Directed oxidative cyclizations to C2- or C4-positions of indole: Efficient construction of the bicyclo[4.3.1]decane core of welwitindolinones

Article abstract of DOI:10.1021/ol201122f

Regiocontrolled oxidative cyclizations of 3-substituted indoles are described herein. Specifically, it is shown that the installation of a chloride at C2 alters the inherent propensity for cyclization at the 2-position of indole so as to favor the 4-posit

Full text of DOI:10.1021/ol201122f

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3214–3217
Directed Oxidative Cyclizations to C2- or
C4-Positions of Indole: Efficient
Construction of the Bicyclo[4.3.1]Decane
Core of Welwitindolinones
Vikram Bhat, James A. MacKay, and Viresh H. Rawal*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue, Chicago,
Illinois 60637, United States
vrawal@uchicago.edu
Received April 27, 2011
ABSTRACT
Regiocontrolled oxidative cyclizations of 3-substituted indoles are described herein. Specifically, it is shown that the installation of a chloride at C2 alters the
inherent propensity for cyclization at the 2-position of indole so as to favor the 4-position, enabling the construction of the unique framework found in most
welwitindolinone alkaloids. The chloride functions here as more than a blocking group, as it also provides ready access to the corresponding oxindole.
The structural challenges presented by natural products
have often stimulated the development of new chemical
methods and the exploration of innovative synthetic stra-
tegies. For example, the welwitindolinone family of indole
alkaloids,1 possessing the unique bicyclo[4.3.1]decane ske-
leton (Figure1), has inspiredthe investigationof numerous
(1) (a) Stratmann, K.; Moore, R. E.; Bonjouklian, R.; Deeter, J. B.;
Patterson, G. M. L.; Shaffer, S.; Smith, C. D.; Smitka, T. A. J. Am.
Chem. Soc. 1994, 116, 9935. (b) Jimenez, J. I.; Huber, U.; Moore, R. E.;
Patterson, G. M. L. J. Nat. Prod. 1999, 62, 569.
(2) For approaches toward welwitindolinone alkaloids, see: (a)
Konopelski, J. P.; Deng, H.; Schiemann, K.; Keane, J. M.; Olmstead,
M. M. Synlett 1998, 1105. (b) Wood, J. L.; Holubec, A. A.; Stoltz, B. M.;
