Practical Asymmetric Synthesis of (S)-MA20565, a Wide-Spectrum Agricultural Fungicide

Article abstract of DOI:10.1021/jo991271z

A practical asymmetric synthesis of a wide-spectrum agricultural fungicide, (S)-MA20565 (1), is described. The convergent synthesis was achieved starting from commercially available 3-(trifluoromethyl)aniline (7) in 44% overall yield through five steps and 2-bromobenzaldehyde (9) in 48% overall yield through four steps, respectively. (S)-O-[1-(3-Trifluoromethylphenyl)ethyl]hydroxylamine (2), a key intermediate of 1, was prepared via ruthenium(II)-catalyzed asymmetric transfer hydrogenation of 1-(3-trifluoromethylphenyl)ethanone (6) followed by chlorination using methanesulfonyl chloride and oxyamination using potassium acetohydroxamate with high level of stereocontrol.

Full text of DOI:10.1021/jo991271z

432
J . Org. Chem. 2000, 65, 432-437
P r a ctica l Asym m etr ic Syn th esis of (S)-MA20565, a Wid e-Sp ectr u m
Agr icu ltu r a l F u n gicid e
Ken Tanaka,* Manabu Katsurada,* Fumihiko Ohno, Yasushi Shiga, and Masatsugu Oda
Yokohama Research Center, Mitsubishi Chemical Corporation, 1000 Kamoshida-cho,
Aoba-ku, Yokohama, Kanagawa 227-8502, J apan
Miwa Miyagi, J un Takehara, and Kazuya Okano*
Tsukuba Research Center, Mitsubishi Chemical Corporation, 8-3-1 Chuo,
Ami, Inashiki, Ibaragi 300-0332, J apan
Received August 10, 1999
A practical asymmetric synthesis of a wide-spectrum agricultural fungicide, (S)-MA20565 (1), is
described. The convergent synthesis was achieved starting from commercially available 3-(trifluo-
romethyl)aniline (7) in 44% overall yield through five steps and 2-bromobenzaldehyde (9) in 48%
overall yield through four steps, respectively. (S)-O-[1-(3-Trifluoromethylphenyl)ethyl]hydroxylamine
(2), a key intermediate of 1, was prepared via ruthenium(II)-catalyzed asymmetric transfer
hydrogenation of 1-(3-trifluoromethylphenyl)ethanone (6) followed by chlorination using methane-
sulfonyl chloride and oxyamination using potassium acetohydroxamate with high level of stereo-
control.
In tr od u ction
didate, (S)-MA20565 (1), bearing an N-methylmethoxy-
iminoacetamide as a pharmacophore and a substituted
aldoxime ether side chain, that shows the potent fungi-
cidal activity against wide range of crop diseases.6 The
commercial importance of (S)-MA20565 has prompted us
to design and develop a practical asymmetric synthesis
of the compound.
Strobilurins A and B, a new class of antifungal
antibiotics, were first isolated from fermentation of
Strobilurus tenacellus.1 Anke et al. reported the fungi-
cidal activities and the mode of action of strobilurins A
and B to be respiratory inhibition of mitochondria.2 To
date, many studies have been performed with structural
modification of strobilurins.3 In these studies, Zeneca and
BASF groups independently reported the strobilurin
analogues ICIA55044 and BAS-490F5 as new class of
agricultural fungicides with wide fungicidal spectrum
and a new mode of action. These strobilurin variants
consist of structurally two modified regions: a pharma-
cophore and a side chain. ICIA5504 has a methoxyacrylic
acid methyl ester as a pharmacophore and a substituted
pyrimidine ring side chain.4 BAS-490F has a methoxy-
iminoacetic acid methyl ester as a pharmacophore and a
substituted phenoxy methyl side chain.5 Recently, Mit-
subishi Chemical group has reported a promising can-
Resu lts a n d Discu ssion
The target compound 1, which has two oxime ethers
and one chiral center at the benzylic position, would be
constructed from two key intermediates, an (S)-oxyamine
2 and an amide 3, as shown in Scheme 1. The key
transformation in the synthesis is the practical asym-
metric synthesis of 2. The (S)-oxyamine 2 was efficiently
prepared via enantioselective hydrogenation of 1-(3-
trifluoromethylphenyl)ethanone (6) followed by chlorina-
tion and oxyamination with inversion of the chiral center
twice. For the present synthesis, we practically improved
Noyori’s ruthenium(II)-catalyzed asymmetric transfer
hydrogenation7 using formic acid and triethylamine.7d
Efficient chlorination, using methanesulfonyl chloride
and pyridine in DMF/n-heptane, and oxyamination using
potassium acetohydroxamate prepared in situ from in-
expensive hydroxylamine hydrochloride and acetic an-
(1) (a) Anke, T.; Oberwinkler, F.; Steglich, W.; Schramm, G. J .
Antibiot. 1977, 30, 806. (b) Schramm, G.; Steglich, W.; Anke, T.;
Oberwinkler, F. Chem Ber. 1978, 111, 2779. (c) Anke, T.; Schramm,
G.; Schwalge, B.; Steffan, B.; Steglich, W. Liebigs Ann. Chem. 1984,
1616.
(2) (a) Anke, T.; Hecht, H. J .; Schramm, G.; Steglich, W. J . Antibiot.
1979, 32, 1112. (b) Trowitsch, W.; Reifenstahl, G.; Wray, V.; Gerth, K.
J . Antibiot. 1980, 33, 1480. (c) Becker, W. F.; J agow, G.; Anke, T.;
Steglich, W. FEBS Lett. 1981, 132, 329. (d) Xia, D.; Yu, C.-A.; Kim,
H.; Xia, J .-Z.; Kachurin, A. M.; Zhang, L.; Yu, L.; Deisenhofer, J . Science
1997, 277, 60.
(6) Oda, M.; Katsurada, M.; Shiga, Y.; Ohno, F.; Tanaka, K.; Tomita,
Y.; Okano, K.; Shirasaki, M.; Takehara, J .; Iwane, H. WO 98/23582,
1998.
