Targeting bioactive heterocycles: synthetic studies toward zaragozic acids, a new concise route to 5-disubstituted hydantoins and synthesis of profluorescent nucleobase analogues
thesisposted on 01.03.2017, 05:13 by McKay, Victoria Alison
The family of structurally unrivalled fungal metabolites, the zaragozic acids (ZAs), have been a favoured synthetic challenge of organic chemists for over 20 years. ZAs uniquely contain a highly oxygenated 4,6,7 trihydroxy 2,8 dioxabicyclo[3.2.1]octane-3,4,5-tri-carboxylic acid core; a construct including six contiguous stereocentres, four of which are quaternary sites. Chapters 1 and 2 describe the discovery and biological significance of the ZAs – extensively covering recent works published toward their synthesis – concluding with our intended synthetic approach toward development of the ZA core. Chapter 3 encompasses research and conclusions concerning the synthesis of pinacol reaction substrates and their transition-metal-mediated coupling – including the elucidation of a number of novel heterocycles during these processes. Chapter 4 describes the optimisation and scope of a new, concise protocol deriving 5-disubstituted imidazoldine-2,4-diones from α ketoacids and carbodiimides, and applies the new method to the construction of an analogue of the marine metabolite, Polyandrocarpamide D. Chapter 5 communicates our synthetic work toward the development of pro-fluorescent derivatives of fluorescent isomorphic nucleosides. The maximal homology of isomorphic nucleosides ensures that these non-native nucleosides are well tolerated upon incorporation into DNA or RNA, with only minimal impact on sequence folding, while still allowing discrete localisation, and expedient sensitivity and responsiveness to microenvironments. Chapter 5 includes description of our investigations toward a robust synthetic methodology for the production of “pro-fluorescent” C 5/C 6-reduced, uridine/thymidine nucleobase analogues. These analogues possess the potential to report on oxidative microenvironments; whereby exposure to oxidative conditions in vivo or in vitro results in conversion to their fluorescent counterparts, consequently expressing analysable photophysical characteristics. Our synthetic approach to the desired C-5/C-6-reduced base motif utilises a pathway developed by the Perlmutter group, using [3+3]-sigmatropic rearrangement of an acyl hydroxamic acid, followed by intramolecular trapping of the substrate during a Curtius reaction, to obtain the profluorescent nucleobase analogue.
Principal supervisorPatrick Perlmutter
Year of Award2015
Department, School or CentreChemistry
FacultyFaculty of Science
Open accessCarbodiimideSamariumthesis(doctorate)HydantoinPinacol2015α-ketoacidZaragozicCurtius rearrangementIsoascorbic acidethesis-20151005-162951ProfluorescentFluorescent isomorphic nucleoside[3+3]-sigmatropic rearrangementPolyandrocarpamide DZaragozic acidImidazoldine-2,4-dionemonash:163619Profluorescent nucleobase analogueZyzzin1959.1/1225397