Stereoselective synthesis of chiral β-amino trifluoromethyl alcohol: Development of a manufacturing process for a key intermediate in the production of a novel elastase inhibitor, AE-3763

Article abstract of DOI:10.1016/j.tetasy.2010.06.038

We have successfully synthesized chiral β-amino trifluoromethyl alcohol (2S,3S)-7a, which is a key intermediate in the production of AE-3763, by stereoselective reduction of N-Cbz-protected 5-hydroxy-5-(trifluoromethyl)- 1,3-oxazolidine 4 prepared from L-valine in 3 steps followed by alkaline hydrolysis. This new method can be applied to the industrial-scale synthesis of AE-3763.

Full text of DOI:10.1016/j.tetasy.2010.06.038

Tetrahedron: Asymmetry 21 (2010) 1855–1860
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Tetrahedron: Asymmetry
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Stereoselective synthesis of chiral b-amino trifluoromethyl alcohol:
development of a manufacturing process for a key intermediate
in the production of a novel elastase inhibitor, AE-3763
*
Yasunao Inoue , Tomoki Omodani, Ryotaro Shiratake, Fuminori Sato
Drug Research Division, Dainippon Sumitomo Pharma Co., Ltd, Enoki-cho 33-94, Suita, Osaka 564-0053, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
We have successfully synthesized chiral b-amino trifluoromethyl alcohol (2S,3S)-7a, which is a key inter-
mediate in the production of AE-3763, by stereoselective reduction of N-Cbz-protected 5-hydroxy-5-(tri-
fluoromethyl)-1,3-oxazolidine 4 prepared from L-valine in 3 steps followed by alkaline hydrolysis. This
new method can be applied to the industrial-scale synthesis of AE-3763.
Received 9 April 2010
Accepted 22 June 2010
Available online 31 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
hydrolysis were unsuccessful. We also attempted with no success
the acid hydrolysis of compound 4, in which the Boc-group of 3
b-Amino trifluoromethyl alcohol 2 is a key intermediate in the
production of AE-3763,1 a human neutrophile elastase (HNE)
inhibitor (Fig. 1) developed by Dainippon Sumitomo Pharma Co.,
Ltd. Generally, b-amino perfluoroalkyl alcohols are valuable com-
pounds as intermediates for protease inhibitors and synthetic
methods for these alcohols have been developed.2 One of the most
frequently used methods consists of nucleophilic addition to enan-
was converted to a Cbz-group at the N-terminal protecting group.
We considered that the reduction of compound 4 followed by
alkaline hydrolysis would provide the desired (3S)-3-amino-
1,1,1-trifluoro-4-methylpentan-2-ol 2. Based on these findings,
we focused our efforts on the conversion of compound 4 to 2.
2. Results and discussion
tiopure a-amino aldehyde derivatives, such as N-protected L-phe-
nylalaninal. In this route,
a trifluoromethyl trimethylsilane
2.1. Reduction of compound 4
(TMSCF3, the Ruppert Reagent),3 which is an efficient trifluorome-
thylating reagent of carbonyl compounds, is added to N-protected
The N-Cbz-protected 5-hydroxy-5-(trifluoromethyl)-1,3-oxa-
zolidine 4 was prepared as a single isomer at the C-5 position in
good yield according to Schofield’s procedure,7 with a minor mod-
ification. Reduction of compound 4 using sodium borohydride in
ethanol at 0 °C led to a mixture of (2S,3S)-isomer 6a and (2R,3S)-
isomer 6b in 55:45 ratio as confirmed by HPLC. Complete depro-
tection of the N-hydroxymethyl group by alkaline hydrolysis gave
the (2S,3S)-isomer 7a, the by-product 8b,8 benzyl alcohol, and an-
other product without the (2R,3S)-isomer 7b (Fig. 3). We therefore
decided to investigate the mechanism underlying the production
of the by-product.
a-amino aldehydes in the presence of tetrabutylammonium
fluoride (TBAF) or CsF to give a diastereomeric mixture of b-amino
trifluoromethyl alcohols in moderate yields.4 However, this
method cannot be applied to
the isopropyl group.
