770 J . Org. Chem., Vol. 67, No. 3, 2002
Kim et al.
Acr ylic Acid (1S,5E)-6-[(1S,2R,4S)-4-Meth oxym eth oxy-
2-n itr om eth ylcyclopen tyl]-1-m eth ylh ex-5-en yl Ester (18).
To a mixture of alcohol 17 (46 mg, 0.15 mmol) and pyridine
(0.12 mL, 1.48 mmol) in dry CH2Cl2 (10 mL) was added
acryloyl chloride (0.11 mL, 1.35 mmol) at 0 °C. After 30 min,
the mixture was diluted with CH2Cl2 and washed with d-HCl,
NaHCO3 solution, and brine. The organic layer was dried over
anhydrous MgSO4 and concentrated at reduced pressure. The
residue was purified by column chromatography on silica gel
(EtOAc/hexane, 1:4) to give acrylate 18 (38 mg, 70%) as a thick
syrup: 1H NMR (CDCl3, 500 MHz) δ 6.31 (dd, J ) 17.3, 1.5
Hz, 1H), 6.03 (dd, J ) 17.8, 10.4 Hz, 1H), 5.72 (dd, J ) 10.4,
1.4 Hz, 1H), 5.36 (ddd, J ) 15.2, 6.6, 6.6 Hz, 1H), 5.26 (dd, J
) 15.2, 8.6 Hz, 1H), 4.93-4.90 (m, 1H), 4.54 (s, 2H), 4.37 (dd,
J ) 12.1, 4.8 Hz, 1H), 4.14-4.08 (m, 2H), 3.28 (s, 3H), 2.50-
2.42 (m, 1H), 2.21 (ddd, J ) 13.9, 8.0, 6.3 Hz, 1H), 2.06-1.92
(m, 4H), 1.59-1.42 (m, 4H), 1.40-1.28 (m, 2H), 1.18 (d, J )
6.3 Hz, 3H); 13C NMR (CDCl3, 50 MHz) δ 165.9, 132.0, 131.8,
130.2, 129.1, 95.3, 78.7, 76.0, 71.0, 55.3, 45.6, 42.1, 40.2, 37.4,
35.3, 32.0, 25.0, 19.9; IR (neat) 1721, 1553 cm-1; [R]20D ) -6.1
CH3CN (1:99, 4 mL) was added Mo(CO)6 (14 mg, 0.053 mmol)
at room temperature. The mixture was refluxed for 1.5 h, and
the solvent was removed in vacuo. The resulting residue was
dissolved in EtOAc, and the solution was washed with
saturated NaHCO3 solution and brine. The organic layer was
dried over anhydrous MgSO4 and concentrated in vacuo to
afford the crude â-hydroxy ketone (15.9 mg). This crude alcohol
was dissolved in CH2Cl2 (5.0 mL), and Et3N (0.13 mL, 0.93
mmol) and methanesulfonyl chloride (0.04 mL, 0.52 mmol)
were added to the solution. After 2 h at room temperature,
the reaction mixture was diluted with CH2Cl2 and washed with
saturated citric acid, saturated NaHCO3 solution and brine.
