Intramolecular [3 + 2]-cycloaddition reaction of push-pull dipoles across heteroaromatic π-systems

Article abstract of DOI:10.1021/ol048915w

(Chemical Equation Presented) Push-pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides containing tethered heteroaromatic rings undergo successful [3 + 2]-cycloaddition across the 2,3-π-bond to provide novel pentacyclic compounds in

Full text of DOI:10.1021/ol048915w

ORGANIC
LETTERS
2
004
Vol. 6, No. 19
241-3244
Intramolecular [3 + 2]-Cycloaddition
Reaction of Push−Pull Dipoles Across
Heteroaromatic π-Systems
3
Jos e´ M. Mej ´ı a-Oneto and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received June 9, 2004
ABSTRACT
Push−pull dipoles generated from the Rh(II)-catalyzed reaction of diazo imides containing tethered heteroaromatic rings undergo successful
3 + 2]-cycloaddition across the 2,3-π-bond to provide novel pentacyclic compounds in good to excellent yields in a stereocontrolled fashion.
The facility of the cycloaddition is critically dependent on conformational factors in the transition state.
[
The dimeric Catharanthus alkaloids vinblastine (3) and
vincristine (4) are clinically useful anticancer agents that
problem would involve the coupling of synthetic catharan-
1
thine (1) with readily available vindoline (2). This approach
would also permit the synthesis of a variety of dimeric
analogues.
are routinely used for the treatment of a number of human
2
-3
cancers.
These two natural products have been isolated
from the leaves of the Madagascan periwinkle plant Catha-
4
ranthus roseus but are present in only very low concentra-
tion. Consequently, numerous research groups have been
actively engaged in developing methods for the synthesis of
5
-7
the upper (catharanthine (1)) and lower (vindoline (2))
halves as well as the critical coupling reaction.8-10 Although
vindoline (2) is the major alkaloid in Catharanthus roseus
and is readily isolated and purified, catharanthine (1) is only
a minor constituent and is substantially more difficult to
obtain and purify.11 An attractive solution to the supply
(
1) Noble, R. L.; Beer, C. T.; Cutts, J. H. Ann. N. Y. Acad. Sci. 1958,
6, 882.
2) Neus, N.; Neus, M. N. The Therapeutic Use of Bisindole Alkaloids
7
(
from Catharanthus. In The Alkaloids; Brossi, A., Suffness, M., Eds.;
Academic Press: New York, 1990; Vol. 37, p 232.
(
3) Cordell, G. A.; Saxton, J. E. Bisindole Alkaloids. In The Alkaloids;
Rodrigo, R. G. A., Ed.; Academic Press, Inc.: San Diego, 1981; Vol. 20.
4) Blasko, G.; Cordell, G. A. Isolation, Structure Elucidation and
(
Biosynthesis of the Bisindole Catharanthus. In The Alkaloids; Brossi, A.,
Suffness, M., Eds.; Academic Press: New York, 1990; Vol. 37, p 12.
(5) For a review on synthetic studies of vinblastine, see: Antitumor
Bisindole Alkaloids from Catharanthus roseus (L.). In The Alkaloids; Brossi,
A., Suffness, M., Eds.; Academic Press: New York, 1990; Vol. 37, Chapter
(()-Catharanthine (1) has been the target of numerous
successful and formal total syntheses. The previous routes
to 1 generally make use of a preexisting indolyl framework
2
, pp 77-131.
6) Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org. Chem. 1991,
6, 513.
1
2
(
5
1
0.1021/ol048915w CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/18/2004

