A versatile approach to anti-asthmatic compound CMI-977 and its six- membered analogue

Article abstract of DOI:10.1055/s-2000-6376

The synthesis of the anti-asthmatic compound CMI-977 is described. The tetrahydrofuran ring was effectively constructed by involving olefin metathesis while the stereoselective introduction of the 1-N- hydroxyureidylbut-3-yn-4-yl side-chain was achieved b

Full text of DOI:10.1055/s-2000-6376

PAPER
557
A Versatile Approach to Anti-Asthmatic Compound CMI-977 and its Six-
Membered Analogue
Mukund K. Gurjar,*a L. Murali Krishna,a B. Sridhar Reddy,a Mukund S. Chorghadeb
aNational Chemical Laboratory, Pune 411008, India
bLeukoSite Inc., 215 First Street, Cambridge, MA 02142, USA
Received 23 October 1999; revised 12 December 1999
The approach to incorporate 4-N-hydroxyureidyl-1-buty-
nyl side chain of CMI-977 was based on Ley’s
alkylation5 of 2-benzenesulfonyl tetrahydrofuran. For this
endeavour, compound 6 was treated with benzenesulfinic
acid in CH2Cl2 to give 2-benzenesulfonyltetrahydro-2H-
furan derivative 7 in 81% yield. Subsequent C-C bond for-
mation at C-2 was carried out by treating compound 7
with dialkyl zinc reagent derived from BrMg-C∫C-CH2-
CH2-OTHP and ZnBr2 followed by deprotection with
p-toluenesulfonic acid (PTSA) in methanol to give a 7:3
mixture of trans-cis isomers. The pure trans isomer 8 was
isolated in 50% yield after crystallization from Et2O/light
petroleum. The spectral and analytical data were in com-
plete agreement with reported values.3b Introduction of N-
hydroxy urea group was achieved in two steps involving
Mitsunobu reaction of 8 with N,O-bis(phenoxycarbon-
yl)hydroxylamine followed by treatment of 9 with ammo-
nia in methanol to give CMI-977 1. The structure of 1
was proved by comparison of its 1H NMR, mass spectra,
[a]D and melting point data with those of an authentic
sample3b (Scheme 1).
Abstract: The synthesis of the anti-asthmatic compound CMI-977
is described. The tetrahydrofuran ring was effectively constructed
by involving olefin metathesis while the stereoselective introduc-
tion of the 1-N-hydroxyureidylbut-3-yn-4-yl side-chain was
achieved by C-alkylation of the 2-benzenesulfonyl derivative.
Key words: anti-asthmatic, olefin metathesis, stereoselective syn-
thesis, tetrahydrofuran, tetrahydropyran, nucleophilic displacement
The role of leukotrienes in inflammatory and allergic re-
sponses including arthritis, asthma, psoriasis, and throm-
botic disease has been well recognized. The urge to
develop antagonists or inhibitors of leukotriene biosyn-
thesis to prevent inflammatory responses is an ongoing
process.1 Various 2,5-disubstituted tetrahydrofuran deriv-
atives have been reported with lipoxygenase inhibitory
activity.2 However, (2S,5S)-5-(4-fluorophenoxylmethyl)-
2-(1-N-hydroxyureidylbut-3-yn-4-yl)tetrahydrofuran
(CMI-977) (1) is by far the most potent compound report-
ed in this series.3 In this communication, we report a new
approach to 2,5-disubstituted tetrahydrofuran (CMI-977)
as well as to the corresponding six-membered 2,6-disub-
stituted pyran analogue 2 based on (i) the olefin
metathesis4 and (ii) a stereoselective alkylation of 2-ben-
zenesulfonyl derivatives.5
Recently we have reported an efficient approach to a (S)-
glycidyl-4-fluorophenylether 3 in 92% ee by involving
hydrolytic kinetic resolution technique.6 Subsequent reac-
tion of 3 with vinylmagnesium bromide in the presence of
CuCN provided compound 4 in 78% yield. The conver-
sion of free OH group into the vinyl ether7 5 was accom-
plished by treatment of 4 with ethyl vinyl ether and
Hg(OCOCF3)2. The ring-closing metathesis of 5 in the
presence of Grubb’s catalyst (5 mol%) in refluxing ben-
zene for 20 h gave the dihydrofuran derivative 6 in 52%
yield.8 The 1H and 13C NMR spectra of 6 were in complete
agreement with the assigned structure.
