Synthesis of the pyrrolo[2,3-c]carbazole core of the dictyodendrins

Article abstract of DOI:10.1039/b822933n

The pyrrolo[2,3-c]carbazole 1, the common core of the marine alkaloids known as the dictyodendrins, has been synthesised. The sequence is based on a Suzuki cross-coupling reaction between the pyrrole fragment 2 and the indole fragment 3, followed by tandem photochemical 6π-electrocyclisation/ aromatisation.

Full text of DOI:10.1039/b822933n

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of the pyrrolo[2,3-c]carbazole core of the dictyodendrins†‡
a,c
Carles Ayats,*a Roger Soley,a Fernando Albericioa,b and Mercedes Alvarez*
´
Received 19th December 2008, Accepted 19th December 2008
First published as an Advance Article on the web 13th January 2009
DOI: 10.1039/b822933n
The pyrrolo[2,3-c]carbazole 1, the common core of the
marine alkaloids known as the dictyodendrins, has been
synthesised. The sequence is based on a Suzuki cross-
coupling reaction between the pyrrole fragment 2 and
the indole fragment 3, followed by tandem photochemical
6p-electrocyclisation/aromatisation.
pyrrolo[2,3-c]carbazole core but differ in their respective sub-
stituents at the a position of the pyrrole ring and in their oxidation
degree. Interestingly, compounds with the same core structure,
isolated from a marine sponge of the same genus, have been
reported as aldose reductase inhibitors.2 Dictyodendrins A–E
are the first marine natural products with telomerase inhibitory
properties, showing 100% inhibition at 50 mg/mL. This enzyme is
activated in more than 85% of cancer cells studied to date, but not
in normal cells.3
Dictyodendrins A–E (Fig. 1) are a family of alkaloids isolated
from the sponge Dictyodendrilla verongiformis that was recently
collected off the south Japanese coast.1 They have a common
Hence, the dictyodendrins are fascinating marine prod-
ucts which could be used as excellent candidates for cancer
chemotherapy.
The potent antitumour activity and structural features of dicty-
odendrins A–E render these marine natural products formidable
targets for total syntheses. However, to date, only Fu¨rstner et al.
have synthesised these compounds.4 Their strategy consisted
of generating the indole nucleus through a titanium-induced
reductive ketoamide coupling reaction.5 This reaction type has
already been used by the same group to prepare more complex
indole derivatives.6
We endeavoured to prepare pyrrolo[2,3-c]carbazole 1 as a
simplified common core of the dictyodendrins. We envisioned
that it would be accessible via the bond disconnections shown
in Scheme 1. The synthetic strategy employs intermediates 2 and
3 and is based on a Pd(0)-catalysed cross-coupling reaction and a
photochemical 6p-electrocyclisation.
Fig. 1 Structures of dictyodendrins A–E.
aInstitute for Research in Biomedicine, Barcelona Scientific Park-University
of Barcelona, Baldiri Reixach 10–12, E-08028 Barcelona, Spain
bDepartment of Organic Chemistry, University of Barcelona, E-08028
Barcelona, Spain
cLaboratory of Organic Chemistry, Faculty of Pharmacy, University
of Barcelona, E-08028 Barcelona, Spain. E-mail: mercedes.alvarez@
irbbarcelona.org; Fax: (+34) 934037126; Tel: (+34) 934037086
Scheme 1 Retrosynthetic analysis of pyrrolo[2,3-c]carbazole core 1.
