Gold(I)-catalyzed tandem cyclization approach to tetracyclic indolines

Article abstract of DOI:10.1021/ol100153h

Chemical equation presented Two highly stereoselective cationic gold(I)-catalyzed tandem cyclization reactions of alkynylindoles are described. These reactions demonstrated a novel and general strategy to rapidly construct highly functionalized polycyclic indolines. This approach was successfully employed for a formal synthesis of the akuammiline alkaloid minfiensine.

Full text of DOI:10.1021/ol100153h

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1448-1451
Gold(I)-Catalyzed Tandem Cyclization
Approach to Tetracyclic Indolines
Yongxiang Liu, Wenqing Xu, and Xiang Wang*
Department of Chemistry and Biochemistry, UniVersity of Colorado,
Boulder, Colorado 80309
xiang.wang@colorado.edu
Received January 21, 2010
ABSTRACT
Two highly stereoselective cationic gold(I)-catalyzed tandem cyclization reactions of alkynylindoles are described. These reactions demonstrated
a novel and general strategy to rapidly construct highly functionalized polycyclic indolines. This approach was successfully employed for a
formal synthesis of the akuammiline alkaloid minfiensine.
Indoline alkaloids are a class of molecules, many of which
were discovered from natural sources that have been widely
used in traditional medicine and have shown a variety of
biological activities.1 However, further biological studies of
these molecules are often hampered by their limited supplies.
Their diverse and complex architectures (see representative
structures in Figure 1A) have attracted the attention of a
number of synthetic research groups worldwide and have
led to the development of many novel synthetic methods and
strategies,2,3 such as the Diels-Alder/amine cyclization
approach,3e the Heck-iminium cyclization approach,3b and
the tandem [4 + 2]/[3 + 2] cycloaddition approach.3a
However, novel approaches are still urgently needed for the
practical synthesis of bioactive indoline alkaloids.
Recent studies have shown that noble metals, such as
gold and platinum, are excellent Lewis acids for the
selective activation of unsaturated carbon-carbon bonds
and are able to catalyze a large number of organic
transformations with high efficiency at ambient condi-
tions.4 However, applications of these methods to the
synthesis of complex natural products5 have not reached
their full potential.
(2) For reviews, see: (a) Rahman, A.; Basha, A. Indole Alkaloids ; Taylor
& Francis: Amsterdam, 1998; Vol. 2 pp 324. (b) Hudlicky´, T.; Reed, J. W.
The Way of Synthesis: EVolution of Design and Methods for Natural
Products; Wiley-VCH: Weinheim, 2007; p 759. (c) Higuchi, K.; Kawasaki,
T. Nat. Prod. Rep. 2009, 26, 803, and previous articles in this series.
(3) For examples on recent syntheses of indole alkaloids, see: (a)
Ishikawa, H.; Colby, D. A.; Boger, D. L. J. Am. Chem. Soc. 2008, 130,
420. (b) Dounay, A. B.; Humphreys, P. G.; Overman, L. E.; Wrobleski,
A. D. J. Am. Chem. Soc. 2008, 130, 5368. (c) Newhouse, T.; Baran, P. S.
J. Am. Chem. Soc. 2008, 130, 10886. (d) Newhouse, T.; Lewis, C. A.; Baran,
P. S. J. Am. Chem. Soc. 2009, 131, 6360. (e) Jones, S. B.; Simmons, B.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 13606.
(1) (a) Pearce, H. L. In The Alkaloids; Brossi, A., Suffness, M., Eds;
Academic: San Diego, 1990; Vol. 37, p 145. (b) Anthoni, U.; Christophersen,
C.; Nielsen, P. H. In Alkaloids: Chemical and Biological PerspectiVes;
Pelletier, S. W., Ed.; Wiley: New York, 1999; Vol. 13, p 163. (c) Rocha,
L. G.; Almeida, J. R. G. S.; Maceˆdo, R. O.; Barbosa-Filho, J. M.
Phytomedicine 2005, 12, 514. (d) Gigant, B.; Wang, C.; Ravelli, R. B. G.;
Roussi, F.; Steinmetz, M. O.; Curmi, P. A.; Sobel, A.; Knossowl, M. Nature
2005, 435, 519.
10.1021/ol100153h  2010 American Chemical Society
Published on Web 03/02/2010

