Stereoselective synthesis of (2S,7S)-7-(4-phenoxymethyl)-2-(1-N- hydroxyureidyl-3-butyn-4-yl)oxepane: A potential anti-asthmatic drug candidate

Article abstract of DOI:10.1016/j.tetasy.2005.01.024

We have achieved a short, efficient stereoselective synthesis of 7-membered oxepane derivatives with potential against asthma. Highlights of our synthetic strategy are regioselective oxidation of a hydroxyl group and efficient ring closure of an open chai

Full text of DOI:10.1016/j.tetasy.2005.01.024

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 935–939
Stereoselective synthesis of (2S,7S)-7-(4-phenoxymethyl)-
2-(1-N-hydroxyureidyl-3-butyn-4-yl)oxepane: a potential
anti-asthmatic drug candidate
Mukund K. Gurjar,a B. Venkateswara Rao,b L. Murali Krishna,a
Mukund S. Chorghadec,* and Steven V. Leyd
aNational Chemical Laboratory, Pune 411008, India
bIndian Institute of Chemical Technology, Hyderabad 50007, India
cChorghade Enterprises, 14 Carlson Circle, Natick, MA 01760-4205, USA
dDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Received 18 August 2004; revised 13 September 2004; accepted 6 January 2005
Abstract—We have achieved a short, efficient stereoselective synthesis of 7-membered oxepane derivatives with potential against
asthma. Highlights of our synthetic strategy are regioselective oxidation of a hydroxyl group and efficient ring closure of an open
chain aldehyde to a 2-benzenesulfonyl oxepane derivative with PhSO2H. Surprisingly the cis-isomer showed better activity than the
trans-isomer.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Millions of people of every age group, all over the
world, suffer the debilitating effects of chronic asthma.
The occurrence of this disease keeps increasing at a phe-
nomenal rate despite advances in molecular biology and
asthma chemotherapy. Extensive research has been con-
ducted on the clinical management of asthma; a paucity
of effective medications and curative agents has led to
patients exploring alternative therapies. A dramatic
example is seen in the month of June in Hyderabad, a
southern city of India. Millions of people flock to the
city for a traditional medicine popularly known as Ôfish
medicine,Õ where for several years, a herbal concentrate
has been administered through a small fish into the
mouth of a patient.1a
Intensive research is being conducted around the world
for safer and target specific drugs for asthma.1b–h Vari-
ous structural scaffolds and templates have been ex-
plored. Our attention was drawn to (2S,5S)-trans-5-
[(4-fluorophenoxy)methyl]-2-(4-N-hydroxyureidyl-1-but-
ynyl) tetrahydrofuran 1, a compound that was ini-
tially studied as CMI-977 and later renamed as LDP-
977. This compound was initially under clinical investi-
gation2 as a promising candidate for chronic asthma. It
acts primarily by inhibiting the 5-lipoxygenase pathway,
thereby blocking the production of inflammation medi-
atory leukotrienes. It had successfully been evaluated in
animal models; and showed a high degree of potency,
excellent oral bioavailability and an exceptionally
O
O
O
O
F
O
H
H
O
N
NH2
H
H
F
N
NH2
OH
1
OH
2
*
Corresponding author. E-mail: chorghade@comcast.net
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.01.024

936
M. K. Gurjar et al. / Tetrahedron: Asymmetry 16 (2005) 935–939
favourable safety profile.3 Several important structural
features and biological activity of this compound
prompted us to design additional analogues. As part
of an extensive investigation of structure–activity rela-
tionships and preparation of designed combinatorial
libraries we undertook the challenging synthesis of the
seven membered analogue 2.4 Accordingly, the synthesis
was initiated from (S)-4-fluorophenyl glycidyl ether,
which was obtained from the hydrolytic kinetic resolu-
tion of (+)-4-fluorophenylglycidyl ether 3.4f Regioselec-
trans-isomer 2 as a colourless crystalline solid (Scheme
2).
