Asymmetric synthesis of N-1-(heteroaryl)ethyl-N-hydroxyureas

Article abstract of DOI:10.1016/j.tetasy.2008.03.026

The asymmetric synthesis of two 5-lipoxygenase inhibitors (R)-N-1-(benzofuran-2-yl)ethyl-N-hydroxyurea, 99% ee, and (R)-N-1-(benzo[b]thiophen-2-yl)ethyl-N-hydroxyurea, 95% ee, is described. The enantioselective reduction of 1-(benzofuran-2-yl)ethanone oxime O-benzyl ether and 1-(benzo[b]thiophen-2-yl)ethanone oxime O-benzyl ether with borane oxazaborolidine, generated from (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol, was used for the formation of the stereogenic centres.

Full text of DOI:10.1016/j.tetasy.2008.03.026

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 956–963
Asymmetric synthesis of N-1-(heteroaryl)ethyl-N-hydroxyureas
a
a
b
a,
*
´
Mariusz J. Bosiak, Marek P. Krzeminski, Parasuraman Jaisankar and Marek Zaidlewicz
aDepartment of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, 87-100 Torun´, Poland
bIndian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Jadavpur, Calcutta, India
Received 22 February 2008; accepted 28 March 2008
Dedicated to Professor Marian Mikołajczyk on the occasion of his 70th birthday
Abstract—The asymmetric synthesis of two 5-lipoxygenase inhibitors (R)-N-1-(benzofuran-2-yl)ethyl-N-hydroxyurea, 99% ee, and (R)-
N-1-(benzo[b]thiophen-2-yl)ethyl-N-hydroxyurea, 95% ee, is described. The enantioselective reduction of 1-(benzofuran-2-yl)ethanone
oxime O-benzyl ether and 1-(benzo[b]thiophen-2-yl)ethanone oxime O-benzyl ether with borane oxazaborolidine, generated from
(1R,2S,3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol, was used for the formation of the stereogenic centres.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
ses of (R)-2 using chiral pool precursors or chiral auxilia-
ries have also been reported.16–18
Certain N-substituted N-hydroxyureas derived from are-
nes, furan, benzofuran, thiophene and benzo[b]thiophene,
exhibit 5-lipoxygenase inhibiting activity.1–4 5-Lipoxyge-
nase initiates the biosynthesis of leukotrienes, potent medi-
ators of vascular inflammation and contraction of smooth
muscles, involved in diseases such as allergy, asthma,
psoriasis, inflammatory bowel disease and various cardio-
pulmonary diseases.5–7 N-1-(Heteroaryl)ethyl-N-hydroxy-
ureas 1 and 2 (Fig. 1) were the first 5-lipoxygenase
inhibitors representing a new class of therapeutic agents
containing the N-hydroxyurea functionality.1–8 ZileutonÒ
2 has been introduced commercially as an anti-asthmatic
and anti-inflammatory drug. Several syntheses of racemic
2,1,9–14 a resolution procedure15 and three multistep synthe-
Recently, we developed an asymmetric synthesis of (S)-
N-1-(aryl)ethyl-N-hydroxyureas and (S)-N-(6-benzyloxy-
2,3-dihydrobenzofuran-3-yl)-N-hydroxyurea.19 Herein, we
report on the asymmetric synthesis of (R)-1 and (R)-2 via
the enantioselective reduction of 1-(benzofuran-2-yl)etha-
none, its oxime ethers and 1-(benzo[b]thiophen-2-yl)etha-
none oxime O-benzyl ether, respectively, as the key
transformation generating stereogenic centres.
2. Results and discussion
1-(Benzofuran-2-yl)ethanone 3, readily prepared from
salicylic aldehyde and chloroacetone,20 was reduced with
borane/oxazaborolidine 4, generated in situ from triiso-
propoxyborane and (1S,3S,4R,6R)-4-amino-3,7,7-tri-
methylbicyclo[4.1.0]heptan-3-ol,21 producing (S)-1-(benzo-
furan-2-yl)ethanol 5, 98% ee (Scheme 1). The reduction
Me
NH2
X
N
of
3 with borane/oxazaborolidines, generated from
HO
O
(1S,2R)-norephedrine or (S)-diphenylvalinol, resulted in a
lower enantiomeric excess of 5. In the next step, 5 was
reacted with N,O-bis(diphenoxycarbonyl)hydroxylamine
under Mitsunobu conditions.22 The substitution product
was treated with ammonia and (R)-1, 50% ee, was obtained
in 76% yield.
1, X = O
2, X = S, Zileuton® (Abbott Laboratories)
Figure 1.
*
The approach is short and convenient, but unfortu-
nately, the substitution step results in partial racemization.
Corresponding author. Tel.: +48 56 6114522; fax: +48 56 6542477;
e-mail: zaidlevi@chem.uni.torun.pl
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.03.026

M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
957
BOPri
O
NH
, BH /THF
4
3
Me
O
Me
OH
THF, 0 ºC, 4 h
O
O
3
5
97%, 98% ee
O
O
HN
O
OPh
OPh
Me
Me
N
, DIAD, PPh3
NH2
O
NH3
t-BuOH, rt, 12 h
O
O
N
COOPh
THF, 0 ºC, 18 h
PhOOCO
HO
6
1
(R)-
54%
76%, 50% ee
Scheme 1.
Apparently, the electron donating effect of the benzofuran-
2-yl substituent at the reaction centre makes it prone to
racemization, similar to secondary ortho- and para-
alkoxybenzylic alcohols in the Mitsunobu reaction.23,24
tiomeric excesses, 64% and 71% ee, respectively. The reduc-
tion of 8 with borane/oxazaborolidine 15, generated from
(S)-diphenylvalinol, produced (S)-9 in only 34% ee. In con-
trast, borane/oxazaborolidine 16, generated from (1R,2S,
3R,4S)-3-amino-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol
21, derived from (1R)-camphor 18 (Scheme 3), reduced 8
giving (R)-9 in 92% ee (Scheme 2). Debenzylation of
(R)-9 by catalytic hydrogenolysis on Pd/C or Pd(OH)2/C
resulted in nitrogen–oxygen bond cleavage, while debenzyl-
ation with boron trichloride gave a mixture of products.
Consequently, (R)-9 was transformed into its N-benzyl-
oxyurea derivative 17, which was readily debenzylated by
In the second approach, 3 was converted into oxime 7, and
its O-benzyl ether 8 was reduced with borane/oxazaborol-
idine 14, generated from (1S,2R)-norephedrine, to give
(R)-9, 75% ee, in 64% yield (Scheme 2). Searching for high-
er enantioselectivity, m-methoxybenzyl and benzhydryl
derivatives, 10 and 12, were reduced with the same reagent.
