Total syntheses of the telomerase inhibitors dictyodendrin B, C, and E

Article abstract of DOI:10.1021/ja0617800

Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2), C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or -stannanes met with failure.

Full text of DOI:10.1021/ja0617800

Published on Web 05/24/2006
Total Syntheses of the Telomerase Inhibitors Dictyodendrin B,
C, and E
Alois Fu¨rstner,* Mathias M. Domostoj, and Bodo Scheiper
Contribution from the Max-Planck-Institut fu¨r Kohlenforschung,
D-45470 Mu¨lheim/Ruhr, Germany
Received March 15, 2006; E-mail: fuerstner@mpi-muelheim.mpg.de
Abstract: Concise and flexible total syntheses of the pyrrolo[2,3-c]carbazole alkaloids dictyodendrin B (2),
C (3), and E (5) are described. These polycyclic telomerase inhibitors of marine origin derive from the
common intermediate 18 which was prepared on a multigram scale by a sequence comprising a TosMIC
cycloaddition with formation of the pyrrole A-ring, a titanium-induced reductive oxoamide coupling reaction
to generate an adjacent indole nucleus, and a photochemical 6π-electrocyclization/aromatization tandem
to forge the pyrrolocarbazole core. Conversion of 18 into dictyodendrin C required selective manipulations
of the lateral protecting groups and oxidation with peroxoimidic acid to form the vinylogous benzoquinone
core of the target. Zinc-induced reductive cleavage of the trichloroethyl sulfate ester then completed the
first total synthesis of 3. Its relatives 2 and 5 also originate from compound 18 by a selective bromination
of the pyrrole entity followed by elaboration of the resulting bromide 27 via metal-halogen exchange or
cross-coupling chemistry, respectively. Particularly noteworthy in this context is the generation of the very
labile p-quinomethide motif of dictyodendrin E by a palladium-catalyzed benzyl cross-coupling reaction
followed by vinylogous oxidation of the resulting product 41 with DDQ. The Suzuki step could only be
achieved with the aid of the borate complex 40 formed in situ from p-methoxybenzylmagnesium chloride
and 9-MeO-9-BBN, whereas alternative methods employing benzylic boronates, -trifluoroborates, or
-stannanes met with failure.
Introduction
Small molecule telomerase inhibitors, however, are still
rare.6,7 Thereby, it is particularly striking that telomerase
inhibitors of marine origin are largely unknown even though
the sea has yielded a huge number of novel bioactive metabolites
including some of the most promising leads for the development
of anticancer drugs during the past decades.8 In view of this
conspicuous lack of inhibitors, a recent publication from
Fusetani et al. deserves particular attention, disclosing a new
Eukaryotic chromosomes are terminated by nonencoding,
single-stranded telomeric ends, which play essential roles in
chromosome protection, positioning, and cell division. Most
notably, they are progressively shortened by ca. 50-200
nucleotides in each successive round of replication; once a
critical length is reached, a signaling pathway is triggered
leading to apoptotic cell death to prevent further aging. The
telomeres hence constitute a decisive mitotic clock that is
ultimately responsible for the finite lifespan of somatic cells.1
More than 85% of malignant tumors are reprogrammed to
circumvent this protective mechanism by upregulation of human
telomerase. This ribonucleoprotein with reverse-transcriptase
properties is capable of adding TTAGGG repeats to the 3′-ends
of telomers which thereby keep a certain length, escape from
apoptosis, and hence gain cellular immortality as the charac-
teristic trait of cancer.2,3 Therefore, it comes as no surprise that
inhibition of telomerase activity might be considered as cancer’s
“Achilles heel” and considerable efforts are presently directed
to exploit this cancer-specific vulnerability in the quest for more
selective chemotherapeutic agents and/or the development of
adjuvant clinical regimens.4,5
(4) Reviews: (a) Neidle, S.; Parkinson, G. Nat. ReV. Drug DiscoVery 2002, 1,
383. (b) Neidle, S.; Thurston, D. E. Nat. ReV. Cancer 2005, 5, 285. (c)
Kelland, L. R. Eur. J. Cancer 2005, 41, 971. (d) Beltz, L. A.; Manfredi,
K. P. Med. Chem. ReV.-Online 2005, 2, 325.
(5) See the following for leading references and literature cited therein: (a)
Kim, N. W.; Piatyszek, M. A.; Prowse, K. R.; Harley, C. B.; West, M. D.;
Ho, P. L. C.; Coviello, G. M.; Wright, W. E.; Weinrich, S. L.; Shay, J. W.
Science 1994, 266, 2011. (b) Herbert, B.-S.; Pitts, A. E.; Baker, S. I.;
Hamilton, S. E.; Wright, W. E.; Shay, J. W.; Corey, D. R. Proc. Natl.
Acad. Sci. U.S.A. 1999, 96, 14276. (c) Keppler, B. R.; Jarstfer, M. B.
Biochemistry 2004, 43, 334. (d) Hahn, W. C.; Stewart, S. A.; Brooks, M.
W.; York, S. G.; Eaton, E.; Kurachi, A.; Beijersbergen, R. J.; Knoll, J. H.
M.; Meyerson, M.; Weinberg, R. A. Nat. Med. 1999, 5, 1164.
(6) For leading references on synthetic telomerase inhibitors, see the following
references and literature cited therein: (a) Moore, M. J. B.; Schultes, C.
M.; Cuesta, J.; Cuenca, F.; Gunaratnam, M.; Tanious, F. A.; Wilson, W.
