A new efficient route to (±)-physostigmine and (±)-physovenine by means of 5-exo selective aryl radical cyclization of o-bromo-N- acryloylanilides

Article abstract of DOI:10.1016/S0040-4020(00)00051-X

Bu₃SnH-mediated aryl radical cyclization of o-bromo-N-acryloylanilides 16 and 17 proceeded in a 5-exo manner exclusively to give, in high yields, oxindoles 3 and 4, the key intermediates for the synthesis of (±)- physostigmine and (±)-physoveni

Full text of DOI:10.1016/S0040-4020(00)00051-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 1469–1473
A New Efficient Route to (^)-Physostigmine and (^)-Physovenine
by Means of 5-exo Selective Aryl Radical Cyclization
of o-Bromo-N-acryloylanilides
*
Hiroyuki Ishibashi, Tetsuya Kobayashi, Noriko Machida and Osamu Tamura
Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi, Kanazawa 920-0934, Japan
Received 16 December 1999; accepted 17 January 2000
Abstract—Bu3SnH-mediated aryl radical cyclization of o-bromo-N-acryloylanilides 16 and 17 proceeded in a 5-exo manner exclusively to
give, in high yields, oxindoles 3 and 4, the key intermediates for the synthesis of (^)-physostigmine and (^)-physovenine, respectively.
᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results and Discussion
Physostigmine (1) and physovenine (2), the alkaloids from
the African Calabar bean, have interesting physiological
effects such as anticholinergic and miotic activities.1,2
More importantly, physostigmine and its derivatives have
recently been found to be useful for relieving symptoms of
Alzheimer’s disease.3 Therefore, the synthesis of this class
of alkaloids has received renewed attention. The first synth-
esis of (^)-physostigmine was reported by Julian and Pikl4
using the 5-ethoxy congener of 3,3-disubstituted oxindole 3
as an intermediate, and thereafter a number of methods have
been reported for the preparation of (^)- and (Ϫ)-3 and their
analogs5 and for the improvement in synthesis of physostig-
mine from these intermediates.6 Herein we report a new
synthesis of (^)-3 using 5-exo selective aryl radical cycli-
zation of o-bromo-N-acryloylanilides 16 as a key step. An
application of this method to the synthesis of (^)-4, an
intermediate for the synthesis of (^)-physovenine, is also
presented (Scheme 1).
We began our investigation by examining the cyclization of
7. The Horner–Emmons reaction of anilide 6, prepared by
acylation of o-iodo-N-methylaniline (5)7 with pyruvyl
chloride8 (91%), with diethylphosphonoacetonitrile
occurred effectively to give compound 7 in 95% yield.
1
The H NMR spectrum of 7 showed it to be a mixture of
two isomers in a ratio of ca. 6:1, although it is unknown
whether the mixture consists of the stereoisomers of olefin
or the rotamers of amide (Scheme 2).
When a solution of anilide 7 in boiling benzene was treated
slowly with a mixture of Bu3SnH and AIBN, the 3,3-disub-
stituted oxindole (^)-8 was obtained in 89% yield as a sole
product. The spectral properties of (^)-8 thus obtained were
identical to the reported values.5h In the light of the previous
work on other Bu3SnH-mediated aryl radical cyclizations of
anilides, the present result is of great interest. Thus, the
anilides 9 having a methyl substituent on the carbon a to
Scheme 1.
Keywords: anilides; cyclization; indolines/indolinones; radicals and radical reactions.