† Dedicated to Professor Josep Font on the occasion of his retirement from
the Universitat Auto`noma de Barcelona
‡ Electronic supplementary information (ESI) available: Full experimental
procedures and spectroscopic data for all new compounds. Crystallo-
graphic information file (CIF) of (Z)-14. CCDC reference number 704582.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/b822933n
The synthesis began with construction of the pyrrole fragment 2
from the corresponding halo derivatives 9 and 10, which were pre-
pared via halogenation, deprotection and subsequent alkylation
of 6 (Scheme 2). The procedure described below, based on using
a boronic ester instead of a boronic acid, provided much higher
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Scheme 2 Synthesis of the pyrrole fragment 2. Reagents and conditions:
(a) n-BuLi, THF, -78 ◦C; then 2-methoxy-4,4,5,5-tetramethyl-1,3,2-
dioxaborolane; (b) p-bromoanisole, Pd(PPh3)4, Na2CO3, MeOH/toluene,
reflux, 81% (2 steps from 4); (c) NBS, THF, -78 ◦C-RT; then TBAF, THF,
RT, 13–52% of 7 (2 steps from 6) or I2, Hg(OAc)2, CH2Cl2, -78 ◦C; TBAF,
THF, RT; (d) 4-methoxyphenethyl bromide, K2CO3, DMF, 80 ◦C, 90% of
9, 49% of 10 (3 steps from 6).
yield (81% vs. 60%) than that obtained in previous reports7 of the
synthesis of 6. Pyrrole 6 was prepared by Suzuki cross-coupling
between p-bromoanisole and pyrrole boronic ester 5,8 which had
been previously synthesised from 49 by bromine-lithium exchange
followed by reaction with commercially available 2-methoxy-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane.10 Although N-alkylation
of 7 with 4-methoxyphenethyl bromide in DMF using K2CO3 as
Scheme 3 Synthesis of the indole fragment (Z)-18, with the nOe and
HMBC effects of selected compounds shown. Reagents and conditions:
(a) n-BuLi, THF, -78 ◦C; then Me3SnCl, RT; then 4-MeOC6H4CH2COCl,
PdCl2(PPh3)2, CuI, toluene, reflux, 65%; (b) (MeO)2SO2, NaH, DMF,
78%; (c) NBS, THF, -78 ◦C–RT; (d) Cs2CO3, THF/MeOH, 60 ◦C, 98%
of (Z)-15, quant. of (Z)-16; (e) NBS, NaOMe, MeOH, RT; (f) NaH, TsCl,
THF, 0 ◦C–RT, 72% [2 steps from (Z)-15].
◦
a base at 80 C led to the desired target 9 in good yield (90%),11
bromination of 6 with 1 equiv. of NBS in THF at -78 ◦C followed
by deprotection with TBAF gave 7 in variable yields,12 probably
due to competitive bromination at the pyrrole 2 position,13 which
afforded the very unstable 2-bromo-3-(4-methoxyphenyl)pyrrole
as a minor byproduct. To prevent formation of the said byproduct,
we sought an alternative route for the introduction of a bulky
halogen. Thus, we studied formation of the iodide derivative 10.
6 was iodinated with iodine in the presence of mercuric acetate
at -78 ◦C using equimolar quantities of the three reactants. In
these conditions, only the 3-iodo compound was isolated. TBAF
deprotection, followed by N-alkylation, provided 10 in 49% overall
yield. Finally, 2 was synthesised from 10 by employing the same
conditions used to prepare 5.
The indole fragment was assembled from ketone 12, which
had been previously obtained by our group (Scheme 3).14 The
enol ether (Z)-13 was obtained in 78% yield by reaction of 12
with NaH and dimethyl sulfate in DMF.15 We expected that
bromination of the enol ether (Z)-13 with NBS in THF at
-78 ◦C and subsequent warming to room temperature would
give (Z)-18, the brominated product at the indole 3 position.