D.; Neidle, S. J. Med. Chem. 2006, 49, 582. (b) Pascolo, E.; Wenz, C.;
Lingner, J.; Hauel, N.; Priepke, H.; Kauffmann, I.; Garin-Chesa, P.; Rettig,
W. J.; Damm, K.; Schnapp, A. J. Biol. Chem. 2002, 277, 15566.
(7) For selected studies of natural products with telomerase inhibitory properties,
see: (a) Shin-ya, K.; Wierzba, K.; Matsuo, K.; Ohtani, T.; Yamada, Y.;
Furihata, K.; Hayakawa, Y.; Seto, H. J. Am. Chem. Soc. 2001, 123, 1262.
(b) Lambert, T. H.; Danishefsky, S. J. J. Am. Chem. Soc. 2006, 128, 426.
(c) Kim, M.-Y.; Vankayalapati, H.; Shin-ya, K.; Wierzba, K.; Hurley, L.
H. J. Am. Chem. Soc. 2002, 124, 2098. (d) Warabi, K.; Hamada, T.; Nakao,
Y.; Matsunaga, S.; Hirota, H.; van Soest, R. W. M.; Fusetani, N. J. Am.
Chem. Soc. 2005, 127, 13262.
(1) (a) Telomeres; Blackburn, E. H., Greider, C. W., Eds.; Cold Spring Harbor
Lab: Plainview, NY, 1995. (b) Cech, T. R. Angew. Chem., Int. Ed. 2000,
39, 34.
(2) (a) Greider, C. W.; Blackburn, E. H. Cell 1985, 43, 405. (b) Morin, G. B.
Cell 1989, 59, 521.
(3) For a very recent first structural investigation on telomerase, see: Jacobs,
S. A.; Podell, E. R.; Cech, T. R. Nat. Struct. Mol. Biol. 2006, 13, 218.
(8) Drugs from the Sea; Fusetani, N., Ed.; Karger: Basel, 2000.
9
10.1021/ja0617800 CCC: $33.50 © 2006 American Chemical Society
J. AM. CHEM. SOC. 2006, 128, 8087-8094
8087

A R T I C L E S
Fu¨rstner et al.
present the first total synthesis of three prototype members of
this family, which is concise and efficient, maps the pertinent
chemical behavior of these compounds, and is also flexible by
design to allow for substantial variations at a later stage.14,15
Results and Discussion
Retrosynthetic Considerations and Preparation of a Com-
mon Synthesis Platform. The individual dictyodendrins 1-5
differ only with regard to their oxidation pattern and the
substituents attached to the C.2 position of the pyrrole A-ring.
Therefore, it seemed possible to access the entire family by
suitable manipulations of a common synthetic intermediate of
type 9 (Scheme 1). Any such attempt, however, must consider
the lability of the conspicuous sulfate decorating compounds
1-5. Most likely, it is advantageous to introduce this group at
a very late stage of the synthesis, thus making a suitable and
orthogonal protection of the phenolic position at C.10 necessary;
the presence of the intact sulfate group, however, was reported
to be essential for telomerase inhibitory activity.9
Moreover, it is known that the individual dictyodendrins
undergo rapid fragmentation in aqueous acidic media by which
they lose their C.2 substituents as well as the sulfate groups
and converge to compound 8 as the common “degradation”
product.9 This information suggests that the vinylogous quinone
in 8 represents a thermodynamic sink that benefits from
additional stabilization by the lone pairs of the flanking N-atoms.
In recognition of this chemical bias, we envisaged the generation
of this characteristic structural motif in the projected synthesis
of dictyodendrin C (3) directly from compound 9, provided that
an oxidant can be found that selectively attacks the C.14 OH
group and the electronically coupled C-H bond at the remote
C.2 position. Although such a transformation should ultimately
open access to dictyodendrin C (3) as the most stable compound
of this series, its higher congeners would also derive from the
same precursor 9 via suitable acylation or alkylation/oxidation
of the pyrrole A-ring.
family of alkaloids isolated from the sponge Dictyodendrilla
Verongiformis collected off the South Japanese coast.9 The
dictyodendrins 1-5 were claimed to be the first marine natural
products with telomerase inhibitory properties (100% inhibition
at 50 µg/mL concentration), although no further details or
biochemical profiling has been reported. They are closely related
to the aldose reductase inhibitors 6 and 7 previously isolated
from a Dictyodendrilla sp.10 Collectively, these tyramine-derived
alkaloids feature a characteristic and unique pyrrolo[2,3-c]-
carbazole moiety that is decorated with electron-rich arene rings
and carries at least one sulfate group in the periphery. As such,
the dictyodendrins are distantly related to a series of other marine
pyrrole alkaloids such as the lamellarins, lukianol, ningalin,
storniamide, polycitone, purpurone, or halitulin, many of which
are also potent anticancer agents.11-13 Overall, the scarcity of
the dictyodendrins, the as of yet incomplete understanding of
their physiological properties, the promise of efficient telomerase
inhibition, and their compact and demanding structural char-
acteristics render these marine natural products formidable
targets for a synthesis-driven investigation at the chemistry/
biology interface. As the initial step of this endeavor, we now
The preparation of a suitably functionalized surrogate of the
common synthesis platform 9 commenced with readily available
(12) For selected studies directed to the synthesis of such pyrrole alkaloids,
see, e.g.: (a) Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger, D. L. J.
