Synthesis of visoltricin and fungerin: Imidazole derivatives of Fusarium sp.

Article abstract of DOI:10.1016/S0040-4039(02)00298-8

The synthesis of two imidazole derivatives of Fusarium sp. is described. 3-[1-Methyl-4-(3-methyl-2-butenyl)-1H-imidazol-5-yl]-2(E)-propenoic acid methylester was synthesized for the first time and spectroscopic data showed differences to the reported data

Full text of DOI:10.1016/S0040-4039(02)00298-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2375–2376
Synthesis of visoltricin and fungerin: imidazole derivatives of
Fusarium sp.
Johann M. Rieder and Johann Lepschy*
Bayerische Landesanstalt f u¨ r Bodenkultur und Pflanzenbau, V o¨ ttingerstr. 38, 85354 Freising, Germany
Received 3 January 2002; accepted 5 February 2002
Abstract—The synthesis of two imidazole derivatives of Fusarium sp. is described. 3-[1-Methyl-4-(3-methyl-2-butenyl)-1H-imida-
zol-5-yl]-2(E)-propenoic acid methylester was synthesized for the first time and spectroscopic data showed differences to the
reported data. Naturally occurring visoltricin proved to be identical to fungerin and the structure of visoltricin is revised. © 2002
Elsevier Science Ltd. All rights reserved.
Visoltricin is reported to be an active metabolite pro-
duced by Fusarium tricinctum. It is toxic in Artemia
salina test, cytotoxic against human tumor cell lines and
et al. the final N-methylating step with NaH/MeJ in
THF yielded 2 in 96%, without producing the isomer 1.
This result needed further investigation. A first attempt
in THF produced the expected mixture of 2 and 1 in a
mass ratio of 10:1, after separation on reversed phase
1
shows a miotic effect on rabbit eyes caused in parts by
2
the anticholinesterase activity of visoltricin. Its struc-
ture was elucidated by spectroscopic means and was
6
HPLC. Using acetonitrile as solvent the mass ratio
suggested to be 3-[1-methyl-4-(3-methyl-2-butenyl)-1H-
7
could be shifted in favour of 1 to 4:1 (Scheme 1), albeit
3
imidazol-5-yl]-2(E)-propenoic
according to structure 1.
acid
methylester,
the yield was only moderate.
To confirm the correct position of the two side chains
in 1, H– N HMBC technique was used (Fig. 1). The
Independently fungerin 2 was isolated from a strain of
Fusarium sp. with good antifungal activity against Peni-
cillium chrysogenum, Colletotrichum langenarium,
Alternaria mali and Pyricularia oryzae. Fungerin was
established as 3-[1-methyl-5-(3-methyl-2-butenyl)-1H-
1
15
8
N-methyl (N-1) l 159.1 was correlated with the H-2 of
N
the imidazole ring at lH 7.40, the N-methyl protons at
lH 3.66 and showed long-range correlation with H-3% at
4
lH 7.58. The second N of the imidazole ring (N-3) at l
imidazol-4-yl]-2(E)-propenoic acid methylester.
N
2
60.3 correlated with H-2 and H-4% at lH 3.38. The
chemical shifts in fungerin for N-1 and N-3 are
reported to be l 142.3 and 228.8 referred to
Synthesis of 1 and 2 was performed using a modified
procedure by Benhida et al. who recently presented the
N
5
15
first synthesis of fungerin. In the protocol of Benhida
NH NO in DMSO-d .
4
3
6
O
O
8
'
2
'
O Me
1' O Me
4
'
N
N
N
1
4
N 4 3'
a
6'
5
3'
'
7'
7'
+
1
5'
6'
N 5
N 5
4
'
H
Me
Me
1
' O Me
2'
8'
3
1 O
2
Scheme 1. Reagents and conditions: (a) NaH, MeI, MeCN, rt, 15 min (46% 2, 12% 1).
Keywords: antifungals; natural products; imidazole; visoltricin; fungerin.
*
Corresponding author. Tel.: +00498161713978; fax: +00498161714407; e-mail: johann.lepschy@lbp.bayern.de
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00298-8