However, (R)-11 and (R)-13 were obtained in lower enan-
1. NaH, DMF, 0 ºC,1 h
2. BnCl, rt, 18 h
Me
N
Me
Me
HN OR
14—16
BMS,
1. THF,0 ºC, 6 h
O
OH
O
N
OR
rt, 24 h
O
2. HCl aq, rt,18 h
yield, %
7
8 10, 12
9 11 13
, ,
,
R
ee, % yield, %
iPr
HN
90
Ph
H
N
Ph
Me
HN
Ph
8
8
8
10
12
PhCH2
PhCH2
PhCH2
m-MeOC6H4CH2
Ph2CH
14
(R)-9
(S)-9
(R)
75
34
92
64
37
61
56
49
15
O
BH
O
O
16
-9
B
H
15
B
H
99
99
14
14
(R)-11 64
(R)-13 71
14
16
1. ClSO2NCO
Me
Me
N
1. H2, Pd(OH)2/C
MeOH, rt, 2 h
2. Crystallization
THF, — 78 ºC, 2 h
NH2
O
NH2
O
-9
(R)
2. H2O, rt, 18 h
O
O
N
C
C
92% ee
HO
BnO
17
95%
(R)-1
83%, 99% ee
Scheme 2.

958
M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
OH
1. t-BuOK, THF, -30 ºC, 10 min
2. i-AmONO, —30 ºC, 10 min
N
NH2
OH
3. H2O, reflux, 18 h, N2
LiAlH4
THF, reflux, 24 h
+ stereoisomers
80%
O
19
21 (crude)
80%
1. H2NOH·HCl
AcONa,
1. (Cl3CO)2CO,
CH2Cl2, —5 ºC,1 h, rt, 2.5 h
2. Crystallization
EtOH/H2O,
93%
18
O
reflux, 20 min
2. H2O, reflux, 18 h, N2
> 99% ee
SeO2
NH2
OH
O
NH
3M NaOH
Ac2O, reflux,18 h
O
EtOH/H2O
O
reflux, 6 h
O
21
98%, >99% ee
20
94%
22
78%
Scheme 3.
palladium catalyzed hydrogenolysis producing (R)-1, 92%
ee, upgraded by crystallization to 99% ee (Scheme 2).
only 30–33% yield. Fortunately, treatment of crude 21 with
triphosgene produced 22 in 78% yield, which was crystal-
lized and then hydrolyzed to give pure 21, as indicated by
1H NMR spectrum lacking signals of impurities present
in the spectrum of the crude product.
Although the synthesis of amino alcohol 21 (Scheme 3), via
reduction of camphoroquinone monoxime with lithium tet-
rahydridoaluminate, has been reported several times,25–34
the purification procedures resulted in low yields. We pre-
pared camphoroquinone E-monoxime 19 by heating an
E/Z mixture in refluxing water.35 The mixture was
obtained either by nitrosation of (1R)-camphor 18 or oxi-
mation of camphoroquinone 20 (Scheme 3). Oxime 19
was reduced with lithium tetrahydridoaluminate to give a
crude amino alcohol 21. The stepwise reduction of 19, first
with sodium tetrahydroborate, followed by lithium tetra-
hydridoaluminate,34 leads to 21 containing less impurities
as compared to the product of direct reduction with lithium
tetrahydridoaluminate. All attempts to purify crude 21, by
crystallizing it or its salts with methanesulfonic, tartaric or
oxalic acid, failed. The reaction with diethyl carbonate or
1,10-carbonyldiimidazole (CDI) gave oxazolidone 22 in
The approach via the reduction of an oxime ether was
also applied to the asymmetric synthesis of (R)-2. Thus,
1-(benzo[b]thiophen-2-yl)ethanone 23, readily prepared
from thiosalicylic acid,36 was converted into oxime 24
and its O-benzyl ether 25 (Scheme 4). The reduction of
25 with borane/oxazaborolidine 14 gave 26, 80% ee, in
49% yield. A higher enantioselectivity was achieved in the
reduction of 25 with borane/oxazaborolidine 16 producing
26, 95% ee. Treatment of 26 with chlorosulfonyl isocyanate
gave
N-1-(benzo[b]thiophen-2-yl)ethyl-N-benzyloxyurea
27. In contrast to 17, debenzylation with hydrogen/palla-
dium on carbon could not be achieved. Debenzylation with
ammonium formate in the presence of Pd/C in ethanol, as
reported earlier in the synthesis of (R)-2 by a different
1. NaH, DMF,
Me H2NOH· HCl
AcONa
Me
N
Me
0 ºC, 1 h
16
BH3 ·SMe2,
2. BnCl, rt,18 h
EtOH/H2O
THF, rt, 24 h
S
S
S
O
OH
N
OBn
reflux, 2 h
23
24
95%
25
99%
1. ClSO2NCO,
Me
NH
Me
Me
NH2
N
THF, —78 ºC, 2 h
HCOONH4, Pd/C
EtOH, rt, 24 h
NH2
O
2. H2O, rt, 18 h
S
S
S
N
BnO
BnO
HO
O
26
27
89%
2
(R)-
50%, 95% ee
70%, 95% ee
Scheme 4.

M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
959
approach,16 required a substantial load of 10% Pd/C and
gave (R)-2, 95% ee, in 70% yield.
The mixture was cooled to 0 °C and a solution of 3
(2.40 g, 15 mmol) in tetrahydrofuran (20 mL) was added
with a syringe pump in 3 h, and then stirred for 1 h. Meth-
anol (5 mL) was added and the mixture was stirred over-
night at room temperature. Solvents were removed and
the product was isolated by column chromatography on
3. Conclusion
The highly enantioselective reduction of 1-(benzofuran-2-
yl)ethanone with borane/oxazaborolidine, generated from
(1S,3S,4R,6R)-4-amino-3,7,7-trimethylbicyclo[4.1.0]heptan-
2-ol, gave (S)-1-(benzofuran-2-yl)ethanol in 98% ee. Its
reaction with N,O-bis(diphenoxycarbonyl)hydroxylamine
under Mitsunobu conditions, followed by reaction with
ammonia resulted in partial racemization to produce (R)-
1 in 50% ee. Asymmetric synthesis of (R)-1, 99% ee and
(R)-2, 95% ee, was achieved via the enantioselective reduc-
tion of 1-(benzofuran-2-yl)ethanone oxime O-benzyl ether
and 1-(benzo[b]thiophen-2-yl)ethanone oxime O-benzyl
ether with borane/oxazaborolidine 16, respectively, as the
key transformation generating the stereogenic centre. Our
synthesis of (R)-2 is the shortest described asymmetric
approach to this compound.
