Notes
J . Org. Chem., Vol. 63, No. 21, 1998 7551
by silica gel flash chromatography (Et NH/Et O/hexane, 1:100:
at the same temperature, the reaction mixture was poured into
2
2
the mixture of saturated aqueous NH
4
Cl and AcOEt. The whole
200) to yield a mixture of the desired compound and the C-4
epimer. To a mixture of acetal and a small amount of MS 3A in
mixture was stirred vigorously and filtered over a Celite pad.
The organic layer of the filtrate was separated, and the aqueous
layer was extracted with AcOEt. The combined organic layers
CH
2
Cl
2
(10 mL) were added EtSH (4 mL) and BF
3
2
‚Et O (0.27
mL, 2.13 mmol) at 0 °C. After being stirred for 17 h at the same
temperature, and for additional 12 h at room temperature, the
reaction mixture was quenched with saturated aqueous NaH-
were washed with brine, dried (Na
give a residue which was then purified by silica gel flash
chromatography (Et NH/Et O/hexane, 1:50:50) to give the amine
1 (275.1 mg, 0.643 mmol; 96%) as an oil. IR (neat) 2931, 1727,
2 4
SO ), and concentrated to
2
2
CO
was extracted with CH
washed with saturated aqueous NaHCO
concentrated to give a residue which was then purified by silica
gel flash chromatography (Et NH/Et O/hexane, 1:50:200) to give
the thioacetal 14 (69.4 mg, 0.179 mmol; 66%) as a foam and the
3
. The organic layer was separated, and the aqueous layer
Cl . The combined organic layers were
, dried (Na SO ), and
1
1
1
-
1 1
2
2
458 cm ; H NMR (500 MHz, C
6 6
D ) δ 8.54 (m, 1H), 7.40 (m,
3
2
4
H), 7.32 (m, 1H), 7.25 (m, 1H), 5.52 (q, J ) 5.9 Hz, 1H), 4.51 (t,
J ) 4.3 Hz, 1H), 3.20-3.13 (m, 4H), 3.18 (s, 3H), 3.17 (s, 3H),
2
1
2
2
.86 (m, 1H), 2.80 (d, J ) 4.3 Hz, 2H), 2.61 (m, 1H), 2.46 (m,
H), 1.85 (m, 1H), 1.76 (m, 1H), 1.57 (d, J ) 5.9 Hz, 3H), 1.41
2
1
1
3
C-4 epimer (9.9 mg, 0.026 mmol; 9%) as a solid. [R]
) +111
(s, 9H), 1.43-1.37 (m, 1H); C NMR (125 MHz, C
6
D
6
) δ 150.7,
D
-
1 1
1
1
1
41.8, 136.8, 136.0, 130.4, 123.7, 122.8, 121.5, 117.9, 116.5, 116.0,
04.3, 82.5, 53.8, 53.3, 53.2, 51.1, 36.6, 30.7, 28.1, 27.4, 21.7,
3.0; EI-MS m/z 428 (M ), 353 (M - CH(OCH
(c 2.62, CHCl
3
) (99% ee); IR (CHCl
3
) 3469, 2927 cm ; H NMR
(500 MHz, CDCl
3
) δ 7.91 (br-s, 1H), 7.53 (m, 1H), 7.27 (m, 1H),
+
+
3
)
2
); EI-HRMS
7.14-7.03 (m, 2H), 4.19 (t, J ) 2.9 Hz, 1H), 4.06 (dd, J ) 7.6,
6.4 Hz, 1H), 3.10 (dd, J ) 13.5, 7.6 Hz, 1H), 2.81-2.60 (m, 6H),
2.56 (dd, J ) 11.3, 4.3 Hz, 1H), 2.47 (dd, J ) 13.5, 6.4 Hz, 1H),
+
Calcd for C25
H N O (M ): 428.2675, Found: 428.2684.
36 2 2
Syn t h esis of (R)-2-[1-[N-(2,2-Dim et h oxyet h yl)a m in o-
m eth yl]-1-p r op en yl]-1,2,3,4-tetr a h yd r o-9H-ca r ba zole (12).
To a mixture of carbamate 11 (1.17 g, 2.73 mmol) in anisole (3
mL, 27.1 mmol) was added trifluoroacetic acid (30 mL) at 0 °C.