Scheme 1
Scheme 3
carbonyl ylide dipole. Subsequent intramolecular cycload-
dition across the tethered vinyl group in the model system
1
1 furnished cycloadduct 12 in 95% isolated yield, thereby
demonstrating the facility of the cascade sequence (Scheme
). We were pleased to find that the analogous vinyl-indolyl-
3
substituted diazo imide 13 underwent a related Rh(II)-
catalyzed cyclization to give the azapolycyclic cycloadduct
15 in 92% yield. The cascade sequence was extremely facile
and do not allow for the ready construction of analogues
substituted on the aromatic ring.12 In earlier work from our
laboratory we had described a synthetic route to 4-oxo-6,7-
dihydrovindorosine that involved an intramolecular [3 +
and took place at room temperature. When the Rh(II)-
catalyzed reaction was carried out at 50 °C or higher, the
only product isolated corresponded to the ring-opened
pyridone 16. Control experiments demonstrated that heating
a pure sample of 15 in ether provided 16 in 90% yield
(Scheme 4).
2
]-cycloaddition of a carbonyl ylide dipole across a tethered
13
indole ring. The sequence of reactions used is part of our
general approach to the total synthesis of various azaspiro-
cyclic natural products based on the tandem cyclization-
cycloaddition reaction of rhodium carbenoids as the key
Scheme 4
1
4
strategic element. Prompted by our earlier studies, we
became interested in using a related Rh(II)-catalyzed cascade
sequence for the eventual synthesis of catharanthine and its
modified analogues. Our synthetic plan is shown in antithetic
format in Scheme 1 and is centered on the construction of
the key oxabicyclic intermediate 6, which, by analogy with
our previous work should be available by the tandem
rhodium(II)-catalyzed cyclization-cycloaddition of diazo
amide 5.15
The potential of this methodology for the synthesis of
catharanthine and related iboga alkaloids prompted us to first
carry out some model studies to probe the likelihood of the
key [3 + 2]-cycloaddition across a tethered vinyl group. The
starting diazo imido substrates (i.e., 9) were easily prepared
by treating the stable N-H diazo amides 8 with an
appropriate acid chloride in the presence of 4 Å molecular
sieves (Scheme 2). Formation of the push-pull 1,3-dipole
Armed with these promising results, we set out to explore
the cycloaddition chemistry of the homologous indolyl diazo
imide 17, which is a more suitable model for an eventual
Scheme 2
(
7) Magnus, P.; Mendoza, J. S.; Stamford, A.; Ladlow, M.; Willis, P. J.
Am. Chem. Soc. 1992, 114, 10232.
8) (a) Potier, P.; Langlois, N.; Langlois, Y.; Gueritte, F. J. Chem. Soc.,
(
Chem. Commun. 1975, 670. (b) Mangeney, P.; Andriamialisoa, R. Z.;
Langlois, N.; Langlois, Y.; Potier, P. J. Am. Chem. Soc. 1979, 101, 2243.
(9) (a) Kutney, J. P.; Ratcliffe, A. H.; Treasurywalla, A. M.; Wunderly,
S. Heterocycles 1975, 3, 639. (b) Vucovic, J.; Goodbody, A. E.; Kutney, J.
P.; Misawa, M. Tetrahedron 1988, 44, 325. (c) Kutney, J. P.; Choi, L. S.
L.; Nakano, J.; Tsukamoto, H.; McHugh, M.; Boulet, C. A. Heterocycles
1
2 4
0 was achieved by reaction of 9 with Rh (OAc) , which
1
988, 27, 1845.
afforded a rhodium carbenoid species that underwent ready
cyclization onto the neighboring imido carbonyl to form the
(10) Yokoshima, S.; Ueda, T.; Kobayashi, S.; Sato, A.; Kuboyama, T.;
Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
3242
Org. Lett., Vol. 6, No. 19, 2004

