Expanding the scope of Mn(OAc)3-mediated cyclizations: Synthesis of the tetracyclic core of tronocarpine

Article abstract of DOI:10.1021/ol061698+

Pyrroles, indoles, and surprisingly, indolines, when equipped with a pendant malonyl group on the nitrogen atom, were effective substrates in a Mn(III)-mediated oxidative cyclization reaction, yielding the 1,2-annulated products in good to excellent yields. When indole acetonitrile was used as a substrate this method provided a rapid synthesis of a tetracyclic tronocarpine subunit.

Full text of DOI:10.1021/ol061698+

ORGANIC
LETTERS
2006
Vol. 8, No. 20
4561-4564
Expanding the Scope of
Mn(OAc)3-Mediated Cyclizations:
Synthesis of the Tetracyclic Core of
Tronocarpine
Jakob Magolan and Michael A. Kerr*
Department of Chemistry, The UniVersity of Western Ontario, London, Ontario,
Canada N6A 5B7
makerr@uwo.ca
Received July 10, 2006
ABSTRACT
Pyrroles, indoles, and surprisingly, indolines, when equipped with a pendant malonyl group on the nitrogen atom, were effective substrates
in a Mn(III)-mediated oxidative cyclization reaction, yielding the 1,2-annulated products in good to excellent yields. When indole acetonitrile
was used as a substrate this method provided a rapid synthesis of a tetracyclic tronocarpine subunit.
Among the vast numbers of indole and pyrrole alkaloids1
there exists a small number which bear a six-membered ring
fused to the 1,2-positions and which have an all-carbon
quaternary center attachment at the heterocyclic 2-position.
Several of these alkaloids are shown in Figure 1.2 While
A brief retrosynthesis of tronocarpine is shown in Scheme
1. Deconstruction of the bridging enone moiety via an aldol
Scheme 1. Retrosynthesis of Tronocarpine
and an enolate alkylation leads to precursor 1. Lactam
formation would occur in a traditional manner, whereas the
key bond between the quaternary center and the indole
Figure 1. Tronocarpine, mersicarpine. and rhazinal.
rhazinal has succumbed to total synthesis by Banwell and
co-workers,3 tronocarpine and mersicarpine await their first
chemical preparation.
(1) (a) Gul, W.; Hamann, M. T. Life Sci. 2005, 78, 442. (b) Cordell, G
G. A. The Alkaloids: Chemistry and Biology; Elsevier Science: San Diego,
2003; Vol. 60.
10.1021/ol061698+ CCC: $33.50
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Published on Web 08/31/2006