Am. Chem. Soc. 2005, 127, 10767. (b) Pla, D.; Marchal, A.; Olsen, C. A.;
Albericio, F.; Alvarez, M. J. Org. Chem. 2005, 70, 8231. (c) Ploypradith,
P.; Kagan, R. K.; Ruchirawat, S. J. Org. Chem. 2005, 70, 5119. (d) Handy,
S. T.; Zhang, Y.; Bregman, H. J. Org. Chem. 2004, 69, 2362. (e) Iwao,
M.; Takeuchi, T.; Fujikawa, N.; Fukuda, T.; Ishibashi, F. Tetrahedron Lett.
2003, 44, 4443. (f) Bullington, J. L.; Wolff, R. R.; Jackson, P. F. J. Org.
Chem. 2002, 67, 9439. (g) Gupton, J. T.; Clough, S. C.; Miller, R. B.;
Lukens, J. R.; Henry, C. A.; Kanters, R. P. F.; Sikorski, J. A. Tetrahedron
2003, 59, 207. (h) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C.
A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54. (i) Boger, D. L.; Soenen, D.
R.; Boyce, C. W.; Hedrick, M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479.
(j) Banwell, M. G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R. Chem.
Commun. 1997, 207. (k) Liu, J.-H.; Yang, Q.-C.; Mak, T. C. W.; Wong,
H. N. C. J. Org. Chem. 2000, 65, 3587. (l) Peschko, C.; Winklhofer, C.;
Steglich, W. Chem.-Eur. J. 2000, 6, 1147. (m) Peschko, C.; Steglich, W.
Tetrahedron Lett. 2000, 41, 9477.
(13) (a) Fu¨rstner, A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60, 6637.
(b) Fu¨rstner, A.; Krause, H.; Thiel, O. R. Tetrahedron 2002, 58, 6373. (c)
Fu¨rstner, A. Angew. Chem., Int. Ed. 2003, 42, 3582.
(14) Preliminary communication: Fu¨rstner, A.; Domostoj, M. M.; Scheiper, B.
J. Am. Chem. Soc. 2005, 127, 11620.
(15) For studies on other bioactive pyrrole alkaloids from our group, see: (a)
Fu¨rstner, A.; Radkowski, K.; Peters, H. Angew. Chem., Int. Ed. 2005, 44,
2777. (b) Fu¨rstner, A.; Reinecke, K.; Prinz, H.; Waldmann, H. ChemBio-
Chem 2004, 5, 1575. (c) Fu¨rstner, A.; Grabowski, E. J. ChemBioChem
2001, 2, 706. (d) Fu¨rstner, A.; Grabowski, J.; Lehmann, C. W.; Kataoka,
T.; Nagai, K. ChemBioChem 2001, 2, 60. (e) Fu¨rstner, A.; Krause, H. J.
Org. Chem. 1999, 64, 8281. (f) Fu¨rstner, A.; Grabowski, J.; Lehmann, C.
W. J. Org. Chem. 1999, 64, 8275. (g) Fu¨rstner, A.; Szillat, H.; Gabor, B.;
Mynott, R. J. Am. Chem. Soc. 1998, 120, 8305.
(9) Warabi, K.; Matsunaga, S.; van Soest, R. W. M.; Fusetani, N. J. Org. Chem.
2003, 68, 2765.
(10) Sato, A.; Morishita, T.; Shiraki, T.; Yoshioka, S.; Horikoshi, H.; Kuwano,
H.; Hanzawa, H.; Hata, T. J. Org. Chem. 1993, 58, 7632.
(11) (a) Bailly, C. Curr. Med. Chem.: Anti-Cancer Agents 2004, 4, 363. (b)
Handy, S. T.; Zhang, Y. Org. Prep. Proced. Int. 2005, 17, 411.
9
8088 J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006

Syntheses of the Telomerase Inhibitors Dictyodendrins
A R T I C L E S
graphite prepared from TiCl3 and KC8 (2 equiv)21 as the reagent,
although other sources of low-valent titanium also provide good
to excellent results in many cases.22 Such intramolecular
reductive coupling reactions are distinguished by an exceptional
driving force and a remarkable chemoselectivity profile,23 which
allows for applications even to fairly elaborate cases.19-24
This notion was confirmed by the application of this protocol
to ketoamide 16 which afforded the desired indole 17 in up to
93% isolated yield on exposure to titanium-graphite in refluxing
DME. Thereby, it was necessary to buffer the slightly Lewis-
acidic reaction medium with pyridine to prevent partial cleavage
of the labile enol ether moiety of the substrate. During the
synthesis campaign described herein, this transformation was
carried out repeatedly on different scales and has provided
multigram amounts of indole 17, thus attesting to the robustness
and reliability of this methodology for reductive heterocycle
synthesis.
Scheme 1. Envisaged Generation of the Individual Dictyodendrins
from a Common Precursor 9 and Their Known Degradation,
Converging to Compound 8a
Indole 17 thus formed is set up for subsequent closure of the
dictyodendrin core by a 6π-electrocyclization. This pivotal
transformation proceeded smoothly upon irradiation with UV
light (Hanovia Hg lamp, 250 W) in MeCN; addition of Pd/C
and nitrobenzene to the reaction medium causes concomitant
aromatization of the product initially formed,25 thus giving rise
to the desired pyrrolocarbazole 18 in 81% yield in a single
operation.26 Since 18 represents a fully functional intermediate
for the preparation of all individual members of the dictyoden-
drin family, a very short, convenient, and scaleable gambit of
our total synthesis project has been secured employing only
inexpensive starting materials (seven steps, ca. 40% overall
yield). Moreover, the chosen route should allow for substantial
variations as desirable for a synthesis-driven exploration of
pertinent structure/activity relationships of this series of alkaloids
at a later stage.
