An interrupted fischer indolization approach toward fused indoline-containing natural products

Article abstract of DOI:10.1021/ol901383j

An efficient method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted Fischer indolization sequence. Our studies show that the approach will likely be amenable to the synthesis of complex targets, such as the communesin natural products.

Full text of DOI:10.1021/ol901383j

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3458-3461
An Interrupted Fischer Indolization
Approach toward Fused
Indoline-Containing Natural Products
Ben W. Boal, Alex W. Schammel, and Neil K. Garg*
Department of Chemistry and Biochemistry, UniVersity of California,
Los Angeles, California 90095-1569
neilgarg@chem.ucla.edu
Received June 19, 2009
ABSTRACT
An efficient method to access the fused indoline ring system present in a multitude of bioactive molecules has been developed. The strategy
involves the condensation of hydrazines with latent aldehydes to ultimately deliver indoline-containing products by way of an interrupted
Fischer indolization sequence. Our studies show that the approach will likely be amenable to the synthesis of complex targets, such as the
communesin natural products.
The discovery of efficient methods to synthesize complex
bioactive molecules continues to be a vital area of research.1
A subset of compounds that have received substantial interest
due to their medicinal properties and impressive structures
are those that possess a fused indoline motif of the type 1
shown in Figure 1. Such compounds include the acetylcho-
linesterase inhibitors physovenine (2) and physostigmine
(3)2,3 and the anticancer agents diazonamide A (4),4 bipleio-
phylline (5),5 communesin B (6),6 aspidophylline A (7),7 and
echitamine chloride (8).8 The importance of indoline-
containing compounds has prompted the development of a
number of methods to access such motifs, with numerous
studies particularly in the area of pyrrolidinoindoline syn-
thesis. In most cases, the fused indoline ring systems are
assembled in a stepwise fashion by the initial synthesis of a
substituted indole9 or oxindole10 intermediate, which is then
further elaborated to the target 1. Herein, we report a
(4) For biological studies, see: (a) Williams, N. S.; Burgett, A. W. G.;
Atkins, A. S.; Wang, X.; Harran, P. G.; McKnight, S. L. Proc. Natl. Acad.
Sci. U.S.A. 2007, 104, 2074–2079. (b) Wang, G.; Shang, L.; Burgett,
A. W. G.; Harran, P. G.; Wang, X. Proc. Natl. Acad. Sci. U.S.A. 2007,
104, 2068–2073. For a review of synthetic studies, see: (c) Lachia, M.;
Moody, C. J. Nat. Prod. Rep. 2008, 25, 227–253.
(1) (a) Hudlicky, T.; Reed, J. W. The Way of Synthesis; Wiley-VCH:
Weinheim, 2007. (b) Wender, P. A.; Verman, V. A.; Paxton, T. J.; Pillow,
T. H. Acc. Chem. Res. 2008, 41, 40–49.
(5) Kam, T.-S.; Tan, S.-J.; Ng, S.-K.; Komiyama, K. Org. Lett. 2008,
10, 3749–3752.
(6) (a) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai, K.; Usami,
Y.; Matsumura, E.; Imachi, M.; Ito, T.; Hasegawa, T. Tetrahedron Lett.
1993, 34, 2355–2358. (b) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.;
Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat. Prod. 2004, 67,
78–81. For a comprehensive review, see: (c) Siengalewicz, P.; Gaich, T.;
Mulzer, J. Angew. Chem., Int. Ed. 2008, 47, 8170–8176.
(2) For a review of these alkaloids, see: Takano, S.; Ogasawara, K.
Alkaloids 1989, 36, 225–251
.
(3) Physostigmine (3) has been used to treat glaucoma, Alzheimer’s
disease, and myasthenia gravis. For a pertinent review, see: Triggle, D. J.;
Mitchell, J. M.; Filler, R. CNS Drug ReV. 1998, 4, 87–136
.
10.1021/ol901383j CCC: $40.75
Published on Web 07/14/2009
 2009 American Chemical Society

