Effective strategy for the preparation of indolocarbazole aglycons and glycosides: Total synthesis of tjipanazoles B, D, E, and I

Article abstract of DOI:10.1021/ol035418r

(Matrix presented) An effective strategy has been developed for the rapid and efficient preparation of ortho-nitrostyrenes, which can be converted to unsymmetrical 2,2′-biindoles. A unique condensation of these 2,2′-biindoles with (dimethylamino)-acetalde

Full text of DOI:10.1021/ol035418r

ORGANIC
LETTERS
2003
Vol. 5, No. 20
3721-3723
Effective Strategy for the Preparation of
Indolocarbazole Aglycons and
Glycosides: Total Synthesis of
Tjipanazoles B, D, E, and I
Jeffrey T. Kuethe,* Audrey Wong, and Ian W. Davies
Department of Process Research, Merck & Co., Inc., Rahway, New Jersey 07065
jeffrey_kuethe@merck.com
Received July 28, 2003
ABSTRACT
An effective strategy has been developed for the rapid and efficient preparation of ortho-nitrostyrenes, which can be converted to unsymmetrical
2,2 -biindoles. A unique condensation of these 2,2 -biindoles with (dimethylamino)-acetaldehyde diethyl acetal affords the indolocarbazole ring
′
′
system of the tjipanazole aglycon alkaloids in three synthetic steps and good to excellent overall yield. The first total synthesis of the tjipanazole
glycoside alkaloids B and E is also discussed.
The indolo[2,3-a]carbazole ring system constitutes the core
skeleton of a family of structurally unique natural products
possessing a wide range of biological activity.1 Indolocar-
bazole glycosides with either one or two glycosidic linkages
have been shown to be potent inhibitors of protein kinase C
and topoisomerases and exhibit excellent antitumor activity.1,2
The aglycons have been shown to be potent and selective
inhibitors of human cytomegalovirus.3 The selectivity and
potency of many of the indolocarbazoles depends on the
substituents about the aglycon as well as the nature of the
carbohydrate moiety. To fully define biological profiles, a
strategy is required to allow rapid access to functionalized
aglycones and effective methods for glycosidation. These
are formidable challenges for organic synthesis since the
aromatic substituents are displayed in an unsymmetrical
manner.
(1) For leading references, see: (a) Bergman, J.; Janosik, T.; Wahlstro¨m,
N. AdV. Heterocycl. Chem. 2001, 80, 1. (b) Pindur, U.; Kim, Y.-S. Curr.
Med. Chem. 1999, 6, 29. (c) Bergman, J. Stud. Nat. Prod. Chem., A 1988,
1, 3. (d) Steglich, W. Fortschr. Chem. Org. Naturst. 1987, 51, 216. (e)
Gribble, G. W.; Berthel, S. J. Stud. Nat. Prod. Chem. 1993, 12, 365. (f)
Prudhomme, M. Curr. Pharm. Design 1997, 3, 265.
(2) (a) Tamaoki, T.; Nomoto, H.; Takahishi, I.; Kato, Y.; Morimoto, M.;
Tomita, F. Biochem. Biophy. Res. Commun. 1986, 135, 397. (b) Omura,
S.; Sasaki, Y.; Iwai, T.; Takashima, H. J. Antibiot. 1995, 48, 535.
(3) Slater, M. J.; Cockerill, S.; Baxter, R.; Bonser, R. W.; Gohil, K.;
Gowrie, C.; Robinson, J. E.; Littler, E.; Parry, N.; Randall, R.; Snowden,
W. Bioorg. Med. Chem. 1999, 7, 1067.
The indolocarbazole alkaloids isolated from Tolypothrix
tjipanasensis contain both chlorine and glycosidic (â-D-
10.1021/ol035418r CCC: $25.00
© 2003 American Chemical Society
Published on Web 09/03/2003