L-valinal due to steric hindrance at
Several methods for the synthesis of 2 have been reported.5
However, these methods consist of many steps and some of them
require resolution leading to very low yields. In 2004, Andres et al.6
reported the diastereoselective synthesis of N-dibenzyl-b-amino
trifluoromethyl alcohol from N-dibenzyl-a-amino aldehyde in
moderate yield and 84:16 diastereomeric ratios of the (2S,3S)-
and (2R,3S)-isomer. However, this method requires the isolation
of each diastereomer using flash chromatography, which is
impractical on an industrial scale. We therefore decided to develop
a new, simpler method for the synthesis of the optically active 2.
Schofield et al. reported the synthesis of compound 37 from
The reduction of compound 4 using sodium borohydride pro-
vided compounds 6a and 6b in almost equal amounts. In the case
of compound 6a, the isopropyl group and trifluoromethyl group of
the resultant product 8a are located on the same side. Due to the
steric repulsion of the isopropyl group and trifluoromethyl group,
it was thought that the nucleophilic reaction toward the carbonyl
group of compound 6a did not occur. In contrast, the isopropyl
group and trifluoromethyl group of 8b, which was formed from
compound 6b, are located on the opposite side, suggesting that
the by-products would be produced by nucleophilic reaction
L-valine (Fig. 2). However, their efforts to convert 3 to 5 using acid
* Corresponding author. Tel.: +81 6 6337 5903; fax: +81 6 6337 6010.
E-mail address: yasunao-inoue@ds-pharma.co.jp (Y. Inoue).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.06.038

1856
Y. Inoue et al. / Tetrahedron: Asymmetry 21 (2010) 1855–1860
O
O
N
N
N
CF3
OH
HO
N
H
H2N
CF3
3 steps
5 steps
I
N
H
O
O
O
O
2
1
AE-3763
Figure 1. Synthetic method for AE-3763.
O
F3C
F3C
H+
OH
O
OH
CF3
1) NaBH4
2) OH-
O
CF3
O
NH
O
N
O
N
H2N
3) deprotection
OH
(3S)-2
O
O
O
5
4
3
Figure 2. Synthetic route for chiral 2.
O
O
F3C
N
OH
CF3
CF3
OH
O
N
O
N
reduction
O
OH
O
HO
HO
O
(2S,3S)-6a
4
(2R,3S)-6b
CF3
alkaline hydrolysis
O
HO
N
O
O
CF3
CF3
OH
O
N
H
8b
O
N
O
H
OH
OH
(2S,3S)-7a
Figure 3. Synthetic method for the N-protected b-amino trifluoromethyl alcohol.
(2R,3S)-7b
toward the carbonyl group followed by an intramolecular ring-
closing reaction. Therefore, we considered that an improvement
in the stereoselective reduction of compound 4 might provide
the desired 7a in high yield. (Fig. 4)
2.2. Stereoselective reduction of compound 4
Next, we examined the solvent effect on using sodium borohy-
dride as the reductive reagent. Since compounds 6a and 6b were
O
steric repulsion
K2CO3
CF3
CF3
O
N
HO
N
O
OH
8a
HO
O
6a
O
CF3
K2CO3
O
N
H
OH
(2S,3S)-7a
O
K2CO3
CF3
CF3
HO
N
O
N
OH
O
OH
HO
O
6b
8b
Figure 4. Mechanism for the production of the by-products.

Y. Inoue et al. / Tetrahedron: Asymmetry 21 (2010) 1855–1860
1857
too unstable to isolate, the degree of stereoselectivity was deter-
mined by HPLC. As a result, the degree of stereoselectivity was im-
proved by using a bulky solvent, such as tert-butyl alcohol,
tetrahydrofuran, or 2-propanol, and the desired (2S,3S)-6a was
formed as the major component with (2R,3S)-6b as the minor
one. In contrast, the degree of stereoselectivity was adversely af-
fected by using a solvent containing water and the undesired
(2R,3S)-6b was formed as the major component with (2S,3S)-6a
as the minor one (Table 1).
