Synthetic studies towards the 2-aminopyrimidine alkaloids variolins and meridianins from marine origin

Article abstract of DOI:10.1016/S0040-4039(00)00728-0

A nine-step synthesis of 9-amino-4-methoxypyrido[3',2':4,5]pyrrolo[1,2- c]pyrimidine, a tricyclic ring system present in the marine alkaloids variolins is described. The natural marine products meridianins C-E have been synthesized for the first time starting from N-protected 3-acylindoles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00728-0

Tetrahedron Letters 41 (2000) 4777±4780
Synthetic studies towards the 2-aminopyrimidine alkaloids
variolins and meridianins from marine origin
Pilar M. Fresneda,* Pedro Molina,* Santiago Delgado and Juan A. Bleda
Â
Departamento de Quõmica Organica, Facultad de Quõmica, Universidad de Murcia, Campus de Espinardo,
Â
Â
E-30071, Murcia, Spain
Received 22 March 2000; accepted 4 May 2000
Abstract
A nine-step synthesis of 9-amino-4-methoxypyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine, a tricyclic ring sys-
tem present in the marine alkaloids variolins is described. The natural marine products meridianins C±E
have been synthesized for the ®rst time starting from N-protected 3-acylindoles. # 2000 Elsevier Science
Ltd. All rights reserved.
Keywords: phosphine imines; natural products; sponges; indolization; pyrimidines.
Certain secondary metabolites of marine organisms are nontraditional guanidine-based
alkaloids1 that possess a broad spectrum of powerful biological activities. The guanidine moiety
is frequently found in the guise of an 2-aminoimidazol ring2 or a 2-aminopyrimidine ring.3
In 1994, Blunt and Munro reported the structure of variolins which were isolated from the
Antarctic sponge Kirkpatrickia varialosa.4 These alkaloids were isolated after the examination of
extracts which were shown to be active against P388 murine leukemia cells. Subsequently,
variolin B was found to be the most active in tests which included antiviral activity (Herpes
simplex type I, polio type I).
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00728-0

