One-pot synthesis of diazine-bridged bisindoles and concise synthesis of the marine alkaloid hyrtinadine A

Article abstract of DOI:10.1002/ejoc.201100680

Diazine-bridged bisindoles are readily obtained from N-Bocprotected 3-iodoindoles and 3-iodo-7-azaindole in a pseudo three-component reaction involving a one-pot Masuda borylation-Suzuki arylation sequence. Some of the title com-pounds display promising c

Full text of DOI:10.1002/ejoc.201100680

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100680
One-Pot Synthesis of Diazine-Bridged Bisindoles and Concise Synthesis of the
Marine Alkaloid Hyrtinadine A
Boris O. A. Tasch,[a] Eugen Merkul,[a] and Thomas J. J. Müller*[a]
Dedicated to Prof. em. Dr. Leonhard Birkofer on the occasion of his 100th birthday
Keywords: Alkaloids / Arylation / Boron / C–C coupling / Multicomponent reactions / Palladium
Diazine-bridged bisindoles are readily obtained from N-Boc-
protected 3-iodoindoles and 3-iodo-7-azaindole in a pseudo
three-component reaction involving a one-pot Masuda bo-
rylation–Suzuki arylation sequence. Some of the title com-
pounds display promising cytotoxic properties. The versatil-
ity of this methodology is illustrated by a very concise total
synthesis of the marine alkaloid hyrtinadine A.
Introduction
Results and Discussion
The Suzuki–Miyaura cross-coupling reaction is one of
the most versatile tools for the preparation of biaryls in a
short and efficient manner.[10] Pinacolboronates[11] are
stable esters and can be readily applied as coupling partners
in Suzuki coupling reactions. Most advantageously, their
preparation proceeds by palladium-catalyzed Miyaura[12] or
Masuda[13] borylation under mild conditions and tolerates
a lot of polar functionality. The Masuda borylation has the
advantage of using pinacolborane as a borylating agent,
which is definitely more atom economical and elegant than
applying bispinacolato diboron. Therefore, the advantages
of performing a Masuda borylation and a subsequent Su-
zuki coupling in a one-pot sequence lie at hand. Prior to
our studies, this sequence has not generally been used for
the preparation of heteroaromatic biaryls.[14] Just recently,
we established this conceptually elegant sequence for N-het-
erocycles, such as indoles and pyrroles,[8] which are both
ubiquitous in nature and constitute important building
Heterocycles bridging two identical indole substituents
are common scaffolds in many pharmaceutically interesting
natural products,[1] such as hamacanthins,[2] nortopsen-
tins,[3] and lynamicins.[4] Inspired by marine alkaloids of the
meridianin and variolin family,[5,6] we identified the struc-
turally related, novel bisindole alkaloid hyrtinadine A
(Scheme 1)[7] as a suitable target to scrutinize the scope of
the Masuda borylation–Suzuki coupling sequence[8] of ni-
trogen heterocycles, which we applied recently in a concise
synthesis of meridianin A and 7-azaindole analogues. Hyrt-
inadine A, isolated from an Okinawan marine sponge of the
Hyrtios genus, was found to be highly cytotoxic against mu-
rine leukemia L1210 and human epidermoid carcinoma KB
cell lines. The sole total synthesis of hyrtinadine A was real-
ized by a Pd-catalyzed coupling of indiumorganyls as a key
step.[9] Although a twofold cross-coupling with heterocyclic
substrates and an unsymmetrical substitution of the pyrimi-
dyl core were achieved, this methodology appears to be very
limited. A major drawback is the overstoichiometrical use
of the precious indolyl organoindium reagent, which is also
associated with the need for organolithium or organomag-
nesium precursors not tolerant towards functional groups.
Herein we report the adaptation of the Masuda borylation–
Suzuki coupling sequence to diheteroaryl-substituted diaz-
ines and its application to a concise total synthesis of hyrti-
nadine A.
[a] Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf
Universitätsstr. 1, 40225 Düsseldorf, Germany
Fax: +49-211-81-14324
E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100680.
