Yu et al.
on silica gel (CHCl3/MeOH ) 40:1) to provide ester 39 (28 mg,
88%): [R]D ) +4.6 (c 1.0, MeOH) [lit.44 [R]D ) +3.6 (c 1.0,
Ca ta lytic Deben zyla tion of (6S,10S)-(-)-9-Oxo-12-ben -
zyl-6,7,8,9,10,11-h exa h yd r o-6,10-im in o-5-m eth ylcyclooct-
[b]in d ole (15b) To P r ovid e (6S,10S)-5-Meth yl-(-)-9-oxo-
12H -6,7,8,9,10,11-h e xa h yd r o-6,10-im in ocyclooct [b]in -
d ole (42). Tetracyclic ketone 15b (10.0 g, 30.3 mmol) was
suspended in anhydrous EtOH (100 mL), and ethanolic HCl
(5%, 15 mL) was added dropwise to form a clear solution. The
solvent was removed under reduced pressure. The residue was
then dissolved again in dry EtOH (80 mL), and the solvent
was removed under reduced pressure. This process was
repeated for three times after which Pd/C (10%, 2.0 g) was
added. The mixture that resulted was allowed to stir at rt
under an atmosphere of hydrogen (Parr hydrogenator) for 5
h. Analysis by TLC (silica gel plate was exposed to NH3 vapor)
indicated the absence of starting material 15b. The catalyst
was removed by filtration, and the solid was washed with
EtOH (3 × 100 mL). The solvent was removed under reduced
pressure. The residue was dissolved in a mixture of CH2Cl2
and 15% aq NH4OH (5:1, 500 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 100 mL). The combined organic
layers were washed with brine (2 × 200 mL) and dried (K2-
CO3). Removal of the solvent under pressure afforded the crude
product, which was purified by chromatography on silica gel
(CHCl3/MeOH ) 25:1) to provide pure Na-Me, Nb-H tetracyclic
MeOH)]; FTIR (CHCl3) cm-1 1H NMR (300 MHz, CDCl3) δ
;
1.54 (3H, d, J ) 6.7 Hz), 1.66 (1H, dt, J ) 12.0, 2.6 Hz), 1.95
(1H, t, J ) 10.6 Hz), 2.42 (1H, d, J ) 7.7 Hz), 2.51 (1H, d, J )
15.2 Hz), 2.90 (1H, dd, J ) 15.2, 5.1 Hz), 3.09 (1H, m), 3.45
(3H, m), 3.59 (3H, s), 3.59 (3H, s), 4.09 (1H, d, J ) 8.6 Hz),
5.24 (1H, q, J ) 7.8 Hz), 6.93 (1H, t, J ) 6.9 Hz), 7.01 (1H, t,
J ) 6.0 Hz), 7.28 (1H, d, J ) 7.9 Hz), 7.36 (1H, d, J ) 7.5 Hz),
10.71 (1H, s); 13C NMR (75.5 MHz, CDCl3) δ 12.86, 27.25,
28.87, 33.21, 46.84, 49.45, 51.80, 52.75, 55.59, 102.49, 111.43,
115.77, 117.89, 118.64, 120.76, 127.44, 136.01, 136.51, 139.39,
173.86; EIMS (m/e, relative intensity) 322 (M+, 36), 307 (11),
263 (19), 168 (100). Anal. Calcd for C20H22N2O2‚0.3H2O: C,
73.26; H, 6.76; N, 8.55. Found: C, 73.13; H, 6.86; N, 8.29.
Con ver sion of th e (+)-Meth yl-3-eth ylid en e-1,3,4,7,12,
12b-h exa h yd r o-2H,6H-2,6-m eth a n oin d ole[2,3-r]qu in oli-
zin e-13-ca r boxyla te (39) in to (-)-Alk a loid Q3 (4). Ester
39 (32 mg, 0.1 mmol) was dissolved in anhydrous THF (2 mL),
and then MeI (5 equiv, 161 mg, 0.5 mmol) was added at 0 °C.
