A flexible, convergent approach to polycyclic indole structures: Formal synthesis of (±)-mersicarpine

Article abstract of DOI:10.1021/ol900996k

The formal synthesis of (±)-mersicarpine was achieved using an lntermolecular radical addition-radical cyclization cascade. This key reaction represents a flexible, convergent route to numerous polycyclic indole derivatives.

Full text of DOI:10.1021/ol900996k

ORGANIC
LETTERS
2009
Vol. 11, No. 13
2800-2803
A Flexible, Convergent Approach to
Polycyclic Indole Structures: Formal
Synthesis of (()-Mersicarpine
Aure´lien Biechy and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, De´partement de Chimie,
Ecole Polytechnique, 91128 Palaiseau, France
zard@poly.polytechnique.fr
Received May 7, 2009
ABSTRACT
The formal synthesis of (()-mersicarpine was achieved using an intermolecular radical addition-radical cyclization cascade. This key reaction
represents a flexible, convergent route to numerous polycyclic indole derivatives.
Mersicarpine 1 was isolated in 2004 by Kam and co-workers1
from the Kopsia species of plants, which contains a large
range of alkaloids with challenging carbon frameworks. This
unusual tetracyclic compound is part of a class of indole
alkaloids bearing a six-membered ring fused to the 1,2-
positions and containing a typical quaternary center (Figure
1).
The first total synthesis of mersicarpine 1 was reported
Figure 1. Indole alkaloids from Kopsia species.
by Kerr et al. in 2008.2 Inspired by his original strategy, we
envisaged the obtention of key intermediate 4 by a different,
but simpler and more convergent, route. Our synthetic
approach to structure 1 is based on a radical cascade, whereby
radical species 5 undergoes first an intermolecular addition
onto the double bond of olefin 6 followed by a cyclization
on the 2-position of the indole ring (Scheme 1). Subsequent
conversion of indole 4 into mersicarpine 1 through oxidation
and formation of the 7-membered ring imine were reported
by Kerr et al. and proceed in good yield.2
(1) Kam, T. S.; Subramaniam, G.; Lim, K. H.; Choo, Y. M. Tetrahedron
Lett. 2004, 45, 5995.
In a preliminary study,3 xanthate 7 was easily prepared
via the acylation of indole with chloroacetyl chloride
(2) Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437.
(3) Seguin, S. Ph.D. Dissertation, Ecole Polytechnique, Palaiseau, 1999.
10.1021/ol900996k CCC: $40.75
Published on Web 06/02/2009
 2009 American Chemical Society