Scheme 1. Retrosynthetic analysis of hyrtinadine A.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4532–4535

One-Pot Synthesis of Diazine-Bridged Bisindoles
blocks of many biologically active compounds with signifi- Moreover, the Boc protecting group is concomitantly
cant relevance in medicinal chemistry.[15]
cleaved under the terminal Suzuki conditions, accounting
Our retrosynthetic analysis of hyrtinadine A suggests the for the efficiency of the sequence. As a consequence, N-Boc-
Masuda borylation–Suzuki coupling as a key transform 3-iodo-5-methoxyindole and 5-bromo-2-iodopyrimidine are
(Scheme 1), which is projected as a one-pot reaction in the the electrophilic coupling partners; the former is readily
sense of a sequentially palladium-catalyzed process.[16] available from commercially available starting materials.[17]
According to this strategy, we first scouted the applica-
bility of the sequence to the synthesis of structural subunits
3a–c, using the standard conditions[8] for the sequence
(Scheme 2).
Scheme 2. One-pot Masuda borylation–Suzuki arylation synthesis
of heteroaryl-substituted indoles 3.
Scheme 3. Synthesis of isomeridianin A (4) by demethylation of 3c.
Scheme 4. One-pot Masuda borylation–Suzuki arylation synthesis of diazine-bridged bisheteroaryls 6.
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B. O. A. Tasch, E. Merkul, T. J. J. Müller
SHORT COMMUNICATION
After generating the boronate intermediate by Masuda ity assays with HCT116 (colon carcinoma) and A2780
borylation of indoles 1 with pinacolborane, methanol, 2- (ovarian carcinoma) cell lines (Table 1).[22] Interestingly,
bromopyrimidine (2a), 5-bromopyrimidine (2b), or 4- O,OЈ-dimethyl hyrtinadine A (6f) as well as the chloro ana-
chloro-2-aminopyrimidine (2c), and cesium carbonate were logue (6c) show a low micromolar activity in viability as-
subsequently added to the reaction mixture to give, after says, which however seems not to be correlated with kinase
the Suzuki arylation step, 3-pyrimidyl-substituted indoles 3 inhibitory activity. Fascinatingly, precursor 6f was more
in good to excellent isolated yields. For quenching the ex- active than the natural product in viability assays.
cess amount of pinacolborane, the addition of anhydrous
Table 1. Biological data of selected compounds 3, 4, 6, and 7.
methanol has proven to furnish highest yields in the two-
Number of kinases with
Ͼ50% inhibition at 1 μm /
Number of kinases tested
IC50 (HCT116)
IC50 (A2780)
step sequence. For demethylation of 3c, heating in the melt
of pyridinium chloride (PyHCl)[18] was applied to give the
literature unknown isomeridianin A (4) in a very good yield
(Scheme 3).
With this convenient sequential Masuda borylation–
Suzuki arylation protocol in hand we set out to perform
the sequence as a pseudo-three-component synthesis, that 6c
is, the ratio of the in situ generated heterocyclic pinacolester
to the dihalodiazine was chosen as 2:1. Starting from 3-
iodo-substituted heterocycles such as indoles 1a, 1c–g, 7-
azaindole (1b), 2-ethyl-5-thien-2-yl-furane (1h),[19] and 5-(p-
anisyl)pyrrole (1i),[20] after Masuda borylation with pinac-
olborane the Suzuki arylation step with various diiodo-, di-
bromo-, or bromoiodo-substituted diazines 5 furnishes
bis(heteroaryl) substituted diazines 6 in a one-pot fashion
in moderate to good yields (Scheme 4).
[μm][a]
[μm][a]
3c
4
6a
6b
7/110
8/110
0/102
7/121
1/121
0/121
0/110
0/121
3/121
Ͼ10
Ͼ10
Ͼ10
Ͼ10
5.3
Ͼ10
3.7
Ͼ10
Ͼ10
Ͼ10
Ͼ10
Ͼ10
Ͼ10
0.9
Ͼ10
4.5
3.3
Ͼ10
6e
6f
6m
7
[a] IC50: concentration reducing cell proliferation by 50%.
