Total Synthesis of Carbazoquinocin C: Application of the o-Benzannulation of Fischer Carbene Complexes to Carbazole-3,4-quinone Alkaloids

Article abstract of DOI:10.1021/ol0360445

(Matrix presented) The photoinduced o-benzannulation of 3-(2-vinyl)indolylcarbene complexes provides a direct route to carbazole derivatives that are oxygenated in the 3- and 4-positions. This reaction is quite efficient and provides for a unique synthesi

Full text of DOI:10.1021/ol0360445

ORGANIC
LETTERS
2004
Vol. 6, No. 3
329-332
Total Synthesis of Carbazoquinocin C:
Application of the o-Benzannulation of
Fischer Carbene Complexes to
Carbazole-3,4-quinone Alkaloids
Manish Rawat and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
wulff@cem.msu.edu
Received October 17, 2003
ABSTRACT
The photoinduced o-benzannulation of 3-(2-vinyl)indolylcarbene complexes provides a direct route to carbazole derivatives that are oxygenated
in the 3- and 4-positions. This reaction is quite efficient and provides for a unique synthesis of the lipid peroxidation inhibitor carbazoquinocin
C.
The carbazole-3,4-quinone unit has been found in a number
of molecules which have been discovered largely upon
Scheme 1
screening several microorganims for compounds possessing
activity against lipid peroxidation and for those possessing
neuronal cell protecting activity.1 These molecules include
carbazoquinocins A-F, carquinostatins A and B and la-
vanduquinocin (Scheme 1). The potency of these molecules
together with the unique carbazole-3,4-quinone substructure
in these molecules have prompted the development of a
number of synthetic strategies to this family of natural
products.2 The syntheses reported to date include carbazo-
quinocins A,2h B,2e C,2a-g D,2e,h E-F,2e carquinostatin A,2b,i,j
and lavanduquinocin.2k,l
We report a unique approach to the synthesis of the
carbazole-3,4-quinone alkaloids in which the o-quinone unit
is constructed via an o-benzannulation reaction of a doubly
unsaturated Fischer carbene complex. Inspired by the pio-
neering work of Hegedus,3 we envisioned the possibility of
(1) (a) Shin-Ya, K.; Tanaka, M.; Furihata, K.; Hayakawa, Y.; Seto, H.
Tetrahedron Lett. 1993, 34, 4943. (b) Shin-Ya, K.; Shimizu, S.; Kunigami,
T.; Furihata, K.; Furihata, K.; Seto, H. J. Antibiot. 1995, 48, 574. (c) Tanaka,
M.; Shin-Ya, K.; Furihata, K.; Seto, H. J. Antibiot. 1995, 48, 326. (d) Shin-
Ya, K.; Kunigami, T.; Kim, J.-S.; Furihata, K.; Hayakawa, Y.; Seto, H.
such a reaction that involves the photoinduced coupling of
Biosci. Biotech. Biochem. 1997, 61, 1768. (e) Grammel, H.; Wolf, H.; Gilles,
E.-D.; Huth, F.; Laatsch, H. Z. Naturforsch. 1998, 53c, 325.
a carbon monoxide ligand and a carbene ligand to give a
10.1021/ol0360445 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/06/2004

