Intramolecular Amidofuran Cycloadditions across an Indole π-Bond: An Efficient Approach to the Aspidosperma and Strychnos ABCE Core

Article abstract of DOI:10.1021/ol027024q

(Matrix Presented) The intramolecular Diels-Alder reaction between an amidofuran moiety tethered onto an indole component was examined as a strategy for the synthesis of Aspidosperma and Strychnos alkaloids. Furanyl carbamate 13 was acylated using the mix

Full text of DOI:10.1021/ol027024q

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4643-4645
Intramolecular Amidofuran
Cycloadditions across an Indole
π-Bond: An Efficient Approach to the
Aspidosperma and Strychnos ABCE
Core
Stephen M. Lynch, Scott K. Bur,† and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received October 3, 2002
ABSTRACT
The intramolecular Diels−Alder reaction between an amidofuran moiety tethered onto an indole component was examined as a strategy for
the synthesis of Aspidosperma and Strychnos alkaloids. Furanyl carbamate 13 was acylated using the mixed anhydride 16 to provide amidofuran
12 in 68% yield. Further N-acylation of this indole furnished 17 in 88% yield. Cyclization precursors were prepared by removing the carbamate
moiety followed by N-alkylation with the appropriate alkyl halides. Thermolysis of 25 provided the novel tetracyclic ketone 26 in 74% yield.
Indole alkaloids,1 which include the Strychnos and Aspi-
dosperma families, are widely encountered natural products
that continue to challenge synthetic chemists. The medicinal
importance and interesting architecture of alkaloids such as
vindoline (1)2 have spurred many researchers to meet this
synthetic challenge through a variety of creative approaches.3
BE junction represents a very efficient strategy for the
construction of this polycyclic array that is also present in
many of the Strychnos alkaloids.4 Kuehne’s5 use of a tandem
ammonium ion rearrangement/intramolecular Diels-Alder
cycloaddition and the more recent amido-diene cycloaddition
sequence reported by Rawal6 are the only approaches that
construct both the C ring and the BE junction in one synthetic
step.7
In recent years, we have been investigating the intramo-
lecular [4 + 2]-cycloaddition/rearrangment cascade of 2-
(2) The Alkaloids; Brossi, A., Suffness, M., Eds.; Academic Press: San
Diego, 1990; Vol. 37, pp 145-204.
(3) Overman, L. E.; Sworin, M. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley-Interscience: New York, 1985;
Vol. 3, pp 275-307.
One of the specific problems posed by the Aspidosperma
skeleton, typified by aspidospermidine (2), involves the
construction of the quaternary C(7) center. Because this
center is contained within the six-membered C ring, a
reaction that fashions both the C ring and the spirocyclic
(4) Aimi, N.; Sakai, S.-I. In The Alkaloids; Brossi, A., Ed.; Academic
Press: San Diego, 1989; Vol. 36, pp 1-68.
(5) (a) Kuehne, M. E.; Roland, D. M.; Hafter, R. J. Org. Chem. 1978,
43, 3705-3710. (b) Kuehne, M. E.; Bornmann, W. G.; Earley, W. G.;
Marko, I. J. Org. Chem. 1986, 51, 2913-2927.
(6) (a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030-3031. (b) Rawal, V. H.; Iwasa, S. J. Org. Chem. 1994,
59, 2685-2686.
† NIH Postdoctoral Fellow; Grant GM20666.
(1) Saxton, J. E. Nat. Prod. Rep. 1993, 10, 349-395.
10.1021/ol027024q CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/05/2002