* Corresponding author. Tel.: ϩ81-76-234-4474; fax: ϩ81-76-234-4476; e-mail: ishibashi@dbs.p.kanazawa-u.ac.jp
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00051-X

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H. Ishibashi et al. / Tetrahedron 56 (2000) 1469–1473
Scheme 2. (a) MeCOCOCl, pyridine, CH2Cl2; (b) (EtO)2P(O)CH2CN, BuLi, THF, Ϫ78ЊC to r.t.; (c) Bu3SnH, AIBN, benzene, reflux.
the carbonyl group were reported to usually provide
radical precursor 16. This compound was then treated
with Bu3SnH and AIBN in boiling benzene to give the
expected oxindole (^)-3 in 98% yield.
mixtures of the 5-exo and the 6-endo cyclization products
10 (major) and 11 (minor).9 This is also the case for cycli-
10b
zations with Co(II)–RMgBr,10a SmI2
or Co(I)–salen
complex.11 The exclusive formation of oxindole 8 from 7
may be rationalized by assuming that the radical intermediate
A formed by 5-exo cyclization of the aryl radical generated
from 7 is highly stabilized by an adjacent nitrile group
(Scheme 3).
Next, we examined the cyclization of the ester congener 17,
which was prepared by reaction of 15 with methyl dimethyl-
phosphonoacetate in 88% yield (Scheme 4). When a boiling
solution of 17 in benzene was treated with Bu3SnH and
AIBN, oxindole-3-acetic ester (^)-4, whose physical data
were identical with those of the literature values,13 was
obtained in 87% yield as a sole product. The exclusive
formation of (^)-4 from 17 might also be ascribed to a
radical stabilizing effect of the ester group similar to that
of the cyano group for the radical intermediate A. Since
compound (^)-4 has already been converted into
(^)-physovenine (2),13 the whole sequence of the reactions
described herein means in a formal sense a synthesis of
(^)-physovenine.
Given the success in forming oxyindole 8 from the 5-exo
selective aryl radical cyclization of 7, we then applied the
method to the synthesis of the key intermediate (^)-3 for
(^)-physostigmine.
The starting 2-bromo-4-methoxyaniline (12)12 was prepared
by treating p-anisidine with Br2 in AcOH in 44% yield. This
compound was then converted into the corresponding
N-methyl derivatives (14) (Scheme 4) using a procedure
similar to that reported for the synthesis of 8 from o-iodo-
aniline.7 Thus, condensation of 12 with formaldehyde and
succinimide in boiling EtOH gave 13 in 84% yield, which
was reduced by NaBH4 in DMSO to give 14 in 91% yield.
Sequential treatment of 14 with pyruvyl chloride followed
by diethylphosphonoacetonitrile furnished the requisite
Thus, we revealed that anilides 16 and 17 having a nitrile or
an ester group at the terminus of their acryloyl group under-
went aryl radical cyclization in a 5-exo manner with a high
degree of efficiency to enable a straightforward synthesis of
the key intermediates (^)-3 and (^)-4 for (^)-physostig-
mine14,15 and (^)-physovenine.16,17
Scheme 3.
Scheme 4. (a) 36% HCHO, succinimide, EtOH, reflux; (b) NaBH4, DMSO, 50ЊC; (c) MeCOCOCl, pyridine, CH2Cl2; (d) (EtO)2P(O)CH2CN (for 16),
(MeO)2P(O)CH2CO2Me (for 17), BuLi, THF, Ϫ78ЊC to r.t.; (e) Bu3SnH, AIBN, benzene, reflux.

H. Ishibashi et al. / Tetrahedron 56 (2000) 1469–1473
1471
Experimental
solution were added to the residue, and the whole was
vigorously stirred at room temperature for 1 h. The organic
phase was separated and the aqueous phase was further
extracted with Et2O. The combined organic phase was
washed with brine, dried (MgSO4) and concentrated. The
residue was chromatographed on silica gel (hexane–AcOEt,
2:1) to give 85h (86.3 mg, 89%) as an oil: IR (CHCl3) n
Melting points are uncorrected. IR spectra were recorded
with a shimadzu FTIR-8100 spectrophotometer. H NMR
1
spectra were measured on a JEOL JNM-GSX 500
(500 MHz), a JEOL JNM-EX 270 (270 MHz), or a Hitachi
R-1200 (60 MHz) spectrometer for solutions in CDCl3. d
values quoted are relative to tetramethylsilane. High reso-
lution mass spectra (HRMS) were obtained with a JEOL
JMS-SX 102 instrument. Column chromatography was
performed on Silica gel 60 PF254 (Nacalai Tesque) under
pressure.
