Enantiospecific Total Syntheses
(c 0.30, MeOH) {lit.1 [R]D ) +58.80° (c 0.25, MeOH)}; 1H
NMR (300 MHz, CDCl3) δ 1.66 (3 H, dt, J ) 6.8, 1.9 Hz),
1.83-2.00 (2 H, m), 2.32 (1 H, m), 2.85 (1 H, q, J ) 3.0 Hz),
3.48 (1 H, t, J ) 11.6 Hz), 3.64 (3 H, s), 3.76-3.87 (4 H, m),
4.11 (1 H, dd, J ) 9.7, 3.8 Hz), 5.36 (1 H, q, J ) 6.7 Hz), 5.66
(1 H, d, J ) 7.5 Hz), 7.16 (1 H, td, J ) 7.9, 1.2 Hz), 7.24 (1 H,
td, J ) 7.9, 1.2 Hz), 7.33 (1 H, d, J ) 7.3 Hz), 7.72 (1 H, d, J
) 7.3 Hz); 13C NMR (75.5 MHz, CDCl3) δ 12.8, 27.0, 27.4, 29.1,
38.8, 47.5, 56.1, 59.6, 64.8, 71.4, 103.6, 108.8, 113.9, 118.8,
119.6, 121.3, 126.2, 137.3, 138.9, 143.3; EIMS (m/z, relative
intensity) 306 (M+, 60), 196 (30), 182 (100). Anal. Calcd for
C20H22N2O: C, 78.40; H, 7.24; N, 9.14. Found: C, 78.04; H,
7.03; N, 8.86.
Exp er im en ta l Section
Gen er a l Meth od s. Reagent and solvent purification, work-
up procedures, and analyses were performed in general as
described previously.22
Con ver sion of th e P en ta cyclic Keton e (9) in to (+)-3-
E t h ylid en e-12-m et h yl-1,3,4,7,12,12b -h exa h yd r o-2H ,6H -
2,6-m eth a n o-13-m eth ylen e-in d ole[2,3-a ]qu in olizin e (10)
via th e Wittig Rea ction . A mixture of anhydrous potassium
tert-butoxide (3.24 g, 2.75 mmol) and methyltriphenylphos-
phonium bromide (8.93 g, 2.5 mmol) in dry benzene (150 mL)
was allowed to stir at room temperature for 1 h. The penta-
cyclic ketone 9 (1.46 g, 0.50 mmol) in THF (50 mL) was then
added into the above orange-colored solution dropwise at room
temperature. The mixture that resulted was stirred at room
temperature for 4 h. The mixture was diluted with EtOAc (500
mL), washed with H2O (3 × 50 mL) and brine (100 mL), and
dried (K2CO3). The solvent was removed under reduced pres-
sure, and the oil that resulted was chromatographed (silica
gel, CHCl3/MeOH ) 40:1) to provide the olefin 10 (1.30 g,
90%): FTIR (CHCl3) 3439 cm-1; 1H NMR (300 MHz, CDCl3) δ
1.67 (3 H, dt, J ) 6.8, 1.8 Hz), 1.87 (1 H, dt, J ) 9.2, 2.8 Hz),
2.25 (1 H, ddd, J ) 11.8, 10.0, 1.7 Hz), 3.02 (1 H, dd, J ) 15.4,
1.3 Hz), 3.24 (1 H, dd, J ) 15.5, 5.2 Hz), 3.35 (1 H, m), 3.60 (3
H, s), 3.84 (2 H, m), 3.93 (1 H, m), 4.35 (1 H, dd, J ) 9.9, 2.3
Hz), 4.86 (2 H, t, J ) 2.4 Hz), 5.34 (1 H, q, J ) 7.0 Hz), 7.08
(1 H, td, J ) 6.9, 1.2 Hz), 7.20 (1 H, td, J ) 6.9, 1.1 Hz), 7.27
(1 H, d, J ) 7.6 Hz), 7.50 (1 H, td, J ) 7.6 Hz); 13C NMR (75.5
MHz, CDCl3) δ 12.4, 26.2, 29.2, 35.3, 36.3, 49.6, 56.1, 56.8,
103.8, 105.4, 108.7, 115.4, 118.1, 118.8, 120.9, 127.0, 136.4,
137.3, 138.2, 151.6; EIMS (m/z, relative intensity) 290 (M+,
100), 275 (13), 182 (76). Anal. Calcd for C20H22N2: C, 82.72;
H, 7.04; N, 9.65. Found: C, 82.84; H, 7.29; N, 9.46.
