Total syntheses of (-)-mesembrane and (-)-mesembrine via palladium-catalyzed enantioselective allylic substitution and zirconium-promoted cyclization

Article abstract of DOI:10.1021/jo9701187

4-Arylhexahydroindole derivatives 5 were synthesized from 2-arylcyclohexenyl allylamine derivatives 4, which have a large protecting group on nitrogen, using zirconium-promoted cyclization. Reaction of 4e with Cp₂ZrBu₂, followed by treatment with MeMgBr and then O₂, gave 2a in 63% yield by a one-pot reaction, since the approach of O₂ to zirconium was prevented by the aryl group. The total syntheses of (+)-mesembrane and (+)-mesembrine were achieved starting from 2a. To synthesize these natural products in a chiral form, the starting allylamine derivative 24 (80% yield, 86% ee, recrystallized from MeOH, 99% ee with 79% recovery) was prepared from allyl carbonate 22a and N-tosylallylamine 23 using palladium-catalyzed asymmetric amination in the presence of (S)-BINAPO as a chiral ligand. (-)-Mesembrane and (-)-mesembrine were synthesized from this allylamine 24.

Full text of DOI:10.1021/jo9701187

J . Org. Chem. 1997, 62, 3263-3270
3263
Tota l Syn th eses of (-)-Mesem br a n e a n d (-)-Mesem br in e via
P a lla d iu m -Ca ta lyzed En a n tioselective Allylic Su bstitu tion a n d
Zir con iu m -P r om oted Cycliza tion
Miwako Mori,* Shinji Kuroda, Chang-Shan Zhang, and Yoshihiro Sato
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060, J apan
Received J anuary 22, 1997X
4-Arylhexahydroindole derivatives 5 were synthesized from 2-arylcyclohexenyl allylamine deriva-
tives 4, which have a large protecting group on nitrogen, using zirconium-promoted cyclization.
Reaction of 4e with Cp2ZrBu2, followed by treatment with MeMgBr and then O2, gave 2a in 63%
yield by a one-pot reaction, since the approach of O2 to zirconium was prevented by the aryl group.
The total syntheses of (()-mesembrane and (()-mesembrine were achieved starting from 2a . To
synthesize these natural products in a chiral form, the starting allylamine derivative 24 (80% yield,
86% ee, recrystallized from MeOH, 99% ee with 79% recovery) was prepared from allyl carbonate
22a and N-tosylallylamine 23 using palladium-catalyzed asymmetric amination in the presence of
(S)-BINAPO as a chiral ligand. (-)-Mesembrane and (-)-mesembrine were synthesized from this
allylamine 24.
Zirconium-promoted diyne, enyne, and diene cycliza-
tions are very useful in synthetic organic chemistry
because regio- and stereocontrolled carbon-carbon bonds
can be formed between these multiple bonds.1 This
procedure is very attractive for the synthesis of natural
products.2,3a,d Recently, we reported the synthesis of
perhydroindole derivatives using zirconium-promoted3a
or zirconium-catalyzed3e cyclization.
Since many alkaloids have a cis-3a-aryloctahydroindole
skeleton, zirconium-promoted diene cyclization should be
useful in their synthesis. Typical alkaloids with a cis-
3a-aryloctahydroindole skeleton are shown in Figure 1.
X Abstract published in Advance ACS Abstracts, May 1, 1997.
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K. D.; J effs, P. W.; McPhail, A. T. J . Chem. Soc., Perkin Trans. 2 1977,
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Chem. Commun. 1985, 518. (c) Stevens, R. V.; Wentland, P. J . Am.
Chem. Soc. 1968, 90, 5580. (d) For a total synthesis of (-)-mesem-
brane, see Takano, S.; Imamura, Y.; Ogasawara, K. Tetrahedron Lett.
1981, 22, 4479. Meyers, A. I.; Hanreich, R.; Hanner, K. T. J . Am.
Chem. Soc. 1985, 107, 7776. Kosugi, H.; Miura, Y.; Kanna, H.; Uda,
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Fukumoto, K. J . Org. Chem. 1995, 60, 6785 (references of a total
synthesis of (()-mesembrine are cited therein).
F igu r e 1.
Our retrosynthetic study of (-)-mesembrane and (-)-
mesembrine is shown in Scheme 1.
In this plan, an important problem is whether dienes
with large substituents on the alkene can be cyclized by
Cp2ZrBu2. Another is how to prepare the chiral starting
diene 3. We report here the total syntheses of (-)-
mesembrane (1a ) and (-)-mesembrine (1b)4 using pal-
ladium-catalyzed enantioselective allylic substitution and
zirconium-promoted cyclization as the key steps.
Syn th esis of cis-Octa h yd r oin d ole Der iva tives
Usin g Zir con iu m -P r om oted Cycliza tion
Cyclization of diene 4a , which has a phenyl group on
the alkene, was tried first. To a THF solution of Cp2-
ZrBu2 prepared from Cp2ZrCl2 and BuLi5 was added a
THF solution of 4a at -78 °C, and the solution was
stirred at room temperature for 4 h. After hydrolysis of
the reaction mixture, hexahydroindole derivative 5a was
obtained in 26% yield along with deallylation product 6a
(47% yield) (Scheme 2).
(5) Neigishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett.
1986, 27, 2829.
S0022-3263(97)00118-7 CCC: $14.00 © 1997 American Chemical Society

3264 J . Org. Chem., Vol. 62, No. 10, 1997
Mori et al.
Sch em e 1. Retr osyn th etic Stu d y
Sch em e 4
Sch em e 2
Ta ble 1. Effects of th e Nitr ogen Su bstitu en t
yields (%)
run
R1
R2
substrate
time (h)
5
6
Sch em e 5
1
2
3
4
H
H
H
H
CH2Ph
Ha
CH3
4a
4b
4c
4d
4
4
2
4
26
-
47
50
56
17
-
CHPh2
58
a
BuLi (1 equiv) was added to the substrate.
Sch em e 3
formed from 4e is also cis.2b To synthesize mesembrane
(1a ) and mesembrine (1b), zirconacycle 11e was then
treated with O2, since the hydroxymethyl group at the
3-position could be easily removed.
However, the desired product 2a was obtained in only
14% yield. Zirconacycle 11e was treated with 10% DCl-
D2O to give 5e-D in 73% yield, with a D-content of 56%,
which indicates that the carbon-zirconium bond of 11e
is retained until it is reacted with O2 and the approach
of O2 to zirconium is prevented by the large aryl group.
To overcome this problem, we attempted the transmeta-
lation of zirconium to magnesium.7 Our idea is shown
in Scheme 5.
Zirconacycle 11 is treated with Grignard reagent to
give complex 12, which is in a state of equilibrium with
13a or 13b, treatment of which with O2 should afford
diol 14. Thus, diene 4e was treated with Cp2ZrBu2 and
the solution was stirred at room temperature for 2 h. To
To improve the yield of the desired cyclized product 5,
the effects of the substituent on nitrogen were investi-
gated, and the results are shown in Table 1. While small
substituents, such as H or Me, did not give the cyclized
product (runs 2 and 3), good results were obtained with
large substituents (runs 1 and 4). For the syntheses of
mesembrane (1a ) and mesembrine (1b), we tried to react
diene 4e with Cp2ZrBu2. The starting allylamine 4e was
prepared as shown in Scheme 3.
Suzuki-Miyaura coupling6 of 3,4-dimethoxyphenylbo-
ric acid (7) and 2-bromo-2-cyclohexen-1-ol 8 proceeded
smoothly in the presence of Pd(PPh3)4 and Na2CO3. Allyl
alcohol 9 was treated with CBr4 and PPh3 and then
allylamine to give 10. Nitrogen was protected with
diphenylmethyl chloride in the presence of K2CO3 in CH3-
CH2CN to provide 4e. The reaction of diene 4e with
Cp2ZrBu2, was carried out in a similar manner to give
the cyclized product 5e in 61% yield (Scheme 4). NOE
experiments with the cyclized product 5e indicated that
the ring junction of 5e is cis, which means that the ring
junction of the 5,5-membered ring of the zirconacycle 11e
(7) (a) Dzhemilev, U. M.; Vastrikova, O. S.; Tolstikov, G. A. J .
Organomet. Chem. 1986, 304, 17. (b) Takahashi, T.; Seki, T.; Nitto,
Y.; Saburi, M.; Rousset, C. J .; Negishi, E.-i. J . Am. Chem. Soc. 1991,
113, 6266. Suzuki, N.; Kondakov, D. Y.; Takahashi, T. J . Am. Chem.
Soc. 1993, 115, 8485. (c) Hoveyda, A. H.; Xu, Z. J . Am. Chem. Soc.
1991, 113, 5079. Hoveyda, A. H.; Xu, Z.; Morken, J . P.; Houri, A. F.
J . Am. Chem. Soc. 1991, 113, 8950. Hoveyda, A. H.; Morken, J . P.;
Houri, A. F.; Xu, Z. J . Am. Chem. Soc. 1992, 114, 6692. Houri, A. F.;
Didiuk, M. T.; Xu, Z.; Horan, N. R.; Hoveyda, A. H. J . Am. Chem. Soc.
1993, 115, 6614. Morken, J . P.; Didiuk, M. T.; Hoveyda, A. H. J . Am.
Chem. Soc. 1993, 115, 6997. Hoveyda, A. H.; Morken, J . P. J . Org.
Chem. 1993, 58, 4237. (d) Lewis, D. L.; Muller, P. M.; Whitby, R. J .;
J ones, R. V. H. Tetrahedron Lett. 1991, 32, 6769. (e) Knight, K. S.;
Waymouth, R. M. J . Am. Chem. Soc. 1991, 113, 6268. Wischmeyer,
U.; Knight, K. S.; Waymouth, R. M. Tetrahedron Lett. 1992, 33, 7735.
(6) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.

Total Syntheses of (-)-Mesembrane and (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 10, 1997 3265
Sch em e 6
Sch em e 8
Sch em e 7
Sch em e 9
this solution was added a THF solution of BuMgCl (5
equiv), and the solution was stirred at room temperature
for 5 h. The atmosphere of argon was then changed to
oxygen and the solution was stirred at room temperature
overnight. After hydrolysis with 10% HCl, alcohol 2a
was obtained in 17% yield. Since it was considered that
BuMgCl was too large, MeMgBr was used for this
reaction to give 2a in 63% yield. In this case, the
intermediate magnesium complex should be 15 via
magnesium complex 13a (Scheme 6).