Weiss, M. M.; Dixon, J. A.; Doan, B. D.; Shamji, M. F.; Chen, J. M.;
Heffron, T. P. J. Am. Chem. Soc. 1999, 121, 6326. (c) Kaoudi, T.; Ouiclet-
Sire, B.; Seguin, S.; Zard, S. Z. Angew. Chem., Int. Ed. 2000, 39, 731.
(d) Deng, H.; Konopelski, J. P. Org. Lett. 2001, 3, 3001. (e) Jung, M. E.;
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Slowinski, F. Tetrahedron Lett. 2001, 42, 6835. (f) Lopez-Alvarado, P.;
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2002, 1702. (g) Ready, J. M.; Reisman, S. E.; Hirata, M.; Weiss, M. M.;
Tamaki, K.; Ovaska, T. V.; Wood, J. L. Angew. Chem., Int. Ed. 2004, 43,
1270. (h) Baudoux, J.; Blake, A. J.; Simpkins, N. S. Org. Lett. 2005, 7,
4087. (i) Greshock, T. J.; Funk, R. L. Org. Lett. 2006, 8, 2643. (j) Lauchli,
R.; Shea, K. J. Org. Lett. 2006, 8, 5287. (k) Xia, J.; Brown, L. E.;
Konopelski, J. P. J. Org. Chem. 2007, 72, 6885. (l) Richter, J. M.; Ishihara,
Y.; Masuda, T.; Whitefield, B. W.; Llamas, T.; Pohjakallio, A.; Baran,
P. S. J. Am. Chem. Soc. 2008, 130, 17938. (m) Boissel, V.; Simpkins, N. S.;
Bhalay, G.; Blake, A. J.; Lewis, W. Chem. Commun. 2009, 1398. (n) Boissel,
V.; Simpkins, N. S.; Bhalay, G. Tetrahedron Lett. 2009, 50, 3283. (o) Tian,
X.; Huters, A. D.; Douglas, C. J.; Garg, N. K. Org. Lett. 2009, 11, 2349.
(p) Trost, B. M.; McDougall, P. J. Org. Lett. 2009, 11, 3782. (q) Brailsford,
J. A.; Lauchli, R.; Shea, K. J. Org. Lett. 2009, 11, 5330. (r) Freeman, D. B.;
et al. Tetrahedron 2010, 66, 6647. (s) Heidebrecht, R. W., Jr.; Gulledge, B.;
Figure 1. Representative welwitindolinones alkaloids.
creative routes from organic synthesis laboratories around
the globe.2 In our own work on these alkaloids, we
employed a palladium-catalyzedenolate arylation reaction
to construct the carbon framework of the bridged welwi-
tindolinones (5, Scheme 1).3 This strategy proved successful
and culminated in the total synthesis of N-methylwelwi-
tindolinone D isonitrile (3).4 The path to the final target
ꢀ
Martin, S. F. Org. Lett. 2010, 12, 2492. (t) Ruiz, M.; Lopez-Alvarado, P.;
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Menendez, J. C. Org. Biomol. Chem. 2010, 8, 4521.
r
10.1021/ol201122f
Published on Web 05/26/2011
2011 American Chemical Society