1
2255, 1715 cmϪ1; H NMR (500 MHz) d 1.53 (3 H, s),
2.56 (1 H, d, Jˆ16.5 Hz), 2.85 (1 H, d, Jˆ16.5 Hz), 3.25
(3 H, s), 6.91 (1 H, d, Jˆ7.3 Hz), 7.14 (1 H, td, Jˆ7.3,
1.0 Hz), 7.36 (1 H, td, Jˆ7.3, 1.0 Hz), 7.48 (1 H, d,
Jˆ7.3 Hz).
2-Bromo-4-methoxyaniline (12). To a solution of p-anisi-
dine (5.0 g, 40.6 mmol) in AcOH (125 ml) was added drop-
wise a solution of bromine (6.51 g, 40.7 mmol) in AcOH
(125 ml) during 2.5 h. After the solvent had been evaporated
off, a 2 N aq. NaOH solution (100 ml) was added to the
residue, and the whole was extracted with AcOEt. The
extract was washed successively with an aq. Na2S2O3 solu-
tion (50 ml) and brine (50 ml), dried (MgSO4), and concen-
trated. The residue was chromatographed on silica gel
(hexane–AcOEt, 7:1) to give 1212 (3.58 g, 44%) as an oil:
1H NMR (270 MHz) d 3.72 (3 H, s), 3.75 (2 H, br s), 6.70 (1
H, d, Jˆ6.3 Hz), 6.73 (1 H, dd, Jˆ6.3, 2.0 Hz), 6.99 (1 H, d,
Jˆ2.0 Hz).
Pyruvyl chloride. Dichloromethyl methyl ether (8.34 g,
72.5 mmol) was added dropwise to pyruvic acid (6.32 g,
71.8 mmol) at room temperature, and the mixture was
heated at 50ЊC for 30 min. The reaction mixture was
distilled to give pyruvyl chloride (4.02 g, 53%), bp 50–
52ЊC/130 mmHg (lit.8 bp 53ЊC/126 mmHg).
2-Iodo-N-methylpyruvanilide (6). A solution of pyruvyl
chloride (53.4 mg, 0.50 mmol) in CH2Cl2 (1.5 ml) was
added dropwise to a solution of 2-iodo-N-methylaniline
(5)7 (79.9 mg, 0.36 mmol) and pyridine (47.8 mg,
0.57 mmol) in CH2Cl2 (1.5 ml) at 0ЊC, and the mixture
was stirred at room temperature for 2 h. A saturated aq.
NaHCO3 solution (30 ml) was added to the reaction mixture
and the whole was extracted with AcOEt. The extract was
washed with brine, dried (MgSO4), and concentrated. The
residue was chromatographed on silica gel (hexane–AcOEt,
2:1) to give 6 (98.7 mg, 91%), mp 88–90ЊC (from hexane–
N-(2-Bromo-4-methoxyanilinomethyl)succinimide (13).
To a solution of 12 (2.0 g, 9.9 mmol) in EtOH (15 ml)
were added successively a formaldehyde solution (36%
w/w) (1.0 ml) and succinimide (1.18 g, 11.95 mmol), and
the mixture was heated at reflux for 4 h. An additional
formaldehyde solution (0.5 ml) was added to the mixture,
and the mixture was further heated at reflux for 1.5 h. After
cooling the mixture at 0ЊC, the precipitates were collected
by suction to give 13 (1.908 g). The filtrate was con-
centrated, and the residue was chromatographed on silica
gel (CHCl3) to give an additional 13 (711 mg, total 84%
yield), mp 123–124ЊC (from EtOH–H2O): IR (CHCl3) n
;
AcOEt): IR (CHCl3) n 1725, 1655 cmϪ1 1H NMR
(60 MHz) d 2.35 (3 H, s), 3.25 (3 H, s), 6.70–7.60 (3 H,
m, ArH), 7.85 (1 H, d, Jˆ8.0 Hz). Anal. Calcd for
C10H10INO2: C, 39.63; H, 3.33; N, 4.62. Found: C, 39.54;
H, 3.24; N, 4.48.
