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|Title: ||The synthesis of medium-sized ring containing libraries using oxidative fragmentation and rearrangement strategies|
|Authors: ||Jones, Alan M.|
|Supervisors: ||Westwood, Nicholas J.|
|Keywords: ||Oxidative fragmentation|
|Issue Date: ||26-Jun-2009|
|Abstract: ||This thesis describes the development of a synthetic route that encodes a library of compounds containing medium-sized ring systems, with particular emphasis on the use of oxidative fragmentation and rearrangement strategies.
Chapter 1 introduces diversity oriented synthesis (DOS) with particular emphasis on medium-sized ring synthesis and fragmentation/rearrangement protocols to achieve diversity. A more detailed discussion of oxidative fragmentation and rearrangement methods is also presented.
Chapter 2 describes strategies for the synthesis of a collection of heterocyclic compounds known as diazabenz[e]aceanthrylenes. The scope of the reaction was explored as a function of a range of substituents and of the ring size of the N-aryl lactam that was used. Spectroscopic observations associated with this set of compounds are also discussed.
Chapter 3 describes the development of an m-CPBA-mediated oxidative fragmentation of the diazabenz[e]aceanthrylenes. Analysis of the products from these reactions revealed the presence of atropisomerism due to restricted rotation about the N sp²-C(aryl) sp² bond.
Chapter 4 focuses on a related example of oxidative fragmentation from the literature. A previously overlooked stereogenic axis is explored in this system using X-ray crystallographic analysis and variable temperature ¹H NMR spectroscopy. Reinterpretation of the reported mechanism-probing experiment led to the isolation of an alternative isomeric product and an improved interpretation for the reaction outcome is presented. Variable temperature ¹H NMR spectroscopic experiments revealed the energy barrier to racemisation in the medium-sized ring-containing analogues and based on this data the mode of ring inversion is discussed.
Chapter 5 describes three rearrangements of the medium-sized ring system created in Chapter 3 including the formation of an azepinoindole ring structure, a Favorskii reaction and spiro-oxindole synthesis. A rationalisation for these reaction outcomes is included along with experimental support of mechanistic proposals. The generality and scope of the reactions are demonstrated including a nucleophile screen.
Chapter 6 describes the synthesis of a library of 69 compounds consisting of examples of the core structures described in Chapters 2, 3 and 5. A discussion of the selection process and adaption of the protocol to parallel synthesis is presented. This chapter concludes with preliminary screening of the library against a variety of strains of yeasts and bacteria.|
|Publisher: ||University of St Andrews|
|Appears in Collections:||Chemistry Theses|
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