Gold-catalyzed cycloisomerization of N-propargylindole-2-carboxamides: Application toward the synthesis of lavendamycin analogues

Article abstract of DOI:10.1021/ol801385h

(Chemical Equation Presented) A series of N-propargylindole-2-carboxamides were found to undergo a AuCl₃-catalyzed cycloisomerization to give β-carbolinones in high yield. The corresponding β-chlorocarboline derivative was prepared and used for

Full text of DOI:10.1021/ol801385h

ORGANIC
LETTERS
2008
Vol. 10, No. 16
3631-3634
Gold-Catalyzed Cycloisomerization of
N-Propargylindole-2-carboxamides:
Application toward the Synthesis of
Lavendamycin Analogues
Dylan B. England and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received June 19, 2008
ABSTRACT
A series of N-propargylindole-2-carboxamides were found to undergo a AuCl3-catalyzed cycloisomerization to give ꢀ-carbolinones in high
yield. The corresponding ꢀ-chlorocarboline derivative was prepared and used for Pd(0)-catalyzed cross-coupling chemistry directed toward
the synthesis of lavendamycin analogues.
The number of reports describing the utility of gold
complexes as homogeneous catalysts for the formation of
C-X and C-C bonds has dramatically increased in recent
years.1 Gold catalysts can be considered as powerful soft
Lewis acids for the activation of C-C triple bonds toward
nucleophilic attack.2 A variety of nucleophilic reagents, such
as H2O/alcohols,3 alkynes,4 azides,5 and carbonyl groups,6
have been utilized. These catalytic cyclization reactions
generally proceed under extremely mild conditions and are
characterized by high turnover numbers. Gold complexes are
also particularly active in promoting the intermolecular and
intramolecular hydroarylation of alkynes7 and allenes.8
Recently, the Echavarren group reported that indoles react
intramolecularly with alkynes in the presence of gold
catalysts to give six- to eight-membered ring annulated
(1) For some recent reviews of gold chemistry, see: (a) Dyker, G. Angew.
Chem., Int. Ed. 2000, 39, 4237. (b) Hofmann-Roder, A.; Krause, N. Org.
Biomol. Chem. 2005, 3, 387. (c) Zhang, L.; Sun, J.; Kozmin, S. A. AdV.
Synth. Catal. 2006, 348, 2271. (d) Hashmi, A. S. K.; Hutchings, G. J. Angew.
Chem., Int. Ed. 2006, 45, 7896. (e) Jime´nez-Nun˜ez, E.; Echavarren, A. M.
Chem. Commun. 2007, 333. (f) Hashmi, A. S. K. Catal. Today 2007, 122,
211. (g) Hashmi, A. S. K. Chem. ReV. 2007, 107, 3180. (h) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395.
(2) (a) Hashmi, A. S. K. Gold Bull. 2003, 36, 3. (b) Echavarren, A. M.;
Nevado, C. Chem. Soc. ReV. 2004, 33, 431. (c) Bruneau, C. Angew. Chem.,
Int. Ed. 2005, 44, 2328.
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Giuseppe, S.; Marinelli, F.; Rossi, E. AdV. Synth. Catal. 2001, 343, 443.
(c) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005, 127,
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Soc. 2003, 125, 11925. (d) Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka,
M. Angew. Chem., Int. Ed. 2002, 41, 4563.
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Chem., Int. Ed. 2000, 39, 2285. (b) Asao, N.; Takahashi, K.; Lee, S.;
Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. (c) Asao,
N.; Aikawa, H.; Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 7458. (d)
Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164.
(7) (a) Nevado, C.; Echavarren, A. M. Synthesis 2005, 167. (b) Lalonde,
R. L.; Sherry, B. D.; Kang, E. J.; Toste, F. D. J. Am. Chem. Soc. 2007,
129, 2452.
(4) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc.
2000, 122, 11553. (b) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D.
J. Am. Chem. Soc. 2004, 126, 4526. (c) Staben, S. T.; Kennedy-Smith, J. J.;
Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350. (d) Zhang, L.; Kozmin,
S. A. J. Am. Chem. Soc. 2004, 126, 11806. (e) Zhang, L.; Kozmin, S. A.
J. Am. Chem. Soc. 2005, 127, 6962. (f) Gagosz, F. Org. Lett. 2005, 7, 4129.
(g) Fu¨rstner, A.; Morency, L. Angew. Chem., Int. Ed. 2008, 47, 5030.
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10.1021/ol801385h CCC: $40.75
Published on Web 07/16/2008
2008 American Chemical Society