Cbz-protection at N-terminal of
L
-Val followed by formylation to
give the known oxazolidin-5-one 109 in excellent yield. The addi-
tion of TMS–CF3 to oxazolidin-5-one 10 followed by deprotection
of the TMS group by methanol provided compound 4 in excellent
yield. Finally, stereoselective reduction of compound 4 using zinc
chloride and sodium borohydride in tert-butyl methyl ether fol-
lowed by alkaline hydrolysis provided, after purification by recrys-
tallization from heptane–IPE (3:1), the desired (2S,3S)-7a as a
white crystalline powder in good chemical yield and excellent ste-
reoselectivity (>99% de).
From these results, it was considered that compound 4 formed
an intramolecular hydrogen bond between the N-hydroxyl methyl
group and the trifluoromethyl ketone. Therefore, we decided to use
zinc chloride for the chelate formation with compound 4a so that
the conformation of compound 4a remains strongly fixed.
Based on the above-mentioned results, we examined the possi-
bility of stereoselective reduction with other reducing agents such
as NaBH4–CeCl3, LiBHEt3, DIBAH, Vitride, LiBH4, and Zn(BH4)2, but
no significant effect on the stereoselectivity was observed. How-
ever, a remarkable improvement in the stereoselectivity was ob-
served when using zinc chloride and sodium borohydride
(Table 2). We have not yet investigated the mechanism for the high
stereoselectivity, but it was assumed that zinc cation was chelated
by compound 4a, and so the conformation of compound 4a re-
mains strongly fixed. Optimization of the reaction conditions was
carried out for the stereoselective reduction of (2S,3S)-6a, and
treatment of compound 4 with 1 equiv of zinc chloride and 2 equiv
of sodium borohydride in tert-butyl methyl ether at room temper-
ature gave, after alkaline hydrolysis, the corresponding (2S,3S)-7a
in good chemical yield and excellent stereoselectivity (>90%). In
addition, crude compound 7a could be purified by recrystallization
from heptane–IPE (3:1), and so our new method did not require the
use of column chromatography.
The absolute configurations of (2S,3S)-7a and (2R,3S)-7b were
determined by measurement of the nuclear Overhauser effect
(NOE) difference spectrum for compounds 12a and 12b, which
were converted from 7a and 7b (Scheme 2). When a weak radiofre-
quency wave was radiated at the hydrogen of compounds 12a and
12b at the C-4 position, the NOE difference spectrum between the
4-hydrogen and the 5-hydrogen of compound 12a was determined
as 12.2% while for compound 12b, it was determined as 2.6%. In
addition, the coupling constant between the 4-hydrogen and the
5-hydrogen of compound 12a was observed at 7.9 Hz and the
one for compound 12b was observed at 3.5 Hz. From these find-
ings, it is indicated that the 4-hydrogen and the 5-hydrogen of
compound 12a had a cis-configuration and the absolute structure
of 7a was the (2S,3S)-isomer. On the other hand, compound 12b
had a trans-configuration and the absolute structure of 7b was
the (2R,3S)-isomer.10
3. Conclusion
In conclusion, we have synthesized in this study chiral b-amino
trifluoromethyl alcohol (2S,3S)-7a, which is a key intermediate in
the production of AE-3763, by stereoselective reduction of com-
This new method was applicable to an industrial-scale synthe-
sis. The synthesis, represented in Scheme 1, started with the
pound 4 prepared from
L-valine, followed by alkaline hydrolysis.
