Concise total synthesis of 9-methoxystrobilurin A

Article abstract of DOI:10.1016/S0040-4039(00)00559-1

Total synthesis of a potent antifungal and cytostatic 9- methoxystrobilurin A was achieved by developing a concise and general route to β-methoxy acrylate. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00559-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 4165–4168
Concise total synthesis of 9-methoxystrobilurin A
Hiromi Uchiro, Koh Nagasawa, Yasuyuki Aiba and Susumu Kobayashi ∗
Faculty of Pharmaceutical Sciences, Science University of Tokyo, Ichigaya-Funagawara-machi, Shinjuku-ku, Tokyo 162-0826,
Japan
Received 10 March 2000; revised 28 March 2000; accepted 31 March 2000
Abstract
Total synthesis of a potent antifungal and cytostatic 9-methoxystrobilurin A was achieved by developing a
concise and general route to β-methoxy acrylate. © 2000 Elsevier Science Ltd. All rights reserved.
9-Methoxystrobilurin A (1) was isolated by Anke and Steglich et al. in 19951 as a new and potent
analogue of antifungal β-methoxyacrylates.2 Structurally complicated strobilurin K (2)1,3 and L (3)6
were also isolated in 1996, and they have a unique triene moiety including two electron-rich and acid-
sensitive methyl enol ethers as common substructures. Interestingly, this 9-methoxystrobilurin family
was found to exhibit potent cytostatic activity toward human-derived tumor cell lines in addition to
the originally reported antifungal activity. As an example, 9-methoxystrobilurin A and K inhibited the
growth of HeLa S3 cell at very low concentration (the IC50 value reached 8.5 nM) without showing any
significant cytotoxity (Fig. 1).
Fig. 1. Structures of strobilurin antibiotics
The total synthesis of strobilurin A has already been reported by several groups.7 However, these
approaches seem not be directly applicable to the synthesis of a 9-methoxy analogue since these
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00559-1
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compounds have a different oxidation level in their triene moiety. In this paper, we would like to report the
first total synthesis of 9-methoxystrobilurin A by a concise route which might be applicable to synthesis
of 2 or 3.
Our synthetic strategy for the 9-methoxystrobilurin analogue is shown in Scheme 1. A simple and
convergent synthetic route was desired for future studies of the structure–activity relationships on the
9-alkoxy group and an oxygenated side chain attached to the hydrophobic aromatic ring. A key step of
our convergent approach is the Heck reaction of aryl bromide with vinyl ketone. We expected that the
mildness of the Heck reaction would be applicable for the coupling of vinyl ketone and aryl bromide
with a highly oxygenated side chain such as for strobilurin K and L. Vinyl ketone might be prepared
from commercially available monomethyl ester of itaconic acid.8
Scheme 1. Synthetic strategy of 9-methoxystrobilurins
First, the olefin part of monomethyl itaconate 4 was hydrogenated and the resulting saturated mono-
ester (monomethyl methylsuccinate) 5 was successively converted to the corresponding acid chloride
6 without isolation. Stille coupling reaction of the acid chloride with vinyl-tributylstannane9 gave the
desired vinyl ketone 7 in good yield (three steps, 86%). Thus, an efficient preparative method for the
vinyl ketone 7 was developed (Scheme 2).
Scheme 2. Synthesis of vinyl ketone
Next, Heck reaction of the above vinyl ketone 7 with bromobenzene 8a was tried to obtain the
corresponding α,β-unsaturated ester. The reaction proceeded smoothly and the desired coupling product
9a was obtained in high yield (81%) when 2 equivalents of vinyl ketone 7 were used.10 In the presence
of a catalytic amount of p-toluenesulfonic acid, the α,β-unsaturated ketone 9a was refluxed for 1 h
with trimethylorthoformate and methanol. After evaporation of volatile materials, trimethylorthoformate
was added again to the residue, and refluxed for 2 h to obtain the corresponding methyl enol ether

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10a as a geometrical mixture (ca. 1:1). Treatment of the 10a with sodium hydride-methyl formate,
followed by the successive addition of dimethylsulfate and potassium carbonate gave a mixture of the
geometrical isomers of strobilurin A. The mixture was successively isomerized by the irradiation of an
ultraviolet lamp (λ: 365nm) and the desired 9-methoxystrobilurin A (1) was isolated in 28% yield (three
steps) along with unseparable mixture of other two isomers (28% yield, 12a:13a=17:11) after silicagel
column chromatography (Scheme 3).11 The undesired isomers were again subjected to UV-mediated
isomerization, affording 1 in 42% yield and 39% of starting mixture was recovered (12a:13a=15:24).
Spectral data of the synthetic 9-methoxystrobilurin A12 were in good accordance with those of the natural
product reported by Anke’s group.1
Scheme 3. Total synthesis of 9-methoxystrobilurin A
The present procedure was also applied to the synthesis of a dimethoxy analogue of 9-
methoxystrobilurin A which is structurally more close to 9-methoxystrobilurin K (2) and L (3). All
steps, including the Heck reaction, proceeded in a similar manner to give 2,3,9-trimethoxystrobilurin.13
Thus, the first total synthesis of 9-methoxystrobilurin A which is the simplest analogue of 9-
methoxystrobilurins was successfully achieved. The concise and convergent approach developed by

