Novel [1,5] sigmatropic rearrangements of cyclohexadienones generated from fischer carbene complexes. A new strategy for installing the C-20 angular ethyl group in aspidospermidine alkaloids

Article abstract of DOI:10.1021/ol990063q

(Equation Presented) We report here the first examples of a [1,5] sigmatropic rearrangement in a 4a-alkyl-4a-hydrocarbazol-4-one to yield a 3-alkylcarbazol-4-one with a re-aromatized indole nucleus. The reaction of 1-methyl-3-substituted-indole-2-carbene

Full text of DOI:10.1021/ol990063q

ORGANIC
LETTERS
1999
Vol. 1, No. 1
161-164
Novel [1,5] Sigmatropic Rearrangements
of Cyclohexadienones Generated from
Fischer Carbene Complexes. A New
Strategy for Installing the C-20 Angular
Ethyl Group in Aspidospermidine
Alkaloids
John F. Quinn, Mary Ellen Bos, and William D. Wulff*
Department of Chemistry, Searle Chemistry Laboratory, The UniVersity of Chicago,
Chicago, Illinois 60637
wulff@rainbow.uchicago.edu
Received April 29, 1999
ABSTRACT
We report here the first examples of a [1,5] sigmatropic rearrangement in a 4a-alkyl-4a-hydrocarbazol-4-one to yield a 3-alkylcarbazol-4-one
with a re-aromatized indole nucleus. The reaction of 1-methyl-3-substituted-indole-2-carbene complexes 1 with terminal alkynes yields 3,4a-
dialkyl-1-methoxy-9-methylcarbazol-4-ones 2. These 4a-substituted carbazolones thermally rearrange to cleanly give the more highly aromatic
3,3-dialkyl-1-methoxy-9-methylcarbazol-4-ones 3. This reaction provides a convenient entry to the Aspidosperma family of alkaloids, which
contain a 3,3-disubstituted carbazole nucleus.
In the course of investigating the synthetic applications of
Fischer carbene complex chemistry to indole alkaloid
synthesis, we have recently discovered a novel [1,5] sigma-
tropic rearrangement.1 Sigmatropic rearrangements have
proven to be extremely powerful tools for the construction
of complex carbon frameworks.2 Anion accelerated [3,3]
processes such as the oxy-Cope and Claisen rearrangements
have received the most attention,3 while [1,5] shifts other
than hydrogen are relatively unknown.4
Our approach5 to the synthesis of the pentacyclic Aspi-
dosperma indole alkaloid, vindoline 7,6 involves the cyclo-
hexadienone annulation7 of the 1,3-disubstituted-indol-2-yl
carbene complex 5 with alkyne 4 to yield the 4a-substituted
carbazol-4-one 6. These compounds were anticipated to
furnish the required pentacyclic skeleton via a double
intramolecular reductive amination (Scheme 1).
Initial investigations to demonstrate the feasibility of this
strategy centered around the simplified 1,3-dimethylindole
carbene complex 8. We previously reported that this complex
would react with a number of alkynes to give the desired
cyclohexadienones in good yields as is illustrated by its
reactions with 1-pentyne and 3-hexyne in Scheme 2, which
gave the 4a-carbazolones 9a and 9b in 85 and 95% yields,
respectively.8
(3) For reviews, see: (a) Wilson, S. R. Org. React. 1993, 43, 93. (b)
Bronson, J. J. In ComprehensiVe Organic Synthesis; Trost, B. M., Flemming,
I., Eds.; Pergamon Press: 1991; Vol. 5, p 999.
(4) For examples of anion-accelerated [1,5] alkyl shifts, see: Battye, P.
J.; Jones, D. W. J. Chem. Soc., Chem. Commun. 1984, 990.
(5) Bauta, W. E.; Wulff, W. D.; Pavkovic, S. F.; Zaluzec, E. J. J. Org.
Chem. 1989, 54, 3249.
(1) For reviews on [1,5] thermal sigmatropic rearrangements, see: (a)
Spangler, C. W. Chem. ReV. 1976, 76, 187. (b) Mironov, V. A.; Fedorovich,
A. D.; Akhrem, A. A. Russ. Chem. ReV., 1981, 50, 666.
(2) For a review on the Cope and Claisen rearrangements, see: Rhoads,
S. J.; Raulins, N. R. Org. React. 1975, 22, 1.
10.1021/ol990063q CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/26/1999