(3) Reviews: (a) Clough, J . M.; Godfrey. C. R. A. In The Strobilurin
Fungicides; Hutson, D. H.; Miyamoto, J ., Ed.; Wiley: Chichester, 1998;
p 109. (b) Sauter, H.; Steglich, W.; Anke, T. Angew. Chem., Int. Ed.
Engl. 1999, 38, 1328.
(4) (a) Godfrey, C. R. A.; Streeting, I.; Cheetham, R. EP-A 382,375,
1989. (b) Godfrey, C. R. A.; Anthony, V. M.; Clough, J . M.; Godfrey. C.
R. A. Brighton Crop Protection Conference-Pests and Diseases; British
Crop Protection Council: Farnham, U.K., 1992; Vol. 1, p 435.
(5) (a) Wenderoth, B.; Rentzea, C.; Ammermann, E.; Pommer, E.
H.; Steglich, W.; Anke, T EP-A 253, 213, 1986. (b) Ammermann, E.;
Lorenz, G.; Schelberger, K.; Wenderoth, B.; Sauter, H.; Rentzea, C.
Brighton Crop Protection Conference-Pests and Diseases; British Crop
Protection Council: Farnham, UK, 1992; Vol. 1, 403.
(7) (a) Hashiguchi, S.; Fujii, A.; Takehara, J .; Ikariya, T.; Noyori,
R. J . Am. Chem. Soc. 1995, 117, 7562. (b) Takehara, J .; Hashiguchi,
S.; Fujii, A.; Inoue, S.; Ikariya, T.; Noyori, R. J . Chem. Soc., Chem.
Commun. 1996, 233. (c) Gao, J .-X.; Ikariya, T.; Noyori, R. Organome-
tallics 1996, 15, 1087. (d) Fujii, A.; Hashiguchi, S.; Uematsu, N.;
Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1996, 118, 2521. (e) Uematsu,
N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc.
1996, 118, 4916. (f) Haack, K.-J .; Hashiguchi, S.; Fujii, A.; Ikariya, T.;
Noyori, R. Angew. Chem., Int. Ed. Engl. 1997, 36, 285. (g) Hashiguchi,
S.; Fujii, A.; Haack, K.-J .; Matsumura, K.; Ikariya, T.; Noyori, R.
Angew. Chem., Int. Ed. Engl. 1997, 36, 288. (h) Matsumura, K.;
Hashiguchi, S.; Ikariya, T.; Noyori, R. J . Am. Chem. Soc. 1997, 119,
8738. (i) Noyori, R.; Hashiguchi, S. Acc. Chem. Res. 1997, 30, 97.
10.1021/jo991271z CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/22/1999

Asymmetric Synthesis of (S)-MA20565
J . Org. Chem., Vol. 65, No. 2, 2000 433
Sch em e 1
Sch em e 3
Ta ble 1. Asym m etr ic Tr a n sfer Hyd r ogen a tion of 6 w ith
F or m ic Acid a
Sch em e 2
HCO2H
(equiv)
Et3N
(equiv) (°C)
T
time yieldb
eeb
(%)
entry
S/C
(h)
(%)
1c
2c
200
500
11.5
11.5
4.6
4.6
25
25
24
25
46
77
24
30
66
8
37
95
99
96
94
hydride were developed with high level of stereocontrol.
The synthetic methods will be described in detail in this
paper.
93
95
93
91
3
4
1000
5000
1.05
1.05
1.05
1.05
25
50
P r ep a r a tion of 1-(3-Tr iflu or om eth ylp h en yl)eth a -
n on e (6). A Grignard reaction of aryl bromide and acetic
anhydride is one of the practical choice for the prepara-
tion of acetophenone derivatives.8 However, this reaction
could not be applied to the synthesis of 6 due to high
explosibility of a Grignard reagent prepared from 3-bro-
mobenzotrifluoride.9 Beech reaction10 was the method of
choice because of its safe operation and the low cost of
3-(trifluoromethyl)aniline (7).11 Thus, the diazonium salt
of 7 was treated with acetaldoxime in the presence of
AcONa and CuSO4 followed by treatment with aqueous
HCl to give 6 in 62% yield (Scheme 2).
P r ep a r a tion of (S)-O-[1-(3-Tr iflu or om eth ylp h e-
n yl)eth yl]h yd r oxyla m in e (2). To access an (S)-alcohol
5, Noyori’s ruthenium(II)-catalyzed asymmetric transfer
hydrogenation of 1-(3-trifluoromethylphenyl)ethanone (6)
was examined from the practical point of view such as
no need of an expensive high-pressure autoclave, safeness
of operations, low cost of catalyst, and getting high optical
purity.7
In the first attempt, i-PrOH was used as the hydrogen
source.7a To a solution of the ruthenium catalyst 87f
[substrate/catalyst (S/C) mole ratio ) 500], i-PrOH, and
KOH was added the ketone 6, and the resulting mixture
(0.66 M concentration of 6) was stirred at reduced
pressure (45-55 mmHg) to give 5 in 99% yield with 88%
ee (Scheme 3). As the reverse reaction with acetone
caused the decline of the yield and the optical purity of
5, in the reaction at atmospheric pressure, the employ-
ment of lower concentration (0.1 M) gave 5 in higher yield
(up to 97%) and optical purity (90-91% ee). On the other
hand, the employment of higher concentration (1 M) gave
a
b
The ketone 6 (10 g) was used. Determined by GC. c HCO2H-
Et3N (5:2) azeotrope was used.
5 in lower yield (<94%) and optical purity (88-89% ee).12
The removal of acetone at reduced pressure could raise
the yield of 5 and keep the optical purity of 5; however,
this operation was not practical due to small difference
of boiling point between acetone and i-PrOH.
