Indol-2-one intermediates: Mechanistic evidence and synthetic utility. Total syntheses of (±)-flustramines A and C

Article abstract of DOI:10.1021/ol047532v

(Chemical Equation Presented) A variety of 3,3-disubstituted 2-indolinones have been prepared by treatment of 3-bromo-3-alkyl-2-indolinones with dienophiles/nucleophiles in the presence of cesium carbonate. Application of this general strategy has facilit

Full text of DOI:10.1021/ol047532v

ORGANIC
LETTERS
2005
Vol. 7, No. 4
677-680
Indol-2-one Intermediates: Mechanistic
Evidence and Synthetic Utility. Total
Syntheses of (±)-Flustramines A and C
James R. Fuchs and Raymond L. Funk*
Department of Chemistry, PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
rlf@chem.psu.edu
Received December 1, 2004
ABSTRACT
A variety of 3,3-disubstituted 2-indolinones have been prepared by treatment of 3-bromo-3-alkyl-2-indolinones with dienophiles/nucleophiles
in the presence of cesium carbonate. Application of this general strategy has facilitated the total syntheses of the reverse prenylated marine
natural products (±)-flustramine A and (±)-flustramine C.
Recently, we reported the total synthesis of (()-perophora-
midine via a key base-promoted tryptamine “dimerization”
reaction of indolin-2-one 2 with indole 1.1 We proposed that
the transformation proceeded via a putative indol-2-one
intermediate 3 through either a Diels-Alder cycloaddition2
or Michael addition pathway to produce indolenine 4
(Scheme 1).3 Our initial study of this reaction drew upon
the seminal observations of Hinman and Bauman who
reported the substitution reactions of 3-bromo-3-methylin-
dolin-2-one with hetero nucleophiles (Scheme 2),4 although
the intermediacy of 3-methylindol-2-one was not advanced
in these studies. Herein we report an extensive investigation
of the base-promoted reactions of 3-alkyl-3-bromoindolin-
2-ones with dienophiles/nucleophiles, further document the
utility of this method in the construction of C(3) reverse
prenylated pyrrolidinoindoline natural products, and provide
evidence that suggests that transient indol-2-ones are indeed
generated under these conditions.
Scheme 1
(1) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126, 5068.
(2) For the generation and Diels-Alder cycloaddition of the related
2-azacyclopenta-2,4-dien-1-one with polymer-supported acetylene-dicar-
boxylate, see: (a) Gavina, F.; Costero, A. M.; Andreu, M. R.; Carda, M.;
Luis, S. V. J. Am. Chem. Soc. 1988, 110, 4017. (b) Yokotsuji, D. L. S.;
Dailey, W. P.; Kende, A. S.; Birzan, L.; Liu, K. J. Phys. Chem. 1995, 99,
15870.
(3) Alternative pathways for the formation of indolenine 4 were also
envisaged, including direct displacement and transfer alkylation.
(4) (a) Hinman, R. L.; Bauman, C. P. J. Org. Chem. 1964, 29, 2431.
For further examples of reactions that may occur via generation of indol-
2-one intermediates, see: (b) Labroo, R. B.; Labroo, V. M.; King, M. M.;
Cohen, L. A. J. Org. Chem. 1991, 56, 3637. (c) Rajeswaran, W. G.; Labroo,
R. B.; Cohen, L. A.; King, M. M. J. Org. Chem. 1999, 64, 1369. (d)
Kobayashi, M.; Aoki, S.; Gato, K.; Matsunami, K.; Kurosu, M.; Kitagawa,
I. Chem. Pharm. Bull. 1994, 42, 2449. For an example of an intramolecular
displacement of a tertiary mesylate with inversion of stereochemistry, see:
Monde, K.; Taniguchi, T.; Miura, N.; Nishimura, S.-I.; Harada, N.; Dukor,
R. K.; Nafie, L. A. Tetrahedron Lett. 2003, 44, 6017.
10.1021/ol047532v CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/20/2005

