The development of new synthetic methods for the assembly of the angucycline skeleton and xanthones: a foray at utilizing a biorenewable carbon resource and greener chemical reactions

Abstract

The work detailed in this PhD thesis can be broadly separated into two parts, both focusing on the use of certain principles of Green Chemistry in organic synthesis. The aim of the first part was to feature catalysis as our major application of Green Chemistry in the formal synthesis of the angucycline natural product 1,8-dihydroxy-3-methyltetraphene-7,12-dione, also known as tetrangulol. Other principles of Green Chemistry were also integrated as part of our design strategy, where possible. Previously in our laboratory, a methodology was developed for the synthesis of tetrangulol, that involved a PtCl2- and a AuCl3- mediated cycloisomerization as the key step to construct the B ring of the angucycline. However, significant amounts of the side product 1,10,12- trimethoxy-8-methylchrysene were produced. We therefore set out to attempt to improve this synthesis of tetrangulol, and in so doing incorporate some principles of Green Chemistry. We anticipated using the recently developed carbonyl-olefin metathesis catalyzed by the earth abundant FeCl3 as the key step to construct the B ring of tetrangulol. A palladium- catalyzed Suzuki-Miyaura coupling reaction was used to synthesize the highly congested, carbonylolefin containing biaryl intermediate 2-[1,4-dimethoxy-3-(2-methylprop-1-en-1- yl)naphthalen-2-yl]-3-methoxy-5-methylbenzaldehyde. This precursor was then subjected to carbonyl-olefin metathesis conditions, in the presence of 27 mol% of FeCl3, to furnish the desired tetracyclic core, 1,7,12-trimethoxy-3-methyltetraphene. The unexpected formation of quinone 1-methoxy-3-methyltetraphene-7,12-dione was also observed as a side product of this reaction, albeit in poor yields. A late-stage C-H functionalization protocol was subsequently used to introduce a hydroxyl group, however; this led instead to the unforeseen formation of the two chlorocyclinones 2,4-dichloro-11-hydroxy-1-methoxy-3-methyltetraphene-7,12-dione and 2,4-dichloro-6-hydroxy-1-methoxy-3-methyltetraphene-7,12-dione, rather than tetrangulol. The second part of this PhD thesis details the use of cashew nut shell liquid-derived cardanol as a bio-renewable feedstock to synthesize a small library of UV-absorbing hydroxyxanthones. A ceric ammonium sulfate-mediated oxidation that was developed in our laboratory was used to efficiently construct the xanthones, for example 2-methoxy-6-pentadecyl-9Hxanthen-9-one, from benzophenone intermediates, such as (2,5-dimethoxyphenyl)(2-hydroxy4-pentadecylphenyl)methanone. Late-stage oxidation procedures were subsequently used to introduce a hydroxyl functionality ortho to the carbonyl moiety of the xanthones, to deliver for example 1-hydroxy-7-methoxy-3-pentadecyl-9H-xanthen-9-one. The hydroxy-containing xanthones, as well as benzophenone intermediates, were tested for their UV absorption capabilities. Although all compounds tested displayed good UV absorption profiles, the hydroxy-xanthone 1-hydroxy-6,7-dimethoxy-3-pentadecyl-9H-xanthen-9-one was found to show excellent UV absorption in both the UVA and UVB regions of the UV spectrum with molar extinction coefficients of 20320 L mol-1 cm-1 at 290 nm, and 13949 L mol-1 cm-1 at 368 nm, qualifying it for a broad-spectrum UV protectant