Scheme 1
Scheme 3
Scheme 2
since the rearranged product 14 has never been seen in the
reaction of 10. However, it was found that 9a could be
partially rearranged to 14 by refluxing in xylenes for 48 h.
The formation of cyclohexadienones from the reaction of
aryl carbene complexes in which both ortho positions are
substituted up until now has been limited to indole carbene
complexes.10 It has been previously reported that the reaction
of the 2,6-dimethylphenyl complex 15 in butyl ether with
diphenylacetylene gave the indenes 16 and 17 in a total yield
of 52%.11 We have reinvestigated the reaction of complex
15 with a number of different alkynes, and the results are
presented in Scheme 4. The reaction gives excellent yields
with a number of internal alkynes in benzene, but reactions
with terminal alkynes only give small quantities of charac-
terizable materials and this may be due to the multiple
insertion of the alkyne to give oligiomers. The formation of
the indene 16e in 84% yield as a 13:1 mixture of regio-
isomers demonstrates that silylated alkynes can be used as
synthons for terminal alkynes. While we did not detect any
CO insertion products from the intermolecular reaction of
complex 15 with alkynes, we did find that the intramolecular
reaction of complex 18 gave a 37% yield of the cyclohexa-
dienone 20 and a 17% yield of the indanone 19 resulting
from the hydrolysis of an indene product. This is the first
example of the formation of a cyclohexadienone from a 2,6-
disubstituted-phenyl carbene complex.12
Upon cyclohexadienone annulation of 1-pentyne with the
more highly functionalized carbene complex 10 derived from
a silyl-protected tryptophol,9 it was found that, in addition
to the desired cyclohexadienone product 12, the product
resulting from a [1,5] sigmatropic rearrangement of 12 was
also present (Scheme 3). If the reaction is carried out at 55
°C for 90 min, only the cyclohexadienone 12 was observed
and the same reaction for 48 h provided only the rearranged
cyclohexadienone 13. Initially, this result seemed surprising
(6) For reviews, see: (a) Saxton, J. E. Nat. Prod. Rep. 1987, 4, 591. (b)
Overman, L. E.; Sworin, M. In Alkaloids, Chemical and Biological
PerspectiVes, Vol. 3; Pelletier, S. W., Ed.; Wiley: New York, 1985; p 275.
(c) Cordell, G. A. In The Alkaloids; Manske, R. H. F., Rodrigo, R. G. A.,
Eds.; Academic Press: New York, 1979; Vol. XVII, p 199. For citations,
see: (d) Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P., Acc. Chem.
Res. 1984, 17, 35. For recent citations, see: (e) Feldman, P. L.; Rapoport,
H. J. Am. Chem. Soc. 1987, 109, 1603. (f) Node, M.; Nagasawa, H.; Fuji,
K. J. Am. Chem. Soc. 1987, 109, 7901. (g) Kuehne, M. E.; Zebovitz, T. C.
J. Org. Chem. 1987, 52, 4331. (h) Brennan, J. P.; Saxton, J. E. Tetrahedron
1987, 43, 191. (i) Cardwell, K.; Hewitt, B.; Ladlow, M.; Magnus, P. J.
Am. Chem. Soc. 1988, 110, 2242. (j) Hugel, G.; Pfeuffer, L. Tetrahedron
Lett. 1987, 28, 1773. (k) Ogawa, M.; Kitagawa, Y.; Natsuma, M.
Tetrahedron Lett. 1987, 28, 3985. (l) Jackson, A. H.; Shannon, P. V. R.;
Wilkens, D. J. Tetrahedron Lett. 1987, 28, 4901.
(7) (a) Tang, P. C.; Wulff, W. D. J. Am. Chem. Soc. 1984, 106, 1132.
(b) Wulff, W. D.; Yang, D. C. J. Am. Chem. Soc. 1984, 106, 7565. (c)
Wulff, W. D.; Gilbertson, S. R. J. Am. Chem. Soc. 1985, 107, 503. (d)
Wulff, W. D.; Kaesler, R. W.; Peterson, G. A.; Tang, P. C. J. Am. Chem.
Soc. 1985, 107, 1060. (e) Semmelhack, M. F.; Park, J. Organometallics
1986, 5, 2550.
(10) (a) Do¨tz, K. H.; Dietz, R.; Appenstein, C. K.; Neugebauer, D.;
Schubert, U. Chem. Ber. 1979, 112, 3682. (b) Do¨tz, K. H.; Sturm, W. J.
Organomet. Chem. 1986, 310, C22. (c) Bos, M. E.; Wulff, W. D.; Wilson,
K. J. J. Chem. Soc., Chem. Commun. 1996, 1863. (d) Harrity, J. P. A.;
Kerr, W. J.; Middlemiss, D.; Scott, J. S. J. Organomet. Chem. 1997, 532,
219.
(8) Bauta, W. E.; Wulff, W. D.; Pavkovic, S. F.; Zaluzec, E. J. J. Org.
Chem. 1989, 54, 3249.
(9) The carbene complex 10 was prepared in 67% yield from N-methyl-
O-tert-butyldimethylsilyltryptophol by the method shown for complex 37
in Scheme 7.
(11) Do¨tz, K. H.: Dietz, R.; Appenstein, C. K.; Neugebauer, D.; Schubert,
U. Chem. Ber. 1979, 112, 3682.
162
Org. Lett., Vol. 1, No. 1, 1999