20-Iodo-N-methyl-3-cyano-2-methylpropenanilide (7). BuLi
(1.57 M hexane solution) (1.53 ml, 2.41 mmol) was added
to a solution of diethylphosphonoacetonitrile (417 mg,
2.45 mmol) in THF (6 ml) during 3 min at Ϫ78ЊC, and the
mixture was stirred at the same temperature for 20 min. To
this solution was added a solution of 6 (532 mg, 1.75 mmol)
in THF (6 ml), and the mixture was stirred at room tempera-
ture for 2 h. A saturated aq. NH4Cl solution (50 ml) was
added to the reaction mixture, and the whole was extracted
with AcOEt. The extract was washed with brine, dried
(MgSO4), and concentrated. The residue was chromato-
graphed on silica gel (hexane–AcOEt, 1:1) to give 7
(542 mg, 95%) as an oily mixture of two isomers in a
1
3425, 1705 cmϪ1; H NMR (270 MHz) d 2.67 (4 H, s),
3.72 (3 H, s), 5.00 (2 H, d, Jˆ7.3 Hz), 5.10 (1 H, t,
Jˆ7.3 Hz), 6.80 (1 H, dd, Jˆ9.0, 2.7 Hz), 7.02 (1 H, d,
Jˆ9.0 Hz), 7.03 (1 H, d, Jˆ2.7 Hz). Anal. Calcd for
C12H13BrN2O3: C, 46.03; H, 4.18; N, 8.95. Found: C,
45.87; H, 4.20; N, 8.82.
2-Bromo-4-methoxy-N-methylaniline (14). To a solution
of 13 (233.8 mg, 0.75 mmol) in dimethyl sulfoxide (0.7 ml)
was added sodium borohydride (28.7 mg, 0.76 mmol) by
portions, and the mixture was stirred at 120ЊC for 30 min.
After cooling the mixture, water (30 ml) was added, and the
whole was extracted with AcOEt. The extract was washed
with brine, dried (MgSO4), and concentrated. The residue
was chromatographed on silica gel (hexane–AcOEt, 7:1) to
give 14 (146.4 mg, 91%) as an oil: IR (CHCl3) n 3430,
1
ratio of ca. 6:1: IR (CHCl3) n 2225, 1655 cmϪ1; H NMR
(270 MHz) d 1.93 (1/7×3 H, d, Jˆ1.7 Hz), 2.07 (6/7×3 H,
d, Jˆ1.0 Hz), 3.26 (6/7×3 H, s), 3.32 (1/7×3 H, s), 5.12 (1/7
H, q, Jˆ1.7 Hz), 5.46 (6/7 H, q, Jˆ1.0 Hz), 7.05–7.66 (3 H,
m), 7.90 (1 H, dd, Jˆ7.9, 1.7 Hz). HRMS Calcd for
C12H11IN2O: 325.9916. Found: 325.9918.
1
1515 cmϪ1; H NMR (270 MHz) d 2.83 (3 H, s), 3.71 (3
H, s), 3.95 (1 H, br s), 6.55 (1 H, d, Jˆ8.9 Hz), 6.80 (1 H, dd,
Jˆ8.9, 3.0 Hz), 7.04 (1 H, d, Jˆ3.0 Hz). Anal. Calcd for
C8H10BrNO: C, 44.47; H, 4.66; N, 6.48. Found: C, 44.57; H,
4.74; N, 6.29.