silica gel 80–200 mesh, petroleum ether–ethyl acetate
23
(4:1), 2.36 g, 97%, ½aꢁD ¼ ꢀ35:0 (c 1.15, CHCl3), 98% ee,
by HPLC analysis on an OD-H chiral column, n-hexane–
isopropanol, 9:1 (tR 20.57 S; f = 0.4 mL/min; T = 15 °C;
p = 21 kg f/cm2). The racemate was also analyzed. Lit.37
20
½aꢁD ¼ ꢀ33:3, (c 10.17, CHCl3), 91% ee. 1H NMR
(300 MHz, CDCl3) d 1.64 (d, J = 6.6 Hz, 3H, CH3), 2.07
(d, J = 4.8 Hz, 1H, OH), 5.03 (dq, J = 4.8, 6.6 Hz, 1H,
CH), 6.62 (t, J = 1.0 Hz, 1H, CH), 7.21 (td, J = 7.5,
1.2 Hz, 1H, CH), 7.27 (td, J = 7.2, 1.5 Hz, 1H, CH), 7.46
(ddd, J = 7.8, 1.0, 0.5 Hz, 1H, CH), 7.54 (ddd, J = 7.9,
1.2, 0.5 Hz, 1H, CH). 13C NMR (75 MHz, CDCl3) d
21.39 (CH3), 64.17 (CH), 101.76 (CH), 111.18 (CH),
121.04 (CH), 122.75 (CH), 124.15 (CH), 128.10 (C),
154.75 (C), 160.17 (C).
4.4. 1-(Benzofuran-2-yl)ethanone oxime 7
4. Experimental
4.1. General
A mixture of 3 (14.41 g, 90 mmol), hydroxylamine hydro-
chloride (12.50 g, 180 mmol), sodium acetate (20.50 g,
250 mmol), ethanol (75 mL) and water (90 mL) was stirred
at reflux for 3 h. The mixture was cooled in a refrigerator,
and the precipitated solid was filtered off, dried and crystal-
lized from dichloromethane, 14.97 g, 95%, mp 153–154 °C.
Experiments with air and moisture sensitive materials were
carried under a nitrogen atmosphere. Glassware was oven
dried for several hours, assembled hot, and cooled in a
stream of nitrogen. 1H and 13C NMR spectra were re-
corded on a Varian Gemini 200 multinuclear instrument
and on a Bruker AMX 300 MHz instrument. MS spectra
were recorded on an AMD 604 spectrometer. Optical rota-
tions were measured on an automatic polarimeter, PolAAr
3000, Optical Activity Ltd. GC analyses were performed on
a Perkin–Elmer AutoSystem XL chromatograph, and
HPLC analyses on a Shimadzu LC-10AT chromatograph.
Melting points were determined in open glass capillaries
and are uncorrected. Elemental analyses were performed
by the Microanalysis Laboratory, Institute of Organic
Chemistry, Polish Academy of Sciences, Warsaw.
1
Lit.38 154–155 °C. H NMR (300 MHz, DMSO-d6) d 2.16
(s, 3H, CH3), 7.20 (d, J = 0.9 Hz, 1H, CH), 7.24 (ddd,
J = 7.5, 7.2, 1.0 Hz, 1H, CH), 7.325 (ddd, J = 8.4, 7.2,
1.5 Hz, 1H, CH), 7.56 (ddd, J = 8.1, 1.8, 0.9 Hz, 1H,
CH), 7.64 (ddd, J = 7.0, 1.5, 0.6 Hz, 1H, CH), 11.62 (s,
1H, OH). 13C NMR (50 MHz, DMSO-d6) d 11.06 (CH3),
105.53 (CH), 111.35 (CH), 121.40 (CH), 123.16 (CH),
125.24 (CH), 127.89 (C), 145.88 (C), 152.75 (C), 154.33
(C@N).
4.5. 1-(Benzofuran-2-yl)ethanone oxime O-benzyl ether 8
4.2. Materials
A 60% dispersion of sodium hydride in mineral oil (0.80 g,
20 mmol) was washed with n-hexane (2 ꢂ 10 mL), after
which DMF (10 mL) was added and the mixture was
cooled to 0 °C. A solution of 7 (3.07 g, 17.5 mmol) in
DMF (20 mL) was added and the mixture was stirred for
1 h at room temperature. Benzyl chloride (2.53 g, 20 mmol)
was added and the mixture was stirred for 18 h at room
temperature. The solvent was removed under reduced pres-
sure and the product was extracted with diethyl ether
(3 ꢂ 10 mL). Extracts were washed with saturated brine
(40 mL) and dried with anhydrous magnesium sulfate.
Ether was removed and the product 4.20 g, 90%, mp 81–
83 °C was obtained. Lit.39 mp 84 °C. 1H NMR (300
MHz, DMSO-d6) d 2.24 (s, 3H, CH3), 5.25 (s, 2H, CH2),
7.23–7.43 (m, 8H, CH), 7.60 (ddd, J = 5.4, 1.2, 0.6 Hz,
1H, CH), 7.66 (ddd, J = 5.2, 1.0, 0.4 Hz, 1H, CH). 13C
NMR (75 MHz, DMSO-d6) d 12.01 (CH3), 75.77 (CH2),
107.64 (CH), 111.32 (CH), 121.65 (CH), 123.32 (CH),
125.82 (CH), 127.60 (C), 127.78 (CH), 127.84 (2CH),
Silica Gel 60, Merck 230–400 mesh, was used for prepara-
tive column flash chromatography. Analytical TLC was
performed using Macherey-Nagel Polygram Sil G/UV254
0.2 mm plates. THF was freshly distilled from sodium
benzophenone ketyl. (1S,3S,4R,6R)-4-Amino-3,7,7-tri-
methylbicyclo[4.1.0]heptan-3-ol,21 1-(benzofuran-2-yl)etha-
none,20 N,O-bis(diphenoxycarbonyl)hydroxylamine22 and
1-(benzo[b]thiophen-2-yl)ethanone36
according to the literature.
were
prepared
4.3. (S)-(ꢀ)-1-(Benzofuran-2-yl)ethanol 5
A solution of (1S,3S,4R,6R)-4-amino-3,7,7-trimethylbi-
cyclo[4.1.0]heptan-3-ol (0.23 g, 1.5 mmol) and triisopropo-
xyborane (0.31 g, 1.65 mmol) in tetrahydrofuran (75 mL)
was stirred for 1 h at room temperature, and 0.5 M
borane–tetrahydrofuran (30 mL, 15 mmol) was added.

960
M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
128.32 (2CH), 137.69 (C), 147.12 (C), 151.30 (C), 154.46
(C@N). Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70;
N, 5.28. Found: C, 76.58; H, 5.61; N, 5.44.
111.25 (CH), 120.84 (CH), 122.67 (CH), 124.16 (CH),
128.11 (C), 128.55 (2CH), 128.73 (CH), 129.02 (2CH),
134.81 (C), 154.60 (C), 156.80 (C), 161.44 (C@O). MS
(ESI) m/z 333.1 (M++Na, 100). MS (EI, 70 eV) 235
(13.51), 208 (12.36), 203 (13.10), 160 (17.91), 146 (16.81),
145 (66.61), 144 (19.68), 117 (10.34), 115 (18.15), 108
(10.69), 91 (100.00), 79 (13.14), 77 (15.36). Anal. Calcd
for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03. Found: C,
69.81; H, 5.78; N, 8.89.