Sch em e 10
Tota l Syn th esis of (()-Mesem br a n e a n d
(()-Mesem br in e
To synthesize mesembrane (1a ), alcohol 2a was con-
verted into 168 in the usual manner, which was then
oxidized to aldehyde 17. Deformylation of 17 with RhCl-
(PPh3)3 gave perhydroindole 18 in 62% yield. The tosyl
group of 18 was converted into a methyl group, and we
could obtain 1a , whose spectral data agreed with those
reported for mesembrane3c (Scheme 7).
On the other hand, the protecting group of 2d was
converted into the methoxycarbonyl group, and then
allylic oxidation of 2e with CrO3 gave enone 19, which
was subjected to hydrogenation and ketalization to give
20. Using a treatment similar to that for the synthesis
of mesembrane from 16, we synthesized (()-mesembrine
(1b)4d from 20 (Scheme 8). The spectral data of 1b agreed
with those reported in the literature.4d
Thus, we next tried to synthesize (-)-mesembrane and
(-)-mesembrine. For that purpose, the optically active
diene 4e was required.
Our plan for the palladium-catalyzed asymmetric
synthesis is shown in Scheme 9. Palladium-catalyzed
alkylation or amination of compound I should give
compound III via π-allylpalladium complex II. If a chiral
ligand is used for this reaction, optically active IIIa or
IIIb should be formed from racemic I.
When a DMSO solution of allyl carbonate 22a , which
was prepared from 9, and N-tosylallylamine 23 was
warmed in the presence of Pd2dba3‚CHCl3 (2.8 mol %)
and dppb (5.6 mol %) as a ligand at 50 °C for 13 h, the
desired tosylamide 24 was obtained in 36% yield (Table
2, run 1). The same reaction was carried out in the
presence of (S)-BINAP9 or (+)-2510 as a chiral ligand, but
the reaction rate was lower and good results were not
obtained (runs 2 and 3). We were very surprised to find
that when the reaction was carried out in the presence
of palladium catalyst and (S)-BINAPO,11 the reaction
proceeded smoothly at room temperature for 3 h and the
desired product 24 was obtained in 51% yield with 70%
ee (run 4). Use of 22b as a substrate did not affect the
ee (run 5), but the reaction rate was lower. With regard
to the solvent, nonpolar solvent gave good results. When
P a lla d iu m -Ca ta lyzed Asym m etr ic Syn th esis of a
Key In ter m ed ia te of (-)-Mesem br a n e a n d
(-)-Mesem br in e
Although we succeeded in the total syntheses of
mesembrane and mesembrine, they are racemic forms.
(8) Hydrogenation of compound 2b with 10% Pd/C for
a short
reaction time gave 2c, which was unstable under hydrogenation. Thus,
the nitrogen of 2c was protected with a tosyl group and further
hydrogenation was carried out to give 2d .
(9) Noyori, R.; Takaya, H. Acc. Chem. Res. 1990, 23, 345.
(10) Trost, B. M.; Van Vranken, D. L.; Gingel, C. J . Am. Chem. Soc.
1992, 114, 9327.
(11) (a) Grubbs, R. H.; DeVries, R. A. Tetrahedron Lett. 1977, 1879.
(b) Trost, B. M.; Murphy, D. J . Organometallics 1985, 4, 1143.

3266 J . Org. Chem., Vol. 62, No. 10, 1997
Mori et al.
Ta ble 2. Rea ction of 22 w ith 23 u n d er Va r iou s
Con d ition sa
In conclusion, zirconium-promoted cyclization is useful
for the synthesis of cis-3a-aryloctahydroindole deriva-
tives. In this reaction, diene with a large aryl group on
the alkene gave cyclized products in good yields when
the substrate had a large protecting group on the
nitrogen. The reaction of zirconacycle with O2 proceeded
using the transmetalation of zirconium to magnesium.
This procedure could be useful for further carbon-carbon
bond formation by the reaction of magnesium complex
15 with the carbon nucleophile. To synthesize the chiral
natural products, we obtained the chiral amine 4e by
palladium-catalyzed asymmetric amination. As a result,
we succeeded in the total synthesis of (-)-mesembrane
and (-)-mesembrine.
temp time yield eeb
run substrate
ligand
dppb
(S)-BINAP
(+)-25
(S)-BINAPO DMSO
(S)-BINAPO DMSO
(S)-BINAPO DMF
(S)-BINAPO toluene rt
(S)-BINAPO CH3CN rt
(S)-BINAPO CH2Cl2 rt
solvent
(°C)
(h)
(%) (%)
1
2
3
4
5
6
7
8
9
22a
22a
22a
22a
22bd
22a
22a
22a
22a
22a
22a
DMSO 50
DMSO 60-75
THF
13
50
98
3
27
3
31
4
2
36
12
0
51
64
70
76
68
75
-
9
-
70
68
71
80
66
73
50
rt
rt
Exp er im en ta l Section
rt
Gen er a l. All manipulations were performed under an
argon atmosphere unless otherwise mentioned. Solvents were
distilled under an argon atmosphere from sodium-benzophe-
none (THF, Et2O, toluene, and benzene), CaH2 (CH2Cl2, CH3-
CN, CH3CH2CN), or sodium (EtOH). All other solvents and
reagents were purified when necessary using standard pro-
cedures. Column chromatography was performed on silica gel
60 (Merck, 70-230 or 230-400 mesh) using the indicated
solvent.
10
11
(S)-BINAPO THF
(S)-BINAPO THF
rt
0
19
216
80 86e
53 87
a
All of the reactions (except for run 10) were carried out in the
presence of 23 (1.1 equiv), Pd2dba3‚CHCl3 (2.8 mol %), and (S)-
BINAPO (5.6 mol %). The reaction in run 10 was carried out in
the presence of 23 (1.1 equiv), Pd2dba3‚CHCl3 (1.0 mol %), and
b
(S)-BINAPO (2.0 mol %). The ees were determined by HPLC
N-Allyl-N-ben zyl-2-ph en yl-2-cycloh exen -1-ylam in e (4a).
To a solution of 2-phenyl-2-cyclohexen-1-ol13 (98.8 mg, 0.567
mmol) and CBr4 (241 mg, 0.726 mmol) in CH2Cl2 (1 mL) was
added PPh3 (229 mg, 0.860 mmol) at 0 °C and the solution
was stirred at room temperature for 2.5 h. The solvent was
evaporated and the residue was purified by column chroma-
tography on silica gel (hexane/ethyl acetate, 20/1) to give
3-bromo-2-phenylcyclohexene, which was dissolved in CH3CN
(6.0 mL). To this solution were added K2CO3 (166 mg, 1.20
mmol) and benzylamine (0.19 mL, 1.70 mmol), and the solution
was stirred at room temperature for 15 h. Water was added
at 0 °C and the aqueous layer was extracted with ethyl acetate.
The organic layer was washed with brine, dried over Na2SO4,
and concentrated. The residue was purified by column chro-
matography on silica gel (hexane/AcOEt, 6/1) to give a colorless
oil, N-benzyl-2-phenyl-2-cyclohexen-1-ylamine (127 mg,
85%): 1H-NMR (270 MHz, CDCl3) δ 1.46 (bs, 1 H), 1.58-1.88
(m, 3 H), 1.98 (m, 1 H), 2.09-2.28 (m, 2 H), 3.68 (d, J ) 13.2
Hz, 1 H), 3.73 (bs, 1 H), 3.81 (d, J ) 13.2 Hz, 1 H), 6.06 (dd,
J ) 3.9 Hz, 3.9 Hz, 1 H), 7.15-7.30 (m, 10 H); 13C-NMR (126
MHz, CDCl3) δ 17.8, 26.2, 27.4, 51.3, 51.9, 126.1, 126.7, 126.8,
128.2, 128.3, 128.5, 139.6, 140.5, 141.0; IR (neat) ν 3335, 1642,
1599 cm-1; EI-MS m/z 263 (M+), 172, 156, 91, 77; HRMS calcd
for C19H21N 263.1674, found 263.1699. To a solution of the
above amine (388 mg, 1.47 mmol) in CH3CN (10.0 mL) were
added K2CO3 (630 mg, 4.56 mmol) and allyl bromide (0.25 mL,
2.89 mmol) at 0 °C, and the solution was stirred at room
temperature for 44 h. After removal of the solvent, water was
added and the aqueous layer was extracted with ethyl acetate.
The organic layer was washed with brine, dried over Na2SO4,
and concentrated. The residue was purified by column chro-
matography on silica gel (hexane/AcOEt, 50/1) to give a
colorless oil, 4a (435 mg, 97%): 1H-NMR (270 MHz, CDCl3) δ
1.56-2.00 (m, 4 H), 2.16 (m, 2 H), 2.90 (dd, J ) 8.7, 13.8 Hz,
1 H), 3.05 (m, 1 H), 3.25 (d, J ) 13.5 Hz, 1 H), 3.67 (d, J )
13.5 Hz, 1 H), 3.98 (m, 1 H), 4.96-5.07 (m, 2 H), 5.47-5.62
(m, 1 H), 6.06 (m, 1 H), 6.80 (m, 2 H), 7.11-7.13 (m, 3 H),
7.18-7.30 (m, 5 H); 13C-NMR (126 MHz, CDCl3) δ 21.3, 21.3,
26.0, 52.6, 53.2, 54.7, 116.2, 126.1, 126.4, 127.3, 127.4, 127.7,
128.8, 130.2, 137.6, 140.5, 141.5, 142.2; IR (neat) ν 1640, 1600
cm-1; EI-MS m/z 303 (M+), 212, 156, 91, 77; HRMS calcd for
C22H25N3O3 303.1987, found 303.1982.
analysis. (DAICEL CHIRALCEL OJ , hexane/iPrOH, 9/1). c The
d
starting material was recovered in 89% yield. NaH was used as
a base. e Recrystallized from MeOH, 24 was obtained in 99% ee
(79% recovery).
Sch em e 11
the reaction was carried out in THF at room temperature
for 19 h, we obtained chiral diene 24 in 80% yield with
86% ee (run 10), which was recrystallized from MeOH
to give 24 with 99% ee (79% recovery).