Total Synthesis of Dictyodendrin C. In a first attempt,
compound 18 was reacted with BBr3 in CH2Cl2 at -78 °C in
the presence of excess cyclohexene as an acid scavenger
(Scheme 3). Although the peripheral methyl- and isopropyl
ethers could not be distinguished under these conditions and
were cleaved off concomitantly, we were pleased to observe
that the resulting polyphenol underwent spontaneous air oxida-
tion during the acidic/basic workup, thus furnishing compound
8 in an unoptimized 49% isolated yield. As described above,
this compound represents the common degradation product of
all naturally occurring dictyodendrins.9 Its spontaneous forma-
tion also supports the notion that the vinylogous p-quinone motif
embedded into its core constitutes a formidable thermodynamic
sink, thus auguring well for the final stages of the projected
total synthesis of dictyodendrin C.
a Numbering scheme used throughout this paper.
acetophenone 10,16 which was converted into isopropyl ether
11 prior to base-induced condensation with p-methoxybenzal-
dehyde (Scheme 2). The resulting chalcone 12 cleanly reacted
with toluenesulfonylmethyl isocyanide (TosMIC) in the presence
of NaH at low temperature17 to give a pyrrole which was
N-alkylated in situ with p-MeOC6H4(CH2)2Br. Reduction of the
nitro group in the resulting product 13 with Fe/HCl furnished
aniline 14 in excellent yield on a multigram scale, which was
condensed with acid chloride 1518 under standard conditions to
give amide 16 without incident.
(19) (a) Fu¨rstner, A.; Hupperts, A.; Ptock, A.; Janssen, E. J. Org. Chem. 1994,
59, 5215. (b) Fu¨rstner, A.; Jumbam, D. N. Tetrahedron 1992, 48, 5991.
(20) (a) Fu¨rstner, A.; Bogdanovic, B. Angew. Chem., Int. Ed. Engl. 1996, 35,
2442. (b) McMurry, J. E. Chem. ReV. 1989, 89, 1513.
(21) Fu¨rstner, A. Angew. Chem., Int. Ed. Engl. 1993, 32, 164.
(22) (a) Fu¨rstner, A.; Hupperts, A. J. Am. Chem. Soc. 1995, 117, 4468. (b)
Fu¨rstner, A.; Hupperts, A.; Seidel, G. Org. Synth. 1999, 76, 142. (c)
Fu¨rstner, A.; Seidel, G. Synthesis 1995, 63.
(23) (a) Fu¨rstner, A.; Jumbam, D. N. J. Chem. Soc., Chem. Commun. 1993,
211. (b) Fu¨rstner, A.; Ptock, A.; Weintritt, H.; Goddard, R.; Kru¨ger, C.
Angew. Chem., Int. Ed. Engl. 1995, 34, 678.
(24) (a) Fu¨rstner, A.; Ernst, A. Tetrahedron 1995, 51, 773. (b) Fu¨rstner, A.;
Ernst, A.; Krause, H.; Ptock, A. Tetrahedron 1996, 52, 7329. (c) Fu¨rstner,
A.; Jumbam, D. N.; Seidel, G. Chem. Ber. 1994, 127, 1125.
Previous investigations from this laboratory had shown that
ketoamides, on treatment with “low-valent” titanium, convert
to indole derivatives even in the presence of other reducible
sites.19,20 This reaction is best performed with titanium on
(16) Butenandt, A.; Hallmann, G.; Beckmann, R. Chem. Ber. 1957, 90, 1120.
(17) van Leusen, A. M.; Siderius, H.; Hoogenboom, B. E.; van Leusen, D.
Tetrahedron Lett. 1972, 13, 5337.
(18) Prepared in three simple steps from commercial p-hydroxyphenylpyruvic
acid; for details, consult the Supporting Information.
(25) Rawal, V. H.; Jones, R. J.; Cava, M. P. Tetrahedron Lett. 1985, 26, 2423.
(26) Reviews on carbazole synthesis: (a) Kno¨lker, H.-J.; Reddy, K. R. Chem.
ReV. 2002, 102, 4303. (b) Kawasaki, T.; Sakamoto, M. J. Indian Chem.
Soc. 1994, 71, 443.
9
J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006 8089

A R T I C L E S
Fu¨rstner et al.
Scheme 2. Preparation of the Common Synthesis Intermediatea
a [a] 2-Bromopropane, K2CO3, DMF, 100 °C, 99%; [b] p-MeOC6H4CHO, NaOMe, MeOH, 70 °C, 74%; [c] (i) TosMIC, NaH, THF, -30 °C; (ii)
p-MeOC6H4(CH2)2Br, reflux, 83%; [d] Fe powder, aq. HCl, EtOH, 96%; [e] acid chloride 15, CH2Cl2, Et3N, DMAP catalyst, 89%; [f] TiCl3/2KC8, DME,
pyridine, reflux, 71-93%; [g] hν, MeCN, Pd/C catalyst, C6H5NO2, 81%.
Scheme 3. Preparation of Desulfated Dictyodendrin Ca
Compound 21 was then treated with excess zinc dust and
ammonium formate in MeOH to effect reductive cleavage of
the trichloroethyl ester moiety.27 Even though partial reduction
of the quinone with formation of 22 was observed, removal of
the excess zinc dust followed by stirring of the crude mixture
under an oxygen atmosphere resulted in the formation of a single
product which was isolated in 76% yield over two steps. The
analytical and spectroscopic data of this compound were in
excellent agreement with those of dictyodendrin C (3) reported
in the literature,9 thus finishing the first total synthesis of this
structurally unique marine alkaloid in the form of its ammonium
a [a] BBr3, cyclohexene, CH2Cl2, -78 °C f room temperature, 49%.
salt.