Scheme 1. Proposed Cascade Sequence To Access Indoline 1
the past 50 years,13-15 most notably by Grandberg13 and
Takano,14 a general and mild method to access compounds
of type 1 using the strategy outlined in Scheme 1 has not
been discovered. Moreover, the notion that such a method
could be used to prepare the indoline scaffold present in a
multitude of complex biologically important compounds
(e.g., 4-8) has not been realized. In this paper, we describe
the development and scope of this powerful cascade reaction,
which provides access to an array of indoline scaffolds,
including the complex polycyclic framework observed in
communesin B. In addition, a one-step formal total synthesis
of physovenine is disclosed.
Figure 1. Parent indoline 1 and representative natural products 2-8.
powerful cascade reaction that allows direct access to 1 from
simple starting materials under mild aqueous conditions.
Our approach to the indoline scaffold 1 of compounds 2-8
is inspired by the classic Fischer indole synthesis11,12 and is
presented in Scheme 1. We envisaged that phenylhydrazine
(9) and an R-disubstituted aldehyde 10 would react in the
presence of acid to afford enamine intermediate 11. Subse-
quent [3,3]-sigmatropic rearrangement and rearomatization
would provide aniline 12, which in turn would cyclize with
loss of NH3 to furnish transient indolenine 13. Intramolecular
attack by a proximal heteroatom substituent (X ) NR or O)
would deliver the desired product 1. The successful imple-
mentation of this interrupted Fischer indolization process
would lead to the formation of three new bonds, two
heterocyclic rings, and two stereogenic centers, one of which
is quaternary (C3).
Scheme 2. Lactols and Hemiaminals as Latent Aldehydes
Our studies commenced with the identification of an
efficient method for accessing the key substituted aldehyde
reaction partners 10 (Scheme 2). It was noted that isomeric
lactols and hemiaminals 14 would likely serve as suitable
aldehyde surrogates in the desired transformation, following
a strategy sometimes employed in modifications of the
Fischer indole synthesis.16 This approach was considered
Although scattered examples of interrupted Fischer in-
dolization reactions have been reported in the literature over
(7) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.; Komiyama,
K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1783–1789
.
(8) (a) Jagetia, G.; Baliga, M. S.; Venkatesh, P.; Ulloor, J. N.; Mantena,
S. K.; Genebriera, J.; Mathuram, V. J. Pharm. Pharmacol. 2005, 57, 1213–
1219. (b) Ram´ırez, A.; Garc´ıa-Rubio, S. Curr. Med. Chem. 2003, 10, 1891–
(13) In a seminal study, Grandberg demonstrated that a C2-substituted
pyrrolidinoindoline could be prepared by the reaction of phenylhydrazine
and 5-chloro-3-methylpentan-2-one. However, this method is not applicable
to the synthesis of furoindolines or to the more complex ring systems
encountered in numerous natural products, such as 4-7; see: (a) Grandberg,
I. I.; Zuyanova, T. I.; Afonina, N. I.; Ivanova, T. A. Dokl. Akad. Nauk
SSSR 1967, 176, 583-585. For a synthesis of furoindolines, albeit in modest
yield, see: (b) Grandberg, I. I.; Tokmakov, G. P. Khim. Geterotsikl. Soedin.
1915
.
(9) For examples of pyrrolidinoindoline and furoindoline syntheses from
substituted indoles, see: (a) Depew, K. M.; Marsden, S. P.; Zatorska, D.;
Zatorski, A.; Bornmann, W. G.; Danishefsky, S. J. J. Am. Chem. Soc. 1999,
121, 11953–11963. (b) Austin, J. F.; Kim, S. G.; Sinz, C. J.; Xiao, W. J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5482–5487.
(c) Movassaghi, M.; Schmidt, M. A. Angew. Chem., Int. Ed. 2007, 46, 3725–
3728. (d) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Science 2009, 324,
1975, 207–210
.
(14) Takano has synthesized a pyrrolidinoindoline product using an
interrupted Fischer indolization reaction; see: (a) Takano, S.; Moriya,
M.; Iwabuchi, Y.; Ogasawara, K. Chem. Lett. 1990, 109–112. (b) Takano,
S.; Ogasawara, K.; Iwabuchi, R.; Moriya, M. JP 03112989 A 19910514,
1991.
238–241
.
(10) For examples of pyrrolidinoindoline and furoindoline syntheses from
substituted oxindoles, see: (a) Matsuura, T.; Overman, L. E.; Poon, D. J.
J. Am. Chem. Soc. 1998, 120, 6500–6503. (b) Trost, B. M.; Zhang, Y. J. Am.
(15) For other examples, see: (a) Tsuji, R.; Nakagawa, M.; Nishida, A.
Heterocycles 2002, 58, 587–593. (b) Britten, A. Z.; Bardsley, W. G.; Hill,
C. M. Tetrahedron 1971, 27, 5631–5639. (c) Rosenmund, P.; Sadri, E.
Liebigs Ann. Chem. 1979, 927–943. (d) Rosenmund, P.; Gektidis, S.; Brill,
H.; Kalbe, R. Tetrahedron Lett. 1989, 30, 61–62. (e) Nishida, A.; Ushigome,
Chem. Soc. 2006, 128, 4590–4591
(11) For reviews, see: (a) Robinson, B. Chem. ReV. 1963, 63, 373–401.
(b) Robinson, B. Chem. ReV. 1969, 69, 227–250
(12) (a) Fischer, E.; Jourdan, F. Ber. 1883, 16, 2241–2245. (b) Fischer,
.
.
E.; Hess, O. Ber. 1884, 17, 559–568
.
S.; Sugimoto, A.; Arai, S. Heterocycles 2005, 66, 181–185.
Org. Lett., Vol. 11, No. 15, 2009
3459