the initial dissociation of a CO ligand is no longer the rate-
limiting step of the reaction. It is possible that the electro-
cyclic ring closure of the vinyl ketene intermediate is now
the slow step in the sequence, and this would explain the
results described above.
Scheme 4
The reason that the intramolecular reaction of complex
18 gives cyclohexadienone 20 may be related to a conforma-
tion restriction in the vinyl ketene that is favorable to the
transition state for ring closure. In no reactions were the
isoindene 25 or the isomeric cyclohexadienone 23 isolated.
These intermediates undergo [1,5] sigmatropic migration of
methyl faster than the corresponding indole intermediate 9a,
which can be isolated and which only undergoes rearrange-
ment slowly at 140 °C. This is presumably due to the fact
that there is a greater driving force in the restoration of
aromaticity in the phenyl systems compared to the indole
intermediates.14 Assuming that the methyl groups in 21 do
not slow the rate of CO insertion, the isolation of indenes as
the only product in the intermolecular reaction would require
that CO insertion was reversible. While there is no experi-
mental or theroetical evidence for this, it is not unreasonable
in these ortho-disubstituted complexes. What is not so clear
is why the cyclization to the isoindene 25 would be more
favorable than that to the cyclohexadienone 23. Perhaps the
[1,5] sigmatropic shift is rate-limiting in each case and is
faster in 25 than in 23 due to better orbital overlap.
The normal course of events in the reaction of alkynes
with aryl Fischer carbene complexes containing at least one
ortho hydrogen substituent is initial loss of a carbon
monoxide ligand, insertion of an alkyne to generate a vinyl
carbene complexed intermediate of the type 21, insertion of
a CO ligand to give a vinyl ketene complex of the type 22,
electrocyclic ring closure to give a cyclohexadienone inter-
mediate of the type 28, and then finally tautomerization to
the naphthol 29 which is the ultimate product of the reaction
(Scheme 5).13 Two differences that are seen in the intermo-
lecular annulations of 2,6-disubstituted phenyl complexes are
that CO-inserted products are not seen and that the temper-
atures required are 50-60 °C higher under otherwise similar
conditions. The higher temperature requirement suggests that
The [1,5] sigmatropic shifts of alkyl substituents observed
for the carbazolones 12 and 9a prompted the consideration
of a new strategy for the synthesis of members of the
Aspidospermidine alkaloid family which is outlined in
Scheme 6. It begins with a cyclohexadienone annulation of
a 3-ethyl-2-indolyl carbene complex like 33 with an N-
protected 1-amino-4-pentyne like 34. The thermal rearrange-
ment of the carbazolone 32 will relocate the ethyl group to
the nascent C-20 position of the aspidospermidine ring
system. After installation of the piperidine ring to produce
the tetracycle 30, all that would remain is to append the
pyrrolidine ring to complete the construction of the penta-
cyclic Aspidosperma carbon skeleton.15
Scheme 5
Scheme 6
Org. Lett., Vol. 1, No. 1, 1999
163