The synthesized (2S,3S)-7a was obtained in excellent yield, while
Table 1
Studies on the reduction of compound 4 (variation of solvent)
F3C
CF3
OH
O
O
O
NaBH4
CF3
OH
CF3
OH
O
O
N
O
N
O
N
O
N
HO
(2S,3S)-6a
HO
(2R,3S)-6b
O
OH
O
4a
4
Entry
Solvent 1a
Solvent 2a
Ratiob (%) (6a:6b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
MeOH
MeOH
MeOH
EtOH
EtOH
EtOH
EtOH
IPA
—
H2O
IPA
—
H2O
IPA
t-BuOH
—
H2O
—
H2O
IPA
t-BuOH
—
40:60
21:79
45:55
55:45
13:87
25:75
41:19
69:31
28:72
32:68
15:85
24:76
37:63
67:33
14:86
54:46
72:28
27:73
79:21
IPA
DMF
DMF
DMF
DMF
THF
THF
THF
THF
t-BuOH
t-BuOH
H2O
IPA
t-BuOH
H2O
IPA
a
Equal ratio of solvent 1 and solvent 2.
Determined by HPLC.
b

1858
Y. Inoue et al. / Tetrahedron: Asymmetry 21 (2010) 1855–1860
Table 2
Studies on reduction of compound 4 (optimization conditions)
O
O
F3C
OH
O
CF3
CF3
CF3
aq. K2CO3
O
N
H
O
N
NaBH4
O
O
N
OH
O
N
OH
OH
HO
(2R,3S)-6b
HO
O
4
(2S,3S)-7a
(2S,3S)-6a
Entry
NaBH4 (equiv)
ZnCl2 (equiv)
Solvent
Ratioa (%) (6a:6b)
Yieldb (%) 7a
1
2
3
4
5
6
7
1
1
1
1
1
1.5
2
—
IPA-t-BuOH
EtOH
THF
79:21
NRc
77:23
87.0:13.0
87.8:12.2
95.2:4.8
95.7:4.3
52
—
—
61
55
74
87
0.5
0.5
0.5
0.5
0.75
1
Et2O
t-BuOMe
t-BuOMe
t-BuOMe
a
b
c
Determined by HPLC.
Each yield was obtained after purification by recrystallization from heptane/IPE (3:1).
No reaction.
O
O
O
O
CF3
O
CF3
OH
OH
OH
a
b
O
N
OH
O
N
H
O
N
H
c
d
O
N
H2N
L-Val
28.9kg
O
O
quant.
O
91.2%
76.9%
97.7%
O
9
10
4
(2S,3S)- 7a
(>99% de)
51.6kg
Scheme 1. Reagents and conditions: (a) Cbz-Cl, aq NaOH, toluene, rt; (b) (CH2O)n, p-toluenesulfonic acid monohydrate, toluene, 80 °C; (c) (i) CF3TMS, CsF, THF, 10 °C, (ii)
MeOH, 10 °C; (d) (i) NaBH4, ZnCl2, t-BuOMe, rt, (ii) K2CO3, aq MeOH, rt.
O
O
CF3
OH
b
a
c
CF3
OH
CF3
HN
O
N
H
O
N
O
O
O
7a and 7b
11
4
(3 : 1)
12.2% NOE
J=7.9Hz
2.6% NOE
J=3.5Hz
H
H
N
H
N
H
CF3
O
O
CF3
O
O
cis-configuration
trans-configuration
12a
12b
Scheme 2. Reagents and conditions: (a) (i) NaBH4, EtOH, 0 °C; (ii) aq K2CO3; (b) (i) Pd(OH)2–C, H2, AcOEt, rt, (ii) CDI, toluene, rt; (c) BnBr, K2CO3, DMF, rt.
our method did not require the use of column chromatography. As
this new method can be applied on an industrial scale, it allows the
industrial synthesis of AE-3763.
