A novel and simple asymmetric synthesis of CMI-977 (LDP-977): A potent anti-asthmatic drug lead

Article abstract of DOI:10.1016/S0957-4166(03)00157-5

A practical gram scale asymmetric synthesis of CMI-977 is described. A tandem double elimination of an α-chlorooxirane and concomitant intramolecular nucleophilic substitution was used as the key step. Jacobsen hydrolytic kinetic resolution and Sharpless

Full text of DOI:10.1016/S0957-4166(03)00157-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 1363–1370
A novel and simple asymmetric synthesis of CMI-977
(LDP-977): a potent anti-asthmatic drug lead
Mukund K. Gurjar,a,* A. M. S. Murugaiah,a P. Radhakrishna,a C. V. Ramanaa and
Mukund S. Chorghadeb
aNational Chemical Laboratory, Pune 411 008, India
bChorghade Enterprise, 14, Carlson Circle, Natick, MA 01760, USA
Received 31 January 2003; accepted 17 February 2003
Abstract—A practical gram scale asymmetric synthesis of CMI-977 is described. A tandem double elimination of an a-chloro-
oxirane and concomitant intramolecular nucleophilic substitution was used as the key step. Jacobsen hydrolytic kinetic resolution
and Sharpless asymmetric epoxidation protocols were applied for the execution of the synthesis of the key chiral building block.
© 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
tion. CMI-977 blocked LTB4 production with IC50 of
117 nm and 10 mg/kg inhibited eosinophil influx by
63%. Data from phase IIa trial out of one randomized,
double-blind, placebo-controlled analysis to evaluate
the pharmacokinetics (PK) and pharmacodynamics
(PD) of a single dose of CMI-977 in normal subjects,
showed that PK/PD profile is comparable with a single
dose of zileuton, i.e. it may administered orally once or
twice a day. Overall, CMI-977 has shown a high degree
of potency, excellent oral bioavailability and exception-
ally favorable safety profile.3 CMI-977 belongs to the
lignan family of 2,5-disubstituted tetrahydrofurans, fea-
turing with diverse substitution and trans-juxtaposi-
tioned ring and is stereo specific (all other three
stereoisomers have shown poor pharmacological
profile). The unique structural ensemble, featured with
diverse substitution and a trans-juxtapositioned ring
invited the synthetic community to undertake a ‘single
enantiomer synthesis’ that would deliver the target
The alarming rise of asthma constitutes the biggest
mystery in modern health care at the beginning of this
century and the exact reasons still evade researchers
despite the advances in molecular biology and asthma
chemotherapy.1a,b This has led to the worldwide intense
search for safer and target-specific drugs for asthma.1c–g
CMI-977, (2S,5S)-trans-5-[(4-fluorophenoxy)methyl]-2-
(4-N-hydroxyureidyl-1-butynyl)tetrahydrofuran
1
renamed later as LDP-977 is being developed by
Cytomed Inc. USA, as a promising candidate for
chronic asthma2 (Fig. 1). It acts primarily by inhibiting
the 5-lipoxygenase pathway and thus blocking the pro-
duction of inflammatory mediatory leukotrienes. CMI-
977 has successfully been evaluated in animal models.
In guinea pigs, oral administration of CMI-977 effec-
tively blocks ovalbumin-induced bronchoconstriction,
airway eosinophil accumulation, and plasma extravasa-
molecule
with
relevant
stereochemistry
and
functionalities.4,5
The inaugural synthetic route4 for CMI-977, choosing
(S)-(+)-hydroxymethyl-g-butyrolactone as chiron,
a
was plagued with several problems such as poor selec-
tivity and complicated separation of diastereomers
which mitigated against efficient scale up and cost
effective production of the target molecule. During the
course of our efforts5 to solve the problems encoun-
tered in the reported approach, we devised and exe-
Figure 1.
* Corresponding author. Tel.: +91-20-5882456; fax: +91-20-5893614;
e-mail: gurjar@dalton.ncl.res.in
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0957-4166(03)00157-5

1364
M. K. Gurjar et al. / Tetrahedron: Asymmetry 14 (2003) 1363–1370
cuted three novel routes simultaneously in our labora-
tory that effectively addressed the aforesaid problems,
resulting in the cost-effective syntheses of CMI-977,
which are amenable for large scale production.
Amongst these three approaches the first two
approaches can be coined as second generation syn-
thetic routes which addressed the diastereoselective
problems encountered in the original synthetic route
and our third report provides an alternative route for
the synthesis of the key intermediate that had been used
in the first generation as well in our previous two
approaches.
substitution of suitably positioned leaving group would
result in a tetrahydrofuran ring. It was envisaged that
the functionality present in 3 could be installed using a
combination of both Jacobsen’s hydrolytic kinetic reso-
lution on 5 and a Sharpless asymmetric expoxidation
step.
Synthesis of key intermediate 5 began from the readily
available 4-fluorophenol 7 and rac-epichlorohydrin 8.
