratory, for their encourage-
ment throughout this work.
)
25
Cu Ka (k ¼ 1:5418)
45–49
2h range of reflections for
cell determination (deg)
Scan mode
x–2h
2–100
3672
3628
References and notes
26 range of data collection (deg)
No of unique reflections
No of reflections used for refinement
ðF P 2rðF ÞÞ
1. Itoh, H.; Yoneda, R.; Tobitsuka, J.; Matsuhisa, T.;
Kajino, H.; Ohta, H.; Hayashi, N.; Takahi, Y.; Tsuda,
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Chem. 2002, 10, 4029.
R
Rw
0.050
0.063
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6.14. Preventive activity against rice blast by submerged
application
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Rice seedlings (variety Sachikaze) at the three-leaf stage
were flooded to a depth of 1 cm with water in pots and
then exposed to the test compound by mixing it into the
water. After keeping the seedlings in a greenhouse for
7 days, the rice seedlings were sprayed with a spore
suspension of the fungus P. oryzae and then kept in a
moist chamber (relative humidity: 100%) for 7 days at
25–27 ꢁC. The number of grams per 10 acres required to
eradicate rice blast was determined after 7 days. The
results are shown in Table 1.
10. Whitesell, J. K.; Chen, H. H.; Laurence, R. M. J. Org.
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6.15. Preventive activity against rice sheath blight by
submerged application
Rice seedlings (variety Sachikaze) at the three-leaf stage
were flooded to a depth of 1 cm with water in pots and
then exposed to the test compound by mixing it into the
water. After keeping the seedlings in a greenhouse for
7 days, 4–5 oat grains cultured with R. solani were