A New Method for the Formation of Octahydroindole Alkaloids via the Intramolecular Diels-Alder Reaction of 2-Amidofurans

Full text of DOI:10.1021/jo980815e

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304
J . Org. Chem. 1998, 63, 5304-5305
A New Meth od for th e F or m a tion of
Octa h yd r oin d ole Alk a loid s via th e
In tr a m olecu la r Diels-Ald er Rea ction of
Sch em e 1
2
-Am id ofu r a n s
†
Albert Padwa,* Michael A. Brodney, and
Martin Dimitroff
Department of Chemistry, Emory University,
Atlanta, Georgia 30322
Received May 1, 1998
Octahydroindole-based alkaloids possess diverse physi-
ological properties, as well as structural complexity, and
have attracted the interest of synthetic chemists.1 A plethora
of strategies based on both convergent and divergent meth-
ods have been developed for the synthesis of these azabicyclic
compounds.2 Despite the availability of many synthetic
Sch em e 2
methods, there still exists a need to develop more efficient
procedures than those currently in existence. Herein, we
report our preliminary results regarding the intramolecular
[4 + 2] cycloaddition of 2-amidofurans, which represents a
new and general method for the synthesis of the hexahy-
droindolinone ring system.
Our initial interest in this area was stimulated by the
prospect of designing a stereoselective entry to a variety of
Amaryllidaceae alkaloids according to the strategy outlined
in Scheme 1. The key feature of our approach is based upon
3
an intramolecular Diels-Alder reaction (IMDAF) of 2-ami-
nofurans such as 1. The initially formed cycloadduct 2 was
expected to undergo ready ring opening to be followed by a
subsequent hydrogen shift of the resulting zwitterion 3. In
this paper, we report the first examples of this protocol and
provide applications of the method toward the core skeleton
presence of base. We first examined the Diels-Alder
cycloaddition (165 °C) of the acyclic monosubstituted alkenyl
furans 5 and 6 (R ) H), which furnished the cyclized
aromatic carbamates 7 and 8 as the only isolable products
(Scheme 2). In both cases, the initial oxa-bridged cycload-
4
5
6
of the dendrobium, lycorane, and strychnos alkaloid ring
systems.
ducts were not isolated, as they readily underwent ring
opening followed by subsequent dehydration.8
In previous work, we demonstrated that 2-aminofurans
react with various dienophiles in an intermolecular fashion
To avoid the dehydration step, we prepared the disubsti-
tuted olefinic amidofurans 9-11 (R * H). In these cases,
subjection of all three furans to the thermal conditions (165
7
with high regioselectivity. The resultant ring-opened cy-
cloadducts were readily dehydrated to give polysubstituted
anilines. To establish the viability of the IMDAF sequence
outlined in Scheme 1, several 2-amidofurans containing
olefinic tethers were prepared from the reaction of N-tert-
butylfuranyl carbamate with various alkenyl halides in the
°
8
C) afforded the rearranged ketones 12-14 in 71%, 77%, and
7% yield, respectively. The isolation of these hexahydroin-
dolinones is in full agreement with the proposed cycloaddi-
tion/ ring opening/ rearrangement sequence outlined in
Scheme 1.
It was envisioned that the enamide functionality present
in the rearranged keto system could be used to facilitate
bond construction at several locations in the molecule.
Access to the lycorane ring skeleton was achieved by
utilization of ketone 12, as shown in Scheme 3. Acid
hydrolysis of 12 gave imine 15 as a labile oil that was
immediately converted to enamide 16 in 72% overall yield.
Intramolecular Heck cyclizations generally show a prefer-
†
Recipient of a Graduate Fellowship from the Organic Chemistry
Division of the American Chemical Society (1997-1998) sponsored by
Dupont Merck Pharmaceutical Co.
(
1) Martin, S. F. In The Alkaloids; Brossi, A., Ed.; Academic Press Inc.:
New York, 1987; Vol. 30, pp 251-377. Lewis, J . R. Nat. Prod. Rep. 1994,
1, 329. J effs, P. W. In The Alkaloids; Rodrigo, R. G. A., Ed.; Academic
Press: New York, 1981; Vol. 19, pp 1-80.
2) For some leading references, see: Banwell, M. G.; Wu, A. W. J . Chem.
1
(
Soc., Perkin Trans. 1 1994, 2671. Grothjahn, D. B.; Vollhardt, K. P. C.
Synthesis 1993, 579. Pearson, W. H.; Schkeryantz, J . M. J . Org. Chem. 1992,
9
5
7, 6783. Backvall, J . E.; Andersson, P. G.; Stone, G. B.; Gogoll, A. J . Org.
Chem. 1991, 56, 2988. J olly, R. S.; Livinghouse, T. J . Am. Chem. Soc. 1988,
10, 7536. Stork, G.; Mah, R. Heterocycles 1989, 28, 723.
3) For some leading references concerning the intramolecular Diels-
ence for the exo mode of cyclization. By following a protocol
10
reported by the Rigby group, we found that treatment of
1
1
1
6 using the J effrey palladium catalyst system1 (Pd(OAc)2
(
Alder reaction of furans (IMDAF), see: Kappe, C. O.; Murphree, S. S.;
Padwa, A. Tetrahedron 1997, 53, 14179. Sternbach, D. D.; Rossana, D. M.;
Onon, K. D. J . Org. Chem. 1984, 49, 3427. J ung, M. E.; Gervay, J . J . Am.
Chem. Soc. 1989, 111, 5469.
(10 mol %), n-Bu4NCl (2 equiv), KOAc (5 equiv), DMF (0.2
M, 100 °C)) provided only pentacycle 17 derived from the
endo cyclization pathway in 50% unoptimized yield.
1
2
(4) Aimi, N.; Goto, T.; Irie, H.; Ishii, H.; Ito, S.; Kodama, M.; Natori, S.;
Oishi, T.; Sakai, S.; Yamazaki, M. In Natural Products Chemistry; Nakan-
ishi, K., Goto, T., Ito, S., Natori, S., Nozoe, S., Eds.; Academic Press: New
York, 1975; Vol. 2, pp 257-261.
(8) For an earlier example of an IMDAF reaction of a nitrogen-substituted
furan, see: Himbert, G.; Schlindwein, H. J . Liebigs Ann. Recl. 1997, 435.
(9) Grigg, R.; Santhakumar, V.; Sridharan, V.; Thornton-Pett, M.; Bridge,
A. W. Tetrahedron 1993, 49, 5177. Overman, L. E. Pure Appl. Chem. 1994,
66, 1423.
(10) Rigby, J . H.; Hughes, R. C.; Heeg, M. J . J . Am. Chem. Soc. 1995,
117, 7834.
(
5) Dalton, D. R. The Alkaloids: Fundamental Chemistry. A Biogenetic
Approach; Marcel Dekker: New York, 1979.
6) Husson, H. P. In The Chemistry of Heterocyclic Compounds; Weiss-
berger, A., Taylor, E. D., Eds.; Wiley: New York, 1983; Vol. 25, Part IV, pp
(
2
93-330.
(
7) Padwa, A.; Dimitroff, M.; Waterson, A. G.; Wu, T. J . Org. Chem. 1997,
(11) J effrey, T. J . Chem. Soc., Chem. Commun. 1984, 1287. J effrey, T.
Synthesis 1987, 70.
6
2, 4088; 1998, 63, 3986.
S0022-3263(98)00815-9 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/11/1998