consumption of xanthate was observed, the crude reaction
mixture of cyclized products was therefore heated with
excess manganese dioxide (MnO2, 10 equiv) to completely
aromatize 18a into the desired indole 18 (74%).
Scheme 1. Retrosynthesis of Mersicarpine 1
Addition of the radical derived from xanthate 10 to
methallyl acetate furnishes intermediate 11, which then
undergoes a 6-exo cyclization to the indole ring. The ensuing
radical 12 is now stabilized by the tert-butyl ester group,
and this extra favorable factor drives the equilibrium in the
crucial step forward.8 Disproportionation of radical 12 leads
presumably to compounds 18 and 18a. The former can also
be produced by electron transfer to the peroxide, accounting
for its higher relative yield (Scheme 3).
followed by nucleophilic substitution of the chlorine atom
by potassium O-ethyl xanthate salt. Previous works in this
field indicated that cyclization should occur regioselectively
at the 2-position of the indole ring.2,4
However, portionwise addition of lauroyl peroxide (DLP)
to xanthate 7 and several equivalents of allylacetate in
refluxing 1,2-dichloroethane gave rise to only a very poor
yield of desired cyclic compound 8 (Scheme 2).5
Scheme 3
.
Preparation of Xanthate 10 and Mechanism of the
Cascade Cyclization
Scheme 2
These disappointing results led us to examine the effect
of activating the indole double bond by a functional group
that could be subsequently removed. To this end, xanthate
10 bearing an electron-withdrawing tert-butoxycarbonyl
group in the 3-position was prepared6 from tert-butylindole-
3-carboxylate 9, which is readily available by treatment of
indole-3-carboxylic acid with oxalyl chloride, followed by
exposure of the intermediate acid chloride to potassium tert-
butoxide in t-butyl alcohol.7
When a stoichiometric amount of DLP was added in
portions (over 1-2 h) to a refluxing solution of 10 and
methallyl acetate (5 equiv) in chlorobenzene, addition to the
olefin and subsequent annelation to the 2-position of the
indole ring took place to give 18 in 49% yield, along with
a mixture of diastereoisomers (18a, 24%), arising from the
premature reduction of radical species 12. Once the total
The same sequence was applied to other olefins to give
tricyclic derivatives 13-22 in comparable overall yield
(Table 1). The results shown in Table 1 are uniformly good.
This process can thus be applied to a large variety of terminal
olefins bearing various types of substituents. Even polym-
erization-prone methyl acrylate could be used (entry 5),
although the yield was slightly lower than average. In this
case, the kinetics of the cascade reaction seem to be fast
enough to circumscribe the untoward tendency to polymer-
ization of methyl acrylate.To expand the scope of the
reaction, the analogous cyclizations using xanthate deriva-
tives of commercially available indole-3-acetic acid,9 indole-
3-carboxaldehyde, and 3-acetylindole were next investigated.
(4) (a) Reyes-Gutie´rrez, P. E.; Torres-Ochoa, R. O.; Mart´ınez, R.;
Miranda, L. D. Org. Biomol. Chem. 2009, 7, 1388. (b) Guerrero, M. A.;
Miranda, L. D. Tetrahedron Lett. 2006, 47, 2517. (c) Osornio, Y. M.; Cruz-
Almanza, R.; Jime´nez-Montan˜o, V.; Miranda, L. D. Chem. Commun. 2003,
2316. (d) Magolan, J.; Kerr, M. Org. Lett. 2006, 8, 4561. (e) Gross, S.;
Reissig, H. U. Org. Lett. 2003, 5, 4305
.
(5) For reviews of the xanthate transfer chemistry, see: (a) Zard, S. Z.
Angew. Chem., Int. Ed. Engl. 1997, 36, 672. (b) Zard, S. Z. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH; Weinheim
2001, Vol. 1, p 90. (c) Quiclet-Sire, B.; Zard, S. Z. Chem.sEur. J. 2006,
12, 6002. (d) Quiclet-Sire, B.; Zard, S. Z. Top. Curr. Chem. 2006, 264,
201. (e) Zard, S. Z. Org. Biomol. Chem. 2007, 5, 205.
(6) (a) Coste, A.; Toumi, M.; Wright, K.; Razafimahale´o, V.; Couty,
F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841. (b) Toumi, M.; Couty,
F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 5027.
(8) The addition of radicals to aromatic rings is known to be reversible.
See: (a) Citterio, A.; Minisci, F.; Porta, O.; Sesana, G. J. Am. Chem. Soc.