terminal alkyne of alkynylindoles (e.g., 1, Figure 1B) and
promote either endo- or exo-cyclization. The resulting
iminium ions should be susceptible to nucleophilic attack
and provide highly functionalized indolines (e.g., endo- and
exo-2, Figure 1B) after protonation of the vinylmetal species.
Herein, we describe two stereoselective cationic gold(I)-
catalyzed tandem cyclization reactions to construct highly
functionalized tetracyclic indolines.
Scheme 1
.
First Attempt of Tandem Cyclization Using
Alkynylindole 3
Figure 1. Representative indoline alkaloid natural products and our
proposed approach.
We envisioned a novel and potentially general approach
to polycyclic indolines by using noble metal catalysis as
shown in Figure 1B.6 This approach may rapidly construct
polycyclic indolines bearing two quaternary stereocenters.
A gold or platinum catalyst may selectively activate the
We began our studies with an alkynylindole 3 (Scheme
1), which is easily synthesized in five steps from the protected
indole.7 Compound 3 also contains a secondary alcohol,
which may serve as an internal nucleophile in a second
cyclization step. We were pleased to find that when 3 was
treated with 5 mol % of AuCl3 in dichloromethane at room
temperature, cyclized product 4 was obtained in 32% yield
as a single regioisomer and diastereomer (Scheme 1). Its
structure was assigned based on a series of 1D and 2D NMR
studies and was further confirmed by X-ray crystallographic
analysis (Scheme 1).7 The substrate undergoes a 6-exo-dig
cyclization upon activation by the catalyst, and the stereo-
chemistry at the two quaternary centers is controlled solely
by the stereochemistry of the secondary alcohol.
Next we surveyed several other catalysts (Table 1) to
improve this tandem cyclization reaction. Platinum(II)
chloride and triflic acid are also capable of promoting this
reaction (Table 1, entries 2 and 3); however, significant
decomposition of the substrate is also observed in these
conditions. Attempts to use weaker acids such as AgSbF6
and p-toluenesulfonic acid failed to provide any desired
product (Table 1, entries 4 and 5). Ph3PAuCl-promoted
process requires higher temperature, longer reaction time,
but provides slightly higher yield (Table 1, compare entries
1 and 6) of 4. Good to high yields of the isolated products
are obtained (67-83%; see Table 1, entries 7-9) by using
(4) For recent reviews on gold and/or platinum catalysis, see: (a) Zhang,
L.; Sun, J.; Kozmin, S. A. AdV. Synth. Catal. 2006, 348, 2271. (b) Fu¨rstner,
A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (c) Jime´nez-
Nu´nˇez, E.; Echavarren, A. M. Chem. Commun. 2007, 333. (d) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395. (e) Chianese, A. R.; Lee, S. J.; Gagne´,
M. R. Angew. Chem., Int. Ed. 2007, 46, 4042. (f) Hashmi, A. S. K. Chem.
ReV. 2007, 107, 3180. (g) Michelet, V.; Toullec, P. Y.; Geneˆt, J. P. Angew.
Chem., Int. Ed. 2008, 47, 4268. (h) Shen, H. C. Tetrahedron 2008, 64,
3885. (i) Li, Z.; Brouwer, C.; He, C. Chem. ReV. 2008, 108, 3239. (j) Arcadi,
A. Chem. ReV. 2008, 108, 3266. (k) Jime´nez-Neu´nˇz, E.; Echavarren, A. M.
Chem. ReV. 2008, 108, 3326. (l) Gorin, D. J.; Sherry, B. D.; Toste, F. D.
Chem. ReV. 2008, 108, 3351. (m) Marion, N.; Nolan, S. P. Chem. Soc.
ReV. 2008, 37, 1776. (n) Fu¨rstner, A. Chem. Soc. ReV. 2009, 38, 3208.
(5) For recent applications of gold and/or platinum catalysis on target-
oriented synthesis, see: (a) Zhu, J.; Germain, A. R.; Porco, J. A., Jr. Angew.
Chem., Int. Ed. 2004, 43, 1239. (b) Staben, S. T.; Kennedy-Smith, J. J.;
Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem.,
Int. Ed. 2006, 45, 5991. (c) Li, Y.; Zhou, F.; Forsyth, C. J. Angew. Chem.,
Int. Ed. 2007, 46, 279. (d) Fu¨rstner, A.; Heilmann, E. K.; Davies, P. W.
Angew. Chem., Int. Ed. 2007, 46, 4760. (e) Veitch, G. E.; Beckmann, E.;
Burke, B. J.; Boyer, A.; Maslen, S. L.; Ley, S. V. Angew. Chem., Int. Ed.
2007, 46, 7629. (f) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew.
Chem., Int. Ed. 2007, 46, 7671. (g) Trost, B. M.; Dong, G. Nature 2008,
456, 485. (h) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J. Angew. Chem.,
Int. Ed. 2008, 47, 1780. (i) Kozak, J. A.; Dake, G. R. Angew. Chem., Int.
Ed. 2008, 47, 4221. (j) Sethofer, S. G.; Staben, S. T.; Hung, O. Y.; Toste,
F. D. Org. Lett. 2008, 10, 4315. (k) Simmons, E. M.; Hardin, A. R.; Guo,
X.; Sarpong, R. Angew. Chem., Int. Ed. 2008, 47, 6650.
(6) For recent references on noble metal catalysis involving indoles, see:
(a) Toullec, P. Y.; Genin, E.; Leseurre, L.; Gene´t, J. P.; Michelet, V. Angew.
Chem., Int. Ed. 2006, 45, 7427. (b) Ferrer, C.; Amijs, C. H. M.; Echavarren,
A. M. Chem.sEur. J. 2007, 13, 1358. (c) Wang, M. Z.; Wong, M. K.;
Che, C. M. Chem.sEur. J. 2008, 14, 8353. (d) Bandini, M.; Eichholzer,
A. Angew. Chem., Int. Ed. 2009, 48, 9533.
(7) See the Supporting Information for details.
Org. Lett., Vol. 12, No. 7, 2010
1449