4.6. (R)-(+)-N-(1-(Benzofuran-2-yl)ethyl)-O-benzylhydr-
oxylamine 9
To a solution of (1R,2S,3R,4S)-3-amino-1,7,7-trimethylbi-
cyclo[2.2.1]heptan-2-ol (1.02 g, 6.0 mmol) in THF (30 mL)
was added 10 M borane–dimethyl sulfide (1.2 mL,
12 mmol) and the mixture was stirred for 1 h at room tem-
perature. A solution of 8 (1.32 g, 5.0 mmol) in THF
(10 mL) was added over 1.5 h at room temperature and
the mixture was stirred for 48 h. Then 3 M hydrochloric
acid (20 mL, 60 mmol) was added at 0 °C and the mixture
was stirred for 18 h. Tetrahydrofuran was removed under
reduced pressure and the remaining mixture was basified
with 10% aqueous sodium hydroxide to pH 12, stirred
for 30 min, and extracted with ethyl acetate (3 ꢂ 20 mL).
The combined extracts were dried with anhydrous magne-
sium sulfate, the solvent was removed and the product was
isolated by flash chromatography on silica gel, n-hexane–
4.8. (R)-(+)-N-1-(Benzofuran-2-yl)ethyl-N-hydroxyurea
(R)-1
4.8.1. From 17 by hydrogenolysis. To a solution of 17
(0.50 g, 1,6 mmol) in methanol (15 mL) was added 20%
Pd(OH)2/C (0.1 g). The mixture was degassed and hydro-
genated under 1.0 atm pressure for 2 h at room tempera-
ture. The catalyst was filtered off and volatiles were
removed under reduced pressure, 0.29 g, 83%, 92% ee by
HPLC analysis on a chiral OJ column, n-hexane–isopropa-
nol 9:1 (tR 21.00 S, 22.87 R; f = 0.7 mL/min; T = 35 °C;
p = 24 kg f/cm2). The product was crystallized from ethyl
22
acetate–n-hexane 2:1, mp 147–148 °C, ½aꢁD ¼ þ14:4 (c
22
ethyl acetate, 4:1, pale yellow oil, 0.82 g, 61%, bp 150–
20
154 °C/0.1 mmHg, ½aꢁD ¼ þ46:6 (c 1.77, CHCl3), 92% ee,
0.42, DMSO), ½aꢁD ¼ þ52:9 (c 0.44, MeOH), >99% ee by
by HPLC analysis on a chiral OJ column, n-hexane–isopro-
panol 9:1 (tR 22.40 S, 26.87 R; f = 0.7 mL/min; T = 35 °C;
p = 25 kg f/cm2). The racemate was also analyzed. 1H
NMR (300 MHz, DMSO-d6) d 1.36 (d, J = 6.6 Hz, 3H,
CH3), 4.26 (quintet, J = 6.6 Hz, 1H, CH), 4.53 (d,
J = 11.7 Hz, 1H, CH2), 4.56 (d, J = 11.7 Hz, 1H, CH2),
6.74 (s, 1H, CH), 6.93 (d, J = 6.0 Hz 1H, NH), 7.15–7.40
(m, 7H, CH), 7.52 (dm, J = 7.5 Hz, 1H, CH), 7.56 (dm,
J = 7.5, 1H, CH). 13C NMR (75 MHz, DMSO-d6) d
16.67 (CH3), 53.62 (CH), 75.64 (CH2), 102.88 (CH),
110.92 (CH), 120.78 (CH), 122.64 (CH), 123.68 (CH),
127.43 (CH), 128.08 (4CH), 128.22 (C), 138.13 (C),
153.91 (C), 159.74 (C). MS: EI 70 eV m/z: 267 (M+, 1.6),
235 (27.2), 208 (17.8), 146 (11.1), 145 (77.6), 92 (15.0), 91
(100.00). Anal. Calcd for C17H17NO2: C, 76.38; H, 6.41;
N, 5.24. Found: C, 76.81; H, 6.48; N, 5.19.
HPLC analysis on a chiral OJ column, n-hexane–isopropa-
nol 9:1 (tR 23.94 R; f = 0.7 mL/min; T = 35 °C; p =
1
22 kg f/cm2). The racemate was also analyzed. H NMR
(200 MHz, DMSO-d6) d 1.45 (d, J = 7.0 Hz, 3H, CH3),
5.46 (qd, J = 7.0, 1.0 Hz, 1H, CH), 6.46 (s, 2H, NH2),
6.71 (dd, J = 1.0, 0.8 Hz, 1H, CH), 7.18 (td, J = 7.6,
2.2 Hz, 1H, CH), 7.23 (td, J = 7.6, 2.2 Hz, 1H, CH), 7.49
(dm, J = 8.0, 1H, CH), 7.54 (dm, J = 7.0, 1H, CH), 9.16
(s, 1H, OH). 13C NMR (50 MHz, CDCl3) d 14.86 (CH3),
50.44 (CH), 103.48 (CH), 110.87 (CH), 120.72 (CH),
122.56 (CH), 123.74 (CH), 128.10 (C), 153.86 (C), 158.22
(C), 161.42 (C@O). MS (EI, 70 eV) m/z 220 (M+, 3), 203
(30.14), 160 (22.98), 146 (19.55), 145 (100.00), 144
(22.20), 117 (16.41), 115 (21.16), 91 (12.03). Anal. Calcd
for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C,
59.79; H, 5.52; N, 12.75.
4.7. (R)-(ꢀ)-N-1-(Benzofuran-2-yl)ethyl-N-benzyloxyurea
4.8.2. From 5 by substitution. To a solution of 5 (0.97 g,
17
6.0 mmol),
N,O-bis(phenoxycarbonyl)hydroxylamine
(1.80 g, 6.6 mmol) and triphenylphosphine (1.89 g,
7.2 mmol) in tetrahydrofuran (30 mL) was slowly added
at 0 °C over 2 h a solution of diisopropyl azodicarboxylate
(1.46 g, 7.2 mmol) in tetrahydrofuran (6 mL) and the mix-
ture was left overnight at room temperature. The solvent
was removed and the yellow oil (1.31 g), isolated by flash
chromatography on silica gel, petroleum ether–ethyl ace-
tate, 9:1, was added to a mixture of tert-butanol (8 mL)
and liquid ammonia (8 mL) at ꢀ78 °C in a glass pressure
vessel and was stirred overnight at room temperature.
The vessel was cooled, opened and ammonia was evapo-
rated at room temperature. Volatiles were removed under
reduced pressure at room temperature and the product
was isolated by flash chromatography on silica gel, dichlo-
romethane–methanol 95:5, 0.55 g, 76%, mp 139–140 °C,
Chlorosulfonyl isocyanate (1.13 g, 8.0 mmol) was added
dropwise to a solution of 9 (1.34 g, 5.0 mmol) at ꢀ78 °C
and the mixture was stirred for 2 h at this temperature.