compounds.9,10 We envisioned taking advantage of a some-
what related cycloisomerization for a synthesis of various
analogues of the antitumor antibiotic lavendamycin.
Scheme 1
Lavendamycin (1) was isolated and characterized in 1981
by Doyle from the fermentation broths of Streptomyces
laVendulae11 and is structurally and biosynthetically related
to streptonigrin (2),12 another potent antitumor antibiotic
(Figure 1). Both of these compounds have been shown to
formation and further D-ring construction by a thermolytic
nitrene insertion.18 Herein, we describe a highly efficient
route toward the synthesis of various lavendamycin analogues
utilizing a gold-catalyzed cycloisomerization of N-propar-
gylindole-2-carboxamides.
Figure 1. Some potent antitumor antibiotics.
possess cytotoxic properties and exhibit significant activity
against topoisomerases.13 Consequently, these target mol-
ecules have been the focus of much synthetic effort since
their initial structural identification.14 A limitation to exploit-
ing the biological properties of lavendamycin is its toxicity
that may be partly due to the presence of the quinone moiety
in the A-ring. Synthetic approaches toward lavendamycin
and its structural analogues generally involve either a
Bischler-Napieralski cyclodehydration15 or a Pictet-Spengler
cyclization to build the C-ring.16 The Boger group’s synthesis
of 1 was based upon the formation of the B-ring by a
Friedlander condensation.17 Still another approach that had
been used involves a modified Knoevenagel-Stobbe pyridine
Our synthetic plan is shown in antithetic format in Scheme
1. Thus, a retrosynthetic analysis of the much simpler
Scheme 2
(9) (a) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45,
1105. (b) Ferrer, C.; Amijs, C. H. M.; Echavarren, A. M. Chem. Eur. J.
2007, 13, 1358
.
(10) For some related transition-metal-catalyzed annulations of indoles,
see: (a) Beccalli, E. M.; Broggini, C. Tetrahedron Lett. 2003, 44, 1919. (b)
Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2003, 125, 9578. (c) Liu,
C.; Han, X.; Wang, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126,
3700. (d) Liu, C.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 10250.
(e) Bressy, C.; Alberico, D.; Lautens, M. J. Am. Chem. Soc. 2005, 127,
13148. (f) Bhanu Prasad, B. A.; Yoshimoto, F. K.; Sarpong, R. J. Am. Chem.
Soc. 2005, 127, 12468
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(11) Doyle, T. W.; Balitz, R. E.; Nettletone, D. E.; Gould, S. J.; Tann,
C. H.; Moews, A. E. Tetrahedron Lett. 1981, 22, 4595.
(12) (a) Rao, K. V.; Cullen, W. P. Antibiot. Annu. 1959, 950. (b) Rao,
K. V.; Biemann, K.; Woodward, R. B. J. Am. Chem. Soc. 1963, 85, 2532.
(c) Chiu, Y. Y. H.; Lipscomb, W. N. J. Am. Chem. Soc. 1975, 97, 2525.
(13) Boger, D. L.; Yasuda, M.; Mitscher, L. A.; Drake, S. D.; Kitos,
P. A.; Thompson, S. C. J. Med. Chem. 1987, 30, 1918.
(14) For some leading references, see: Nourry, A.; Legoupy, S.; Huet,
F. Tetrahedron 2008, 64, 2241.
(15) (a) Kende, A. S.; Ebetino, F. H. Tetrahedron Lett. 1984, 25, 923.
(b) Kende, A. S.; Ebetino, F. H.; Battista, R.; Boatman, R. J.; Lorah, D. P.;
Lodge, E. Heterocycles 1984, 21, 91.
(16) (a) Hibino, S.; Okazaki, M.; Sato, K.; Morita, I.; Ichikawa, M.
Heterocycles 1983, 20, 1957. (b) Hibino, S.; Okazaki, M.; Ichikawa, M.;
Sato, K.; Ishizu, T. Heterocycles 1985, 23, 261.
(17) (a) Boger, D. L.; Panek, J. S. Tetrahedron Lett. 1984, 25, 3175.
(b) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org. Chem. 1985,
50, 5782. (c) Boger, D. L.; Duff, S. R.; Panek, J. S.; Yasuda, M. J. Org.
Chem. 1985, 50, 5790.
3632
Org. Lett., Vol. 10, No. 16, 2008