glucosyl, â-D-deoxygulosyl, â-L-rhamnosyl, or â-D-xylosyl)
substituents on the polyaromatic core.4 The aglycon tjipana-
zoles (1, 2) and the glycosidic tjipanazoles (3-6) are natural
products. While approaches exist for the synthesis of some
tjipanazole alkaloids,3,4 many of the tjipanazole natural
products have eluded synthesis. Synthetic methods that
provide rapid assembly of the indole ring and tolerate a wide
range of functional groups leading to increasing molecular
complexity are important synthetic tools. Our general ap-
proach to the indolocarbazoles was inspired by the unique
versatility of nitrobenzenes, which are able to serve as both
electrophilic and nucleophilic partners. Reductive cyclization
of a suitably substituted ortho-nitrostyrene would give access
to unsymmetrical 2,2′-biindoles and with appropriate elabo-
ration would lead to indolocarbazole aglycons. In this Letter,
we report our preliminary findings in this area.
Table 1. Preparation of Nitrostyrenes and Biindoles
Our first challenge was preparation of the ortho-nitrosty-
renes. Reaction of TMS-nitro compound 75 and indole
carboxaldehyde 8 with a catalytic amount of tetrabutylam-
monium fluoride (TBAF) afforded the desired alcohol 9
(Scheme 1).6 Direct addition of TFAA to the reaction mixture
Scheme 1
a Isolated yields determined by flash chromatography on silica gel. b BOC
group was cleaved under the reaction conditions.
was followed by elimination of the corresponding trifluo-
roacetate with DBU at 60 °C and afforded trans-nitrostyrene
10 in 85% overall yield. Reductive cyclization of 10 under
the classic Cadogan/Sundberg conditions [P(OEt)3] gave
biindole 11 in 73% yield.7-9 Alternatively, palladium-
catalyzed reductive cyclization of 10 using So¨derberg condi-
tions10 gave biindole 11 in 96% yield. The reaction sequence
was general and gave access to a diverse array of both
symmetrical and unsymmetrical nitrostyrenes and biindoles
in modest to excellent yield for each synthetic step (Table
1).
Preparation of the indolocarbazole ring system of the
tjipanazoles from 2,2′-biindoles appears to be unprecen-
dented.9,11 An operationally trivial procedure for the incor-
poration of the two-carbon fragment of the indolocarbazole
ring with the correct oxidation state involved condensation
with (dimethylamino)-acetaldehyde diethyl acetal in acetic
acid (Scheme 2).12 For example, tjipanazoles I and D were
obtained in 79 and 71% yields from biindoles 30 and 33,
respectively. In similar fashion, the indolocarbazole 34 was
(4) Bonjouklian, R.; Smitka, T. A.; Doolin, L. E.; Molloy, R. M.; Debono,
M.; Shaffer, S. A.; Moore, R. E.; Stewart, J. B.; Patterson, G. M. L.
Tetrahedron 1991, 47, 7739.
(5) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Todesco, R. E. J. Org. Chem.
1986, 51, 3694.
(6) Bartoli, B.; Bosco, M.; Caretti, D.; Dalpozzo, R.; Todesco, R. E. J.
Org. Chem. 1987, 52, 4381.
(7) (a) Cadogan, J. I. G.; Cameron-Wood, M. Proc. Chem. Soc. 1962,
361. (b) Cadogan, J. I. G.; Mackie, R. K.; Todd, M. J. J. Chem. Soc., Chem.
Commun. 1966, 491.
(8) Sundberg, R. J. J. Org. Chem. 1965, 30, 3604.
(9) Merlic, C. A.; You, Y.; McInnes, D. M.; Zechman, A. L.; Miller,
M. M.; Deng, Q. Tetrahedron 2001, 57, 5199.
(11) For the synthesis of substituted indolocarbazoles from 2,2′-biindoles,
see: (a) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J. J. Am. Chem. Soc. 1995,
117, 10413. (b) Wood, J. L.; Stoltz, B. M.; Dietrich, H.-J.; Pflum, D. A.;
Petsch, D. T. J. Am. Chem. Soc. 1997, 119, 9641.
(10) So¨derberg, B. C.; Shiver, J. A. J. Org. Chem. 1997, 62, 5838.
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Org. Lett., Vol. 5, No. 20, 2003