Tota l Syn th esis of (-)-Mesem br a n e a n d
(-)-Mesem br in e
Detosylation of 24 with sodium naphthalenide pro-
ceeded smoothly to give amine in 71% yield, which was
converted into diene 4e. From 4e, we succeeded in the
total synthesis of (-)-mesembrane (1a ). The melting
point and the [R]D value of 1a agreed with those of the
natural product reported previously.3a Moreover, we also
achieved the total synthesis of (-)-mesembrine12 from (S)-
5e.
N-Allyl-2-p h en yl-2-cycloh exen -1-yla m in e (4b). To a
solution of the crude 3-bromo-2-phenylcyclohexene in CH3CN
(20 mL), prepared from 2-phenyl-2-cyclohexen-1-ol (654 mg,
3.75 mmol), CBr4 (1.76 g, 5.31 mmol), and PPh3 (1.57 g, 5.99
(12) The absolute configuration of 24 was determined to be S by
the syntheses of (-)-mesembrane and (-)-mesembrine.
(13) Wender, P. A.; Erhardt, J . M.; Letendre, L. J . J . Am. Chem.
Soc. 1981, 103, 2114.

Total Syntheses of (-)-Mesembrane and (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 10, 1997 3267
mmol), were added K2CO3 (1.04 g, 7.52 mmol) and allylamine
(0.85 mL, 11.3 mmol), and the solution was stirred at room
temperature for 15 h. Water was added at 0 °C and the
aqueous layer was extracted with ethyl acetate. The organic
layer was washed with brine, dried over Na2SO4, and concen-
trated. The residue was purified by column chromatography
on silica gel (hexane/AcOEt, 10/1 ∼ 1/1) to give 4b (716 mg,
89%): 1H-NMR (500 MHz, CDCl3) δ 1.23 (bs, 1 H), 1.62 (m, 1
H), 1.67-1.82 (m, 2 H), 1.91 (m, 1 H), 2.11-2.25 (m, 2 H), 3.15
(dd, J ) 6.8, 13.9 Hz, 1 H), 3.26 (dd, J ) 5.5, 13.9 Hz, 1 H),
3.74 (dd, J ) 3.8, 3.8 Hz, 1 H), 5.01 (dd, J ) 1.3, 10.1 Hz, 1
H), 5.07 (dd, J ) 1.3, 17.1 Hz, 1 H), 5.79 (dddd, J ) 5.5, 6.8,
10.1, 17.1 Hz, 1 H), 6.04 (dd, J ) 3.9, 3.9 Hz, 1 H), 7.23 (dd, J
) 7.5, 7.5 Hz, 1 H), 7.31 (dd, J ) 7.5, 7.5 Hz, 2 H), 7.37 (d, J
) 7.5 Hz, 2 H); 13C-NMR (126 MHz, CDCl3) δ 17.58, 26.03,
27.53, 50.03, 51.96, 115.61, 126.02, 126.71, 128.23, 128.28,
137.11, 139.56, 141.14; IR (neat) ν 3336, 1642, 1598 cm-1; EI-
MS m/z 213 (M+), 212, 156 (bp), 136, 77; HRMS calcd for
C15H19N 213.1518, found 213.1533.
N-Allyl-N-(2-p h en yl-2-cycloh exen yl)d ip h en ylm et h yl-
a m in e (4d ). A solution of 4b (306 mg, 1.43 mmol), K2CO3
(774 mg, 5.60 mmol), and diphenylmethyl chloride (0.50 mL,
2.82 mmol) in CH3CN (7 mL) was refluxed for 10 days. After
usual workup, the residue was purified by column chroma-
tography on silica gel (hexane/EtOAc, 50/1) to give 4d (318
mg, 60%) and the starting amine (25%): 1H-NMR (500 MHz,
CDCl3) δ 1.40 (m, 1 H), 1.61-1.67 (m, 2 H), 1.80 (m, 1 H),
2.05-2.12 (m, 2H), 3.18 (dd, J ) 7.4, 15.0 Hz, 1 H), 3.23 (dd,
J ) 5.9, 15.0 Hz, 1 H), 4.07 (bs, 1 H), 4.67 (dd, J ) 1.0, 17.2
Hz, 1 H), 4.73 (dd, J ) 1.0, 10.0 Hz, 1 H), 4.90 (s, 1 H), 5.56
(dddd, J ) 5.9, 7.4, 10.0, 17.2 Hz, 1 H), 5.99 (dd, J ) 4.5, 5.1
Hz, 1 H), 6.91-6.93 (m, 2H), 7.03-7.07 (m, 3 H), 7.19-7.35
(m, 10 H); 13C-NMR (126 MHz, CDCl3) δ 21.6, 24.7, 25.9, 50.4,
56.0, 61.4, 68.8, 115.0, 126.2, 126.3, 126.8, 127.3, 127.6, 127.6,
128.1, 128.4, 129.3, 130.9, 138.4, 141.9, 142.9, 143.1, 143.5.
IR (neat) ν 1638, 1598 cm-1; MS m/z 379 (M+), 302, 224, 212,
167, 77; HRMS calcd for C28H29N 379.2300, found 379.2318.
2-(3,4-Dim eth oxyp h en yl)-2-cycloh exen -1-ol (9). To a
solution of 2-bromo-2-cyclohexenol (8)14 (890 mg, 5.03 mmol)
and Pd(PPh3)4 (289 mg 0.250 mmol) in benzene (36 mL) was
added a 2 M solution of Na2CO3 (5 mL, 10.0 mL). To this
solution was added a solution of 3,4-dimethoxyphenylboric acid
(7)15 (965 mg, 5.33 mmol) in EtOH (24 mL), and the mixture
was warmed at 80 °C for 1.3 h under argon. After cooling,
H2O2 (1.6 mL) was added at 0 °C and the solution was stirred
at room temperature for 1 h. Water was added and the
aqueous layer was extracted with Et2O. The organic layer was
washed with brine, dried over Na2SO4 and concentrated. The
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate, 3/1) to give a colorless oil, 2-(3,4-
dimethoxyphenyl)-2-cyclohexen-1-ol (798 mg, 68%): 1H-NMR
(500 MHz, CDCl3) δ 1.63 (d, J ) 5.3 Hz, 1 H), 1.68 (m, 1 H),
1.74-1.89 (m, 2 H), 1.97 (m, 1 H), 2.16 (m, 1 H), 2.26 (ddd, J
) 4.5, 9.1, 18.5 Hz, 1 H), 3.88 (s, 3 H), 3.90 (s, 3 H), 4.68 (bd,
J ) 4.1 Hz, 1 H), 6.09 (dd, J ) 3.9, 3.9 Hz, 1 H), 6.85 (d, J )
8.9 Hz, 1 H), 7.01 (d, J ) 2.0 Hz, 1 H), 7.02 (dd, J ) 2.0, 8.9
Hz, 1 H); 13C-NMR (126 MHz, CDCl3) δ 17.81, 26.47, 32.01,
56.32, 56.37, 66.09, 110.03, 111.68, 118.69, 128.00, 133.68,
139.23, 148.88, 149.45; IR (neat) ν 3416 cm-1; MS m/z 234 (M+),
216, 151; HRMS m/z calcd for C14H18NO3 234.1254, found
234.1229.
N -Allyl-2-(3,4-d im e t h oxyp h e n yl)-2-cycloh e xe n -1-yl-
a m in e (10). To a solution of 9 (783 mg, 3.34 mmol) and CBr4
(2.20 g, 6.63 mmol) in CH2Cl2 (20 mL) was added PPh3 (3.47
g, 13.2 mmol) at 0 °C and the solution was stirred at the same
temperature for 2 h. After the usual workup, the residue was
purified by column chromatography on silica gel (hexane/
AcOEt, 2/1) to give N-allyl-2-(3,4-dimethoxyphenyl)-2-cyclo-
hexen-1-ylamine (682 mg, 75%): 1H-NMR (500 MHz, CDCl3)
δ 1.24 (bs, 1 H), 1.60-1.79 (m, 3 H), 1.91 (m, 1H), 2.12-2.23
(m, 2H), 3.16 (dd, J ) 6.8, 13.9 Hz, 1H), 3.30 (dd, J ) 5.4,
13.9 Hz, 1H), 3.68 (bs, 1H), 3.88 (s, 3H), 3.89 (s, 3H), 5.03 (dd,
J ) 1.0, 9.9 Hz, 1H), 5.10 (dd, J ) 1.0, 17.0 Hz, 1H), 5.80 (dddd,
J ) 5.4, 6.8, 9.9, 17.0 Hz, 1H), 5.98 (dd, J ) 3.8, 3.8 Hz, 1H),
6.83 (d, J ) 8.2 Hz, 1H), 6.93 (dd, J ) 1.7, 8.2 Hz, 1H), 6.95
(d, J ) 1.7 Hz, 1H); 13C-NMR (126MHz, CDCl3) d: 17.60, 26.06,
27.52, 50.21, 52.20, 55.76, 55.86, 109.77, 111.13, 115.74,
118.26, 127.25, 134.31, 137.22, 139.25, 148.12, 148.77; IR
(neat) ν 3334, 1642, 1602 cm-1; MS m/z 273 (M+), 216; HRMS
calcd for C17H23NO2 273.1729, found 273.1718.