ideal for the present study because of the ready availability
of substituted lactones and lactams 15, which would serve
as precursors to the desired substrates. Thus, a variety of
substrates of the type 14 were accessible in a straightforward
fashion.17
(entries 1-6). Of note, these furoindoline and pyrrolidinoin-
doline motifs are present in an array of medicinally important
compounds, such as physovenine (entry 1), physostigmine
(entry 2),2 flustramine B (entry 4),20 and the hodgkinsine
alkaloids (entry 6).21 Furthermore, 6-membered homologues
of the furoindoline and pyrrolidinoindoline frameworks were
accessible using this methodology (entries 7 and 8).
The feasibility of the proposed cascade reaction sequence
of Scheme 1 was established from the reaction between
commercially available phenylhydrazine (9) and latent al-
dehyde 16 (1 equiv) under a variety of acidic conditions
(Table 1). Lewis acids were examined and found to be
ineffective (entries 1 and 2). However, use of p-toluene-
sulfonic acid, trifluoroacetic acid, or HCl each afforded the
desired product 17 in modest yield (entries 3-5). Sulfuric
acid-mediated reaction conditions were also explored and
ultimately provided the desired product in 87% yield (entry
6). Recognizing that a milder acid source would be more
generally useful, acetic acid was examined. Although the
use of neat acetic acid afforded modest product yields (entry
7), employment of a 1:1 mixture of acetic acid and water at
60 °C furnished indoline 17 in 89% isolated yield (entry 8).18
Table 2. Variation of the Surrogate Aldehyde Coupling Partner
Table 1. Survey of Acids To Promote Furoindoline Synthesis
a Conditions: 9 (1 equiv), 1:1 AcOH/H2O, 60 °C. b Conditions: 9 (1
equiv), 1:1 AcOH/H2O, 100 °C. c Isolated yield.
entry
acid source
conditions
yielda (%)
As shown in Table 3, the transformation is broad in scope
with respect to the hydrazine component.22 N-Methyl- and
N-benzyl-substituted hydrazines were deemed competent
coupling partners (entries 1-4). Whereas the N-benzyl group
can be used as a protective group in multistep synthesis, the
N-Me group is present in a number of natural products (e.g.,
2, 3, and 6, Figure 1). In addition, para and ortho substituents
were tolerated under the reaction conditions (entries 5-14).
Importantly, use of chlorohydrazines furnished haloindolines
(entries 9-12), which could be further functionalized by
transition-metal-catalyzed cross-coupling chemistry. Finally,
the transformation proceeded smoothly with p-methoxyphe-
nylhydrazine as a substrate, thus affording C5-oxygenated
products in good yields (entries 13 and 14).23
1
2
3
4
5
6
7
8
PCl3
ZnCl2
benzene, 60 °C
EtOH, 100 °C
<5
<5
51
64
70
87
52
89b
TsOH
TFA
5% HCl
4% H2SO4
AcOH
AcOH
EtOH, H2O, 60 °C
CH3CN, 60 °C
CH3CN, 60 °C
CH3CN, 60 °C
AcOH, 60 °C
1:1 AcOH/H2O, 60 °C
a Unless otherwise noted, yields determined by 1H NMR analysis.
b Isolated yield.
Having identified suitable conditions for indoline forma-
tion, we evaluated the scope of the transformation. Gratify-
ingly, both lactols and hemiaminal substrates could be
utilized,19 thereby furnishing oxygen- and nitrogen-contain-
ing indoline products, respectively (Table 2). For both classes
of compounds, fused indolines possessing methyl, allyl, and
phenyl substituents at C3 could be prepared in good yields
Several significant features of the reactions shown in
Tables 2 and 3 should be noted: (a) both coupling partners
employed are readily accessible entities (i.e., substituted
hydrazines and aldehyde surrogates), (b) the reaction condi-
tions employed (i.e., aqueous acetic acid) are inexpensive,
operationally simple, and do not require costly transition-
metal catalysts, and (c) the strategy is convergent, broad in
(16) (a) Campos, K. R.; Woo, J. C. S.; Lee, S.; Tillyer, R. D. Org. Lett.
2004, 6, 79–82. (b) Brodfuehrer, P. R.; Chen, B.-C.; Sattelberg, T. R.; Smith,
P. R.; Reddy, J. P.; Stark, D. R.; Quinlan, S. L.; Reid, J. G.; Thottathil,
J. K.; Wang, S. J. Org. Chem. 1997, 62, 9192–9202. (c) Adachi, H.;
Palaniappan, K. K.; Ivanov, A. A.; Bergman, N.; Gao, Z.-G.; Jacobson,
K. A. J. Med. Chem. 2007, 50, 1810–1827.
(20) Carle, J. S.; Christophersen, C. J. Am. Chem. Soc. 1979, 101, 4012–
4013.
(17) See the Supporting Information for details.
(21) Gue´ritte-Voegelein, F.; Se´venet, T.; Pusset, J.; Adeline, M.-T.;
Gillet, B.; Beloiel, J.-C.; Gue´nard, D.; Potier, P.; Rasolonjanahary, R.;
Kordon, C. J. Nat. Prod. 1992, 55, 923–930.
(18) For the use of H2O/AcOH to facilitate the Fischer indole synthesis,
see: (a) Desaty, D.; Kegleviæ, D. Croat. Chem. Acta 1964, 36, 103–109.
(b) Kegleviæ, D.; Stojanac, N.; Desaty, D. Croat. Chem. Acta 1961, 33,
83–88.
(22) Hydrazines could be employed in either free-base form or as the
hydrochloric acid salts; see the Supporting Information for details.
(23) Use of p-(trifluoromethyl)phenylhydrazine as a substrate afforded
low yields of product.
(19) All lactol and hemiaminal substrates were employed as an
inconsequential mixture of diastereomers.
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Org. Lett., Vol. 11, No. 15, 2009

