Palladium-catalyzed intramolecular arylation of an anilide enolate, application to an efficient formal total synthesis of physovenine

Article abstract of DOI:10.1016/S0040-4039(02)00059-X

An expedient formal total synthesis of the calabar alkaloid physovenine was reported. The key step involves an oxindole synthesis via palladium-catalyzed intramolecular arylation of o-bromoanilide.

Full text of DOI:10.1016/S0040-4039(02)00059-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1363–1365
Palladium-catalyzed intramolecular arylation of an anilide
enolate, application to an efficient formal total
synthesis of physovenine
Tony Y. Zhang* and Hongbin Zhang†
Chemical Process Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center,
Indianapolis, IN 46285-4813, USA
Received 26 November 2001; accepted 4 January 2002
Abstract—An expedient formal total synthesis of the calabar alkaloid physovenine was reported. The key step involves an oxindole
synthesis via palladium-catalyzed intramolecular arylation of o-bromoanilide. © 2002 Elsevier Science Ltd. All rights reserved.
Physostigmine (1) and physovenine (2) are natural alka-
loids isolated from the seeds of Physostigma venenosum
(calabal beans). With interesting and potent biological
properties, such as anticholinergic and miotic activi-
ties,1 these compounds and derivatives have been found
to be clinically useful for relieving symptoms of
Alzheimer’s disease. As a result of their biological
activities and unique structures, they have been popular
targets for total syntheses and many innovative syn-
thetic methodologies have been developed for their
preparation.2 Reported herein are the results from our
recent study on the construction of pivotal intermediate
3 using palladium-catalyzed intramolecular arylation of
amides, a strategy which is similar to Overman’s Heck
reaction approach3 but with a saturated substrate
butananilide 4 instead of butenanilide 5.
The direct coupling of hard enolates with aromatic
halides has been a reaction of limited scope until pio-
neering developments by the Buldwald, Hartwig and
other groups.4 In particular, oxindoles have been pre-
pared by this methodology.5 During the course of our
work to prepare a variety of oxindoles for medicinal
chemistry, we were intrigued by the possibility of utiliz-
ing these reactions for natural alkaloid synthesis.
The o-bromobutananilde 9 was prepared in a straight-
forward manner (Scheme 1). Subjecting this compound
to a mixture of KN(SiMe3)2, R-BINAP6 and a catalytic
amount of Pd(OAc)2 acetate in toluene afforded oxin-
dole 10 in 24% yield, with concomitant formation of a
significant amount of elimination product 1,3-dimethyl-
3-vinyl-5-methoxy-2-oxindole. However, when the reac-
Me
Me
Me
Me
N
O
N
O
H
O
H
N
Me
O
H
O
N
H
N
Me
Me
1 (-) Physostigmine
2 (-) Physovenine
OR'
Me
R'O
I
OR'
R'O
Br
N
OR'
O
R'O
O
O
N
Me
N
Me
Me
Me
Me
4
3
5
* Corresponding author. E-mail: zhang@lilly.com
† Present address: Department of Chemistry, Yunan University, Kunming, Yunan, China.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00059-X