Table 1. Cycloisomerization of Indolo-Substituted
Propargylcarboxamides
Table 2. Cross-Coupling Reactions of ꢀ-Chorocarboline 15
ꢀ-carboline CDE ring system of lavendamycin (i.e., 3)
revealed to us that this skeletal framework could be obtained
from a cross-coupling reaction of two key intermediates,
namely the ꢀ-substituted carboline 4 and pyridinylstannane
5. Compound 4 was envisioned to result from 1H-pyrido-
[3,4-b]indol-1-one 6, which in turn would arise from a gold-
catalyzed intramolecular cycloisomerization of N-(prop-2-
ynyl)-1H-indole-2-carboxamide 7. Finally, a Pd-catalyzed
cross-coupling of 4 and 5 would lead to the synthesis of
various lavendamycin analogues.
On the basis of earlier reports in the literature dealing with
the cyclization reactions of N-propargylcarboxamides,19 we
reasoned that treating carboxamide 7 with a Au(III) catalyst
would result in an initial activation of the triple bond by the
electrophilic metal species. Two modes of cycloisomerization
are possible depending on the nature of the R2 substituent
(Scheme 2). In the case where R2 ) H, backside attack by
the amide carbonyl group on the π-coordinated alkyne
complex 8 via path A would eventually produce oxazole 11
by a protodemetalation of the aurated enol ether species 9
followed by a subsequent isomerization of a transient
5-methylene-substituted 4,5-dihydrooxazole 10. This type of
reactivity has been described by both Hashmi20 and Echa-
varren.9 However, if the amido nitrogen atom contains a
substituent other than hydrogen, we envisioned that a 6-exo-
dig cyclization reaction would occur by attack at the C3-
position of the indole ring via path B. Following protode-
metalation of 12 and isomerization of 13, carbolinone 14
would be produced.
In the first study that was carried out, treating a sample of
N-(prop-2-ynyl)-1H-indole-2-carboxamide 7a with a catalytic
Org. Lett., Vol. 10, No. 16, 2008
3633

quantity of AuCl3 in CH2Cl2 at 25 °C led to the exclusive
formation of the expected oxazole 11a in 75% overall yield.
Gratifyingly, the related N-substituted propargylcarboxamide
7b underwent smooth cycloisomerization in the presence of
catalytic AuCl3 to give the desired ꢀ-carbolinone 14b in 85%
yield using similar reaction conditions. The scope of the
cyclization was further studied, and the results obtained with
amides 7c-f are shown in Table 1. Various protecting groups
on the amido nitrogen were allowed, and in all cases, the
cyclization proceeded with good to excellent efficiencies.
The next phase of our investigations was aimed at both
developing the chemistry required to construct the requisite
ꢀ-carboline coupling partner 4 and determining the functional
group compatibility of this methodology. ꢀ-Chlorocarboline
15 was synthetically more accessible from pyridoindolone
14f than its triflate analogue and was therefore chosen as
the prime coupling partner to be used for the synthesis of
various lavendamycin analogues. Thus, the reaction of
carboxamide 7f with AuCl3 gave carbolinone 14f in 60%
yield. Deprotection of the Boc group with trifluoroacetic acid
followed by reaction with phosphorus oxychloride gave 15
in 80% yield over the two steps. The transition-metal-
catalyzed cross-coupling of organometallic reagents with aryl
halides represents a powerful method for the preparation of
substituted biaryls.21 The synthesis of various heterobiaryls
by Pd(0) cross-coupling using halopyridine derivatives is also
known but has not been as well documented.22 We were
pleased to discover that ꢀ-chlorocarboline 15 underwent
smooth coupling with 2-(tributylstannyl)pyridine under clas-
sic Stille conditions to give ꢀ-carboline 16 in 79% yield
(Table 2). The coupling of 15 with phenylboronic acid under
traditional Suzuki conditions also gave the related ꢀ-phenyl-
substituted carboline 17 in 77% yield. Cross-coupling of 15
with both tributyl(vinyl)stannane and phenyl acetylene also
proceeded smoothly and afforded carbolines 18 (56%) and
19 (88%).
In conclusion, we have developed a simple, efficient
method for the synthesis of various lavendamycin type
analogues in good yield via the AuCl3-catalyzed cycloi-
somerization of N-propargylindole-2-carboxamides. The
resulting ꢀ-carbolinone system was used for subsequent
cross-coupling chemistry. Application of the methodology
toward lavendamycin is currently under investigation, the
results of which will be disclosed in due course.
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (CHE-
0742663).
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.
OL801385H
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