First synthesis of parazoanthine-A and its O-Me derivative

Article abstract of DOI:10.1016/j.tetlet.2012.10.066

Parazoanthine A (7.0% overall yield) and its O-methyl derivative (6.2% overall yield) were prepared by a concise biomimetic synthesis based on the coupling reaction of l-arginine methyl ester dihydrochloride with isocyanate derivatives of p-coumaric acid and 4-methoxy-cinnamic acid, respectively. The synthetic approach is designed to obtain a wider class of parazoanthine analogs.

Full text of DOI:10.1016/j.tetlet.2012.10.066

Tetrahedron Letters 53 (2012) 7083–7084
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Tetrahedron Letters
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First synthesis of parazoanthine-A and its O-Me derivative
⇑
Emiliano Manzo , Dario Pagano, Genoveffa Nuzzo, Margherita Gavagnin, Maria Letizia Ciavatta
Istituto di Chimica Biomolecolare, CNR, Via Campi Flegrei 34, I 80078-Pozzuoli (Na), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Parazoanthine A (7.0% overall yield) and its O-methyl derivative (6.2% overall yield) were prepared by a
Received 11 September 2012
Revised 12 October 2012
Accepted 17 October 2012
Available online 24 October 2012
concise biomimetic synthesis based on the coupling reaction of L-arginine methyl ester dihydrochloride
with isocyanate derivatives of p-coumaric acid and 4-methoxy-cinnamic acid, respectively. The synthetic
approach is designed to obtain a wider class of parazoanthine analogs.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Parazoanthine
Hydantoin
Chemical synthesis
O
Parazoanthines are a group of unique naturally-occurring mar-
ine alkaloids reported to date only from the Mediterranean sea
anemone Parazoanthus axinellae.1 These molecules exhibit the
chemical framework characterized by the presence of a 3,5-alkyl
disubstituted hydantoin core bearing a terminal guanidine and
an aromatic ring. Even though hydantoins and derivatives have
been widely used in biological screenings in numerous pharma-
ceutical applications including convulsants2 and antimuscarinics,3
antiulcers and antiarrythmics,4 antivirals, antidiabetics,5 serotonin
and fibrinogen receptor antagonists,6 inhibitors of the glycine
binding site of the NMDA receptor,7 and antagonists of leukocyte
cell adhesion,8 no relevant biological activity has been evidenced
for parazoanthines.1 With the aim of getting natural parazoanth-
ines along with the new derivatives to be used in biological screen-
ing programs, we started with the chemical synthesis of the first
member of the group, parazoanthine A (1) and a concurrent inves-
tigation of a sample of P. axinellae.9
NH
H
3
6
10
N
H
NH2
N
5
17
15
13
NH
O
RO
1, R=H
2, R=Me
Figure 1. Parazoanthine A (1) and its O-Me derivative (2).
triphenylphosphine, and trichloroacetonitrile in acetonitrile11 to
give the corresponding intermediate azide derivatives 5 and 5a.
The subsequent Curtius rearrangement of 5 and 5a in toluene at
68 °C overnight12 led to the isocyanates 3 and 3a, respectively,
which were freshly used due to their instability.
In Stilz et al. procedure10 the use of N-ethylmorpholine in DMF
led to the formation of an urea derivative which was cyclized to
give the hydantoin framework only by the subsequent treatment
with 6 N HCl under reflux. We observed that in our case the forma-
tion of the hydantoin moiety just occurred after the treatment with
N-ethylmorpholine in DMF (Fig. 2) whereas the following use of
6 N HCl revealed to be disadvantageous because of the formation
of a complex mixture of products. Thus, this step was not consid-
ered in our synthetic scheme.
Here we report a simple biomimetic strategy for the synthesis
of parazoanthine A (1). The corresponding O-Me derivative (2),
not previously reported, but detected as the minor component of
parazoanthine mixture,9 was also prepared (Fig. 1).
The key-step of the strategy was the coupling reaction (Fig. 2)
between the commercially available -arginine methyl ester dihy-
L
drochloride and the opportunely prepared isocyanates 3 and 3a,
by using N-ethylmorpholine in N,N-dimethylformamide according
to Stilz et al.10
The preparation of compounds 3 and 3a is illustrated in
Figure 3. Commercially available p-coumaric acid (4) and
4-methoxy-cinnamic acid (4a) were treated with sodium azide,
In the coupling reaction (Fig. 2) the obtained yields were quite
low if compared to those reported by Stilz et al. (Ref. 10). This
was probably due to the less nucleophilic reactivity of the isocya-
nate nitrogen atom being this functional conjugated to the double
bond. However, with the aim at improving the yields, different
experimental conditions in the coupling step were used. In
particular, the temperature was varied in the range of 20–60 °C,
distinct solvents including DMF, DMSO, and THF were used, and
N-ethylmorpholine was added in the range of 1–3 equiv.
⇑
Corresponding author. Tel.: +39 0818675310; fax: +39 0818041770.
E-mail address: emanzo@icb.cnr.it (E. Manzo).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.066