Scheme 1. Synthesis of Welwitindolinone Skeletona
Scheme 2. Synthesis of Cyclization Precursors
a See ref 3.
was, however, less than straightforward. Indeed, while
facing seemingly insurmountable hurdles, we alsoexplored
alternate methods for the arylative cyclization to yield the
bicyclo[4.3.1]decane ring system. Particularly attractive
among these was the possibility of intramolecular oxidative
arylation to close the seven-membered ring. An examination
of the literature identified the formative work of Muchowski5
and Chuang6 on the intramolecular oxidative cyclizations
of pyrroles and indoles bearing a pendant malonyl group.
Significant further advances to this area have come from
the laboratories of Kerr7 and Li.8 What is noteworthy in all
these examples is that the tether through which the new
ring is formed is attached at either the nitrogen or the C3-
position of the indole, such that the newly formed 5-, 6-, or
7-membered rings are fused to the 1,2- or 2,3-positions of
the heterocycles.9 In other words, the cyclization takes
place on the pyrrolo part of the indole, not the benzo unit.
Toourknowledge, thereappeartobeno reports describing
intramolecular oxidative cyclizations at the 4-position of
indole. The development of such a cyclization pathway
would not only extend the scope of these oxidative cycliza-
tions but also generate the sought-after welwitindolinone
skeleton (Figure 2).
derivatives, synthesized by the general route shown in
Scheme 2. Thus, ketone 8a was prepared by alkylative
coupling of alcohol 7a with the silyl enol ether of
cyclohexanone.3,10 Substitution of the sulfonyl group with
a methyl group and carbomethoxylation11 gave the re-
quired substrate, 10a. Subjection of ketoester 10a to
standard oxidative cyclization conditions12;heating in
acetic acid in the presence of Mn(OAc)3;afforded tetra-
cycle 11 cleanly and in high yield (entry 1, Table 1).13 Given
the precedents of Kerr and others, we were not surprized
to find that the product was tetracycle 11, arising from
cyclization at the 2-position of indole. The connectivity
present in 11 was established unambiguously through
X-ray crystallography (Figure 3).
In an effort to overcome the inherent propensity for
cyclization at C2, we sought to install a blocking group at
With the welwitindolinones in mind, we examined the
oxidative cyclization of several 3-substituted indole
(3) MacKay, J. A.; Bishop, R. L.; Rawal, V. H. Org. Lett. 2005, 7,
3421.
(4) Bhat, V.; Allan, K. M.; Rawal, V. H. J. Am. Chem. Soc. 2011, 133,
5798.
(5) Artis, D. R.; Cho, I.-S.; Muchowski, J. M. Can. J. Chem. 1992, 70,
1838.
(6) (a) Chuang, C. P.; Wang, S. F. Tetrahedron Lett. 1994, 35, 1283.
(b) Tsai, A.-I.; Lin, C.-H.; Chuang, C. P. Heterocycles 2005, 65, 2381.
(7) (a) Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561. (b)
Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437.
(8) Chen, P.; Cao, L.; Tian, W.; Wang, X.; Li, C. Chem. Commun.
2010, 46, 8436.
(9) For other methods, see: (a) Tucker, J. W.; Narayanam, J. M. R.;
Krabbe, S. W.; Stephenson, C. R. J. Org. Lett. 2010, 12, 368. (b) Tanaka,
M.; Ubukata, M.; Matsuo, T.; Yasue, K.; Matsumoto, K.; Kajimoto,
Y.; Ogo, T.; Inaba, T. Org. Lett. 2007, 9, 3331.
(10) (a) Muratake, H.; Natsume, M. Tetrahedron 1990, 46, 6331. (b)
Sakagami, M.; Muratake, H.; Natsume, M. Chem. Pharm. Bull. 1994,
42, 1393.
(11) Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1983, 24, 5425.
(12) For comprehensive reviews on oxidative cyclization reactions,
see: (a) Snider, B. B. Chem. Rev. 1996, 96, 339. (b) Snider, B. B.
Manganese(III)-Based Oxidative Free-Radical Cyclizations. In Transi-
tion Metals for Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Ed.;
Wiley-VCH Verlag: Weinheim, 2004; Vol. 1, pp 483À490.
(13) For synthesis of structurally similar bicyclo[3.3.1]nonanes, see:
(a) Trost, B. M.; Fortunak, J. M. D. Organometallics 1982, 1, 7. (b)
Butkus, E.; Berg, U.; Malinauskiene, J.; Sandstroem, J. J. Org. Chem.
2000, 65, 1353. (c) Butkus, E.; Malinauskiene, J.; Stoncius, S. Org.
Biomol. Chem. 2003, 1, 391. (d) Baranova, T. Y.; Zefirova, O. N.;
Averina, N. V.; Boyarskikh, V. V.; Borisova, G. S.; Zyk, N. V.; Zefirov,
N. S. Russ. J. Org. Chem. 2007, 43, 1196.
Figure 2. Complementary approach to current methods.
Org. Lett., Vol. 13, No. 12, 2011
3215