Thus the reaction of 4-fluorophenol 7 with rac-
epichlorohydrin in the presence of K2CO3 in refluxing
acetone gave rac-4-fluorophenyl glycidyl ether 4 in 84%
yield. The glycidyl ether 5 was subjected to HKR7
conditions with 0.55 equiv. of water in t-butylmethyl
ether using the catalyst (R,R)-(salen)CoIII(OAc) 9
(Scheme 2) to provide enantiomerically-pure (S)-4 and
(R)-diol 10 in 46% yield each. To confirm its absolute
stereochemistry, 10 was obtained from the treatment of
the known tosylate 68 with 4-fluophenoxide, and subse-
quent hydrolysis of the resulting acetonide 11. The
physical data were identical in all respects (1H NMR,
specific rotation, etc.).
2. Results and discussion
Our general synthetic strategy (Scheme 1) toward the
total synthesis of CMI-977 envisaged the synthesis of
the key intermediate 2 following a tandem fragmenta-
tion/nucleophilic substitution sequence. Thus fragmen-
tation of a-chlorooxirane
3
would lead to
propargylalkoxide6 and concomitant intramolecular
Scheme 1. Retrosynthetic analysis of 1.
Scheme 2. Reagents and conditions: (a) K2CO3, acetone, reflux, 6 h, 84%; (b) 9, t-BuOMe–H2O, 0°C–rt, 5 h, 46% of each (S)-5
and 10; (c) NaH, THF–DMF, 0°C–rt, 12 h, 82%; (d) HCl, MeOH, rt, 12 h, 89%.

M. K. Gurjar et al. / Tetrahedron: Asymmetry 14 (2003) 1363–1370
1365
The diol 10 was converted to the desired epoxide (R)-5
through the cyclic orthoester methodology of Sharpless
et al.9 in one pot. Accordingly, 10 was treated with a
slight excess of trimethyl orthoacetate in the presence of
TMSCl in dichloromethane (Scheme 3). The subsequent
exposure of the chloroacetate to K2CO3 in methanol
afforded the epoxide (R)-5 in excellent yield.
ppm as a quartet whereas olefinic protons at 5.77 and
6.73–6.98 ppm. An intense IR adsorption at 1708 cm−1
was characteristic for a,b-unsaturated ester. The allyl
alcohol 4 was secured in excellent yield through the
reduction of ester 14 with DIBAL-H at −78°C in
advance of installing the second chiral centre. The
structural identity was secured from the interpretation
1
of H and 13C NMR, IR, EI and HRMS spectral data.
Epoxide (R)-5 upon exposure to allylmagnesium
bromide10 gave the alcohol 12 in excellent yield. The
alcohol was then converted to benzenesulphonate ester
13 with benzenesulphonyl chloride and Et3N. The
The methylene group of allyl alcohol resonated between
3.84 and 4.13 ppm in the H NMR spectrum.
1
The next phase of endeavor was Sharpless asymmetric
epoxidation (SAE) of the allyl alcohol 4. The epoxida-
tion was performed with Ti(OiPr)4-(+)-DIPT11 complex
and cumene hydroperoxide. The product 15 was
obtained after column chromatography in 92% yield.
1
structure of product 13 was confirmed by the H NMR
spectrum with additional evidence from 13C NMR, IR,
EI and HRMS spectral data. The chemical shift of the
methine proton bearing the sulphonate group moved
downfield (compared to 12) and appeared at 4.82 ppm
and the protons in PhSO2 group appeared as two sets,
1
The spectral information from H and 13C NMR, IR,
EI and HRMS studies proved the structure of 15
beyond doubt. The multiplet between 2.84 and 3.01
ppm revealed the identity of the epoxy protons,
whereas the two olefinic protons disappeared in the
region of 5.5–6.5 ppm. The rest of the protons res-
onated at the expected chemical shift regions. The
elemental composition was confirmed by a molecular
ion peak at (m/z) 396.1043 in HRMS (FAB) studies.
Reaction of epoxymethanol 15 with triphenylphosphine
(TPP) in refluxing CCl4 gave the required epoxymethyl
chloride 3 in poor yield, with the additional formation
of ring-opened products in substantial ratio. The for-
mation of side products was subdued considerably by
addition of CHCl3 to enable the solubility of starting
material in reaction medium and the product 3 was
obtained in 64% yield. The methylene group (CH2Cl)
moved upfield and resonated as two doublets of dou-
blet at 3.43 ppm (J=5.5, 8.0 Hz) and 3.58 ppm in the
1H NMR spectrum.
1
resonating between 7.44 and 7.91 ppm in the H NMR
spectrum. In the IR spectrum, two intense peaks at
1170 and 1339 cm−1 characteristic of sulphonyl group
were observed. The EI mass spectrum gave a molecular
ion peak at (m/z) 350, which was subsequently con-
firmed by HRMS.
The olefin 13 was then submitted to reductive ozonoly-
sis to provide the corresponding aldehyde, which was
then elongated on reaction with a stable Wittig ylide to
provide the corresponding a,b-unsaturated ester 14.