2-position would be formed via a malonic radical cyclization
of 2. The choice of this disconnection was inspired by the
seminal work of Snider4 and others.5
Table 1. Cyclizations of Malonyl Radicals to Indoles
Notwithstanding the excellent contributions of Chuang and
co-workers,5 who have demonstrated the viability of malonic
radical additions to indoles, a survey of the literature revealed
that the cyclization of malonic radicals onto aromatics and
especially heteroaromatics is an underdeveloped and under-
exploited synthetic method. In this paper, we report an
expansion of the scope of this reaction with the significant
adVance that indolines (rather than indoles) may be em-
ployed as substrates since they are oxidized to indoles under
the radical cyclization conditions.
These Mn(OAc)3-mediated cyclizations are postulated6 to
proceed through the oxidation of a malonic enolate derived
from 3 to yield a malonic radical 4 (Scheme 2). Cyclization
Scheme 2. Mechanism of Malonic Radical Cyclizations
onto the 2-position of an indole or pyrrole yields a resonance
stabilized radical 5 which may undergo further oxidation to
carbonium ion 6. Aromatization via proton loss gives the
product 7.
A variety of commercially available indoles and pyrroles
were acylated or alkylated with malonyl-containing chains
and subjected to oxidative cyclization with Mn(OAc)3 in
methanol. Table 1 shows the oxidative radical cyclization
of N-acyl indoles 8-13 and the N-alkyl derivative 14. While
methanol was our preferred solvent for this transformation,
acetic acid, the most common solvent for Mn(OAc)3
chemistry, also yielded satisfactory results. It is likely that
sensitive functionality in more complicated substrates will
be more tolerant of methanol than acetic acid.
The yields in Table 1 are uniformly good with the
exception of the indole-3-carboxaldehyde 13, which decom-
posed under the reaction conditions with only trace amounts
of 13 recovered. This surprised us since we were expecting
the additional conjugation to make this substrate a better
radical acceptor. Substitution at the indole 3-position did not
appear to be a problem. In fact, the improved yield is
consistent with the expected improved ease of formation of
the radical of type 5 and subsequent oxidation of this radical
by Mn(OAc)3.3a The N-alkyl substrate 14 was also a willing
participant in the radical cyclization yielding 21 in 67% yield.
Compounds such as 14, however, were more tedious to
prepare than the N-acyl counterparts.
(2) (a) Tronocarpine: Kam, T.-S.; Sim, K.-M.; Lim, T.-M. Tetrahedron
Lett. 2000, 41, 2733. (b) Mersicarpine: Kam, T.-S.; Subramaniam, G.; Lim,
K.-H.; Choo, Y.-M. Tetrahedron Lett. 2004, 45, 5995. (c) Rhazinal: Kam,
T.-S.; Tee, Y.-M.; Subramaniam, G. Nat. Prod. Lett. 1998, 12, 307.
(3) Banwell, M. G.; Edwards, A. J.; Jolliffe, K. A.; Smith, J. A.; Hamel,
E.; Verdier-Pinard, P. Org. Biomol. Chem. 2003, 1, 296
(4) For comprehensive reviews of Mn(OAc)3 chemistry, see: (a) Snider,
B. B. Chem. ReV. 1996, 96, 339. (b) Snider, Barry B. Manganese(III)-based
oxidative free-radical cyclizations. In Transition Metals for Organic
Synthesis, 2nd ed.; Beller, M., Bolm, C., Ed.; Wiley-VCH Verlag GmbH
& Co. KGaA: Weinheim, Germany, 2004; Vol. 1, pp 483-490.
(5) (a) Tsai, A.-I.; Lin, C.-H.; Chuang, C. P. Heterocycles 2005, 65, 2381.
(b) Chuang, C. P.; Wang, S. F. Tetrahedron Lett. 1994, 35, 1283. (c) Artis
D. R.; Cho I.-S.; Muchowski, J. M. Can. J. Chem. 1992, 70, 1838.
(6) (a) Fristad, W. E.; Peterson, J. R. J. Org. Chem. l985, 50, 10. (b)
Fristad, W. E.; Hershberger, S. S. J. Org. Chem. 1985, 50, 1026. (c) Fristad,
W. E.; Peterson, J. R.; Ernst, A. B. J. Org. Chem. 1985, 50, 3143. (d) Yang,
F. Z.; Trost, M. K.; Fristad, W. E. Tetrahedron Lett. 1987, 28, 1493.
The analogous cyclizations onto pyrroles also proceeded
as expected. Substrates 22-24 were prepared and subjected
to typical cyclization conditions. Cyclization of the N-alkyl
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Org. Lett., Vol. 8, No. 20, 2006

