Tandem Diels-Alder N-acyliminium ion cyclization reactions. A new entry into the erythrinane skeleton

Full text of DOI:10.1021/jo960818w

4888
J . Org. Chem. 1996, 61, 4888-4889
Sch em e 1
Ta n d em Diels-Ald er N-Acylim in iu m Ion
Cycliza tion Rea ction s. A New En tr y in to
th e Er yth r in a n e Sk eleton
Albert Padwa,* C. Oliver Kappe, and
Thomas S. Reger
Department of Chemistry, Emory University,
Atlanta, Georgia 30322
Received May 7, 1996
The Erythrina family of alkaloids are a well-known
class of natural products that have received considerable
attention over the past few decades.1 Many members of
this family possess curare-like activity, and the alkaloidal
extracts have been used in indigenous medicine. The
vast majority of naturally occurring Erythrina alkaloids
possess the tetracyclic framework and substitution pat-
tern shown in structure 5 (Scheme 1). Following the
early pioneering studies by Mondon2 on the assembly of
the basic erythrinane skeleton, a wide array of methods
have been developed for the synthesis of this class of
natural products.
Tandem or cascade processes belong to a growing
family of reactions that allow the regio- and stereo-
controlled formation of several carbon-carbon bonds and/
or ring systems in a single operation.3 Important con-
tributions to this area have been realized utilizing a
combination of cationic, anionic, radical, carbenoid, or
pericyclic processes.4 Few reactions can compete with
the Diels-Alder cycloaddition with respect to the degree
of complexity that can be accomplished in a single
synthetic step.5 Carbon-carbon bond-forming reactions
involving N-acyliminium ions play an equally important
role in the synthesis of nitrogen heterocycles and alka-
loidal target molecules.6
A sequential combination of these two powerful syn-
thetic methods would allow for the rapid, stereocontrolled
synthesis of a variety of azapolycyclic products. Of
particular interest to us in this context is the possibility
of using 2-amino substituted furans such as 1 containing
both a suitable leaving group (LG) and an olefinic tether
to allow for an intramolecular Diels-Alder reaction
(Scheme 1). The resulting cycloadduct 2 is expected to
readily undergo ring-opening to generate a vinylogous
C-acyliminium ion of type 3. Iminium ions such as 3
have great potential for undergoing subsequent cycliza-
tion chemistry.6 As outlined in Scheme 1, this sequence
of reactions allows for a rapid entry into the erythrinane
skeleton 5, where the key ABC ring system is assembled
in a single operation (1 f 4), and which also allows the
oxygen functionality to be placed in the appropriate
position. In this paper we report on some model studies
leading to the stereoselective synthesis of the 3,4-benzo-
erythrinane skeleton utilizing this novel triple cascade
process.
Recent work in our laboratory has shown that the
R-thiocarbocation generated from the Pummerer reaction
of an o-amido-substituted sulfoxide can be intercepted
by the adjacent carbonyl group to produce an R-amino
isobenzofuran.7 This transient intermediate then un-
dergoes a subsequent bimolecular Diels-Alder cycload-
dition with added dienophiles.7 This observation led us
to study the intramolecular cycloaddition reaction of
sulfoxides 7 and 8 (Scheme 2). Slow addition of the
sulfoxides to a refluxing mixture of p-xylene, acetic
anhydride (10 equiv), and p-toluenesulfonic acid (5 mol
%)8 led to the formation of aminonaphthols 12 and 13 in
75 and 59% yield, respectively. The isolation of these
oxindoles supports the proposed cyclization-cycloaddi-
tion/ ring-opening/ elimination sequence 7/8 f 9 f 10
f 11. With these systems, the initially formed iminium
ion 11 rapidly undergoes deprotonation followed by
O-acetylation to afford the isolated products 12 and 13.
Having established the facility with which the requisite
N-acyliminium ion intermediate can be formed, we next
focused our attention on the final cyclization step of the
proposed cascade process. The requisite sulfoxide pre-
cursor 15, possessing a diactivated aromatic π-tether, was
readily synthesized in four steps from the known car-
boxylic acid 14. Subjection of 15 to the standard Pum-
merer reaction conditions did not lead to the desired
benzoerythrinane derivative, but gave benzoindole 21 in
78% yield (Scheme 3). An analogous process occurred
with the isomeric amido sulfoxide 16, producing indole
22 in 76% yield. In both cases, the deprotonation of the
initially formed iminium ion (20; R ) H) is much faster
than spirocyclization. The driving force associated with
this rapid deprotonation undoubtedly involves formation
(1) Deulofeu, V. In Curare and Curarelike Agents; Bovet, D., Bovet-
Nitti, F., Marini-Bettolo, G. B., Eds.; Elsevier: Amsterdam, 1959; p
163.
