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Abstract
This thesis is focussed on the use of the diene-regenerative Diels-Alder reaction to assemble bicyclic molecular frameworks that are commonly found in bioactive natural products.
Chapter 1 examines the history of natural products in pharmaceuticals, and introduces the concept of natural product derivatisation to improve biological activity. The development of focussed libraries of compounds to discover potent natural product derivatives is contrasted with combinatorial chemistry, using two illustrative case studies. The diene-regenerative Diels-Alder reaction is introduced, and key literature examples of this transformation are discussed.
Chapter 2 describes the application of the diene-regenerative Diels-Alder reaction to the synthesis of functionalised 1,2,3,4-tetrahydroisoquinolines bearing aromatic substituents at the C(5)-position. This strategy provides access to a number of compounds that would be difficult to generate using existing methods for 1,2,3,4-tetrahydroisoquinoline synthesis. The diene-regenerative Diels-Alder reaction was tolerant to a broad range of substrates in terms of both sterics and electronic character. Furthermore, the reaction was used to prepare a 1,2,3,4-tetrahydroisoquinoline containing three contiguous synthetic handles in the form of an aryl silane, aryl bromide and aryl ether.
In Chapter 3, the use of the diene-regenerative Diels-Alder reaction in the preparation of carbocylic compounds is discussed. Ten 1,5,6,7,8,8a-hexahydronaphthalenes were prepared in this manner. One of these compounds was selected as a model substrate and subjected to a variety of conditions to illustrate the broad spectrum of reactivity these 1,5,6,7,8,8a-hexahydronaphthalenes exhibit. This enabled the synthesis of a variety of highly functionalised molecules containing a decalin scaffold.
A summary of the work described in this thesis, and the future directions for the project, is provided in Chapter 4. Full experimental procedures are listed in Chapter 5.