Water (20 mL) was added, and stirring was continued for
24 h at room temperature. The organic layer was separated
and the aqueous layer extracted with dichloromethane
(3 ꢂ 15 mL). The combined organic solutions were dried
with anhydrous magnesium sulfate. The solvent was
removed and the product was isolated by flash chromato-
graphy on silica gel, petroleum ether–ethyl acetate, 1:1,
24
1.50 g, 95%, mp 103–105 °C. ½aꢁD ¼ ꢀ39:7 (c 0.39, CHCl3)
1H NMR (200 MHz, CDCl3) d 1.67 (d, J = 7.0 Hz, 3H,
CH3), 4.48 (d, J = 10.4 Hz, 1H, CH2), 4.66 (d,
J = 10.4 Hz, 1H, CH2), 5.37 (br s, 2H, NH2), 5.66 (dq,
J = 7.0, 1.0 Hz, 1H, CH), 6.73 (dd, J = 1.4, 1.0 Hz, 1H,
CH), 7.20–7.60 (m, 9H, CH). 13C NMR (50 MHz, CDCl3)
d 14.40 (CH3), 52.15 (CH), 78.74 (CH2), 104.49 (CH),
25
1
½aꢁD ¼ þ7:4 (c 0.95, DMSO). H and 13C NMR spectra
the same as described above. HPLC analysis on a chiral
OJ column, n-hexane–ethanol 9:1 (tR 21.00 S, 22.87 R;

M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
961
f = 0.7 mL/min; T = 35 °C; p = 24 kg f/cm2) showed 50%
with dichloromethane (3 ꢂ 20 mL). The extracts were com-
bined and dried with anhydrous magnesium sulfate. The
solvent was removed under reduced pressure, and the prod-
uct was isolated by flash chromatography on silica gel, n-
hexane–ethyl acetate, 9:1, 0.71 g, 50%, mp 58–60 °C,
ee. The racemate was also analyzed.
4.9. 1-(Benzo[b]thiophen-2-yl)ethanone oxime 24
20
20
A
mixture of 1-(benzo[b]thiophen-2-yl)ethanone 23
½aꢁD ¼ þ34:7 (c 1.70, CHCl3). Lit.16 ½aꢁD ¼ þ35:9 (c 1.70,
CHCl3). HPLC analysis on a chiral OJ column, n-hex-
ane–isopropanol 8:2 (tR 23.71 R, 30.54 S; f = 0.7 mL/
min; T = 35 °C; p = 5 kg f/cm2) showed 95% ee. The race-
(15.86 g, 90 mmol), hydroxylamine hydrochloride
(12.50 g, 180 mmol), sodium acetate (20.50 g, 250 mmol),
ethanol (100 mL) and water (100 mL) was refluxed for
4 h, cooled and left overnight in a refrigerator. The crystal-
line product was filtered off, washed with cold water
(10 mL) and dried, 16.43 g, 95%, mp 188–189 °C. Lit.40
1
mate was also analyzed. H NMR (300 MHz, CDCl3) d
1.51 (d, J = 6.6 Hz, 3H, CH3), 4.51 (q, J = 6.6 Hz, 1H,
CH), 4.72 (s, 2H, CH2), 5.66 (br s, 1H, NH), 7.21–7.44
(m, 8H, CH), 7.70 (dm, J = 6.5 Hz, 1H, CH), 7.82 (dm,
J = 6.5 Hz, 1H, CH). 13C NMR (50 MHz, CDCl3) d,
20.25 (CH3), 56.75 (CH), 76.84 (CH2), 120.82 (CH),
122.29 (CH), 123.19 (CH), 123.87 (CH), 124.03 (CH),
127.74 (CH), 128.26 (2CH), 128.45 (2CH), 137.66
(C), 139.48 (C), 139.49 (C), 147.71 (C). MS (EI, 70 eV)
m/z 283 (M+, 4.85), 251 (25.78), 250 (22.21), 224 (15.87),
162 (14.07), 161 (100.00), 160 (16.94), 128 (17.77), 91
(94.16). Anal Calcd for C17H17NOS: C, 72.05; H, 6.05;
N, 4.94; S, 11.31. Found: C, 72.26; H, 6.00; N, 4.83; S,
11.40.
1
mp 183–184 °C. H NMR (300 MHz, DMSO-d6) d 2.34
(s, 3H, CH3), 7.32 (t, J = 2.8, 1H, CH), 7.35 (t, J = 2.8,
1H, CH), 7.68 (s, 1H, CH), 7.80 (m, 1H, CH), 7.86 (m,
1H, CH), 11.53 (s, 1H, OH). 13C NMR (75 MHz,
DMSO-d6) d 11.46 (CH3), 122.22 (CH), 123.12 (CH),
123.91 (CH), 124.48 (CH), 125.40 (CH), 138.81 (C),
139.36 (C), 141.32 (C), 149.95 (C@N).
4.10. 1-(Benzo[b]thiophen-2-yl)ethanone oxime O-benzyl
ether 25
A 60% dispersion of sodium hydride in mineral oil (2.40 g,
50 mmol) was washed with n-hexane (2 ꢂ 15 mL), after
which DMF (70 mL) was added and the mixture was
cooled to 0 °C. A solution of 24 (8.61 g, 45 mmol) in
DMF (80 mL) was added dropwise, the mixture was stirred
for 30 min at 0 °C and for 30 min at room temperature. It
was cooled to 0 °C, after which benzyl chloride (8.22 g,
50 mmol) was added, and stirring was continued for 18 h
at room temperature. The solvent was removed under
reduced pressure, water (150 mL) was added and the
mixture was extracted with diethyl ether (3 ꢂ 50 mL).
The combined extracts were washed with saturated brine
and dried over anhydrous magnesium sulfate. The solvent
was removed and the product, 12.50 g, 98%, mp 92–94 °C,
4.12. (R)-(ꢀ)-N-1-(Benzo[b]thiophen-2-yl)ethyl-N-benzyl-
oxyurea 27
A solution of 26 (0.85 g, 3.0 mmol) in dichloromethane
(8 mL) was cooled to ꢀ78 °C, after which chlorosulfonyl
isocyanate (0.70 g, 4.8 mmol) was added and the mixture
was stirred for 2 h at ꢀ78 °C. Water (15 mL) was added
and stirring was continued for 18 h at room temperature.
