9190 J . Org. Chem., Vol. 62, No. 26, 1997
Kalaus et al.
1
for 12 h and then was diluted with water (110 mL), and the
solution was extracted with ether three times (50 mL each).
The combined organic layers were dried with MgSO4, filtered,
and concentrated in vacuo. The residue was distilled to yield
7 (3.60 g, 43%): bp 105-115 °C (15 Torr); IR (neat) νmax 1738,
1684, 1608 cm-1; 1H NMR (CDCl3) δ 2.35 (s, 3H, COCH3), 2.47
(m, 2H, 2-H2), 2.60 (m, 2H, 3-H2), 3.67 (s, 3H, OCH3), 5.86 +
6.06 (2 × 1H, 5-H2); 13C NMR (CDCl3) δ 25.7, 26.2, 32.8, 51.5,
126.1, 147.2, 173.2, 199.1.
3417, 1741, 1703, 1674, 1639, 1622 cm-1; H NMR (CDCl3) δ
1.75 + 2.04 (2 × ddd, J gem ) 12.2, J 5,6 ) 5.6 + 1.5 and 11.6 +
6.6 Hz, respectively, 2 × 1H, 6-H2), 1.97 (s, 3H, 18-H3), 2.12-
2.23m + 2.36m + 2.63m (4H, 14-H2 + 15-H2), 2.62 + 2.93 (2
× d, J gem ) 15.5 Hz, 2 × 1H, 17-H2), 2.69 + 3.01 (2 × ddd,
J gem ) 9.5 Hz, 2 × 1H, 5-H2), 3.55 + 3.79 (2 × s, 2 × 3H, 2 ×
OCH3), 3.76 + 4.17 (2 × d, J gem ) 13.2 Hz, 2 × 1H, NCH2C6H5),
4.00 (d, J lr ) 2.0 Hz, 1H, 21-H), 6.80 (d, 1H, 12-H), 6.95 (dd,
1H, 10-H), 7.16 (dd, 1H, 11-H), 7.19 (d, 1H, 9-H), 7.25-7.50
(m, 5H, C6H5), 8.75 (br s, 1H, NH); 13C NMR (CDCl3) δ 25.9,
27.9, 28.7, 30.5, 42.4, 51.1, 51.8, 53.0, 58.5, 59.1, 61.7, 68.3,
89.7, 109.5, 121.2, 122.1, 127.1, 127.8, 128.4, 128.6, 137.2,
139.2, 142.5, 166.8, 167.8, 172.9, 211.5; MS m/z 488 (3.0, M+),
455 (8.0), 332 (15.0), 274 (100). Anal. Calcd for C29H32N2O5:
C, 71.29; H, 6.60; N, 5.73. Found: C, 71.32; H, 6.61; N, 6.04.
The less polar compound (13, Rf ) 0.54) was obtained as
white crystals after crystallization from methanol (0.18 g,
19%): mp 131-132 °C; IR (KBr) νmax 3365, 1738, 1690, 1615
Meth yl 4-Br om o-4-(br om om eth yl)-5-oxoh exa n oa te (8).
To a solution of 7 (10.00 g, 64 mmol) in CH2Cl2 (50 mL) was
added a solution of 3.5 mL (68 mmol) of bromine in 10 mL of
CH2Cl2 dropwise at rt. After the solution was stirred for 1 h,
the excess bromine was removed by washing with aqueous
sodium thiosulfate until the solution was discolored. The
organic layer was separated and washed with water (20 mL),
dried with MgSO4, and concentrated in vacuo. The residue
was crystallized from methanol to yield 8 (15.60 g, 78%); mp
1
1
55-56 °C; IR (KBr) νmax 1730, 1727 cm-1; H NMR (CDCl3) δ
cm-1; H NMR (CDCl3) δ 1.14m + 1.92m + 2.00-2.12m (4H,
2.36-2.69 (m, 4H, 2-H2 + 3-H2), 2.46 (s, 3H, COCH3), 3.72 (s,
3H, OCH3), 3.76 + 4.09 (2 × d, J gem ) 10.6 Hz, 2 × 1H, 4-CH2-
Br); 13C NMR (CDCl3) δ 24.4, 30.0, 31.0, 34.1, 52.0, 66.8, 172.5,
199.0.