Communications
J . Org. Chem., Vol. 63, No. 16, 1998 5305
Sch em e 3
Sch em e 4
Sch em e 5
So that a cross section of additional information could be
obtained with regard to the scope and generality of the
sequence outlined in Scheme 1, it was necessary to evaluate
a series of 2-amidofurans containing a variety of π-bonds.
In this regard, we first investigated the IMDAF chemistry
of 18, which possesses a tethered cyclopentenyl group.
Heating a sample of furan 18 afforded azapolycycle 19 as a
single diastereomer in 78% yield (Scheme 4). To further
illustrate the viability of this sequence as a practical strategy
for the synthesis of complex alkaloids, we have explored the
utility of this reaction in the context of a total synthesis of
To test this proposition, the thermal behavior of indolyl-
substituted 2-amidofuran 23 was investigated. It was found,
however, that thermolysis of the tert-butyl carbamate 23a
did not lead to the desired cycloaddition but instead gave
products derived from loss of the thermally labile t-Boc
group. Heating a sample of the corresponding N-ethylcar-
bamate 23b, on the other hand, resulted in the formation
of 24 in 62% yield (Scheme 5). This is presumably a
reflection of the greater thermal stability of the N-ethylcar-
bamate, which allows the intramolecular [4 + 2] cycloaddi-
tion reaction to take place across the indole π-bond at 240
(
()-dendrobine (22).13 This alkaloid is the principle com-
ponent of the Chinese Folk medicine “Chin-Shih-Hu” and
has been shown to exhibit antipyretic and hypotensive
activity.14 The key step in our plan for the synthesis of (()-
dendrobine involves the intramolecular Diels-Alder reaction
of 2-amidofuran 20 to give hexahydroindolinone 21 with
three of the asymmetric centers established. We were
gratified to find that the thermolysis of 20 proceeded in 74%
yield to produce 21 as a 2:1 mixture of diastereomers.
Further transformations of 21 to 22 using the existing
functional groups to establish the remaining asymmetric
centers are currently underway.
°C. Further efforts to streamline this protocol and to utilize
it to complete total syntheses of the strychnos alkaloids are
in progress and will be reported in due course.
In summary, a highly convergent synthesis of octahy-
droindole derivatives has been devised. Application of this
methodology toward the construction of more complex
alkaloids containing the octahydroindole skeleton is cur-
rently in progress in our laboratory and will be reported at
a later date.
Given the success in forming the azatricyclic ring system
from the IMDAF reaction of 2-amidofurans 18 and 20, it
seemed to us that a related process could be used to
synthesize the strychnos or aspidosperma alkaloid skeletons.
Ack n ow led gm en t. This research was supported by the
National Institutes of Health (CA-26751). We thank Tian-
hua Wu for some experimental assistance.
(
12) We wish to thank Professor J im Rigby for providing experimental
conditions for the endo cyclization of enamide 16.
13) For several pertinent references dealing with some successful total
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures, compound characterization data and copies of spectra (20
pages).
(
and formal syntheses of (()-dendrobine, see: Sha, C. K.; Chiu, R. T.; Yang,
C. F.; Yao, N. T.; Tseng, W. H.; Liao, F. L.; Wang, S. L. J . Am. Chem. Soc.
1
997, 119, 4130.
14) Martin, S. F.; Li, W. J . Org. Chem. 1991, 56, 642.
(
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