Synthesis of novel annulated hymenialdisine analogues via palladium-catalyzed cross-coupling reactions with aryl boronic acids

Article abstract of DOI:10.1055/s-0029-1218573

Palladium-catalyzed Suzuki cross-coupling reactions of an indole vinyl triflate provides an efficient pathway for the synthesis of a diverse class of novel hymenialdisine analogues. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218573

LETTER
211
Synthesis of Novel Annulated Hymenialdisine Analogues via Palladium-
Catalyzed Cross-Coupling Reactions with Aryl Boronic Acids
Novel Annulated
H
a
ymenialdis
v
ine
A
nalogu
e
es enkumar Mangu,a,b Anke Spannenberg,a Matthias Beller,a,b Man-Kin Tse*a,b
a
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Center for Life Science Automation (CELISCA), Universität Rostock, Friedrich-Barnewitz-Str. 8, 18119 Rostock-Warnemünde,
b
Germany
Fax +49(381)128151158; E-mail: man-kin.tse@catalysis.de
Received 14 October 2009
icant interest for researchers in a number of areas of
medicinal chemistry.
Abstract: Palladium-catalyzed Suzuki cross-coupling reactions of
an indole vinyl triflate provides an efficient pathway for the synthe-
sis of a diverse class of novel hymenialdisine analogues.
N
RHN
H2N
N
Key words: hymenialdisine analogues, cross-coupling, silica gel,
palladium, heterocycles
O
O
HN
HN
R
NH
Protein kinases have emerged as one of the major drug tar-
get classes that are amenable to the development of small-
molecule inhibitors.1 Because protein kinases play critical
roles in cellular signaling networks, the development and
application of small-molecule kinase inhibitors as poten-
tial therapeutic agents and experimental tools to help un-
derstand the physiological role of these enzymes, has
generated much interest.2,3 Towards this end, intense ef-
forts have been devoted to the identification and develop-
ment of such small-molecule inhibitors to fight diseases;
such drug discovery projects currently account for 20–
30% of research and development work at many pharma-
ceutical companies.3 Currently, several small-molecule
kinase inhibitors are either approved or being developed
for use in the treatment of various human diseases includ-
ing cancer, cardiovascular disorders, and inflammation.3–5
Among them, the natural product hymenialdisine (HMD;
1), and its annulated analogues (2), exhibited promising
results in inhibiting various kinases selectively
(Figure 1).6 For example, Meijer et al. reported the crystal
structure of hymenialdisine (1) as a complex in the ATP
(adenosine triphosphate) binding pocket of the protein
kinase CDK2. Hymenialdisine (1) binds to the CDK2
pocket in a competitive manner. The crucial structural el-
ements of the molecule were identified as the NH–CO–C–
NH sequence on the lower part of the molecule, and the
heterocycle connected at the a-position of the upper part
of the molecule (for its effective hydrogen bonding).7 In
agreement with this analysis, it was also reported that the
kinase-inhibiting activity of HMDs varies significantly
depending on the heterocycle that is attached to its core
structure.6 It should be also noted that stevensine (or
odiline; 3), a marine alkaloid with a similar structural
scaffold, showed antitumor and weak antimicrobial activ-
ity.7,8 Hence, the synthesis of HMD analogues is of signif-
NH
N
Br
N
H
O
H
O
annulated analogues
of hymenialdisine 2
hymenialdisine 1
H2N
N
HN
R
Br
NH
NH
Br
N
N
H
O
H
O
new annulated
hybrid analogues 4
stevensine
or odiline 3
Figure 1
As part of our program devoted to the application of cata-
lytic methods to the synthesis of potential bio-active com-
pounds,9 and because of our background in catalytic
oxidation methodologies,10 we became interested in pre-
paring a novel compound library of small-molecule ki-
nase inhibitors using the hymenialdisine (1) scaffold as
backbone. Our initial efforts in this field recently culmi-
nated in the synthesis of novel annulated HMD-type bis-
indoles employing ring-opening reactions of aziridines
and epoxides.11 In order to investigate structure–activity
relationships of these novel analogues,11d we set out to
prepare a set of novel hybrid annulated analogues (4) of
hymenialdisine (1) and stevensine (3) by introducing ar-
enes and heteroarenes instead of the imidazole ring on its
core scaffold (Figure 1). Here, we report a convenient,
diversified synthetic strategy using palladium-catalyzed
Suzuki coupling reactions of indole triflate derivatives.12
Initially, we prepared ketone 6 from commercially avail-
able indole-2-carboxylic acid (5) following a protocol re-
ported previously by us (Scheme 1).11 In order to increase
the solubility and purity, the crude ketone 6 was treated
with excess (Boc)2O, DMAP, and triethylamine in dichlo-
romethane at room temperature to obtain the pure, stable
di-Boc-protected ketone 7 in 25–28% yield from 5.
SYNLETT 2010, No. 2, pp 0211–0214
x
x.
x
x.
2
0
1
0
Advanced online publication: 14.12.2009
DOI: 10.1055/s-0029-1218573; Art ID: G35009ST
© Georg Thieme Verlag Stuttgart · New York