doubly unsaturated ketene of the type 5 which undergoes
electrocyclic ring closure to give an o-methoxyphenol of type
6 (Scheme 2). In fact, we found that the photolysis of
Scheme 4
Scheme 2
complex 7 indeed gives the phenol 8 which would be
expected from this process.4 It was later shown that the yield
of the reaction could be improved if the reaction was
performed under a carbon monoxide atmosphere.5 In this
paper, we describe the synthesis of carbazoquinocin C with
the o-benzannulation as the key step.
It was envisioned that this 3-(2-vinyl)indolylcarbene complex
could be prepared from the commercially available indole-
2-carboxylic acid.
The n-heptyl-2-indolyl ketone 12 was efficiently prepared
from the acid 11 via Grignard addition to the Weinreb’s
amide (Scheme 4). The conversion of 12 to intermediates
17 and 18 (Scheme 5), the precursors to the carbene complex
The strategy for the synthesis of carbazoquinocin C
involves the intermediacy of the 3-hydroxy-4-methoxycar-
bazole 9 from which the natural product can be generated
by oxidation of the phenol ring (Scheme 3). The key step in
Scheme 3
Scheme 5
the synthesis is thus to be the photoinduced CO insertion/
cyclization of the R,â,γ,δ-unsaturated carbene complex 10.
(2) (a) Kno¨lker, H.-J.; Fro¨hner, W.; Reddy, K. R. Synthesis 2002, 557.
(b) Kno¨lker, H.-J.; Reddy, K. R. Synlett 1999, 596. (c) Kno¨lker, H.-J.;
Fro¨hner, W.; Tetrahedron Lett. 1997, 38, 1535. (d) Kno¨lker, H.-J.; Reddy,
K. R.; Wagner, A. Tetrahedron Lett. 1998, 39, 8267. (e) Choshi, T.; Sada,
T.; Fujimoto, H.; Nagayama, C.; Sugino, E.; Hibino, S. J. Org. Chem. 1997,
62, 2535. (f) Aygu¨n, A.; Pindur, U. J. Heterocycl. Chem. 2003, 40, 411.
(g) Alparslan, A.; Pindur, U. Synlett 2000, 1757. (h) Shin, K.; Ogasawara,
K. Synlett 1996, 922. (i) Kno¨lker, H.-J.; Fro¨hner, W. Synlett 1997, 1108.
(j) Kno¨lker, H.-J.; Basum, E.; Reddy, K. R. Tetrahedron Lett. 2000, 41,
1171. (k) Kno¨lker, H.-J.; Fro¨hner, W. Tetrahedron Lett. 1998, 39, 2537.
(l) Kno¨lker, H.-J.; Baum, E.; Reddy, K. R. Chirality 2000, 526.
10, requires N-protection, olefination, and bromination, and
some time was spent investigating the optimal order of these
steps. Bromination of ketone 12 was successful to give the
(3) McGuire, M. A.; Hegedus, L. S. J. Am. Chem. Soc. 1982, 104, 5538.
(4) (a) Yang, D. C. Ph.D. Thesis, University of Chicago, 1986, p 28. (b)
Wulff, W. D., In AdVances in Metal-Organic Chemistry; Liebeskind, L.
S., Ed.; JAI Press: Greenwich, CT, 1989; Vol. 1, p 336.
(5) Merlic, C. A.; Xu, D. J. Am. Chem. Soc. 1991, 113, 7418.
330
Org. Lett., Vol. 6, No. 3, 2004