Conclusions
In summary we have successfully adapted the one-pot
Masuda borylation–Suzuki arylation sequence to a general
synthesis of diazine-bridged bisheteroaryls in the sense of a
one-pot pseudo-three-component reaction. The procedure
is another showcase for sequential Pd-catalyzed processes,
which can be easily performed without the need for exotic
ligands or the excessive use of expensive reagents. Besides
the concise total synthesis of the marine alkaloid hyrtinad-
ine A, several bisheteroaryl analogues have been efficiently
prepared in a straightforward fashion. Studies directed
towards the syntheses of structurally more complex marine
alkaloids, kinase inhibitors, and oligomeric heteroarenes
using the Masuda borylation–Suzuki arylation are cur-
rently underway.
In particular, 2,5-bis(methoxyindol-3-yl)pyrimidines 6e–
g can be readily obtained by this one-pot procedure, with
the literature unknown compound 6f being O,OЈ-dimethyl
hyrtinadine A, a precursor of the natural product. Thus, by
virtue of the one-pot Masuda borylation–Suzuki arylation
sequence as a key step, the total synthesis of hyrtinadine A
can be conducted in a very concise fashion. Starting from
commercially available 5-methoxy-1H-indole, after iodin-
ation, Boc protection, and Masuda borylation–Suzuki cou-
pling sequence, dimethyl hyrtinadine A (6f) is accessible in
good yield.
However, unexpectedly the final demethylation with
PyHCl furnished hyrtinadine A (7) in only 39% yield.
Therefore, we sought an alternative deprotection
method.[21] Gratifyingly, demethylation of 6f using BBr3
gave hyrtinadine A in 78% yield (Scheme 5).
Experimental Section
Synthesis of 6f: Tetrakis(triphenylphosphane)palladium(0) (69 mg,
0.06 mmol, 3 mol-%) and tert-butyl 3-iodo-5-methoxy-1H-indole-
1-carboxylate (1f; 746 mg, 2.00 mmol) were placed under an argon
atmosphere in a dry screw-cap vessel with a septum. Then, dry 1,4-
dioxane (10 mL) was added, and the mixture was degassed with
argon (5 min). Dry triethylamine (1.0 mL) and 4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (0.45 mL, 3.00 mmol) were successively added
to the mixture, which was then stirred at 80 °C (preheated oil bath)
for 3 h (monitored by TLC). Then, after cooling to room tempera-
ture (water bath), dry methanol (10 mL), 5-bromo-2-iodopyrimid-
ine (5a; 289 mg, 1.00 mmol), and cesium carbonate (1.63 g,
5.00 mmol) were successively added. The mixture was stirred at
100 °C overnight (preheated oil bath). Then, after cooling to room
temperature, the solvents were removed under reduced pressure.
The residue was purified by flash chromatography on silica gel
(dichloromethane/methanol/aqueous ammonia) to give compound
6f as a yellow solid (238 mg, 0.64 mmol, 64% yield). For full ana-
Scheme 5. Synthesis of hyrtinadine A (7) by demethylation of O,OЈ-
dimethyl hyrtinadine A (6f).
The biological activities of O-methyl isomeridianin A
(3c), isomeridianin A (4), selected diazine-bridged bishet-
eroaryls 6, and hyrtinadine A (7) were evaluated by screen-
ing against a broad panel of 102–121 kinases at the Division
of Signal Transduction Therapy (DSTT), University of
Dundee, UK, and by determining the IC50 values in viabil- lytical details, see the Supporting Information.
4534 Eur. J. Org. Chem. 2011, 4532–4535
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One-Pot Synthesis of Diazine-Bridged Bisindoles
[8] E. Merkul, E. Schäfer, T. J. J. Müller, Org. Biomol. Chem. 2011,
9, 3139–3141.
[9] Á. Mosquera, R. Riveiros, J. P. Sestelo, L. A. Sarandeses, Org.
Lett. 2008, 10, 3745–3748.