To achieve the hydrogenation in higher concentration,
formic acid was examined as hydrogen source to avoid
reverse reaction.7f Although the use of triethylammonium
formate was attractive on the point of the optical purity
(94% ee), the reaction rate was very low (Table 1, entry
1). A detailed investigation of the time-course of the
alcohol formation revealed the induction period before
the main acceleration of the reaction (Table 1, entry 2).
We found that a slight excess formic acid to the substrate
was sufficient to complete the reaction, and excess base
against the formic acid is necessary to keep high reaction
rate (Table 1, entry 3). Under the optimum reaction
conditions, the reaction completely proceeded under S/C
) 5000 to give 5 in 96% yield with 91% ee (Table 1, entry
4). Direct fractional distillation of the reaction mixture
could be employed to give pure 5 and triethylamine,
which could be reused.
A direct amination of the (S)-alcohol 5 with NH2Cl13
or NH2OSO3H14 was examined, but the desired (S)-
oxyamine 2 was not obtained at all. Therefore, two-step
operations were examined via a (R)-chloride 4. The
preparation of 4 from 5 was investigated as summarized
in Table 2, using enantiopure 5 prepared by lipase-
catalyzed transesterification with vinyl laurate using
TOYOZYME LIP (Pseudomonas sp.). The use of SOCl2
(8) Newman, M. S.; Booth, W. T., J r. J . Am. Chem. Soc. 1954, 76,
154.
(9) (a) Renoll, M. W. J . Am. Chem. Soc. 1946, 68, 1159 (b) Prout. F.
S.; Cason, J .; Ingersoll, A. W. J . Am. Chem. Soc. 1948, 70, 298. (c)
Vingiello, F. A.; Buese, G. J .; Newallis, P. E. J . Org. Chem. 1958, 23,
1139.
(10) Beech, W. F. J . Chem. Soc. 1954, 1297.
(11) Aldrich catalog (1998-1999, J apan): 3-bromobenzotrifluoride;
11 000 yen (100 g), 3-(trifluoromethyl)aniline; 4900 yen (100 g).
(12) Recently, asymmetric transfer hydrogenation of 6 was improved
up to 97% ee by chiral rhodium complex. Murata, K.; Ikariya, T.;
Noyori, R. J . Org. Chem. 1999, 64, 2186.
(13) Truitt, P.; Long, L. M.; Mattison, M. J . Am. Chem. Soc. 1948,
70, 2829.
(14) Wyss, H.; Mettler, H. P.; Previdoli, F. EP 341,693, 1989.

434 J . Org. Chem., Vol. 65, No. 2, 2000
Tanaka et al.
Sch em e 5a
Ta ble 2. Ch lor in a tion of 5 in Va r iou s Rea ction
Con d ition s
time
(h)
yielda
(%)
eea
(%)
entry
conditions
1b
2c
3b
4b
5b
6b
7b
SOCl2, Py, DMF (cat), t-BuOMe
MsCl, Py
MsCl, Py, DMF
8
24
87
99
3 (24) 88 (99) 90 (86)
74
96
MsCl, Py, NMP
24
15
8
8
96
7
86
96
96
96
MsCl, Py, DMF/i-Pr2O (2:5)
MsCl, Py, DMF/i-Pr2O (1:50)
MsCl, Py, DMF/n-Heptane (2:5)
3
96
a
b
Determined by GC. To a solution of 5 (1.0 g, >99% ee),
pyridine (1.1 equiv), and solvent (50 mL) was added SOCl2 or MsCl
(1.1 equiv) at 0 °C, and the mixture was stirred at 25 °C. c Pyridine
(5.0 mL) was used.
a
Sch em e 4a
Key: (a) ethylene glycol, p-toluenesulfonic acid, toluene, reflux,
97%; (b) (1) Mg, THF, (2) diethyl oxalate, toluene/THF, <-2 °C,
(3) aqueous HCl, 0-8 °C, pH 6-7, 83%; (c) CH3ONH2‚HCl, N,N-
diethylaniline, EtOH, 25 °C; (d) (1) 40% aqueous CH3NH2, 25 °C,
(2) crystallization from n-heptane/N,N-diethylaniline, 64% from
11 (E/ Z ) 98:2).
with 1.1 equiv of methanesulfonyl chloride and 1.1 equiv
of pyridine in DMF/n-heptane [1:9 (v/v)] to give the (R)-
chloride 4 in 96% yield with 88% ee. The (R)-chloride 4
was treated with n-Bu4NBr and potassium acetohydrox-
amate prepared in situ from hydroxylamine hydrochlo-
ride, Na2CO3, acetic anhydride, and KOH followed by the
treatment with aqueous HCl to give the crude (S)-
oxyamine 2. The crude 2 was purified by distillation to
give 2 in 80% yield from 4 with >98% purity and 86%
ee. Furthermore, the enantioenriched 2 (86% ee) could
be purified by the crystallization with L-tartaric acid from
THF/i-Pr2O to give an L-tartaric acid salt of 2 in 70% yield
with >99% ee.15
a
Key: (a) HCO2H, Et3N, 8 (S/C ) 1900), 50 °C, 98%, 91% ee;
(b) MsCl, Py, DMF/n-heptane [1:9 (v/v)], 25 °C, 96%, 88% ee; (c)
Na2CO3, Ac2O, KOH, EtOH/H2O, 25 °C; (d) (1) n-Bu4NBr, 70 °C,
(2) concd HCl, 70 °C, (3) neutralization and distillation, 80% from
4, 86% ee; (e) crystallization with L-tartaric acid from THF/i-Pr2O,
70%, >99% ee.