1977, 99, 7960. (b) Griller, D.; Marriott, P. R.; Nonhebel, D. C.; Perkins,
M. J.; Wong, P. C. J. Am. Chem. Soc. 1981, 103, 7761. The reverse reaction,
i.e., the fragmentation of the cyclohexadienyl radicals, has been elegantly
applied in synthesis. For a review, see: (c) Walton, J. C.; Studer, A. Acc.
Chem. Res. 2005, 38, 794.
(7) (a) Janosik, T.; Shirani, H.; Wahlstro¨m, N.; Malky, I.; Stensland,
B.; Bergman, J. Tetrahedron 2006, 62, 1699. (b) Ludwig, J.; Lehr, M. Synth.
Commun. 2004, 34, 3691. (c) Battaglia, S.; Boldrini, E.; Da Settimo, F.;
Dondio, G.; La Motta, C.; Marini, A. M.; Primofiore, G. Eur. J. Med. Chem.
1999, 34, 93. (d) Stanovnik, B.; Tisˇler, M.; Carlock, J. T. Synthesis 1976,
754.
ˇ
(9) For the preparation of the corresponding methyl ester, see: Casar,
Z.; Bevk, D.; Svete, J.; Stanovnik, B. Tetrahedron 2005, 61, 7508.
Org. Lett., Vol. 11, No. 13, 2009
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Table 1. Annulation Sequence of Indole Xanthate 10
Scheme 4
.
Preparation of Xanthates 23-25 and Synthesis of
Corresponding Tricyclic Compounds
a PhCl was replaced by 1,2-DCE; single addition of DLP (1.4 equiv);
no MnO2 oxidation was required.
stabilizes the radical intermediate and/or facilitates its
oxidation by the peroxide.
With a good cyclization process in hand, we proceeded
to construct N-acyl indole 4, the key intermediate reported
by Kerr et al. in their elegant synthesis of mersicarpine 1.2
To this end, olefin 6 was prepared according to a procedure10a
previously used in the synthesis of the indole alkaloid
aspidospermidine by Magnus and co-workers.10b This olefin
a Yield without MnO2 oxidation. b PhCl was replaced by 1,2-DCE.
Scheme 5
.
Preparation of Olefin 6 and Formal Synthesis of
(()-Mersicarpine
Xanthates 23-25 were prepared by acylation of the
corresponding indoles with chloroacetyl chloride followed
by chloride displacement with potassium O-ethyl xanthate.
Access to 24 and 25 proved more troublesome than for 10
and 23. Nevertheless, all three derivatives turned out to be
good precursors for the radical cyclization with methallyl
acetate (Scheme 4).
These results indicate that 3-acetyl, 3-carboxyaldehyde,
or even a -CH2CO2Me group are compatible with the
process, extending the potential field of the reaction to a
wider spectrum of available indole precursors (tryptamine,
tryptophan, etc.).4a The important factor appears to be the
presence of a substituent on position 3 of the indole that
(10) (a) McCaffery, E. L.; Shalaby, S. W. J. Organomet. Chem. 1967,
8, 17. (b) Exon, C.; Gallagher, T.; Magnus, P. J. Am. Chem. Soc. 1983,
105, 4739.
(11) It may be interesting to replace the tert-butoxycarbonyl group
in 10 with a carboxamide derived from a non-racemic chiral amine, as
this may allow control of the absolute stereochemistry in the cyclization
step.
2802
Org. Lett., Vol. 11, No. 13, 2009

contains both the ethyl and the protected amino groups
required for the synthesis of mersicarpine. Pleasingly, the
radical cascade of xanthate 10 and olefin 6 proceeded
normally to afford 29 in good yield (78%). A one-pot
deprotection of the tert-butyl ester group and decarboxylation
were performed in trifluoroacetic acid, followed by subse-
quent reprotection of the amine as its tert-butyl carbamate
to give 4 in 84% yield (Scheme 5). This completes the formal
synthesis of mersicarpine 1.11
In summary, we have developed a simple convergent and
flexible route to polycyclic indole derivatives bearing various
functional groups. These could prove to be useful new
scaffolds for medicinal chemistry. The fact that an acetate
group can be present on the indole partner (as in compound
26) indicates that the same strategy employed for the
synthesis of mersicarpine could be applied to the construction
of leuconoxine 3 and, with some variation, to tronocarpine
2.
Acknowledgment. We respectfully dedicate this paper to
Professor E. J. Corey (Harvard University). A.B. thanks
Ecole Polytechnique for a studentship.
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data, and copies of H and 13C
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL900996K
Org. Lett., Vol. 11, No. 13, 2009
2803