N-Allyl-N-[2-(3,4-d im et h oxyp h en yl)-2-cycloh exen yl]-
d ip h en ylm eth yla m in e (4e). A solution of 10 (682 mg, 2.49
mmol), K2CO3 (1.38 g, 9.98 mmol), and diphenylmethyl
chloride (0.880 mg, 4.96 mmol) in CH3CH2CN (10 mL) was
warmed at 90 °C for 9 days. After the usual workup, the
residue was purified by column chromatography on silica gel
(hexane/AcOEt, 2/1) to give 4e (490 mg, 45%), and the starting
material was recovered in 44% yield: 1H-NMR (500 MHz,
CDCl3) δ 1.42 (m, 1 H), 1.64-1.71 (m, 2 H), 1.80 (m, 1 H),
2.06-2.07 (m, 2 H), 3.19 (dd, J ) 7.4, 15.0 Hz, 1 H), 3.27 (dd,
J ) 5.7, 15.0 Hz, 1 H), 3.90 (s, 3 H), 3.93 (s, 3 H), 4.03 (bs, 1
H), 4.67 (d, J ) 17.2 Hz, 1 H), 4.72 (d, J ) 9.9 Hz, 1 H), 4.92
(s, 1 H), 5.57 (dddd, J ) 5.7, 7.4, 9.9, 17.2 Hz, 1 H), 5.95 (bs,
1 H), 6.84-6.85 (m, 3 H), 6.96-6.98 (m, 2 H), 7.04-7.09 (m, 3
H), 7.19-7.31 (m, 5 H); 13C-NMR (126 MHz, CDCl3) δ 21.4,
24.9, 25.8, 50.6, 55.9, 56.0, 56.1, 68.9, 110.7, 111.0, 114.8, 119.7,
126.3, 126.8, 127.6, 127.9, 128.1, 128.4, 129.2, 130.3, 136.1,
138.5, 141.5, 143.2, 143.5, 147.7, 148.2; IR (neat) ν 1638, 1600,
1582 cm-1; MS m/z 439 (M+), 362, 272, 167; HRMS m/z calcd
for C30H33NO2 439.2511, found 439.2524. For (S)-4e, [R]29
-41.1 (c 1.05, CH3OH) (99% ee).
D
Th e Gen er a l P r oced u r e for th e Cycliza tion Usin g Cp 2-
Zr Bu 2. To a THF solution of Cp2ZrCl2 (1.3 equiv) was added
BuLi (ca. 1.6 M in hexane, 2.6 equiv) at -78 °C, and the
solution was stirred at the same temperature for 1 h. To this
solution was added the diene (1 equiv) at -78 °C and the
solution was stirred at room temperature. After 10% HCl was
added to this solution at 0 °C, the mixture was stirred for 1 h,
and the aqueous layer was made basic by K2CO3, and extracted
with ethyl acetate. The organic layer was washed with brine,
dried over Na2SO4, and concentrated. The residue was puri-
fied by column chromatography on silica gel to give the cyclized
product.
(3S *,3a R *,7a R *)-1-B e n zy l-3-m e t h y l-3a -p h e n y l-2,3,
3a ,6,7,7a -h exa h yd r oin d ole (5a ). A crude product, which
was prepared from Cp2ZrCl2 (62.3 mg, 0.213 mmol), BuLi (1.69
M in hexane, 0.240 mL, 0.406 mmol), and 4a (49.2 mg, 0.162
mmol), was purified by column chromatography on silica gel
(hexane/AcOEt, 50/1-20/1) to give 5a (13.3 mg, 27%): 1H-NMR
(500 MHz, CDCl3) δ 0.74 (d, J ) 5.7 Hz, 3 H), 1.32 (m, 1 H),
1.52 (m, 1 H), 1.82 (ddd, J ) 5.3, 5.3, 17.3 Hz, 1 H), 2.35 (m,
1 H), 2.66 (bs, 3 H), 2.96 (bs, 1 H), 3.49 (d, J ) 13.7 Hz, 1 H),
3.91 (d, J ) 13.7 Hz, 1 H), 5.62 (dd, J ) 1.1, 10.0 Hz, 1 H),
5.97 (dd, J ) 4.9, 10.0 Hz, 1 H), 7.12-7.36 (m, 10 H); 13C-
NMR (67.8 MHz, CDCl3) δ 12.7, 20.8, 22.0, 41.1, 52.3, 59.2,
59.5, 71.0, 125.9, 126.5, 126.7, 127.6, 128.1, 128.1, 128.4, 129.5,
140.9, 145.4; IR (neat) ν 1598 cm-1; MS m/z 303 (M+), 212, 91,
77; HRMS calcd for C22H25N 303.1987, found 303.1980.
(3S*,3aR*,7aR*)-1-(Diph en ylm eth yl)-3-m eth yl-3a-ph en -
yl-2,3,3a ,6,7,7a -h exa h yd r oin d ole (5d ). A crude product,
which was prepared from Cp2ZrCl2 (55.3 mg, 0.189 mmol),
BuLi (1.69 M in hexane, 0.210 mL, 0.355 mmol), and 4d (52.7
mg, 0.139 mmol), was purified by column chromatography on
silica gel (hexane/CH2Cl2, 20/1-1/1) to give 5d (30.7 mg,
58%): 1H-NMR (500 MHz, CDCl3) δ 0.71 (d, J ) 6.8 Hz, 3 H),
1.11 (m, 1 H), 1.19 (dddd, J ) 1.7, 4.9, 11.6, 11.6 Hz, 1 H),
1.81 (bd, J ) 17.4 Hz, 1 H), 2.41-2.47 (m, 2 H), 2.77 (dd, J )
10.6, 10.6 Hz, 1 H), 2.93 (dd, J ) 7.7, 10.6 Hz, 1 H), 3.22 (bd,
J ) 3.0 Hz, 1 H), 4.97 (s, 1 H), 5.65 (d, J ) 10.3 Hz, 1 H), 6.12
(ddd, J ) 1.7, 5.0, 10.3 Hz, 1 H), 7.14-7.37 (m, 15 H); 13C-
NMR (126 MHz, CDCl3) δ 11.7, 21.2, 21.4, 40.7, 52.9, 56.9,
68.6, 71.1, 125.9, 126.7, 126.8, 127.6, 127.9, 128.0, 128.2, 128.7,
128.7, 130.4, 143.0, 143.6, 145.3; IR (neat) ν 1653, 1598 cm-1
;
MS m/z 379 (M+), 302, 212, 167, 91, 77; HRMS m/z: calcd for
C28H29N 379.2300, found 379.2292.
(3R*,3a S*,7a S*)-1-(Dip h en ylm eth yl)-3-m eth yl-3a -(3,4-
d im eth oxyp h en yl)-2,3,3a ,6,7,7a -h exa h yd r oin d ole (5e). A
crude product, which was prepared from Cp2ZrCl2 (42.5 mg,
0.146 mmol), BuLi (1.71 M in hexane, 0.160 mL, 0.274 mmol),
(14) Sonnenberg, J .; Winstein, S. J . Org. Chem. 1962, 27, 748.
(15) Morgan, J .; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1990,
715. Huber, M. L.; Pinhey, J . T. J . Chem. Soc., Perkin Trans. 1 1990,
721.

3268 J . Org. Chem., Vol. 62, No. 10, 1997
Mori et al.
and 4e (49.3 mg, 0.112 mmol), was purified by column
chromatography on silica gel (hexane/CH2Cl2, 1/3-1/10) to give
5e (10.8 mg, 61%): 1H-NMR (500 MHz, CDCl3) δ 0.71 (d, J )
6.8 Hz, 3 H), 1.21-1.23 (m, 2 H), 1.83 (dd, J ) 3.2, 16.5 Hz, 1
H), 2.30 (ddd, J ) 6.8, 7.6, 10.7 Hz, 1 H), 2.46 (m, 1 H), 2.77
(dd, J ) 10.7, 10.7 Hz, 1 H), 2.97 (dd, J ) 7.6, 10.7 Hz, 1 H),
3.21 (bs, 1 H), 3.83 (s, 3 H), 3.86 (s, 3 H), 4.99 (s, 1 H), 5.64 (d,
J ) 10.2 Hz, 1 H), 6.13 (ddd, J ) 2.0, 5.1, 10.2 Hz, 1 H), 6.78
(d, J ) 2.0 Hz, 1 H), 6.79 (d, J ) 8.3 Hz, 1 H), 6.85 (dd, J )
2.0, 8.3 Hz, 1 H), 7.17-7.39 (m, 10 H); 13C-NMR (126 MHz,
CDCl3) δ 11.6, 21.2, 21.3, 41.0, 52.4, 55.8, 55.8, 56.4, 68.3, 70.5,
110.6, 111.0, 119.9, 126.6, 126.8, 127.9, 128.2, 128.7, 128.8,
130.4, 137.9, 142.6, 143.6, 147.2, 148.5; IR (neat) ν 1734, 1654,
1600 cm-1; MS m/z 439 (M+), 362, 272, 167, 91; HRMS calcd
for C30H33NO2 439.2511, found 439.2491.
p-toluenesulfonyl chloride (45.8 mg, 0.240 mmol), and the
mixture was stirred at room temperature for 12 h. After usual
workup, the crude 2d was obtained. A suspension of the crude
2d and 10% Pd on charcoal (53.3 mg) in methanol (3 mL) was
stirred at room temperature for 10 h under an atmosphere of
hydrogen. After the catalyst was filtered off, the solvent was
evaporated. The residue was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, 2/1-1/2) to give 16
(36.2 mg, 48% from 2b): 1H-NMR (270 MHz, CDCl3) δ 1.00
(bs, 1 H), 1.26 (m, 1 H), 1.35-1.49 (m, 2 H), 1.59-1.76 (m, 4
H), 1.84-2.08 (m, 2 H), 2.47 (s, 3 H), 3.41-3.45 (m, 2 H), 3.45
(dd, J ) 11.2, 11.2 Hz, 1 H), 3.65 (bs, 1 H), 3.76 (s, 3 H), 3.84
(dd, J ) 9.0, 11.2 Hz, 1 H), 3.84 (s, 3 H), 6.56 (d, J ) 2.2 Hz,
1 H), 6.73 (dd, J ) 2.2, 8.5 Hz, 1 H), 6.79 (d, J ) 8.5 Hz, 1 H),
7.39 (d, J ) 8.1 Hz, 2 H), 7.79 (d, J ) 8.1 Hz, 2 H); 13C-NMR
(67.8 MHz, CDCl3) δ 19.7, 21.5, 21.9, 24.7, 25.2, 48.7, 52.0,
52.1, 55.7, 60.5, 66.7, 109.9, 111.1, 119.3, 127.7, 129.7, 133.4,
133.8, 143.5, 147.6, 148.9; IR (Nujol) ν 3397 cm-1; MS m/z 445
(M+), 290, 162; HRMS calcd for C24H31NO5S 445.1923, found
(3R,3a S,7a S)-1-(Dip h en ylm eth yl)-3-(h yd r oxym eth yl)-
3a -(3,4-d im e t h oxyp h e n yl)-2,3,3a ,6,7,7a -h e xa h yd r oin -
d ole (2a ). To a stirred solution of 4e (496 mg, 1.13 mmol),
Cp2ZrCl2 (497 mg, 1.70 mmol) in THF (15 mL) was added BuLi
(1.58 M in hexane, 2.1 mL, 3.32 mmol) at -78 °C, and the
mixture was stirred at the same temperature for 1 h and then
at room temperature for 3.2 h. To the resultant solution was
added MeMgBr (0.87 M in THF, 12.0 mL, 10.4 mmol) at -78
°C, and the mixture was stirred at room temperature for 3 h.