Dichloromethane (20 mL) was added, after which the
organic layer was separated, and the aqueous layer was
extracted with dichloromethane (2 ꢂ 10 mL). The combined
organic solutions were dried with anhydrous magnesium
sulfate. The solvent was removed under reduced pressure
and the product was isolated by flash chromatography on
silica gel, n-hexane–ethyl acetate, 2:1, 0.87 g, 89%, mp
1
was obtained. H NMR (300 MHz, CDCl3) d 2.34 (s, 3H,
CH3), 5.27 (s, 2H, CH2), 7.30–7.48 (m, 8H, CH), 7.70–
7.80 (m, 2H, CH). 13C NMR (75 MHz, CDCl3) d 12.55
(CH3), 76.60 (CH2), 122.16 (CH), 123.11 (CH), 123.78
(CH), 124.26 (CH), 125.35 (CH), 127.90 (CH), 128.34
(2CH), 128.38 (2CH), 137.51 (C), 139.34 (C), 139.95 (C),
140.75 (C), 151.10 (C@N). MS (EI, 70 eV) m/z 281 (M+,
24.21), 91 (100.00). Anal. Calcd for C17H15NOS: C,
72.57; H, 5.37; N, 4.98; S, 11.40. Found: C, 72.47; H,
5.33; N, 4.96; S, 11.58.
25
25
134–136 °C, ½aꢁD ¼ ꢀ63:3 (c 1.33, EtOH); ½aꢁD ¼ ꢀ39:1 (c
20
1.00, CHCl3). Lit.16 ½aꢁD ¼ ꢀ40:5 (c 1.11, CHCl3). 1H
NMR (300 MHz, CDCl3) d 1.74 (d, J = 6.9 Hz, 3H,
CH3), 4.68 (d, J = 10.5 Hz, 1H, CH2), 4.79 (d, J =
10.5 Hz, 1H, CH2), 5.22 (br s, 2H, NH2), 5.75 (q,
J = 6.0 Hz, 1H, CH), 7.26–7.38 (m, 8H, CH), 7.735 (dm,
J = 6.6 Hz, 1H, CH), 7.40 (dm, J = 6.6 Hz, 1H, CH). 13C
NMR (50 MHz, CDCl3) d 17.35 (CH3), 54.53 (CH),
79.11 (CH2), 122.15 (CH), 122.24 (CH), 123.44 (CH),
124.10 (CH), 124.15 (CH), 128.60 (2CH), 128.72 (CH),
128.91 (2CH), 134.91 (C), 139.22 (C), 139.64 (C), 144.81
(C), 161.46 (C@O). MS (EI, 70 eV) m/z 236 (M+), 219
(24.15), 176 (16.04), 175 (12.11), 162 (26.737), 161
(100.00), 160 (33.40), 134 (17.27), 128 (29.40), 115
(13.48), 89 (13.56), 43 (10.26).
4.11. (R)-(+)-N-(1-(Benzo[b]thiophen-2-yl)ethyl)-O-benz-
ylhydroxylamine 26
A
9 M borane–dimethyl sulfide complex (1.33 mL,
12.0 mmol) was added to a solution of 21 (1.01 g,
6.0 mmol) in THF (10 mL) at room temperature and the
mixture was stirred for 1 h. A solution of 25 (1.41 g,
5.0 mmol) in THF (15 mL) was slowly added in 2.5 h and
the mixture was stirred for 40 h at room temperature. A
3 M hydrochloric acid (20 mL) was added at 0 °C and
the mixture was stirred for 18 h at room temperature. Tet-
rahydrofuran was removed under reduced pressure, and
the aqueous solution was alkalized with 10% aqueous so-
dium hydroxide to pH 11, stirred for 30 min and extracted
4.13. (R)-(+)-N-1-(Benzo[b]thiophen-2-yl)ethyl-N-hydroxy-
urea (R)-2
To a degassed solution of 27 (0.17 g, 0.52 mmol) in ethanol
(12 mL) were added ammonium formate (0.94 g, 15 mmol)
and palladium catalyst (1.4 g, 10% Pd/C E101.NE/
W + 50% H2O), and the mixture was stirred for 4 h at

962
M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
room temperature. The catalyst was filtered off through a
pad of Celite. Ethanol was removed from the filtrate under
reduced pressure. Water (20 mL) was added and the prod-
uct was extracted with ethyl acetate (3 ꢂ 10 mL). The com-
bined extracts were dried with anhydrous magnesium
sulfate. The solvent was removed under reduced pressure
and the product was isolated by flash chromatography on
silica gel, dichloromethane–methanol 95:5 and purified by
4.15. (1R,2S,6R,7S)-(ꢀ)-1,10,10-Trimethyl-3-oxa-5-azatri-
cyclo[5.2.1.02,6]decan-4-one 22
A solution of 19 (7.25 g, 40 mmol) in diethyl ether (30 mL)
was added dropwise to a solution of lithium tetrahydrido-
aluminate (4.55 g, 120 mmol) in diethyl ether (40 mL) and
the mixture was refluxed for 24 h. It was cooled in an ice-
water bath, after which ethyl acetate (4.6 mL) was added
dropwise with stirring, followed after 5 min with 10% aque-
ous sodium hydroxide solution (4.6 mL), water (10 mL),
diethyl ether (100 mL), and stirring was continued for 4 h
at room temperature. The mixture was filtrated, washed
with saturated brine (10 mL) and dried with anhydrous
magnesium sulfate. Ether was removed and to the crude
solid product 21 (6.42 g), dimethoxyethane (230 mL) and
6 M aqueous sodium hydroxide solution (22 mL,
130 mmol) were added. A solution of triphosgene (4.37 g,
14.7 mmol) in dichloromethane (90 mL) was added
dropwise at ꢀ5 °C, stirring was continued for 1 h at this
temperature, and for 2.5 h at room temperature. Water
(50 mL) was added and the organic layer was separated.
The aqueous layer was extracted with dichloromethane
(2 ꢂ 50 mL), and the combined organic solutions were
washed with 10% acetic acid (100 mL), water (50 mL)
and dried over anhydrous magnesium sulfate. Solvents
were removed under reduced pressure and the product
was isolated by flash chromatography on silica gel, petro-
leum ether–ethyl acetate (1:1), 5.29 g, 67%. After crystalliz-
preparative HPLC on C18 column, methanol–water 4:1,
22
0.087 g, 71%, mp 148–149 °C. ½aꢁD ¼ þ44:9 (c 0.315,
MeOH), 95% ee, by HPLC analysis on a chiral OJ column,
n-hexane–isopropanol 8:2 (tR 14.02 S, 16.47 R; f = 0.7 mL/
min; T = 35 °C; p = 25 kg f/cm2). Lit.17 mp 148–149 °C,
24
½aꢁD ¼ þ47:0 (c 1.1, MeOH), lit.16 [a]D = +50.3 (c 0.35,
MeOH). 1H NMR (300 MHz, DMSO-d6) d 1.50 (d,
J = 6.9 Hz, 3H, CH3), 5.55 (qd, J = 6.9, 0.9 Hz, 1H,
CH), 6.44 (s, 2H, NH2), 7.25 (dd, J = 1.0, 0.9 Hz, 1H,
CH), 7.28 (td, J = 7.2 Hz, 1H, CH), 7.32 (td, J = 7.2 Hz,
1H, CH), 7.76 (dm, J = 6.6 Hz, 1H, CH), 7.87 (dm, J =
6.5 Hz, 1H, CH), 9.22 (s, 1H, OH). 13C NMR (75 MHz,
CDCl3) d 17.86 (CH3), 52.32 (CH), 121.26 (CH), 122.12
(CH), 123.19 (CH), 123.89 (CH), 124.06 (CH), 138.92
(C), 139.05 (C), 146.10 (C), 161.35 (C@O). Anal. Calcd
for C11H12N2O2S: C, 55.91; H, 5.12; N, 11.87; S, 13.57.