[10] a) M. Prieto, E. Zurita, E. Rosa, L. Muoz, P. Lloyd-Williams,
E. Giralt, J. Org. Chem. 2004, 69, 6812–6820; b) A. Suzuki, J.
Organomet. Chem. 2002, 653, 83–90; c) S. P. Stanforth, Tetrahe-
dron 1998, 54, 263–303; d) N. Miyaura, A. Suzuki, Chem. Rev.
1995, 95, 2457–2483; e) N. Miyaura, T. Yanagi, A. Suzuki,
Synth. Commun. 1981, 11, 513–519.
Synthesis of 7 (Demethylation of Compound 6f; Synthesis of Hyrtin-
adine A): 3,3Ј-(Pyrimidine-2,5-diyl)bis(5-methoxy-1H-indole) (6e;
185 mg, 0.50 mmol) was placed in a dry screw-cap vessel under an
argon atmosphere. Then, dry dichloromethane (15 mL) was added.
The suspension was cooled to –78 °C (acetone/dry ice bath) and
tribromoborane (0.58 mL, 6.00 mmol) was slowly added. The mix-
ture was allowed to reach room temperature and continuously
stirred for 20 h. The reaction progress was monitored by TLC.
Then the mixture was cooled to 0 °C (water/ice bath), and water
(3 mL) followed by saturated potassium carbonate solution
(30 mL) were slowly added. The resulting yellow precipitate was
filtered and purified by flash chromatography on silica gel (dichlo-
romethane/methanol/aqueous ammonia) to give hyrtinadine A (7)
as a yellow solid [147 mg, 0.43 mmol, 78% yield (contained one
molecule of MeOH)]. For full analytical details, see the Supporting
Information.
[11] C. E. Tucker, J. Davidson, P. Knochel, J. Org. Chem. 1992, 60,
3482–3485.
[12] T. Ishiyama, M. Murata, N. Miyaura, J. Org. Chem. 1995, 60,
7508–7510.
[13] a) K. L. Billingsley, S. L. Buchwald, J. Org. Chem. 2008, 73,
5589–5591; b) C. S. Krämer, T. J. Zimmermann, M. Sailer,
T. J. J. Müller, Synthesis 2002, 1163–1170; c) M. Murata, T. Oy-
ama, S. Watanabe, Y. Masuda, J. Org. Chem. 2000, 65, 164–
168; d) M. Murata, S. Watanabe, Y. Masuda, J. Org. Chem.
1997, 62, 6458–6459.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, spectroscopic and analytical data
and copies of the NMR spectra of compounds 3, 4, 6, and 7.
[14] a) H. A. Duong, S. Chua, P. B. Huleatt, C. L. L. Chai, J. Org.
Chem. 2008, 73, 9177–9180; b) A. S. Abreu, P. M. T. Ferreira,
M.-J. R. P. Queiroz, I. C. F. R. Ferreira, R. C. Calhelha, L. M.
Estevinho, Eur. J. Org. Chem. 2005, 2951–2957; c) P.-E. Brou-
ˇ
tin, I. Cernˇa, M. Campaniello, F. Leroux, F. Colobert, Org.
Acknowledgments
Lett. 2004, 6, 4419–4422; d) M. Penhoat, V. Levacher, G.
Dupas, J. Org. Chem. 2003, 68, 9517–9520; e) O. Baudoin, M.
Cesario, D. Guénard, F. Guéritte, J. Org. Chem. 2002, 67,
1199–1207; f) O. Baudoin, D. Guénard, F. Guéritte, J. Org.
Chem. 2000, 65, 9268–9271.
The authors cordially thank Merck KGaA, Darmstadt and the
Fonds der Chemischen Industrie (scholarship to B. O. A. T.) for fi-
nancial support and Dr. Dieter Dorsch and Dr. Christian Sirren-
berg (Merck Serono R&D, Merck KGaA Darmstadt) for providing
biological tests.