spectra were recorded on a JNMLA300 (JEOL, 300 MHz) or
JNMLA400 (JEOL, 400 MHz), and chemical shifts are expressed in
ppm downfield from internal TMS. Mass spectra were recorded
with electron spray ionization (ESI) and liquid secondary ion
(LSI) on LTQ Orbitrap Discovery (Thermo Fisher Scientific) or M-
1000 (Hitachi). Optical rotation was measured with P-1020 (JAS-
CO). Silica gel column chromatography was performed on a Silica
Gel 60 (70–230 mesh, Merck). Reactions requiring anhydrous con-
ditions were performed under argon atmosphere. Solutions were
evaporated under reduced pressure on a rotary evaporator. Syn-
thetic yields of all compounds were not optimized. The following
abbreviations are used: NaCl, sodium chloride; H2SO4, sulfuric
4. Experimental
4.1. General methods
Unless otherwise noted, reagents were obtained from commer-
cial suppliers and used without further purification. Melting points
were determined on a cover glass with an electrothermal melting
point apparatus and are given as uncorrected values. 1H NMR

Y. Inoue et al. / Tetrahedron: Asymmetry 21 (2010) 1855–1860
1859
acid; MgSO4, anhydrous magnesium sulfate; NaHCO3, sodium
hydrogen carbonate; K2CO3, potassium carbonate; THF, tetrahy-
drofuran; DMF, N,N-dimethylformamide; CHCl3, chloroform;
DMSO, dimethyl sulfoxide; MeOH, methanol; EtOH, ethanol;
AcOEt, ethyl acetate; and CDCl3, chloroform-d.
gas, after which the reaction solution was stirred at room temper-
ature for 10 min. To this solution was added dropwise a solution of
compound 4 in t-butyl methyl ether (232 L) at 20–35 °C, and the
mixture was stirred at the same temperature for 13 h. To this mix-
ture was added dropwise a solution of citric acid monohydrate
(86.8 kg) in water (261 L) at 30 °C or less, and the organic layer
was split. The aqueous layer was then extracted with AcOEt
(289 L), and the combined organic layer was washed with NaCl
(45.1 kg) in water (128 L) and concentrated under reduced pres-
sure. To the residue were added MeOH (173 L) and water (173 L)
at 20–30 °C, and further added K2CO3 (30.1 kg), and the mixture
was stirred at the same temperature for 1 h. The reaction solvent
was then evaporated until reduced by half under reduced pressure,
and thereto was added AcOEt (289 L). The solution was next ex-
tracted with AcOEt, and the aqueous layer was again extracted
with AcOEt (289 L). The combined organic layer was washed with
NaCl (45.1 kg) in water (128 L), and the organic layer was dried
over MgSO4. Finally the solvent was evaporated under reduced
pressure. The residue was recrystallized from a mixture of heptane
(174 L) and IPE (58.2 L) to give the desired 7a (51.6 kg, 76.9%) as a
4.2. Stereoselective synthesis of chiral 7a
4.2.1. N-benzyloxycarbonyl-L-valine 9
To a suspension containing
L
-valine (28.9 kg) and water (20 L)
were added 48% NaOH (19.4 kg) in water (16.2 L) and toluene
(40.5 L) at 10–15 °C, followed by benzyloxycarbonyl chloride
(41.3 kg) added dropwise and 48% NaOH (21.1 kg) in water
(17.9 L) at 15–30 °C to keep the pH 10–11. The reaction mixture
was then stirred at the same temperature for 2 h and left to stand.
The aqueous layer was washed with toluene (40.5 L), brought to an
acidic pH <1.5 with 50% sulfuric acid (28.9 L), and extracted with
toluene (161.8 L, 31.8 L, 31.8 L). The combined organic layer was
washed with Na2SO4 (4.0 kg) in water (75.1 L) and concentrated
under reduced pressure to give the desired 9 (60.6 kg, 97.7%) as a
colorless oil. This product was used as a starting material in the
next step without further purification.
white crystalline powder: mp 103–104 °C; ½a D24
¼ ꢁ20:3 (c 1.0,
ꢀ
CHCl3); HRMS (ESI, positive) m/z calcd for C14H19O3NF3 [(M+H)+]
306.1312, found 306.1308; 1H NMR (400 MHz, CDCl3, d): 0.97
(3H, d), 1.03 (3H, d), 2.01 (1H, m), 3.70 (1H, d), 3.85 (1H, d),
4.13 (1H, m), 4.82 (1H, d), 5.11 (1H, d), 5.16 (1H, d), 7.26–7.39
(5H, m).