Reagents and conditions: (a) CH2 = CHMgBr, CuCN, THF, 1.5 h;
(b) Hg(OCOCF3)2, ethyl vinyl ether, 12 h; (c) Grubb’s catalyst, C6H6,
D, 20 h; (d) PhSO2H, CH2Cl2, 2 h; (e) (i) i-PrMgBr, HC∫C-CH2-CH2-
OTHP, ZnBr2, THF, 4 h, (ii) PTSA, MeOH, 1 h; (f) Ph3P,
PhOCONHOCO2Ph, DEAD, THF, 4 h; (g) NH3/MeOH, 12 h
Scheme 1
Inspired by an efficient approach to 2,5-disubstituted tet-
rahydrofuran as described above, we sought to explore the
versatility of this approach in the preparation of the so far
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558
M. K. Gurjar et al.
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gel glass plates Merck 60 F254. NMR spectra were recorded on
Brucker spectrometers (AC-200, MSL-300 or DRX-500) with TMS
as an internal standard. Mass spectra were recorded on Finnigan
MAT-1020, and high-resolution mass spectra on VG Autospec
spectrometer at 5 or 7 k resolution using perfluoro kerosene as an
internal reference compound. Optical rotations were determined on
JASCO 370 digital polarimeter with sodium light source. Mps were
recorded on Mettler B-540 melting point apparatus.
unknown six-membered 2,6-disubstituted tetrahydropyr-
an analogue 2 of CMI-977. Availability of 2 and its bio-
logical profile is useful to evaluate the influence of ring
size on the biological activity of these anti-asthmatic com-
pounds.
Compound 3 was converted into the diene derivative 11
by first reacting with allylmagnesium bromide in the pres-
ence of CuCN to open the epoxide group followed by O-
vinylation with ethyl vinyl ether-Hg(OCOCF3)2. The ring
closing metathesis with Grubb’s catalyst gave the dihy-
dropyran derivative 12, which was consequently convert-
ed into 2-benzenesulfonyltetrahydropyran derivative 13.
The carbon-carbon bond formation with BrMg-C∫C-
CH2-CH2-OTHP and ZnBr2 followed by deprotection
gave trans-(2S,6S)-6-(4-fluorophenoxymethyl)-2-(1-hy-
droxybut-3-yn-4-yl)tetrahydropyran (14) as a single dias-
tereomeric product. The formation of a single isomer
during the C-C bond formation with tetrahydropyran sul-
fonyl derivative 13 compared to the tetrahydrofuran pre-
cursor 7 (with 7:3 selectivity) was indeed gratifying and
this observation was attributed to the anomeric effect,
favouring the axial bond formation.5a The all trans stere-
ochemical assignment was provided by the extensive
NOE studies carried out on this intermediate. The intro-
duction of N-hydroxy urea was essentially carried out by
the approach reported above for CMI-977 to give the six-
membered analogue (2S,6S)-6-(4-fluorophenoxymethyl)-
2-(1-N-hydroxyureidylbut-3-yn-4-yl)tetrahydropyran (2),
whose structure was proved by 1H and 13C NMR spectral
analysis. The lipoxygenase inhibitory activity of 2 is cur-
rently under investigation (Scheme 2).
(2S)-1-(4-Fluorophenoxy)pent-4-en-2-ol (4)
To a suspension of magnesium (1.63 g, 67.9 mmol) in dry THF
(20 mL) at 0 °C was added a solution of vinyl bromide (3.6 g, 33.9
mmol) in dry THF (15 mL). After 0.5 h, CuCN (60 mg, 0.68 mmol)
and (S)-4-fluorophenyl glycidyl ether (4.0 g, 23.8 mmol) were add-
ed. After stirring for 1 h at r.t., the mixture was quenched with sat.
NH4Cl, concentrated and the residue partitioned (EtOAc/H2O). The
organic layer was washed with brine, dried (Na2SO4) and concen-
trated. The crude product was purified on silica gel using EtOAC/
light petroleum (1:4) to give 4 (3.64 g, 78%); [a]25D +15 (c 2.3,
CHCl3).
1H NMR (200 MHz, CDCl3): d = 2.35 (dt, 2H, J = 7.3, 1.4 Hz), 2.51
(br s, 1H), 3.84 (dd, 1H, J = 9.3, 5.8 Hz), 3.92 (dd, 1H, J = 9.3, 4.4
Hz), 4.0 (m, 1H), 5.14 (m, 2H), 5.84 (m, 1H), 6.82 (m, 2H), 6.95 (m,
2H).