3-bromoindole 13 but all attempts to carry out a Wittig
reaction on this substrate failed. In contrast, the olefination
of the ketone 12 proceeded smoothly to give the 2-vinyl-
indole 16 in 93% yield as a 1.0:0.84 mixture of E/Z isomers.
The bromination of 16 was successful; however, the resulting
3-bromoindole 14 is not particularly stable. Immediate
treatment with TBSCl and NaH gave the stable N-silylated
indole 15 in 45% yield for the two steps. Given the instability
of bromoindole 14, the reverse of the bromination/protection
sequence was investigated and found to be far more practical.
The 2-vinylindole 16 was first protected either as the
N-benzyl- or N-p-methoxybenzyl derivatives 17 and 18 in
70% and 72% yield, respectively. Bromination gave the
carbene precursors 19 and 20 in excellent yields (Scheme
5). Carbene complexes 21-23 were prepared by the standard
Fischer procedure in moderate yields. These complexes were
usually obtained with a small amount of a side product
resulting from reduction of the bromide in the precursors
19 and 20. These reduced products were not easily separated
from the carbene complexes and thus were carried on to the
next step where they could be removed. The yields for the
carbene complexes 21-23 have the amount of the reduced
products factored out. We have not been able to prepare a
carbene complex from the TBS-protected indole 15. The only
observable product is the 3-unsubstituted indole resulting
from reduction of the bromide in 15.
indole nitrogen. Deprotection of the N-benzylindole 25 was
resistant to initial efforts. Hydrogenation with palladium on
carbon led to over-reduced products.
Deprotection with AlCl38 or with sodium thioethoxide9 lead
to the destruction of the starting material. Deprotection of
25 was only achieved when the phenol function was
derivatized as its methyl ether. Benzyl cleavage could then
be achieved with potassium tert-butoxide in DMSO in the
presence of oxygen10 to give the dimethyl ether 27 in 94%
yield for the two steps. The reverse of this sequence did not
prove to be viable. Although oxidation of 25 and 26 with
CAN gave the corresponding o-quinones 28 and 29 in good
yields, all attempts to remove the benzyl group in 28 met
with failure presumably due to the sensitivity of carbazo-
quinocin C.
Final conversion of the 3,4-dimethoxylcarbazole 27 to
carbazoquinocin C is a two-step process. The direct oxidation
of 27 to the natural product with CAN did not give a clean
conversion. Following the protocol introduced by Kno¨lker,2c
this transformation was achieved in two steps beginning with
the cleavage of the methyl ethers with boron tribromide.
Kno¨lker reported that the resulting hydroquinone would
readily undergo oxidation in air to give carbazoquinocin C.2c
Our finding is that this air oxidation is not clean and gives
other products in addition to the natural product. Silver oxide
gives a mixture of products that is very similar to that
observed upon air oxidation. Carbazoquinocin C binds tightly
to silica gel, and attempts to purify the natural product by
silica gel chromatography result in substantial loss of
material. Thus, we decided to look for oxidizing agents that
would give clean conversion of the hydroquinone, and such
a condition was found with sodium meta-periodate. Simple
filtration of the crude reaction mixture through Celite and
removal of solvent gave carbazoquinocin C that was pure
Although the o-benzannulation of certain electron-rich
complexes has been reported to fail,6 the photolysis of the
3-indolylcarbene complexes 21 and 22 under an atmosphere
of carbon monoxide gave the carbazoles 25 and 26 in 65%
and 62% yield, respectively (Scheme 6).7 All that remains
Scheme 6
1
by H and 13C NMR and had a melting point identical to
that reported for the natural product.
An alternate synthesis of carbazoquinocin C was achieved
by the thermal ortho-benzannulation involving isonitrile
insertion.11 The reaction of carbene complex 21 with tert-
Scheme 7
to complete the synthesis of carbazoquinocin C is the
adjustment of the oxidation state and deprotection of the
(6) Merlic, C. A.; Xu, D.; Gladstone, B. G. J. Org. Chem. 1993, 58,
538.
(7) Merlic, C. A.; You, Y.; McInnes, D. M.; Zechman, A. L.; Miller,
M. M.; Deng, Q. Tetrahedron 2001, 57, 5199.
Org. Lett., Vol. 6, No. 3, 2004
331

butylisonitrile in refluxing THF gave the 3-aminocarbazole
30 in 86% yield (Scheme 7). This could be readily deben-
zylated with tert-butoxide in DMSO to give 32 in good yield.
Considerable effort was extended to directly oxidize 32 to
carbazoquinocin C to no avail. Compound 32 was resistant
to reaction with sodium meta-periodate, and other oxidizing
agents, including DDQ, CAN, KMnO4, Pb(OAc)4, Ag2O, and
FeCl3, led to complex mixtures of products.
Given the success in oxidation of the hydroquinone derived
from 27 with sodium m-periodate (Scheme 6), we attempted
to remove the methyl ether in 32 by treatment with BBr3
but this led to the formation of unidentified products. Final
success began with the preparation of the MOM-protected
carbene complex 23. This complex reacted with tert-
butylisonitrile to give the carbazole 31 in 72% yield, and
which could be debenzylated to give 33 in 76% yield. The
MOM group could be cleaved in intermediate 33 with HCl,
and the resulting o-aminophenol could be oxidized with
sodium meta-periodate to give carbazoquinocin C in 82%
yield for the last two steps.
This work describes the successful synthesis of Fischer
indole carbene complexes 21 and 23 and their application
to the synthesis of carbazoquinocin C via the photochemical
ortho-benzannulation with carbon monoxide and the thermal
ortho-benzannulation with isonitriles. An improved method
for the oxidation of the hydroquinone of the natural product
carbazoquinocin C has also been developed.
Acknowledgment. This work was supported by the
National Institutes of Health (Grant No. GM 33589).
(8) Watanabe, T.; Kobayashi, A.; Nishiura, M.; Takahashi, H.; Usui, T.;
Kamiyama, I.; Mochizuki, N.; Noritake, K.; Yokoyama, Y.; Murakami, Y.
Chem. Pharm. Bull. 1991, 39, 1152.
(9) Feutrill, G. I.; Mirrington, R. N. Aust. J. Chem. 1972, 25, 1719.
(10) Haddach, A. A.; Kelleman, A.; Deaton-Rewolinski, M. V. Tetra-
hedron Lett. 2002, 43, 399.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, S. Y. J. Am. Chem. Soc.
1992, 114, 8722.
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