Scheme 5
Scheme 6
synthesis of catharanthine. Most surprisingly, subjection of
17 to Rh(II) catalysis led exclusively to cycloadduct 18 (95%)
where cycloaddition of the 1,3-dipole occurred preferentially
across the indole π-bond rather than with the tethered vinyl
group (Scheme 5). Although there are examples in the
literature where the 2,3-double bond of indole participates
16-18
in [4 + 2]-cycloaddition chemistry,
the indole ring
generally shows only a low tendency to act as a dienophile
with electron-rich dienes.1
9,20
In bimolecular Diels-Alder
reactions that occur with normal electron demand, indole acts
as a 2π-substrate only if electron-withdrawing groups are
present in the 1- and 3-positions.1 Intramolecular cycload-
dition reactions, however, benefit from higher reactivity and
greater control of stereoselectivity relative to their intermo-
lecular counterparts. More than likely, the initially formed
dipole derived from 17 resides in a conformation where the
cyclopentadiene.21 The reactivity of these heteroaromatic
dipolarophiles is, however, sharply decreased because of the
loss of aromaticity in the cycloaddition transition states. A
vast amount of information is available concerning the
reactivity of heteroaromatics in cycloadditions where the
5,16
2
2
heteroaromatics function as 4
π
s components, but a study
4π-array of the carbonyl ylide dipole is able to better overlap
of their dipolarophilic reactivity has not been extensively
2
0,23
in the traditional two-plane orientation approach with the
indolyl π-bond than with the vinyl group, thereby controlling
the periselectivity of the cycloaddition.
In the context of extending the above cycloaddition
reaction to other ring systems, we wondered whether the
push-pull dipole found in 10 might also undergo intramo-
lecular dipolar cycloaddition with different heteroaromatic
π-bonds. Five-membered-ring heteroaromatics such as furan,
thiophene, and benzofurans have, despite their aromaticity,
frontier orbital energies and shapes similar to those of
examined to date.
Consequently, we initiated a study to
determine whether push-pull dipoles of type 10 would
undergo cycloaddition with several other heteroaromatic
π-systems.
Our initial efforts focused on the Rh(II)-catalyzed reaction
of the benzofuranyl-substituted diazo imide 19. Gratifyingly,
treatment of 19 with rhodium(II) pivalate at 100 °C in
benzene using a microwave reactor afforded the polyhet-
erocyclic adduct 20 in 90% yield and with complete
diastereospecificity. The regio- and relative stereochemistry
1
of 20 was assigned by H NMR and confirmed by single-
(
11) Svoboda, G. H.; Neuss, N.; Gorman, M. J. Am. Pharm. Assoc., Sci.
Ed. 1959, 48, 659.
12) For some leading references, see those cited in: Reding, M. T.;
Fukuyama, T. Org. Lett. 1999, 1, 973.
13) (a) Padwa, A.; Price, A. T. J. Org. Chem. 1995, 60, 6258. (b) Padwa,
A.; Price, A. T. J. Org. Chem. 1998, 63, 556.
14) (a) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223. (b)
Padwa, A.; Hornbuckle, S. F. Chem. ReV. 1991, 91, 263.
15) Antithetical conversion of 6 into 7 would require a number of
crystal X-ray analysis. A similar product (i.e., 22) was
obtained in 95% yield using the related indolyl-substituted
(
2
4
diazo imide 21 (Scheme 6).
(
Bolstered by these positive results, we next examined the
Rh(II)-catalyzed behavior of the cyclic diazo imide contain-
ing a tethered furan ring. Treatment of 23 with rhodium(II)
pivalate at 90 °C in benzene furnished cycloadduct 24 but
only in 35% yield. The lower yield encountered with this
system is probably related to its greater aromaticity relative
to the benzo-fused systems. Thiophene has a lower lying
HOMO level than does furan, which increases the energy
(
(
additional steps including an oxabicyclic ring-opening reaction followed
by a subsequent elimination of the EWG group (i.e., SO2Ph, CN, etc.) as
well as an eventual intramolecular nucleophilic N-C bond formation.
(
16) (a) Wenkert, E.; Piettre, S. R. J. Am. Chem. Soc. 1988, 53, 5850.
(
b) Wenkert, E.; Moeller, P. D. R.; Piettre, S. R. J. Am. Chem. Soc. 1988,
10, 7188.
17) (a) Kraus, G. A.; Raggon, P. J.; Thomas, P. J.; Bougie, D.
1
(
1
9
gap between the interacting FMOs. This is probably why
so little is known about dipolar cycloadditions across
thiophene rings. We found, however, that no significant
Tetrahedron Lett. 1988, 29, 5605. (b) Kraus, G. A.; Bougie, D.; Jacobsen,
R. A.; Su, Y. J. Org. Chem. 1989, 54, 2425.
(
intramolecular Diels-Alder/dipolar cycloaddition sequence of a 1,3,4-
oxadiazole across the indole double bond, see: Wilkie, G. D.; Elliott, G.
I.; Blagg, B. S.; Wolkenberg, S. E.; Soenen, D. R.; Miller, M. M.; Pollack,
S.; Boger, D. L. J. Am. Chem. Soc. 2002, 124, 11292.
18) For a similar approach to the Vinca alkaloids using a tandem
(21) Del Bene, J.; Jaffe, H. H. J. Chem. Phys. 1968, 48, 4050.
(22) (a) Sauer, J. Angew Chem., Int. Ed. Engl. 1967, 6, 16. (b) Carruthers,
W. Cycloaddition Reactions in Organic Synthesis; Pergamon Press: Oxford,
1990. Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (c) Woo, S.; Keay, B. A.
Synthesis 1996, 669.
(
19) (a) Biolatto, B.; Kneeteman, M.; Paredes, E.; Mancini, P. M. E. J.
Org. Chem. 2001, 66, 3906. (b) Magnus, P.; Gallagher, T.; Brown, P.;
Pappalardo, P. Acc. Chem. Res. 1984, 17, 35.
(
20) Indole is quite a good dienophile in inverse electron demand Diels-
(23) For some leading references, see: (a) Padwa, A.; Hertzog, D. L.;
Nadler, W. R. J. Org. Chem. 1994, 59, 7072.
(24) Conversion of 21 to 22 was previously described in ref 13.
Alder cycloadditions; see: Lee, L.; Snyder, J. K. AdVances in Cycloaddition
Chemistry; Harmata, M., Ed.; JAI Press: 1999; Vol. 6, p 119.
Org. Lett., Vol. 6, No. 19, 2004
3243

