Synthetic approaches towards phorbols
The work described herein is concerned with the synthesis of phorbol natural products. The approach to these biological derivatives explored in this study utilised an intramolecular Diels- Alder reaction of a furan diene (IMDAF) precursor to establish the tigliane hydrocarbon skeleton and an intramolecular aldol cyclisation to construct the functionalised A-ring. Additionally, the subsequent elaboration of the phorboid cycloadducts could access highly functionalised ingenane analogues by Wagner-Meerwein rearrangement. Chapter 1 contains a review of the biological activity and biosynthesis of some naturally occurring phorbols. A literature survey on approaches to tigliane, daphnane, and ingenane analogues is described as well as a report on the previous success of the IMDAF strategy. Chapter 2 describes the development of an intramolecular aldol condensation to establish IMDAF precursors containing both a cyclopentenone A-ring and unactivated dienophilic moiety. A strategy to introduce benzylthiofuryl diene activation was developed. The cycloaddition of 3-furyl-2-pentenylcyclopent-2-enones bearing an unactivated dienophile was found to be unsuccessful. Chapter 3 describes a model study of the C-ring tigliane-ingenane rearrangement in a 7- oxabicyclo[2.2.1]heptyl system. The successful isolation of a hydrogenated cycloadduct suitable for migration studies is reported. The biomimetic carbocyclic rearrangement of phenylthio- activated model substrates was not observed. Chapter 4 describes an approach towards IMDAF precursors that contain mono- and diactivated dienophiles. Elaboration of the dienophile was investigated both before and after the intramolecular cyclisation of the A-ring and a synthetic route to (benzylthiofuryl)cyclopentenones containing an oxopentenyl dienophilic tether established. Direct introduction of tigliane C-4 oxygenation into IMDAF substrates was prevented by an unfavourable aldol cyclisation equilibrium. The observation of an IMDAF cycloadduct was facilitated by subjecting 3-[(5-(2-benzylthio)furyl]-2-(3-oxopent-4-enyl)cyclopent-2-enone to 19 kbar pressure but isolation of phorboid analogues containing unsaturation at the A-B ring junction was not possible.