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This new class of alkaloids is also interesting from both the structural and biogenetic points of
view as the variolins are unique in their structural features; they represent the ®rst example of
natural products with a pyridopyrrolopyrimidine ring, strictly a pyrido[30,20:4,5] pyrrolo[1,2-
c]pyrimidine. There is only one report dealing with the preparation of a thio-functionalized
derivative of this ring system.5
In connection with our synthetic e€orts on the synthesis of alkaloids from a marine origin,6 we
became interested in the synthesis of the family of variolins and of the closely related meridianins.
A recent report7 dealing with the preparation of 3-heteroaryl-7-azaindoles prompted us to report
our own results on the synthesis of the appropriately substituted pyridopyrrolo pyrimidine ring
system and the ®rst synthesis of meridianins C±E.
The ortho-lithiation of 4-methoxypyridine using mesityllithium as the metalating base8
followed by reaction with N,N-dimethylformamide gave a 77% of 3-formyl-4-methoxypyridine 1.
Condensation of 1 with ethyl azidoacetate in the presence of NaOEt at ^15ꢀC provided the
vinylazide 2 in 61% yield. When compound 2 was exposed to heat in o-xylene at re¯ux temperature
for a short time, indolization took place by a nitrene insertion process to give the key intermediate
7-azaindole 3 in 67% yield.
The next task was to e€ect a pyrimido annelation which allows incorporation of the amine
functionality, necessary for the preparation of the natural product, in the pyrimidine ring. Taking
into account that the tandem aza-Wittig/heterocumulene-mediated ring-closure has been
successfully applied to the synthesis of fused pyrimidines,9 we decided to apply this methodology
to build up the target tricyclic ring system. To this end, we required the 2-formyl-7-azaindole 7,
which was prepared from 3 by the following sequence: reduction with AlLiH4/THF gave 5 in
93% yield which in turn was converted into 7 in 60% yield by reaction with MnO2. However, in
the reaction of 7 with ethyl azidoacetate under basic conditions, only numerous intractable
decomposition products were formed. Therefore, we examined the same type of sequence of
reactions, although we decided to protect the 7-azaindole ring prior to reduction/oxidation. The
best results were obtained by the following three-step sequence: (a) N-SEM protection of 3 under
standard conditions provided 4 in 94% yield: (b) reduction with AlLiH4 in THF at re¯ux tem-
perature gave 6 in 93% yield; and (c) oxidation with MnO2 in CH2Cl2 at room temperature
a€orded 8 in 86% yield.
Condensation of N-SEM-protected 2-formyl-7-azaindole 8 with ethyl azidoacetate under the
same conditions used for the preparation of 2 furnished the vinylazide 9 in 76% yield. The
Staudinger reaction of 9 with triphenylphosphine in dry CH2Cl2 at room temperature gave the
expected iminophosphorane derivative 10 in 82% yield. Treatment of the N-SEM-protected 7-
azaindole 10 with tetrabutylammonium ¯uoride (TBAF)-SiO2 under microwave heating for 1 min
proved advantageous and cleanly removed the SEM group to give 11 in 70% yield, without
a€ecting the iminophosphorane group. The use of TBAF/THF as deprotecting agent resulted
even after an extended reaction time in a low yield of 11 with a considerable amount of the
product derived from the hydrolytic cleavage of the iminophosphorane moiety. Aza-Wittig
reactions of iminophosphorane 11 with several aromatic isocyanates and ethoxycarbonyl
isothiocyanate in dry THF at room temperature directly gave the desired pyrimido annelation
products 12 in yields higher than 90%, thus completing the tricyclic pyridopyrrolopyrimidine ring
of the variolins bearing suitable functionalities for the preparation of the natural products10
(Scheme 1).
As far as the construction of the second 2-aminopyrimidine ring is concerned, we have
performed the synthesis of 3-(2-aminopyrimidin-4-yl)indoles in a parallel study. This method has

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Scheme 1. Reagents and conditions: (a) N3CH2COOEt, NaEtO, EtOH, ^15ꢀC, 2 (61%), 9 (76%); (b) o-xylene, re¯ux
(67%); (c) NaH, DMF, SEMCl (94%); (d) AlLiH4, THF, re¯ux, 5 (93%), 6 (93%); (e) MnO2, CH2Cl2, rt, 7 (60%), 8
(86%); (f) Ph3P, CH2Cl2, rt (82%); (g) TBAF±SiO2, THF, MW (70%); (h) RNCO, THF, rt (90%)
been successfully applied for the synthesis of the alkaloids meridianins isolated from the tunicate
Aplidinium meridianum, which show cytotoxicity towards murine tumor cell lines.3 As shown in
Scheme 2, the synthesis of these alkaloids was realized through a four-step procedure.
Scheme 2. Reagents and conditions: (a) DMF±DMA, DMF, 110ꢀC, 14a (74%), 14b (83%), 14c (41%); (b)
.
H2N(ˆNH)NH2 HCl, 2-methoxyethanol, K2CO3, 15a (72%), 15b (78%), 15c (82%); (c) H2, Pd/C 10%, EtOH (88%)
N-Tosyl-3-acylindoles 13 were used for the construction of the 2-aminopyrimidine ring. The
best results for the preparation of 13a and 13b were obtained when the corresponding brominated
indole11 was N-protected by the p-toluenesulfonyl group (90±94%) and then acylated with acetyl
chloride in the presence of SnCl4 (80±85%). However, the preparation of 13c was carried out by
an initial acylation of the 4-benzyloxy-7-bromoindole (89%) followed by N-protection (55%).
When compounds 13 were treated with dimethylformamide dimethylacetal in DMF at 110ꢀC the
corresponding enaminones 14 were obtained in yields ranging from 41 to 83%. Direct conversion