After being stirred for 30 min at the same temperature, the
reaction mixture was poured into a vigorously stirred mixture
2
.25 (m, 1H), 2.17 (m, 1H) 1.89 (dt, J ) 12.2, 2.9 Hz, 1H), 1.80
(
m, 1H), 1.74 (t, J ) 11.3 Hz, 1H), 1.29 (t, J ) 7.3 Hz, 3H), 1.25
t, J ) 7.3 Hz, 3H), 1.27-1.23 (m, 2H), 0.93 (t, J ) 7.6 Hz, 3H);
C NMR (125 MHz, CDCl ) δ 136.3, 135.7, 128.0, 120.8, 119.6,
3
(
13
1
2
-
18.3, 110.3, 107.4, 62.6, 51.0, 49.9, 41.4, 34.2, 28.8, 24.6, 24.5,
of 6 N aqueous NaOH and CH
organic layer was separated, and the aqueous layer was ex-
tracted with CH Cl . The combined organic layers were washed
with brine, dried (Na SO ), and concentrated to give a residue
which was then purified by silica gel flash chromatography (Et
NH/Et O, 1:150) to give the indole compound 12 (0.878 g, 2.67
mmol; 98%) as a solid. IR (KBr) 2926, 1468 cm ; H NMR (500
MHz, C ) δ 7.59 (m, 1H), 7.28-7.13 (m, 3H), 6.86 (br-s, 1H),
2 2
Cl via cannula at 0 °C. The
+
+
4.3, 22.6, 18.4, 14.6, 14.2, 11.5; EI-MS m/z 388 (M ), 251 (M
+
CH(SCH
88.2031, Found: 388.2007.
Syn t h esis of (-)-Tu bifolid in e (1). To a mixture of di-
2
CH
3
)
2
); EI-HRMS Calcd for
C
22
H
32
N
2
S
2
(M ):
2
2
3
2
4
2
-
2
methyl(methylthio)sulfonium fluoroborate (DMTSF) (84.0 mg,
-1 1
0.428 mmol) in CH Cl (15 mL) was added thioacetal 14 (79.2
2
2
6
D
6
mg, 0.204 mmol) in CH
for 2 h at the same temperature, the reaction mixture was
quenched with saturated aqueous NaHCO . The organic layer
was separated, and the aqueous layer was extracted with CH
Cl . The combined organic layers were washed with brine, dried
Na SO ), and concentrated to give a residue which was then
purified by silica gel flash chromatography (Et NH/Et O/hexane,
2
Cl (5 mL) at 0 °C. After being stirred
2
5
2
2
1
C
1
1
.51 (q, J ) 6.8 Hz, 1H), 4.52 (t, J ) 5.5 Hz, 1H), 3.34-3.10 (m,
H), 3.19 (s, 3H), 3.17 (s, 3H), 2.96 (m, 1H), 2.84-2.77 (m, 4H),
.64 (m, 1H), 2.36 (dd, J ) 15.9, 4.9 Hz, 1H), 1.94-1.78 (m, 2H),
3
2
-
1
3
.58 (d, J ) 6.8 Hz, 3H), 1.03 (br-s, 1H); C NMR (125 MHz,
2
6
D
6
) δ 142.0, 136.8, 134.2, 128.5, 121.6, 121.4, 119.6, 118.4,
(
2
4
10.9, 109.9, 104.5, 53.8, 53.5, 53.4, 51.3, 36.4, 28.8, 28.1, 21.9,
3.2; EI-MS m/z 328 (M ), 253 (M - CH(OCH
+
+
2
2
3
)
2
); EI-HRMS
+
1:100:100) to give the imine (45.5 mg, 0.140 mmol; 68%) as a
foam. To a mixture of imine (17.5 mg, 53.7 µmol) in THF (2
Calcd for C20
H N O (M ): 328.2151, Found: 328.2153.
28 2 2
Syn th esis of (1S,5R)-2-(2,2-Dim eth oxyeth yl)-4-eth yliden e-
,2,3,4,5,6-h exah ydr o-1,5-m eth an oazocin o[4,3-b]in dole (13).
mL) was added LiAlH
stirred for 2 h at the same temperature, the reaction mixture
was quenched with saturated aqueous Na SO (3 drops). The
mixture was stirred vigorously for 1 h at room temperature and
then dried (MgSO ). The whole mixture was filtered over a
4
(10 mg, 0.26 mmol) at 0 °C. After being
1
To a mixture of amine 12 (16.6 mg, 50.5 µmol) and Na
2
HPO
72 mg, 0.51 mmol) in degassed THF (2 mL) was added DDQ
12.6 mg, 55.5 µmol) in degassed THF (2 mL) during 20 min at
20 °C. The mixture was allowed to warm to 0 °C in 30 min.
After being stirred for additional 1 h at the same temperature,
the reaction mixture was quenched with saturated aqueous
4
(
(
-
2
4
4
Celite pad and concentrated to give the amine, which was used
without further purification. To a mixture of amine in EtOH (1
mL) was added Raney Ni (W2) (excess). After being stirred for
NaHCO
3
and diluted with AcOEt. The organic layer was
separated, and the aqueous layer was extracted with AcOEt.