4.2.2. Benzyl (4S)-5-oxo-4-(propan-2-yl)-1,3-oxazolidine-3-
carboxylate 109
To a solution of N-benzyloxycarbonyl-L-valine (60.6 kg) in tolu-
ene (112.7 L) were added paraformaldehyde (13.0 kg) and p-tolu-
enesulfonic acid monohydrate (0.87 kg), and the reaction mixture
was stirred at 75–85 °C for 5 h. The reaction solution was washed
with NaHCO3 (11.5 kg) in water (115.4 L) twice, then with water
(40.5 L), and then concentrated under reduced pressure. The resi-
due was recrystallized from toluene to give the desired 10
(57.9 kg, 91.2%) as a white crystalline powder: Mp 54–55 °C;
4.3. Synthetic method for compounds 12a and 12b
4.3.1. Benzyl [(3S)-1,1,1-trifluoro-2-hydroxy-4-methylpentan-3-
yl]carbamate 7a and 7b
To a solution of compound 4 (5.0 g) in EtOH (50 mL) was added
sodium borohydride (570 mg) at 0 °C, and the reaction solution
was stirred at 0 °C for 30 min. To the reaction solution was added
dropwise a solution of K2CO3 (2.1 g) in water (50 mL) at room tem-
perature, and then the mixture was stirred at the same tempera-
ture for 15 h. The reaction solvent was evaporated until reduced
by half under reduced pressure, and thereto was added AcOEt
(50 mL). The solution was extracted with AcOEt (50 mL) three
times, and the combined organic layer was washed with saturated
brine. The organic layer was then dried over MgSO4, and the sol-
vent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography [solvent; hexane/
AcOEt (4:1)] to give the desired mixture of 7a and 7b (3.0 g, 66%)
as a white crystalline powder. This mixture had a ratio of about
3:1 of two diastereomers bearing an asymmetric carbon atom at
the 2-position. The ratio of the isomers was determined by HPLC:
MS (LSI, positive) m/z 306 [(M+H)+].
½
a 2D4
ꢀ
¼ þ98:2 (c 1.0, CHCl3); MS (LSI, positive) m/z 264 [(M+H)+];
1H NMR (300 MHz, CDCl3, d): 1.01 (3H, d), 1.08 (3H, d), 2.35 (1H,
m), 4.23 (1H, br s), 5.15–5.60 (4H, m), 7.32–7.41 (5H, m).
4.2.3. Benzyl (4S,5R)-5-hydroxy-4-(propan-2-yl)-5-
(trifluoromethyl)-1,3-oxazolidine-3-carboxylate 4
To a solution of compound 10 (57.9 kg) in THF (176.0 L) was
added cesium fluoride (6.8 kg), and the reaction mixture was
cooled to 0–10 °C. To the reaction solution was added TMSCF3
(37.4 kg) at the same temperature over 30 min, and the mixture
was stirred for more 30 min. The solution was concentrated under
reduced pressure to dryness, and the residue was dissolved in
methanol (57.9 L) at 0–10 °C. The reaction solution was then stir-
red at the same temperature for 30 min and concentrated under re-
duced pressure. To the residue were added AcOEt (289 L) and
water (173 L), and the mixture was extracted with AcOEt. The
aqueous layer was extracted with AcOEt (145 L), and the combined
organic layer was washed with NaCl (45.1 kg) in water (127 kg),
dried over MgSO4, and concentrated under reduced pressure to
give the desired 4 (73.3 kg, quant.) as a colorless oil. A part of this
product was purified by silica gel column chromatography (hex-
4.3.2. (4S)-4-(Propan-2-yl)-5-(trifluoromethyl)-1,3-oxazolidin-
2-one 116
To a solution of the mixture of 7a and 7b (3.0 g), which had a
ratio of about 3:1, in AcOEt (70 mL) was added 20% palladium
hydroxide (300 mg) at room temperature and the mixture was stir-
red at the same temperature for 2 h under a hydrogen atmosphere.