difference in yield occurred when the related thiophenyl-
substituted diazo imide 25 was treated with the Rh(II)
catalyst. The major product formed in 38% yield cor-
responded to cycloadduct 26. This result stands in contrast
to other literature reports, where it is known that the greater
aromatic character of thiophene considerably limits its ability
to undergo cycloaddition chemistry.15 The above example
also represents the first instance of an intramolecular [3 +
a potential method for the synthesis of various alkaloidal
targets. The results of this investigation will be reported in
due course.
Acknowledgment. We appreciate the financial support
provided by the National Institutes of Health (GM 59384)
for generous support of this work. We thank our colleague,
Dr. Kenneth Hardcastle, for his assistance with the X-ray
crystallographic studies and the University Research Com-
mittee of Emory University for funds to acquire a microwave
reactor.
2
]-cycloaddition of a 1,3-dipole across the thiophene 2,3-
π-bond.
In conclusion, we have demonstrated that push-pull
dipoles generated from the Rh(II)-catalyzed reaction of diazo
imides undergo successful 1,3-dipolar cycloaddition across
heteroaromatic π-bonds to provide novel pentacyclic com-
pounds in good to excellent yield and in a stereocontrolled
fashion. The facility of the cycloaddition is critically de-
pendent on conformational factors in the transition state. We
are currently investigating the scope and limitations of the
intramolecular cycloaddition of these push-pull dipoles as
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds together with an ORTEP drawing for cycloadduct
2
0. This material is available free of charge via the Internet
at http://pubs.acs.org.
OL048915W
3244
Org. Lett., Vol. 6, No. 19, 2004