The argon atmosphere in the reaction vessel was exchanged
to oxygen, and the mixture was stirred for 10 h under oxygen.
After 10% HCl was added to this solution at 0 °C, the mixture
was stirred for 1 h, and the aqueous layer was made basic by
K2CO3. The aqueous layer was extracted with ethyl acetate,
and the organic layer was washed with brine, dried over Na2-
SO4, and concentrated. The residue was purified by column
chromatography on silica gel (hexane/ethyl acetate, 2/1) to give
2a (324 mg, 63%): 1H-NMR (500 MHz, CDCl3) δ 1.24-1.37
(m, 2 H), 1.54 (bs, 1 H), 1.82 (m, 1 H), 2.38 (m, 1 H), 2.57 (m,
1 H), 2.88 (dd, J ) 10.1, 10.1 Hz, 1 H), 3.06 (dd, J ) 8.0, 10.1
Hz, 1 H), 3.17 (bd, J ) 2.8 Hz, 1 H), 3.51 (dd, J ) 7.7, 10.6 Hz,
1 H), 3.62 (dd, J ) 5.8, 10.6 Hz, 1 H), 3.83 (s, 3 H), 3.85 (s, 3
H), 4.99 (s, 1 H), 5.67 (d, J ) 10.2 Hz, 1 H), 6.12 (ddd, J ) 2.6,
4.8, 10.2 Hz, 1 H), 6.79 (d, J ) 8.4 Hz, 1 H), 6.85 (d, J ) 2.1
Hz, 1 H), 6.89 (dd, J ) 2.1, 8.4 Hz, 1 H), 7.17-7.39 (m, 10H);
13C-NMR (126 MHz, CDCl3) δ 11.4, 20.5, 21.0, 49.3, 51.4, 52.7,
55.8, 55.8, 62.9, 68.2, 69.6, 110.6, 110.6, 119.5, 126.7, 126.9,
127.1, 128.0, 128.2, 128.4, 128.8, 130.5, 138.6, 141.6, 143.2,
147.3, 148.5; IR (neat) ν 3494, 1600 cm-1; MS m/z 455 (M+),
424, 378, 288, 216, 167; HRMS calcd for C30H33NO3 455.2461,
445.1945; [R]30 +88.0 (c 1.04, CH3OH) (99% ee).
D
(3R ,3a S ,7a S )-1-(p -T o ly ls u lfo n y l)-3-fo r m y l-3a -(3,4-
d im eth oxyp h en yl)-2,3,3a ,4,5,6,7,7a -octa h yd r oin d ole (17).
To a solution of 9 (24.2 mg, 0.050 mmol) in CH2Cl2 (1.7 mL)
was added Dess-Martin reagent (60.4 mg, 0.140 mmol) at 0
°C, and the mixture was stirred at the same temperature for
20 min and then at room temperature for 1 h. The reaction
mixture was diluted with ethyl acetate, and the mixture was
washed with saturated aqueous NaHCO3 and brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/ethyl
acetate, 2/1) to give 17 (19.6 mg, 80%): 1H-NMR (500 MHz,
CDCl3) δ 1.25-1.44 (m, 4 H), 1.55-1.77 (m, 4 H), 2.47 (s, 3
H), 2.66 (dd, J ) 9.9, 11.3 Hz, 1 H), 3.65 (dd, J ) 9.9, 11.3 Hz,
1 H), 3.80 (s, 3 H), 3.83-3.84 (m, 1 H), 3.87 (s, 3 H), 3.96 (dd,
J ) 11.3, 11.3 Hz, 1 H), 6.67 (s, 1 H), 6.83 (s, 2 H), 7.34 (d, J
) 7.9 Hz, 2 H), 7.78 (d, J ) 7.9 Hz, 2 H), 9.36 (s, 1 H); 13C-
NMR (67.8 MHz, CDCl3) δ 19.4, 21.5, 21.8, 25.2, 26.5, 29.7,
46.9, 50.0, 55.9, 60.8, 66.1, 109.9, 111.4, 119.2, 127.6, 129.8,
132.5, 133.9, 143.8, 148.2, 149.2, 199.6; IR (Nujol) ν 1716 cm-1
;
MS m/z 443 (M+), 288; HRMS calcd for C24H29NO5S 443.1767,
found 443.1752; [R]30 +93.8 (c 1.00, CH3OH) (99% ee).
D
(3aS,7aS)-1-(p-Tolylsu lfon yl)-3a-(3,4-dim eth oxyph en yl)-
2,3,3a ,4,5,6,7,7a -octa h yd r oin d ole (18). A solution of 17
(29.1 mg, 0.060 mmol) and RhCl(PPh3)3 (55.5 mg, 0.060 mmol)
in CH3CH2CN (4.0 mL) was refluxed for 24 h. After being
cooled to room temperature, the mixture was diluted with
EtOH and filtered. After removal of the solvent, the residue
was purified by column chromatography on silica gel (hexane/
ethyl acetate, 5/1) to give 18 (17.1 mg, 62%): 1H-NMR (400
MHz, CDCl3) δ 1.33-1.48 (m, 3 H), 1.69-1.91 (m, 5 H), 2.02
(m, 1 H), 2.18 (ddd, J ) 7.8, 7.8, 12.7 Hz, 1 H), 2.38 (s, 3 H),
3.30 (ddd, J ) 7.8, 7.8, 9.8 Hz, 1 H), 3.55 (ddd, J ) 4.9, 7.8,
9.8 Hz, 1 H), 3.80 (s, 3 H), 3.84 (s, 3 H), 3.90 (dd, J ) 5.4, 7.8
Hz, 1 H), 6.61 (d, J ) 2.4 Hz, 1 H), 6.63 (d, J ) 8.3 Hz, 1 H),
6.69 (dd, J ) 2.4, 8.3 Hz, 1 H), 7.12 (d, J ) 8.1 Hz, 2 H), 7.50
(d, J ) 8.1 Hz, 2 H); 13C-NMR (67.8 MHz, CDCl3) δ 21.4, 22.0,
22.5, 29.7, 30.0, 33.8, 35.5, 45.7, 48.3, 55.7, 64.0, 109.7, 110.6,
117.8, 127.0, 129.2, 135.6, 138.1, 142.8, 147.4, 148.6; IR (Nujol)
ν 1598, 1464, 1336 cm-1; MS m/z 415 (M+), 260, 122; HRMS
found 455.2475; [R]30 + 13.6 (c 1.01, CH3OH) (99% ee).
D
(3R ,3a S ,7a S )-1-(Dip h e n ylm e t h yl)-3-[((t er t -b u t yld i-
m et h ylsilyl)oxy)m et h yl]-3a -(3,4-d im et h oxyp h en yl)-2,3,
3a ,6,7,7a -h exa h yd r oin d ole (2b). A solution of 2a (210 mg,
0.461 mmol), imidazole (68.0 mg, 1.00 mmol), and tert-
butyldimethylsilyl chloride (104 mg, 0.690 mmol) in CH2Cl2
(3 mL) was stirred at room temperature for 3 h. After usual
workup, the residue was purified by column chromatography
on silica gel (hexane/ethyl acetate, 20/1) to give 2b (239 mg,
85%): 1H-NMR (500 MHz, CDCl3) δ -0.14 (s, 3 H), -0.13 (s,
3 H), 0.74 (s, 9 H), 1.28 (m, 1 H), 1.38 (m, 1 H), 1.81 (dd, J )
3.6, 17.2 Hz, 1 H), 2.35-2.46 (m, 2 H), 2.84 (dd, J ) 10.2, 10.2
Hz, 1 H), 3.05 (dd, J ) 7.9, 10.2 Hz, 1 H), 3.17 (bd, J ) 2.9 Hz,
1 H), 3.41 (dd, J ) 9.7, 9.7 Hz, 1 H), 3.52 (dd, J ) 5.3, 9.7 Hz,
1 H), 3.81 (s, 3 H), 3.85 (s, 3 H), 4.98 (s, 1 H), 5.58 (d, J ) 10.2
Hz, 1 H), 6.06 (ddd, J ) 2.5, 4.9, 10.2 Hz, 1 H), 6.77 (d, J )
8.4 Hz, 1 H), 6.79 (d, J ) 1.9 Hz, 1 H), 6.85 (dd, J ) 1.9, 8.4
Hz, 1 H), 7.18-7.40 (m, 10 H); 13C-NMR (126 MHz, CDCl3) δ
-5.5, -5.4, 18.1, 20.7, 21.1, 25.8, 49.5, 51.6, 52.6, 55.8, 55.9,
63.0, 68.2, 69.3, 110.7, 110.8, 119.8, 126.6, 126.9, 127.6, 128.0,
128.1, 128.4, 129.1, 129.8, 139.0, 141.6, 143.5, 147.2, 148.5;
IR (Nujol) ν 1600, 1586 cm-1; MS m/z 569 (M+), 167; HRMS
calcd for C23H29NO4S 415.1818, found 415.1796; [R]31 +54.0
D
(c 1.02, CH3OH) (99% ee).
(3a S ,7a S )-1-(Me t h oxyca r b on yl)-3a -(3,4-d im e t h oxy-
p h en yl)-2,3,3a ,4,5,6,7,7a -octa h yd r oin d ole. To a solution of
18 (16.1 mg, 0.030 mmol) in THF (1.0 mL) was added soldium
naphthalenide (0.14 M solution in THF, 3.5 mL, 0.490 mmol)
at -78 °C, and the mixture was stirred at -78 °C for 30 min.
After the reaction mixture was quenched by the addition of
water, the mixture was extracted with ethyl acetate, and the
organic layer was washed with brine and dried over Na2SO4.
After removal of the solvent, to the residue in CH2Cl2 (2.0 mL)
were added K2CO3 (139 mg, 1.00 mmol) and methyl chloro-
formate (0.05 mL, 0.647 mmol), and the mixture was stirred
at room temperature for 19 h. After the usual workup, the
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate, 2/1) to give the desired (methoxycarbo-
nyl)indole derivative (7.2 mg, 59%): 1H-NMR (400 MHz, CDCl3,
calcd for C36H47NO3Si 569.3326, found 569.3309; [R]27 +19.6
D
(c 1.06, CH3OH) (99% ee).