Table 1. Mn(III)-Promoted Oxidative Cyclizations
a Compound 15 was isolated in 34% yield.
this position. The requirements for the blocking group
were that it must not only impart steric and electronic
deactivation of the 2-position, but it must also withstand
the oxidative cyclization conditions and allow future
conversion to an oxindole, the functionality found in the
welwitindolinones. These requirements appeared to be met
by chloride. The necessary 2-chloro-substituted keto-
ester 10b was prepared through the route outlined in
Scheme 2, starting from ketone 6b.14
Table 1). To the best of our knowledge this result repre-
sents the first example of an oxidative cyclization onto the
4-position of indole. Up to 10% of the C2-cyclized product
(11) was also obtained. The structure assigned to the
The key oxidative cyclization was carried out using the
previously employed conditions, with Mn(OAc)3 as the
oxidant. Gratifyingly, the primary product of the reaction
was tetracycle 17, obtained in 66% yield, wherein the
cyclization had taken place on the benzene ring (entry 5,
Figure 3. ORTEP image of tetracycle 11.
Org. Lett., Vol. 13, No. 12, 2011
(14) See the Supporting Information for details.
3216

cyclized product was confirmed through its independent
synthesis, by chlorination of tetracyclic ketoester 5, which
was prepared by the Pd-catalyzed arylation route.3
The strategy of modulating regioselectivity by positioning
a blocking group at C2 proved to be general and provided
good yields of the bicyclo[4.3.1]decane welwitindolinone
skeletons with chloride at the 2-position (entries 5À8) and
bicyclo[3.3.1]nonanes (entries 1À4) in the absence of
chloride at C2. The reaction conditions are tolerant of a
variety of functional groups including alkyl chlorides
(entries 2 and 7), acetals (entries 6 and 7), and aryl
bromides (entry 4). Of particular interest to us was the
arylative cyclization of vinylogous acids (i.e., R-formyl
ketones), for which there are few precedents in the
literature.4,15 To that end, treatment of acid 14 (entry 3)
under the standard conditions cleanly furnished the
expected cyclization product, 15. Interestingly, the
corresponding 2-chlorosubstituted compound (22,
entry 8) did not undergo the desired cyclization but,
instead, produced the C2-cyclized tetracyclic aldehyde
15 in 34% yield.
Scheme 3. Synthesis of Oxindole 25
indoles, unsubstituted at the 2-position, undergo selective
cyclizations at the 2-position. On the other hand, 2-chloro-
substituted indoles display altered reactivity, favoring
cyclization at the 4-position, on the benzene ring. This
simple modification enables the efficient synthesis of the
complex bicyclo[4.3.1]decane core of the welwitindoli-
nones. The chloride group at the 2-position is more than
just a blocking group, diverting the cyclization to the
4-position; it also provides a handle for further manipula-
tions. The broad functional group tolerance makes this an
attractiveroutetowardwelwitindolinonesand conceivably
other intricate indole alkaloids.
A brief solvent study identified acetic acid as the opti-
mum solvent for these reactions, with methanol delivering
slightly lower yields. The use of NaOAc as an additive was
beneficial for the C2-cyclization reactions (entries 1À4),
yet had no advantageous effect on the C4-cyclization
substrates (entries 5À8). Other oxidants such as CAN,
Mn(pic)3, and Fe(ClO4)3 9H2O gave essentially none of
3
the desired products.
Entries 6 and 7 are of special interest as they represent
highly advanced intermediates toward welwitindolinones
BÀD (1À3). Deprotection of the acetal group in 19 readily
yielded the diketone 24 (Scheme 3). The oxindole function-
ality was then revealed through acidic hydrolysis of
2-chloroindole 24 affording oxindole 25 which is suitably
adorned for further elaboration to the aforementioned
targets.16
Acknowledgment. Generous financial grant from the
National Cancer Institute of the NIH (R01 CA101438) is
gratefully acknowledged. We thank Dr. I. M. Steele
(University of Chicago) and Dr. A. Jurkiewicz (University
of Chicago) for X-ray crystallographic and NMR spectro-
scopic assistance, respectively. J.A.M gratefully acknowl-
edges postdoctoral fellowship support (no. PF-04-016-01-
CDD) from the American Cancer Society.
The results presented above illustrate the possibility of
divergent oxidative cyclization reactivity of 3-substituted
indoles. Consistent with literature precedent, simple
Supporting Information Available. Full experimental
procedures, characterization data, NMR spectra, com-
plete ref 2r, and X-ray crystal data (CIF) for 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(15) (a) Collins, D. J.; Cullen, J. D.; Fallon, G. D.; Gatehouse, B. M.
€
P. S. Org. Lett. 2009, 11, 4774.
(16) Oxindole 25 was obtained as a single diastereomer; however, the
absolute configuration at the C3-position was not determined.
Aust. J. Chem. 1984, 37, 2279. (b) Krawczuk, P. J.; Schone, N.; Baran,
Org. Lett., Vol. 13, No. 12, 2011
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