Efficient synthesis of (+/-)-erysotramidine using an NBS-promoted cyclization reaction of a hexahydroindolinone derivative.

Article abstract of DOI:10.1021/ol036106r

An NBS-promoted intramolecular electrophilic aromatic substitution reaction of a hexahydroindolinone derivative was used to assemble the tetracyclic core of the erythrinane skeleton. The resulting cyclized product was transformed into (+/-)-erysotramidine

Full text of DOI:10.1021/ol036106r

ORGANIC
LETTERS
2
003
Vol. 5, No. 26
067-5070
Efficient Synthesis of (±)-Erysotramidine
Using an NBS-Promoted Cyclization
Reaction of a Hexahydroindolinone
Derivative
5
Hyoung Ik Lee, Michael P. Cassidy, Paitoon Rashatasakhon, and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received October 28, 2003
ABSTRACT
An NBS-promoted intramolecular electrophilic aromatic substitution reaction of a hexahydroindolinone derivative was used to assemble the
tetracyclic core of the erythrinane skeleton. The resulting cyclized product was transformed into (±)-erysotramidine in three additional steps.
The cyclization reaction is also successful using variously substituted aryl and furanyl bicyclic lactams under acidic conditions.
5
The Erythrina family of alkaloids are a well-known class of
natural products that have received considerable attention
over the past few decades. Many members of this family
constructed by intramolecular cyclization; (2) C-ring forma-
6
tion by electrophilic substitution; (3) A-ring formation by
an intramolecular aldol reaction; (4) A-ring formation from
a benzoindolizidine fragment; (5) B-ring formation utilizing
a C-5 spiro-isoquinoline system; (6) B- and C-ring formation
1
7
8
possess curare-like activity, and the alkaloidal extracts have
2
9
been used in indigenous medicine. Erythrina alkaloids are
generally classified into two groups according to their
3
structural features; those whose D-rings are aromatic (e.g.,
3
(1) (a) Dyke, S. F.; Quessy, S. N. In The Alkaloids; Rodrigo, R. G. A.,
Ed.; Academic Press: New York, 1981; Vol. 18, pp 1-98. (b) Chawla, A.
S.; Kapoor, V. K. In The Alkaloids: Chemical and Biological Perspec-
tiVes: Pelletier, S. W., Ed.; Pergamon: 1995; Vol. 9, pp 86-153.
(2) Deulofeu, V. In Curare and Curarelike Agents; Bovet, D.; Bovet-
Nitti, F.; Marini-Bettolo, G. B., Eds.; Elsevier: Amsterdam, 1959; p 163.
-demethoxyerythratidinone (1) and erysotramidine (2)) and
the others whose D-rings possess an unsaturated lactone (e.g.,
4
cocculolidine (3)). Many different approaches have been
(
3) Tsuda, Y.; Sano, T. In The Alkaloids; Cordell, G. A., Ed.; Academic
Press: San Diego, 1996; Vol. 48, pp 249-337.
4) Kawasaki, T.; Onoda, N.; Watanabe, H.; Kitahara, T. Tetrahedron
Lett. 2001, 42, 8003.
5) (a) Belleau, B. J. Am. Chem. Soc. 1953, 75, 5765. (b) Mondon, A.;
(
(
Hansen, K. F. Tetrahedron Lett. 1960, 5. (c) Ishibashi, H.; Sato, T.;
Takahashi, M.; Hayashi, M.; Ikeda, M. Heterocycles 1988, 27, 2787. (d)
Tsuda, Y.; Hosoi, S.; Ishida, K.; Sangai, M. Chem. Pharm. Bull. 1994, 42,
204. (e) Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z. Tetrahedron
Lett. 1998, 39, 8995. (f) Rigby, J. H.; Deur, C.; Heeg, M. J. Tetrahedron
Lett. 1999, 40, 6887. (g) Parsons, A. F.; Williams, D. A. Tetrahedron 2000,
5
6, 7217. (h) Toyao, A.; Chikaoka, S.; Takeda, Y.; Tamura, O.; Muraoka,
O.; Tanabe, G.; Ishibashi, H. Tetrahedron Lett. 2001, 42, 1729. (i) Miranda,
L. D.; Zard, S. Z. Org. Lett. 2002, 4, 1135. (j) Allin, S. M.; James, S. L.;
Elsegood, M. R. J.; Martin, W. P. J. Org. Chem. 2002, 67, 9464.
employed for the synthesis of this class of natural products.
Taking the final step of bond formation into consideration,
the methods for building up the erythrinan ring system can
be loosely classified into seven different reaction types: (1)
C-ring formation with the C-5 quaternary center being
(
6) (a) Toda, J.; Niimura, Y.; Takeda, K.; Sano, T.; Tsuda, Y. Chem.
Pharm. Bull. 1998, 46, 906. (b) Jousse, C.; Dema e¨ le, D. Eur. J. Org. Chem.
999, 909.
(7) Wasserman, H. H.; Amici, R. M. J. Org. Chem. 1989, 54, 5843.
1
1
0.1021/ol036106r CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/05/2003