2,3-Dihydro-1,3-dimethyl-2-oxo-1H-indole-3-acetonitrile
(8). To a boiling solution of 7 (158.2 mg, 0.485 mmol) in
benzene (48 ml) was added dropwise a solution of Bu3SnH
(189 mg, 0.65 mmol) and AIBN (10.1 mg, 0.06 mmol) in
benzene (24 ml) via a syringe during 1 h. After evaporation
of the solvent, Et2O (50 ml) and an 8% aq. KF (50 ml)
2-Bromo-4-methoxy-N-methylpyruvanilide (15). Using a
procedure similar to that described above for the preparation

1472
H. Ishibashi et al. / Tetrahedron 56 (2000) 1469–1473
of 6, aniline 14 (127.6 mg, 0.59 mmol) was treated with
pyruvyl chloride (92.3 mg, 0.87 mmol) in the presence of
pyridine (81.6 mg, 0.97 mmol) in CH2Cl2 (3 ml). After
work-up, the crude material was chromatographed on silica
gel (hexane–AcOEt, 2:1) to give 15 (157.2 mg, 93%) as an
oil: IR (CHCl3) n 1720, 1655 cmϪ1; 1H NMR (270 MHz) d
2.30 (3 H, s), 3.24 (3 H, s), 3.81 (3 H, s), 6.85 (1 H, dd,
Jˆ8.6, 3.0 Hz), 7.12 (1 H, d, Jˆ3.0 Hz), 7.22 (1 H, d,
Jˆ8.6 Hz). Anal. Calcd for C11H12BrNO3: C, 46.18; H,
4.23; N, 4.90. Found: C, 45.94; H, 4.27; N, 4.76.
described above for the preparation of 8, compound 17
(105.3 mg, 0.31 mmol) was treated with Bu3SnH
(114.2 mg, 0.39 mmol) in the presence of AIBN (6.2 mg,
0.04 mmol) in benzene (45 ml). After work-up, the crude
material was chromatographed on silica gel (hexane–
AcOEt, 1:1) to give 4 (70.1 mg, 87%), mp 83–84ЊC (from
AcOEt–petroleum ether) (lit.13 mp 83–84ЊC): IR (CHCl3) n
1740, 1700 cmϪ1; 1H NMR (270 MHz) d 1.37 (3 H, s), 2.82
(1 H, d, Jˆ16.5 Hz), 3.00 (1 H, d, Jˆ16.5 Hz), 3.23 (3 H, s),
3.48 (3 H, s), 3.79 (3 H, s), 6.75–6.85 (3 H, m).
20-Bromo-40-methoxy-N-methyl-3-cyano-2-methylpro-
penanilide (16). Using a procedure similar to that described
above for the preparation of 7, diethylphosphonoacetonitrile
(90.1 mg, 0.53 mmol) was treated with BuLi (1.57 M
hexane solution) (0.3 ml, 0.47 mmol) and then with
compound 15 (107.1 mg, 0.38 mmol). After work-up, the
crude material was chromatographed on silica gel (hexane–
AcOEt, 1:1) to give 16 (82.8 mg, 72%) as an oily mixture of
two isomers in a ratio of ca. 9:5: IR (CHCl3) n 2225,
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports
and Culture of Japan.
References
1
1650 cmϪ1; H NMR (270 MHz) d 1.93 (5/14×3 H, d,
Jˆ1.7 Hz), 2.05 (9/14×3 H, d, Jˆ1.3 Hz), 3.23 (9/14×3
H, s), 3.29 (5/14×3 H, s), 3.83 (5/14×3 H, s), 3.84 (9/
14×3H, s), 5.11 (5/14 H, q, Jˆ1.7 Hz), 5.40 (9/14 H, q,
Jˆ1.3 Hz), 6.80–7.20 (2ϩ9/14 H, m), 7.52 (5/14 H, d,
Jˆ8.6 Hz). Anal. Calcd for C13H13BrN2O2: C, 50.51; H,
4.24; N, 9.06. Found: C, 50.29; H, 4.35; N, 8.90.
1. Takano, S.; Ogasawara, K. The Alkaloids 1989, 36, 225.
2. Brossi, A. J. Med. Chem. 1990, 33, 2311.
3. Grieg, N. H.; Pei, X.-F.; Soncrant, T. T.; Ingram, D. K.; Brossi,
A. Med. Res. Rev. 1995, 15, 3.
4. Julian, P. L.; Pikl, J. J. Am. Chem. Soc. 1935, 57, 563 (see also
p. 755).