13C NMR (125 MHz, CDCl3): d = 37.54, 69.06, 71.80, 115.28,
115.34 (2C), 115.52, 117.60, 133.61, 154.46, 157.99.
EI (MS): m/z (%) = 196 (M+, 46), 137 (20), 112 (100), 95 (26).
Anal. Calcd for (C11H13FO2): C, 67.35; H, 6.63. Found: C, 67.45; H,
6.73.
(2S)-2-(4-Fluorophenoxymethyl)-2,3-dihydro-2H-furan (6)
Compound 4 (3.6 g, 18.4 mmol), ethyl vinyl ether (350 mL) and
Hg(OCOCF3)2 (0.8 g, 1.8 mmol) were stirred for 12 h at r.t. The re-
action mixture was neutralized by addition of sat. NaHCO3 and con-
centrated. The aqueous layer was extracted with Et2O, dried
(Na2SO4) and concentrated. The residue was purified on silica gel
using EtOAc/light petroleum (1:50) to give (2S)-2-(1-ethenoxy)-1-
(4-fluorophenoxy)pent-4-ene (5) (2.85 g, 70%).
1H NMR (200 MHz, CDCl3): d = 2.49 (dt, 2H, J = 7.3, 1.5 Hz), 3.97
(m, 2H), 4.04 (dd, 1H, J = 6.8, 1.9 Hz), 4.14 (m, 1H), 4.34 (dd, 1H,
J = 14.2, 1.9 Hz), 5.15 (m, 2H), 5.84 (m, 1H), 6.38 (dd, 1H,
J = 14.2, 6.8 Hz), 6.84 (m, 2H), 6.95 (m, 2H).
A solution of 5 (2.8 g, 12.6 mmol) and Grubb’s catalyst (0.52 g,
0.63 mmol) in benzene (750 mL) was heated under reflux for 20 h,
evaporated, and the residue chromatographed on silica gel using
EtOAc/light petroleum (1:50) to give 6 (1.27 g, 52%); [a]25D +95 (c
2.3, CHCl3).
1H NMR (300 MHz, CDCl3): d = 2.48 (m, 1H), 2.82 (m, 1H), 3.89
(dd, 1H, J = 9.9, 6.6 Hz), 4.03 (dd, 1H, J = 9.9, 4.2 Hz), 4.90 (m,
2H), 6.29 (d, 1H, J = 2.2 Hz), 6.81 (m, 2H), 6.95 (m, 2H).
Reagents and conditions: (b) Hg(OCOCF3)2, ethyl vinyl ether, 12 h;
(c) Grubb’s catalyst, C6H6, D, 20 h; (d) PhSO2H, CH2Cl2, 2 h; (e) (i) i-
PrMgBr, HC∫C-CH2-CH2-OTHP, ZnBr2, THF, 6 h, (ii) PTSA, Me-
OH, 1 h; (f) Ph3P, PhOCONHOCO2Ph, DEAD, THF, 4 h; (g) NH3/
MeOH, 12 h; (h) CH2 = CHCH2MgBr, CuCN, Et2O, 1.5 h
13C NMR (75 MHz, CDCl3): d = 31.77, 70.68, 78.77, 98.85, 115.58,
115.79, 115.88 (2C), 145.24, 155.01, 159.10.
Scheme 2
(2S,5S)-5-(4-Fluorophenoxymethyl)-2-(1-hydroxybut-3-yn-4-
yl)tetrahydrofuran (8)
In conclusion, we have reported a short and stereoselec-
tive approach to CMI-977 and its six-membered ana-
logue. The extension of this approach to synthesize other
diastereomers of CMI-977 and higher analogues are un-
der progress.
Compound 6 (1.2 g, 6.2 mmol) and benzenesulfinic acid (1.1 g, 7.4
mmol) in CH2Cl2 (20 mL) were stirred for 2 h at r.t., and filtered
through Celite. The filtrate was washed with sat. NaHCO3, brine,
dried (Na2SO4) and concentrated. The residue was purified on silica
gel using EtOAc/light petroleum (1:7) to give (2S,5S)-2-(benzene-
sulfonyl)-5-(4-fluorophenoxymethyl)tetrahydrofuran (7) (1.68 g,
81%).