The predominant (E)-olefinic ester, obtained after chro-
matographic removal of minor (Z)-isomer, was charac-
terized by 1H and 13C NMR spectroscopy. The
coupling constant values (J=16.0 Hz) of olefinic pro-
tons confirmed the (E)-geometry of olefin. The signals
due to methyl group of -OCH2CH3 appeared at 1.30
ppm as triplet (J=7.1 Hz) and the methylene at 4.17
Scheme 3. Reagents and conditions: (a) i. TMSCl, CH3C(OMe)3, CH2Cl2, 0°C–rt, 1 h, ii. K2CO3, MeOH, rt, 2 h, 91%; (b)
allyl-MgBr, ether, CuCN, −22°C, 0.5 h, 84%; (c) PhSO2Cl, Et3N, DMA, CH2Cl2, 0°C–rt, 92%; (d) O3, CH2Cl2, −78°C, 0.5 h, then
Me2S, rt, 12 h; (e) Ph3PꢀCHCO2Et, benzene, 60°C, 5 h, two steps, 70%; (f) DIBAL-H, CH2Cl2, −78°C, 45 min, 82%; (g) Ti(OiPr)4,
,
(+)-disiopropyltartarate, cumene hydroperoxide, 4 A sieves, CH2Cl2, −20°C, 2.5 h, 92%; (h) PPh3, NaHCO3, CCl4, CHCl3, reflux,
3 h, 64%; (i) LDA, THF, −40°C, 1 h, 60%.

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M. K. Gurjar et al. / Tetrahedron: Asymmetry 14 (2003) 1363–1370
Scheme 4. Reagents and conditions: (a) n-BuLi, BF3·OEt2, ethylene oxide, THF, −78°C, 0.5 h, 90%; (b) PPh3, DIAD,
bis(phenoxycarbonyl)hydroxylamine, THF, 0°C–rt, 5 h, 80%; (c) NH3, MeOH, 0°C, 0.5 h, 70%.
The key transformation was next effected by exposure
of 3 to 3 equiv. of LDA,6 which resulted in the genera-
tion of propargyl alkoxide through double elimination
followed by concomitant intramolecular SN2 cyclization
ventional chiral pool approach and considerable flexi-
bility for substitution tuning at any position with
required stereochemistry.
1
to provide the THF–acetylene derivative 2. In the H
4. Experimental
NMR spectrum, the resonances of two ring-junction
protons at C-5 and C-2 appeared between l 4.38–4.53
and 4.74 ppm, respectively, the acetylenic proton as a
doublet at l 2.39 ppm and the rest of the protons at the
relevant positions. Thus, this central key transforma-
tion expediently framed the main skeleton in one pot
with appropriate substitution and crucial stereo-
chemistry.
4.1. ( )-2,3-Epoxy-1-(4-fluorophenoxy)propane, 5
A mixture of p-fluorophenol, 7 (5.0 g, 44.6 mmol),
rac-epichlorohydrin, 8 (16.5 g, 178.4 mmol) and K2CO3
(24.6 g, 178.4 mmol) in anhydrous acetone (100 mL)
was heated under reflux for 6 h with vigorous stirring.
The reaction mixture was filtered, evaporated and
excess epichlorohydrin was removed by distillation at
120–130°C and the residue was distilled under reduced
pressure (bp 100°C at 4 mmHg) to give rac-5 (6.3 g,
84%) as a colorless oil.
Two carbon homologation of 2 was successfully
achieved through BF3·OEt2 facilitated opening of
ethyleneoxide at −78°C with incipient acetylide gener-
ated from 2 with n-butyllithium (Scheme 4). The poor
NOE enhancement observed during the double irradia-
tion of protons at C-2 and C-5 suggested that these
protons are not in close proximity, i.e. the relative
stereochemistry of the junction is trans. The chiral
homogenity of 16 was checked by matching the specific
rotation with the authentic sample supplied by M/S
Steroids, Chicago, USA {[h]D=−34.3 (c 1.4, CHCl3),
lit.4 [h]D=−34 (c 1, CHCl3)}. The final endeavor was
attachment of the N-hydroxyuriedyl moiety to 16,
which was effectively accomplished through Abbott
technology,12 using N-hydroxyurea equivalent N,O-
bis(phenoxycarbonyl)hydroxylamine. Thus, Mitsunobu
reaction of 15 with Abbott reagent in the presence of
TPP and DIAD gave the fully-protected derivative 17
whose structure was deduced from the 1H NMR,
FABMS and HRMS spectral data. Ammonolysis of
urethane derivative 17 on exposure to methanolic
ammonia solution culminated in the total synthesis of
target compound 1, which was identical in all respects,
1
4.1.1. Spectral data for rac-5. H NMR (CDCl3, 200
MHz): l 2.68 (dd, J=2.2, 4.5 Hz, 1H, H-3), 2.85 (t,
J=4.5 Hz, 1H, H-3%), 3.27 (m, 1H, H-2), 3.89 (dd,
J=6.7, 15.7 Hz, 1H, H-1), 4.11 (dd, J=4.5, 15.7 Hz,
1H, H-1%), 6.74–7.02 (m, 4H). EIMS at (m/z): 57 (100),
73 (23), 83 (80), 95 (31), 112 (98), 125 (20), 168 (54).