Scheme 2
Table 1. Intermolecular Addition of Nucleophiles to
3-Bromo-3-methylindolin-2-one
We first surveyed the intermolecular reaction of various
nucleophiles/dienophiles with 3-bromo-3-methylindolin-2-
one (1, Table 1) using our standard reaction conditions (Cs2-
CO3, CH2Cl2, rt).5 Allyl stannanes (entries 1 and 2) and
methallyltrimethylsilane (entry 3) cleanly provided the 3-
allyl-substituted oxindoles. However, the less nucleophilic
allyltrimethylsilane6 failed to provide any product. Electron-
rich aromatic compounds such as N,N-dimethylaniline (Table
1, entry 4) and N-methylpyrrole (entry 5) also served as
competent nucleophiles, whereas anisole and 1,3-dimethoxy-
benzene were unreactive. The examples shown in entries 6
and 7 demonstrate that enamides and cyclic enol ethers also
react with the putative indol-2-one intermediate via Diels-
Alder or Michael-type pathways eventually leading to
products containing regenerated enamide/enol ether func-
tionality. Nucleophiles that can be generated in situ by
deprotonation with cesium carbonate proceed smoothly, as
shown in entries 9 and 10. Much to our dismay, it was found
that poor Michael donors, yet competent dienophiles, such
as the electron-neutral 2-butyne or electron-poor diethyl
fumarate/dimethyl acetylenedicarboxylate gave no product
and resulted only in the decomposition of the starting
3-bromo-3-methylindolin-2-one.
We next turned to the intramolecular variant of this
reaction, namely, the cyclization of appropriately substituted
3-alkyl-3-bromoindolin-2-ones (Table 2). For example, the
triflamide shown in entry 1 (prepared through NBS-mediated
oxidation of the corresponding indole) gave rise to the
spirocyclic indolin-2-one upon treatment with cesium car-
bonate. Entry 2 suggests that electrophilic aromatic substitu-
tion reactions with electron-rich aromatic rings can indeed
be accomplished if performed intramolecularly,7 albeit in low
yield. Finally, the silyl enol ether shown in entry 3 reacted
in the presence of base to provide a mixture of the
corresponding E/Z exocyclic silyl enol ether products that
was subsequently hydrolyzed to provide a 1.5:1 mixture of
the diastereomeric aldehydes.
(Scheme 3). However, the preparation of this substrate
necessitated the development of a strategy that avoided the
relatively harsh brominating conditions (NBS, t-BuOH/THF
(1:1), rt, 1 h) employed in our standard procedure, halooxi-
dation of 3-substituted indoles. To that end, the dianion of
oxindole (5) was alkylated with the 6-iodo-2-hexyne ac-
cording to the procedure of Kende.8 Subsequent formation
of the dianion of the alkylated oxindole 6 and treatment with
NBS at low temperature led to the formation of the 3-alkyl-
3-bromoindolin-2-one 7. It should be noted that the 3-alkyl-
3-bromoindolin-2-ones shown in entries 2 and 3 of Table 2,
It was hoped that convincing evidence for an indol-2-one
intermediate might be obtained by subjecting the 3-(4-
hexynyl)indolin-2-one 7 to our standard reaction conditions
(5) These conditions had been previously employed for the generation
of N-acyl and N-sulfonyl-aza-ortho-xylylenes. Steinhagen, H.; Corey, E. J.
Angew. Chem., Int. Ed. 1999, 38, 1928.
(6) For a reference scale of π-nucleophilicity, see: (a) Mayr, H.; Kempf,
B.; Ofial, A. R. Acc. Chem. Res. 2003, 36, 66. (b) Mayr, H.; Bug, T.; Gotta,
M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial, A.
R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001, 123, 9500.
(7) Previous studies have suggested that the seven-membered ring closure
is preferred geometrically in internal electrophilic aromatic substitution
reactions. Fuchs, J. R.; Funk, R. L. Org. Lett. 2001, 3, 3349.
(8) Kende, A. S.; Hodges, J. C. Synth. Commun. 1982, 12, 1.
Org. Lett., Vol. 7, No. 4, 2005
678

