A concise synthesis of meridianin F

Article abstract of DOI:10.1016/j.tetlet.2011.06.073

A concise synthesis of the protein kinase inhibitor meridianin F has been achieved in good overall yield starting from 5,6-dibromoindole-3-carbaldehyde.

Full text of DOI:10.1016/j.tetlet.2011.06.073

Tetrahedron Letters 52 (2011) 4537–4538
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A concise synthesis of meridianin F
Jonathan Sperry
School of Chemical Sciences, University of Auckland, 23 Symonds Street, Auckland, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
A concise synthesis of the protein kinase inhibitor meridianin F has been achieved in good overall yield
starting from 5,6-dibromoindole-3-carbaldehyde.
Received 17 May 2011
Revised 9 June 2011
Accepted 17 June 2011
Available online 2 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
5,6-Dibromoindole
Meridianin
Alkaloid
Natural product
Protein kinase
Meridianins A–G (1–7) are a family of alkaloids isolated from
the south Atlantic tunicate Aplidium meridianum.1 These natural
products all possess a molecular architecture comprising an indole
substituted at C3 with a 2-aminopyrimidine ring. Furthermore, the
meridianins have been shown to display varying degrees of protein
kinase inhibition, with some derivatives also demonstrating anti-
tumour activity (Fig. 1).1,2
Due to the unique structure and potent biological activity of the
meridianin family of natural products, synthetic studies have been
readily forthcoming from several groups. Numerous syntheses of
members of the family exist,3,5 as well as syntheses of several ana-
logues4,5 that emphasize the importance of this class of com-
pounds as potential leads in cancer chemotherapy.
meridianin F (6)7a prompts us to disclose our own efforts in this
field.
Meridianin F (6) is the only member of the family to possess the
rare 5,6-dibromoindole moiety, which appears to be partly respon-
sible for its low micromolar inhibition of several protein kinases.1b
For these reasons, and intrigued that meridianin F (6) is a minor
component not originally detected in the extracts of A. meridia-
num,1a,c we decided to initiate the synthesis of meridianin F (6).
The retrosynthesis of meridianin F (6) is shown in Scheme 1.
We planned to use the well-established Bredereck 2-aminopyrim-
idine synthesis3b,8 between enaminone 8 and guanidine followed
by N-debenzylation. The enaminone 8 was to be accessed by reac-
Our laboratory has an ongoing interest in alkaloids bearing unu-
sual halogenation patterns that have subsequently led to the first
syntheses of several natural products possessing the rare 5,6-dib-
romoindole moiety.6 The unusual bromination pattern was
installed using an historic dibromination of an indole-3-carboxyl-
ate,6 a result that was simultaneously reported by Grainger and
co-workers.7a Until these reports, synthetic studies towards com-
pounds possessing the 5,6-dibromoindole moiety were sparse
and the desired materials were often only obtained as unwanted
by-products. In a recent development, Mollica et al. have reported
the first asymmetric route to a 5,6-dibromotryptophan derivative
that relies on the selective monobromination of 6-bromoisatin fol-
lowed by reduction to 5,6-dibromoindole,7b thus providing a
valuable addition to current methods available for the synthesis
of this heterocyclic moiety. Furthermore, the aforementioned re-
port by Grainger and co-workers describing the first synthesis of
H2N
N
N
R1
R2
3
R3
N
H
R4
meridianin A (1) R1 = OH, R2 = R3 = R4 = H
meridianin B (2) R1 = OH, R2 = R4 = H, R3 = Br
meridianin C ( ) R1 = R3 = R4 = H, R2 = Br
3
meridianin D (4) R1 = R2 = R4 = H, R3 = Br
meridianin E (5) R1 = R2 = R3 = H, R4 = Br
meridianin F (6) R1 = R4 = H, R2 = R3 = Br
meridianin G (7)
R
1 = R2 = R3 = R4 = H
E-mail address: j.sperry@auckland.ac.nz
Figure 1. Meridianins A–G.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.073