HRMS calcd for C9H9FO2: 168.0586. Found: 168.0581.
4.2. Hydrolytic kinetic resolution of rac-5
The compound rac-5 (10 g, 59.5 mmol) and (R,R)-
(salen)CoIII(OAc) catalyst 9 (215 mg, 0.32 mmol) were
taken in t-butyl methyl ether (20 mL) and cooled to
0°C. Conducting water (0.6 mL, 32.7 mmol) was then
added dropwise for 1 h and stirred for an additional 5
h at rt (monitored by HPLC). The reaction mixture was
eluted through a short silica gel column to obtain
epoxide (S)-5 (4.6 g, 46%) and diol 10 (5.06 g, 46%, 1:1
ethyl acetate:hexane).
1
viz. H and 13C NMR, IR, EI spectra, specific rotation
and melting point with that of authentic sample.
4.2.1. Physical data of (2S)-2,3-epoxy-1-(4-fluorophe-
noxy)propane, (S)-5. [h]D=+5.0 (c 1.0, CHCl3).
3. Conclusion
4.2.2. Physical data of (2R)-1-(4-fluorophenoxy)propane-
2,3-diol, 10. Mp 58–59°C. [h]D=−10 (c 1.0, CHCl3). IR
(CHCl3): 3200 (br), 3020, 1493, 1044, 846 cm−1. 1H
NMR (CDCl3, 200 MHz): l 2.09 (br s, 1H, OH, D2O
exchangeable), 2.65 (d, 1H, J=3.4 Hz, OH), 3.60–3.87
(m, 2H), 3.91–4.12 (m, 3H), 6.73–7.03 (m, 4H). 13C
NMR (CDCl3, 50 MHz): l 63.6, 69.6, 70.4, 115.4,
115.6, 116.1, 154.4 and 155.0, 159.8. EIMS at (m/z): 43
(21), 57 (34), 83 (34), 95 (21), 112 (100), 186 (9) [M+].
HRMS calcd for C9H11FO3: 186.0692. Found:
186.0693.
In conclusion, we have described a total synthesis of
CMI-977 in a completely stereocontrolled fashion. The
assembly of tetrahydrofuran ring with suitable
appendages of appropriate stereochemistry through the
central transformation ‘double elimination and
intramolecular SN2 ring closure’. Our enantioselective
synthesis of CMI-977 is characterized by a linear
approach with absolute structure authentification of
key intermediates by alternatively deriving it from con-

M. K. Gurjar et al. / Tetrahedron: Asymmetry 14 (2003) 1363–1370
1367
4.3. Preparation of (2R)-1-(4-fluorophenoxy)propane-
quenched with saturated NH4Cl solution and the result-
ing suspension stirred for another 30 min. Inorganic
solid material was filtered off and washed with ether.
The combined ether layer were dried (Na2SO4) and
concentrated to furnish the residue, which on filtration
over silica gel column (20% ethyl acetate in hexane)
gave 12 (2.2 g, 84%) as a colorless oil.
2,3-diol, 10 from 6
Sodium hydride (1.9 g, 80 mmol) was added slowly to
a solution of 4-fluorophenol (6.54 g, 58 mmol) in a
mixture of THF and DMF (4:1, 60 mL) at 0°C. After
being stirred for 30 min, a solution of 6 (15.5 g, 54
mmol) in THF (40 mL) was added at rt. The reaction
mixture was stirred overnight and quenched with water.
After the removal of solvent, the residue was parti-
tioned between ether (200 mL) and water (200 mL).
The organic layer was dried (Na2SO4), concentrated,
and the residue purified by silica gel chromatography
(10% ethyl acetate in hexane) to give 11 (10.8 g, 82%) as
4.5.1. Physical data of 12. [h]D=−16.3 (c 1.5, CHCl3).
IR (CHCl3): 3400, 2930, 1530, 1215, 830 cm−1. 1H
NMR (CDCl3, 400 MHz): l 1.58–1.73 (m, 2H, H-3, 3%),
2.16–2.40 (m, 2H, CH2-C), 3.80 (t, J=8.4 Hz, 1H,
H-1), 3.91 (d, J=11.0 Hz, 1H, H-1%), 3.96–4.03 (m, 1H),
5.0 (d, J=10.2 Hz, 1H, one of CH2ꢀ), 5.07 (d, J=17.4
Hz, 1H, one of CH2ꢀ), 5.76–5.91 (m, 1H, CHꢀ), 6.78–
6.88 (m, 2H), 6.98 (t, J=9.0, 2H). 13C NMR (CDCl3,
50 MHz): l 29.6, 32.1, 69.4, 72.7, 115.0, 115.5, 115.6,
116.0, 138.0, 154.6 and 154.9, 159.7. EIMS (m/z): 43
(34), 57 (22), 112 (110), 210 (12) [M+].