4780
of 14a and 14b into 15a meridianin C and 15b meridianin D, which involves formation of the
2-aminopyrimidine ring and N-tosyl deprotection, was achieved in 72±78% yield in one step by
treatment with guanidine chlorohydrate in the presence of anhydrous Na2CO3.12 Meridianin E
was obtained in a straightforward manner from 15c by standard O-benzyl deprotection (H2, Pd/C)
(Scheme 2).
In conclusion, we have developed a new approach to the synthesis (nine steps) of the
appropriately substituted pyrido[30,20:4,5]pyrrolo[1,2-c]pyrimidine ring system present in the
marine alkaloids variolins, and the ®rst synthesis of the alkaloids meridianins starting from
N-protected 3-acylindoles.
Acknowledgements
We gratefully acknowledge the ®nancial support of the Direccion General de Investigacion
Cientõ®ca y Tecnica (PB95-1019). S.D. thanks the `Fundacion Seneca' (CARM) for a studentship.
References
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Biorganic Marine Chemistry; Scheuer, P. J., Ed.; Springer: Berlin, 1992; Vol 6, pp. 158±248.
2. Molina, P.; Fresneda, P. M.; Sanz, M. A. J. Org. Chem. 1999, 64, 2540±2544, and references cited therein.
3. Franco, I. H.; Jo€e, E. B. K.; Puricelli, L.; Tatian, M.; Seldes, A. M.; Palermo, J. A. J. Nat. Prod. 1998, 61, 1130±
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7. Alvarez, M.; Fernandez, D.; Joule, J. Synthesis 1999, 615-620.
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1
10. Spectroscopy data for 12 (R=4-CH3C6H4). H NMR (300 MHz, CDCl3) ꢀ 1.47 (t, 3H, J=6.9 Hz, CH3CH2O),
2.36 (s, 3H, CH3-Ar), 4.0 (s, 3H, CH3O), 4.43 (q, 2H, J=6.9 Hz, CH3CH2O), 6.7 (s, 1H, H-5), 6.72 (d, 1H, J=5.7
Hz, H-7), 7.21 (d, 2H, J=8.1 Hz, Hm), 7.65 (s, 1H, H-4), 7.96 (d, 2H, J=8.1 Hz, Ho), 8.25 (d, 1H, J=5.7 Hz,
H-8), 11.87 (s, 1H, NH). 13C NMR (75 MHz, CDCl3) ꢀ 14.3 (CH3CH2O), 20.8 (CH3-Ar), 55.7 (CH3O), 61.2
(CH3CH2O), 91.7 (C-5), 100.4 (C-7), 107.4 (C-4), 114.4 (C-5a), 120.1 (Co), 129.4 (Cm), 132.6 (Cp), 134.1 (C-4a),
136.2 (C-3), 136.3 (Ci), 142.7 (C-8), 143.5 (C-9a), 144.4 (C-1), 159.4 (C-6), 165.6 (COOEt). IR (nujol) ꢁ 3300 (m),
1715 (s), 1636 (m), 1605 (s) cm^1. Anal. calcd for C21H20N4O3: C, 67.01; H, 5.36; N, 14.88. Found: C, 66.94; H,
5.43; N, 14.75.
11. The previously unreported 4-benzyloxy-7-bromoindole was prepared from 5-bromo-2-hydroxybenzaldehyde by
the following ®ve-step sequence: (a) O-benzyl protection with benzyl bromide in the presence of HNa (96%); (b)
condensation with ethyl azidoacetate (75%); (c) indolization by heating in toluene at re¯ux temperature (66%); (d)
hydrolysis of the ester group with LiOH/THF/H2O (100%); (e) decarboxylation by heating at 230ꢀC in quinoline
in the presence of copper (72%).
12. The spectroscopic data for the meridianins C±E were identical to those reported3 for the natural products.