derivative of pyrrole itself 23 was slightly lower yielding
than that of the N-acyl derivative of pyrrole 22. The presence
of a phenyl substituent at the 3-position of pyrrole 26 set up
regiochemical considerations. The 3-phenyl group would be
expected to stabilize the putative intermediate radical favor-
ing cyclization proximal and not distal to the 3-phenyl
substituent. This was in fact borne out and 24 yielded a 2:1
mixture of isomers 27 and 28 which were inseparable but
could be easily differentiated in the proton NMR spectrum
(Table 2).
Scheme 3. Synthesis of Cyclization Substrates
Table 2. Cyclizations of Malonyl Radicals to Pyrroles
excellent yields of the N-acyl species 34 when indoline 33
was treated with acid chloride 30 in the presence of
triethylamine, while the N-alkyl compound 36 was accessed
in a manner similar to the preparation of 14. Moreover, we
found that we could access the related compounds with a
one-carbon shorter tether by employing indoline in a ring
opening reaction with cyclopropane diesters. To this end,
indoline 33 was treated with either the commercially avail-
able 1,1-carbomethoxycyclopropane or its phenyl-substituted
counterpart9 under the influence of Yb(OTf)3 to effect the
synthesis of the substrates 37 and 38 in good yields.
When surveying dehydrogenation methods for conversion
of indolines to indoles we quickly realized that Mn(OAc)3
could also be used to this end.10 We then reasoned that both
the dehydrogenation and cyclization may occur in one pot.
We subjected 34, 36-38 to the standard cyclization condi-
tions (now with 5 equiv of Mn(OAc)3 and were pleased to
observe clean conversion to the 1,2-cyclized compounds.
Table 3 illustrates the results. Indolines 36-38 underwent
smooth reaction in methanol whereas the anilide 34 required
refluxing acetic acid. In the case of anilide 34, the methanolic
conditions were insufficient to affect dehydrogenation in
good yields, only trace amounts of the desired product 15
One of the challenges with this synthetic method for the
formation of complex indole scaffolds was, oddly enough,
the preparation of the substrates. Scheme 3 summarizes their
preparation. Substrates 8-13 were prepared by treatment of
the deprotonated indole with a rather sensitive acid chloride
30.7 Although this was a reasonable method for preparing
enough of the N-acyl indoles for this study the method was
less than ideal. The N-alkyl substrates were prepared by first
alkylating the indolate with 1,3-dibromopropane8 and treat-
ment of the resulting monobromide with sodium malonate.
In an effort to improve the overall efficiency of this
synthetic methodology, we turned to acylation and alkylation
of indolines rather than indoles. It was reasoned that the
increased nucleophilicity of the indoline nitrogen would lead
to improved reactivity in the acylation and alkylation
chemistry. The indoline could then be dehydrogenated to the
indole using traditional methods. We were pleased to realize
(7) Compound 30 was prepared from the corresponding carboxylic
acid: Prabhu, K. R.; Pillarsetty, N.; Gali, H.; Katti, K. V. J. Am. Chem.
Soc. 2000, 122, 1554.
(9) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(10) Ketcha, D. M. Tetrahedron Lett. 1988, 29, 2151.
(8) Dehaen, W.; Hassner, A. J. Org. Chem. 1991, 56, 896.
Org. Lett., Vol. 8, No. 20, 2006
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Scheme 4. Synthesis of a Tronocarpine Substructure
Table 3. Cyclizations of Malonyl Radicals to Indolines
In conclusion, we have demonstrated that the intramo-
lecular cyclization of a malonic radical, generated with Mn-
(OAc)3, onto the 2-position of indoles and pyrroles is an
effective method for the generation of annulated heterocycles.
Indoline substrates can also be employed as they are oxidized
to indoles under the reaction conditions. The application of
this method to the synthesis of the tetracyclic core of the
natural product tronocarpine has also been illustrated. Efforts
are underway to employ this synthetic methodology to the
preparation of both tronocarpine and mersicarpine.
were obtained until acetic acid was used. For the aniline
substrates 36-38, the milder methanolic conditions were
ideal for both conversion to the indole and subsequent
cyclization. That this was indeed two sequential oxidations
and not some sort of C-H activation was indicated by the
fact that at incomplete conversion the dehydrogenated but
uncyclized indole could be isolated. If refluxing acetic acid
was used as the medium in the cases of 36-38 only
decomposition was observed. It is likely that the aniline was
protonated leading to a species resistant to oxidation.
The application of the above methodology to the synthesis
of a tetracyclic subunit of tronocarpine is illustrated in
Scheme 4. As indicated in Table 1, indole-3-acetonitrile was
acylated with acid chloride 30 to yield 12 which was treated
with Mn(OAc)3 in methanol to effect cyclization and produce
19 in 72% yield. Treatment of nitrile 19 with H2 (4 atm)
over Raney nickel resulted in reduction to the tryptamine
derivative which spontaneously cyclized to 41 under the
reaction conditions. Amide 41 contains four of the five rings
of tronocarpine as well as suitable functionality for conver-
sion to the natural product.11
Acknowledgment. We thank the Natural Sciences and
Engineering Research Council of Canada, the Ontario
Ministry of Science and Technology, and GlaxoSmithKline
for funding. Acknowledgment is made to the Donors of the
American Chemical Society Petroleum Research Fund for
partial support of this research. We are grateful to Mr. Doug
Hairsine of the UWO mass spectroscopy facility for per-
forming MS analyses and to fellow group member Mr. Alex
Driega for helpful discussions. J.M. is an Ontario Graduate
Scholarship holder.
Supporting Information Available: Full experimental
procedures and spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL061698+
(11) Compound 41 has been reported in the literature (Mahboobi, v. S.;
Burgemeister, T.; Kastner, F. Arch. Pharm. Weinheim, Ger. 1995, 328, 29).
For a comparison of spectral data, see the Supporting Information.
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