The development of new synthetic methods for chromone and ergochrome construction

Abstract

The ergochromes possess useful anti-tumour properties whilst chromones are useful drugs for the treatment of allergic asthma. The aim of the project was to synthesise ergoflavin or an analogue for the first time, and to this end novel synthetic methods for α,β-unsaturated ketones and oxygenated dienes were developed.

Two major routes are described: The first uses aliphatic starting materials and allows the construction of highly substituted chromones by an intramolecular Diels-Alder reaction. To achieve this a synthetic method to novel phenylthio substituted 3-unsaturated ketone equivalents (α'-phenylthio-β-amidoketones) was developed. It consisted of nitrile oxide additions to l-phenylthioprop-2-ene, whilst additions to 1-phenylsulphinyl-l,2-propadiene were also investigated.

The second route involved the use of a preformed aromatic ring and; (a) an intramolecular Diels-Alder reaction to form a pyrone ring or - (b) an intermolecular Diels-Alder reaction and subsequent Friedel-Crafts cyclisation to give a pyrone ring.

For this, a selenium dlene protection, alkylatlon and deprotection methodology was developed. Depending upon the substrate and oxidative conditions α,β-unsaturated ketones, allylic alcohols, dienes and lactones were obtained. A second route to 4-oxygenated-l,3-butadienes provided the impetus to develop a titanium reagent for the oleflnation of 4-substltuted-3-buten-2-ones.

Finally, an investigation into radical cyclisatlons of allylically substituted phenylseleno substrates was made.

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