Dictyodendrin B. The conversion of the relay compound 18
into dictyodendrin B (2) seemed straightforward, requiring
In fact, a slight modification of the deprotection regime paved
acylation of the pyrrolic C.2 position32 and suitable protecting
group management only. Exploratory studies using the per-
methylated compound 2333 as a model, however, showed that
this seemingly conventional transformation is far more delicate
than anticipated (Scheme 5).
Although substrate 23 was completely consumed on reaction
with p-methoxybenzoyl chloride in the presence of SnCl4, none
of the expected ketone was obtained. Rather, the new product
24 formed in 64% yield had the same mass as the substrate
and gave very similar NMR spectra as well, thus suggesting
that an isomerization rather than the attempted Friedel-Crafts
acylation had occurred under the chosen conditions. Since no
incorporation of the acid part was observed, it came as no
the way to this particular target (Scheme 4). Specifically, the
selective cleavage of the isopropyl ether of 18 was achieved in
75% yield simply upon switching from BBr3 to BCl3 as the
reagent. The resulting phenol 19 was reacted with trichloroethyl
chlorosulfuric acid ester27 to afford aryl sulfate 20 which turned
out to be hydrolytically labile and had to be processed without
undue delay. Gratifyingly, however, it withstood exhaustive
deprotection of the remaining methyl groups with the aid of
BCl3 and tetra-n-butylammonium iodide in CH2Cl2.28 Rather
than relying on air oxidation,29 the resulting phenol was reacted
with H2O2 in MeCN to give quinone 21 in a superbly clean
transformation; it is believed that peroxyimidic acid is the actual
oxidant under these conditions.30,31
(30) For a discussion, see the following for leading references and literature
cited therein: (a) Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807. (b) Payne,
G. B.; Deming, P. H.; Williams, P. H. J. Org. Chem. 1961, 26, 659.
(31) For related oxidations of pyrroles, see: (a) Shrout, D. P.; Lightner, D. A.
Synthesis 1990, 1062. (b) Auerbach, J.; Franck, R. W. J. Chem. Soc. D
1969, 991.
(32) For a related maneuver in the total synthesis of a complex pyrrole alkaloid,
see: (a) Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1998, 120, 2817. (b)
Fu¨rstner, A.; Weintritt, H. J. Am. Chem. Soc. 1997, 119, 2944.
(33) The preparation of compound 23 essentially follows the route described
for 18; details will be reported in a forthcoming paper describing various
analogues of the naturally occurring dictyodendrins.
(27) (a) Liu, Y.; Lien, I. F.; Ruttgaizer, S.; Dove, P.; Taylor, S. D. Org. Lett.
2004, 6, 209. (b) For a recent application, see: Yamaguchi, T.; Fukuda,
T.; Ishibashi, F.; Iwao, M. Tetrahedron Lett. 2006, 47, 3755.
(28) Brooks, P. R.; Wirtz, M. C.; Vetelino, M. G.; Rescek, D. M.; Woodworth,
G. F.; Morgan, B. P.; Coe, J. W. J. Org. Chem. 1999, 64, 9719.
(29) As observed in the case of 8, the air oxidation occurs during the acidic/
basic workup. Because the sulfate group of 3, however, is labile under
these conditions, the H2O2/MeCN protocol had to be implemented. This
method has the additional advantage that no extractive workup is necessary,
thus making the isolation of the very polar final product much more efficient
and convenient.
9
8090 J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006

Syntheses of the Telomerase Inhibitors Dictyodendrins
A R T I C L E S
Scheme 4. Total Synthesis of Dictyodendrin Ca
Scheme 5 a
a [a] p-MeOC6H4COCl, SnCl4, 1,2-dichloroethane, reflux, 64%.
Scheme 6 a
a [a] BCl3, CH2Cl2, 0 °C, 75%; [b] Cl3CCH2OSO2Cl, DABCO, THF,
71%; [c] (i) BCl3, (n-Bu)4NI, CH2Cl2, 0 °C; (ii) aq. H2O2 (30% w/w),
MeCN, 57%; [d] Zn, HCOONH4, MeOH; [e] O2 (1 atm), MeOH, 76%
(combined yield).
surprise that the same product was formed in similar yield on
treatment with SnCl4, TiCl4, or BF3‚Et2O only. Extensive
spectroscopic studies finally revealed that the p-methoxyphenyl
ring attached to the C.3 position in 23 had migrated to the vicinal
carbon atom C.2. This rearrangement presumably involves
complexation of the Lewis acid at the most electron-rich C.3
carbon atom with formation of a resonance-stabilized iminium
cation 25 that is prone to intramolecular electrophilic attack onto
the arene moiety giving rise to the bridging Wheland complex
26.34 Subsequent collapse of this reactive intermediate readily
explains this unusual 3f2 aryl shift.
This unexpected behavior enforced a redesign of our synthesis
strategy (Scheme 6). To this end, compound 18 was treated with
NBS in THF at 0 °C, which resulted in selective bromination
at C.2 with formation of product 27. Although this compound
can be stored for some time in the freezer in solid form, it is
subject to a rapid “bromine dance” when kept in CDCl3 solution
at ambient temperature.35 This vectorial process shifts the
bromine substituent from the A-ring in 27 to the electron-rich
a [a] NBS, THF, 0 °C, 69%; [b] CHCl3, room temperature, cf. text; [c]
(i) MeLi, THF, -78 °C; (ii) n-BuLi, -78 °C; (iii) p-MeOC6H4CHO, -78
°C f room temperature, 97%.