(3R,3a S,7a S)-1-(p -Tolylsu lfon yl)-3-(h yd r oxym et h yl)-
3a -(3,4-d im eth oxyp h en yl)-2,3,3a ,4,5,6,7,7a -octa h yd r oin -
d ole (16). A suspension of 2b (98.8 mg, 0.173 mmol) and 10%
Pd on charcoal (93.2 mg) in methanol (3 mL) was stirred at
room temperature for 9 h under an atmosphere of hydrogen.
After the catalyst was filtered off, the solvent was evaporated
to give the crude 2c, which was dissolved in CH2Cl2. To this
solution were added pyridine (0.025 mL, 0.307 mmol) and

Total Syntheses of (-)-Mesembrane and (-)-Mesembrine
J . Org. Chem., Vol. 62, No. 10, 1997 3269
at 55 °C) δ 1.27-1.69 (m, 6 H), 1.94 (m, 1 H), 2.05 (m, 1 H),
2.14 (bs, 1 H), 2.34 (ddd, J ) 9.3, 9.3, 12.8 Hz, 1 H), 3.15 (m,
1 H), 3.39 (m, 1 H), 3.66 (s, 3 H), 3.84 (s, 3 H), 3.85 (s, 3 H),
4.21 (bs, 1 H), 6.79-5.86 (m, 3 H); 13C-NMR (100 MHz, CDCl3)
δ 22.4, 23.4, 35.9, 43.6, 52.1, 56.1, 56.2, 59.9, 110.1, 111.8,
118.0, 140.5, 147.7, 149.2, 155.4; IR (neat) ν 1694 cm-1; MS
m/z 319 (M+), 304, 288, 260; HRMS calcd for C18H25NO4
319.1784, found 319.1758.
zole (478 mg, 4.97 mmol) at -10 °C, and the mixture was
stirred at the same temperature for 30 min. To the resulting
solution was added a solution of 2e (49.4 mg, 0.099 mmol) in
CH2Cl2 (2.0 mL), and the mixture was stirred at the same
temperature for 20 h. The reaction mixture was diluted with
Et2O, and filtered through Florisil. The filtrate was concen-
trated, the residue was dissolved in ethyl acetate, and the
solution was washed with 10% HCl, saturated aqueous NaH-
CO3, and brine and dried over Na2SO4. After removal of the
solvent, the residue was purified by column chromatography
on silica gel (hexane/ethyl acetate, 2/1) to give 19 (32.8 mg,
(3a S ,7a S )-1-Me t h y l-3a -(3,4-d im e t h o x y p h e n y l)-2,3,
3a ,4,5,6,7,7a -octa h yd r oin d ole ((-)-Mesem br a n e, 1a ). To
a solution of the above (methoxycarbonyl)indole (7.2 mg, 0.023
mmol) in Et2O (1.0 mL) was added LiAlH4 (4.2 mg, 0.111
mmol) at 0 °C, and the mixture was stirred at 0 °C for 4 h.
The reaction mixture was quenched by the addition of Na2-
SO4·10H2O, and the solution was stirred at room temperature
for 1 h. The mixture was diluted with Et2O and filtered. The
filtrate was concentrated to give the crude product, which was
purified by column chromatography on aluminum oxide (hex-
ane/ethyl acetate, 20/1) to give (-)-mesembrane (1a ) (4.8 mg,
74%): 1H-NMR (500 MHz, CDCl3) δ 1.47-1.63 (m, 5 H), 1.77-
1.91 (m, 3 H), 1.92-1.95 (m, 2 H), 2.29 (m, 1 H), 2.32 (s, 3 H),
2.58 (bs, 1 H), 3.24 (ddd, J ) 4.5, 9.1, 9.1 Hz, 1 H), 3.87 (s, 3
H), 3.89 (s, 3 H), 6.81 (d, J ) 8.3 Hz, 1 H), 6.90 (d, J ) 2.1 Hz,
1 H), 6.92 (dd, J ) 2.1, 8.3 Hz, 1 H); 13C-NMR (100 MHz,
CDCl3) δ 20.4, 22.9, 23.7, 36.0, 40.7, 41.0, 47.6, 54.4, 55.9, 56.0,
68.7, 110.7, 110.8, 118.9, 140.3, 146.9, 148.6; IR (neat) ν 1588,
1520 cm-1; MS m/z 275 (M+), 274, 260, 232; HRMS calcd for
C17H25NO2 275.1885, found 275.1878; [R]20D -14.6 (c 1.15, CH3-
OH) (99% ee).
1
65%): H-NMR (500 MHz, CDCl3) δ 2.46 (s, 3 H), 2.50 (dd, J
) 3.1, 16.8 Hz, 1 H), 2.69 (m, 1 H), 3.08 (dd, J ) 11.6, 11.6
Hz, 1 H), 3.16 (dd, J ) 2.9, 16.8 Hz, 1 H), 3.68 (s, 3 H), 3.81 (s,
3 H), 3.87 (s, 3 H), 3.96 (dd, J ) 7.1, 11.6 Hz, 1 H), 4.02 (dd,
J ) 8.6, 11.3 Hz, 1 H), 4.08 (bs, 1 H), 4.13 (dd, J ) 5.0, 11.3
Hz, 1 H), 6.40 (d, J ) 10.4 Hz, 1 H), 6.57 (d, J ) 2.1 Hz, 1 H),
6.69 (dd, J ) 1.7, 10.4 Hz, 1 H), 6.71 (dd, J ) 2.1, 8.3 Hz, 1
H), 6.82 (d, J ) 8.3 Hz, 1 H), 7.36 (d, J ) 8.1 Hz, 2 H), 7.74 (d,
J ) 8.1 Hz, 2 H). 13C-NMR (126 MHz, CDCl3), δ 21.5, 38.3,
46.4, 51.2, 52.6, 54.9, 55.8, 55.9, 64.5, 67.0, 109.1, 111.4, 119.6,
127.6, 128.7, 129.9, 132.6, 134.7, 144.1, 144.3, 149.1, 149.6,
155.2, 195.9; IR (Nujol) ν 1748, 1692 cm-1; MS m/z 515 (M+),
360; HRMS calcd for C26H31NO8S 515.1615, found 515.1616;
[R]26 +138.0 (c 0.97, CH3OH) (99% ee).
D
(3R ,3a S ,7a S )-1-(p -T o ly ls u lfo n y l)-3-[((m e t h o x y c a r -
b on yl)oxy)m et h yl]-3a -(3,4-d im et h oxyp h en yl)-6-oxo-2,3,
3a ,4,5,6,7,7a -octa h yd r oin d ole. A suspension of 19 (68.2 mg,
0.132 mmol) and 10% Pd on charcoal (71.2 mg) in CH2Cl2 (2
mL) was stirred at room temperature for 3.5 h under an
atmosphere of hydrogen. After the catalyst was filtered off,
the solvent was evaporated. The residue was purified by
column chromatography on silica gel (hexane/ethyl acetate,
1/1) to give the indolinone (58.0 mg, 79%): 1H-NMR (500 MHz,
CDCl3) δ 2.22 (m, 1 H), 2.34-2.43 (m, 5 H), 2.47 (s, 3 H), 3.23
(dd, J ) 2.5, 15.8 Hz, 1 H), 3.33 (dd, J ) 11.0, 11.0 Hz, 1 H),
3.68 (s, 3 H), 3.83 (s, 3 H), 3.87 (s, 3 H), 3.87 (dd, J ) 9.3, 11.0
Hz, 1 H), 4.00, (d, J ) 6.9 Hz, 2 H), 4.32 (bs, 1 H), 6.72 (s, 1
H), 6.84 (s, 2 H), 7.37 (d, J ) 8.1 Hz, 2 H), 7.76 (d, J ) 8.1 Hz,
2 H); 13C-NMR (126 MHz, CDCl3) δ 21.5, 24.7, 36.7, 41.0, 48.2,
49.1, 50.8, 54.9, 55.9, 56.1, 65.5, 67.8, 109.6, 111.6, 118.8, 127.7,
129.9, 131.1, 134.3, 144.1, 148.6, 149.6, 155.2, 207.4; IR (Nujol)
ν 1748, 1717 cm-1; MS m/z 517 (M+), 362; HRMS calcd for
C26H31NO8S 517.1771, found 517.1745.
(3R,3a S,7a S)-1-(p -Tolylsu lfon yl)-3-(h yd r oxym et h yl)-
3a -(3,4-d im e t h oxyp h e n yl)-2,3,3a ,6,7,7a -h e xa h yd r oin -
d ole. To a solution of 2d (178 mg, 0.319 mmol) in THF (3.0
mL) was added Bu4NF (1.0 M in THF, 0.64 mL, 0.64 mmol)
at 0 °C, and the mixture was stirred at room temperature for
30 min. Water was added to the mixture, and the mixture
was extracted with ethyl acetate. The organic layer was
washed with brine and dried over Na2SO4. After removal of
the solvent, the residue was purified by column chromatog-
raphy on silica gel (hexane/ethyl acetate, 1/1) to give the
1
alcohol (143 mg, 100%): H-NMR (270 MHz, CDCl3) δ 1.29-
1.65 (m, 2 H), 1.98 (m, 1 H), 2.12-2.24 (m, 2 H), 2.38 (m, 1
H), 2.47 (s, 3 H), 3.22 (dd, J ) 11.5, 11.5 Hz, 1 H), 3.37-3.50
(m, 2 H), 3.63 (bs, 1 H), 3.73 (s, 3 H), 3.84 (s, 3 H), 3.92 (dd, J
) 7.2, 11.5 Hz, 1 H), 5.46 (ddd, J ) 1.4, 1.4, 10.4 Hz, 1 H),
6.21 (dd, J ) 4.9, 10.4 Hz, 1 H), 6.49 (d, J ) 2.2 Hz, 1 H), 6.63
(dd, J ) 2.2, 8.4 Hz, 1 H), 6.74 (d, J ) 8.4 Hz, 1 H), 7.38 (d, J
) 8.1 Hz, 2 H), 7.80 (d, J ) 8.1 Hz, 2 H); 13C-NMR (67.8 MHz,
CDCl3) δ 20.4, 22.0, 23.0, 49.4, 52.0, 52.7, 56.2, 56.3, 61.4, 68.0,
110.4, 111.4, 120.3, 125.2, 128.1, 130.2, 133.1, 135.0, 135.2,
143.9, 148.5, 149.3; IR (neat) ν 3526, 1654, 1598 cm-1; MS m/z
443 (M+), 288; HRMS calcd for C24H29NO5S 443.1767, found
(3R ,3a S ,7a S )-1-(p -T o ly ls u lfo n y l)-3-[((m e t h o x y c a r -
bon yl)oxy)m eth yl]-3a -(3,4-d im eth oxyp h en yl)-6,6-(eth yl-
en ed ioxy)-2,3,3a ,4,5,6,7,7a -octa h yd r oin d ole. To a solution
of the above indolinone (54.1 mg. 0.105 mmol) in CH2Cl2 (1.5
mL) were added TMSOTf (1.0 µL, 5.2 µmol) and 1,2-bis-
(trimethylsiloxy)ethane (0.050 mL, 0.204 mmol) at -30 °C,
and the mixture was stirred at the same temperature for 6 h.