1
a colorless oil. H NMR (CDCl3, 200 MHz): l 1.32,
1.38 (2s, 6H, 2×CH3), 3.73–3.88 (m, 2H, H-3, 3%), 3.95
(dd, J=5.0, 10.0 Hz, 1H, H-1), 4.06 (t, J=10.0 Hz, 1H,
H-1%), 4.33 (quint., J=6.0 Hz, 1H), 6.68–6.81 (m, 2H),
6.89 (t, J=8.8 Hz, 2H). A solution of 6 (4.26 g, 18.8
mmol) in methanolic HCl (10%, 25 mL) was stirred
overnight, quenched with solid NaHCO3, filtered and
evaporated. The residue on silica gel chromatographic
purification (50% ethyl acetate in hexane) gave 10 (8.14
A solution of 12 (7.4 g, 35.2 mmol), triethylamine (10
mL, 71.7 mmol) and 4-N,N%-dimethylaminopyridine
(0.43 g) in dry CH2Cl2 (50 mL) at 0°C was treated with
a solution of benzenesulphonyl chloride (5 mL, 38.9
mmol) in CH2Cl2 (10 mL). After stirring at rt for 6 h,
the reaction mixture was concentrated and the residue
passed through short silica gel column (1:4 ethyl ace-
tate:hexane) to afford 13 (11.3 g, 92% yield) as a
colorless solid.
1
g, 89%) as a solid. The characterization data from H
NMR, IR, EI and HRMS spectra were identical in all
respects with that of 10 obtained in Section 4.2.
4.4. (2R)-2,3-Epoxy-1-(4-fluorophenoxy)propane, (R)-5
Trimethylsilyl chloride (3.0 mL, 20 mmol) was added to
a solution of diol 10 (3.72 g, 20 mmol) and trimethyl
orthoacetate (3.0 mL, 20 mmol) in CH2Cl2 (60 mL) at
0°C. The solution was stirred for 60 min, then evapo-
rated to obtain crude chloroacetate. The crude product
was dissolved in dry methanol (40 mL) and K2CO3
(6.80 g, 49 mmol) was added. The suspension was
stirred vigorously for 2 h, then filtered and the residue
washed with CH2Cl2. The filtrate was evaporated and
the residue was distilled under vacuum to obtain (R)-5
as a colorless liquid (3 g, 91%).
4.5.2. Physical data of 13. Mp 63–64°C. [h]D=+5.4 (c
2.6, CHCl3). IR (CHCl3): 3415 (br), 1493, 1339, 1170,
923 cm−1. 1H NMR (CDCl3, 200 MHz): l 1.88 (q,
J=7.7 Hz, 2H, H-3, 3%), 2.0–2.23 (m, 2H, H-4, 4%),
3.88–4.08 (m, 2H, OCH2), 4.82 (quint., J=6.4 Hz, 1H,
H-5), 4.90–5.05 (m, 2H, CH2ꢀ), 5.59–5.82 (m, 1H,
CHꢀ), 6.64 (m, 2H), 6.90 (t, J=9.1 Hz, 2H), 7.44–7.68
(m, 3H, PhSO2), 7.91 (d, J=6.4 Hz, 2H, PhSO2). 13C
NMR (CDCl3, 50 MHz): 28.7, 30.6, 69.1, 80.2, 115.4,
115.5, 115.7 and 116.0, 127.7, 129.1, 133.6, 136.6, 137.0,
154.1, 155.1, 159.8. EIMS (m/z): 77 (100), 112 (16), 141
(48), 162 (12), 234 (12), 350 (10) [M+]. HRMS calcd for
C18H19FO4S: 350.0988. Found: 350.0996.
4.4.1. Physical data of (R)-5. Bp 102°C at 4 mmHg.
[h]D=−5.2 (c 1.1, CHCl3). IR (neat): 831, 1215, 1493,
2892 cm−1. 1H NMR (CDCl3, 400 MHz): l 2.73 (m, 1H,
H-3), 2.88 (t, J=4.5 Hz, 1H, H-3%), 3.30 (m, 1H, H-2),
3.92 (dd, J=6.7, 15.7 Hz, 1H, H-1), 4.16 (dd, J=4.5,
15.7 Hz, 1H, H-1%), 6.78–7.09 (m, 4H). EIMS (m/z): 51
(100), 75 (23), 83 (80), 95 (31), 112 (98), 125 (20), 168
(54) [M+]. HRMS calcd for C9H9FO2: 168.0586. Found:
168.0580.