The mixture that resulted was stirred at rt for 4 h. The solvent
was removed under reduced pressure, and the residue was
chromatographed (flash) on silica gel (CHCl3/MeOH ) 9:1) to
provide iodomethylated salt 40 (42 mg, 90%). The salt was
dissolved in anhydrous MeOH (2 mL), and this was followed
by addition of AgCl97 (72 mg, 0.5 mmol). The mixture that
resulted was stirred at rt for 2 days. The excess AgCl and
formed AgI were removed by filtration and washed with MeOH
(3×10 mL). After removal of the solvent under reduced
pressure, the crude product was purified by chromatography
on silica gel (CHCl3/MeOH ) 9:1) to afford alkaloid Q3 (4) (29
mg, 85%): [R]D ) -21.3 (c 0.15, MeOH) [lit.46 [R]D ) -23 (c
1
ketone 42 (6.80 g, 94%): FTIR (CHCl3) 3419, 1705 cm-1; H
NMR (300 MHz, CDCl3) δ 2.15 (2H, m), 2.25 (1H, bs), 2.85
(1H, d, J ) 16.5 Hz), 3.16 (1H, dd, J ) 16.5, 6.9 Hz), 3.70 (3H,
s), 3.97 (1H, d, J ) 6.8 Hz), 4.42 (1H, m), 7.13 (1H, t, J ) 6.8
Hz), 7.25 (1H, t, J ) 6.9 Hz), 7.33(1H, d, J ) 8.1 Hz), 7.50
(1H, d, J ) 7.8 Hz); 13C NMR (75.5 MHz, CDCl3) δ 25.80, 29.26,
31.38, 34.86, 44.86, 59.66, 106.42, 108.80, 118.70, 119.23,
121.56, 126.44, 135.07, 136.89, 210.53; EIMS (m/e, relative
intensity) 240 (M+, 28), 183 (100), 168 (17). Anal. Calcd for
0.15, MeOH)]; FTIR (NaCl) 3040, 1594 cm-1 1H NMR (300
;
C
15H16N2O‚0.25H2O: C, 73.59; H, 6.79; N, 11.44. Found: C,
MHz, CD3OD) δ 1.68 (3H, ddd, J ) 8.3, 2.3, 2.2 Hz), 2.26 (1H,
dd, J ) 13.3, 3.2 Hz), 2.58 (1H, ddd, J ) 12.1, 10.3, 1.7 Hz),
3.03 (1H, dd, J ) 7.7, 1.8 Hz), 3.08 (1H, br d, J ) 17.5 Hz),
3.17 (3H, s), 3.33 (1H, m), 3.41 (1H, dd, J ) 17.4, 4.9 Hz), 3.60
(1H, m), 3.76 (3H, s), 4.30 (1H, d, J ) 15.5 Hz), 4.45 (1H, m),
4.56 (1H, dt, J ) 15.5, 2.4 Hz), 4.98 (1H, d, J ) 10.2 Hz), 5.58
(1H, q, J ) 6.8 Hz), 7.1 (1H, ddd, J ) 8.0, 7.1, 1.1 Hz), 7.2
(1H, ddd, J ) 8.2, 7.1, 1.2 Hz), 7.40 (1H, dt, J ) 8.1, 0.8 Hz),
7.52 (1H, dt, J ) 7.8, 0.9 Hz); 13C NMR (75.5 MHz, CD3OD) δ
11.43, 23.41, 27.20, 30.95, 46.83, 47.17, 51.57, 60.39, 62.51,
64.24, 100.02, 111.17, 117.93, 119.53, 120.79, 122.46, 125.87,
126.59, 130.52, 137.38, 170.52; EIMS (m/e, relative intensity)
336 (M+, 14), 322 (100), 307 (37), 291 (11), 263 (44), 225 (20),
168 (71). The spectral data were in complete agreement with
the natural product.
73.60; H, 6.57; N, 11.19.
Alk yla tion of (6S,10S)-5-Meth yl-9-oxo-12H-6,7,8,9,10,-
11-h exa h yd r o-6,10-im in ocyclooct[b]in d ole (42) To P r o-
vid e (6S,10S)-5-Meth yl-9-oxo-12-((Z)-2′-iod o-2′-bu ten yl)-
6,7,8,9,10,11-h exa h yd r o-6,10-im in ocyclooct[b]in d ole (43).
