Synthesis, functionalisation and biological evaluation of tetrahydroxanthones

• Main Author: Samiullah, Ph. D.
• Published: University of Warwick 2012
• Subjects: 547.59; QD Chemistry
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.560321

This thesis describes the development of new methods for the synthesis of mono-, diand trihydroxylated tetrahydroxanthones which are structural elements of a range of important natural products including the anti-cancer agents known as the kigamicins. In Chapter One, work on the isolation, biological significance and chemical synthesis of xanthones, dihydroxanthones, and tetrahydroxanthones is reviewed, with special focus on the polycyclic tetrahydroxanthone natural products. Chapter Two describes the development of methods for the synthesis of tetrahydroxanthones mimicking the ABC rings of kigamicin A which contain a hydroxyl group at C-3 of the saturated ring. A 5 step synthesis of 228 was achieved via palladium catalysed assembly of tetrahydroxanthone nucleus, followed by enantiocontrolled reduction of the C=O group via asymmetric transfer hydrogenation, and glycosidation using a novel trichloroacetimidate donor 225. In Chapter Three, a short route to the cis and trans1,4-diol functionality found in the tetrahydroxanthone fragment of 1,3,5-trihydroxy-8-β-D-glucopyranosyl, puniceaside B, puniceaside C, albofungin, and simaomicins is achieved. Excellent enantiocontrol (99% ee) was realised through use of an asymmetric ketone transfer hydrogenation. Subsequent enolate hydroxylation with the Davis oxaziridine facilitated installation of the second hydroxyl group albeit with low levels of diastereocontrol. The structure of cis-277 was verified by X-ray crystallography after conversion to the corresponding diacetate 279. Similar enolate hydroxylations were used to access the triol substitution patterns found in kibdelones and isokibdelones. Attempts to develop synthetic routes to the fully functionalised A-ring fragments of the actinoplanones and kigamicins are described. This culminated in the preparation of advanced synthetic intermediate 322 in 4 steps from hydroxyl selenide tetrahydroxanthone. In a key step in this sequence, an unusual syn-selective dihydroxylation of a PMB-protected homoallylic alcohol (321) was unearthed. Finally, the biological effects of the new dihydroxanthones, dihydroxy, and trihydroxytetrahydroxanthones synthesised in the laboratory were evaluated against human pancreatic cancer cell line (PANC-1), grown separately in nutrient rich medium (NRM) and nutrient deprived medium (NDM). In Chapter Four, detailed experimental and characterisation data for the new compounds are described.