[15] For recent reviews, see: a) A. J. Kochanowska-Karamyan,
M. T. Hamann, Chem. Rev. 2010, 110, 4489–4497; b) H. Fan,
J. Peng, M. T. Hamann, J. F. Hu, Chem. Rev. 2008, 108, 264–
287.
[16] T. J. J. Müller, Top. Organomet. Chem. 2006, 19, 149–205.
[17] B. Witulski, N. Buschmann, U. Bergsträßer, Tetrahedron 2000,
56, 8473–8480.
[18] a) C. R. Schmid, C. A. Beck, J. S. Cronin, M. A. Staszak, Org.
Process Res. Dev. 2004, 8, 670–673; b) V. Prey, Ber. Dtsch.
Chem. Ges. 1941, 74, 1219–1225; c) V. Prey, Ber. Dtsch. Chem.
Ges. 1942, 75, 350–356.
[19] For a one-pot preparation of (di)substituted (3)4-iodofurans,
see: a) A. S. Karpov, E. Merkul, T. Oeser, T. J. J. Müller, Chem.
Commun. 2005, 2581–2583; b) A. S. Karpov, E. Merkul, T.
Oeser, T. J. J. Müller, Eur. J. Org. Chem. 2006, 2991–3000.
[20] For a one-pot preparation of 2-substituted N-Boc-4-iodopyr-
roles, see: E. Merkul, C. Boersch, W. Frank, T. J. J. Müller, Org.
Lett. 2009, 11, 2269–2272.
[21] BBr3 has been used for demethylation in the synthesis of hyr-
tiosine B: J. Bergman, T. Janosik, A.-L. Johnsson, Synthesis
1999, 4, 580–582.
[22] G. R. Nakayama, M. C. Caton, M. P. Nova, Z. Parandoosh, J.
Immunol. Methods 1997, 204, 205–208. A2780 [ovarian tumor
cell line; European Collection of Cell Culture (ECACC)
93112519] or HCT116 (colon tumor cell line; ATCC CCL-247)
(for a description of kinase assays and viability assays, see the
Supporting Information). Collaboration with Merck Serono.
Received: May 13, 2011
[1] a) K. S. Ryan, C. S. Drennan, Chem. Biol. 2009, 16, 351–364;
b) for a review on bis- and trisindols, see: L. Gupta, A. Talwar,
P. M. S. Chauhan, Curr. Med. Chem. 2007, 14, 1789–1803; c)
for a review on bisindoles, see: C.-G. Yang, H. Huang, B. Jiang,
Curr. Org. Chem. 2004, 8, 1691–1720.
[2] a) X. Guinchard, Y. Vallée, J.-N. Denis, Org. Lett. 2007, 9,
3761–3764; b) S. P. Gunasekera, P. J. McCarthy, M. Kelly-
Borges, J. Nat. Prod. 1994, 57, 1437–1441.
[3] a) P. Diana, A. Carbone, P. Barraja, A. Montalbano, A. Mar-
torana, G. Dattolo, O. Gia, J. D. Via, G. Cirricione, Bioorg.
Med. Chem. Lett. 2007, 17, 2342–2346; b) F. Y. Miyake, K.
Jakushijin, D. A. Horne, Org. Lett. 2000, 2, 2121–2123.
[4] K. A. McArthur, S. S. Mitchell, G. Tsueng, A. Rheingold, D. J.
White, J. Grodberg, K. S. Lam, B. C. M. Potts, J. Nat. Prod.
2008, 71, 1732–1737.
[5] For a recent review on variolins and related alkaloids, see: S. R.
Walker, E. C. Carter, B. C. Huff, J. C. Morris, Chem. Rev. 2009,
109, 3080–3098.
[6] For a synthesis of meridianins by carbonylative Sonogashira
coupling, see: A. S. Karpov, E. Merkul, F. Rominger, T. J. J.
Müller, Angew. Chem. 2005, 117, 7112–7117; Angew. Chem. Int.
Ed. 2005, 44, 6951–6956.
[7] T. Endo, M. Tsuda, J. Fromont, J. Kobayashi, J. Nat. Prod.
2007, 70, 423–424.
Published Online: July 13, 2011
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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