P r ep a r a tion of Am id e 13. An amide 13 was prepared
from 2-bromobenzaldehyde (9) in three steps as shown
in Scheme 5. The aldehyde 9 was treated with ethylene
glycol in the presence of p-toluenesulfonic acid employing
azeotropic dehydration followed by distillation to give an
acetal 10 in 97% yield. A Grignard reagent prepared from
10 was added to a solution of diethyl oxalate and toluene
at below -2 °C followed by hydrolysis with aqueous HCl
at 0-8 °C (pH 6-7) to give a crude ketoester 11 in 83%
yield. The oxime ether formation from 11 was investi-
gated with methoxylamine hydrochloride and base. It
was consequently found that base was crucial for the
success of this transformation. The best base, by far, was
N,N-diethylaniline, which could minimize the deprotec-
tion of acetal. Thus, the crude ketoester 11 was treated
with 1.5 equiv of methoxylamine hydrochloride in the
presence of 1.65 equiv of N,N-diethylaniline at 25 °C for
24 h to generate an oxime ether 12 (E/Z ) 86:14). The
oxime ether 12 was subsequently treated with 40%
aqueous CH3NH2 without isolation. After distillation of
methanol, the crude mixture was crystallized by the
addition of n-heptane and water to give 13 in 64% yield
and pyridine gave 4 in modest yield and optical purity
(87%, 74% ee; Table 2, entry 1). On the other hand, the
use of methanesulfonyl chloride in pyridine increased the
yield and optical purity of 4 (99%, 96% ee; Table 2, entry
2). When the chlorination was carried out in DMF, the
amount of pyridine could be reduced to 1.1 equiv, but the
optical purity of 4 was gradually decreased during the
reaction period (Table 2, entry 3). The use of 1-methyl-
2-pyrrolidinone (NMP) in place of DMF decreased the
reaction rate (Table 2, entry 4). To avoid the racemization
of 4, the less polar solvents which hardly dissolve
pyridine hydrochloride was partially employed in place
of DMF. Thus, the chlorination was carried out in DMF/
i-Pr2O [2:5 (v/v)] to give 4 in 96% yield and 96% ee along
with higher reaction rate (Table 2, entry 5). Further
reduction of the amount of DMF [DMF/i-Pr2O ) 1:50 (v/
v)] decreased the reaction rate (Table 2, entry 6). Finally,
the use of DMF/n-heptane [2:5 (v/v)] showed the highest
reaction rate, which allowed the simple operations and
low load of waste treatments (Table 2, entry 7).
The (S)-oxyamine 2 was prepared from 6 in a large
scale as shown in Scheme 4. To a solution of the
ruthenium catalyst 8 (S/C ) 1900), 1.09 equiv of formic
acid, and 1.05 equiv of triethylamine was added the
ketone 6, and the solution was stirred at 50 °C for 27 h.
The resulting solution was distilled to give the (S)-alcohol
5 in 98% yield with 91% ee. The (S)-alcohol 5 was treated
(15) Though the resolution of 2 with D-tartaric acid in MeOH/H2O
was more effective than L-tartaric acid in THF/i-Pr2O, L-tartaric acid
was selected due to higher cost of D-tartaric acid. Aldrich catalog
(1998-1999, J apan): D-tartaric acid; 7800 yen (99% ee, 100 g),
L-tartaric acid; 2700 yen (99% ee, 500 g).

Asymmetric Synthesis of (S)-MA20565
J . Org. Chem., Vol. 65, No. 2, 2000 435
Sch em e 6a
L-tartaric acid followed by condensation with the amide
13. This method is highly attractive for a large-scale
preparation of 1 and is expected to contribute to the
development of this novel agricultural fungicide because
of the simple operations and the use of inexpensive
reagents.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points were uncorrected. 1H
and 13C NMR spectra were collected at 300 MHz. Reactions
and purities were determined by HPLC [column: Inertsil ODS-
2, column temperature 40 °C, eluent: MeOH/H2O (75:25); 1.0
mL/min, detect: 254 nm] or GC (column: DB-1; 0.25 mm ×
25 m, detector: FID, carrier gas: He) using biphenyl as an
internal standard unless otherwise noted. Chiral HPLC were
run with CHIRALCEL OJ column [eluent: n-hexane/i-PrOH
(80:20); 1.0 mL/min, detect: 220 nm]. Chiral GC were run with
CHROMPACK Cyclodextrin-â-236M-19 column (0.25 mm ×
50 m, detector: FID, carrier gas: He). Specific rotations were
recorded on a J ASCO DIP-370 polarimeter in the indicated
solvent. All reagents were plant grade and used without
further purification. Formic acid (purity >99%) was purchased
from BASF AG. TOYOZYME LIP was purchased from TOY-
OBO Co. The ruthenium catalyst (8)7f and (()-1-(3-trifluorom-
ethylphenyl)ethanol9 were prepared according to the literature.
1-(3-Tr iflu or om eth ylp h en yl)eth a n on e (6). To a mixture
of 3-(trifluoromethyl)aniline (7) (20.0 g, 0.124 mol), H2O (60
mL), and concentrated HCl (32.0 g, 0.325 mol) was added
NaNO2 (9.4 g, 0.136 mol) at -5-0 °C, and the mixture was
stirred at -5 to 0 °C for 20 min. The resulting mixture was
added to a solution of acetaldoxime (14.8 g, 0.251 mol), CuSO4
(6.6 g, 41 mmol), and AcONa‚3H2O (90.0 g, 0.661 mol) at 0-10
°C, and the mixture was stirred at 10-15 °C for 1.5 h. To the
resulting mixture was added concentrated HCl (55 mL), and
the mixture was refluxed for 2 h. The mixture was cooled to
25 °C and extracted with n-heptane (20 mL). The organic layer
was separated and washed with water. The solvent was
removed under reduced pressure, and the residue was purified
by distillation to give 6 (14.5 g, 77.1 mmol, purity >98% by
GC, 62% yield) as a colorless liquid: bp 96-99 °C/23 mmHg
a
Method A: AcOH/H2O [1:2 (v/v)], 2 (86% ee), 94% from 13,
86% ee. Method B: AcOH/H2O [1:2 (v/v)], L-tartaric acid salt of 2
(>99% ee), 96% from 13, >99% ee.
with >99% purity and high E/Z isomer ratio (E/Z ) 98:
2).16 In this process, N,N-diethylaniline was highly ef-
ficient as not only the base but also the crystallization
solvent, which could selectively dissolve the (Z)-amide
(Z)-13. The use of diethyl acetal instead of 1,3-dioxolane
as the protective group showed the complete decomposi-
tion of the acetal group in the treatment with methoxyl-
amine hydrochloride. The use of 1,3-dioxane, which is
more tolerable than 1,3-dioxolane in this acidic reaction
condition, showed lower E/Z isomer ratio (90:10) of the
amide 3 after crystallization.