The organic layer was dried over anhydrous MgSO4 and
concentrated in vacuo. The resulting residue was purified by
column chromatography on silica gel (EtOAc/hexane, 1:3) to
give lactone 20 (12 mg, 65% for the two steps): 1H NMR
(CDCl3, 500 MHz) δ 7.76 (d, J ) 16.0 Hz, 1H), 6.44 (d, J )
15.8 Hz, 1H), 5.86 (ddd, J ) 15.1, 10.9, 4.1 Hz, 1H), 5.52 (ddd,
J ) 15.2, 9.6, 1.3 Hz, 1H), 4.70-4.61 (m, 1H), 4.63 (s, 2H),
4.12-4.07 (m, 1H), 3.36 (s, 3H), 2.88 (q, J ) 9.1 Hz, 1H), 2.56
(quintet, J ) 9.1 Hz, 1H), 2.30-2.21 (m, 2H), 2.18-2.11 (m,
1H), 2.05-1.98 (m, 1H), 1.96-1.88 (m, 2H), 1.84-1.77 (m, 1H),
1.68-1.58 (m, 2H), 1.33 (d, J ) 6.1 Hz, 3H), 1.27-1.16 (m,
1H); 13C NMR (CDCl3, 100 MHz) δ 200.5, 166.1, 140.2, 135.7,
132.9, 128.3, 95.2, 77.2, 73.7, 56.0, 55.3, 45.2, 40.3, 34.2, 32.7,
(c ) 0.10, CH3OH); HRMS (EI) calcd for C17H26NO5 (M+
-
OMe) 324.1811, found 324.1818.
In tr a m olecu la r Nitr ile Oxid e Cycloa d d ition of Acr y-
la te 18. A mixture of acrylate 18 (52 mg, 0.15 mmol),
p-chlorophenyl isocyanate (246 mg, 1.60 mmol), and Et3N (0.22
mL, 1.60 mmol) in benzene (49 mL) was refluxed for 18 h. The
reaction mixture was filtered through a short pad of Celite
and concentrated in vacuo. The residue was purified by column
chromatography on silica gel (EtOAc/hexane, 1:4). The first
fraction was collected and rechromatographed (EtOAc/hexane,
1:5) to give fused isomer 19 (21 mg, 38%) as a white solid: 1H
NMR (CDCl3, 500 MHz) δ 5.44 (ddd, J ) 15.3, 9.7, 5.0 Hz,
1H), 5.19 (dd, J ) 15.3, 7.2 Hz, 1H), 5.12-5.07 (m, 1H), 4.62
(dd, J ) 8.8, 8.1 Hz, 1H), 4.61 (s, 2H), 4.39 (dd, J ) 10.9, 8.8
Hz, 1H), 4.28-4.23 (m, 1H), 3.96 (dd, J ) 10.9, 8.1 Hz, 1H),
3.36 (s, 3H), 2.84-2.77 (m, 2H), 2.37 (ddd, J ) 13.8, 7.0, 7.0
Hz, 1H), 2.22-2.15 (m, 2H), 1.89-1.82 (m, 1H), 1.63-1.49 (m,
5H), 1.25-1.15 (m, 1H), 1.21 (d, J ) 6.5 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 166.6, 157.3, 132.2, 132.1, 95.2, 76.8, 71.7,
70.6, 58.3, 55.4, 48.1, 41.6, 40.4, 39.6, 31.7, 30.2, 20.4, 17.9;
32.2, 25.6, 20.2; IR (neat) 1725, 1042 cm-1; [R]18 ) -18.5 (c
D
) 0.50, CH3OH); HRMS (EI) calcd for C17H22O4 (M+ - MeOH)
290.1518, found 290.1541.