212
N. Mangu et al.
LETTER
Table 1 Suzuki Coupling Reactions of Indole Triflate 8a
O
1) Pd(PPh3)4, R-B(OH)2
aq Na2CO3
toulene–ethanol (1:1)
70 °C, overnight
25–28%
over 4 steps
NBoc
R
COOH
TfO
N
H
N
O
NH
Boc
NBoc
7
5
2) activated silica
100 °C, 1 h
N
O
H
N
O
O
2
Boc
3
9a–k
8
NH
Entry
1
R
Product
Yield (%)b
N
H
O
6
9a
75
74
Scheme 1 Synthesis of di-Boc-protected ketone 7
MeO
Initial attempts to transform compound 7 into triflate 8 us-
ing methods such as LDA/triflimide at –78 °C or Hünig’s
base/triflimide, were unsuccessful.13 However, to our de-
light, the reaction proceeded smoothly in good yield (60%
with 30% recovery of 7) to give triflate 8 using trifluo-
romethanesulfonic anhydride in dichloromethane in the
presence of 2,6-di-tert-butyl-4-methylpyridine at 0 °C for
eight hours (Scheme 2).14 Our repeated attempts to en-
courage the reaction to proceed further towards comple-
tion by varying the reaction conditions, such as increasing
the amount of base/triflic anhydride and prolonged reac-
tion time, were not successful but showed a tendency to
decrease the yield (14 h, 35%; 20 h, 27%). This is ex-
plained by slow decomposition of 8 in the reaction mix-
ture.15
2
3
9b
9c
52
F3C
MeO
4
5
6
9d
9e
9f
63
40
60
NC
N
O
TfO
O
Tf2O
NBoc
7
8
9g
9h
50
78
NBoc
2,6-di-tert-butyl-
4-methylpyridine
0 °C, 8 h
N
O
N
Boc
O
Boc
8 60%
(30% recovery of 7)
7
S
Scheme 2 Synthesis of indole triflate 8
9
10
11
9i
0c
Nevertheless, with the key building block 8 in hand, we
envisioned the synthesis of novel hymenialdisine ana-
logues following standard Suzuki coupling protocols.16
Treatment of 8 with 4-methoxyphenyl boronic acid (1.1
equiv) in the presence of Pd(PPh3)4 (1 mol%) and aqueous
sodium carbonate (2 M) as base in a mixture of toluene
and ethanol (1:1) at 70 °C for 12–16 h, gave the desired
product along with minor amounts of the deprotected
O
9j
9k
59
52
S
O
a Reaction conditions: (1) triflate 8 (600 mg, 1.10 mmol), boronic acid
compound 9a (R = 4-methoxyphenyl). Because the next (1.2 mmol), 2 M Na2CO3 (0.55 mL), Pd(PPh3)4 (0.011 mmol), tolu-
ene–EtOH (1:1, 6 mL), Argon, 70 °C, overnight; (2) activated silica
step involves removal of the protecting groups, to simpli-
fy the synthetic procedure we used the crude mixture di-
(0.040–0.063 mm, 2.46 g), argon, 100 °C, 1 h.
b Isolated yield.
rectly. Thus, the reaction mixture was adsorbed onto
activated silica gel using dichloromethane and the mixture
was heated at 100 °C for one hour following our previous
deprotection protocol,12 which yielded 9a in 75% yield
over two steps (Table 1, entry 1).
c Compound 6 was formed as the major product (75%).
starting from triflate 8 (Table 1). Most of the boronic ac-
ids reacted smoothly to give 9a–k in moderate to good
yields (40–78%).17 Functional groups on the boronic acids
such as electron-rich (methoxy) and electron-withdrawing
(trifluoromethyl and cyano) were tolerated (Table 1, en-
Consequently, we applied this protocol to the preparation
of a number of novel hybrid analogues of hymenialdisine
Synlett 2010, No. 2, 211–214 © Thieme Stuttgart · New York