Found: C, 56.00; H, 5.32; N, 11.61; S, 13.45.
4.14. (E)-(1R)-(+)-3-Hydroxyimino-1,7,7-trimethylbi-
cyclo[2.2.1]heptan-2-one 19
ation from n-hexane–ethyl acetate (2:1), mp 154–155 °C,
26
½aꢁD ¼ ꢀ44:8 (c 1.72, CHCl3). Lit.29 mp 156–158 °C,
22
A solution of (1R)-(+)-camphor 18 (7.61 g, 50 mmol) in
tetrahydrofuran (10 mL) was slowly added to a solution
of potassium tert-butoxide (6.73 g, 60 mmol) in tetrahydro-
furan (20 mL) at ꢀ30 °C, and the mixture was stirred for
10 min. Isoamyl nitrite (7.03 g, 60 mmol) was added over
20 min at ꢀ30 °C, the mixture was stirred for 10 min, and
then left overnight at room temperature. Tetrahydrofuran
was removed under reduced pressure, after which water
(50 mL) was added, and the solution was extracted with
diethyl ether (3 ꢂ 15 mL). The aqueous solution was di-
luted with water (150 mL) and acidified with acetic acid
to pH 6. A pale yellow precipitate was filtered off, washed
with water (10 mL) and dried, 7.80 g, 80%, mp 116–119 °C.
1H NMR (CDCl3) analysis showed a mixture of E/Z iso-
mers, 26:74. Diagnostic signals in the spectrum: Z-isomer,
2.72 (d, J = 4.2 Hz, 1H, CH), E-isomer, 3.25 (d,
J = 4.5 Hz, 1H, CH). A mixture of isomers (7.50 g) was
refluxed with water (25 mL) for 18 h under nitrogen. After
cooling to room temperature, the mixture was extracted
with diethyl ether (2 ꢂ 25 mL), and the extract was dried
with anhydrous magnesium sulfate. Ether was removed
½aꢁD ¼ ꢀ43:4 (c 2.02, CHCl3). 1H NMR (300 MHz,
CDCl3) d 0.91 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.11 (s,
3H, CH3), 0.95–1.07 (m, 2H, 2CH2), 1.48–1.60 (m, 1H,
CH2), 1.65–1.80 (m, 1H, CH2), 1.85 (d, J = 4.5 Hz, 1H,
CH), 3.76 (d, J = 8.0 Hz, J = 1,2 Hz, 1H, CH–N), 4.39
(d, J = 8.0 Hz, 1H, CH–O), 5.68 (br s, 1H, NH). 13C
NMR (75 MHz, CDCl3) d 19.44 (CH3), 23.26 (2CH3),
24.76 (CH2), 31.74 (CH2), 46.36 (C), 48.18 (C), 48.68
(CH), 60.54 (CH), 88.40 (CH), 160.41 (C@O).
4.16. (1R,2S,3R,4S)-(ꢀ)-3-Amino-1,7,7-trimethylbi-
cyclo[2.2.1]heptan-2-ol 21
A mixture of 22 (3.90 g, 20.0 mmol), sodium hydroxide
(3.20 g, 80 mmol), ethanol (45 mL) and water (25 mL)
was refluxed for 6 h. The solution was concentrated under
vacuum to half of its volume, and extracted with diethyl
ether (3 ꢂ 25 mL). The combined extract was dried with
anhydrous magnesium sulfate, after which ether was
removed, and a white crystalline product was obtained,
22
3.32 g, 98%, mp 211–212 °C, ½aꢁD ¼ ꢀ8:2 (c 1.15, MeOH).
22
1
and a pale yellow product was obtained, 7.35 g, 98%, mp
Lit.29 mp 200 °C, ½aꢁD ¼ ꢀ6:2 (c 1.01, MeOH). H NMR
(300 MHz, CDCl3) d 0.76 (s, 3H, CH3), 0.92 (s, 3H,
CH3), 1.03 (s, 3H, CH3), 0.93–1.06 (m, 2H, 2CH2), 1.34–
1.46 (m, 1H, CH2), 1.53 (d, J = 4.5 Hz, 1H, CH), 1.59–
1.73 (m, 1H, CH2), 2.51 (br s, 3H, –OH, –NH2), 3.02 (d,
J = 7.2 Hz, 1H, CH–N), 3.35 (d, J = 7.2 Hz, 1H, CH–O).
13C NMR (75 MHz CDCl3) d 11.35 (CH3), 21.16 (CH3),
21.88 (CH3), 26.83 (CH2), 33.07 (CH2), 46.55 (C), 48.64
(C), 53.30 (CH), 57.28 (CH), 79.44 (CH). Anal. Calcd for
C10H19NO: C, 70.96; H, 11.31; N, 8.28. Found: C, 70.81;
H, 11.32; N, 8.11.
26
150–151 °C, ½aꢁD ¼ þ199 (c 1.41, CHCl3). Lit.39 mp
25
1
150 °C, ½aꢁD ¼ þ185 (c 4.5, CHCl3). H NMR (300 MHz,
CDCl3) d 0.86 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.03 (s,
3H, CH3), 1.50–1.63 (m, 2H, CH2), 1.70–1.84 (m, 1H,
CH2), 1.99–2.12 (m, 1H, CH2), 3.25 (d, J = 4.5 Hz, 1H,
CH), 8.50 (s, 1H, OH). The spectrum also contains a small
doublet (3%) at 2.72 ppm (Z-isomer). 13C NMR (50 MHz,
CDCl3) d 8.90 (CH3), 17.60 (CH3), 20.66 (CH3), 23.75
(CH2), 30.66 (CH2), 44.89 (C), 46.62 (CH), 58.51 (C),
159.71 (C@N), 204.30 (C@O).

M. J. Bosiak et al. / Tetrahedron: Asymmetry 19 (2008) 956–963
963
16. Hsiao, C.-N.; Kolasa, T. Tetrahedron Lett. 1992, 33, 2629–
2632.
Acknowledgement
17. Basha, A.; Henry, R.; McLaughlin, M. A.; Ratajczyk, J. D.;
Wittenberger, S. J. J. Org. Chem. 1994, 59, 6103–6106.
18. Rohloff, J. C.; Alfredson, T. V.; Schwartz, M. A. Tetrahedron
Lett. 1994, 35, 1011–1014.