3-[(1R,2S,4S)-2-[(1E,6S)-6-(ter t-Bu tyl-d im eth ylsila n yl-
oxy)h ep t-1-en yl]-4-m eth oxym eth oxycyclop en tyl]-4,5-d i-
h yd r oisoxa zole-5-ca r boxylic Acid Meth yl Ester (21). (1)
P r otection of Hyd r oxyl Gr ou p . A mixture of alcohol 17 (54
mg, 0.18 mmol), TBDMSCl (35 mg, 0.23 mmol), and imidazole
(18 mg, 0.26 mmol) in DMF (3.0 mL) was stirred for 5 h at
room temperature. The mixture was diluted with EtOAc and
washed with water. The organic layer was dried over anhy-
drous MgSO4 and concentrated in vacuo. The resulting residue
was purified by column chromatography on silica gel (EtOAc/
hexane, 1:7) to give the silyl ether (71 mg, 95%): 1H NMR
(CDCl3, 500 MHz) δ 5.45 (ddd, J ) 15.2, 6.7, 6.7 Hz, 1H), 5.31
(dd, J ) 15.2, 8.6 Hz, 1H), 4.61 (s, 2H), 4.45 (dd, J ) 12.1, 4.7
Hz, 1H), 4.20-4.15 (m, 2H), 3.78 (dddd, J ) 11.9, 5.9, 5.9, 5.9
Hz, 1H), 3.35 (s, 3H), 2.56-2.48 (m, 1H), 2.28 (ddd, J ) 13.9,
7.8, 6.4 Hz, 1H), 2.12-2.05 (m, 2H), 2.00-1.94 (m, 2H), 1.66-
1.54 (m, 3H), 1.46-1.31 (m, 3H), 1.11 (d, J ) 6.1 Hz, 3H), 0.88
(s, 9H), 0.05 (s, 3H), 0.04 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 132.6, 131.3, 95.3, 78.7, 76.0, 68.4, 55.3, 45.7, 42.2, 40.2, 39.1,
37.4, 32.3, 25.9, 25.5, 23.8, 18.1, -4.4, -4.7; IR (neat) 1553,
1044 cm-1; [R]17D ) -13.2 (c ) 1.5, CH3OH); HRMS (EI) calcd
for C21H40NO5Si (M+ - C4H9) 358.2050, found 358.2061.
(2) In t er m olecu la r Nit r ile Oxid e Cycloa d d it on . A
mixture of the above silyl ether (60 mg, 0.14 mmol), methyl
acrylate (0.25 mL, 2.78 mmol), p-chlorophenyl isocyanate (236
mg, 1.54 mmol) and Et3N (0.22 mL, 1.58 mmol) in benzene
(20 mL) was refluxed for 10 h. The mixture was cooled to room
temperature. The white precipitate was filtered off through a
pad of Celite and the filtrate was concentrated in vacuo. The
resulting residue was dissolved in EtOAc/hexane (1:3) and
insoluble material was removed by filtration. Concentration
of the filtrate and purification of the residue by column
chromatography on silica gel (EtOAc/hexane, 2:3) afforded a
1:1 mixture of isoxazoles 21 (58 mg, 85%) as a thick syrup:
1H NMR (CDCl3, 500 MHz) δ 5.47-5.35 (m, 2H), 4.96 (ddd, J
) 11.4, 6.3, 2.5 Hz, 1H), 4.62 (s, 2H), 4.23-4.19 (m, 1H), 3.79-
3.74 (m, 4H), 3.35 (s, 3H), [3.28 (dd, J ) 17.1, 6.3 Hz) and
3.24 (dd, J ) 17.1, 11.1 Hz), 1H], [3.13 (dd, J ) 16.9, 6.7 Hz)
and 3.10 (dd, J ) 16.9, 11.3 Hz), 1H], 2.81 (quintet, J ) 9.3
Hz, 1H), 2.45 (dddd, J ) 18.4, 9.1, 9.1, 9.1 Hz, 1H), 2.30 (ddd,
J ) 14.0, 8.1, 6.2 Hz, 1H), 2.09-1.94 (m, 4H), 1.61-1.55 (m,
1H), 1.45-1.31 (m, 3H), 1.11 (d, J ) 6.1 Hz, 3H), 0.88 (s, 9H),
0.87-0.80 (m, 1H), 0.04 (s, 6H); 13C NMR (CDCl3, 100 MHz) δ
170.9, 160.04, 159.95, 132.18, 132.16, 131.6, 95.24, 95.22,
77.17, 77.14, 76.9, 76.48, 76.45, 68.48, 68.46, 55.4, 52.7, 46.5,
46.4, 42.4, 42.2, 40.4, 40.2, 39.7, 39.2, 37.2, 37.1, 32.4, 29.7,
IR (neat) 1721 cm-1; [R]18 ) +99 (c ) 0.10, CH3OH); HRMS
D
(EI) calcd for C18H27NO5 (M+) 337.1889, found 337.1873.