by intramolecular annulation of dibenzazonine10 and (7) an
assortment of miscellaneous methods.11 Despite the avail-
ability of many synthetic methods for the Erythrina alkaloids,
there still exists a need to develop procedures more efficient
than those currently in existence. In earlier studies, our group
had reported on the use of a tandem Diels-Alder/N-
acyliminium ion cyclization cascade as well as a thionium-
promoted Mannich strategy13 for assemblage of the eryth-
rinan skeleton. In this paper, we describe an alternative
approach to construct the tetracyclic core of the Erythrina
family which makes use of an NBS-induced cyclization of
a hexahydroindolinone derivative.
Scheme 1
12
On the basis of our earlier work with the Erythrina
skeleton, we reasoned that a suitably substituted hexa-
hydroindolinone N-acyliminium ion precursor might allow
for a facile entry to the tetracyclic core of erysotramidine
1
4
(
2) (vide infra). This approach which, in the event, proved
successful was initially tried using several model compounds.
Our synthesis of the starting bicyclic lactam substrates
followed a methodology similar to that previously described
15
in the literature. Condensation of the appropriate amine with
a (1-substituted 2-oxocyclohexyl)acetic acid derivative (i.e.,
reported syntheses of the nonaromatic erythroidine alkaloids
have employed this strategy of assemblage. To demonstrate
17
4
or 5) under Dean-Stark conditions in xylene at 160 °C
that this methodology could also be used for â-phenethyl-
for 1 h afforded the desired bicyclic lactams in high yield.
The resulting aryl lactam precursors (i.e., 6 and 7) were
smoothly converted to the desired tetracyclic products in
essentially quantitative yield when treated with either tri-
fluoroacetic acid (9) or trifluoromethanesulfonic acid (10).
The formation of a single lactam diastereomer is the result
of the stereoelectronic preference for axial attack by the
aromatic ring of the N-acyliminium ion (8) from the least
hindered side (Scheme 1).16
18
amine pharmacophores possessing the homoerythrina skel-
eton, the homologous furan 12 (n ) 2) was subjected to the
acid-catalyzed cyclization conditions (Scheme 2). Interest-
Scheme 2
We were pleased to find that the analogous furanyl-
substituted hexahydroindolinone system 11 also underwent
a related acid-induced cyclization to give the tetracyclic
substituted lactam 14 in 78% yield. This cyclization is
especially noteworthy considering that none of the previously
(8) (a) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.; Tsuda, Y. Chem.
Pharm. Bull. 1987, 35, 479. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko,
C.; Sano, T. Heterocycles 1992, 33, 497.
(
9) (a) Danishefsky, S. J.; Panek, J. S. J. Am. Chem.. Soc. 1987, 109,
17. (b) Ahmed-Schofield, R.; Mariano, P. S. J. Org. Chem. 1987, 52, 1478.
c) Irie, H.; Shibata, K.; Matsuno, K.; Zhang, Y. Heterocycles 1989, 29,
033. (d) Kawasaki, T.; Onoda, N.; Watanabe, H.; Kitahara, T. Tetrahedron
Lett. 2001, 42, 8003.
10) (a) Gervay, J. E.; McCapra, F.; Money, T.; Sharma, G. M. J. Chem.
9
(
1
(
Soc., Chem. Commun. 1966, 142. (b) Tanaka, H.; Shibata, M.; Ito, K. Chem.
Pharm. Bull. 1984, 32, 1578. (c) Chou, C. T.; Swenton, J. S. J. Am. Chem.
Soc. 1987, 109, 6898.
(11) (a) Mondon, A.; Ehrhardt, M. Tetrahedron Lett. 1966, 2557. (b)
Haruna, M.; Ito, K. J. Chem. Soc., Chem. Commun. 1976, 345. (c) Ishibashi,
H.; Sato, K.; Ikeda, M.; Maeda, H.; Akai, S.; Tamura, Y. J. Chem. Soc.,
Perkin Trans. 1 1985, 605. (d) Westling, M.; Smith, R.; Livinghouse, T. J.
Org. Chem. 1986, 51, 1159. (e) Chikaoka, S.; Toyao, A.; Ogasawara, M.;
Tamura, O.; Ishibashi, H. J. Org. Chem. 2003, 68, 312.
ingly, the only product isolated in 54% yield corresponded
to the novel dimeric furanyl bis-lactam 15 which is derived
by bimolecular trapping of the N-acyliminium ion at the more
(
12) (a) Padwa, A.; Kappe, C. O.; Reger, T. S. J. Org. Chem. 1996, 61,
4
1
888. (b) Padwa, A.; Hennig, R.; Kappe, C. O.; Reger, T. S. J. Org. Chem.
998, 63, 1144.
(16) (a) Wilkens, H. J.; Traxler, F. HelV. Chim. Acta 1975, 58, 1512.
(b) Mondon, A.; Hansen, K. F.; Boehme, K.; Faro, H. P.; Nestler, H. J.;
Vilhuber, H. G.; B o¨ ttcher, K. Chem. Ber. 1970, 103, 615. (c) Mondon, A.;
Nestler, H. J. Chem. Ber. 1979, 112, 1329. (d) Dean, R. T.; Rapoport, H.
A. J. Org. Chem. 1978, 43, 4183.
(
13) Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235.
(14) (a) Ito, K.; Suzuki, F.; Haruna, M. J. Chem. Soc., Chem. Commun.
1
978, 733. (b) Tsuda, Y.; Hosoi, S.; Katagiri, N.; Kaneko, C.; Sano, T.
Chem. Pharm. Bull. 1993, 41, 2087. (c) Hosoi, S.; Nagao, M.; Tsuda, Y.;
Isobe, K.; Sano, T.; Ohta, T. J. Chem. Soc., Perkin Trans. 1 2000, 1505.
(17) The â-erythroidine skeleton has been prepared by an oxidative
degradation of the aromatic ring (ring A) in erythrinans as the key step;
see: Isobe, K.; Mohri, K.; Itoh, Y.; Toyokawa, Y.; Takeda, N.; Taga, J.;
Hosoi, S.; Tsuda, Y. Chem. Pharm. Bull. 1992, 40, 2632.
(15) (a) Ragan, J. A.; Claffey, M. C. Heterocycles 1995, 41, 57. (b) Ennis,
M. D.; Hoffman, R. L.; Ghazal, N. B.; Old, D. W.; Mooney, P. A. J. Org.
Chem. 1996, 61, 5813.
(18) Bentley, K. W. Nat. Prod. Rep. 2001, 18, 148.
5068
Org. Lett., Vol. 5, No. 26, 2003

