A novel route to trans-THFs and the synthesis of sylvaticin

Thesis

trans-2,5-Disubstituted-tetrahydrofurans (THFs) are a common structural motif in many biologically active natural products, particularly in the Annonaceous acetogenins. This thesis develops a new route for their synthesis and applies it to the total synthesis of the Annonaceous acetogenin sylvaticin. Chapter 1: Introduction – Synthetic routes to trans-2,5-substituted tetrahydrofurans This chapter reviews methods for the synthesis of trans-2,5-THFs that have been applied to natural products synthesis. Chapter 2: Results & Discussion – A Novel Route to trans-THFs The rearrangement of activated 2,5-disubstituted cis-THFs is reviewed and is developed into a new synthetic method for the synthesis of trans-THFs. The reaction proceeds via a hydride shift mechanism to form an oxonium ion. Intramolecular reduction by a tethered hydrosilane stereoselectively forms the trans-THF. The mechanism of the rearrangement is investigated with the use of different stereoisomers and a deuterium labelling study. A cross-over study is carried out which confirms the reaction occurs via the proposed hydride shift mechanism. Chapter 3: Introduction – The Annonaceous Acetogenins This chapter introduces the Annonaceous acetogenins, a biologically active class of natural products often found with THF rings in their structure. The three key areas for their synthesis are explored- the synthesis of the THF core, the synthesis of the butenolide ring, and their coupling. Chapter 4: Results & Discussion – The Synthesis of Sylvaticin The Annonaceous acetogenin sylvaticin is introduced, and its isolation in nature and biological activity reviewed. With the aid of a model system study to extend the scope of the reaction, the methodology developed in Chapter 2 is then applied to the synthesis of sylvaticin. The synthesis, the first to be reported, is completed in a total of 19 linear steps starting from commercially available tetradecatetraene. In order to prove the obtained structure is that found in nature, a comprehensive investigation is undertaken using Mosher ester derivatives and the synthesis of its bis-epimer, 4,36-epi,epi sylvaticin. Chapter 5: Experimental Full experimental procedures and characterisation of compounds are reported.

Authors: Williams, OMH

• Publication date: 2009
• DOI: 10.5287/ora-jx98vbzed
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: hydride shift; trans-THF; sylvaticin; THF; osmium
• Subjects: Organic chemistry; Catalysis; Heterocyclic chemistry; Organic synthesis; Chemistry & allied sciences; Spectroscopy and molecular structure