Table 1. Optimization of the Tandem Cyclization Conditions
entry
catalyst/additivea
time/temp (h/°C)
conversionb (%)
yieldc (%)
1
2
3
4
5
6
7
8
9
AuCl3
PtCl2
TfOH
AgSbF6
0.5/23
12/80
12/23
12/23
12/23
12/80
1/23
100
50
70
0
32
14d
35
0
TsOH
0
0
Ph3PAuCl
Ph3PAuCl/ AgBF4
Ph3PAuCl/ AgOTf
Ph3PAuCl/ AgSbF6
80
100
100
100
1
55e
78
67
83
1/23
1/23
a 5 mol %. Reaction conversions were based on the consumption of 3 calculated by the integration of H NMR spectra. c Average isolated yield of at
b
least two runs. d In toluene. e In acetonitrile.
cationic gold(I) species, and antimony hexafluoride was
found to be the optimal counterion providing the product in
83% yield (Table 1, entry 9).
substituted alkynes (Table 2, entries 2, 3, 5, and 9) require
longer reaction time and provide slightly lower yields of the
desired products. The olefin geometry of the products was
determined to be E by 1D NOE studies,7 which is consistent
with literature reports on several other gold-catalyzed cy-
clizations.8 However, alkyl-substituted alkynes did not
produce any desired cyclization product but afforded the
corresponding enones instead.9
These tandem cyclization reactions are not limited to
alcohol nucleophiles. Sulfonamides or carbamates also served
as nucleophiles in the second cyclization reaction and
afforded the desired tetracyclic indolines with good yields
and selectivities (Table 2, entries 11-14). However, the
acetamide substrates cyclized to form 5-methylene-4,5-
dihydrooxazoles instead of the desired tetracyclic indo-
lines.7,10
A variety of substrates were then screened using the
optimized conditions, the reactions remained very good in
all cases as shown in Table 2. No other regioisomers or
diastereomers were identified from the reaction mixtures.
Indoles possessing substitution at C3 and C5, including
tryptamine derivatives (Table 2, entries 6 and 10), are
generally well tolerated. The indole nitrogen requires an
electron-withdrawing group, such as a methoxycarbonyl, a
Boc, or a tosyl group, for the reaction to provide the desired
products. The Nin-Me or Nin-H substrates failed to cyclize
under the standard reaction conditions and provided a
complex mixture of products at higher temperature. Phenyl-
Table 2. Scope of Gold(I)-Catalyzed Tandem Cyclization
Reaction
Scheme 2
.
Gold(I)-Catalyzed Tandem Cyclization Using
Enantioenriched Substrate 5o
entry
5
R1/ R2/ R3/ R4
X
yielda (%)
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
H/Et/COOMe/H
O
O
O
O
O
O
O
O
O
O
83
65
67
85
75
84
85
88
64
82
78
75
79
70
An enantioenriched substrate 5o (81% ee) was also
prepared and afforded the desired product 6o in 81% ee under
the standard conditions (Scheme 2).7 This result proved
H/Me/COOMe/Ph
H/H/COOMe/Ph
OMe/Et/COOMe/H
OMe/Et/COOMe/Ph
H/CH2CH2NPhth /Boc/H
H/Me/Ts/H
OMe/Et/Ts/H
OMe/Et/Ts/Ph
H/CH2CH2NPhth/Ts/H
OMe/Et/COOMe/H
OMe/Et/COOMe/H
(8) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D.
Angew. Chem., Int. Ed. 2004, 43, 5350. (c) Harkat, H.; Weibel, J. M.; Pale,
P. Tetrahedron Lett. 2007, 48, 1439. (d) Amijs, C. H. M.; Lo´pez-Carrillo,
V.; Raducan, M.; Pe´rez-Gala´n, P.; Ferrer, C.; Echavarren, A. M. J. Org.
Chem. 2008, 73, 7721.
9
10
11
12
13
14
5j
5k
5l
(9) (a) Egi, M.; Yamaguchi, Y.; Fujiwara, N.; Akai, S. Org. Lett. 2008,
9, 1867. (b) Ramo´ny, R. S.; Marionz, N.; Nolan, S. P. Tetrahedron 2009,
65, 1767.
NCOOMe
NTs
NCOOMe
5m OMe/Et/Ts/H
5n OMe/Et/COOMe/H
(10) (a) Hashmi, A. S. K.; Weyrauch, J. P.; Frey, W.; Bats, J. W. Org.
Lett. 2004, 6, 4391. (b) Robles-Mach´ın, R.; Adrio, J.; Carretero, J. C. J.
Org. Chem. 2006, 71, 5023. (c) Buzas, A.; Gagosz, F. Synlett 2006, 2727.
(d) Lee, E. S.; Yeom, H. S.; Hwang, J. H.; Shin, S. Eur. J. Org. Chem.
NNs
a Average isolated yield of at least two runs.
2007, 3503
.
1450
Org. Lett., Vol. 12, No. 7, 2010