During this work we were also able to synthesize the cis
derivative by elaboration of the minor product obtained
from nucleophilic displacement of the sulfone. These
compounds were then tested for Leukotriene B4 inhibi-
tion in the human whole blood assay. Test compound
activity was determined as per the Cayman LTD enzyme
immunoassay (EIA) and evaluated as IC50 [nM]. The
cis-isomer had an IC50 of 518 nM, whereas the trans-iso-
mer had a value of 1339 nM. Surprisingly, the cis-isomer
showed better activity than the trans-isomer. This could
establish a new paradigm in the pathology of asthma,
wherein generally, it has been proven that the trans-
substituted compounds (mostly 5-membered) are more
effective compounds with good inhibitory activity.
tive opening of epoxide
3
with (4-benzyloxy)
butylmagnesium bromide 4, in the presence of cuprous
cyanide in dry THF gave (2S)–7-benzyloxy-(4-fluoro-
phenoxy)heptane-2-ol 5 in 73% yield.5 Hydroxy com-
pound 6 was obtained by the hydrogenolysis of 5 with
10% Pd–C in ethanol under a hydrogen atmosphere.
The primary hydroxyl group in 6 was selectively oxi-
dized by the slow addition of 2-iodoxy benzoic acid6
in dry DMSO to furnish 7. Surprisingly, the compound
existed solely in the open chain form 7, as evidenced by
the presence of an aldehyde peak and the absence of any
peaks pertaining to the tautomeric lactol in the 1H
NMR spectra.
3. Conclusion
In summary, we have achieved a short, efficient, stereo-
selective synthesis of 7-membered oxepane derivatives
with promise against asthma. Highlights of our syn-
thetic strategy are the regioselective oxidation of a
hydroxyl group and efficient ring closure of an open
chain aldehyde to a 2-benzenesulfonyl oxepane deriva-
tive with PhSO2H. Further efforts are being directed to-
wards a combinatorial library of similar compounds.
The pivotal step of the synthetic strategy, that is, the
diastereoselective installation of the side chain at the
C-2 position was to be performed next. This might be
possible only if hydroxy-aldehyde 7 isomerizes, at least
during the reaction, into the corresponding lactol, which
can then be captured as an oxenium ion in the presence
of any acid by a nucleophile. This strategy is similar to
Lewis acid mediated C-alkylation of glycals and their
methyl derivatives. Recently, Ley et al. have demon-
strated the utility of 2-arenesulfonyl cyclic ether deriva-
tives as synthetic equivalents of less-stable glycal and its
derivatives.7
4. Experimental
All solvents and reagents were purified and dried accord-
ing to procedures described in VogelÕs Text Book of Prac-
tical Organic Chemistry. Melting points were recorded on
Buchi 535 melting point apparatus and are uncorrected.
Optical rotations were measured with a JASCO DIP
Accordingly, we exposed the hydroxy-aldehyde 7 to
benzenesulfinic acid to obtain 2-benzenesulfinyloxepane
derivative 8. The acidity of the reaction medium and the
stability of the benzenesulfonyl derivative may provide
the driving force for the cyclization of 7 to the tauto-
meric glycal and the subsequent facile conversion of
the latter to 8. Nucleophilic displacement of sulfone 8
with tetrahydropyranyloxy-1-butynylmagnesium bro-
mide, in the presence of anhydrous zinc bromide, gave
the THP derivative 9.7a,b Deprotection of the THP
group furnished 10 as the major component in 75% yield
(Scheme 1). This was confirmed as the trans derivative
by NOE experiments in which irradiation of the H-2
proton did not show any enhancement of the H-7
1
370 digital polarimeter. H and 13C NMR spectra were
recorded on Varian FT-200 MHz and Varian Unity-
400 MHz spectrometers using tetramethylsilane (TMS)
as an internal standard. Mass spectra were recorded on
a Finnigan Mat 1210 or MICRO MASS 7070 spectro-
meter at 70 eV using a direct inlet system. FABMS were
recorded on a VG autospec mass spectrometer at 70 eV
using a direct inlet system. Silica gel (60–120) used for col-
umn chromatography was purchased from ACME
Chemical Company, Mumbai, India.