activated 5-position of the furan ring. When this position is
blocked by the incorporation of an ethyl substituent, intra-
molecular cyclization occurs at the 3-position of the furan
ring to give tetracyclic lactam 16 in 96% yield.
Scheme 4
We were now in a position to apply the experience gained
from our model studies to the synthesis of erysotramidine
(2) itself. To this end, bicyclic lactam 18 was prepared in
73% yield by condensation of 3,4-dimethoxyphenethylamine
with ketoester 5 in the presence of TFA (Scheme 3). The
Scheme 3
formation of the R,â-unsaturated ene-amide 18 presumably
involves initial generation of the expected hexahydroindoli-
none 17 followed by an acid-catalyzed elimination of the
phenylsulfanyl group. With 18 in hand, we attempted to
induce an acid-promoted cyclization but all of our efforts
failed to produce any characterizable products, perhaps as a
consequence of the antiaromatic character of the resulting
cationic intermediate.
into alcohol 25 by treatment with acetyl chloride in ethanol.19
Finally, compound 25 was converted into (()-erysotramidine
We were pleased to discover, however, that bicyclic lactam
(
2) in 91% yield by O-methylation using KOH/MeI in THF
18 underwent an extremely smooth cyclization to the desired
1
4
according to Tsuda’s method (Scheme 5).
erythrinan skeleton (i.e., 20) in 78% yield when treated with
NBS in acetonitrile. It is of interest to note that this reaction
is markedly dependent on the nature of the solvent and that
acetonitrile is the only solvent used which favors cyclization
Scheme 5
2 2
(Scheme 4). Thus, when 18 was subjected to NBS in CH Cl ,
bromo ene-amide 21 was obtained in 87% yield and its
formation can be attributed to a competitive deprotonation
of the presumed N-acyliminium ion intermediate 19. The
reaction of 18 with NBS in THF furnished aminal 22 in 77%
yield which, in turn, gave a 5:3 mixture of 20 and 21 when
heated with a trace of p-TsOH in CH CN. These un-
3
anticipated findings can be linked to the polarity of the
solvent and consequently the reactivity of the incipient
N-acyliminium ion 19. The more polar solvent (CH
stabilizes the N-acyliminium ion and allows the cyclization
2
to proceed. The other solvents favor deprotonation (CH Cl )
3
CN)
2
or trapping of the cation by some adventitious water that
was present in THF.
Subjection of 20 to DBU in refluxing xylene furnished
the R,â,γ,δ-unsaturated diene amide 23 in 75% yield. This
product is presumably formed by an initial dehydrobromi-
nation followed by isomerization of the π-bond into the
thermodynamically most stable position. Stereoselective
allylic oxidation with selenium dioxide in the presence of
formic acid gave a 1:1-mixture of formate 24 and alcohol
In summary, we have shown that the intramolecular
electrophilic aromatic substitution reaction of hexahydro-
indolinones allows for the rapid construction of the tetracyclic
erythrinane skeleton. We expect that the total syntheses of
other nonaromatic erythroidine alkaloids will also benefit
25 in 60% yield (based on recovered starting material) as
single diastereomers. The stereochemical outcome of the
oxidation involves attack by the oxidant from the least hin-
dered R-position. Formate 24 was quantitatively transformed
(19) Lee, Y. S.; Lee, J. Y.; Kim, D. W.; Park, H. Tetrahedron 1999, 55,
4631.
Org. Lett., Vol. 5, No. 26, 2003
5069

from this general strategy. These investigations are currently
under way.
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (Grant No.
CHE-0132651).
OL036106R
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Org. Lett., Vol. 5, No. 26, 2003