2
376
J. M. Rieder, J. Lepschy / Tetrahedron Letters 43 (2002) 2375–2376
1
15
Figure 1. H– N HMBC spectrum of 1.
Figure 2. MS (EI, 70 eV) of 1 (top) and 2 (bottom).
Large differences in the chemical shifts were also
Institute of Physical and Chemical Research, Wako,
Japan for a sample of fungerin. We are grateful to Dr.
R. Haessner, TU M u¨ nchen for NMR measurements.
1
3
observed in the C NMR for the annular tautomeric
C-atoms of the imidazole ring, which were reported to
4
be lC 134.14 (C-4), lC 134.18 (C-5) for fungerin and
3
l 134.3 (C-4), l 134.2 (C-5) for visoltricin. The shifts
C
C
of C-4 and C-5 in 1 appeared at lC 147.43 and lC
20.63 and were remarkably different from the values
in fungerin, which resonance accidentally at nearly the
same frequency.
References
1
1. Visconti, A.; Solfrizzo, M. Ital. Pat. 022630, reg. A, Dec.
1989.
2
. Visconti, A.; Solfrizzo, M. Food Add. Cont. 1995, 12,
515–519.
9
1
and 2 could also be distinguished by GC and by the
fragmentation pattern of their MS. 1 showed a base
3. Visconti, A.; Solfrizzo, M. J. Agric. Food Chem. 1994, 42,
195–199.
4. Kato, Y.; Koshino, H.; Uzawa, J.; Anzai, K. Biosci.
Biotech. Biochem. 1996, 60, 2081–2083.
+
+
peak at m/z 175 [M+H−MeOH−CO] and the [M+H]
peak had a relative intensity of 65%. Minor characteris-
tic peaks appeared at m/z (rel. intensity) 219 (25)
+
+
[
M−Me] and m/z 203(5) [M+H−MeOH] . In contrast,
5. Benhida, R.; Lezama, R.; Fourrey, J.-L. Tetrahedron Lett.
the base peak in 2 was the molecular peak at m/z 235
1998, 39, 5963–5964.
+
[
M+H] and prominent peaks were m/z 202 (60) [M−
6. Kromasil C18, 5m, 250×20 mm, precolumn Kromasil C18,
10m, 50×20 mm, 60% aq. MeOH, 20 ml/min, retention
times: 1 17.0 min, 2 12.6 min.
+
+
MeOH] , m/z 187 (15) [M−MeOH−Me] , m/z 173 (40)
+
[
M−MeOH−Me−CH ] and m/z 159 (80) [M−MeOH−
2
+
Me−CO] (Fig. 2).
7. 1: white to pale yellow solid, withstanding crystallization
from diethyl ether, mp (residue from tert-butyl-
MeOH
An antifungal metabolite that we have isolated from a
strain of Fusarium sp. from surface sterilized grain and
authentic samples of naturally visoltricin (from Dr.
Visconti) and fungerin (from Dr. Koshino) showed the
same retention time in GC and identical MS spectra as
methylether, stream of N ) 62–64°C. UV u
309 (19700). H NMR (400 MHz, CDCl ) 1.69 (s, 3H,
nm (m)
2
max
1
3
Me), 1.71 (s, 3H, Me), 3.38 (d, 2H, J=6.8 Hz, CH ), 3.66
2
(s, 3H, NMe), 3.75 (s, 3H, OMe), 5.26 (t, 1H, J=6.8 Hz,
CH), 6.05 (d, 1H, J=16.2 Hz, CH), 7.40 (s, 1H, CH), 7.58
13
2
. This result shows that the naturally produced isomer
(d, 1H, J=16.2 Hz, CH). C NMR (100 MHz, CDCl3)
17.90, 25.59, 27.84, 33.05, 51.55, 114.18, 120.63, 123.66,
130.26, 133.04, 139.84, 147.43, 167.65. HRMS: 234.1364,
calcd 234.1368.
was in all three cases fungerin and that the structure of
visoltricin has to be revised. This means that the
reported biological activities of visoltricin are due to
fungerin.
8
. l , lN calculated with ‘gross-theta’=0.101329118 referred
H
to liquid NH /25°C=0 ppm, Wishart, D. S., et al. J.
3
Biomol. NMR 1995, 6, 135–140.
Acknowledgements
9. DB-5MS (J&W), 30 m×0.25 mm i.d., 0.25 mm film, He 20
cm/s, 0.6 bar, 60°C for 1 min, then 10°C/min to 310°C (10
min), total injection, split open after 1 min, detection: MS
ITD 800 (Finnigan Mat) directly coupled to the GC
(Dani), retention times: 1 1224 s, 2 1312 s.
We thank Dr. M. Solfrizzo, Istituto tossine e micoto-
ssine da parassiti vegetali, Bari, Italy for an authentic
sample of visoltricin and Dr. H. Koshino, Rieken, The