Quinones as Key Intermediates in Natural Products Synthesis. Syntheses of Bioactive Xanthones from Hypericum perforatum

Two bioactive xanthones from Hypericum perforatum have been synthesized by direct routes. Benzo[c]xanthone 5 can be prepared from intermediate 4.


Introduction
Because of their extensive use as botanical dietary supplements, there is increasing interest in the chemical constituents of Hypericum and Echinacea [1]. Although some components of Hypericum species such as hypericin and hyperforin are well known, these species contain many additional bioactive components, including flavones, procyanidins and xanthones [2]. Among the many xanthones found in Hypericum species, euxanthone (1) and 1-methoxy-7-hydroxyxanthone (2) are found in Hypericum perforatum [3].
Euxanthone exhibits a range of potentially useful biological activities. Recently, researchers reported that euxanthone promotes neurite outgrowth by selectively activating the MAP kinase pathway [4]. Euxanthone showed inhibitory effects on the growth of Plasmodium falciparum with IC 50 values in the milligram/milliliter level [5]. Euxanthone also inhibited HIV-1 reverse transcriptase with IC 50 values at the milligram/milliliter level [6]. In the vasodilatation assay, both xanthones 1 and 2 exhibited relaxing activity on the contractions evoked by potassium chloride in rat thoracic aorta rings in a dose-dependent manner [7]. Euxanthone has been synthesized by heating hydroquinone and ethyl OPEN ACCESS 2,6-dihydroxybenzoate in boiling diphenyl ether to make 1 [8]. Our synthetic route to 1 requires three steps from two commercially available starting materials and is amenable to scale up.

Results and Discussion
As shown below, the key step in our synthetic route involves a photoacylation [9] using 2,6dimethoxybenzaldehyde and benzoquinone. We developed the photoacylation of quinones as a green alternative to certain Friedel-Crafts reactions. This reaction, which is a nice example of atom economy, produces adducts which have been used in syntheses of benzodiazepines and natural products such as frenolicin [9]. Before the synthesis of 3, we had not demonstrated this reaction with hindered aldehydes. Since this reaction occurs via an acyl radical, we were concerned that an intramolecular radical translocation to the methyl of the methoxyl group might intervene before the desired intermolecular reaction of the acyl radical with the quinone. To show the scope of this reaction we synthesized adduct 4 in 76% yield from naphthoquinone. Adduct 4 could be converted into xanthone 5 in 61% yield by demethylation with boron tribromide, followed by heating at 180 °C for 16 hours.

Scheme 2. Cyclization to xanthone 5.
To synthesize xanthone 2, we treated adduct 3 with potassium hydroxide in boiling methanol for 12 hours [10]. Demethylation of 2 using boron tribromide afforded euxanthone (1)  In summary, two bioactive components from Hypericum perforatum have been synthesized by direct routes. These results further extend the synthetic utility of the photoacylation of quinones.

General
Unless stated otherwise, all reactions were magnetically stirred and monitored by thin-layer chromatography (TLC) using 0.25 mm precoated silica gel F254 plates (Sigma-Aldrich). Column or flash chromatography was performed with the indicated solvents using silica gel (230-400 mesh) purchased from Dynamic Adsorbents, LLC. All melting points were obtained on a Laboratory Devices capillary melting point apparatus and are uncorrected. 1 H-and 13 C-NMR spectra were recorded in CDCl 3 on a Bruker VXR-400 (400/100 MHz) spectrometer. Chemical shifts are reported relative to internal chloroform ( 1 H, 7.26 ppm; 13 C, 77.23 ppm). High resolution mass spectra were performed at the Iowa State University Mass Spectrometry Laboratory.