4.6. Ethyl (2E,6R)-6-benzenesulphonyloxy-7-(4-fluoro-
phenoxy)hept-2-en-1-oate, 14
Ozone was purged through a solution of 13 (11.3 g,
32.2 mmol) in dry CH2Cl2 (100 mL) at −78°C, until the
blue color persisted (ꢀ30 min). The reaction mixture
was brought to rt and then a stream of N2 gas passed
to remove excess of ozone. After cooling again to
−78°C, dimethyl sulfide (13.9 mL, 32.5 mmol) was
added. The reaction mixture was brought to rt, stirred
further for 12 h, washed with water and brine, and
concentrated to afford the crude aldehyde (10.8 g),
which was treated with ethoxycarbonyl methylene-
triphenylphosphorane (11.5 g, 33 mmol) in benzene
(100 mL). After being stirred for 5 h at 60°C, the
reaction mixture was concentrated and the residue
chromatographed on silica gel (1:3 ethyl ace-
tate:hexane) to afford 14 (9.6 g, 70%) as a colorless oil.
4.5. (2R)-2-Benzenesulphonyloxy-1-(4-fluorophenoxy)-5-
hexene, 13
To a mixture of magnesium (0.89 g, 36.6 mmol) and
iodine (a crystal) in ether (15 mL), a solution of allyl
bromide (3.0 g, 24.8 mmol) in ether (10 mL) was slowly
added. After stirring for 30 min at rt, cuprous cyanide
(22 mg) was then added in one portion, resulting with
color change of reaction mixture into dark brown.
After cooling to −22°C, epoxide (R)-5 (2.05 g, 12.2
mmol) in ether (25 mL) was added dropwise. The
reaction mixture was stirred for 30 min at −22°C,

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M. K. Gurjar et al. / Tetrahedron: Asymmetry 14 (2003) 1363–1370
4.6.1. Physical data of 14. [h]D=+5.8 (c 1.5, CHCl3). IR
4.8.1. Physical data of 15. Mp 109–110°C. [h]D=+2.1 (c
1
(CHCl3): 2923, 1708, 1493, 1339, 1170, 830 cm−1. H
1.0, CHCl3). IR (CHCl3): 3546, 2923, 1508, 1360, 1170,
1
NMR (CDCl3, 200 MHz): l 1.30 (t, J=7.1 Hz, 3H,
CH3), 1.94 (q, J=6.6 Hz, 2H, H-5, 5%), 2.10–2.40 (m,
2H, H-4, 4%), 3.89–4.10 (m, 2H, CH2O), 4.17 (q, J=7.1
Hz, 2H, OCH2), 4.82 (quint., J=6.6 Hz, 1H, H-6), 5.77
(d, J=16.0 Hz, 1H, H-3), 6.60–6.90 (m, 5H, aromatic
and H-2), 7.47–7.98 (m, 5H). 13C NMR (CDCl3, 50
MHz): l 14.0, 27.0, 29.8, 60.1, 69.0, 79.5, 115.4, 115.5,
116.0, 122.3, 127.7, 129.1, 133.7, 136.7, 146.4, 153.9,
155.1, 160.0, 166.1. EIMS (m/z): 41 (34), 43 (52), 55
(30), 57 (36), 77 (100), 96 (28), 125 (40), 142 (37), 152
(21), 422 (3) [M+]. HRMS calcd for C21H23FO6S:
422.1199. Found: 422.1180.
908, 831, 754 cm−1. H NMR (CDCl3, 200 MHz): l
1.39–2.07 (m, 4H, H-4, 4%, 5, 5%), 2.84–3.01 (m, 2H, H-2,
3), 3.54–3.72 (m, 1H, H-1), 3.82–4.08 (m, 3H, H-1, 7,
7%), 4.88 (quint., J=6.0 Hz, 1H, H-6), 6.63 (dd, J=4.0,
9.0 Hz, 2H) and 6.92 (t, J=9.0 Hz, 2H), 7.47–7.72 (m,
3H) and 7.93 (d, J=7.5 Hz, 2H). 13C NMR (CDCl3, 50
MHz): l 27.0, 28.1, 55.1 and 58.2, 61.4, 69.1, 80.3,
115.45, 115.54, 116.0, 127.7, 129.1, 133.7, 136.9, 154.0,
155.1, 160.0. EIMS (m/z): 41 (28), 43 (40), 67 (43), 77
(100), 84 (39), 96 (39), 114 (42), 142 (27), 152 (34), 196
(13), 272 (9), 396 (8) [M+]. HRMS calcd for
C19H21FO6S: 396.1043. Found: 396.1024.
4.7.(2E,6R)-6-Benzenesulphonyloxy-7-(4-fluorophenoxy)-
hept-2-en-1-ol, 4
4.9. (2R,3S,6R)-6-Benzenesulphonyloxy-1-chloro-2,3-
epoxy-7-(4-fluorophenoxy)heptane, 3
DIBAL-H (14.2 mL, 14.2 mmol, 1 M solution in
toluene) was added dropwise over 5 min to a solution
of 14 (3 g, 7.1 mmol) in CH2Cl2 (30 mL) under N2 at
−78°C. The solution was stirred at the same tempera-
ture for 45 min, quenched with saturated NH4Cl solu-
tion. The reaction mixture was filtered through a pad of
Celite, dried (Na2SO4) and concentrated. The residue
was eluted through a column of short silica gel (50%
ethyl acetate in hexane) to obtain 4 (2.23 g, 82%) as a
colorless solid.
