Elsevier

Tetrahedron

Volume 62, Issue 17, 24 April 2006, Pages 4214-4226
Tetrahedron

Synthesis of cicerfuran, an antifungal benzofuran, and some related analogues

https://doi.org/10.1016/j.tet.2006.02.015Get rights and content

Abstract

Routes were investigated for the synthesis of cicerfuran, a hydroxylated benzofuran from wild chickpea implicated in resistance to Fusarium wilt, and some of its analogues. A novel method is described for the synthesis of oxygenated benzofurans by epoxidation and cyclisation of 2′-hydroxystilbenes. The stilbene intermediates required could be synthesised by palladium-catalysed coupling of styrenes with mono-oxygenated aryl halides but not with di-oxygenated aryl halides. Stilbenes corresponding to the latter were synthesised by Wittig reactions.

Introduction

Benzofurans and their analogues constitute a major group of naturally-occurring compounds that are of particular interest because of their biological activity and role in plant defence systems.1 The hydroxylated benzofuran cicerfuran (1a, Fig. 1) was first obtained from the roots of a wild species of chickpea, Cicer bijugum, and reported to be a major factor in the defence system against Fusarium wilt.2

Several methodologies are available for the synthesis of simple benzofurans3 but less attention has been given to the synthesis of hydroxylated benzofurans. Methodologies reported to date for the synthesis of natural hydroxylated benzofurans involve formation of a C–C bond between benzofuran and a substituted aryl halide,4 arylation of a benzofuranone,5 cyclisation of an arylbenzylketone,6 coupling of cuprous acetylides with aryl halides,7 Sonogashira coupling of terminal acetylenes with aryl halides,8 coupling of a diphenylketone with the lithium salt of trimethylsilyldiazomethane9 and use of an intramolecular Wittig reaction.10

Recently, the first synthesis of cicerfuran (1a) was reported by Sonogashira coupling of 2-methoxy-4,5-methylenedioxyphenylacetylene with dioxygenated aryl halides.11 Our study employs an alternative strategy for the production of both cicerfuran and related analogues and was developed independently of the work of Novak and colleagues.11 The essential features (Scheme 1) are palladium-catalysed coupling of a styrene and a 2-hydroxyaryl halide to generate a stilbene, followed by epoxidation, cyclisation and dehydration.

Two analogues (1c, 1d) of cicerfuran (1a) were synthesised successfully by this method, but the palladium coupling step did not proceed with the dioxygenated aryl halides that are required for synthesis of cicerfuran itself (Scheme 1, R2=OH). Palladium-catalysed coupling of the more reactive aryl acetylenes12, 13, 14 with 2-iodophenol proceeded well to give two analogues (1b, 1c) of cicerfuran directly. Use of this approach, essentially as described by Novak et al.11 gave cicerfuran (1a) only in low yields. Returning to the original synthetic plan, the stilbene required was synthesised by a Wittig reaction between 2-methoxy-4,5-methylenedioxybenzyltriphenylphosphonium bromide and 2,4-di-tert-butyldimethylsiloxy-benzaldehyde. Epoxidation and cyclisation gave an alternative route to cicerfuran (1a) in quantities sufficient for further biological assays. In addition, the synthetic and natural cicerfuran were compared directly and shown to have identical spectroscopic and chromatographic properties, confirming the proposed structure for the natural compound. Two further analogues (1e, 1f) of cicerfuran were prepared by this route but were not characterised fully due to decomposition during the purification.

Section snippets

Synthesis of styrenes

Styrene precursors for use in palladium-catalysed coupling (Scheme 1) were styrene itself (5) and methylenedioxystyrenes (6ac) prepared from the corresponding benzaldehydes (4ac) by a Wittig reaction with methyltriphenylphosphonium bromide and n-butyllithium (Scheme 2). 3,4-Methylenedioxystyrene (6a) was obtained in 97% yield from piperonal (3,4-methylenedioxybenzaldehyde) (4a).

Sesamol (3,4-methylenedioxyphenol) (2) was O-methylated using sodium hydroxide and dimethylsulphate to give anisole

Conclusions

Cicerfuran (1a), an antifungal agent isolated from roots of wild chickpea,2 has been synthesised from sesamol (3,4-methylenedioxyphenol) (2) in seven steps and 37% overall yield. The route involved epoxidation and cyclisation of a dihydroxystilbene intermediate. Two analogues (1e, 1f) were also prepared and characterised by GC–MS. Although they could be recovered in small quantities by HPLC for some bioassays 20 their instability meant it was not possible to isolate enough for NMR analysis. The

General

Thin layer chromatography was performed using Merck 60F-254 aluminium sheets and compounds were visualised under UV light. Gas chromatograms were recorded on a Carlo Erba Strumentazione HRGC with fused silica capillary column (25 m×0.32 mm i.d.) coated with either polar CP Wax 52CB (Carbowax 20 M equiv, Chrompack) or non polar CPSil 5CB (methyl silicone, Chrompack) and flame ionisation detection. Split injection was used with the injector at 220 °C and detector at 250 °C. Typical oven temperature

Acknowledgements

The authors thank the EPSRC National Mass Spectrometry Service Centre, Chemistry Department, University of Wales Swansea, Swansea, UK for high-resolution mass spectroscopy data. The financial support of the Higher Education Funding Council for England (HEFCE) through the University of Greenwich is acknowledged.

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