Inspired by previous reports from these laboratories,
reaction of 2 with R-D-xylopyranosyl chloride 3514 in a
biphasic mixture of MTBE and 45% aqueous KOH and
Aliquat 336 gave protected tjipanazole B as single anomer
in 79% isolated yield.15 Hydrogenation over Pd(OH)2 gave
tjipanazole B (3) in 83% isolated yield. The synthesis of
tjipanazole E was also accomplished by reaction of 2 with
R-D-glycolopyranosyl chloride 3615 to give the protected
glycoside in 89% yield. Hydrogenation over Pd(OH)2 gave
tjipanazole E (4) in 87% yield. The spectroscopic and optical
properties of synthetic 3 and 4 were in full agreement with
the reported values.4
Scheme 2
The sequence demonstrated in the xylo- and gluco-series
should lend itself to the preparation of a variety of other
glycosidic linkages.
In conclusion, we have established a rapid, practical, and
efficient method for the preparation of unsymmetrical 2,2′-
biindoles from o-nitrostyrenes, which can be elaborated to
indolocarbazole aglycons or indolopyrrolocarbazoles16 in
three synthetic steps. Hallmarks of the sequence include a
general biindole synthesis, a novel elaboration to the indolo-
carbazole aglycons, and a high-yielding, stereoselective
glycosidation of an indolocarbazole aglycon. This strategy
allowed for the first reported total synthesis of tjipanazoles
B and E. A full account of related studies in these laboratories
will be forthcoming.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
formed in 73% yield from biindole 21. This synthetic strategy
is particularly noteworthy since it gives access to unsym-
metrical indolocarbazole aglycons in just three synthetic
operations.
OL035418R
The installation of the carbohydrate moiety of the tjipana-
zoles and other indolocarbazole glycosides presents signifi-
cant challenges due to low yields (<10%), control of
anomeric stereochemistry, and control of regiochemistry.4,13a
Although this problem has been partially solved by the
glycosylation of 2,2′-indolylindolines,13 a general approach
employing the direct glycosylation of the indolocarbazole
nitrogen of the tjipanazoles would be advantageous. To this
end, we examined the synthesis of the symmetrical tjipana-
zole alkaloids tjipanazole B (3) and E (4) from indolocar-
bazole 2.
(14) Iversen, T.; Bundle, D. R. Carbohydr. Res. 1982, 103, 29.
(15) Akao, A.; Hiraga, S.; Iida, T.; Kamatani, A.; Kawasaki, M.; Mase,
T.; Nemoto, T.; Satake, N.; Weissman, S. A.; Tschaen, D. M.; Rossen, K.;
Petrillo, D.; Reamer, R. A.; Volante, R. P. Tetrahedron 2001, 57, 8917.
(16) Preliminary studies reveal that the arcyriaflavin class of natural
products are also accessible using this approach; see Supporting Information.
For the synthesis of related compounds, see: Zhu, G.; Conner, S. E.; Zhou,
X.; Shih, C.; Li, T.; Anderson, B. D.; Brooks, H. B.; Cambell, R. M.;
Considine, E.; Dempsey, J. A.; Faul, M. M.; Ogg, C.; Patel, B.; Schultz, R.
M.; Spencer, C. D.; Teicher, B.; Watkins, S. A. J. Med. Chem. 2003, 46,
2027.
(12) Janosik, T.; Bergman, J. Tetrahedron 1999, 55, 2371.
(13) (a) Gilbert, E. J.; Van Vranken, D. L. J. Am. Chem. Soc. 1996,
118, 5500. (b) Gilbert, E. J.; Ziller, J. W.; Van Vranken, D. L. Tetrahedron
1997, 53, 16553. (c) Gilbert, E. J.; Chisholm, J. D.; Van Vranken, D. L. J.
Org. Chem. 1999, 55, 2371.
Org. Lett., Vol. 5, No. 20, 2003
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