As a test of this strategy, the 3-ethyl-2-indolyl Fischer
carbene complex 37 and the alkyne 39 were prepared as
outlined in Scheme 7. The requisite 3-ethylindole was
The cyclohexadienone annulation of complex 37 and
alkyne 39 was carried out in xylenes at 55 °C for 90 min
followed by heating at 140 °C to effect the [1,5] sigmatropic
shift of the ethyl group which was complete after 1 h to
give the 3,3-disubstituted carbazolone 41 in 61% overall yield
(Scheme 8). From the point of view of this new strategy for
Scheme 7
Scheme 8
prepared by a Fischer indole synthesis from phenylhydrazine
and n-butyraldehyde.16 The carbene complex 37 was prepared
from indole 36 by the standard Fischer procedure involving
the reaction of chromium carbonyl with the 2-indolyllithium
which was generated by metalation with tert-butyllithium.17
The preparation of the protected 1-amino-4-pentyne 39 was
accomplished in one pot in 81% yield by a Curtius re-
arrangement of the commercially available acid 38 by the
procedure of Na¨geli where trimethylsilyl azide is substituted
for sodium azide followed by trapping the isocyanate with
benzyl alcohol.18
the synthesis of Aspidospermidine alkaloids, it is important
to note that the [1,5] sigmatropic shift of the ethyl group in
37 was much faster than that for the methyl group in 9a
(Scheme 3). The carbazolone 41 was additionally character-
ized by treatment with ammonium formate in the presence
of palladium on carbon which resulted in deprotection of
the amine, cyclization to the imine, and reduction of the enol
ether to give a single diastereomer of the methyl ether 42 in
92% yield.
(12) An exception is when the rearomatization is thwarted by a
tautomerization: Bos, M. E.; Wulff, W. D.; Wilson, K. J. J. Chem. Soc.,
Chem. Commun. 1996, 1863.
(13) (a) Hofmann, P.; Ha¨mmerle, M.; Unfried, G. New. J. Chem. 1991,
15, 769. (b) Hofmann, P.; Ha¨mmerle, M. Angew. Chem., Int. Ed. Engl.
1989, 28, 908. (b) Gleichmann, M. M.; Do¨tz, K. H.; Hess, B. A., J. Am.
Chem. Soc. 1996, 118, 10551. (c) Torrent, M.; Duran, M.; Sola, M. J. Chem.
Soc., Chem. Commun. 1998, 999. (d) Bos, M. E.; Wulff, W. D.; Miller, R.
A.; Chamberlin, S.; Brandvold, T. A. J. Am. Chem. Soc. 1991, 113, 9293.
(14) In the case of 2,6-disubstituted-4-hydroxyphenyl carbene complexes,
the intermediate tautomerizes faster than it rearranges. Boss, M. E.; Wulff,
W. D.; Wilson, K. J. J. Chem. Soc., Chem. Commun. 1996. 1863.
The successful transformation of indole 36 to the carba-
zolone 41 demonstrates the feasibility of a new strategy for
the synthesis of Aspidospermidine alkaloids involving a [1,5]
sigmatropic shift of an ethyl group from a 3,4a-disubstituted
carbazolone. Further studies to evaluate the overall efficiency
of this strategy will be reported in due course
Acknowledgment. This work was supported by a grant
from the National Institutes of Health.
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) (a) Magnus, P.; Gallagher, T. Tetrahedron 1981, 37, 3889. (b)
Magnus, P.; Gallagher, T. J. Am. Chem. Soc. 1982, 104, 1140. (c) Magnus,
P.; Gallagher, T.; Exon, C. J. Am. Chem. Soc. 1983, 105, 4739. (d)
Gallagher, T.; Magnus, P.; Huffman, J. C. J. Am. Chem. Soc. 1983, 105,
4750. (e) Magnus, P.; Gallagher, T.; Brown, P.; Pappalardo, P. Acc. Chem.
Res. 1984, 17, 35. (f) Magnus, P.; Pappalardo, P. A. J. Am. Chem. Soc.
1986, 108, 212. (g) Magnus, P.; Cairns, P. M. J. Am. Chem. Soc. 1986,
108, 217. (h) Cardwell, K.; Hewitt, B.; Ladlow, M.; Magnus, P. J. Am.
Chem. Soc. 1988, 110, 2242. (i) Amat, M.; Linares, A.; Bosch, J. J. Org.
Chem. 1990, 55, 6299. (j) Amat, M.; Bosch, J. J. Org. Chem. 1992, 57,
5792. (k) Catena, J.; Valls, N.; Bosch, J.; Bonjoch, J. Tetrahedron Lett.
1994, 35, 4433. (l) Husson, H.; Thal, C.; Potier, P.; Wenkert, E. J. Chem.
Soc., Chemm. Commun. 1970, 480. (m) Zeigler, F. E.; Spitzner, E. B. J.
OL990063Q
Am. Chem. Soc. 1973, 95, 7146. (n) Oikawa, Y.; Yonemitsu, O. J. Org.
Chem. 1976, 41, 1118. (o) Natsume, M.; Utsunomiya, I. Heterocycles 1982,
17, 111. (p) Hugel, G.; Cossy, J.; Levy, J. Tetrahedron Lett. 1987, 28, 1773.
(q) Wenkert, E.; Hudlicky, T. J. Org. Chem. 1988, 53, 1953.
(16) Robinson, B. Chem. ReV. 1969, 69, 227.
(17) Fischer, E. O.; Schubert, U.; Kleine, W.; Fischer, H. Inorg. Synth.
1979, 19, 164.
(18) Moller, F. In Methoden der Organischen Chemie, Houben-Weyl;
Georg Thieme Verlag: 1957; Vol 11/1, p 865.
164
Org. Lett., Vol. 1, No. 1, 1999