C.8 position located in the D-ring, thus furnishing the isomeric
product 28; this halide walk can be nicely followed by NMR.36
Gratifyingly, however, the aryllithium species formed on
(34) Carbonium Ions; Olah, G. A., von R. Schleyer, P., Eds.; Wiley: New York,
1970; Vol. 2.
(35) Although base-induced “halogen dance” processes are well-known in
(hetero)arene chemistry (cf.: Duan, X.-F.; Zhang, Z.-B. Heterocycles 2005,
65, 2005 and literature cited therein), uncatalyzed processes are less
common; for a pertinent example, see: Press, J. B.; Eudy, N. H. J.
Heterocycl. Chem. 1981, 18, 1261. Even though strictly neutralized CDCl3
was used, it is assumed that traces of acid are generated upon reaction
with the solvent that might catalyze the observed halide shift, cf. ref 36.
(36) MS analysis shows that traces of a dibrominated compound and a compound
containing one bromine and one chlorine atom are formed as byproducts
during this halide walk. Although incorporation of a chloride derived from
the solvent might give some mechanistic hints, the exact constitution of
these minor products has not been investigated any further.
9
J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006 8091

A R T I C L E S
Scheme 7 a
Fu¨rstner et al.
Scheme 8. Completion of the Total Synthesis of Dictyodendrin Ba
a
[a] TPAP (10%), NMO, MS 4Å, CH2Cl2 at 0.1 M concentration: 22%
(30) + 57% (31); at 0.01 M concentration: 66% (30) + 16% (31).
N-deprotonation of 27 with MeLi followed by metal-halogen
exchange with n-BuLi37 could be quenched with p-MeOC6H4-
CHO to afford alcohol 29 in remarkably high yield.38
The seemingly trivial oxidation of this compound to the
corresponding ketone again posed significant problems. Al-
though the use of classical oxidants either resulted in no
conversion (MnO2, SO3/pyridine) or led to rapid degradation
only (PDC, PCC, Dess-Martin periodinane, TEMPO catalyst/
NaOCl, Swern), the use of catalytic amounts of tetra-n-
propylammonium perruthenate (TPAP, 10 mol %)39 in combi-
nation with N-methylmorpholine-N-oxide (NMO) in CH2Cl2 (0.1
M) afforded a product mixture, of which the desired ketone 30
was the minor constituent only (22%) (Scheme 7). Mass
spectrometry indicated the dimeric nature of the major product
31 (57%) formed under these conditions; however, it took
considerable efforts to unambiguously elucidate its constitution.
Extensive NMR investigations were necessary to show that the
two subunits in 31 are joined by a C-N bond between the
“indolic” nitrogen N.12 of one molecule and the electron-rich
C.8 position of the second entity.40 In recognition of this fact,
we repeated the oxidation under more dilute conditions, hoping
that the dimerization could be disfavored. In fact, the reaction
responded well to the chosen concentration, with c ) 0.01 M
being the best compromise among product distribution, overall
yield, and reaction time. Under these conditions, ketone 30 was
obtained in 66% isolated yield.
a [a] BCl3, CH2Cl2, -20 °C, 85%; [b] Cl3CCH2OSO2Cl, DABCO,
CH2Cl2, 92%; [c] BCl3, TBAI, CH2Cl2, 0 °C f room temperature; [d] Zn,
HCOONH4, MeOH, 58% (over both steps).
33, and reductive cleavage of the remaining trichloroethyl
moiety in 34 with Zn/HCO2NH4 cleanly led to dictyodendrin
B (2) (Scheme 8). All analytical and spectroscopic data of the
synthetic samples perfectly matched those of the natural product
reported in the literature.9
Dictyodendrin E. Dictyodendrin E (5) is arguably the most
challenging target of this family of marine alkaloids. This is
evident from the fact that this particular compound could not
be isolated from the sponge in pure form but was obtained by
Fusetani et al. as an inseparable mixture with a methanol
adduct.9 This information likely indicates the high reactivity of
its vinylogous quinomethide core structure extending from the
benzylidene substituent at C.2 to the carbonyl group at C.14.
Our initial approach to 5 envisaged the vinylogous elimination
of MeOH from product 35, which in turn derives from alcohol
29 by the established protecting group regimen (Scheme 9). This
strategy, however, had to be abandoned because of the
exceptional lability of 35, which decomposed on attempted
purification by flash chromatography.
For a route to 5 to be viable, it was therefore essential to
pass through more robust intermediates. The success of the
oxidation reaction leading to the vinylogous p-quinone moiety
of dictyodendrin C inspired such an alternative strategy,
envisaging formation of the vinylogous quinomethide of 5 by
a similar process. The required substrate 41 carrying a p-
methoxybenzyl substituent at C.2 might derive from bromide
27 that had already served as the key intermediate en route to
dictyodendrin B (see above).
The remaining protecting group manipulations proceeded
uneventfully, following the successful sequence pursued in the
dictyodendrin C series. Thus, cleavage of the isopropyl ether
in 30 with BCl3, attachment of the protected sulfate ester to the
resulting phenol 32, followed by exhaustive demethylation of
(37) The sequential use of MeLi and n-BuLi for a deprotonation/metal-halogen
exchange tandem has precedence in the literature; for an early example
and an instructive discussion, see: Kelly, T. R.; Kim, M. H. J. Am. Chem.