Hyd r obor a tion of (+)-3-Eth ylid en 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-13-m eth ylen e-in -
d ole[2,3-a ]qu in olizin e (10) F ollow ed by Oxid a tion to
P r ovid e (-)-(E)16-Ep ia ffin isin e (1). A solution of com-
mercially available BH3-THF (1.0 M in THF, 5 mL) was
treated with 2-methyl-2-butene (2.0 M in THF, 10 mL) at -5
°C to give a solution of diisoamylborane in THF. A solution of
olefin 10 (290 mg, 1.0 mmol) in THF (12 mL) was added to
the diisoamylborane at 0 °C. The solution was warmed to room
temperature and stirred for 5 h. To the solution was then
added 10% aq NaOH (2 mL), followed by addition of 30% H2O2
(4 mL). The mixture was stirred for 2 h at room temperature,
diluted with CH2Cl2 (200 mL), washed with H2O (3 × 50 mL)
and brine (100 mL), and dried (K2CO3). The solvent was
removed under reduced pressure, and the residue that resulted
was chromatographed (silica gel, CHCl3/MeOH ) 9:1) to
provide the alcohol 1 (246 mg, 80%): FTIR (CHCl3) 3350, 2918
cm-1; [R]D ) -14.04° (c 0.50, MeOH) {lit.1 [R]D ) -18° (c 0.50,
MeOH)}; 1H NMR (300 MHz, CDCl3) δ 1.66 (3 H, dt, J ) 6.8,
1.9 Hz), 1.77 (1 H, dt, J ) 13.0, 3.4 Hz), 1.96 (1 H, m), 2.22 (1
H, m), 2.98 (2 H, m), 3.05 (1 H, dd, J ) 16.2, 5.7 Hz), 3.25 (1
H, t, J ) 8.8 Hz), 3.51-3.70 (5 H, m), 3.78 (2 H, m), 4.28 (1 H,
dd, J ) 10.2, 2.8 Hz), 5.33 (1 H, q, J ) 6.8 Hz), 7.11 (1 H, td,
J ) 6.9, 1.1 Hz), 7.22 (1 H, td, J ) 6.9, 1.1 Hz), 7.29 (1 H, d,
J ) 7.7 Hz), 7.49 (1 H, d, J ) 7.7 Hz); 13C NMR (75.5 MHz,
CDCl3) δ 12.8, 22.5, 26.0, 26.5, 29.2, 42.0, 48.9, 52.4, 56.5, 61.1,
105.0, 108.7, 114.4, 118.2, 118.9, 121.1, 125.9, 137.3, 137.6,
138.8; EIMS (m/z, relative intensity) 308 (M+, 77), 277 (35),
183 (100). Anal. Calcd for C20H24N2O: C, 77.89; H, 7.84; N,
9.08. Found: C, 78.02; H, 7.79; N, 8.83.
Con ver sion of th e P en ta cyclic Keton e (13) in to (+)-3-
Eth yliden e-12-H-1,3,4,7,12,12b-h exah ydr o-2H,6H-2,6-m eth -
a n o-13-m eth ylen e-in d ole[2,3-a ]qu in olizin e (14) via th e
Wittig Rea ction . A mixture of anhydrous potassium tert-
butoxide (300 mg, 0.225 mmol) and methyltriphenylphospho-
nium bromide (958 mg, 0.20 mmol) in dry benzene (10 mL)
was allowed to stir at room temperature for 1 h. The penta-
cyclic ketone 13 (110 mg, 0.04 mmol) in THF (5 mL) was then
added into the above orange-colored solution dropwise at room
temperature. The mixture that resulted was stirred at room
temperature for 4 h. The mixture was diluted with EtOAc (50
mL), washed with H2O (3 × 10 mL) and brine (25 mL), and
dried (K2CO3). The solvent was removed under reduced pres-
sure, and the oil that resulted was chromatographed (silica
gel, CHCl3/MeOH ) 15:1) to provide the olefin 14 (100 mg,
92%): FTIR (CHCl3) 2960, 1739, 1246 cm-1 1H NMR (300
;
MHz, DMSO-d6) δ 1.61 (3 H, d, J ) 6.8 Hz), 1.75 (1 H, dt, J )
6.3, 2.7 Hz), 2.07 (1 H, dd, J ) 11.5, 7.2 Hz), 2.89 (2 H, m),
3.32 (1 H, m), 3.60 (3 H, m), 4.10 (1 H, d, J ) 8.0 Hz), 4.78 (2
H, m), 5.20 (1 H, q, J ) 6.8 Hz), 6.92 (1 H, td, J ) 7.7, 1.1 Hz),
7.24 (1 H, td, J ) 7.7, 1.1 Hz), 7.26 (1 H, d, J ) 7.4 Hz), 7.35
(1 H, d, J ) 7.9 Hz), 10.72 (1 H, s); 13C NMR (75.5 MHz,
DMSO-d6) δ 12.6, 26.4, 36.5, 36.9, 50.1, 55.6, 56.4, 103.4, 104.8,
111.3, 113.8, 117.8, 118.52, 120.6, 127.3, 136.4, 139.0, 139.3,
154.3; EIMS (m/z, relative intensity) 276 (M+, 61), 168 (100).