Financial support from the Committee for Scientific
Research, Warsaw, Grant PBZ-KBN-126/T09/2004, is
acknowledged.
´
19. Ła˛czkowski, K. R.; Pakulski, M. M.; Krzeminski, M. P.;
Jaisankar, P.; Zaidlewicz, M. Tetrahedron: Asymmetry,
doi:10.1016/j.tetasy.2008.03.008.
References
20. Elliot, E. D. J. Am. Chem. Soc. 1951, 73, 754.
1. Stewart, A. O.; Bhatia, P. A.; Martin, J. G.; Summers, J. B.;
Rodriques, K. E.; Martin, M. B.; Holms, J. H.; Moore, J. L.;
Craig, R. A.; Kolasa, T.; Ratajczyk, J. D.; Mazdiyasni, H.;
Kerdesky, F. A. J.; DeNinno, S. L.; Maki, R. G.; Bouska, J.
B.; Young, P. R.; Lanni, C.; Bell, R. L.; Carter, G. W.;
Brooks, C. D. W. J. Med. Chem. 1997, 40, 1955–1968.
2. Lewis, T. A.; Bayless, L.; Eckman, J. B.; Ellis, J. E.; Grewal,
G.; Libertine, L.; Nicolas, J. M.; Scanell, R. T.; Wels, B. C.;
Wenberg, K.; Wypij, D. M. Bioorg. Med. Chem. Lett. 2004,
14, 2265–2268.
´
21. Krzeminski, M. P. PL Pat. Appl. 383483, 10.04, 2007.
22. Stewart, A. O.; Brooks, D. W. J. Org. Chem. 1992, 57, 5020–
5023.
23. Kaufman, T. S. Tetrahedron Lett. 1996, 37, 5329–5332.
24. Hiller, C.; Desrosiers, J.-N.; Marcoux, J.-F.; Grabowski, E. J.
J. Org. Lett. 2004, 6, 573–576.
25. Chittenden, R. A.; Cooper, G. H. J. Chem. Soc. C 1970, 49–
54.
26. Beckett, A. H.; Lan, N. T.; McDonough, G. R. Tetrahedron
1969, 25, 5689–5692.
3. Zaitsev, S. A.; Onuchina, O. A.; Alekseeva, L. M.; Arza-
mastsev, A. P.; Kalinkina, M. A.; Granik, V. G. Pharm.
Chem. J. 2005, 39, 636–640.
27. Davies, S. R.; Mitchel, M. C.; Cain, C. P.; Devitt, P. G.;
Taylor, R. J.; Kee, T. P. J. Organomet. Chem. 1998, 550, 29–
57.
4. Lantos, I.; Flisak, J.; Liu, L.; Matsuoka, R.; Mendelson, W.;
Stevenson, D.; Tubman, K.; Tucker, L.; Zhang, W.-Y.;
Adams, J.; Sorenson, M.; Garigipati, R.; Erhardt, K.; Ross,
S. J. Org. Chem. 1997, 62, 5385–5391.
5. Samuelsson, B.; Dahlen, S. E.; Lindgren, J. A.; Rouzer, C. A.;
Serhan, C. N. Science 1987, 237, 1171–1176.
6. Balkan, A.; Berk, B. Curr. Med. Chem.—Anti-Inflammatory
& Anti-Allergy Agents 2003, 2, 9–18.
7. Osher, E.; Weisinger, G.; Limor, R.; Tordjman, K.; Stern, N.
Mol. Cell. Endocrinol. 2006, 252, 201–206.
8. Brooks, D. W.; Carter, G. W. The Discovery of Zileuton. In
The Search for Anti-Inflammatory Drugs; Merluzzi, V. J.,
Adams, J., Eds.; Birkhauser: Boston, 1995; pp 129–160,
Chapter 5.
9. Summers, J. B.; Gunn, B. P.; Brooks, D. W. U.S. Patent
4873259, October 10, 1989.
10. Basha, A.; Ratajczyk, J. D.; Brooks, D. W. Tetrahedron Lett.
1991, 32, 3783.
11. Stewart, A. O.; Brooks, D. W. J. Org. Chem. 1992, 57,
5020.
28. Yanagi, T.; Kikuchi, K.; Takeuchi, H.; Ishikawa, T.;
Nishimura, T.; Yamamoto, I. Chem. Pharm. Bull. 2001, 49,
1018–1023.
29. Tanaka, K.; Ushio, H.; Kawabata, Y.; Suzuki, H. J. Chem.
Soc., Perkin Trans. 1 1991, 1445–1451.
30. Gawley, R. E.; Zhang, P. J. Org. Chem. 1996, 61, 8103–
8112.
31. Daniel, A.; Pavia, A. A. Bull. Soc. Chim. Fr. 1971, 3, 1060–
1074.
32. Xu, Z.; Chen, C.; Xu, J.; Miao, M.; Yan, W.; Wang, R. Org.
Lett. 2004, 6, 1193–1195.
33. Bonner, M. P.; Thornton, E. R. J. Am. Chem. Soc. 1991, 113,
1299–1308.
34. Cheng, G.-I.; Shei, C.-T.; Sung, K. Chirality 2007, 19, 235–
238.
35. Miljkovic, D.; Petrovic, J.; Stajic, M.; Miljkovic, M. J. Org.
Chem. 1973, 38, 3585–3588.
36. Hsiao, C.-N.; Bhagavatula, L.; Pariza, R. J. Synth. Commun.
1990, 20, 1687–1695.
37. Zaidlewicz, M.; Chechłowska, A.; Prewysz-Kwinto, A.;
Wojtczak, A. Heterocycles 2001, 55, 569–578.
38. Vargha, L.; Ramonczai, J.; Bathory, J. J. Am. Chem. Soc.
1949, 71, 2652–2654.
39. Roy, S.; Chakraborti, A. K. Tetrahedron Lett. 1998, 39,
6355–6356.
40. Brophy, G. C.; Sternhell, S.; Brown, N. M. D.; Brown, I.;
Armstrong, K. J.; Martin-Smith, M. J. Chem. Soc. C 1970,
933–937.
12. Ku, Y.-Y.; Patel, R. R.; Roden, B. A.; Sawick, D. P.
Tetrahedron Lett. 1994, 35, 6017.
13. Brooks, D. W.; Steward, A. O.; Basha, A.; Bhatia, P.;
Ratajczyk, J. D.; Martin, J. G.; Craig, R. A.; Kolasa, T.;
Bouska, J. B.; Lanni, C.; Harris, R. R.; Malo, P. E.; Carter,
G. W.; Bell, R. L. J. Med. Chem. 1995, 39, 4768.
14. Copp, R. R.; Fohey, B. T.; Lannoye, G. Synth. Commun.
2001, 31, 3081.
15. Garigipati, R. S.; Sorenson, M. E.; Erhard, K. F.; Adams, J.
L. Tetrahedron Lett. 1993, 34, 5537–5540.