Solvents were distilled before use. THF and Et2O were dried over
Na-benzophenone reagent. TLC was performed on precoated silica
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PAPER
A Versatile Approach to Anti-Asthmatic Compound CMI-977 and its Six- Membered Analogue
559
To a solution of isopropylmagnesium bromide [prepared from mag-
nesium (0.35 g, 14.7 mmol) and isopropyl bromide (1.2 g, 9.8
mmol) in THF] was added 4-tetrahydropyranoyl-1-butyne (1.5 g,
9.8 mmol) in THF (5 mL). After 30 min, a freshly prepared solution
of ZnBr2 (1 M, 5.9 mL, 5.9 mmol) in THF was introduced followed
by, after 45 min, compound 7 (1.65 g, 4.9 mmol) in THF (5 mL).
The reaction mixture was stirred for 3 h and then quenched with sat.
NH4Cl. THF was removed under reduced pressure and the residue
partitioned between EtOAc and H2O. The organic layer was washed
with brine, dried (Na2SO4) and concentrated. The crude product was
stirred with PTSA (0.02 g) in MeOH (10 mL) for 1 h, neutralized
with Et3N and concentrated. The residue was crystallized from
Et2O/light petroleum to yield 8 (0.65 g, 50%), mp 76 ∞C (Lit.3b mp
77-79 ∞C]; [a]25D -34.2 (c 1.3, CHCl3).
concentrated. The residue was dissolved in EtOAc, washed with
H2O, dried (Na2SO4) and concentrated. The crude product was pu-
rified on silica gel using EtOAc/light petroleum (1:4) to give 10 (3.0
g, 80%); [a]25D+21.4 (c 2.1, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.65 (m, 2H), 2.18 (m, 2H), 2.65
(br s, 1H), 3.85 (m, 2H), 4.0 (m, 1H), 5.02 (m, 2H), 5.83 (m, 1H),
6.85 (m, 2H), 6.95 (m, 2H).
13C NMR (50 MHz, CDCl3): d = 29.55, 32.11, 69.40, 72.75, 115.01,
115.42, 115.50, 115.57, 115.96, 137.91, 154.64, 159.69.
EI (MS): m/z (%) = 210 (M+, 17), 126 (19), 112 (100), 95 (18).
Anal. Calc for C12H15O2F: C, 68.57; H, 7.14. Found: C, 68.35; H,
7.23.
1H NMR (200 MHz, CDCl3): d = 1.88 (m, 1H), 2.05 (m, 1H), 2.24
(m, 2H), 2.48 (t, 2H, J = 6.2 Hz), 3.69 (t, 2H, J = 6.2 Hz), 3.91 (d,
2H, J = 4.7 Hz), 4.45 (m, 1H), 4.73 (m, 1H), 6.85 (m, 2H), 6.94 (m,
2H).
13C NMR (50 MHz, CDCl3): d = 22.97, 27.68, 33.32, 60.74, 68.89,
70.64, 76.76, 81.13, 82.13, 115.35, 115.55, 115.80 (2C), 154.80,
159.55.
(2S)-2-(4-Fluorophenoxymethyl)-3,4-dihydro-2H-pyran (12)
Compound 10 (2.95 g, 14.0 mmol), ethyl vinyl ether (250 mL), and
Hg(OOCCF3) (0.6 g, 1.4 mmol) were stirred for 12 h and worked-
up as described earlier for 5. The residue was purified on silica gel
using EtOAc/light petroleum (1:50) to give (2S)-2-(1-ethenoxy)-1-
(4-fluorophenoxy)hex-5-ene (11) (2.32 g, 70%).
1H NMR (200 MHz, CDCl3): d 1.82 (m, 2H), 2.23 (m, 2H), 3.9-4.2
(m, 4H), 4.34 (dd, 1H, J = 14.2, 1.4 Hz), 5.05 (m, 2H), 5.83 (m, 1H),
6.39 (dd, 1H, J = 14.2, 6.4 Hz), 6.85 (m, 2H), 6.95 (m, 2H).
HRMS (FAB): m/z calc for C15H17FO3 (M+) 264.1161. Found:
264.1152.
The above product 11 (2.3 g, 9.7 mmol), Grubb’s catalyst (0.4 g,
0.48 mmol) in benzene (600 mL) were heated under reflux for 20 h
and processed as described earlier for 6, to give 12 (1.11 g, 55%);
[a]25D +47.3 (c 1.6, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.65-2.4 (m, 4H), 3.83 (dd, 1H,
J = 5, 9.3 Hz), 3.95 (dd, 1H, J = 9.3, 6.1 Hz), 4.16 (m, 1H), 4.71 (m,
1H), 6.39 (d, 1H, J = 5 Hz), 6.8-7.0 (m, 4H).