5. For syntheses of racemic and optically acitive 3 and their
5-alkoxy derivatives, see (a) Robinson, B. J. Chem. Soc. 1965,
3336. (b) Lee, T. B. K.; Wong, G. S. K. J. Org. Chem. 1991, 56,
872. (c) Yu, Q.-S.; Luo, W.-M.; Li, Y.-Q.; Brossi, A. Heterocycles
1993, 36, 1279. (d) Yu, Q.-S.; Lu, B.-Y.; Pei, X.-F. Heterocycles
1994, 39, 519. (e) Pei, X.-F.; Bi, S. Heterocycles 1994, 39, 357. (f)
Pallavicini, M.; Valoti, E.; Villa, L.; Lianza, F. Tetrahedron:
Asymmetry 1994, 5, 111. (g) Pei, X.-F.; Brossi, A. Heterocycles
Methyl 3-(20-Bromo-40-methoxyphenyl-N-methylcarba-
moyl)-3-methyl-2-butenoate (17). Using a procedure
similar to that described above for the preparation of 7,
methyl dimethylphosphonoacetate (84.5 mg, 0.46 mmol)
was treated with BuLi (1.50 M hexane solution) (0.3 ml,
0.45 mmol) and then with compound 15 (100.1 mg,
0.35 mmol). After work-up, the crude material was chromato-
graphed on silica gel (hexane–AcOEt, 1:1) to give 17
(105.3 mg, 88%) as an oily mixture of three isomers in a
ratio of ca. 10:5:3: IR (CHCl3) n 1715, 1640 cmϪ1; 1H NMR
(270 MHz) d 1.85 (10/18×3 H, d, Jˆ1.5 Hz), 2.14 (5/18×3
H, d, Jˆ1.5 Hz), 2.22 (3/18×3 H, d, Jˆ1.5 Hz), 3.16 (3/
18×3 H, s), 3.23 (5/18×3 H, s), 3.28 (10/18×3 H, s), 3.63
(5/18×3 H, s), 3.76 (13/18×3 H, s), 3.81 (3 H, s), 5.55 (10/18
H, q, Jˆ1.5 Hz), 5.87 (3/18 H, q, Jˆ1.5 Hz), 5.90 (5/18 H,
´
1995, 41, 2823. (h) Morales-Rıos, M. S.; Bucio, M. A.; Joseph-
Nathan, P. Tetrahedron 1996, 52, 5339.
6. Yu, Q.-S.; Brossi, A. Heterocycles 1988, 27, 1709. See also
Refs. 5b, 5e and 5f.
7. Kihara, M.; Iwai, Y.; Nagao, Y. Heterocycles 1995, 41, 2279.
8. Ottenheijm, H. C. J.; de Man, J. H. M. Synthesis 1975, 163.
9. Jones, K.; Thompson, M.; Wright, C. J. Chem. Soc., Chem.
Commun. 1986, 115; Clark, A. J.; Jones, K. Tetrahedron Lett.
1989, 30, 5485; Jones, K.; Storey, J. M. D. J. Chem. Soc., Chem.
Commun. 1992, 1766; Jones, K.; Wilkinson, J.; Ewin, R.
Tetrahedron Lett. 1994, 35, 7673; Cossy, J.; Cases, M.; Pardo,
D. G. Tetrahedron Lett. 1998, 39, 2331; Jones, K.; Brunton,
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10. (a) Clark, A. J.; Davies, D. I.; Jones, K.; Millbanks, C. J. Chem.
Soc., Chem. Commun. 1994, 41. (b) Cabri, W.; Candiani, I.;
Colombo, M.; Franzoi, L.; Bedeschi, A. Tetrahedron Lett. 1995,
36, 949.
11. Jones reported that anilide I, upon treatment with Co(I)–salen
complex, gave a mixture of the 5-exo cyclization product II and the
6-endo cyclization product III in a ratio of 3:1 and in 40%
combined yield.12 The product II was converted into IV, the inter-
mediate for the synthesis of physovenine (2) (Scheme 5).