The second fraction was collected and rechromatographed
(EtOAc/hexane, 1:4) to give C2-(R) bridged isomer 2 (10 mg,
19%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 5.77 (ddd,
J ) 15.0, 10.2, 5.0 Hz, 1H), 5.27 (dd, J ) 15.0, 9.0 Hz, 1H),
4.94 (dd, J ) 11.8, 4.6 Hz, 1H), 4.92-4.86 (m, 1H), 4.61 (s,
2H), 4.30-4.26 (m, 1H), 3.41 (dd, J ) 17.3, 11.8 Hz, 1H), 3.35
(s, 3H), 3.01 (dd, J ) 17.3, 4.6 Hz, 1H), 2.70-2.62 (m, 1H),
2.55 (ddd, J ) 11.8, 11.8, 5.0 Hz, 1H), 2.40 (ddd, J ) 13.9, 7.2,
7.2 Hz, 1H), 2.12-1.98 (m, 2H), 1.98-1.86 (m, 2H), 1.82-1.74
(m, 1H), 1.68-1.58 (m, 2H), 1.53-1.47 (m, 1H), 1.28 (d, J )
6.3 Hz, 3H), 1.04-0.96 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ
171.5, 159.2, 132.8, 131.4, 95.1, 77.2, 76.0, 73.3, 55.4, 51.1, 46.1,
42.7, 40.0, 39.0, 32.7, 31.0, 26.2, 20.1; IR (neat) 1728 cm-1
;
[R]18 ) -62 (c ) 0.10, CH3OH); HRMS (EI) calcd for C18H27
-
D
NO5 (M+) 337.1889, found 337.1888.
The third fraction was collected and rechromatographed
(EtOAc/hexane, 1:2) to give C2-(S) bridged isomer 2 (12 mg,
21%) as a white solid: 1H NMR (CDCl3, 500 MHz) δ 5.70 (ddd,
J ) 15.1, 10.1, 4.9 Hz, 1H), 5.27 (dd, J ) 15.1, 8.6 Hz, 1H),
4.99 (dd, J ) 11.1, 2.7 Hz, 1H), 4.94-4.88 (m, 1H), 4.61 (d, J
) 6.8 Hz, 1H), 4.60 (d, J ) 6.8 Hz, 1H), 4.27-4.22 (m, 1H),
3.35 (s, 3H), 3.33 (dd, J ) 16.9, 2.7 Hz, 1H), 3.10 (dd, J )
16.9, 11.1 Hz, 1H), 3.11-3.04 (m, 1H), 2.41-2.29 (m, 2H),
2.05-1.97 (m, 2H), 1.81-1.51 (m, 6H), 1.27 (d, J ) 6.5 Hz,
3H), 1.09-1.02 (m, 1H); 13C NMR (CDCl3, 75 MHz) δ 169.6,
160.1, 132.5, 130.8, 95.3, 77.2, 75.7, 74.4, 55.4, 48.7, 41.6, 40.0,
37.1, 35.8, 33.2, 31.2, 26.1, 20.4; IR (neat) 1734 cm-1; [R]18
)
D
+88 (c ) 0.10, CH3OH); HRMS (EI) calcd for C18H27NO5 (M+)
337.1889, found 337.1888.
(2S,3a R,5E,9S,13E,14a S)-2-Meth oxym eth oxy-9-m eth yl-
2,3,3a ,9,10,11,12,14a -oct a h yd r o-1H -8-oxa -cyclop en t a cy-
clotr id ecen e-4,7-d ion e (20). To a mixture of the two bridged
isomers 2 (8 mg, 0.024 mmol and 9.5 mg, 0.028 mmol) in H2O/
25.9, 25.53, 25.50, 23.8, 18.2, -4.4, -4.7; IR (neat) 1744 cm-1
;