However, these conditions led to a stereoisomeric mixture of
bromides (Z)-14 and (E)-14 in a 2.6:1 ratio (as determined by
peak area [HPLC and 1H-NMR]). Selective crystallisation of this
mixture with acetonitrile gave (Z)-14. The absolute configuration
of (Z)-14 was established by NOESY experiments and X-ray
analysis.16 Semipreparative HPLC was used to obtain pure (E)-
14, whose stereochemistry was determined by NMR studies (See
ESI‡).17
To increase the reactivity of the indole, a deprotection–
bromination–protection sequence was planned for the preparation
of (Z)-18. Elimination of the tosyl protecting group of (Z)-
13, using the mild and convenient method described by Bajwa
et al.,18 provided (Z)-15 in 98% yield.19 Subjecting (Z)-14 to
similar reaction conditions, (Z)-16 was obtained in quantitative
yield.20 Reaction of (Z)-15 with NBS in the presence of sodium
methoxide in methanol,21 followed by protection with TsCl,
afforded the desired brominated product (Z)-1822 in 72% overall
yield. Furthermore, the regioselectivity of the bromination to
1
obtain (Z)-17 from (Z)-15 was corroborated by H/1H COSY
experiments.23
Once 2 and (Z)-18 were prepared, we began the final stage
of the synthesis of the pyrrolo[2,3-c]carbazole core: Suzuki
cross-coupling reaction of the two fragments followed by
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6p-electrocyclisation.24 Thus, the Pd(0)-catalysed reaction of (Z)-
18 with the pyrrole boronic ester 2 afforded (Z)-19 in 59% yield.
The final step involved 6p-electrocyclisation of (Z)-19 by irra-
diation with a medium pressure Hg-lamp (125 W) in acetonitrile.
Aromatization by addition of Pd/C and nitrobenzene25 to the reac-
tion medium afforded the desired pyrrolo[2,3-c]carbazole 1 in 25%
yield. Similarly, Suzuki reaction between 2 and (Z)-14 led to (Z)-
20 in 67% yield, which was then subjected to 6p-electrocyclisation
to provide 21 in 17% yield.26 This reaction sequence was also used
with the stereoisomeric mixture of indoles (Z)-14 and (E)-14 to
obtain compound 22, a regioisomer of 1 (Scheme 4). The Pd(0)-
catalysed reaction of 2 with the mixture of indoles (Z)-14 and (E)-
14, followed by 6p-electrocyclisation, gave the benzo[c]carbazole
21 and the pyrrolo[3,2-c]carbazole 22 in 13% and 4% overall
yields, respectively.
Acknowledgements
This work was partially supported by CICYT (2006-03794/BQU),
Generalitat de Catalunya and the Barcelona Scientific Park.
Notes and references
1 K. Warabi, S. Matsunaga, R. W. M. Van Soet and N. Fusetani, J. Org.
Chem., 2003, 68, 2765.
2 A. Sato, T. Morishita, T. Shiraki, S. Yoshioka, H. Horikoshi, H.
Kuwano, H. Hanzawa and T. Hata, J. Org. Chem., 1993, 58, 7632.
3 S. Neidle and G. Parkinson, Nature Reviews, Drug Discovery, 2002, 1,
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4 (a) A. Fu¨rstner, M. M. Domostoj and B. Scheiper, J. Am. Chem. Soc.,
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J. Am. Chem. Soc., 2006, 128, 8087.
5 A. Fu¨rstner, A. Hupperts, A. Ptock and E. Janssen, J. Org. Chem.,
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6 (a) A. Fu¨rstner and A. Ernst, Tetrahedron, 1995, 51, 773; (b) A.
Fu¨rstner, A. Ernst, H. Krause and A. Ptock, Tetrahedron, 1996, 52,
7329.
7 6 was obtained from 3-iodo-1-(triisopropylsilyl)pyrrole as described by
´
A. Alvarez, A. Guzma´n, A. Ruiz and E. Velarde, J. Org. Chem., 1992,
57, 1653.
8 K. Billingsley and S. L. Buchwald, J. Am. Chem.Soc., 2007, 129, 3358.
9 B. L. Bray, P. H. Mathies, R. Naef, D. R. Solas, T. T. Tidwell, D. R.
Artis and J. M. Muchowski, J. Org. Chem., 1990, 55, 6317.
10 Pyrrole boronic ester 5 was reacted with p-bromoanisole without
previous purification. Note: when 5 was isolated and purified, it was
obtained in very low yield (24%).