Con d en sa tion of (S)-Oxya m in e 2 a n d Am id e 13.
The condensation of the (S)-oxyamine 2 and the amide
13 was investigated using various acids. In the presence
of strong acids, such as HCl or H2SO4, decomposition of
a condensation product 1 was significantly occurred. On
the other hand, the use of acetic acid could minimize the
decomposition of 1. Furthermore, it was found that the
addition of water to this reaction fairly accelerated the
reaction rate and could directly crystallize 1 from the
reaction mixture. Thus, the amide 13 (E/Z ) 98:2) and
1.07 equiv of the (S)-oxyamine 2 (86% ee) was treated in
acetic acid/H2O [1:2 (v/v)] and the crystallization was
directly carried out from the reaction mixture followed
by washing with hot water to give (S)-MA20565 (1) in
94% yield from 13 with >98% purity (E/ Z > 99.5:0.5)
and 86% ee. In this reaction, the equilibration of a (Z)-
aldoxime ether and an (E)-aldoxime ether was observed,17
however, the (E)-aldoxime ether was selectively crystal-
lized from this reaction mixture to give 1 in high E/Z
isomer ratio (E/ Z > 99.5:0.5).18 Alternatively, the amide
13 (E/ Z ) 98:2) and 1.02 equiv of L-tartaric acid salt of
2 (>99% ee) was treated in acetic acid/H2O [1:3 (v/v)],
and the crystallization was directly carried out from the
reaction mixture followed by washing with hot water to
give 1 in 96% yield from 13 with >98% purity (E/ Z >
99.5:0.5) and >99% ee (Scheme 6).
(lit.19 bp 198-200 °C); IR (neat) 1685, 1327, 1119 cm-1
;
1H
NMR (CDCl3) δ 2.61 (3H, s), 7.58 (1H, t, J ) 7.8 Hz), 7.78
(1H, d, J ) 7.8 Hz), 8.10 (1H, d, J ) 7.8 Hz), 8.17 (1H, s); 13
C
NMR (CDCl3) δ 26.48, 123.69, 125.04, 129.28, 129.44, 131.19,
131.44, 137.54, 196.55.
(S)-1-(3-Tr iflu or om et h ylp h en yl)et h a n ol (5): i-P r OH/
KOH Meth od . The ketone 6 (50.0 g, 0.266 mol) and 0.1 M
KOH/i-PrOH solution (15 mL, 1.5 mmol) was added to a
solution of i-PrOH (400 mL) and the ruthenium catalyst 8
(0.339 g, 0.532 mmol), and the resulting solution was stirred
at 25 °C and 45-55 mmHg for 5 h. The yield of 5 determined
by GC was 99%, and the optical purity of 5 determined by
chiral GC was 88% ee.
(S)-1-(3-Tr iflu or om et h ylp h en yl)et h a n ol (5): HCO2H/
Et3N Meth od . Formic acid (134 g, purity >99%, 2.91 mol) was
added to triethylamine (282 g, 2.79 mol) by cooling with an
ice bath. To the solution was added 6 (500 g, 2.66 mol) and a
DMF (7.0 mL) solution of the ruthenium catalyst 8 (0.891 g,
1.40 mmol), and the resulting solution was stirred at 50 °C
for 27 h. The resulting solution was distilled, and the fraction
boiling at 87-94 °C/11 mmHg was collected to give 5 (498 g,
purity >98% by GC, 2.62 mol, 98% yield, 91% ee by chiral GC)
as a colorless liquid.
Su m m a r y
In conclusion, an asymmetric synthesis of enantioen-
riched (S)-MA20565 (1) was achieved starting from
commercially available 3-(trifluoromethyl)aniline (7) and
2-bromobenzaldehyde (9) in an overall yield of 44% and
48%, respectively, with an enantiomeric excess of 86%.
The enantiopure 1 was also synthesized by the crystal-
lization of the enantioenriched (S)-oxyamine 2 with
(S)-1-(3-Tr iflu or om eth ylp h en yl)eth a n ol (5): Lip a se-
Ca ta lyzed Resolu tion . A mixture of (()-1-(3-trifluorometh-
ylphenyl)ethanol (300 g, 1.58 mol), TOYOZYME LIP (100 g),
vinyl laurate (252 g, 1.11 mol), and i-Pr2O (1000 mL) was
stirred at 25 °C for 5 h. The reaction mixture was filtered and
concentrated in vacuo. The residue was extracted with MeOH/
H2O [7:1 (v/v), 1000 mL] twice, and MeOH was removed at
(16) N,N-Diethylaniline and n-heptane could be recycled by frac-
tional distillation of the filtrate.
(17) E/Z isomer ratio of the aldoxime ether group of 1 in the solution
of acetic acid/H2O [2:1 (v/v)] was 95:5.
(18) (Z)-Ketoxime ethers were not detected at all by HPLC.
(19) Corse, J . W.; J ones, R. G.; Soper, Q. F.; Whitehead, C. W.;
Behrens, O. K. J . Am. Chem Soc. 1948, 70, 2837.

436 J . Org. Chem., Vol. 65, No. 2, 2000
Tanaka et al.
reduced pressure. The lower organic layer was separated and
distilled through a Vigreux distilling column, and the fraction
boiling at 73-74 °C/3.2 mmHg was collected to give pure 5
(103 g, purity >99% by GC, 0.542 mol, 34% yield, >99% ee by
(3H, d, J ) 6.6 Hz), 4.72 (1H, q, J ) 6.6 Hz), 5.30 (2H, br),
7.44-7.56 (3H, m), 7.60 (1H, s); 13C NMR (CDCl3) δ 21.73,
82.06, 123.04, 124.20, 124.43, 128.98, 129.67, 130.88, 144.50.