1364
T. Y. Zhang, H. Zhang / Tetrahedron Letters 43 (2002) 1363–1365
1. TBDMSCl
Et3N/ CH2Cl2
MeO
Br
MeO
Br
O
Me3Al, Toluene
95%
OH
2. NaH, CH3I/ THF
81%
N
H
8
NH2
Me
O
6
7
Me
O
Me
MeO
Br
OTBDMS
O
MeO
Pd(OAc)2/R-BINAP
LiN(TMS)2, THF
OTBDMS
O
N
N
60% 11% ee
Me Me
Me
10
9
Me
Me
HN
OH
Me
MeO
LiAlH4
O
Bu4NF/ THF
97%
10
O
O
Ref 11
N
O
H
N
Me
Me
2 (±)-(Physovenine)
11
Scheme 1.
tion was conducted in THF instead of toluene and
using LiN(SiMe3)2 as a base, 10 was isolated in 60%
yield, albeit with low ee.7 In addition to solvent, the
reaction was also sensitive to the ligand employed
(Table 1). Surprisingly, some of the ligands reported to
be useful in promoting oxindole formation5 proved to
be unsatisfactory for 9.
References
1. For reviews on the biological activities of the compounds,
see: (a) Triggle, D. J.; Mitchell, J. M.; Filler, R. CNS Drug
Rev. 1998, 4, 87; (b) Giacobini, E. Neurochem. Int. 1998,
32, 413; (c) Brufani, M.; Castellano, C.; Marta, M.; Mur-
roni, F.; Oliverio, A.; Pagella, P. G.; Pavone, F.; Pomponi,
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Cholinesterase Inhib. 1988, 343; (d) Granacher, R. P.;
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12, 433; (g) Triggle, D. J.; Mitchell, J. M.; Filler, R. CNS
Drug Rev. 1998, 4, 87.
Compound 10 was deprotected uneventfully to the free
alcohol 11, which has been previously converted to
physovenine via straightforward transformations, as
demonstrated by Clark et al.8 The enantiomerically
pure form of 11 was also reported by Overman and
co-workers in their enantioselective synthesis of
phytosigmine.3
2. For selected total synthesis of phytostigamine and
physovenine, (a) Overman, L. E. Pure Appl. Chem. 1994,
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In summary, we have demonstrated the utility of palla-
dium-catalyzed oxindole formation through intramolec-
ular arylation of o-bromoanilide. This has been applied
to the formal total synthesis of physovenine. While the
current enantioselectivity is relatively low, the potential
of a more suitable chiral ligand affording higher ee’s is
being explored.
Table 1. Cyclization of o-bromoanilide 9 to oxindole 10
Catalysts
Reaction
10
conditions
BINAP, Pd(OAc)2 or
Pd2(dba)3
LiN(TMS)2, THF, 50–60% (isolated
68°C
yield)
BINAP, Pd2(dba)3
KN(TMS)2,
toluene, 70°C
B5%, complex
mixture
DPPF, Pd2(dba)3
t-Bu3P, Pd2(dba)3
No catalyst
LiN(TMS)2, THF, B1%
68°C
LiN(TMS)2, THF, B1%
68°C
LiN(TMS)2, THF, B1%
68°C

T. Y. Zhang, H. Zhang / Tetrahedron Letters 43 (2002) 1363–1365
1365
3. Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120,
tert-butyldimethylsiloxyethyl)oxindole (10). Palladium ace-
tate (23 mg, 0.1 mmol) and R-2,2%-bis(diphenylphos-
phino)-1,1%-binaphthyl (78 mg, 0.125 mmol) in dry THF
(20 mL) were stirred at room temperature under nitrogen
for 60 minutes. The bromoanilide (9, 430 mg, 1 mmol) in
THF (5 mL) was added via a syringe. LiN(TMS)2 in THF
(1.0 M, 2 mL, 2 mmol) was added dropwise and the
resultant dark-purple mixture was stirred at 68°C for 16 h.
The reaction mixture was cooled to room temperature
before treating with 1N HCl (2 mL) and water (50 mL).
The mixture was extracted with ethyl acetate (3×25 mL).
The combined organic phases were washed with brine (20
mL) and dried over MgSO4. After removal of the solvents,
the residue was chromatographed on silica gel (hep-
tane:ethyl acetate=8:1“4:1) to afford compound 10 (210
mg, 60%) as pale yellow oil: IR (cm−1) 3016(m); 2951(m);
2928(m); 2854(w); 1696(s); 1597(w); 1499(m); 1470(m);
6500.
,
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1
1288(w); 1249(w); 1111(m); 1085(m); 1030(w); 835(m). H
NMR (300 MHz, CDCl3) l 6.79 (1H, dd, J=0.9, 3.0 Hz);
6.78 (1H, dd, J=3.0, 8.4 Hz); 6.70 (1H, dd, J=0.6, 8.4
Hz); 3.79 (3H, s, OCH3); 3.35 (2H, m); 3.16 (3H, s,
NCH3); 2.21 (1H, ddd, J=7.4, 7.5, 13.5 Hz); 1.94 (1H,
ddd, J=5.4, 6.9, 13.8 Hz); 1.34 (3H, s, CH3); 0.75 (9H, s,
3×CH3); −0.13 (6H, s, 2×CH3). 13C NMR (75 MHz,
CDCl3) l 179.81; 155.70; 136.67; 134.93; 111.52; 110.34;
107.98; 59.53; 55.81; 47.01; 40.40; 26.33; 25.88; 24.98;
18.24; −5.49. MS m/z 350 (M++1); 271; 119. HRMS (FIA):
calcd for C19H32NO3Si (M++1) 350.2152. Found 350.2138.
8. Clark, A. J.; Jones, K. Tetrahedron 1992, 48, 6875.
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(b) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J.
Org. Chem. 1998, 63, 6546.
6. R-BINAP: R-2,2%-bis(diphenylphosphino)-1,1%-binaphthyl:
Takaya, H.; Mashima, K.; Koyano, K.; Yagi, M.;
Kumobayashi, H.; Taketomi, T.; Akutagawa, S.; Noyori,
R. J. Org. Chem. 1986, 51, 629.
7. Experimental procedure: 1,3-Dimethyl-5-methoxy-3-(2%-