A solution of 15 (2.25 g, 5.7 mmol) and triphenylphos-
phine (1.5 g, 5.7 mmol) in a solvent mixture of CHCl3
and CCl4 (40 mL, 1:1 ratio) containing NaHCO3 (0.3 g)
was refluxed for 3 h. Removal of the solvent and
subsequent purification of the residue by silica gel
column chromatography (1:4 ethyl acetate:hexane)
afforded 3 (1.51 g, 64%) as a colorless solid.
4.9.1. Physical data of 3. Mp 59–60°C. [h]D=−5.5 (c
0.6, CHCl3). IR (CHCl3): 2939, 1493, 1369, 1185, 923
1
cm−1. H NMR (CDCl3, 200 MHz): l 1.53 (q, J=6.8
4.7.1. Physical data of 4. Mp 76–77°C. [h]D=+19.5 (c
Hz, 1H, H-5), 1.72–2.09 (m, 3H, H-4, 5, 5%), 2.83 (td,
J=2.3, 5.5 Hz, 1H, H-3), 2.92 (td, J=2.3, 5.5 Hz, 1H,
H-2), 3.43 (dd, J=5.5, 8.0 Hz, 1H, H-1), 3.58 (dd,
J=5.5, 8.0 Hz, 1H, H-1%), 3.87–4.10 (m, 2H, H-7, 7%),
4.86 (q, J=6.8 Hz, 1H, H-6), 6.58–6.74 (m, 2H), 6.92
(t, J=9.0 Hz, 2H), 7.47–7.73 (m, 3H) and 7.92 (d,
J=7.3 Hz, 2H, PhSO2). EIMS (m/z): 41 (19), 67 (31),
77 (100), 81 (24), 83 (31), 95 (25), 125 (25), 141 (55), 145
(55), 414 (10) [M+]. HRMS calcd for C19H20ClFO5S:
414.0704. Found: 414.0721.
0.6, CHCl3). IR (CHCl3): 3562, 2923, 1493, 1323, 1177,
1
1170, 923 cm−1. H NMR (CDCl3, 200 MHz): l 1.30–
1.46 (br s, 1H, OH), 1.82–2.0 (m, 4H, H-4, 4%, 5, 5%),
3.84–4.13 (m, 4H, H-1, 1%, 7, 7%), 4.88 (quint., J=5.6
Hz, 1H, H-6), 5.5–5.73 (m, 2H, H-2, H-3), 6.57–6.72
(m, 2H), 6.92 (t, J=8.1 Hz, 2H), 7.46–7.70 (m, 3H),
7.88–8.01 (d, J=7.7 Hz, 2H). 13C NMR (CDCl3, 50
MHz): l 27.3, 30.8, 63.2, 69.1, 80.3, 115.4, 115.5, 115.6,
116.0, 127.8, 129.1, 130.4, 133.7, 137.0, 154.0, 155.1,
160.1. EIMS (m/z): 41 (40), 55 (25), 67 (46), 77 (100),
93 (91), 112 (52), 141 (22), 152 (16), 380 (3) [M+].
HRMS calcd for C19H21FO5S: 380.1094. Found:
380.1098.
4.10. (2S,5S)-2-Ethynyl-5-[(4-fluorophenoxy)methyl]-
tetrahydrofuran, 2
4.8. (2S,3S,6R)-6-Benzenesulphonyloxy-2,3-epoxy-7-(4-
fluorophenoxy)heptan-1-ol, 15
A solution of 3 (1.0 g, 2.41 mmol) in dry THF (8 mL)
was added to lithium diisopropylamide (7.2 mmol)
[generated in situ by the addition of n-BuLi (7.2 mL,
7.2 mmol) to a solution of diisopropylamine (1.12 mL,
8.6 mmol) in dry THF (6 mL) at −40°C and stirring for
15 min] at −40°C. The reaction was stirred for 1 h at
−40°C, gradually warmed to rt and quenched with
aqueous NH4Cl (1 mL). The reaction mixture was
evaporated under reduced pressure and the residue
taken in ethyl acetate, washed with water and brine,
dried (anhydrous sodium sulphate) and concentrated.
The residue after silica gel chromatographic purification
(1:9 ethyl acetate:hexane) afforded 2 (0.32 g, 60%) as a
colorless liquid.
Titanium tetrakis(isopropoxide) (1.9 g, 6.67 mmol) and
(+)-diisopropyl tartrate (1.08 mL, 6.7 mmol) were
sucessively added to a suspension of powdered molecu-
,
lar sieves (4 A, 3 g), in CH2Cl2 (15 mL). After stirring
for 5 min, cumene hydroperoxide (22.1 mL, 10.94
mmol, 80% solution in cumene) was added dropwise.
After stirring for 15 min, the allyl alcohol 4 (2.54 g,
6.67 mmol) in CH2Cl2 (10 mL) was added dropwise.
