Synthetic approaches towards phorbols
<p>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...
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| Format: | Thesis |
| Language: | English |
| Published: |
1994
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| Summary: | <p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> <p>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.</p> |
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