Soc. 1994, 116, 7072.
(38) In striking contrast, however, attempts to quench the organolithium species
with p-MeOC6H4COCl or the corresponding Weinreb amide were by and
large unsuccessful.
(39) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639.
(40) A related process is reported in: Bringmann, G.; Tasler, S.; Endress, H.;
Kraus, J.; Messer, K.; Wohlfarth, M.; Lobin, W. J. Am. Chem. Soc. 2001,
123, 2703.
Unfortunately, however, our initial attempts to get access to
41 by palladium-catalyzed cross-coupling of bromide 27 with
9
8092 J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006

Syntheses of the Telomerase Inhibitors Dictyodendrins
A R T I C L E S
Scheme 9 a
Scheme 11 a
a [a] (i) BCl3, CH2Cl2, -20 °C, 82%; (ii) Cl3CCH2OSO2Cl, DABCO,
CH2Cl2.
Scheme 10. Different p-Methoxybenzyl Donors and Preparation of
a Borate Complex 40 via the 9-MeO-9-BBN Variant of the Suzuki
Coupling
a [a] Compound 38, Pd(PPh3)4 catalyst, CsF, THF, reflux; or compound
37, (dppf)PdCl2, Cs2CO3, THF/H2O (10:1), reflux; or compound 37,
(dppf)PdCl2, Et3N, iPrOH; or compound 36, Pd(PPh3)4 catalyst, copper
thiophene-2-carboxylate (1.5 equiv), DMF; or compound 36, Pd(PPh3)4
catalyst, CuCl (5 equiv), LiCl (6 equiv), DMSO; or (PPh3)2PdCl2 catalyst,
THF; [b] borate 40 (4 equiv), Pd(OAc)2 (10 mol %), S-PHOS (20 mol
%), DMF/THF, 90%.
suitable benzyl donors (Scheme 10) met with failure. The use
of the stannane 36, the trifluoroborate 37,41 or the boronate 3842
previously recommended for benzylation reactions was not
encouraging. Debromination of the substrate with formation of
compound 18 was the only transformation that occurred under
a variety of experimental conditions (Scheme 11). In view of
this setback, we were particularly pleased to see that the 9-MeO-
9-BBN variant of the Suzuki reaction previously developed by
our group gave much more favorable results.43-45 In this method,
the crucial borate complex serving as the actual nucleophile in
the palladium-catalyzed cross-coupling step is generated in situ
from 9-MeO-9-BBN and a polar organometallic reagent, in the
present case the readily available p-methoxybenzylmagnesium
chloride (Scheme 10). In combination with Pd(OAc)2 and
Buchwald’s sterically encumbered S-PHOS ligand,46,47 the
reactive intermediate 40 thus formed allowed for the almost
quantitative benzylation of the electron-rich and rather labile
bromide 27.
Scheme 12. Preparation of Desulfated Dictyodendrin Ea
a [a] BBr3, CH2Cl2, -78 °C f room temperature; [b] DDQ, THF, 83%
(over both steps).
was processed further by DDQ oxidation in THF at ambient
temperature (Scheme 12). In line with our expectations, the
vinylogous quinomethide 43 was formed in 83% isolated yield
over two steps, which represents desulfated dictyodendrin E.
The compound was stable enough to be isolated in analytically
pure form and could be unambiguously characterized. Its NMR
data are in excellent accordance with those of dictyodendrin E
itself, except for the protons H.7, H.8, and H.9 which are shifted
to a lower field in the natural product because of their vicinity
to the sulfate group residing at the adjacent O.10 position.
The proof of this concept spurred our efforts to complete the
total synthesis of the sulfated natural product 5 as well (Scheme
13). Following the established protocol starting with the selective
removal of the isopropyl group in 41 and subsequent introduc-
tion of the trichloroethyl sulfate moiety,27 compound 45 was
obtained; this product was highly susceptible to hydrolysis and
had to be processed without delay. The cleavage of its methyl
ethers with BCl3/(n-Bu)4NI,28 however, proceeded well affording
the even more sensitive compound 46 which was immediately
For exploratory purposes, the resulting product 41 was
globally deprotected with BBr3 to give polyphenol 42 which
(41) Molander, G. A.; Ito, T. Org. Lett. 2001, 3, 393.
(42) Flaherty, A.; Trunkfield, A.; Barton, W. Org. Lett. 2005, 7, 4975.
(43) (a) Fu¨rstner, A.; Seidel, G. Tetrahedron 1995, 51, 11165. (b) Fu¨rstner, A.;
Leitner, A. Synlett 2001, 290. (c) Fu¨rstner, A.; Nikolakis, K. Liebigs Ann.
1996, 2107. (d) The method was also independently reported by: Soder-
quist, J. A.; Matos, K.; Rane, A.; Ramos, J. Tetrahedron Lett. 1995, 36,
2401.
(44) This method had previously allowed for very efficient allylations of aryl
halides; cf.: Fu¨rstner, A.; Seidel, G. Synlett 1998, 161.
(45) For general reviews on the Suzuki reaction, see, e.g.: (a) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147. (b) Miyaura, N.; Suzuki, A. Chem.
ReV. 1995, 95, 2457.
(46) (a) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685. (b) Walker, S. D.; Barder, T. E.; Martinelli,
J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871.