14-H2 + 15-H2), 1.69 + 2.21 (2 × ddd, J ) 12.2, J 5,6 ) 5.5 +
∼1 and 6.8 + 12.2 Hz, respectively, 2 × 1H, 6-H2), 2.45 (s, 3H,
18-H3), 2.68 + 2.97 (2 × ddd, J gem ) 9.6 Hz, 2 × 1H, 5-H2),
2.88 + 2.93 (2 × d, J gem ) 15.0 Hz, 2 × 1H, 17-H2), 3.28 (d, J lr
) 1.4 Hz, 1H, 21-H), 3.57 + 3.80 (2 × s, 2 × 3H, 2 × OCH3),
3.63 + 4.06 (2 × d, J gem ) 13.0 Hz, 2 × 1H, NCH2C6H5), 6.80
(br d, J 9,10 ) 7.4 Hz, 1H, 9-H), 6.85 (br d, J 11,12 ) 7.6 Hz, 1H,
12-H), 6.86 (ddd, J 10,11 ) 7.4, J 10,12 ) 1.2 Hz, 1H, 10-H), 7.17
(ddd, J 11,12 ) 7.8, J 9,11 ) 1.3 Hz, 1H, 11-H), 7.25-7.37 (m, 5H,
C6H5), 8.97 (br s, 1H, NH); 13C NMR (CDCl3) δ 23.9, 28.6, 28.9,
31.3, 40.4, 51.2, 51.6, 56.3, 57.7, 60.9, 76.4, 88.6, 109.5, 121.0,
122.8, 127.1, 128.2, 128.3, 129.2, 136.6, 138.2, 142.7, 164.6,
168.2, 173.4, 213.3; MS m/z 488 (10.0, M+), 457 (15.0), 445
(17.0), 332 (10.0), 274 (83.0), 91 (100). Anal. Calcd for
C29H32N2O5: C, 71.29; H, 6.60; N, 5.73. Found: C, 71.08; H,
6.66; N, 5.52.
Meth yl 4-Acetyl-5-br om op en t-4-en oa te (9). To a homo-
geneous solution of tetrabutylammonium chloride (11.10 g, 40
mmol) in 25 mL of HMPA was added 8 (10.00 g, 31 mmol)
over a 30 min period at rt. After being stirred for 12 h at rt,
the brown mixture was cooled (0 °C) and quenched with an
aqueous solution of sulfuric acid (1 M, 65 mL) and then
extracted with hexane five times (20 mL each). The combined
organic extracts were washed with water until neutrality of
the aqueous layer. The organic layer was dried with MgSO4
and concentrated in vacuo. The main component was sepa-
rated by column chromatography (eluent: CH2Cl2) to yield 9
(1.19 g, 16%) as an yellow oil (Rf ) 0.47): IR (neat) νmax 1730,
1675, 1582 cm-1; 1H NMR (CDCl3) δ 2.34 (s, 3H, COCH3), 2.43
(t, J ) 7.5 Hz, 2H, 2-H2), 2.77 (t, 2H, 3-H2), 3.67 (s, 3H, OCH3),
7.32 (s, 1H, 5-H); 13C NMR (CDCl3) δ 21.9, 26.0, 31.7, 51.7,
134.8, 142.8, 172.8, 195.1.
(()-3-Oxom in ovin cin e (14). Meth od a . A mixture of
1.00 g of 12 (2.00 mmol) and 0.50 g of 10% palladium/charcoal
in 20 mL of glacial acetic acid was hydrogenated for 1 h at rt
and then filtered. The filtrate was poured into 50 mL of ice-
water and neutralized with saturated Na2CO3 solution. The
solution was extracted three times with CH2Cl2 (30 mL each),
En a m in e 10. To a mixture of 1.00 g (2.48 mmol) of 1,2 0.40
g (4 mmol) of triethylamine, and 100 mL of methanol was
added 0.70 g (3 mmol) of 9. After being stirred for 24 h at rt,
the mixture was concentrated in vacuo. The residue was
purified by column chromatography (eluent: hexane/acetone
1:1) to yield 10 (1.00 g, 70%) as an amorphous solid (Rf )
and the combined organic layers were dried with MgSO4
and
evaporated in vacuo. The main component was separated by
preparative TLC (eluting with hexane/acetone 2:1) to yield a
yellow oil (Rf ) 0.28), which was crystallized from methanol
to afford 14 (0.48 g, 64%) as white crystals: mp 245-246 °C;
0.76): IR (KBr) νmax 3390, 1740, 1730, 1608, 1574 cm-1 1H
;
1
NMR (CDCl3) δ 1.99 (s, 3H, COCH3), 2.29 + 2.34 (2 × ddd,
IR (KBr) νmax 3345, 1702, 1671, 1602 cm-1; H NMR (CDCl3)
J gem ) 15.5, J vic ) 6.0 + 9.8 and 6.0 + 9.3 Hz, respectively, 2
δ 1.77 + 2.17 (2 × ddd, J gem ) 14.0, J 14,15 ) 4.8 + 11.2 and 4.8
+ 5.6 Hz, respectively, 2 × 1H, 15-H2), 1.88 + 1.97 (2 × ddd,
J gem ) 12.2, J 5,6 ) 5.8 + ∼1 and 12.4 + 7.5 Hz, respectively, 2