11 The N-alkylation methodology used was the same as that developed
by Fu¨rstner et al. in the synthesis of storniamide A: A. Fu¨rstner, H.
Krause and O. R. Thiel, Tetrahedron, 2002, 58, 6373.
12 L. B. Snyder, Z. Meng, R. Mate, S. V. D’Andrea, A. Marinier, C. A.
Quesnelle, P. Gill, K. L. DenBleyker, J. C. Fung-Tomc, M. Frosco, A.
Martel, J. F. Barrett and J. J. Bronson, Bioorg. Med. Chem. Lett., 2004,
14, 4735.
13 The generation of 2-bromo-1-(triisopropylsilyl)-3-(4-methoxy-
phenyl)pyrrole was surprising, since we had expected that the steric
hindrance of the TIPS group would prevent it. Bray et al. also obtained
the brominated product at the 2 position as a minor product (ref. 9)
from N-(triisopropylsilyl)pyrrole when using the same bromination
conditions that we did.
´
14 R. Soley, F. Albericio and M. Alvarez, Synthesis, 2007, 10, 1559.
15 Other conditions for enol ether formation (e.g. NaOMe as base) gave
the same compound in lower yield (68%).
16 See ESI‡ for more details.
17 In stereoisomers (Z)-14 and (E)-14 an nOe effect was observed between
indole proton H3 and indole proton H4. Furthermore, in (Z)-14 an
nOe effect was also observed between indole proton H3 and aromatic
protons H2I and 6I.
18 J. S. Bajwa, G.-P. Chen, K. Prasad, O. Repicˇ and T. J. Blacklock,
Tetrahedron. Lett., 2006, 47, 6425–6427.
19 The stereochemistry of (Z)-15 was confirmed by a nOe effect between
indole proton H3 and the enol ether proton.
Scheme 4 Suzuki cross-coupling reactions and 6p-electrocyclisations
(with nOe effect shown). Reagents and conditions: (a) Pd(PPh3)4, Na2CO3,
DMF, reflux; then (Z)-18, 59% of (Z)-19 or then (Z)-14, 67% of (Z)-20
or then (Z)-14 and (E)-14; (b) hn, CH3CN, C6H5NO2, Pd/C, 25% of
1, 17% of 21, 4% of 22 and 13% of 21 [2 steps from (Z)-14 and
(E)-14].
20 COSY correlation was observed between NH and indole proton H3.
21 J. C. Lanter, J. J. Fiordeliso, W. Jiang, G. F. Allan, M.-T. Lai, O. Linton,
D. W. Hahn, S. G. Lundeen and Z. Sui, Bioorg. Med. Chem. Lett., 2007,
17, 123.
22 The structure of (Z)-18 was confirmed by HMBC. A long range 1H-13C
correlation was observed between proton H4 and carbon C3.
23 As opposed to (Z)-16, no 1H/1H COSY correlation with NH was
observed for (Z)-17.
In summary, we have synthesised the pyrrolo[2,3-c]carbazole
1, a simplified common dictyodendrins core, using a convergent
strategy based on a Pd(0) catalysed cross-coupling reaction and
a 6p-electrocyclisation. Furthermore, more complex indole struc-
tures, such as benzo[c]carbazole 21 and pyrrolo[3,2-c]carbazole
22, were also prepared.
24 (a) H.-J. Kno¨lker and K. R. Reddy, Chem. Rev., 2002, 102, 4303; (b) T.
Kawasaki and M. Sakamoto, J. Ind. Chem. Soc., 1994, 71, 443.
25 V. H. Rawal, R. J. Jones and M. P. Cava, Tetrahedron Lett., 1985, 26,
2423.
26 1H-NMR spectra showed two doublets, at 6.60 and 6.96 ppm (J =
2.6 Hz), corresponding to the pyrrole protons H2I and H5I, respectively.
A nOe effect was observed between aromatic protons H1 and H11.
862 | Org. Biomol. Chem., 2009, 7, 860–862
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©