4538
J. Sperry / Tetrahedron Letters 52 (2011) 4537–4538
hydrogenation conditions resulted in a significant amount of
HN
H2N
debromination, a result noted previously when attempting hydro-
genation on 5,6-dibromoindoles.6 However, treatment of 11 with
potassium tert-butoxide in DMSO under an atmosphere of oxygen9
effected swift N-debenzylation, gratifyingly delivering meridianin
F in excellent yield (Scheme 2). The spectroscopic data of synthetic
meridianin F (6) were identical to those of the natural product.1c,10
In conclusion, we have completed a concise synthesis of the
protein kinase inhibitor meridianin F, an alkaloid possessing the
rare 5,6-dibromoindole moiety. The synthetic route proceeds in
good overall yield and each step is readily scalable.
H2N
NH2
N
NMe2
i. Bredereck
2-aminopyrimidine
synthesis
N
O
Br
Br
ii. N-debenzylation
Br
Br
N
N
H
Bn
8
6
DMF-DMA
O
i. N-benzylation
ii. Grignard
iii. [O]
CHO
Acknowledgment
Br
Br
Br
Br
The University of Auckland is acknowledged for financial sup-
port (Project No. 3625886).
N
N
H
Bn
9
10
Scheme 1. Retrosynthesis of meridianin F.
Supplementary data
Supplementary data (experimental details for the preparation
of meridianin F (6), along with relevant spectra) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.06.073.
i) NaH, BnBr
THF, r.t., 2 h
O
ii) MeMgBr, THF
CHO
0 °C-r.t, 20 min
iii) IBX, DMSO
50 ºC, 1 h
Br
Br
Br
Br
References and notes
71%
(3 steps)
N
N
Bn
H
9
1. (a) Hernández Franco, L.; Bal De Kier Joffé, E.; Puricelly, L.; Tatian, M.; Seldes, A.
M.; Palermo, J. A. J. Nat. Prod. 1998, 61, 1130; (b) Gompel, M.; Leost, M.; Bal De
Kier Joffé, E.; Puricelli, L.; Hernández Franco, L.; Palermo, J.; Meijer, L. Bioorg.
Med. Chem. Lett. 2004, 14, 1703; (c) Seldes, A. M.; Brasco, M. F. R.; Hernández
Franco, L.; Palermo, J. A. Nat. Prod. Res. 2007, 21, 555.
2. (a) Radwan, M. A. A.; El-Sherbiny, M. Bioorg. Med. Chem. 2007, 15, 1206; (b)
Jiang, B.; Yang, C.-G.; Xiong, W.-N.; Wang, J. Bioorg. Med. Chem. 2001, 9, 1149;
(c) Akue-Gedu, R.; Debiton, E.; Ferandin, Y.; Meijer, L.; Prudhomme, M.; Anizon,
F.; Moreau, P. Bioorg. Med. Chem. 2009, 17, 4420; (d) Rossignol, E.; Debiton, E.;
Fabbro, D.; Moreau, P.; Prudhomme, M.; Anizon, F. Anti-Cancer Drugs 2008, 19,
789.
3. For syntheses of the meridianins, see: Meridianin D: (a) Jiang, B.; Yang, C.-Y.
Heterocycles 2000, 53, 1489; Meridianins A and C–E: (b) Fresneda, P. M.;
Molina, P.; Delgado, S.; Bleda, J. A. Tetrahedron Lett. 2000, 41, 4777; (c)
Fresneda, P. M.; Molina, P.; Bleda, J. A. Tetrahedron 2001, 57, 2355; Meridianins
C, D and G: (d) Karpov, A. S.; Merkul, E.; Rominger, F.; Müller, T. J. J. Angew.
Chem., Int. Ed. 2005, 44, 6951; Meridianins C and G: (e) Tibiletti, F.; Simonetti,
M.; Nicholas, K. M.; Palmisano, G.; Parravicini, M.; Imbesi, F.; Tollari, S.; Penoni,
A. Tetrahedron 2010, 66, 1280.
10
i) DMF-DMA
DMF, reflux, 8 h
ii) Guanidine.HCl
K2CO3, EtOH
reflux, 36 h
53%
(2 steps)
H2N
H2N
N
N
, KOtBu
DMSO
N
N
O2
Br
Br
Br
Br
r.t., 15 min
88%
N
N
Bn
H
11
meridianin F 6
4. (a) Yu, H.; Yu, Z. Angew. Chem., Int. Ed. 2009, 48, 2929; (b) Rossignol, E.; Youssef,
A.; Moreau, P.; Prudhomme, M.; Anizon, F. Tetrahedron 2007, 63, 10169; (c)
Simon, G.; Couthon-Gourves, H.; Haelters, J.-P.; Corbel, B.; Kervarec, N.;
Michaud, F.; Meijer, L. J. Heterocycl. Chem. 2007, 44, 793; (d) Jakse, R.; Svete,
J.; Stanovnik, B.; Golobic, A. Tetrahedron 2004, 60, 4601; (e) Casar, Z.; Bevk, D.;
Svete, J.; Stanovnik, B. Tetrahedron 2005, 61, 7508; (f) Stanovnik, B.; Svete, J.
Mini-Rev. Org. Chem. 2005, 2, 211; (g) Hernández Franco, L.; Palermo, J. A. Chem.
Pharm. Bull. 2003, 51, 975.
5. For an excellent review on the isolation, biological activity and synthesis of the
variolin and meridianin family of alkaloids, see: Walker, S. R.; Carter, E. J.; Huff,
B. C.; Morris, J. C. Chem. Rev. 2009, 109, 3080.
6. (a) Boyd, E. M.; Sperry, J. Synlett 2011, 826; (b) Sperry, J. Tetrahedron Lett. 2011,
52, 4042.
7. (a) Parsons, T. B.; Ghellamallah, C.; Male, L.; Spencer, N.; Grainger, R. S. Org.
Biomol. Chem. 2011, 9, 5021; (b) Mollica, A.; Stefanucci, A.; Feliciani, F.; Lucente,
G.; Pinnen, F. Tetrahedron Lett. 2011, 52, 2583.
8. Bredereck, H.; Effenberger, F.; Botsch, H.; Rehn, H. Chem. Ber. 1965, 98, 1081.
9. Haddach, A. A.; Kelleman, A.; Rewolinski-Deaton, M. V. Tetrahedron Lett. 2002,
43, 399.
Scheme 2. Synthesis of meridianin F.
tion of dimethylformamide dimethylacetal with the 3-acetylindole
9, which in turn was envisioned to be readily available from 5,6-di-
bromo-3-carbaldehyde 106 by N-benzylation followed by Grignard
reaction and oxidation.
With multigram quantities of 5,6-dibromoindole-3-carbalde-
hyde 10 at hand,6 straightforward benzylation, Grignard reaction
with methylmagnesium bromide and oxidation with iodoxyben-
zoic acid (IBX) gave the key intermediate 9 in excellent yield over
three steps (from 10) which only involved a single purification
operation. Next, 3-acetylindole 9 underwent smooth enaminone
formation followed by immediate treatment with guanidine
hydrochloride in the presence of potassium carbonate, gratifyingly
affording N-benzyl meridianin F (11). Finally, the pivotal N-
debenzylation was attempted. Somewhat unsurprisingly, various
10. See Supplementary data for full details.