A solution of Na-methyl, Nb-H tetracyclic ketone 42 (10.0 g,
41.7 mmol) and (Z)-1-bromo-2-iodo-2-butene (15.1 g, 58.2
mmol) was dissolved in THF (200 mL). At this point, K2CO3
(31.5 g, 228.3 mmol) was added, and the mixture was heated
at 60 °C for 24 h. Analysis by TLC (silica gel, CHCl3/MeOH )
6:1) indicated the absence of tetracyclic ketone. The K2CO3 was
removed by filtration, and the solid was washed with EtOAc
(3 × 100 mL). The solvent was removed from the combined
organic layers under reduced pressure after which the crude
product was purified by chromatography on silica gel (EtOAc/
hexanes ) 15:1) to provide Nb-(Z)-2′-iodo-2′-butenyl tetracyclic
ketone 43 (14.95 g, 85%): 1H NMR (300 MHz, CDCl3) δ 1.84
(3H, d, J ) 6.4 Hz), 2.10 (2H, m), 2.53 (2H, m), 2.78 (1H, d, J
) 17.0 Hz), 3.16 (1H, dd, J ) 16.9, 6.6 Hz), 3.44 (2H, s), 3.69
(3H, s), 3.78 (1H, d, J ) 6.4 Hz), 4.21 (1H, m), 5.94 (1H, q, J
) 6.4 Hz), 7.15 (1H, t, J ) 6.9 Hz), 7.26 (1H, t, J ) 6.9 Hz),
7.36 (1H, d, J ) 8.2 Hz), 7.50 (1H, d, J ) 7.7 Hz); 13C NMR
(75.5 Hz, CDCl3) 20.58, 21.87, 29.35, 34.15, 48.86, 63.30, 63.90,
105.73, 108.89, 118.18, 119.35, 121.72, 126.20, 137.14, 209.80;
EIMS (m/e, relative intensity) 420 (M+, 35), 363 (100), 293
(8.5), 183 (35). Anal. Calcd for C19H21N2OI: C, 54.30; H, 5.04;
N, 6.67. Found: C, 54.06; H, 5.17; N, 6.47.
Con ver sion of (-)-Alk a loid Q3 (4) in to (-)-P a n a r in e
(5). Alkaloid Q3 (4) (37 mg, 0.1 mmol) was treated with 0.1 N
NaOH (1 mL) in MeOH (4 mL) at rt for 6 h. The solution that
resulted was brought with 0.1 N HCl to pH 7. The solvent was
removed, and the crude product was purified by chromatog-
raphy on silica gel (CHCl3/MeOH ) 6:1) to afford panarine
(5) (29 mg, 90%): [R]D ) -24.0 (c 0.10, MeOH) [lit.46 [R]D
)
-28 ( 10 (c 0.05, MeOH)]; IR (KBr) 1738 cm-1; 1H NMR (300
MHz, CD3OD) δ 1.53 (3 H, d, J ) 6.7 Hz), 2.07 (1 H, dd, J )
13.2, 3.8 Hz), 2.43 (1 H, t, J ) 12.3 Hz), 2.51 (1 H, d, J ) 7.6
Hz), 2.88 (1 H, d, J ) 17.3 Hz), 3.03 (1 H, s), 3.24 (1 H, dd, J
) 17.3, 5.0 Hz), 3.36 (1 H, bs), 4.11 (1 H, d, J ) 15.4 Hz), 4.16
(1 H, t, J ) 6.4 Hz), 4.28 (1 H, d, J ) 15.4 Hz), 4.80 (1 H, d, J
) 5.0 Hz), 5.47 (1 H, q, J ) 6.7 Hz), 7.11 (1 H, t, J ) 7.3 Hz),
7.22 (1 H, t, J ) 7.1 Hz), 7.43 (1 H, d, J ) 8.1 Hz), 7.51 (1 H,
d, J ) 7.9 Hz). 13C NMR (75 MHz, CD3OD) δ 12.06, 23.41,
28.21, 31.03, 47.13, 49.03, 60.18, 64.23, 64.69, 100.84, 111.86,
118.39, 119.93, 120.70, 122.74, 125.61, 126.61, 131.59, 136.67,
176.95; EIMS (m/e, relative intensity) 336 [(M + Me)+, 8], 322
(M+, 81), 307 (47), 291(7), 278 (21), 263 (79), 249 (32), 247 (41),
169 (87), 168 (100). A carbon 13 NMR spectrum of a mixed
sample of synthetic and natural panarine indicated the two
compounds were identical since there was only one set of
signals.
P a lla d iu m -Ca ta lyzed Cycliza tion of (6S,10S)-5-Meth yl-
9-oxo-12-((Z)-2′-iod o-2′-bu ten yl)-6,7,8,9,10,11-h exa h yd r o-
6,10-im in ocyclooct[b]in dole (43) To P r ovide 3-Eth yliden e-
12-m eth yl-1,3,4,7,12,12b-h exa h yd r o-2H,6H-2,6-m eth a n o-
in d olo[2,3-a ]qu in olizin -13-on e (44). A mixture of Nb-(Z)-
2′-iodo-2′-butenyl tetracyclic ketone 43 (3.0 g, 7.14 mmol), Pd-
(OAc)2 (47 mg, 0.21 mmol), Bu4NBr (1.88 g, 7.14 mmol), PPh3
(566 mg, 2.14 mmol), and K2CO3 (3.98 g, 28.56 mmol) was
placed in a solution of DMF-H2O (9:1, 131 mL) after which it
was degassed under reduced pressure at rt. The mixture was
then heated to 70 °C (oil bath temperature) for 40 h under an
7580 J . Org. Chem., Vol. 68, No. 20, 2003