amidofurans as a strategy for the synthesis of hexahydroin-
dolinone alkaloids.8 Our experience with this domino se-
quence prompted us to examine a Diels-Alder approach to
the ABCE tetracyclic core 3, wherein an indole moiety
participates as the dienophilic partner (Scheme 1). An
Scheme 2 a
Scheme 1. Intramolecular [4 + 2] Approach to the ABCE
Core
a Reagents: (a) Cs2CO3, 4:1 DMF/THF, 80 °C, 80%; (b)
Bu4NHSO4, NaOH, AcCl, CH2Cl2, rt, 90%; (c) benzene (sealed
tube), 240 °C, 18 h, 30%.
transfer conditions provided 10 in 90% yield. Cyclization
to 11 did occur, but only in 30% isolated yield (62% based
on recovered starting material), after heating at 240 °C for
18 h.
Encouraged by this result, we searched for a way to
increase the efficiency of the reaction. In previous studies,
structural features that facilitate the intramolecular Diels-
Alder reactions of amidofurans were discovered.12,13 Specif-
ically, the incorporation of a carbonyl group such that an
amide linkage joined the dienophile and the furan moieties
resulted in a conformation of the tether that brings the
dienophile into closer proximity with the furan.13
Exploiting this effect in the indole system required an
amidofuran such as 12 (Scheme 3). Initially, we had
envisioned 12 arising from the simple acylation of 13 with
the acid chloride derived from indole acetic acid (14).
However, under a variety of conditions (DMAP, 4 Å
molecular sieves,14 etc.), furanyl carbamate 13 proved to be
remarkably resistant toward acylation. After some experi-
mentation, we found that the addition of 15, formed by the
action of n-BuLi on 13, to a solution of the mixed anhydride
16 provided 12 in 68% yield. Subsequent N-acylation under
phase transfer conditions smoothly produced 17 in 88% yield.
Unfortunately, our attempts to effect the cycloaddition of
17 resulted only in the removal of the thermally labile tert-
butyloxy carbonyl group to give 18. While 18 should still
be a viable cyclization precursor, the use of temperatures
exceeding 300 °C failed to promote the desired cycloaddition;
only starting 18 was recovered.
appropriate cyclization substrate such as 4 would come from
the alkylation of indole derivative 5 with a 2-amidofuran 6
that possesses an electron-withdrawing group on the nitrogen
atom.
The seminal work of Wenkert9a and Kraus9b established
that the C(2)-C(3) double bond of indole can act as a 2π-
partner in [4 + 2]-cycloaddition chemistry.9c This strategy,
however, has not been extensively utilized for the synthesis
of complex azapolycyclic ring systems.9d Some years ago,
we reported the efficient participation of the indole C(2)-
C(3) double bond as the 2π component in 1,3-dipolar
cycloadditions with push-pull carbonyl ylides,10 and Boger’s
recent report outlines a similar dipolar cycloaddition approach
toward vindoline.11 We now report the findings of our
cycloaddition studies using 2-amidofurans as the 4π com-
ponent.
Our initial attempts to build tetracycle 3 started by
N-alkylating furan 7 with 3-(2-bromoethyl)indole (8) to
provide indole 9 in 80% yield (Scheme 2).8b Not unexpect-
edly, thermolysis of 9, which lacks an electron-withdrawing
group on the indole, failed to induce cyclization even at
temperatures above 200 °C. N-Acylation of 9 under phase
(7) For a very recent paper using a related approach, see: Bodwell, G.
J.; Li, J. Angew Chem., Int. Ed. 2002, 41, 3261-3263.
(8) (a) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J. Org. Chem.
1997, 62, 4088-4096. (b) Padwa, A.; Brodney, M. A.; Dimitroff, M. J.
Org. Chem. 1998, 63, 5304-5305. (c) Padwa, A.; Brodney, M. A.; Satake,
K.; Straub, C. S. J. Org. Chem. 1999, 64, 4617-4626.
(9) (a) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc.
1988, 110, 7188-7194. (b) Kraus, G. A.; Raggon, P. J.; Thomas, P. J.;
Bougie, D. Tetrahedron Lett. 1988, 29, 5605-5608. (c) Biolatto, B.;
Kneeteman, M.; Paredes, E.; Mancini, P. M. E. J. Org. Chem. 2001, 66,
3906-3912. (d) For a representative example within the context of indole
alkaloids, see: Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc.
Chem. Res. 1984, 17, 35-41.
(10) (a)Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258-6259.
(b) Padwa, A.; Price, A. T. J. Org. Chem. 1998, 63, 556-565.
(11) Wilkie, G. D.; Elliot, G. I.; Blagg, B. S. J.; Wolkenberg, S. E.;
Soenen, D. R.; Miller, M. M.; Pollack, S.; Boger, D. L. J. Am. Chem. Soc.
2002, 124, 11292-11294.
Upon further consideration, this result is not so surpris-
ing: conformational preferences about an amide bond have
been implicated in the efficiency of other cyclization
reactions.15 The strong preference of secondary amides to
(12) Padwa, A.; Ginn, J. D.; Bur, S. K.; Eidell, C. K.; Lynch, S. M. J.
Org. Chem. 2002, 64, 3412-3424.
(13) Bur, S. K.; Lynch, S. M.; Padwa, A. Org. Lett. 2002, 4, 473-476.
(14) Weinstock, L. M.; Karady, S.; Roberts, F. E.; Hoinowski, A. M.;
Brenner, G. S.; Lee, T. B. K.; Lumma, W. C.; Sletzinger, M. Tetrahedron
Lett. 1975, 16, 3979.
(15) For recent examples, see: (a) Jones, K.; Wilkinson, J.; Ewin, R.
Tetrahedron Lett. 1994, 35, 7673-7676. (b) Tamura, O.; Matsukida, H.;
Toyao, A.; Takeda, Y.; Ishibashi, H. J. Org. Chem. 2002, 67, 5537-5545.
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Org. Lett., Vol. 4, No. 26, 2002