× 1H, CH2COOCH3), 2.64 + 2.70 (2 × ddd, J gem ) 14.0, J vic
)
6.0 + 9.3 and 6.0 + 9.8 Hz, respectively, 2 × 1H, CH2Cd),
3.02 + 3.07 (2 × dt, J gem ) 14.2, J vic ) 7.0 Hz, 2 × 1H, 3-CH2),
3.44 (br, 1H, OH), 3.55 (t, J ) 7.0 Hz, 2H, CH2CN), 3.58 +
3.68 (2 × s, 2 × 3H, 2 × OCH3), 4.00-4.12 (m, 3H, 2-CHCH2),
× 1H, 6-H2
), 2.08 (s, 3H, 18-H3), 2.28 + 3.19 (2 × d, J gem
)
15.5 Hz, 2 × 1H, 17-H2
), 2.34 + 2.43 (2 × ddd, J gem ) 15.6 Hz,
2 × 1H, 14-H2
), 3.48 + 4.24 (2 × ddd, J gem ) 11.6 Hz, 2 × 1H,
)
)
5-H2
(d, 1H, 12-H), 6.97 (dd, 1H, 10-H), 7.21 (dd, 1H, 11-H), 7.28
13C NMR (CDCl3) δ 25.0,
), 3.80 (s, 3H, OCH3), 4.71 (d, J lr ) 2.0 Hz, 1H, 21-H), 6.86
4.46 (s, 2H, NCH2C6H5), 7.09 (ddd, J 4,5 ) 7.8, J 5,6 ) 7.1, J 5,7
1.1 Hz, 1H, 5-H), 7.16 (m, 2H, 2′-H + 6′-H), 7.17 (ddd, J 6,7
8,0, J 4,6 ) 1.3 Hz, 1H, 6-H), 7.22 (s, 1H, -CHd), 7.29 (m, 1H,
4′-H), 7.33 (br d, 1H, 7-H), 7.35 (m, 2H, 3′-H + 5′-H), 7.41 (br
d, 1H, 4-H), 9.04 (br s, 1H, NH); 13C NMR (CDCl3) δ 20.1, 23.9,
24.9, 34.5, 44.8, 51.5, 52.6, 53.6, 57.4, 63.9, 109.3, 109.7, 111.3,
118.0, 119.7, 122.4 126.9, 127.2, 127.8, 128.9, 129.9, 135.7,
137.0, 150.5, 172.6, 174.0, 196.6; MS m/z 507 (4.0, M+), 467
(8.0), 445 (10.0), 332 (17), 274 (80), 91 (100).
(()-2,16-Dideh ydr o-14,16-bis(m eth oxycar bon yl)-3-ph en -
yl-3,14-secoa sp id osp er m id in -19-on e (12) a n d (()-2,16-
Did eh yd r o-14,16-b is(m et h oxyca r b on yl)-3-p h en yl-3,14-
seco-20-ep ia sp id osp er m id in -19-on e (13). A solution of 1.00
g (1.97 mmol) of 10 and 0.01 g (0.06 mmol) of p-toluenesulfonic
acid monohydrate in 100 mL of xylene was refluxed under
argon for 24 h. The reaction mixture was extracted twice with
brine (40 mL), and the combined brine washes were extracted
twice with CH2Cl2 (40 mL each). The combined organic layers
were dried with MgSO4 and evaporated in vacuo. The two
main components were separated by column chromatography
(eluent: CH2Cl2/ether 30:1). The more polar compound (12,
Rf ) 0.48) was obtained as white crystals after crystallization
from methanol (0.18 g, 19%): mp 187-188 °C; IR (KBr) νmax
(d, 1H, 9-H), 8.82 (br s, 1H, NH);
28.6, 28.9, 30.7, 40.3, 43.4, 51.3, 53.7, 57.1, 62.3, 89.7, 109.9,
121.4, 121.7, 128.5, 135.4, 142.4, 165.3, 167.4, 169.8, 209.0;
MS m/z 366 (40.0, M+), 227 (85.0), 214 (100). Anal. Calcd for
C21
H22N2O4: C, 68.84; H, 6.05; N, 7.65. Found: C, 68.67; H,
6.35; N, 7.25. Meth od b. The solution of 1.00 g of 15 in 100
mL of anhydrous toluene and 0.01 g (0.06 mmol) of p-
toluenesulfonic acid monohydrate was refluxed under argon
for 1 h. The reaction mixture was extracted twice with brine
(40 mL each), and the combined aqueous layers were extracted
twice with CH2Cl2 (40 mL each), dried with MgSO4, and
evaporated in vacuo. The main component was separated as
described above to yield 14 (0.39 g, 43%) which was identical
spectroscopically to the material prepared by method a.
Secon d a r y Am in e 15. A mixture of 1.00 g of 13 (2.0 mmol)
and 0.50 g of 10% palladium/charcoal in 20 mL of glacial acetic
acid was hydrogenated for 1 h at rt. The filtrate was worked
up as in the case of compound 14 to yield 15 (0.59 g, 73%, Rf
) 0.77, eluent: hexane/acetone 2:1): mp 186-187 °C (crystal-
lized from methanol); IR (KBr) νmax 3400, 3368, 1731, 1710,
1
1673, 1646, 1619 cm-1; H NMR (CDCl3) δ 1.37 + 1.71 (2 ×