Table 3. Variation of the Hydrazine Coupling Partner
Scheme 3. Formal Total Synthesis of Physovenine (2) and
Synthesis of the Communesin Indoline Scaffold
Diels-Alder product 22, following the general procedure
described by Corey.26 Gratifyingly, exposure of 22 to
N-methylphenylhydrazine (23) in 1:1 AcOH/H2O delivered
indoline 24, which possesses the 6,5,6,6-ring system of the
communesin natural products.27
In summary, we have developed an efficient method to
access the fused indoline ring systems present in a variety
of natural products. The strategy involves the condensation
of readily available hydrazines with latent aldehydes to
ultimately deliver indoline-containing products by way of
an interrupted Fischer indolization sequence. The method is
convergent, mild, operationally simple, and broad in scope.
In addition, our studies show that the approach would likely
be amenable to the synthesis of complex targets, such as
the communesin natural products. The development of
diastereo- and enantioselective variants of the newly de-
scribed transformation is currently underway in our labora-
tory, along with related studies in the realm of natural product
total synthesis.
a Conditions unless otherwise noted: 1:1 ratio of hydrazine to 16 or 18,
1:1 AcOH/H2O, 60 °C. b AcOH. c AcOH, 23 °C. d 100 °C. e 75 °C. f Isolated
yield.
scope, and therefore, could be used to prepare libraries of
compounds possessing the biologically privileged indoline
motif.
As shown in Scheme 3, the methodology is effective in
more complex settings. Reaction of hydrazine 19 with lactol
16 in AcOH furnished furoindoline 20 in 77% yield, which
constitutes a formal total synthesis of physovenine (2).10a,24,25
In addition, known sulfonamide 2126 was reacted with
1-ethoxypropene in the presence of Cs2CO3 to afford hetero-
Acknowledgment. We are grateful to the University of
California, Los Angeles and Boehringer Ingelheim for
financial support. We thank Professors Harran (UCLA) and
Houk (UCLA) for pertinent discussions, the Garcia-Garibay
laboratory (UCLA) for the generous access to instrumenta-
tion, and Dr. John Greaves (UC Irvine) for mass spectra.
Supporting Information Available: Detailed experimen-
tal details and compound characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
(24) For asymmetric routes to 20 (7 and 18 steps, respectively), see ref
10a and: ElAzab, A. S.; Taniguchi, T.; Ogasawara, K. Org. Lett. 2000, 2,
2757–2759
.
(25) Physovenine can be resolved readily, on preparative scale, using
column chromatography with cellulose triacetate; see: Yu, Q.; Liu, C.;
Brzostowska, M.; Chrisey, L.; Brossi, A.; Greig, N. H.; Atack, J. R.;
Soncrant, T. T.; Rapoport, S. I.; Radunz, H. HelV. Chim. Acta 1991, 74,
OL901383J
761–766
(26) Steinhagen, H.; Corey, E. J. Angew. Chem., Int. Ed. 1999, 38, 1928–
1931.
.
(27) Indoline 24 has previously been prepared by an intermolecular aza-
Diels-Alder strategy; see: May, J. A.; Stoltz, B. M. Tetrahedron 2006,
62, 5262–5271.
Org. Lett., Vol. 11, No. 15, 2009
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