(47) In this particular case, the use of (dppf)PdCl2 previously recommended
for Suzuki reactions according to the “9-MeO-9-BBN” protocol failed to
afford the cross-coupling product. This is tentatively ascribed to the electron-
rich nature of substrate 27, which renders the use of the more electron-
donating and sterically demanding S-PHOS ligand imperative for suc-
cessful oxidative insertion of the Pd(0) template.
9
J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006 8093

A R T I C L E S
Fu¨rstner et al.
Scheme 13. Completion of the Total Synthesis of Dictyodendrin
observation that all naturally occurring dictyodendrins ultimately
convert to 3 or its desulfated analogue 8 as the thermodynami-
cally most favorable compounds of this series9 and may forecast
somewhat limited structural flexibility with regard to the
substitution pattern at C.2 in future SAR studies.
Ea
Conclusions
Challenged by the intriguing structures of the telomerase
inhibitors belonging to the dictyodendrin family, a concise
approach to these scarce alkaloids of marine origin was
developed. The chosen route takes advantage of the proclivity
of ketoamides to undergo reductive coupling on treatment with
low-valent titanium20 as well as of an efficient photochemical
6π-electrocyclization, which is rendered irreversible when
performed in tandem with the aromatization of the cyclohexa-
diene derivative initially formed. The densely functionalized
pyrrolo[2,3-c]carbazole 18 thus obtained in multigram quantities
with excellent overall yield served as a common intermediate
for the first total syntheses of the quinoid dictyodendrin C, its
very labile quinomethide analogue dictyodendrin E, and the
acylated congener dictyodendrin B. The individual end games
uncover some of the unique chemical characteristics of these
natural products, most notably their tendency to form extended
quinoid chromophores under oxidative conditions as well as the
lability of substituents at C.2. The migratory aptitude of the
bromide at this position, the preference of a 1,2-aryl shift over
conventional Friedel-Crafts chemistry, and the somewhat
surprising tendency of such compounds to engage in dimeriza-
tion at seemingly remote sites (C.8) are equally remarkable
features. Finally, the success of the palladium-catalyzed ben-
zylation by means of the 9-MeO-9-BBN variant of the Suzuki
coupling is noteworthy, which might be useful in other delicate
applications as well.49 Having completed this first round of
chemical explorations of this interesting class of bioactive
alkaloids, we are now in the phase of redirecting the total
syntheses outlined above toward the preparation of “natural
productlike” analogues as well as to a study of their biochemical
and biological properties. The results of these investigations will
be reported shortly.
a [a] BCl3, CH2Cl2, -20 °C f room temperature; [b] Cl3CCH2OSO2Cl,
DABCO, THF, 83% (over both steps); [c] BCl3, TBAI, CH2Cl2, 0 °C, 85%;
[d] (i) Zn, HCOONH4, MeOH; (ii) DDQ, THF, 75% (over both steps); [e]
MeOH, cf. text; [f] (i) DDQ, THF; (ii) Zn, HCOONH4, MeOH.
Acknowledgment. Generous financial support by the Max-
Planck-Society and the Merck Research Council is gratefully
acknowledged. M.M.D. and B.S. thank the Alexander-von-
Humboldt Foundation and the Fonds der Chemischen Industrie,
respectively, for fellowships. We also thank Prof. N. Fusetani
and Prof. S. Matsunaga, Tokyo, for kindly providing samples
of the dictyodendrins and copies of the original spectra for
comparison as well as Dr. R. Mynott and C. Wirtz for their
invaluable help with the structure assignment of several
intermediates.
subjected to reductive cleavage of the trichloroethyl group
followed by DDQ oxidation. Gratifyingly, this reaction sequence
allowed for the isolation of dictyodendrin E (5) in pure form in
respectable 75% yield over two steps.
For solubility reasons, however, the purification of the product
had to be performed with MeOH. Any delay during this
manipulation or any trace of acid in the mixture at that point
causes partial addition of MeOH with formation of the
inseparable adduct 47, thus confirming Fusetani’s original
finding that the extended quinomethide moiety of 5 acts as an
excellent Michael acceptor for external nucleophiles.9,48 In this
context, it is also worth mentioning that the order of the final
steps leading from 46 to 5 is critical for success: thus, DDQ
oxidation of 46 prior to reductive cleavage of the trichloroethyl
sulfate ester results in an overall fragmentation with loss of the
benzylidene unit at C.2, thereby giving rise mainly to dictyo-
dendrin C 3 (Scheme 13). This finding reinforces the previous
Supporting Information Available: Full experimental details
including analytical and spectroscopic data of all new products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JA0617800
(49) This notion is supported by several recent applications of the 9-MeO-9-
BBN variant of the Suzuki reaction which were difficult or impossible to
achieve under standard conditions; cf.: (a) Fu¨rstner, A.; Turet, L. Angew.
Chem., Int. Ed. 2005, 44, 3462. (b) Lepage, O.; Kattnig, E.; Fu¨rstner, A.
J. Am. Chem. Soc. 2004, 126, 15970. (c) Yuan, Y.; Men, H.; Lee, C. J.
Am. Chem. Soc. 2004, 126, 14720. (d) Marshall, J. A.; Johns, B. A. J.
Org. Chem. 1998, 63, 7885. (e) Mickel, S. J. et al., Org. Process Res.
DeV. 2004, 8, 113-121.
(48) Control experiments showed the MeOH addition to be complete after ca.
1 week at ambient temperature in the absence of external catalysts.
9
8094 J. AM. CHEM. SOC. VOL. 128, NO. 24, 2006