To the mixture was added saturated aqueous NaHCO3 at -30
°C, the mixture was extracted with ethyl acetate, and the
organic layer was washed with brine and dried over Na2SO4.
After removal of the solvent, the residue was purified by
column chromatography on silica gel (hexane/ethyl acetate,
443.1782; [R]30 +193.9 (c 1.04, CH3OH) (99% ee).
D
(3R ,3a S ,7a S )-1-(p -T o ly ls u lfo n y l)-3-[((m e t h o x y c a r -
bon yl)oxy)m eth yl]-3a -(3,4-d im eth oxyp h en yl)-2,3,3a ,6,7,
7a -h exa h yd r oin d ole (2e). A solution of the above alcohol
(104 mg, 0.235 mmol), pyridine (0.17 mL, 2.10 mmol), and
methyl chloroformate (0.09 mL, 1.2 mmol) in CH2Cl2 (2.0 mL)
was stirred at room temperature for 6 h. After the usual
workup, the residue was purified by column chromatography
on silica gel (hexane/ethyl acetate, 2/1) to give 2e (105 mg,
1
1/1) to give the ethylene ketal (55.1 mg, 98%): H-NMR (500
MHz, CDCl3) δ 1.46 (dd, J ) 4.0, 15.0 Hz, 1 H), 1.76-1.82 (m,
2 H), 2.08-2.15 (m, 3 H), 2.46 (s, 3 H), 2.75 (d, J ) 15.0 Hz,
1 H), 3.42 (dd, J ) 11.4, 11.4 Hz, 1 H), 3.66 (s, 3 H), 3.76 (s, 3
H), 3.81-3.87 (m, 3 H), 3.85 (s, 3 H), 3.91-4.02 (m, 3 H), 4.03
(bs, 1 H), 4.10 (dd, J ) 7.1, 14.7, Hz, 1 H), 6.54 (d, J ) 2.1 Hz,
1 H), 6.73 (dd, J ) 2.1, 8.6 Hz, 1 H), 6.78 (d, J ) 8.6 Hz, 1 H),
7.38 (d, J ) 8.1 Hz, 2 H), 7.83 (d, J ) 8.1 Hz, 2 H); 13C-NMR
(126 MHz, CDCl3) δ 21.5, 22.9, 31.2, 32.6, 48.5, 48.7, 51.1, 54.8,
55.8, 55.8, 63.9, 64.4, 65.6, 66.6, 107.0, 109.6, 111.2, 119.1,
127.7, 129.7, 131.7, 134.4, 143.5, 148.0, 149.0, 155.2; IR (Nujol)
1
91%): H-NMR (270 MHz, CDCl3) δ 1.47 (m, 1 H), 1.99 (m, 1
H), 2.17 (m, 1 H), 2.31-2.44 (m, 2 H), 2.47 (s, 3 H), 3.25 (dd,
J ) 11.6, 11.6 Hz, 1 H), 3.63 (bs, 1 H), 3.68 (s, 3 H), 3.74 (s, 3
H), 3.84 (s, 3 H), 3.87-3.95 (m, 3 H), 5.46 (ddd, J ) 1.3, 1.3,
10.4 Hz, 1 H), 6.24 (dd, J ) 4.9, 10.4 Hz, 1 H), 6.48 (d, J ) 2.2
Hz, 1 H), 6.63 (dd, J ) 2.2, 8.5 Hz, 1 H), 6.75 (d, J ) 8.5 Hz,
1 H), 7.38 (d, J ) 8.1 Hz, 2 H), 7.78 (d, J ) 8.1 Hz, 2 H); 13C-
NMR (126 MHz, CDCl3) δ 19.9, 21.5, 22.5, 45.2, 51.7, 51.8,
54.8, 55.7, 55.9, 65.9, 67.2, 109.8, 111.0, 119.9, 124.4, 127.6,
129.8, 133.1, 133.6, 134.8, 143.5, 148.1, 148.9, 155.3; IR (neat)
ν 1742, 1518, 1456 cm-1; MS m/z 501 (M+), 346; HRMS calcd
ν 1750 cm-1; MS m/z 561 (M+), 406, 99; HRMS calcd for C28H35
-
NO9S 561.2033, found 561.2008; [R]30D +59.4 (c 0.88, CH3OH)
(99% ee).
for C26H31NO7S 501.1821, found 501.1841; [R]27 +164.8 (c
(3R,3a S,7a S)-1-(p -Tolylsu lfon yl)-3-(h yd r oxym et h yl)-
3a -(3,4-d i m e t h o x y p h e n y l)-6,6-(e t h y le n e d i o x y )-2,3,
3a ,4,5,6,7,7a -octa h yd r oin d ole (20). To a solution of the
above ethylene ketal (53.2 mg, 0.095 mmol) in CH2Cl2 (1.0 mL)
were added MeOH (1.0 mL) and K2CO3 (41.3 mg, 0.299 mmol),
and the mixture was stirred at room temperature for 2 h. After
D
1.00, CH2Cl2) (99% ee).
(3R,3a S,7a S)-1-(p-Tolylsu lfon yl)-3-[((m eth oxyca r bon y-
l)o x y )m e t h y l)-3a -(3,4-d im e t h o x y p h e n y l)-6-o x o -2,3,-
3a ,6,7,7a -h exa h yd r oin d ole (19). To a solution of CrO3 (485
mg, 4.85 mmol) in CH2Cl2 (5 mL) was added 3,5-dimethylpyra-

3270 J . Org. Chem., Vol. 62, No. 10, 1997
Mori et al.
the usual workup, the residue was purified by column chro-
basic by the addition of K2CO3, and the aqueous solution was
extracted with ethyl acetate. The organic layer was washed
with brine and dried over Na2SO4. After removal of the
solvent, the residue was purified by preparative TLC to give
(-)-mesembrine (1b) (1.0 mg, 35%): 1H-NMR (500 MHz,
CDCl3) δ 1.04-1.61 (m, 3 H), 1.94-2.20 (m, 3 H), 2.26 (s, 3
H), 2.35 (m, 1 H), 2.54 (m, 2 H), 2.89 (m, 1 H), 3.08 (m, 1 H),
3.81 (s, 3 H), 3.88 (s, 3 H), 6.75-6.91 (m, 3 H); IR (neat) ν
1722, 1520 cm-1; MS m/z 289 (M+), 274, 218, 70; HRMS calcd
matography on silica gel (hexane/ethyl acetate, 1/2) to give 20
1
(46.1 mg, 97%): H-NMR (500 MHz, CDCl3) δ 0.94 (bs, 1 H),
1.45 (dd, J ) 4.1, 14.9 Hz, 1 H), 1.76-1.80 (m, 2 H), 1.97 (m,
1 H), 2.09-2.12 (m, 2 H), 2.46 (s, 3 H), 2.75 (d, J ) 14.9 Hz,
1 H), 3.41 (dd, J ) 11.3, 11.3 Hz, 1 H), 3.44 (bs, 1 H), 3.75 (s,
3 H), 3.82-3.87 (m, 2 H), 3.85 (s, 3 H), 3.93 (dd, J ) 7.0, 12.2
Hz, 1 H), 4.00 (m, 2 H), 4.02 (bs, 1 H), 4.12 (dd, J ) 7.2, 14.7
Hz, 1 H), 6.56 (d, J ) 1.7 Hz, 1 H), 6.74 (dd, J ) 1.7, 8.6 Hz,
1 H), 6.77 (d, J ) 8.6 Hz, 1 H), 7.38 (d, J ) 8.1 Hz, 2 H), 7.84
(d, J ) 8.1 Hz, 2 H); 13C-NMR (67.8 MHz, CDCl3) δ 21.5, 23.0,
31.3, 32.7, 48.5, 51.6, 52.2, 55.8, 60.5, 63.9, 64.3, 66.9, 107.2,
109.6, 111.2, 119.0, 127.8, 129.7, 132.6, 134.3, 143.5, 147.9,
149.1; IR (Nujol) ν 3508 cm-1; MS m/z 503 (M+), 348, 99; HRMS
for C17H23NO3 289.1678, found 289.1699; [R]30 -53.0 (c 0.24,
D
CH3OH) (99% ee).
2-(3,4-Dim eth oxyp h en yl)-3-[(m eth oxyca r bon yl)oxy]-1-
cycloh exen e (22a ). To a stirred solution of 9 (261 mg, 1.12
mmol) and pyridine (0.36 mL, 4.46 mmol) in CH2Cl2 (6 mL)
was added methyl chloroformate (0.17 mL, 2.23 mmol) at 0
°C, and the mixture was stirred at room temperature for 3 h.
Water was added to the reaction mixture, and the mixture was
extracted with Et2O. The organic layer was washed with brine
and dried over Na2SO4. After removal of the solvent, the
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate, 3/1) to give 22a (323.2 mg, 99%) as a
calcd for C26H33NO7S 503.1978, found 503.1984; [R]28 +85.6
D
(c 1.15, CH3OH) (99% ee).