This material was used directly in a later step.
Hyd r obor a tion of (+)-3-Eth ylid en e-12-H-1,3,4,7,12,12b-
h exa h yd r o-2H,6H-2,6-m eth a n o-13-m eth ylen e-in d ole[2,3-
a ]qu in olizin e (14) F ollow ed by Oxid a tion to P r ovid e (+)-
(E)16-Ep in or m a cu sin e B (2). A solution of commercially
available BH3-THF (1.0 M in THF, 5 mL) was treated with
2-methyl-2-butene (2.0 M in THF, 10 mL) at -5 °C to give a
solution of diisoamylborane in THF. A solution of olefin 14
(276 mg, 1.0 mmol) in THF (12 mL) was added to the
diisoamylborane at 0 °C. The solution was warmed to room
temperature and stirred for 5 h. To the solution was then
added 10% aq NaOH (2 mL), followed by addition of 30% H2O2
(4 mL). The mixture that resulted was stirred for 2 h at room
temperature, diluted with CH2Cl2 (200 mL), washed with H2O
(3 × 50 mL) and brine (100 mL), and dried (K2CO3). The
solvent was removed under reduced pressure, and the residue
was chromatographed (silica gel, CHCl3/MeOH ) 9:1) to
provide the alcohol 2 (229 mg, 78%): FTIR (CHCl3) 3200, 2918
cm-1; [R]D ) +6.92° (c 0.25, MeOH) {lit.1 [R]D ) +3° (c 0.25,
MeOH)}; 1H NMR (300 MHz, CDCl3) δ 1.64 (3 H, dt, J ) 6.8,
1.8 Hz), 1.84 (2 H, m), 2.24 (1 H, m), 2.89 (1 H, q, J ) 2.8 Hz),
3.01 (2 H, m), 3.27 (1 H, dd, J ) 10.5, 8.5 Hz), 3.48-3.76 (4 H,
m), 4.22 (1 H, dd, J ) 9.0, 4.2 Hz), 5.23 (1 H, q, J ) 6.8 Hz),
7.08 (1 H, td, J ) 7.1, 1.3 Hz), 7.16 (1 H, td, J ) 7.1, 1.3 Hz),
7.36 (1 H, d, J ) 7.3 Hz), 7.49 (1 H, d, J ) 7.3 Hz), 8.60 (1 H,
s); 13C NMR (75.5 MHz, CDCl3) δ 12.7, 22.3, 26.1, 27.0, 41.8,
50.1, 52.8, 55.9, 60.9, 105.6, 111.2, 114.9, 118.1, 119.3, 121.7,
126.0, 135.6, 136.4, 137.4; EIMS (m/z, relative intensity) 306
(M+, 100). Anal. Calcd for C19H22N2O: C, 77.52; H, 7.53; N,
9.52. Found: C, 77.80; H, 7.79; N, 9.34.
Oxid a tive Cycliza tion of Alcoh ol 1 to P r ovid e (+)-
Deh yd r o-16-ep ia ffin isin e (4). To a solution of alcohol 1 (62
mg, 0.20 mmol) in THF (2 mL) was added DDQ (93 mg, 0.40
mmol). The mixture that resulted was heated to reflux for
1 h. The mixture was then diluted with CH2Cl2 (25 mL),
washed with 0.5 M NaHCO3 (10 mL) and brine (2 × 10 mL),
and dried (K2CO3). The solvent was removed under reduced
pressure, and the residue that resulted was chromatographed
(silica gel, CHCl3/MeOH ) 20:1) to provide the cyclic ether 4
(60 mg, 98%): FTIR (CHCl3) 2933, 1468 cm-1; [R]D ) +60.40°
Oxid a tive Cycliza tion of Alcoh ol 2 to P r ovid e (+)-
Deh yd r o-16-ep in or m a cu sin e B (5). To a solution of alcohol
2 (27 mg, 0.09 mmol) in THF (2 mL) was added DDQ (42 mg,
0.18 mmol). The mixture that resulted was heated to reflux
J . Org. Chem, Vol. 68, No. 15, 2003 5857