Elsevier

Tetrahedron Letters

Volume 44, Issue 46, 10 November 2003, Pages 8383-8386
Tetrahedron Letters

Monoalkylation of dihydroxycoumarins via Mitsunobu dehydroalkylation under high intensity ultrasound. The synthesis of ferujol

https://doi.org/10.1016/j.tetlet.2003.09.114Get rights and content

Abstract

Monoalkylation of natural dihydroxycoumarins was carried out by Mitsunobu dehydroalkylation under sonochemical conditions. Aesculetin (6,7-dihydroxycoumarin) was selectively alkylated in good yield with prenyl alcohols at position 7, as clearly shown by NOESY experiments; though less selectively, position 7 was also the most reactive in daphnetin (7,8-dihydroxycoumarin). The synthesis of the phytoestrogen ferujol is also reported for the first time.

The synthesis of the phytoestrogen ferujol is reported for the first time.

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Introduction

The Mitsunobu reaction1 has been exploited in the chemistry of a wide range of naturally occurring compounds like carbohydrates,2., 2.(a), 2.(b) peptides,3 terpenes4 and others with formation of ethers, esters and new CC bonds.5., 5.(a), 5.(b), 5.(c), 5.(d) The nucleophilic substitution of an alcohol group mediated by the triaryl- or trialkyl-phosphine/dialkyl azodicarboxylate redox system is widely used to prepare biologically active compounds with interesting applications in solid phase synthesis6., 6.(a), 6.(b) and combinatorial chemistry.7 The regio- and stereoselectivity of the reaction have been thoroughly reviewed.5., 5.(a), 5.(b), 5.(c), 5.(d) Although its reaction mechanism with saturated alcohols is well known, uncertainty lingers on the factors that govern its course when allyl or prenyl alcohols are employed. Although allylic alcohols react according to the normal SN2 mechanism, some instances are found in the literature of an SN2′ mechanism.5., 5.(a), 5.(b), 5.(c), 5.(d) The reaction normally proceeds with inversion of configuration at the carbon atom bearing the hydroxy group, yet complete retention of configuration has been observed in the lactonization of hindered alcohols.8., 8.(a), 8.(b) As regards regioselectivity, Ko9 found that with syn-2,3-dihydroxy esters only the β-hydroxy group reacted. On the other hand, with 1,3-dicarbonyl compounds, the reaction yields mixtures of C- and O-alkylation products because the enolate charge is delocalized.10 It is well known that 4-hydroxycoumarin usually gives O-alkylation products.11 In a recent paper12 we compared the outcomes of the reaction under conventional and sonochemical conditions, showing that high intensity ultrasound influences only slightly the regioselectivity, while markedly increasing reaction rates and yields. Our preliminary data,13., 13.(a), 13.(b) further developed by Appendino,14 indicate that the Mitsunobu reaction affords an easy way to perform a differential esterification of alcoholic and phenolic hydroxy groups.

We have now found that the Mitsunobu reaction allows a differential etherification of the phenolic groups in dihydroxycoumarins. Although phenol etherification has been widely exploited,15 to the best of our knowledge, this result has never been published.

We wish to present here the first results obtained with several prenyl alcohols reacting with two, commercially available, differently substituted coumarins, namely the 6,7-dihydroxycoumarin (aesculetin) 1 and 7,8-dihydroxycoumarin (daphnetin) 2.

Section snippets

Results and discussion

Using a novel prototype sonochemical reactor,16 the reactions were carried out in anhydrous tetrahydrofuran employing several biologically significant alcohols like prenyl, geranyl, dihydrogeranyl and farnesyl alcohol.17 The 400 MHz 1H NMR spectral patterns of compounds 314 confirmed that all reaction products were O-alkylated coumarin derivatives and that no Claisen rearrangement had occurred.10 Thus, aesculetin 1 (Scheme 1) exclusively afforded in yields better than those obtained employing

Conclusions

In conclusion, our method led to several compounds endowed with biological activities or precursors thereof, e.g. the phytoestrogen ferujol 14b first isolated from Ferula jaeschkeana.20a On the other hand a simple methylation of compound 12a could yield the antiviral and antiplatelet aggregation agent collinine (from Zanthoxylum schinifolium)23., 23.(a), 23.(b), 23.(c) and selective epoxidation of 7-farnesylesculetin 7 could yield some new hopene squalene cyclase inhibitors.13b

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