Anal. Calc for C15H17FO3: C, 68.18; H, 6.44. Found: C, 68.51; H,
6.35.
(2S,5S)-5-(4-Fluorophenoxymethyl)-2-(1-N-hydroxyureidyl-
but-3-yn-4-yl)tetrahydrofuran (1)
A mixture of 8 (0.62 g, 2.3 mmol), Ph3P (0.74 g, 2.8 mmol), N,O-
bis(carbophenoxy)hydroxylamine (0.64 g, 2.8 mmol) and diethyl
azodicarboxylate (DEAD) (0.49 g, 2.8 mmol) in THF (10 mL) was
stirred at r.t. for 4 h, and concentrated. The residue was dissolved in
EtOAc washed with H2O, dried (Na2SO4) and concentrated. The
product was purified on silica gel using EtOAc/light petroleum
(1:6) to give (2S,5S)-5-(4-fluorophenoxymethyl)-2-(1-N,O-
bis(phenoxycarbonyl)hydroxyaminobut-3-yn-4-yl)tetrahydrofuran
(9) (1.1 g, 90%).
1H NMR (200 MHz, CDCl3): d = 1.96 (m, 1H), 2.14 (m, 1H), 2.31
(m, 2H), 2.84 (t, 2H, J = 6.8 Hz), 4.0 (dd, 2H, J = 4.5, 2.0 Hz), 4.14
(t, 2H, J = 6.8 Hz), 4.53 (m, 1H), 4.82 (m, 1H), 7.0 (m, 4H), 7.25-
7.55 (m, 10H).
EI (MS): m/z (%) = 208 (M+, 40), 125 (19), 112 (100), 95 (27), 83
(45).
Anal. Calc for C12H13O2F: C, 69.23; H, 6.25. Found C, 68.97; H,
6.42.
(2S,6S)-6-(4-Fluorophenoxymethyl)-2-(1-hydroxybut-3-yn-4-
yl)tetrahydropyran (14)
A solution of 12 (1.1 g, 5.3 mmol) and benzenesulfinic acid (0.9 g,
6.3 mmol) in CH2Cl2 (20 mL) were stirred for 2 h at r.t. and pro-
cessed as described earlier for 7. The resulting product (2RS,6S)-2-
(benzenesulfonyl)-6-(4-fluorophenoxymethyl)tetrahydropyran (13)
(1.52 g) was reacted with isopropylmagnesium bromide pre-
pared from magnesium (0.3 g) and isopropyl bromide (1.05 g), 4-
tetrahydropyranoylbut-1-yne (1.32 g, 8.6 mmol), ZnBr2 solution (1
M, 5.14 mL, 5.14 mmol) in THF (20 mL). After usual processing,
the product was treated with PTSA (25 mg) in MeOH (10 mL) to
cleave the THP group, neutralized with Et3N and concentrated. The
crude product was chromatographed on silica gel using EtOAc/light
A solution of 9 (1.0 g, 1.9 mmol) in sat. methanolic ammonia
(10 mL) was stirred for 12 h at r.t., and concentrated. The residue
was purified on silica gel using EtOAc/light petroleum (1:1) to give
1 (0.39 g, 64%); mp 107 ∞C (Lit.3b mp 113-114 ºC) [a]25 -47 (c
D
1, MeOH); [Lit.3b [a]25D -47.8 (c 0.3, CD3OD)].
1H NMR (200 MHz, CDCl3): d = 1.82 (m, 1H), 2.01 (m, 1H), 2.22
(m, 2H), 2.54 (t, 2H, J = 7.9 Hz), 3.68 (t, 2H, J = 7.9 Hz), 3.91 (m,
2H), 4.46 (m, 1H), 4.73 (m, 1H), 5.68 (br s, 2H), 6.78-7.02 (m, 4H),
8.95 (s, 1H).
petroleum (1:8) to obtain 14 (0.83 g, 70%); [a]25 -32 (c 1.1,
D
CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.5-2.1 (m, 6H), 2.55 (m, 2H),
3.73 (t, 2H, J = 6.3 Hz), 3.82 (dd, 1H, J = 9.7, 6.4 Hz), 3.98 (dd, 1H,
J = 9.7, 4.7 Hz), 4.22 (m, 1H), 4.8 (s, 1H), 6.83 (m, 2H), 6.93 (m,
2H).