Scheme 3 a
Scheme 4 a
a Reagents: (a) 14, i-BuO2CCl, N-methylmorpholine, filter, then
15, 0 °C, 68%; (b) Bu4NHSO4, NaOH, AcCl, CH2Cl2, rt, 88%; (c)
benzene, sealed tube, 200 °C; (d) MgClO4, Ch3CN, 50 °C, 77%.
adopt an s-cis conformation is well established.16 More than
likely, 18 resides predominantly in the s-cis conformation
where the furan ring is far removed from the indole π-bond
(eq 1). We reasoned that replacing the hydrogen with a larger
group would cause the reactive s-trans conformation to be
be more highly populated, and therefore the cycloaddition
will be more prone to occur.
To test this hypothesis, several tertiary amides derived
from 18 were prepared. This necessitated a more experi-
mentally benign protocol for removing the carbamate moiety
from 17, and we found that MgClO4 in CH3CN efficiently
provided 18.17 Alkylating the sodium salt of 18 with benzyl
bromide or allyl iodide provided 19 or 20 in 82 and 50%
yields, respectively (Scheme 4).
a Reagents: (a) NaH, alkyl halide, DMF, rt; 82% (CH2Ph), 50%
(allyl). (b) Toluene (sealed tube), 200 °C, 12 h (CH2Ph), 56% or 2
h (allyl), 77%. (c) Toluene (sealed tube), 200 °C, 2 h, 91%. (d)
Toluene (sealed tube), 200 °C, 1.5 h, 74%.
the indole nitrogen, readily produced 24 in 91% yield after
heating for 2 h at 200 °C. We also examined the cyclization
of 25, which bears functionality on the side chain that may
allow for eventual functionalization of the D-ring. We were
pleased to note that heating 25 at 200 °C for 1.5 h furnished
the rearranged cycloadduct 26 in 74% yield.
In conclusion, our studies have shown that these [4 +
2]-cycloaddition reactions are remarkably efficient given that
two aromatic systems are compromised in the reaction. These
examples also demonstrate the utility of such an approach
in the rapid construction of the ABCE tetracyclic core found
in both the Aspidosperma and Strychnos families of indole
alkaloids. The application of this approach to natural product
targets is currently under investigation, the results of which
will be disclosed in due course.
Acknowledgment. We thank the National Institutes of
Health (GM59384 and GM60003) for generous support of
this work. We acknowledge the use of shared instrumentation
provided by grants from the NIH and NSF.
Heating a sample of indole 19 at 200 °C for 12 h gave
the novel azatricycle 21 in 56% yield. Similarly, the
thermolysis of 20 cleanly afforded 22 in 77% yield after only
2 h. Furan 23, which contains a methoxycarbonyl group on
Supporting Information Available: Complete descrip-
tion of the synthesis and characterization of all new
compounds prepared in this study. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) (a) Stewart, W. E.; Siddall, T. H. Chem. ReV. 1970, 70, 517-551.
(b) See also: Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic
Compounds; Wiley & Sons: New York, 1994; p 620.
(17) Stafford, J. A.; Brackeen, M. F.; Karanewsky, D. S.; Valvano, N.
L. Tetrahedron Lett. 1993, 34, 7873-7876.
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