The reaction mixture was stirred for 2.5 h at −20°C, left
refrigerated overnight, quenched with 10% tartaric acid
solution (1 mL) at −20°C, and allowed to warm to rt.
After filtration of the reaction mixture over a Celite
pad, the filtrate was dried (anhydrous sodium sulphate),
and concentrated. The chromatographic purification of
the residue on silica gel (1:1 ethyl acetate:hexane)
afforded pure epoxy alcohol 15 (2.41 g, 92%) as a
colorless solid.
4.10.1. Physical data of 2. [h]D=−23.0 (c 0.7, CHCl3).
IR (CHCl3): 3308, 2923, 2123, 1600, 1493, 1212, 1046,
838 cm−1. 1H NMR (CDCl3, 200 MHz): l 1.81–2.37 (m,
4H, H-3, 3%, 4, 4%), 2.39 (d, J=2.3 Hz, 1H, acetylenic),
3.86–4.01 (m, 2H, OCH2), 4.38–4.53 (m, 1H, H-5), 4.74

M. K. Gurjar et al. / Tetrahedron: Asymmetry 14 (2003) 1363–1370
1369
(dt, J=3.0, 5.6 Hz, 1H, H-2), 6.76–7.02 (m, 4H). EIMS
(m/z): 43 (37), 55 (19), 81 (65), 95 (100), 112 (32), 125
(11), 220 (35) [M+]. HRMS calcd for C13H13FO2:
220.0899. Found: 220.0899.
1 h. Rotary evaporation of the solvent, followed by
purification of the residue on elution through a short
silica gel pad (CHCl3:MeOH, 20:1) afforded 1 (1.3 g,
70%) as a colorless solid.
4.11. (2S,5S)-2-(4-Hydroxyl-1-butynyl)-5-[(4-fluorophe-
noxy)methyl]tetrahydrofuran, 16
4.13.1. Physical data of 1. Mp 106–107°C; lit.4 113–
114°C. [h]D=−46.8 (c 1.1, MeOH); lit.4 [h]D=−47.8 (c
1
0.3, CD3OD). H NMR (CDCl3, 200 MHz): l 1.83 (m,
n-BuLi (5 mL, 1 M solution in hexane) was added to a
solution of 15 (0.8 g, 3.6 mmol) in THF (15 mL) at
−78°C. Freshly distilled BF3·OEt2 (1.4 mL, 11.0 mmol)
in THF (2 mL) was then added followed by excess of
ethylene oxide in THF (5 mL). The reaction mixture
was stirred at −78°C for 30 min, quenched with
aqueous NH4Cl solution, and concentrated on rotary
evaporator. The residue was taken in ethyl acetate,
washed with water and brine, dried (Na2SO4), and
concentrated. The crude product was purified by
column chromatography to afford 16 (0.86 g, 90%
yield) as a colorless solid.
1H, H-4), 2.01 (m, 1H, H-4%) 2.22 (m, 2H, H-3, 3%), 2.54
(t, J=7.8 Hz, 2H, ꢁ-CH2), 3.68 (t, J=7.8 Hz, 2H,
CH2N), 3.91 (m, 2H, CH2O), 4.46 (m, 1H, H-5), 4.73
(m, 1H, H-2), 5.68 (br s, 2H, NH2), 6.78–7.02 (m, 4H),
8.95 (s, 1H, N-OH). 13C NMR (CDCl3, 50 MHz): l
17.13, 27.66, 33.28, 48.62, 69.08, 70.72, 76.36, 80.72,
82.80, 115.50, 115.63, 115.97, 154.98, 159.70, 161.84.
FABMS at (m/z): 137 (42), 154 (54), 280 (11), 324 (100)
[M++1].
Acknowledgements
4.11.1. Physical data of 16. Mp 72–73°C; lit.4 77–79°C.
[h]D=−34.3 (c 1.8, CHCl3); lit.4 [h]D=−34.0 (c 1.8,
A.M.S.M. thanks the CSIR for financial support in the
form of a research fellowship.
1
CHCl3). H NMR (CDCl3, 200 MHz): l 1.67–1.77 (br
s, 1H, OH), 1.78–2.37 (m, 4H, H-3, 4, 4%), 2.52 (dt,
J=1.7, 6.4 Hz, 2H, ꢁ-CH2), 3.74 (t, J=6.4 Hz, 2H,
CH2OH), 3.94 (d, J=5.0 Hz, 2H, ArOCH2), 4.40–4.54
(m, 1H, H-5), 4.72–4.83 (m, 1H, H-2), 6.80–7.06 (m,
4H). 13C NMR (CDCl3, 50 MHz): l 23.0, 17.7, 33.3,
60.7, 68.9, 70.6, 76.8, 81.1, 82.1, 115.4, 115.6, 115.8,
154.8, 159.6. EIMS (m/z): 65 (33), 67 (42), 69 (92), 77
(100), 79 (84), 81 (48), 83 (48), 111 (46), 112 (67), 121
(45), 125 (28), 139 (55), 152 912), 264 (8) (M++1).
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