4.1. (2S)-7-Benzyloxy-1-(4-fluorophenoxy) heptan-2-ol 5
1
proton and vice versa. The H NMR spectrum of the
To a suspension of magnesium (1.4 g, 57.6 mmol) in dry
THF (25 mL) was added 1,2-dibromoethane (0.2 mL)
dropwise at room temperature followed by the slow
addition of a solution of 4-benzyloxy-1-bromobutane 4
(7 g, 28.8 mmol) in dry THF (25 mL) under N2 atmo-
sphere. The reaction mixture was stirred for 1 h, cooled
in an ice bath and CuCN (50.0 mg, 0.57 mmol) added
followed by a solution of (S)-4-fluorophenyl glycidyl
ether 3 (2.9 g, 17.3 mmol) in dry THF (30 mL). The
reaction mixture was stirred for 15 min and then
quenched with saturated aqueous ammonium chloride
solution at 0 ꢁC. The organic layer was successively
enantiomerically pure trans product was amenable to
first order splitting. For example, peaks corresponding
to eight methylene protons were observed in the region
of d 1.40–2.12, whereas the oxepane ring protons H-2,
H-7 were localized at d 4.56 and 4.16, respectively.
The molecular formula was confirmed by HRMS analy-
sis with the observed molecular ion peak (M+) at
292.1474 (calcd for C17H21FO3: 292.1477). A Mitsun-
obu8 reaction of 10 with N,O-bis(phenoxycarbonyl)
hydroxylamine 11 gave compound 12. Subsequent treat-
ment of 12 with ammonia in methanol furnished the

M. K. Gurjar et al. / Tetrahedron: Asymmetry 16 (2005) 935–939
937
O
OH
O
a
b
MgBr
F
O
OBn
BnO
+
4
3
F
F
5
OH
OH
c
d
F
O
O
OH
CHO
7
6
e
f
F
O
F
O
O
O
SO2Ph
H
H
H
H
OTHP
8
9
F
O
O
H
OH
10
Scheme 1. Reagents and conditions: (a) 1,2-dibromoethane, CuCN, THF, 0 ꢁC, 1.5 h, 73%; (b) 10% Pd–C, H2, EtOH, rt, 3 h, 93%; (c) IBX, DMSO,
THF, 0 ꢁC–rt, 0.5 h, 62%; (d) PhSO2H, CaCl2, DCM, 0 ꢁC–rt, 3 h, 80.8%; (e) Mg, i-PrBr, 4-tetrahydropyranoyl-1-butyne, ZnBr2, 0 ꢁC–rt, 12 h; (f) p-
TSA, MeOH, rt, 1 h, 10A 70%, 10B 17.5%.
a
F
O
O
F
O
O
O
O
H
H
H
H
OH
O
N
O
OPh
OPh
10
12
b
O
F
O
H
H
N
NH2
2
OH
Scheme 2. Reagents and conditions: (a) 11, PPh3, DEAD, THF, rt, 4 h, 92%; (b) NH3/MeOH, rt, 1 h, 65%.
washed with water and brine, dried over Na2SO4 and
concentrated. The crude product was purified on silica
gel column chromatography using EtOAc–hexane (1:6)
as eluent to give 5 (5.8 g, 73%) as a colourless liquid.