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the present study is noteworthy. Further investigations for the synthesis of the more complicated and
biologically significant 9-methoxystrobilurin K, L and other analogues are now in progress.
References
1. Zapf, S.; Werle, A.; Anke, T.; Klostermeyer, D.; Steffan, B.; Steglich, W. Angew. Chem., Int. Ed. Engl. 1995, 34, 196–198.
2. (a) Sauter, H.; Steglich, W.; Anke, T. Angew. Chem., Int. Ed. Engl. 1999, 38, 1328–1349. (b) Anke, T.; Steglich, W. In
Biologically Active Molecules: Identification, Characterization and Synthesis; Schlunegger, U. P., Ed.; Springer-Verlag:
Berlin, Heidelberg, 1989; pp. 1–8. (c) Clough, J. M. Natural Products Reports 1993, 10, 565–574.
3. Although another structure was originally proposed for 9-methoxystrobilurin K,1 Blunt and Munro et al. claimed a present
structure 2 in 1997.4 Recently, Anke and Steglich et al. formally revised the structure to 2 by the comparison of s synthetic
benzodioxepin moiety with the degradation product of natural strobilurin K. 5
4. Nicholas, G. M.; Blunt, J. W.; Cole, A. L. J.; Munro, M. H. G. Tetrahedron Lett. 1997, 38, 7465–7468.
5. Hellwig, V.; Dasenbrock, J.; Klostermeyer, D.; Kroiß, S.; Sindlinger, T.; Spiteller, P.; Steffan, B.; Steglich, W.; Engler-Lohr,
M.; Semar, S.; Anke, T. Tetrahedron 1999, 55, 10101–10118.
6. Wood, K. A.; Kau, D. A.; Wrigley, S. K.; Beneyto, R.; Renno, D. V.; Ainsworth, A. M.; Penn, J.; Hill, D.; Killacky, J.;
Depledge, P. J. Nat. Prod. 1996, 59, 646–649.
7. (a) Anke, T.; Schramm, G.; Schwalge, B.; Steffan, B.; Steglich, W. Liebig. Ann. Chem. 1984, 1616–1625. (b) Beautement,
K.; Clough, J. M. Tetrahedron Lett. 1987, 28, 475–478.
8. This compound was purchased from Tokyo Kasei Industries, Inc.
9. (a) Milstein, D.; Stille J. K. J. Am. Chem. Soc. 1978, 100, 3636. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J. Organic
Reactions 1997, 50, 1.
10. The yield of the coupling compound was moderate (61%) when 1.2 eqivalent of vinyl ketone was used, probably due to a
thermal polymerization of vinyl ketone during the Heck reaction.
11. The irradiation condition has not yet been optimized in terms of the light density.
12. Spectral data of synthesized 9-methoxystrobilurin A (1): 1H NMR (CDCl3, 300 MHz) δ 1.91 (s, 3H, H-14), 3.68 (s, 3H,
H-17), 3.72 (s, 3H, H-16), 3.82 (s, 3H, H-15), 6.52 (d, 1H, J=16.0 Hz, H-8), 6.71 (d, 1H, J=16.0 Hz, H-7), 7.20 (m, 1H,
H-3), 7.30 (dd, 2H, J=7.3 Hz, 8.0 Hz, H-2 and H-4), 7.37 (d, 2H, J=7.2 Hz, H-1 and H-5), 7.40 (s, 1H, H-12); 13C NMR
(CDCl3, 75.5 MHz) δ 16.3 (C-14), 51.6 (C-16), 59.5 (C-17), 61.8 (C-15), 110.5 (C-11), 118.8 (C-10), 121.5 (C-8), 126.5
(C-1 C-5), 127.3 (C-3) 127.6 (C-7), 128.5 (C-2 C-4), 137.5 (C-6), 152.6 (C-9) 159.3 (C-12), 167.1 (C-13); EI-MS 288
(M+).
13. Spectral data of synthesized 2,3,9-trimethoxystrobilurin A (11b): 1H NMR (CDCl3, 300 MHz) δ 1.91 (s, 3H, H-14), 3.68
(s, 3H, H-17), 3.72 (s, 3H, H-16), 3.82 (s, 3H, H-15), 3.88 (s, 3H, MeO-Ar), 3.90 (s, 3H, MeO-Ar), 6.37 (d, 1H, J=16.0 Hz,
H-8), 6.66 (d, 1H, J=16.0 Hz, H-7), 6.81 (d, 1H, J=8.3 Hz, H-4), 6.89 (d, 1H, J=1.7 Hz, H-1), 6.96 (dd, 1H, J=1.7, 8.3 Hz,
H-5), 7.40 (s, 1H, H-12); 13C NMR (CDCl3, 75.5 MHz) δ 16.2 (C-14), 51.5 (C-16), 55.9 (C-18 C-19), 59.5 (C-17), 61.8
(C-15), 109.4 (C-4), 110.6 (C-11), 111.1 (C-10), 117.8 (C-10), 119.4 (C-5), 119.7 (C-8) 127.4 (C-7), 130.6 (C-6) 148.6
(C-3), 148.9 (C-2), 152.7 (C-9), 159.3 (C-12), 168.2 (C-13); EI-MS 348 (M+).