Anal. Calcd for C9H10F3NO; C, 52.69; H, 4.91; N, 6.83. Found:
C, 52.41; H, 4.62; N, 6.86.
chiral GC) as colorless liquid: [R]22 -27.9 (c 1.64, CH3OH,
D
>99% ee) [lit.20 [R]22D -18.0 (c 1.67, CH3OH, 66% ee)]; IR (neat)
2-(2-Br om op h en yl)-1,3-d ioxola n e (10).21 A solution of 9
(463 g, 2.50 mol), p-toluenesulfonic acid monohydrate (4.76 g,
0.025 mol), ethylene glycol (310 g, 4.99 mol), and toluene (2500
mL) was refluxed for 9 h employing azeotropic dehydration.
After the solution was cooled to 25 °C, aqueous NaHCO3 was
added, and the organic layer was separated and washed with
water. The solvent was removed under reduced pressure
followed by distillation to give 10 (557 g, purity >99% by GC,
2.43 mol, 97% yield) as colorless liquid: bp 126-127 °C/5.0
1
3336, 1325, 1117 cm-1; H NMR (CDCl3) δ 1.46 (3H, d, J )
6.6 Hz), 2.73 (1H, br), 4.89 (1H, q, J ) 6.6 Hz), 7.40-7.52 (3H,
m), 7.61 (1H, m); 13C NMR (CDCl3) δ 25.24, 69.73, 122.17,
124.16, 124.19, 128.79, 128.90, 130.75, 146.75.
(R)-1-Ch lor o-1-(3-tr iflu or om eth ylp h en yl)eth a n e (4). To
a solution of 5 (100 g, purity >98% by GC, 0.526 mol, 91% ee
by chiral GC), pyridine (45.8 g, 0.579 mol), DMF (25 mL), and
n-heptane (225 mL) was added methanesulfonyl chloride (66.3
g, 0.579 mol), keeping the temperature below 5 °C, and the
resulting mixture was stirred at 25 °C for 9 h. The mixture
was washed with 1 M aqueous HCl, 5% aqueous NaHCO3, and
20% aqueous NaCl. The solvent was removed under reduced
pressure to give 4 (110 g, purity 96% by GC, 0.506 mol, 96%
yield, 88% ee by chiral GC) as a pale yellow liquid. An
analytically pure sample was obtained by fractional distillation
1
mmHg; IR (neat) 2887, 1084 cm-1; H NMR (CDCl3) δ 4.00-
4.14 (4H, m), 6.08 (1H, s), 7.16-7.22 (1H, m), 7.28-7.34 (1H,
m), 7.53-7.60 (2H, m); 13C NMR (CDCl3) δ 65.50, 102.64,
122.98, 127.47, 127.90, 130.67, 133.00, 136.70.
Eth yl 2-[2-(1,3-Dioxola n -2-yl)p h en yl]-2-oxoa ceta te (11).
To a mixture of THF (1080 mL) and Mg (58.0 g, 2.39 mol) were
added a Grignard reagent of 10 prepared from Mg (3.05 g,
0.125 mol), THF (57 mL), 10 (28.5 g, 0.124 mol), and I2 (0.1 g)
at 20-24 °C and subsequently 10 (542 g, 2.36 mol) at 35-45
°C. The resulting mixture was stirred at 67-68 °C for 1 h
followed by cooling to 25 °C. The mixture was added to a
solution of toluene (3020 mL) and diethyl oxalate (725 g, 4.96
mol) below -2 °C, and the mixture was stirred at 5-8 °C for
1 h. The resulting mixture was added to a solution of
concentrated aqueous HCl (140 g) and H2O (1400 mL) at 0-8
°C, and the organic layer was separated and washed with
aqueous NaHCO3 and 20% aqueous NaCl. The solvent and
excess diethyl oxalate were removed under reduced pressure
to give crude 11 (613 g, 2.06 mol, purity 84% by GC, 83% yield)
as yellow oil, which was used in the next step without further
purification. An analytically pure sample was obtained by
recrystallization from MeOH as a white crystalline solid: mp
as colorless liquid: bp 68-69 °C/8.0 mmHg; [R]22 +48.7 (c
D
0.930, CHCl3, 88% ee); IR (neat) 1325, 1120 cm-1
;
1H NMR
(CDCl3) δ 1.85 (3H, d, J ) 6.9 Hz), 5.10 (1H, q, J ) 6.9 Hz),
7.44-7.62 (3H, m), 7.67 (1H, s); 13C NMR (CDCl3) δ 21.73,
82.06, 123.04, 124.20, 124.43, 128.98, 129.67, 130.88, 144.50.
Anal. Calcd for C9H8ClF3: C, 51.82; H, 3.87. Found: C, 51.72;
H, 3.52.
(S )-O-[1-(3-Tr iflu or om e t h ylp h e n yl)e t h yl]h yd r oxyl-
a m in e (2). To a mixture of H2O (75 mL), EtOH (75 mL), and
Na2CO3 (138 g, 1.30 mol) was added hydroxylamine hydro-
chloride (80.4 g, 1.16 mol), and the resulting mixture was
stirred at 35 °C for 20 min. To the mixture were added acetic
anhydride (132 g, 1.29 mol) and subsequently EtOH (100 mL),
and the resulting mixture was stirred at 40 °C for 2 h. To the
mixture were added 95% solid KOH (84.9 g, 1.44 mmol) and
n-Bu4NBr (1.5 g, 4.65 mmol), and subsequently a solution of
4 (120 g, purity 96% by GC, 0.553 mol, 88% ee by chiral GC)
and EtOH (50 mL), and the resulting mixture was stirred at
70 °C for 6 h. After the mixture was cooled to 0 °C, concen-
trated HCl (420 g, 4.26 mol) was added to the mixture, and
the resulting mixture was stirred at 50 °C for 2 h. After the
mixture was cooled to 25 °C, H2O (120 mL) and n-heptane (100
mL) were added to the mixture, and the organic layer was
removed. The separated water layer was adjusted at pH 7 with
aqueous NaOH and re-extracted with n-heptane (180 mL). The
organic layer was separated and washed with H2O and brine.
