Construction of polycyclic spiro-indolines via an intramolecular oxidative coupling/cyclization cascade reaction process

Article abstract of DOI:10.1021/ol3003496

An efficient protocol for assembling a polycyclic spiroindoline scaffold is developed, which involves an intramolecular oxidative coupling of dianions derived from indole-embodied β-ketoamides using iodine as the oxidant, and subsequent attack of oxygen anion to the resultant imine moiety. A number of tetracyclic spiroindolines are prepared with moderate to good yields.

Full text of DOI:10.1021/ol3003496

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1405–1407
Construction of Polycyclic Spiro-
indolines via an Intramolecular Oxidative
Coupling/Cyclization Cascade Reaction
Process
Feng Fan,† Weiqing Xie,*,‡ and Dawei Ma*,†,‡
School of Pharmacy, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, China, and State Key Laboratory of Bioorganic and Natural
Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Lu, Shanghai 200032, China
xiewq@mail.sioc.ac.cn; madw@mail.sioc.ac.cn
Received February 13, 2012
ABSTRACT
An efficient protocol for assembling a polycyclic spiroindoline scaffold is developed, which involves an intramolecular oxidative coupling of
dianions derived from indole-embodied β-ketoamides using iodine as the oxidant, and subsequent attack of oxygen anion to the resultant imine
moiety. A number of tetracyclic spiroindolines are prepared with moderate to good yields.
A polycyclic spiroindoline is a complex molecular skel-
eton that often exists in both natural products and phar-
maceutical molecules with potent biological activities.1,2
Its synthesis through novel and practical methodologies
has been extensively pursued.3,4 One of most attractive
methods would be developing a reaction cascade from
simple starting materials that can construct multiple rings
and create several stereocenters in a single step. Such a
methodology would be particularly valuable for medicinal
chemistry because it could provide a convenient approach
to access a library of polycyclic spiroindolines.
Oxidative coupling of carbon anions is one of the most
direct methods for forming CÀC bonds.5,6 However, this
† East China University of Science and Technology.
‡ Chinese Academy of Sciences.
(1) (a) Robinson, R. Experientia 1946, 2, 28. (b) Millson, M. F.;
Robinson, R.; Thomas, A. F. Experientia 1953, 9, 89. (c) Cordell, G. A.
The Alkaloids; Manske, R. H. F., Rodrigo, R. G. A., Eds.; Academic Press:
New York, NY, 1979; Vol. 17, p 199. (d) Jadulco, R.; Edrada, R. A.; Ebel,
R.; Berg, A.; Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat.
Prod. 2004, 67, 78. (e) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.;
Concepcion, G. P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(2) (a) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M.-H.;
Barakat, K. J.; Johnston, D. B. R.; Cheng, K.; Chan, W. W.-S.; Butler,
B.; Hickey, G.; Jacks, T.; Schleim, K.; Pong, S. S.; Chuang, L.-Y. P.;
Chen, H. Y.; Frazier, E.; Leung, K. H.; Chiu, S.-H. L.; Smith, R. G.
Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001. (b) Elliott, J. M.; Brought-
on, H.; Cascieri, M. A.; Chicchi, G.; Huscroft, I. T.; Kurtz, M.;
MacLeod, A. M.; Sadowski, S.; Stevenson, G. I. Bioorg. Med. Chem.
Lett. 1998, 8, 1851.
(4) Examples of total synthesis of communesin alkaloids: (a) Yang,
J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc. 2007, 129, 13794. (b) Liu,
P.; Seo, J. H.; Weinreb, S. M. Angew. Chem., Int. Ed. 2010, 49, 2000. (c)
Zuo, Z.; Xie, W.; Ma, D. J. Am. Chem. Soc. 2010, 132, 13226. (d) Zuo,
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8170. (f) Zuo, Z.; Ma, D. Isr. J. Chem. 2011, 51, 434. (g) Zhang, D.; Song,
H.; Qin, Y. Acc. Chem. Res. 2011, 44, 447.
(5) Selected examples for oxidative homocoupling: (a) Ivanoff, D.;
Spassoff, A. Bull. Soc. Chim. Fr. 1935, 2, 76. (b) Rathke, M. W.; Lindert, A.
J. Am. Chem. Soc. 1971, 93, 4605. (c) Brocksom, T. J.; Petragnani, N.;
Rodrigues, R.; La Scala-. Teixeira, H. Synthesis 1975, 6, 396. (d) Frazier,
R. H.; Harlow, R. L. J. Org. Chem. 1980, 45, 5408. (e) Belletire, J. L.; Fry,
D. F. J. Org. Chem. 1987, 45, 2549. (f) Renaud, P.; Fox, M. A.
J. Org. Chem. 1988, 45, 3745. (g) Quermann, R.; Maletz, R.; Schafer,
H. J. Liegigs Ann. Chem. 1993, 11, 1219. (h) Kise, N.; Tokioka, K.;
Aoyama, Y. J. Org. Chem. 1995, 60, 1100. (i) Langer, T.; Illich, M.;
Felmchen, G. Tetrahedron Lett. 1995, 36, 4409. (j) Kim., J. W.; Lee, J. J.;
Lee, S.-H.; Ahn, K.-H. Synth. Commun. 1998, 28, 1287.
(3) Examples of total synthesis of strychnos alkaloids: (a) Bonjoch,
J.; Sole, D. Chem. Rev. 2000, 100, 3455. (b) Sirasani, G.; Paul, T.;
Dougherty, W.; Kassel, S.; Andrade, R. B. J. Org. Chem. 2010, 75, 3529.
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475, 183.
r
10.1021/ol3003496
2012 American Chemical Society
Published on Web 03/08/2012