13C NMR (125 MHz, CDCl3): d = 18.88, 23.18, 27.04, 30.38, 61.11,
65.52, 69.96, 71.92, 80.08, 84.02, 115.12, 115.63, 115.72, 115.79,
154.97, 158.28.
13C NMR (50 MHz, CDCl3): = d 17.13, 27.66, 33.28, 48.62,
69.08,76.36, 76.72, 80.72, 82.80, 115.50 (2C), 115.63, 115.97,
154.98, 159.70, 161.84.
HRMS (FAB): m/z calc for C16H20N2O4F (M+H+) 323.1407. Found:
323.1424.
(2S)-1-(4-Fluorophenoxy)hex-5-en-2-ol (10)
EI (MS): m/z (%) = 278 (M+, 18), 153 (28), 125 (37), 112 (100), 95
(75), 79 (73).
To a solution of allylmagnesium bromide [prepared from magne-
sium (1.23 g, 51.4 mmol) and allyl bromide (3.1 g, 25.7 mmol) in
dry Et2O (10 mL)] was successively added CuCN (45 mg) and (S)-
4-fluorophenyl glycidyl ether (3.0 g, 18.0 mmol). The reaction mix-
ture was stirred for 15 min at r.t., quenched with sat. NH4Cl and
Anal. Calc for C16H19O3F: C, 69.06; H, 6.83. Found: C, 68.98; H,
7.05.
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M. K. Gurjar et al.
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(2S,6S)-6-(4-Fluorophenoxymethyl)-2-(1-N-hydroxyureidyl
-3-butyn-4-yl)tetrahydropyran (2)
Compound 2 (65%) was obtained from 14 by the same procedure as
described for compound 1.
[a]25D -28.6 (c 1.2, CHCl3).
1H NMR (200 MHz, CDCl3): d = 1.5-2.0 (m, 6H), 2.52 (t, 2H,
J = 7.3 Hz), 3.65 (t, 2H, J = 7.3 Hz), 3.83 (m, 2H), 4.2 (m, 1H), 4.75
(s, 1H), 5.77 (br s, 2H), 6.75-7.0 (m, 4H), 9.0 (br s, 1H).
D. M.; Yeh, C. G.; Young, M. A.; Yu, S. Abstracts of Papers,
214th National Meeting of the American Chemical Society,
Las Vegas, NV, 1997.
(b) Cai, X.; Chorghade, M. S.; Fura, A.; Grewal, G. S.;
Jauregui, K. A.; Lounsbury, H. A.; Scannell, R. T.; Yeh, C. G.;
Young, M. A.; Yu, S.; Guo, L.; Moriarty, R. M.; Penmastu, R.;
Rao, M. S.; Singhal, R. K.; Song, Z.; Staszewski, J. P.;
Tuladhar, S. M.; Yang, S. Org. Process. Res. Dev. 1999, 3, 73.
(4) Schuster, M.; Blechert, S. Angew Chem., Int. Ed. Engl. 1997,
36, 2036.
Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413.
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1, 1998, 371.
(5) (a) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V.;
Tetrahedron. 1989, 45, 4293.
13C NMR (75 MHz, CDCl3): d = 17.15, 18.71, 27.80, 30.40, 48.95,
65.43, 69.98, 72.24, 79.53, 84.54, 115.52, 115.82, 115.94, 116.03,
155.01, 159.01, 161.84.
Anal. Calc for C17H21N2O4F: C, 60.71; H, 6.25, N, 8.33. Found: C,
60.60; H, 6.42; N, 8.25.
(b) Ley, S. V.; Ligo, B.; Sternfeld, F.; Wonnacott, A.
Tetrahedron 1986, 42, 4333.
(c) Ley, S. V.; Ligo, B.; Wonnacott, A. Tetrahedron Lett.
1985, 26, 535.
Acknowledgement
The authors LMK and BSR thank CSIR, New Delhi for financial
support.
(6) Tokunaga, M.; Larrow, J. F.; Kakiuchi, F.; Jacobsen, E. N.
Science 1997, 227, 936.
Gurjar, M. K.; Sadalapure, K.; Adhikari, S.; Sarma, B. V. N.
B. S.; Talukdar, A.; Chorghade, M. S. Heterocycles 1998, 48,
1471.
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Article Identifier:
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Synthesis 2000, No. 4, 557–560 ISSN 0039-7881 © Thieme Stuttgart · New York