The solvent was removed under reduced pressure followed by
distillation to give 2 (93.0 g, purity 98% by GC, 0.444 mol,
80% yield from 4, 86% ee by chiral GC) as a colorless liquid
boiling at 59.5-61 °C/2.0 mmHg.
45-46 °C; IR (neat) 2981, 1732, 1707, 1196 cm-1 1H NMR
;
(CDCl3) δ 1.37 (3H, t, J ) 7.2 Hz), 3.80-3.98 (4H, m), 4.37
(2H, q, J ) 7.2 Hz), 7.41-7.61 (4H, m); 13C NMR (CDCl3) δ
14.00, 62.38, 64.64, 101.65, 126.67, 128.84, 129.37, 131.85,
134.34, 138.91, 161.82, 188.13. Anal. Calcd for C13H14O5; C,
62.39; H, 5.64. Found: C, 62.01; H, 5.61.
(E)-2-[2-(1,3-Dioxola n -2-yl)p h en yl]-2-m eth oxyim in o-N-
m eth yla ceta m id e [(E)-13] a n d (Z)-2-[2-(1,3-Dioxola n -2-
yl)p h en yl]-2-m eth oxyim in o-N-m eth yla ceta m id e [(Z)-13].
A solution of crude 11 (35.8 g, purity 84% by GC, 0.120 mol),
N,N-diethylanilline (29.5 g, 0.198 mol), methoxylamine hy-
drochloride (15.0 g, 0.180 mol), and methanol (30 mL) was
stirred at 25 °C for 24 h. The resulting methanol solution
contained mainly (E)-2-[2-(1,3-dioxolan-2-yl)phenyl]-2-meth-
oxyimino-N-methylacetamide [(E)-12] and (Z)-2-[2-(1,3-diox-
olan-2-yl)phenyl]-2-methoxyimino-N-methylacetamide [(Z)-12]
(E/ Z ) 86:14 by GC). An analytically pure sample of (E)-12
was obtained by conventional workup and recrystallization
from n-hexane/EtOAc as a white crystalline solid: mp 84.5-
Resolu tion of (S)-O-[1-(3-Tr iflu or om eth ylp h en yl)eth -
yl]h yd r oxyla m in e (2) w ith L-Ta r ta r ic Acid . To a solution
of 2 (4.10 g, purity 98% by GC, 19.6 mmol, 86% ee by chiral
GC), THF (24.0 mL), and i-Pr2O (4.0 mL) was added L-tartaric
acid (3.0 g, 20.0 mmol), and the resulting mixture was refluxed
to give a colorless solution. The solution was cooled to 25 °C,
and the resulting slurry was filtered. The product was dried
in vacuo to give L-tartaric acid salt of 2 (4.90 g, 13.8 mmol,
70% yield, >99% ee by GC after neutralization with NaOH)
85.5 °C; IR (neat) 2983, 2941, 2898, 1724 cm-1 1H NMR
;
(CDCl3) δ 1.31 (3H, t, J ) 7.2 Hz), 3.93-3.98 (4H, m), 4.01
(3H, s), 4.32 (2H, q, J ) 7.2 Hz), 5.78 (1H, s), 7.14-7.19 (1H,
m), 7.38-7.44 (2H, m), 7.54-7.58 (1H, m); 13C NMR (CDCl3)
δ 14.15, 61.89, 63.59, 65.00, 102.56, 126.87, 128.76, 128.83,
as a white crystalline solid: mp 138.7-138.8 °C; [R]22 -44.3
129.06, 129.80, 135.96, 150.51, 163.12. Anal. Calcd for C14H17
-
D
(c 1.19, CH3OH); IR (neat) 2945, 2590 cm-1; 1H NMR (DMSO-
d6) δ 1.29 (3H, d, J ) 6.6 Hz), 4.29 (2H, s), 4.64 (1H, q, J ) 6.6
Hz), 7.53-7.64 (4H, m); 13C NMR (DMSO-d6) δ 22.25, 72.61,
80.90, 123.09, 124.31, 126.62, 129.41, 129.72, 130.73, 146.12,
173.60. Anal. Calcd for C13H16F3NO7; C, 43.95; H, 4.54; N, 3.94.
Found: C, 44.23; H, 4.33; N 3.78.
NO5; C, 60.21; H, 6.14; N, 5.02. Found: C, 60.19; H, 6.38; N
4.73.
Aqueous methylamine (40%, 46.6 g, 0.60 mol) was added to
the methanol solution, and the resulting mixture was stirred
at 25 °C for 2 h. Methanol was removed under reduced
pressure, and the mixture was diluted with n-heptane (100
mL) and H2O (100 mL) followed by heating at 60 °C for 30
min. The mixture was cooled to 0 °C, and the resulting slurry
was filtered. The product was washed with n-heptane (25 mL)
and dried in vacuo to give 13 [20.4 g, purity >99% by GC, 77.2
mmol, 64% yield, E/ Z ) 98:2 by GC (column: DB-17ht; 0.25
An analytically pure 2 was obtained by neutralization of
L-tartaric acid salt of 2 (>99% ee) with aqueous NaOH and
distillation as colorless liquid: [R]22 -58.9 (c 0.986, CHCl3,
D
>99% ee); IR (neat) 1327, 1117 cm-1; 1H NMR (CDCl3) δ 1.42
(20) Naemura, K.; Fukuda, R.; Murata, M.; Konishi, M.; Hirose, K.;
Tobe, Y Tetrahedron: Asymmetry 1995, 6, 2385.
(21) Mytko, J . A.; Graf, E.; Weiss, J . J . Org. Chem. 1992, 57, 1015.