method was rarely applied in the total synthesis of complex
natural products due to the lack of selectivity (homocoupling
versus heterocoupling).6 Recently, oxidative coupling of
enolates experienced a renaissance due to its applications in
alkaloid synthesis. For example, Baran and co-workers have
achieved the total synthesis of fischerindole, hapalindole, and
welwitindolinone through intermolecular oxidative coupling
of ketone-derived enolates with indoles.7 The Overman
group has employed an intramolecular oxidative coupling
as a key step in the total synthesis of actinophyllic acid.8 Quite
recently, we finished the first enantioselective total synthesis
of (À)-communesin F4c and communesin A and B4d via an
intramolecular oxidative coupling reaction between indole
and amide-derived enolate, and subsequent annulation of the
resulting indoline with an apendant aniline. In the synthesis
of (À)-communesins,4c,d we had to utilize a stepwise strategy
to establish their polycyclic ring framework due to the lack of
reactivity of the potential cascade reaction precursor. We
thus hypothesized that if the oxidative cyclization precursors
possessed functionalities that are tolerant under conditions of
oxidative coupling and are further capable of a second ring
closure, an efficient reaction cascade could be developed for
preparing complex polycyclic spiroindolines. Accordingly,
we were interested in using β-ketoamides 1 (Scheme 1) as the
substrates for an oxidative coupling reaction. We speculated
that intramolecular oxidative coupling of 1 would initially
afford spiroindolines 2, which should undergo further de-
protonation to provide enolates 4, and the resultant oxygen
anion would attack the imine moiety to produce tetracyclic
spiroindolines 5.
With this idea in mind, an intramolecular oxidative
coupling reaction of 1a was examined under various
conditions. To our delight, treatment of 1a under our
previous conditions (LiHMDS then iodine, THF,
À78 °C to rt)4c,d delivered spiroindoline 5a with 74%
yield (Table 1, entry 1). Its structure was unambigu-
ously confirmed by X-ray crystallography analysis.
Only one isomer was determined in this case, presum-
ably because a cis-fused ring system is more stable.
Interestingly, the other conditions we tested all gave
poor results. For example, decreased yields were ob-
served when LiHMDS was replaced with LDA and
KHMDS (entries 2 and 4), although NaHMDS gave a
similar result (entry 3). Inorganic oxidants like Fe(acac)3,
Cu(OTf)2, and Cu(2-ethylhexate)2, which have pro-
vided the best results in the intermolecular oxidative
coupling of indole and enolate,6d were totally ineffec-
tive in our transformation (entries 5À7). Other solvents
such as ether, toluene, and DME gave inferior results
(entries 8À10). Furthermore, we found that it was
necessary to raise the reaction temperature after the
addition of iodine to obtain a good yield (compare
entries 1 and 11). These results indicated that the
present transformation is quite sensitive to the base,
solvent, oxidant, and reaction temperature used.
Table 1. Condition Screening for Formation of 5a from
β-Ketoamide 1a
Scheme 1
entry
conditions
yield (%)c
1
standard conditionsa
74
46
72
36
2
LDA instead of LHMDS
NaHMDS instead of LHMDS
KHMDS instead of LHMDS
Cu(2-ethylhexate)2 instead of I2
Cu(OTf)2 instead of I2
Fe(acac)3 instead of I2
Et2O instead of THF
3
4
b
5
À
b
6
À
b
7
À
8
15
18
40
48
9
Toluene instead of THF
DME instead of THF
10
11
À78 °C instead of rt
a Standard conditions: 1a (0.2 mmol), LiHMDS (0.44 mmol), THF
(3 mL), À78 °C, 30 min, then addition of iodine (0.22 mmol), À78 °C,
then rt, 30 min. b No oxidative coupling occurred. c Isolated yield.
(6) Selected examples for oxidative heterocoupling: (a) Ito, Y.;
Konoike, T.; Harada, T.; Saegusa, T. J. Am. Chem. Soc. 1977, 99,
1487. (b) Baran, P. S.; Richter, J. M.; Lin, D. W. Angew. Chem., Int. Ed.
2005, 44, 609. (c) Baran, P. S.; DeMartino, M. P. Angew. Chem., Int. Ed.
2006, 45, 7083. (d) Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin,
D. W.; Castroviejo, P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857.
(e) Richter, J. M.; Whitefield, B.; Maimone, T. J.; Lin, D. W.; Castroviejo,
P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 12857. (f) DeMartino, M. P.;
Chen, K.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 11546.
(7) (a) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450.
(b) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394. (c)
Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446, 404. (d)
Richter, J. M.; Ishihara, Y.; Masuda, T.; Whitefield, B. W.; Llamas, T.;
Pohjakallio, A.; Baran, P. S. J. Am. Chem. Soc. 2008, 130, 17938.
(8) (a) Martin, C. L.; Overman, L. E.; Rohde, J. A. J. Am. Chem. Soc.
2010, 132, 4894. (b) Martin, C. L.; Overman, L. E.; Rohde, J. A. J. Am.
Chem. Soc. 2008, 130, 7568.
1406
Org. Lett., Vol. 14, No. 6, 2012