Scheme 4
Table 2. Intramolecular Addition of Nucleophiles
intermediate 15 and subsequent rearomatization. An alterna-
tive SN2′ mechanism involving the direct addition of the
triflamide anion to the aromatic ring seems less likely. The
regiochemical preference of the reaction is consistent with
the calculated LUMO coefficients of the carbons of the indol-
2-one intermediate. The 3-methyl substituent may also act
to sterically inhibit cyclization at C(4).
Having delineated the scope and generality of this
methodology, we turned to its application in natural product
synthesis. The marine natural products flustramine A10 and
flustramine C11 (Scheme 5) are particularly attractive targets
which possess more labile substituents, were also prepared
using this mild and direct route.
We were gratified to discover that treatment of the alkyne
7 with cesium carbonate resulted in the formation of
quinoline 10 in good yield (Scheme 3). This transformation
presumably occurs via cycloaddition of the tethered alkyne
with the intermediate indol-2-one 8 to provide a strained
bridged bicyclic lactam 9.2 The lactam then undergoes a
retrocheleotropic reaction in situ to provide the quinoline
10.
Scheme 5
We have also examined the cyclization of a 3-bromoin-
dolin-2-one possessing a nucleophilic substituent connected
at C(5) rather than C(3) as found in the aforementioned
examples. To that end, indole 12 was prepared via Suzuki
coupling of enamide 11 employing the conditions reported
by Overman.9 The carbamate protecting group was then
removed, and the resulting amine was converted to triflamide
13. Subsequent halooxidation of the indole with N-bromo-
succinimide provided the substituted 3-bromoindolin-2-one
14. Treatment of this compound with cesium carbonate
provided indoline 16 as the major product, presumably by
intramolecular nucleophilic attack upon the indol-2-one
since they embody a reverse prenylated substituent at C(3),12
a functionality that is readily accessible using this methodol-
ogy as previously demonstrated in entry 2 of Table 1. Thus,
it was hoped that both of these natural products could be
constructed from the product derived from 3-bromoindolin-
2-one 17 and tributyl(3-methyl-2-butenyl)tin.
We first directed our attention to the synthesis of flustra-
mine A. To that end, 6-bromoindole 18 was treated with
Scheme 3
(9) Kamatani, A.; Overman, L. E. J. Org. Chem. 1999, 64, 8743.
(10) For the isolation from Flustra foliacea (L.), see: (a) Carle, J. S.;
Christophersen, C. J. Org. Chem. 1980, 45, 1586. For the previous total
synthesis, see: (b) Morales-Rios, M. S.; Suarez-Castillo, O. R.; Trujillo-
Serrato, J. J.; Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186.
(11) For the isolation from Flustra foliacea (L.), see: (a) Carle, J. S.;
Christophersen, C. J. Org. Chem. 1981, 46, 3440. For the previous total
synthesis, see: (b) Kawasaki, T.; Terashima, R.; Sakaguchi, K.; Sekiguchi,
H.; Sakamoto, M. Tetrahedon Lett. 1996, 37, 7525.
(12) For the total synthesis of related pyrrolidinoindoline alkaloids via
reverse prenylation of putative N-acyl-aza-ortho-xylylenium ions, see: (a)
Marsden, S. P.; Depew, K. M.; Danishefsky, S. J. J. Am. Chem. Soc. 1994,
116, 11143. (b) Depew, K. M.; Marsden, S. P.; Zatorska, D.; Zatorski, A.;
Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999, 121, 11953.
(c) Schiavi, B. M.; Richard, D. J.; Joullie, M. M. J. Org. Chem. 2002, 67,
620.
Org. Lett., Vol. 7, No. 4, 2005
679

Scheme 6
Scheme 7
of the nosylamide functionality of compound 24 under the
Fukuyama conditions afforded none of the desired amidine.
However, (()-flustramine C could be obtained by heating
the crude deprotected amine in toluene with an equivalent
of acetic acid.
In conclusion, we have demonstrated that 3-alkyl-3-
bromoindolin-2-ones undergo base-promoted reactions with
a variety of dienophiles/nucleophiles to generate 3,3-disub-
stituted-2-indolinones and have thereby significantly ex-
panded the initial studies of Hinman and Bauman.4 Most
importantly, we have provided substantive evidence for a
pathway proceeding through heretofore unappreciated indol-
2-one reactive intermediates. The concise total syntheses of
(()-flustramine A and (()-flustramine C described herein
further underscore the value of this methodology in natural
product synthesis. Moreover, the discovery of a new strategy
for the preparation of the requisite 3-alkyl-3-bromoindolin-
2-ones that tolerates more nucleophilic substituents should
pave the way for applications featuring intramolecular
cyclizations of indol-2-one intermediates.
NBS to afford the key 3-alkyl-3-bromoindolin-2-one 19.
Treatment of the 3-bromoindolin-2-one with cesium carbon-
ate in the presence of tributyl(3-methyl-2-butenyl)tin cleanly
provided indolin-2-one 20. N-Alkylation of the indolin-2-
one with dimethylallyl bromide and subsequent deprotection
of the secondary amine according to the protocol of Fuku-
yama13 proved to be uneventful. Reduction of the resulting
amine 22 with 2.5 equiv of alane led to formation of
flustramine A as the minor product along with a substantial
amount of fully reduced indoline byproduct resulting from
reduction of the intermediate iminium ion (4:1 ratio).
Fortunately, flustramine A could be obtained as the major
product (3:1) by employing only 1.1 equiv of alane and
decreasing the concentration of indolin-2-one 22 (0.2 f 0.05
M).
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM28553).
The reverse prenylated indolinone 23 was also easily
converted to flustramine C. Thus, treatment of 23 with
Meerwein’s salt provided the cyclic imidate 24. Removal
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.
(13) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373.
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