Taylor, James David
(2011).
Total synthesis of nemorosone and nemorosone II.
University of Birmingham.
Ph.D.
Abstract
The polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of naturally occurring compounds with a characteristic bicyclo core system (either [3.3.1]nonane or [3.2.1]octane). This class of compounds have been shown to have significant biological activity, including activity against cancer, HIV, bacterial infection and depression. The biological activity and the structural challenges that these compounds pose have led to significant interest from the synthetic chemists. A review of the previous synthetic work and the biological activity of the PPAPs is contained within Chapter 1. A total synthesis of the type A PPAP nemorosone (4) is described, using a modified Effenberger cyclisation as the key bicyclo[3.3.1]nonane forming step. Further functionalisation was performed through a difficult bridgehead iodination, followed by halogen-metal exchange and benzoylation. Chapter 2 describes our total synthesisof nemorosone (4) in 13 synthetic steps and 6% overall yield. Chapter 3 describes the first total synthesis of the type C PPAP nemorosone II (150) in 10 synthetic steps and 1.5% overall yield. Once more the key bicyclo[3.3.1]nonane core was formed using the modified Effenberger cyclisation. Alongside the synthesis, biological studies have been performed on the final compounds and a range of intermediates (Chapter 4). Investigations into the difficult bridgehead substitution and resulting halogen-metal exchange reactions are discussed in Chapter 5. Preliminary studies were undertaken into a new shorterroute to nemorosone (4) using a Dieckmann condensation as the keybicyclo[3.3.1]nonane forming step. (Chapter 6).
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