Next, we turned our attention to exploring the
scope and limitations of this transformation. Thus,
a number of β-ketoamides with different substitu-
ents at either the indole ring or the γ-position of
the amide were examined. We were pleased to find
that substrates with both electron-rich and -deficient
indole moieties worked well under our standard
conditions, providing the corresponding products
with moderate to good yields (Table 2, entries 1À8).
When β-ketoamides with 4-substituted indoles were
used, poorer yields were obtained in comparison
to their regioisomers (compare entries 1 and 2, and
5 and 6). This could be ascribed to steric reasons
which can be seen from the crystallography of 5a.
The H4 of the indole was very close to the newly
formed piperidine ring. When this proton was sub-
stituted with other groups, the steric interaction be-
tween the piperidine ring and the group on C4 should
slow down the oxidative coupling reaction. Further
attempts revealed that changing the γ-substituents of
the β-ketoamides was possible to give the desired
products 5jÀ5m (entries 9À12). However, their reac-
tion yields were considerably lower than that ob-
served for a γ-methyl substituted β-ketoamide. This
problem might result from the poor conversion in the
condensative cyclization, because the simple oxida-
tive coupling product was isolated in ∼37% yield in
the case of the formation of 5l. This result indicated
that dihydrofuran ring formation is sensitive to the
steric hindrance of γ-substituents.
Table 2. Synthesis of Tetracyclic Spiroindolines from Different
β-Ketoamidesa
In summary, an oxidative coupling/cyclization
cascade reaction process for preparing polycyclic
spiroindolines from simple β-ketoamides was devel-
oped. This method features the creation of two
new rings and one quaternary carbon center in a
single step. Application of this method in the syn-
thesis of bioactive compounds is being actively
pursued, and the results will be disclosed in due
course.
Acknowledgment. The authors are grateful to the
Chinese Academy of Sciences, National Natural
Science Foundation of China (Grants 20921091 and
20572119), and Ministry of Science & Technology
(Grant 2009CB940900) for their financial support.
Supporting Information Available. Experimental pro-
1
a Reaction conditions: 1a (0.2 mmol), LiHMDS (0.44 mmol), THF
(3 mL), À78 °C, 30 min, then addition of iodine (0.22 mmol), À78 °C,
then rt, 30 min. b Isolated yield. c 15% starting material was recovered.
d 22% starting material was recovered. e Simple oxidative coupling
product was isolated in 37% yield.
cedures and copies of H and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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