The combined organic layers were washed with saturated
1
h under reflux, additional Raney Ni (W2) (excess) was added.
After being stirred for 1 h under reflux, the reaction mixture
was filtered over a Celite pad. The filtrate was concentrated to
give a residue which was then purified by silica gel flash
aqueous NaHCO
residue which was then purified by silica gel flash chromatog-
raphy (Et NH/Et O, 1:300) to give the tetracyclic amine 13 (8.6
mg, 26.3 µmol; 52% (conv. 67%)) as a solid and 12 (3.6 mg, 11.0
3 2 4
, dried (Na SO ), and concentrated to give a
2
2
chromatography (Et
2 2
NH/Et O/hexane, 1:50:50) to give (-)-
tubifolidine (1) (5.0 mg, 18.7 µmol; 35% (two steps)) as a solid.
-
1
1
µmol). IR (KBr) 3405 cm ; H NMR (500 MHz, C
6 6
D ) δ 7.81
1
9
[
R]
D
) -61 (c 0.36, CHCl
3
) (99% ee); IR (KBr) 3171, 2923, 1605
cm ; H NMR (500 MHz, CDCl ) δ 7.06-7.03 (m, 2H), 6.76 (m,
H), 6.63 (m, 1H), 3.63 (dd, J ) 9.2, 7.6 Hz, 1H), 3.31 (t, J ) 3.1
(
m, 1H), 7.24-7.18 (m, 3H), 7.14 (m, 1H), 5.22 (qd, J ) 6.8, 1.5
-
1 1
3
Hz, 1H), 4.69 (dd, J ) 3.4, 2.8 Hz, 1H), 4.35 (dd, J ) 5.1, 5.1 Hz,
1
3
1
H), 3.27 (s, 3H), 3.21 (dd, J ) 13.4, 5.1 Hz, 1H), 3.15 (s, 3H),
.12 (d, J ) 13.8 Hz, 1H), 3.07 (m, 1H), 2.91 (m, 1H), 2.70 (dd,
Hz, 1H), 3.13 (m, 1H), 3.03 (dd, J ) 12.1, 5.2 Hz, 1H), 2.83 (ddd,
J ) 11.9, 8.9, 2.8 Hz, 1H), 2.41 (dt, J ) 13.8, 8.6 Hz, 1H), 2.05
J ) 16.8, 6.4 Hz, 1H), 2.43 (dd, J ) 13.4, 5.1 Hz, 1H), 2.28 (d, J
)
16.8 Hz, 1H), 2.24 (ddd, J ) 11.9, 3.4, 3.4 Hz, 1H), 1.71 (ddd,
(t, J ) 12.2 Hz, 1H), 2.03-1.65 (m, 7H), 1.29 (m, 2H), 0.91 (t, J
1
3
13
J ) 11.9, 2.8, 2.8 Hz, 1H), 1.54 (dd, J ) 6.8, 2.1 Hz, 3H);
C
) 7.3 Hz, 3H); C NMR (125 MHz, CDCl
3
) δ 149.3, 134.2, 127.6,
NMR (125 MHz, C
6
D
6
) δ 140.7, 136.7, 135.7, 129.1, 121.3, 120.2,
122.2, 119.1, 109.5, 66.2, 62.8, 55.2, 54.4, 52.8, 42.9, 40.7, 32.8,
28.5, 27.3, 25.5, 11.5; EI-MS m/z 268 (M ); EI-HRMS Calcd for
(M ): 268.1939, Found: 268.1946.
1
2
7
19.4, 117.1, 111.0, 107.6, 104.3, 59.0, 55.4, 53.3, 53.0, 52.1, 33.4,
+
+
+
9.7, 28.5, 12.6; EI-MS m/z 326 (M ), 251 (M - CH(OCH
3
)
2
),
+
18 24 2
C H N
+
5 (CH(OCH ) ); EI-HRMS Calcd for C20H N O (M ): 326.1994,
3 2 26 2 2
Found: 326.1981.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
Syn t h esis of (1S,4S,5R)-2-[2,2-Bis(et h ylt h io)et h yl]-4-
et h yl-1,2,3,4,5,6-h exa h yd r o-1,5-m et h a n oa zocin o[4,3-b]in -
d ole (14). A suspension of 13 (88.4 mg, 0.271 mmol) and
tris(triphenylphosphine)rhodium(I) chloride (25 mg, 40 µmol) in
benzene (2.0 mL) and 2-propanol (0.4 mL) was stirred vigorously
under 1 atm pressure of hydrogen at room temperature for 27
h. The reaction mixture was filtered over a Celite pad, and the
filtrate was concentrated to give a residue which was purified
spectra of 1, 2, and 6-14 (22 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O981069G