[a]D = +12.0 (c 2.2, CHCl3); 1H NMR (CDCl3,
200 MHz): d 1.35–1.69 (m, 8H, 4 · CH2), 3.45 (t,
J = 6.25 Hz, 2H, CH2OBn), 3.71–3.95 (m, 3H, OCH2,
CHOH), 4.48 (s, 2H, OCH2Ph), 6.82 (m, 2H, Ar), 6.95
(m, 2H, Ar), 7.27–7.35 (m, 5H, Ph); FABMS m/z (rel.
intensity): 332 (M+, 32), 261 (14), 207 (43), 181 (90),
125 (61), 112 (78), 107 (100); HRMS (FAB): calcd for
(C20H25FO3, M+): 332.1787. Found 332.1803.
(rel. intensity): 242 (M+, 9), 126 (13), 112 (100), 95
(31), 43 (78); HRMS (EI): calcd for (C13H19FO3, M+):
242.1318. Found 242.1319.
4.3. (6S)-7-(4-Fluorophenoxy)-6-hydroxyheptanal 7
To a solution of 6 (3.6 g, 14.8 mmol) in dry THF
(60 mL) was added, dropwise, a solution of IBX
(5.0 g, 17.8 mmol) in dry DMSO (4.0 mL) over a period
of 15 min at 0 ꢁC temperature. After 15 min, the reac-
tion mixture was diluted with iced water, filtered
through Celite and concentrated. The residue was ex-
tracted with dry ether, washed with brine, dried over
Na2SO4 and the organic solvent removed under reduced
pressure. The residue was purified by silica gel column
chromatography using EtOAc–hexane (1:9) to give 7
(2.2 g, 62%) as a viscous liquid. [a]D = +12.0 (c 3.77,
CHCl3); IR (neat): 3694–3200 (br), 2941, 1684, 1498,
4.2. (6S)-7-(4-Fluorophenoxy) heptane-1,6-diol 6
A solution of 5 (5.8 g, 17.5 mmol) in ethanol (30 mL),
containing 10% of Pd–C (100 mg) was stirred under an
H2 atmosphere for 3 h. The reaction mixture was filtered
through Celite, washed with ethanol and concentrated.
The residue was purified by silica gel column chroma-
tography using EtOAc–hexane (1:1) to afford 6 (3.92 g,
93%) as a viscous liquid. [a]D = +12.5 (c 3.1, CHCl3);
1H NMR (CDCl3, 200 MHz): d 1.29–1.69 (m, 8H,
4 · CH2), 3.65 (t, J = 6.8 Hz, 2H, CH2OH), 3.82–4.02
(m, 3H, OCH2, CHOH), 6.82 (m, 2H, Ar); EIMS m/z
1
1208, 824 cmÀ1; H NMR (CDCl3, 200 MHz): d. 4–1.8
(m, 6H, 3 · CH2), 2.49 (t, J = 5.47 Hz, 2H, CH2CHO),
3.71–4.05 (m, 4H, OCH2, CHOH), 6.85 (m, 2H, Ar),
6.94 (m, 2H, Ar), 9.8 (s, 1H, CHO); FABMS m/z (rel.
intensity): 240 (M+, 37), 223 (80), 205 (18), 154 (37),
136 (65), 125 (58), 109 (100); HRMS (FAB): calcd for
(C13H17FO3, M+): 240.1161. Found 240.1164.