Asymmetric Synthesis of (S)-MA20565
J . Org. Chem., Vol. 65, No. 2, 2000 437
mm × 30 m, detector: FID, carrier gas: He)] as a white
crystalline solid: mp 104-108 °C; 1H NMR (CDCl3) δ 2.89 [3H,
d, J ) 5.1 Hz, (Z)-isomer], 2.92 [3H, d, J ) 5.1 Hz, (E)-isomer],
3.94 [7H, s, (E)-isomer)], 4.01 [3H, s, (Z)-isomer], 4.03 [4H, s,
(Z)-isomer], 5.87 [1H, s, (E)-isomer], 6.25 [1H, s, (Z)-isomer],
6.74 (1H, br), 7.14-7.17 (1H, m), 7.39-7.44 (2H, m), 7.59-
7.62 (1H, m). An analytically pure sample of (E)-13 was
obtained by washing with n-BuOH as a white crystalline
L-tartaric acid salt of 2 (2.74 g, 7.71 mmol, >99% ee), acetic
acid (3.0 mL), and water (9.0 mL) was added 13 (2.00 g, 7.57
mmol, E/ Z ) 98:2 by GC), and the mixture was stirred at 25
°C for 4 h and at 50 °C for 4 h. The resulting slurry was cooled
to 25 °C and filtered. The product was washed with hot water
and dried in vacuo to give 1 (2.97 g, purity >98% by HPLC,
7.29 mol, 96% yield from 13, >99% ee by chiral HPLC, E/ Z >
99.5:0.5 by HPLC) as a white crystalline solid. An analytically
pure sample was obtained by recrystallization from n-hexane/
EtOAc as a white crystalline solid: mp 89-90 °C; [R]22D -42.7
1
solid: mp 111-112 °C; IR (neat) 3358, 1664 cm-1; H NMR
(CDCl3) δ 2.90 (3H, d, J ) 5.1 Hz), 3.93 (7H, s), 5.86 (1H, s),
6.75 (1H, br), 7.13-7.16 (1H, m), 7.38-7.41 (2H, m), 7.58-
7.61 (1H, m); 13C NMR (CDCl3) δ 26.23, 63.19, 64.86, 102.04,
126.19, 128.59, 128.71, 129.11, 136.73, 151.81, 163.15. Anal.
Calcd for C13H16N2O4; C, 59.08; H, 6.10; N, 10.60. Found: C,
59.02; H, 6.14; N 10.50.
(c 1.00, CHCl3); IR (neat) 3410, 3371, 2989, 2943, 1664 cm-1
;
1H NMR (CDCl3) δ 1.58 (3H, d, J ) 6.6 Hz), 2.87 (3H, d, J )
5.1 Hz), 3.85 (3H, s), 5.31 (1H, q, J ) 6.6 Hz), 6.68 (1H, br),
7.13-7.16 (1H, m), 7.34-7.55 (5H, m), 7.60 (1H, s), 7.66-7.69
(1H, m), 7.96 (1H, s); 13C NMR (CDCl3) δ 21.83, 26.15, 63.25,
80.70, 123.13, 124.22, 124.31, 127.19, 128.84, 129.20, 129.28,
129.32, 129.42, 129.84, 130.27, 130.64, 144.37, 147.70, 150.53,
162.77. Anal. Calcd for C20H20F3N3O3; C, 58.97; H, 4.95; N,
10.31. Found: C, 58.90; H, 4.55; N 10.41.
(E,E)-(S)-2-(Meth oxyim in o)-N-m eth yl-2-[2-[[1-(3-tr iflu -
o r o m e t h y l p h e n y l )e t h o x y i m i n o ]m e t h y l ]p h e n y l ]-
a ceta m id e [(S)-MA20565] (1). Meth od A. To a solution of 2
(24.6 g, purity 98% by GC, 0.117 mol, 86% ee), acetic acid (56
mL), and H2O (112 mL) was added 13 (28.9 g, purity >99%
by GC, 0.109 mol, E/ Z ) 98:2 by GC), and the mixture was
stirred at 30-35 °C for 1 h. Seed crystals of 1 were added to
the mixture, and the resulting slurry was stirred at 30-35 °C
for another 5 h. The slurry was aged at 25 °C for 12 h and at
30-35 °C for 6 h. The product was filtered, washed with hot
water three times, and dried in vacuo to give 1 [41.6 g, purity
>98% by HPLC, 0.102 mol, 94% yield from 13, 86% ee by chiral
HPLC, (E)-aldoxime ether:(Z)-aldoxime ether >99.5:0.5 by
HPLC (column: Inertsil ODS-2, column temperature 40 °C,
eluent: MeOH/H2O (60:40); 1.0 mL/min, detect: 254 nm,
retention time; (E)-aldoxime ether: 24.6 min; (Z)-aldoxime
ether: 20.0 min); (Z)-ketoxime ether was not detected] as a
white crystalline solid: mp 83-85 °C.
Ack n ow led gm en t . We thank Professor Takao
Ikariya of Tokyo Institute of Technology and Professor
Takeshi Kitahara of The University of Tokyo for helpful
discussions. We also thank H. Hashimoto, T. Fukumoto,
S. Kawamura, and T. Asahara of Mitsubishi Chemical
Corp. (MCC) for help in the optimization of the crystal-
lization conditions of 1, K. Yoshida and I. Mitamura of
MCC for their preparation of analytically pure samples,
S. Sakamoto of MCC for his chiral analyses, M. Momo-
chi and E. Enokida of MCC for their elemental analyses,
and Y. Baba and M. Matsumoto of MCC for their
English corrections.
(E,E)-(S)-2-(Meth oxyim in o)-N-m eth yl-2-[2-[[1-(3-tr iflu -
o r o m e t h y l p h e n y l )e t h o x y i m i n o ]m e t h y l ]p h e n y l ]-
a ceta m id e [(S)-MA20565] (1). Meth od B. To a solution of
J O991271Z