Total synthesis of eranthin acetate, ptaeroxylinol acetate, and derivatives thereof

Abstract

In most countries, fungal infections represent an overwhelming problem, particularly in hospitals. Candida albicans is considered the most virulent among other species responsible for the fungal infection, candidiasis. Candidiasis has developed resistance against most of the current antifungal drugs. The 12-O-acetyl derivative of eranthin named obliquumol, isolated from a South African plant, Ptaeroxylon obliquum, was found to exhibit in vitro activity against C. albicans standard strain (ATCC10231). Ptaeroxylinol acetate, the linear isomer of eranthin acetate was also previously isolated from the P. obliquum. The aim of this study was two-fold. The first aim was to synthesise the 12-O-acetyl derivative of eranthin (obliquumol), its linear isomer ptaeroxylinol acetate, and their derivatives, in order to investigate their biological activities. The second aim of study was to synthesise the carbon-14 labelled eranthin acetate and its structural analogues for the in vivo tissue distribution studies.

Two approaches were investigated for the synthesis of the oxepinochromones eranthin acetate and ptaeroxylinol acetate. The first approach involved preparation of the oxepinochromones by employing the Kostanecki-Robinson reaction to synthesise the chromone intermediate, noreugenin, from 2',4',6'-trihydroxyacetophenone. Allylation and Claisen rearrangement resulted in two isomers, 8-allyl-5,7-dihydroxy-2-methyl-4H-chromen-4-one and 6-allyl-5,7-dihydroxy-2-methyl-4H-chromen-4-one. The resultant isomers led to the concurrent synthesis of eranthin acetate and ptaeroxylinol acetate from the 8-allyl isomer and the 6-allyl isomer, respectively. Consequently, the oxepine ring was constructed through a sequence of steps that involved alkylation, ring-closing metathesis (RCM) and a successive deprotection to afford eranthin and ptaeroxylinol, which were successfully acetylated to complete the synthesis of eranthin acetate and ptaeroxylinol acetate in modest yields.

The second approach entailed the construction of oxepine ring from 2',4',6'-trihydroxyacetophenone followed by the synthesis of the chromone scaffold to allow for the incorporation of a C-14 labelled precursor at a more stable position. To achieve the construction of the oxepine ring, various protection and deprotection protocols were investigated. The optimum protocol employed involved the partial protection of phloroacetophenone with MOM protecting groups, allylation and Claisen rearrangement followed by the protection of the hydrogen-bonded hydroxy group with a methyl group. Selective deprotection of one of the MOM groups, a subsequent protection with methyl group, and removal of the remaining MOM group furnished 3-allyl-4-hydroxy-2,6-dimethoxyacetophenone that was alkylated and subjected to RCM reaction to afford the expected oxepine ring and a subsequent deprotection which gave the benzoxepine, 2,5-dihydro-3-(hydroxymethyl)-6,8-dimethoxybenzo[b]oxepin-7-yl)ethanone in 32% yields.

The RCM-deprotection step resulted in decomposition of the product and consequently, loss of material. The procedure was halted. This approach will be optimised in future to assemble the chromone scaffold and ultimately the target compounds. Furthermore, two derivatives were prepared via base-catalysed prenylation from two intermediates prepared during the investigation of the two above-mentioned strategies. Nine of the synthesised compounds were screened for antifungal activity against two genera of fungi, C. albicans and Cryptococcus neoformans. Among the tested compounds, eranthin acetate was found to have best activity against C. albicans while ptaeroxylinol acetate showed best activity against C. neoformans.