(2) Mondon, A. Chem. Ber. 1959, 92, 1461; 1959, 92, 1472. Mondon,
A.; Hansen, K. F. Tetrahedron Lett. 1960, 5. Mondon, A.; Nestler, H.
J . Angew. Chem., Int. Ed. Engl. 1964, 3, 588.
(3) Ho, T. L. Tandem Organic Reactions; Wiley: New York, 1992.
Tietze, L. F. Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
Wender, P. A., Ed. Frontiers in Organic Synthesis. Chem. Rev. 1996,
96, 1-600.
(4) For
a recent classification of cascade/domino reactions, see:
Tietze, L. F. Chem. Rev. 1996, 96, 115.
(5) Roush, W. R. in Advances in Cycloaddition; Curran, D. P., Ed.;
J AI Press: Greenwich, CT, 1990; Vol. 2, p 91.
(6) Hiemstra, H.; Speckamp, W. N. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991;
Vol. 2, pp 1047-1082.
(7) Kappe, C. O.; Cochran, J . E.; Padwa, A. Tetrahedron Lett. 1995,
36, 9285.
(8) Watanabe, M.; Nakamori, S.; Hasegawa, H.; Shirai, K.; Kuma-
moto, T. Bull. Chem. Soc. J pn. 1981, 57, 817.
S0022-3263(96)00818-3 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 15, 1996 4889
Sch em e 2
Sch em e 3
of the conjugated aromatic system present in products
21 and 22.
In order to avoid the deprotonation step, we prepared
sulfoxide 17 possessing a carbomethoxy group attached
to the olefinic tether. Subjection of 17 to the standard
Pummerer reaction conditions (toluene/Ac2O/p-TsOH)8
provided a 2:1 mixture of the N,S- and N,O-ketals 23 and
24, respectively. These products are derived from bimo-
lecular trapping of iminium ion 20 (R ) CO2Me) with a
nucleophilic species present in the reaction medium (i.e.,
EtS-, AcO-). However, both of these products can be
independently converted to the desired benzoerythrinane
derivative 25 by heating in toluene containing 1.1 equiv
of p-TsOH. We found it to be more convenient, however,
to carry out the triple cascade sequence (17 f 25) in a
one-pot fashion by first subjecting sulfoxide 17 to the
Ac2O/p-TsOH conditions, followed by treatment of the
crude reaction mixture (after evaporation of solvent and
excess Ac2O) with an additional quantity (1.1 equiv) of
p-TsOH in refluxing toluene. By using this one-pot
protocol, 3,4-benzoerythrinane 25 was obtained as a
single diastereomer in 65-70% yield from sulfoxide 17.
Alternatively, the tandem sequence could also be trig-
gered at 0 °C by utilizing the more electrophilic trifluo-
roacetic anhydride as the Pummerer promoter (CH2Cl2,
2 equiv of Et3N).8 In this case, cycloadduct 19 (R ) CO2-
Me, X ) O) was isolated and was converted to 25 (70%
overall) by exposure to p-TsOH (1.1 equiv) in refluxing
toluene. The cis-stereochemistry of the A/B ring system
of 25 is supported by a number of related iminium ion
cyclizations reported in the literature1,9 and by the
spirocyclic ABC ring skeleton is assembled in a single
operation. This triple cascade process should be ap-
plicable toward the preparation of ring homologues of the
Erythrina skeleton by simply varying the tether length
of the starting sulfoxides.
Ack n ow led gm en t. We gratefully acknowledge the
National Science Foundation and the National Cancer
Institute (CA-26750), DHEW, for generous support of
this work. C.O.K. wishes to acknowledge the Austrian
Science Foundation (FWF) for an Erwin-Schro¨dinger-
Postdoctoral Fellowship.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the preparation of, as well as spectroscopic data for,
all new compounds (11 pages).
J O960818W
1
distinct H-chemical shift of the methyl ester.10
(10) The high-field chemical shift of the methyl ester (3.21 ppm for
25 vs 3.83 for sulfoxide 17) is due to the fact that the ester functionality
present in cis-25 is situated directly above the plane of the aromatic
D-ring of the erythrina skeleton. This particular stereochemical
relationship is only realized in the cis-Erythrina series and has been
previously utilized to distinguish between the cis- and trans-ring fusion
in Erythrina derivatives.9
In conclusion, the ready conversion of sulfoxide 17 into
benzoerythrinane 25 represents an efficient and novel
approach toward the erythrinane skeleton in which the
(9) Wilkens, H. J .; Traxler, F. Helv. Chim. Acta 1975, 58, 1512.