12. Clark, A. J.; Jones, K. Tetrahedron 1992, 48, 6875.
13. Luo, Y.-L.; Yu, Q.-S.; Chrisey, L.; Brossi, A. Heterocycles
1990, 31, 283.
q, Jˆ1.5 Hz), 6.70–7.60 (3 H, m). HRMS Calcd for
79
C14H BrNO4: 341.0263. Found: 341.0275.
16
2,3-Dihydro-5-methoxy-1,3-dimethyl-2-oxo-1H-indole-3-
acetonitrile (3). Using a procedure similar to that described
above for the preparation of 8, compound 16 (99.2 mg,
0.32 mmol) was treated with Bu3SnH (114.6 mg,
0.39 mmol) in the presence of AIBN (6.4 mg, 0.04 mmol)
in benzene (48 ml). After work-up, the crude material was
chromatographed on silica gel (hexane–AcOEt, 1:1) to give
3 (72.3 mg, 98%), mp 71–73ЊC (from Et2O–hexane) (lit.5h
1
mp 70–72ЊC): IR (CHCl3) n 2255, 1710 cmϪ1; H NMR
(270 MHz) d 1.52 (3 H, s), 2.55 (1 H, d, Jˆ16.5 Hz), 2.84
(1 H, d, Jˆ16.5 Hz), 3.22 (3 H, s), 3.82 (3 H, s), 6.81 (1 H, d,
Jˆ8.6 Hz), 6.86 (1 H, dd, Jˆ8.6, 2.0 Hz), 7.09 (1 H, d,
1
Jˆ2.0 Hz). The H NMR spectral data were identical with
those reported.5f
14. For total or formal syntheses of (Ϫ)-physostigmine, see (a)
Takano, S.; Goto, E.; Hirama, M.; Ogasawara, K. Chem Pharm.
Bull. 1982, 30, 2641. (b) Takano, S.; Moriya, M.; Iwabuchi, Y.;
Methyl 2,3-dihydro-5-methoxy-1,3-dimethyl-2-oxo-1H-
indole-3-acetate (4). Using a procedure similar to that

H. Ishibashi et al. / Tetrahedron 56 (2000) 1469–1473
1473
Scheme 5.
Ogasawara, K. Chem. Lett. 1990, 109. (c) Takano, S.; Moriya, M.;
Ogasawara, K. J. Org. Chem. 1991, 56, 5982. (d) Node, M.;
Itoh, A.; Masaki, Y.; Fuji, K. Heterocycles 1991, 32, 1705. (e)
Marino, J. P.; Bogdan, S.; Kimura, K. J. Am. Chem. Soc. 1992,
114, 5566. (f) Pallavicini, M.; Valoti, E.; Villa, L.; Resta, I.
Tetrahedron: Asymmetry 1994, 5, 363. (g) Node, M.; Hao, X.-J.;
Nishide, K.; Fuji, K. Chem. Pharm. Bull. 1996, 44, 715. (h) Fuji,
K.; Kawabata, T.; Ohmori, T.; Shang, M.; Node, M. Heterocycles
1998, 47, 951. (i) Ashimori, A.; Matsuura, T.; Overman, L. E.;
Poon, D. J. J. Org. Chem. 1993, 58, 6949. (j) Matsuura, T.;
Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6500.
See also Ref. 5b.
15. For recent total or formal syntheses of (^)-physostigmine by
way of the intermediates other than 3, see (a) Smith, R.;
Livinghouse, T. Tetrahedron 1985, 41, 3559. (b) Shishido, K.;
Shitara, E.; Komatsu, H.; Hiroya, K.; Fukumoto, K.; Kametani, T.
J. Org. Chem. 1986, 51, 3007.
16. For total syntheses of (Ϫ)-physovenine, see Refs. 14c and 14j.
17. For total syntheses of (^)-physovenine, see Refs. 13 and 15b.