(3R,3a S,7a S)-1-(p -Tolylsu lfon yl)-3-for m yl-3a -(3,4-d i-
m eth oxyp h en yl)-6,6-(eth ylen ed ioxy)-2,3,3a ,4,5,6,7,7a -oc-
ta h yd r oin d ole. To a solution of 20 (42.9 mg, 0.085 mmol)
in CH2Cl2 (2.5 mL) was added Dess-Martin reagent (72.3 mg,
0.170 mmol) at 0 °C, and the mixture was stirred at the same
temperature for 2 h. The reaction mixture was diluted with
ethyl acetate, and the organic layer was washed with saturated
aqueous NaHCO3 and brine and dried over Na2SO4. After
removal of the solvent, the residue was purified by column
chromatography on silica gel (hexane/ethyl acetate, 1/1) to give
the aldehyde (39.0 mg, 91%): 1H-NMR (500 MHz, CDCl3) δ
1.65 (dd, J ) 4.3, 14.8 Hz, 1 H), 1.68-1.78 (m, 2 H), 2.11 (m,
2 H), 2.21 (m, 1 H), 2.45 (s, 3 H), 2.62 (d, J ) 14.8 Hz, 1 H),
2.77 (dd, J ) 8.6, 8.6 Hz, 1 H), 3.64 (dd, J ) 8.6, 11.8 Hz, 1
H), 3.80 (s, 3 H), 3.87 (s, 3 H), 3.82-4.00 (m, 4 H), 4.06 (dd, J
) 6.6, 14.1 Hz, 1 H) 4.22 (bs, 1 H), 6.68 (s, 1 H), 6.79-6.81 (m,
2 H), 7.35 (d, J ) 8.1 Hz, 2 H), 7.80 (d, J ) 8.1 Hz, 2 H), 9.47
(s, 1 H); 13C-NMR (126 MHz, CDCl3) δ 21.5, 25.5, 31.1, 33.6,
46.6, 49.8, 55.9, 55.9, 60.4, 64.0, 64.4, 66.1, 106.8, 109.6, 111.3,
118.8, 127.7, 129.7, 132.4, 134.5, 143.7, 148.4, 149.3, 199.6;
IR (Nujol) ν 1718 cm-1; MS m/z 501 (M+), 346, 99; HRMS calcd
for C26H31NO7S 501.1825, found 501,1827; [R]30D +78.6 (c 1.08,
CH3OH) (99% ee).
1
colorless solid: H-NMR (270 MHz, CDCl3) δ 1.64-1.94 (m, 3
H), 2.06-2.40 (m, 3 H), 3.71 (s, 3 H), 3.87 (s, 3 H), 3.88 (s, 3
H), 5.72-5.78 (m, 1 H), 6.25 (dd, J ) 4.8, 3.2 Hz, 1 H), 6.82
(brd, J ) 9.1 Hz, 1 H), 6.88-6.94 (m, 2 H); IR (Nujol) ν 1742,
1602, 1580, 1518, 1464, 1448, 1242, 1170, 1148, 1022 cm-1
;
MS m/z 292 (M+), 216. 201, 185, 151, 115, 91, 79. Anal. Calcd
for C16H20O5: C, 65.74; H, 6.90. Found: C, 65.55; H, 6.89.
Typ ica l P r oced u r e for P a lla d iu m -Ca ta lyzed En a n ti-
oselective Allylic Su bstitu tion of 22a (Ta ble 2, Ru n 10).
A solution of Pd2dba3·CHCl3 (6.8 mg, 6.5 µmol), (S)-BINAPO
(9.0 mg, 13.7 µmol), 22a (191 mg, 0.65 mmol), and 23 (152
mg, 0.72 mmol) in THF (6.5 mL) was stirred at room temper-
ature for 19 h. After removal of the solvent, the residue was
dissolved in Et2O, and the organic layer was washed with 10%
aqueous NaOH (three times), saturated aqueous NH4Cl, and
brine and dried over Na2SO4. After removal of the solvent,
the residue was purified by column chromatography on silica
gel (hexane/ethyl acetate, 5/1) to give 24 (223 mg, 80%, 86%
ee) as a colorless solid. A single recrystallization of 24 (4.35
g, 86% ee) from MeOH afforded the nearly enantiomerically
pure 24 (3.44 g, 99% ee, 79% recovery): mp 88-90 °C; 1H-NMR
(270 MHz, CDCl3) δ 1.56-1.98 (m, 4 H), 2.08-2.20 (m, 2 H),
2.40 (s, 3 H), 3.51 (dddd, J ) 16.2, 6.7, 1.2, 1.2 Hz, 1 H), 3.61
(dddd, J ) 16.2, 5.9, 1.2, 1.2 Hz, 1 H), 3.88 (s, 3 H), 3.90 (s, 3
H), 4.86 (ddd, J ) 10.1, 1.6, 1.2 Hz, 1 H), 4.96 (ddd, J ) 17.2,
1.6, 1.2 Hz, 1 H), 5.14-5.25 (m, 1 H), 5.31 (dddd, J ) 17.2,
10.1, 6.7, 5.9 Hz, 1 H), 6.12 (ddd, J ) 4.0, 3.9, 1.8 Hz, 1 H),
6.71 (d, J ) 8.3 Hz, 1 H), 6.79 (dd, J ) 8.3, 2.0 Hz, 1 H), 6.94
(d, J ) 2.0 Hz, 1 H), 7.20 (d, J ) 8.1 Hz 2 H), 7.60 (d, J ) 8.1
Hz, 2 H); IR (Nujol) ν 1638, 1600, 1582, 1518, 1466, 1342, 1330,
1250, 1164, 1024 cm-1; MS m/z 427 (M+), 272, 216, 201, 190,
(3aS,7aS)-1-(p-Tolylsu lfon yl)-3a-(3,4-dim eth oxyph en yl)-
6,6-(eth ylen edioxy)-2,3,3a,4,5,6,7,7a-octah ydr oin dole (21).
A solution of the above aldehyde (37.0 mg, 0.074 mmol) and
RhCl(PPh3)3 (95.9 mg, 0.104 mmol) in CH3CH2CN (3.0 mL)
was refluxed for 24 h. After being cooled to room temperature,
the mixture was diluted with ethanol and filtered. After
removal of the solvent, the residue was purified by column
chromatography on silica gel (hexane/ethyl acetate, 1/1) to give
21 (27.6 mg, 79%): 1H-NMR (270 MHz, CDCl3) δ 1.56-1.65
(m, 2 H), 1.69-1.88 (m, 3 H), 1.98-2.22 (m, 2 H), 2.36 (s, 3
H), 2.40 (m, 1 H), 3.23 (ddd, J ) 7.3, 10.0, 10.0 Hz, 1 H), 3.59
(ddd, J ) 1.8, 8.9, 8.9 Hz, 1 H), 3.80 (s, 3 H), 3.85 (s, 3 H),
3.85-3.93 (m, 4 H), 4.25 (dd, J ) 6.5, 10.0 Hz, 1 H), 6.55 (d,
J ) 8.4 Hz, 1 H), 6.62 (d, J ) 2.3 Hz, 1 H), 6.66 (dd, J ) 2.3,
8.4 Hz, 1 H), 7.00 (d, J ) 8.2 Hz, 2 H), 7.35 (d, J ) 8.2 Hz, 2
H); 13C-NMR (126 MHz, CDCl3) δ 11.4, 21.3, 30.8, 34.0, 39.8,
45.2, 47.8, 55.6, 55.6, 64.4, 64.5, 64.7, 108.0, 109.5, 110.3, 117.6,
126.6, 129.0, 135.6, 137.8, 147.6, 147.6, 148.6; IR (Nujol) ν
1508, 1456 cm-1; MS m/z 473 (M+)m 318, 99; HRMS calcd for
185, 151, 115, 91, 79; [R]30 -27.2 (c 1.02, CH3OH) (99% ee).
D
Anal. Calcd for C24H29NO4S: C, 67.42; H, 6.84; N, 3.28; S, 7.50.
Found: C, 67.31; H, 6.84; N, 3.23; S, 7.57.
Syn th esis of (S)-10 fr om (S)-24. To a sodium naphtha-
lenide solution in THF [ca. 0.17 M, prepared from sodium (739
mg, 32.1 mg atom) and naphthalene (4.53 g, 35.3 mmol) in
THF (190 mL)] was added a solution of (S)-24 (3.44 g, 8.04
mmol) in THF (20 mL) at -78 °C, and the mixture was stirred
at the same temperature for 50 min. Water was added to the
reaction mixture at -78 °C, and the solution was warmed to
room temperature. The aqueous layer was extracted with
Et2O, and the organic layer was washed with brine and dried
over Na2SO4. After removal of the solvent, the residue was
purified by column chromatography on silica gel (hexane/ethyl
C
25H31NO6S 473.1873, found 473.1898; [R]30 +58.5 (c 0.99,
D
CH2Cl2) (99% ee).
(3a S,7a S)-1-Met h yl-3a -(3,4-d im et h oxyp h en yl)-6-oxo-
2,3,3a ,4,5,6,7,7a -octa h yd r oin d ole ((-)-Mesem br in e, 1b).
To a solution of 21 (4.9 mg, 0.010 mmol) in THF (0.5 mL) was
added sodium naphthalenide (0.15 M solution in THF, 1.2 mL,
0.180 mmol) at -78 °C, and the mixture was stirred at -78
°C for 15 min. After the reaction mixture was quenched by
the addition of water, the aqueous layer was extracted with
ethyl acetate, and the organic layer was washed with brine
and dried over Na2SO4. After removal of the solvent, the
residue was dissolved in THF (0.5 mL), and BuLi (1.69 M in
hexane, 0.020 mL, 0.034 mmol) was added to this solution at
-78 °C. To this solution was added MeI (1.0 µL, 16.1 µmol)
at -78 °C, and the solution was stirred at the same temper-
ature for 1 h. The reaction mixture was quenched by the
addition of water, and the resulting mixture was extracted
with ethyl acetate. After removal of the solvent, the residue
was dissolved in 10% HCl and the aqueous solution was stirred
at room temperature for 18 h. The reaction mixture was made
acetate, 10/1-5/1-1/2) to give (S)-10 (1.57 g, 71%): [R]28
-128.0 (c 1.00, CH3OH) (99% ee).
D
Su p p or tin g In for m a tion Ava ila ble: Complete spectro-
scopic characterization, including reproduction of the 1H or 13C
NMR spectra of the compounds discussed (35 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
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J O9701187