The catalyst was removed by filtration, and the filtrate was concen-
trated under reduced pressure to give an oil (1.9 g). To a part of this
residue (506 mg) were added toluene (10 mL) and N,N0-carbonyldi-
imidazole (575 mg), and the mixture was stirred at room temper-
ature for 15 h. The reaction solution was then washed successively
with water and saturated brine and dried over MgSO4. The solvent
was then evaporated under reduced pressure to give the desired 11
(470 mg, 81%) as a colorless oil: MS (LSI, positive) m/z 197
[(M+H)+]. This product was used as starting material in the next
step without further purification.
ane/AcOEt) for the measurement of physical data: ½a D24
¼ þ48:2
ꢀ
(c 1.0, CHCl3); HRMS (ESI, positive) m/z calcd for C15H19O4NF3
[(M+H)+] 334.1261, found 334.1258; 1H NMR (300 MHz, CDCl3,
d): 1.00 (3H, d), 1.05 (3H, d), 2.17–2.26 (1H, m), 3.63 (1H, br s),
4.22 (1H, br s), 4.84 (1H, d), 5.15 (1H, d), 5.20 (1H, d), 5.42 (1H,
br s), 7.34–7.40 (5H, m). This product was used as starting material
in the next step without further purification.
4.2.4. Benzyl [(2S,3S)-1,1,1-trifluoro-2-hydroxy-4-
methylpentan-3-yl]carbamate 7a
To a solution of zinc chloride (22.4 kg) in t-butyl methyl ether
(232 L) was added sodium borohydride (12.5 kg) under nitrogen

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Y. Inoue et al. / Tetrahedron: Asymmetry 21 (2010) 1855–1860
Omodani, T.; Shiratake, R.; Honda, S.; Komiya, M.; Takemura, T. Int. Pat. Appl.
WO 2000/052032, 2000.
4.3.3. (4S,5S)-3-Benzyl-4-(propan-2-yl)-5-(trifluoromethyl)-1,3-
oxazolidin-2-one 12a and (4S,5R)-3-benzyl-4-(propan-2-yl)-5-
(trifluoromethyl)-1,3-oxazolidin-2-one 12b
2. (a) Skiles, J. W.; Fuchs, V.; Leonard, S. F. Bioorg. Med. Chem. Lett. 1991, 1, 69–72;
(b) Skiles, J. W.; Sorcek, R.; Jacober, S.; Miao, C.; Mui, P. W.; McNeil, D.;
Rosenthal, A. S. Bioorg. Med. Chem. Lett. 1993, 3, 773–778; (c) Angelastro, M. R.;
Baugh, L. E.; Bey, P.; Burkhart, J. P.; Chen, T.-M.; Durham, S. L.; Hare, C. M.;
Huber, E. W.; Janusz, M. J.; Koehl, J. R.; Marquart, A. L.; Mehdi, S.; Peet, N. P. J.
Med. Chem. 1994, 37, 4538–4554.
3. Ruppert, I.; Schlich, K.; Volbach, W. Tetrahedron Lett. 1984, 25, 2195–2198.
4. (a) Skiles, J. W.; Fuchs, V.; Miao, C.; Sorcek, R.; Grozinger, K. G.; Mauldin, S. C.;
Vitous, J.; Mui, P. W.; Jacober, S.; Chow, G.; Matteo, M.; Skoog, M.; Weldon, S.
M.; Possanza, G.; Keirns, J.; Letts, G.; Rosenthal, S. S. J. Med. Chem. 1992, 35,
641–662; (b) Walter, M. W.; Felici, A.; Galleni, M.; Soto, R. P.; Adlington, R. M.;
Baldwin, J. E.; Frere, J. M.; Gololobov, M.; Schofield, C. J. Bioorg. Med. Chem. Lett.
1996, 6, 2455–2458; (c) Walter, M. W.; Adlington, R. M.; Baldwin, J. E.;
Schofield, C. J. Tetrahedron 1997, 53, 7275–7290.