quantitative retention of chirality at the secondary propargyl
alcohol, which should be useful for the synthesis of complex
indoline alkaloids.
Scheme 3. Formal Synthesis of Minfiensine
Having proved our hypothesis, we then examined a tandem
cyclization approach on tryptamine derivatives 7 (Table 3),
each of which contains a two-carbon linker between the
indole and the alkyne. To our delight, the reaction proceeded
smoothly using the same catalyst system in toluene at
60 °C and provided 6-endo-dig cyclization products 8
cleanly.
Table 3. Scope of Gold(I)-Catalyzed Tandem Cyclization
Studies for the Synthesis of Akuammilines
total synthesis of the akuammiline alkaloid natural product
minfiensine (Figure 1A).3b
In summary, we have developed a novel approach to the
construction of tetracyclic indolines using stereoselective
cationic gold(I)-catalyzed tandem cyclization reactions. This
approach allows rapid assembly of two rings and two
stereocenters including a quaternary carbon center in a single
step with a wide substrate scope. These two tandem
cyclization reactions have also shown excellent versatility
regarding the functional groups involved. A formal synthesis
of the akuammiline alkaloid natural product minfiensine is
also described. Further mechanistic studies, evaluation of the
biological activities of the synthesized unnatural indoline
alkaloids, and applications of this approach to indoline
alkaloid synthesis are in progress and will be reported in
due course.
entry
7
R1
R2
R3
8
yielda (%)
1
2
3
4
5
6
7
8
7a
7b
7c
7d
7e
7f
Boc
Boc
Boc
Boc
Boc
H
Boc
Boc
Ts
Ns
Ac
Boc
Ac
Ts
H
Ph
H
H
H
H
H
H
8a
8b
8c
8d
8e
8f
75
84
81
88
80
87
83
86
7g
7h
H
Me
8g
8g
a Average isolated yield of at least two runs.
Acknowledgment. We are grateful to Dr. Richard Shoe-
maker (Department of Chemistry and Biochemistry, Uni-
versity of Colorado at Boulder) for NMR spectroscopic
assistance and to Professors Tarek Sammakia and Andrew
Phillips (Department of Chemistry and Biochemistry, Uni-
versity of Colorado at Boulder) for useful discussions.
Financial support for this work was provided by the
University of Colorado.
For all substrates we tested (see Table 3), the reactions
went to completion within 2 h and afforded the core
structures of the akuammiline alkaloids2a,c in good yields
(75-88%); no 5-exo-dig products were detected in all cases.
In addition to carbamates and sulfonamides, secondary
amides (Table 3, entries 5 and 7) also serve as nucleophile
in the second cyclization step. Interestingly, the Nin-H and
Nin-Me substrates also participate in this tandem cyclization
reaction and provide tetracyclic indolines 8 cleanly (Table
3, entries 6-8).
Supporting Information Available: Full experimental
details, including the spectroscopic and analytical data of
all new compounds and X-ray crystallographic data of
compound 4. This material is available free of charge via
the Internet at http://pubs.acs.org.
The aniline of tetracyclic indoline 8f was converted to a
methyl carbamate when treated with triphosgene followed
by quenching with anhydrous methanol (Scheme 3). The
resulting compound (9) is a key intermediate in Overman’s
OL100153H
Org. Lett., Vol. 12, No. 7, 2010
1451