938
M. K. Gurjar et al. / Tetrahedron: Asymmetry 16 (2005) 935–939
4.4. (2RS,7S)-2-(Benzenesulfonyl)-7-(4-fluoromethyl)
oxepane 8
4.6. (2S,7S)-7-(Fluorophenoxymethyl)-2-[N,O-bis(phen-
oxycarbonyl)-3-butyn-4-yl) oxepane 12
To an ice cold mixture of benzenesulfinic acid (1.8 g,
12.4 mmol) and CaCl2 (1.4 g, 12.5 mmol) in dry CH2Cl2
(50 mL) was added, dropwise, a solution of 7 (2 g,
8.3 mmol) in CH2Cl2 (10 mL). The reaction mixture
was stirred for 3 h at room temperature, filtered through
Celite and washed with CH2Cl2. The combined organic
layer was washed with saturated aqueous Na2CO3,
water, brine and dried over Na2SO4. The solvent was re-
moved under reduced pressure and the residue purified
by silica gel column chromatography using EtOAc–hex-
ane (1:6) as eluent to furnish 8 (2.45 g, 80.8%) as a white
A mixture of (2S,7S)-7-(4-fluorophenoxymethyl)-2-(4-
hydroxybutynyl) oxepane, 10A (0.9 g, 3.1 mmol), TPP
(1.0 g, 3.7 mmol) and N,O-bis(carbophenoxy)hydroxyl-
amine 11 (1.0 g, 3.7 mmol) in dry THF (20.0 mL) was
cooled to 0 ꢁC. Diethylazadicarboxylate (0.64 g,
3.7 mmol) was added dropwise and the reaction mixture
stirred at room temperature for 4 h. The solvent was re-
moved on a rotary evaporator. The residue was parti-
tioned between EtOAc and water, washed with brine,
dried over Na2SO4 and concentrated. The product was
purified by silica gel chromatography using EtOAc–hex-
ane (1:9) to give pure 12 (1.55 g, 92%). [a]D = À46.0 (c
2.4, CHCl3); IR (neat) 3600–3200 (br), 2941, 1678,
1
solid. Mp 126–128 ꢁC; H NMR (CDCl3, 200 MHz): d
1.430–2.20 (m, 7H, 3 · CH2, 1/2 CH2), 2.5 (m, 1H, 1/2
CH2), 3.62 (dd, J = 5.84, 10.75 Hz, 1H, OCH2), 3.82
(dd, J = 4.49, 10.75, 1H, OCH2), 4.45 (m, 1H, H-7),
4.72 (dd, J = 6.6, 10.75 Hz, 1H, H-2), 6.75 (m, 2H,
Ar), 6.95 (m, 2H, Ar), 7.49 (m, 3H, Ph), 7.91 (m, 2H,
Ph).
1
1502, 1215, 824 cmÀ1; H NMR (CDCl3, 200 MHz): d
1.39–2.18 (m, 8H, 4 · CH2), 2.70 (t, J = 6.9 Hz, 2H,
@CH2), 3.70–4.05 (m, 4H, CH2OH, OCH2), 4.13 (m,
1H, H-7), 4.51 (m, 1H, H-2), 6.76–6.96 (m, 4H, Ar),
7.13-7.44 (m, 10H, 2 · Ph); FABMS m/z (rel. intensity):
547 (M+, 23), 410 (5), 300 (10), 206 (19), 151 (19), 95
(42), 77 (100).
4.5. (2S,7S)-7-(Fluorophenoxymethyl)-2-(1-hydroxy-3-
butyn-4-yl) oxepane 10
4.7. (2S,7S)-2-(4-Fluorophenoxymethyl)-7-(1-N-hydroxy-
ureidyl-3-butyn-4-yl) oxepane 2
To a suspension of magnesium (0.58 g, 24.2 mmol) in
dry THF (10 mL) was added 1,2-dibromoethane (cata-
lytic amount). This was followed by the dropwise addi-
tion of a solution of isopropyl bromide (1.85 g,
15.1 mmol) in THF (5 mL). The reaction mixture was
stirred for 1 h and the resulting isopropyl magnesium
bromide cannulated into a 50 mL two-necked flask. A
solution of 4-tetrahydropyranoyl-1-butyne (1.86 g,
12.0 mmol) in THF (5 mL) was added and the mixture
was stirred for 30 min. This was followed by the addi-
A solution of (2S,7S)-7-(4-fluorophenoxymethyl)-2-[4-
(N,O-biscarbophenoxy)-1-butynyl] oxepane 12 (1.3 g,
2.44 mmol) in MeOH (25 mL) was cooled to 0 ꢁC, after
which saturated methanolic ammonia solution was
added and the reaction mixture stirred at room temper-
ature for an hour. The solvent was removed and the resi-
due purified by silica gel chromatography using
EtOAc–hexane (1:1) to provide 2 (0.55 g, 65%) as a col-
1
tion of
a
freshly-prepared ZnBr2 solution (1 M,
ourless solid. [a]D = À56.0 (c 2.15, CHCl3); H NMR
7.25 mL, 7.2 mmol) in THF at 0 ꢁC. After 45 min,
(2RS,7S)-2-(benzenesulfinyl)-7-(4-fluorophenoxymethyl)
oxepane (2.2 g, 6.0 mmol) in THF (10 mL) was
added and the mixture stirred for 12 h. The reaction
was quenched with saturated aqueous NH4Cl solution
at 0 ꢁC. THF was removed under reduced pressure
and the residue was partitioned and concentrated to
give (2RS,7S)-7-(4-fluorophenoxymethyl)-2-(4-tetra-
hydropyranoyl-1-butynyl) oxepane 9. The crude prod-
uct was dissolved in MeOH (25 mL) and p-TSA
added. After 1 h, the reaction mixture was neutralized
with saturated Na2CO3 solution and concentrated.