5. (a) Imperiali, B.; Abeles, R. H. Tetrahedron Lett. 1986, 27, 135; (b) Edwards, P. D.;
Andisik, D. W.; Bryant, C. A.; Ewing, B.; Gomes, B.; Lewis, J. J.; Rakiewicz, D.;
Steelman, G.; Strimpler, A.; Trainor, D. A.; Tuthill, P. A.; Mauger, R. C.; Veale, C.
A.; Wildonger, R. A.; Williams, J. C.; Wolanin, D. J.; Zottola, M. J. Med. Chem.
1997, 40, 1876; (c) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.;
Briant, C.; Damewood, J.; Koehl, J. R.; Earley, R.; Feeney, S. W.; Edwards, P. D.;
Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.; Krell, R. D.; Moore, G.; Salcedo, T. W.;
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40, 3173.
To a solution of the above-prepared diastereomer mixture 11
(420 mg) in DMF (10 mL) were added K2CO3 (674 mg) and benzyl
bromide (417 mg), and the reaction mixture was stirred at room
temperature for 3 h. Next, AcOEt (100 mL) was added, and the mix-
ture was washed successively with water and saturated brine. The
organic layer was dried over MgSO4 and the solvent was evaporated
under reduced pressure. The residue was subjected to silica gel col-
umn chromatography, and compound 12a (490 mg, 72%) was ob-
tained from the fractions eluted with hexane/AcOEt (95:5) as
colorless needles (recrystallization from IPE). Compound 12b
(160 mg, 23%) was obtained from the fractions eluted with
hexane/AcOEt (10:1) as a colorless oil. The physiochemical proper-
ties of compound 12a were as follows. Mp 92–93 °C; ½a D24
¼ ꢁ48:1
ꢀ
(c 1.0, CHCl3); HRMS (ESI, positive) m/z calcd for C14H17O2NF3
[(M+H)+] 288.1206, found 288.1202; 1H NMR (300 MHz, CDCl3, d):
1.06 (3H, d), 1.10 (3H, d), 2.18 (1H, dqq), 3.70 (1H, dd), 4.08 (1H,
d), 4.65 (1H, dq), 5.09 (1H, d), 7.26-7.40 (5H, m). The physiochemical
properties of compound 12b were as follows. ½a D24
¼ ꢁ15:0 (c 1.0,
ꢀ
6. Andres, J. M.; Pedrosa, R.; Perez-Encabo, A. Eur. J. Org. Chem. 2004, 1558–1566.
7. Walter, M. W.; Adlington, R. M.; Baldwin, J. E.; Schofield, C. J. J. Org. Chem. 1998,
63, 5179–5192.
CHCl3); HRMS (ESI, positive) m/z calcd for C14H17O2NF3 [(M+H)+]
288.1206, found 288.1201; 1H NMR (300 MHz, CDCl3, d): 0.88 (3H,
d), 0.89 (3H, d), 2.12 (1H, dqq), 3.62 (1H, dd), 4.01 (1H, d), 4.40
(1H, dq), 4.93 (1H, d), 7.26-7.40 (5H, m).
8. The physiochemical properties of compound 8b were as follows. ½a D24
¼ þ9:5 (c
ꢀ
0.2, CHCl3); HRMS (ESI, positive) m/z calcd for C8H13O3NF3 [(M+H)+] 228.0842,
found 228.0839; 1H NMR (300 MHz, CDCl3, d): 0.91 (3H, d, J = 7.0 Hz), 0.96 (3H,
d, J = 7.0 Hz), 2.19 (1H, dqq, J = 3.5, 7.0, 7.0 Hz), 3.62 (1H, m), 3.95 (1H, dd,
J = 3.5, 3.5 Hz), 4.42 (1H, dq, J = 3.5, 6.1 Hz), 4.74 (1H, dd, J = 5.5, 11.0 Hz), 4.91
(1H, dd, J = 2.6, 11.0 Hz).
References
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1990, 904–905.
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