LETTER
Novel Annulated Hymenialdisine Analogues
213
(4) Huwe, A.; Mazitschek, R.; Giannis, A. Angew. Chem. Int.
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tries 3–5). The structure of 9d was confirmed by X-ray
crystal structure analysis (Figure 2).18 Notably, heteroaro-
matic boronic acids were also effective under these condi-
tions, giving the expected products in good yields
(Table 1, entries 7–11).
(6) Meijer, L.; Thunnissen, A.-M. W. H.; White, A. W.; Garnier,
M.; Nikolic, M.; Tsai, L.-H.; Walter, J.; Cleverley, K. E.;
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A.; Arlt, M.; Heinrich, T.; Böttcher, H.; Beller, M. Chem.
Eur. J. 2004, 10, 746. (b) Michalik, D.; Kumar, K.; Zapf,
A.; Tillack, A.; Arlt, M.; Heinrich, T.; Beller, M.
Tetrahedron Lett. 2004, 45, 2057. (c) Tewari, A.; Hein, M.;
Zapf, A.; Beller, M. Tetrahedron Lett. 2004, 45, 7703.
(d) Khedkar, V.; Tillack, A.; Michalik, M.; Beller, M.
Tetrahedron 2005, 61, 7622. (e) Neumann, H.; Strübing, D.;
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(10) For recent publications, see: (a) Gelalcha, F. G.; Anilkumar,
G.; Tse, M. K.; Brückner, A.; Beller, M. Chem. Eur. J. 2008,
14, 7687. (b) Bitterlich, B.; Schröder, K.; Tse, M. K.; Beller,
M. Eur. J. Org. Chem. 2008, 4867. (c) Gelalcha, F. G.;
Bitterlich, B.; Anilkumar, G.; Tse, M. K.; Beller, M. Angew.
Chem. 2007, 46, 7293. (d) Anilkumar, G.; Bitterlich, B.;
Gelalcha, F. G.; Tse, M. K.; Beller, M. Chem. Commun.
2007, 289. (e) Tse, M. K.; Bhor, S.; Klawonn, M.;
Anilkumar, G.; Jiao, H.; Döbler, C.; Spannenberg, A.;
Mägerlein, W.; Hugl, H.; Beller, M. Chem. Eur. J. 2006, 12,
1855. (f) Tse, M. K.; Bhor, S.; Klawonn, M.; Anilkumar, G.;
Jiao, H.; Spannenberg, A.; Döbler, C.; Mägerlein, W.; Hugl,
H.; Beller, M. Chem. Eur. J. 2006, 12, 1875. (g) Tse, M. K.;
Döbler, C.; Bhor, S.; Klawonn, M.; Mägerlein, W.; Hugl, H.;
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Jiao, H.; Gordes, D.; Beller, M.; Tse, M. K. J. Org. Chem.
2007, 72, 8847. (d) The use of these compounds as tools in
activity-based profiling is currently ongoing
Figure 2 Molecular structure of 9d; thermal ellipsoids correspond
to 30% probability18,19
The one exception was 2-furylboronic acid (Table 1, entry
9), which gave 6 in 75% yield. Efforts to elucidate the bi-
ological activity of these novel analogues are currently
underway.
In conclusion, we have developed a convenient method
for the synthesis of novel hybrid annulated analogues of
hymenialdsine (1) and stevansine (3) using a Suzuki-
coupling protocol.17
The strategy described is of particular significance for
providing a synthetic pathway for a diverse class of new
HMD kinase inhibitors and can be applied to other biolog-
ically interesting compounds.
Acknowledgment
The authors thank the Federal Ministry of Education and Research
(BMBF) and the German Research Foundation (DFG) for financial
support of this work. Dr. Anbarasan Pazhamalai and Dr. Benoit Join
are acknowledged for their valuable suggestions and discussions on
this topic. Dr. W. Baumann, Dr. C. Fischer, Mrs. M. Heyken, Mrs.
C. Mewes, Mrs. A. Lehmann, Mrs. S. Buchholz (all Leibniz Institut
für Katalyse e. V. an der Universität Rostock) are acknowledged for
their technical and analytical support.
(12) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104,
2127. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457.
(13) Tessier, P. E.; Nguyen, N.; Clay, M. D.; Fallis, A. G. Org.
Lett. 2005, 7, 767.
(14) Stang, P. J.; Fisk, T. E. Synthesis 1979, 438.
(15) Decomposition of compound 8 was observed on storage (~5 d).
(16) (a) Chacun-Lefèvre, L.; Joseph, B.; Mérour, J.-Y.
Tetrahedron 2000, 56, 4491. (b) Perron, J.; Joseph, B.;
Mérour, J.-Y. Tetrahedron 2003, 59, 6659. (c) Chacun-
Lefèvre, L.; Joseph, B.; Mérour, J.-Y. Synlett 2001, 848;
Note: Although this reference reports a similar kind of
approach, it suffers with the unprotected NH–CO–C–NH
backbone, which is critical for kinase inhibition.
(17) General procedure for the Suzuki coupling of 8 with aryl
boronic acids 9a–k: To a stirring mixture of 8 (600 mg, 1.1
mmol) in toluene (3 mL) and absolute EtOH (3 mL) under
an argon atmosphere, Pd(PPh3)4 (12.6 mg, 0.011 mmol),
boronic acid (1.2 mmol) and 2 M aq Na2CO3 solution (0.55
References and Notes
(1) (a) Bishop, A. C.; Ubersax, J. A.; Petsch, D. T.; Matheos,
D. P.; Gray, N. S.; Blethrow, J.; Shimizu, E.; Tsien, J. Z.;
Schultz, P. G.; Rose, M. D.; Wood, J. L.; Morgan, D. O.;
Shokat, K. M. Nature 2000, 407, 395. (b) Gray, N. S.
Science 1998, 281, 533.
(2) Cohen, P. Nat. Rev. Drug Discovery 2002, 1, 309.
(3) Bogoyevitch, M. A.; Fairlie, D. P. Drug Discovery Today
2007, 12, 622.
Synlett 2010, No. 2, 211–214 © Thieme Stuttgart · New York