The crude product was purified by silica gel chroma-
tography using EtOAc–hexane (1:8) to give (2S,7S)-7-
(4-fluorophenoxymethyl)-2-(4-hydroxybutynyl) oxepane
10 (1.32 g, 70%): [a]D = À74.0 (c 3.63, CHCl3); IR
(CDCl3, 200 MHz): d 1.41–2.18 (m, 8H, 4 · CH2), 2.51
(dt, J = 1.1, 7.1 Hz), 2H, @CH2), 3.69 (t, J = 7.1 Hz,
2H, CH2N), 3.81 (dd, J = 9.52, 4.76 Hz, 1H, OCH2),
3.9 (dd, J = 5.71, 9.52 Hz, 1H, OCH2), 4.13 (m, 1H,
H-7), 4.51 (m, 1H, H-2), 5.25 (s, 2H, CONH2), 7.02
(m, 4H, Ar), 7.69 (s, 1H, N–OH). 13C NMR (CDCl3,
50 MHz): d 17.19 (CH2), 24.59 (CH2), 27.45 (CH2),
32.0 (CH2), 37.13 (@CH2), 48.89 (CH2N), 72.03 (C-7),
72.31 (C-2), 81.57, 82.41 (C@C), 115.51 (2 · CH, Ar),
115.66 (CH, Ar), 115.81 (CH, Ar), 115.97 (CH, Ar),
154.90 (F–C, Ar), 159.66 (O–C, Ar), 161.78 (NCONH2);
FABMS m/z (rel. intensity): 351 (M+1, 100), 308 (8), 291
(6), 154 (27), 111 (6), 95 (17); HRMS (FAB): calcd for
(C18H24FN2O4, M++1): 351.1720. Found 351.1736.
(neat): 3634–3200 (br), 2909, 1498, 824 cmÀ1
;
1H
References
NMR (CDCl3, 400 MHz): d 1.50 (m, 2H, CH2), 1.76
(m, 2H, CH2), 1.89 (m, CH2), 2.12 (m, 2H, CH2),
2.48 (dt, J = 7.17, 1.4 Hz, 2H, @CH2), 3.68 (t,
J = 7.17 Hz, CH2OH), 3.81 (dd, J = 6.04, 9.32 Hz,
1H, OCH2), 3.92 (dd, J = 5.11, 9.32 Hz, 1H, OCH2),
4.16 (m, 1H, H-7), 4.56 (m, 1H, H-2), 6.84 (m, 2H,
Ar), 6.95 (m, 2H, Ar); EIMS m/z (rel. intensity): 292
(M+, 32), 123 (85), 112 (88), 95 (70), 41 (100); HRMS
(E1): calcd for (C17H21FO3, M+): 292.1477. Found
292.1474.
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