7084
E. Manzo et al. / Tetrahedron Letters 53 (2012) 7083–7084
NCO
O
NH
H
N-ethylmorpholine-DMF
RO
N
H
NH2
N
0°C / 1h - r.t. / 5h
3, R=H
NH
3a, R=Me
O
RO
1, R=H, 11%
NH
NH2
H
2, R=Me, 10%
MeOOC
N
H
2 HCl
NH2
Figure 2. Coupling reaction to get parazoanthine A (1) and the O-Me analog (2).
NaN3-Cl3CCN
COOH
CON3
NCO
PPh3
Toluene
68°C/overnight
CH3CN
r.t / 2h
RO
RO
RO
3, R=H 78%
4, R=H
5, R=H 81%
5a, R=Me 78%
3a, R=Me 79%
4a, R=Me
Figure 3. Preparation of synthetic isocyanate precursors of parazoanthine A and its O-Me-analog.
Compounds 1 and 2 were obtained in the best yield of 11% and 10%,
respectively, by carrying out the reaction at rt, in DMF, and with
1.2 equiv of N-ethylmorpholine. The C-5 chirality was preserved
by the coupling reaction.
The spectral data of synthetic parazoanthine A (1) were identi-
cal to those of natural compound.1 O-Me parazoanthine A (2)
showed 1H and 13C NMR spectroscopic data similar to parazoan-
thine A differing only in the presence of the methoxy group on
the aromatic ring instead of the hydroxyl function (see Supplemen-
tary Supporting Information).
References and notes
1. Cachet, N.; Genta-Jouve, G.; Regalado, E. L.; Mokrini, R.; Amade, P.; Culioli, G.;
Thomas, O. P. J. Nat. Prod. 2009, 72, 1612–1615.
2. Thenmozhiyal, J. C.; Wong, P. T. H.; Chui, W. K. J. Med. Chem. 2004, 47, 1527–
1535.
3. (a) Bazil, C. W.; Pedley, T. A. Annu. Rev. Med. 1998, 49, 135–162; (b) Luer, M. S.
Neurol. Res. 1998, 20, 178–182.
4. (a) Matsukura, M.; Daiku, Y.; Ueda, K.; Tanaka, S.; Igarashi, T.; Minami, N. Chem.
Phar. Bull. 1992, 40, 1823–1827; (b) Knabe, J.; Baldauf, J.; Ahlhelm, A. Pharmazie
1997, 52, 912–919.
5. Somsak, L.; Kovacs, L.; Toth, M.; Osz, E.; Szilagyi, L.; Gyorgy-deak, Z.; Dinya, Z.;
Docsa, T.; Toth, B.; Gergely, P. J. Med. Chem. 2001, 44, 2843–2848.
6. (a) Moloney, G. P.; Robertson, A. D.; Martin, G. R.; MacLennan, S.; Mathews, N.;
Dosworth, S.; Sang, P. Y.; Knight, C.; Glen, R. J. Med. Chem. 1997, 40, 2347–2362;
(b) Moloney, G. P.; Martin, G. R.; Mathews, N.; Milne, A.; Hobbs, H.; Dosworth,
S.; Sang, P. Y.; Knight, C.; Williams, M.; Maxwell, M.; Glen, R. J. Med. Chem. 1999,
42, 2504–2526.
This is the first synthetic strategy of a member of parazoanthine
class that could open the way for the preparation of other natural
and not natural analogs.
Acknowledgments
7. Jansen, M.; Potschka, H.; Brandt, C.; Loscher, W.; Dannhardt, G. J. Med. Chem.
2003, 46, 64–73.
8. Last-Barney, K.; Davidson, W.; Cardozo, M.; Frye, L. L.; Grygon, C. A.; Hopkins, J.
L.; Jeanfavre, D. D.; Pav, S.; Qian, C.; Stevenson, J. M.; Tong, L.; Zindel, R.; Kelly,
T. A. J. Am. Chem. Soc. 2001, 123, 5643–5650.
9. A sample of P. axinellae, collected off greek coasts, was chemically analysed, in
the frame of a collaborative project with Professor V. Roussis (University of
Athens). The results of this study will be published elsewhere.
10. Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klingler, O.; Konig, W.; Wehner, V.;
Zoller, G. J. Med. Chem. 2001, 44, 1158–1176.
The authors thank Mr. Alessandro Esposito of ICB-NMR service,
M. Zampa of ‘Servizio di Spettrometria di Massa’ for HRESIMS, and
C. Iodice for spectrophotometric measurements. This work was
partially funded by PRIN-MIUR 2009 Project ‘Prodotti naturali da
molluschi opistobranchi: identificazione di nuovi lead compounds
per lo sviluppo di farmaci antitumorali’.
11. Kim, J. G.; Jang, D. O. Synlett 2008, 2072–2074.
12. Marinescu, L.; Thinggaard, J.; Thomsen, I. B.; Bols, M. J. Org. Chem. 2003, 68,
9453–9455.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
10.066.