214
N. Mangu et al.
LETTER
mL) were added. The mixture was heated at 70 °C overnight
(~12–16 h), then the solvent was removed under reduced
pressure and the mixture was extracted with CH2Cl2 (2 × 20
mL), the combined organic extracts were washed with brine
(25 mL), dried over MgSO4 and concentrated under reduced
pressure to give the crude product, which was used for the
deprotection step without further purification. The above
crude product was dissolved in anhydrous CH2Cl2 (50 mL)
and activated silica (2.46 g, 0.040–0.063 mm) was added.
The solvent was removed under reduced pressure and the
solid mixture was heated under argon at 100 °C for 1 h.
Purification by column chromatography (silica gel 70–230
mesh, hexane–EtOAc, 6:4) yielded pure compounds 9a–k.
Å, b = 100.003 (2)°; V = 1546.55 (8) Å3; Z = 4; rcalcd = 1.307
g·cm–3; 22763 reflections measured, 3292 independent
reflections, of which 2312 were observed [I >2s(I)], final R
indices [I >2s(I)]: R1 = 0.0306, wR2 = 0.0686, R indices (all
data): R1 = 0.0486, wR2 = 0.0715, 217 refined parameters.
Data were collected on a STOE IPDS II diffractometer using
graphite-monochromated MoKa radiation. The structure
was solved by direct methods (SHELXS-97)19 and refined
by full-matrix least-squares techniques on F2 (SHELXL-
97).19 XP (Bruker AXS) was used for graphical represen-
tation. CCDC 748111 contains the supplementary
crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(18) X-ray crystal data for 9d: Empirical formula: C19H16N2O2;
Mr = 304.34; monoclinic; space group: P21/c; cell
dimensions: a = 9.3756 (3), b = 6.5948 (2), c = 25.3990 (8)
(19) Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
Synlett 2010, No. 2, 211–214 © Thieme Stuttgart · New York

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