Synthetic studies towards the total synthesis of lancifodilactone G

Abstract

This thesis presents our studies towards the first total synthesis of the novel anti- HIV agent lancifodilactone G, which has a highly unusual aliphatic enol. The first chapter provides a survey of architecturally diverse nortriterpenoids that were isolated from the Schisandraceae family. A proposed biosynthetic pathway for lancifodilactone G and closely related natural products provides a rationale for the formation of the consecutive 7/8/5 fused carbo cycles that are unique to Schisandra nortriterpenoids. Chapter 1 goes on to outline the reported strategies to access the core of lancifodilactone G and concludes with a retrosynthetic analysis proposed by the Evans group, which includes a biosynthetically inspired single-pot polycyclisation reaction. Chapter 2 describes the highly stereocontrolled synthesis of the eastern fragment (F-G rings) using transition metal-mediated Pauson-Khand reaction. This chapter also reviews the metal-mediated diastereoselective Pauson-Khand reaction directed by the stereogenic centre at C2, with the ample illustration to total synthesis. Attempted strategies for the assembly of the bicyclic cyclopentanone motif via a dienyl Pauson-Khand reaction of silicon- and oxygen- tethered diene-enes are presented. The failure of these strategies at different stages of the synthesis resulted in the exploration of a classical Pauson-Khand approach, which successfully furnished the eastern fragment. Finally, a second-generation synthesis is described which provided the fully functionalised eastern fragment with improved efficiency and overall yield. Chapter 3 discusses the successful synthesis of the western fragment (B-C rings) using a diastereoselective [4+3] cycloaddition strategy. Attempted strategies for the synthesis of the key 2,3-disubstituted furan derivative are presented, which was achieved via a hetero Pauson- Khand reaction. This chapter includes a brief account of the classical [4+3] cycloaddition reactions of furans using an in situ generated oxyallyl cation and also employing vinyl carbenoids in the metal-catalysed version. The review also highlights the application of the [4+ 3] cycloaddition reaction in the expeditious assembly of functionalised 7-membered rings that occur in a number of important biologically active natural products. The third chapter goes on to describe the application of these cycloaddition reactions in the synthesis of the fully functionalised western fragment of Lancifodilactone G. Chapter 4 describes a model study aimed at expediting the synthesis of the western fragment using a rhodium-catalysed allylic substitution reaction. A brief mechanistic discussion on unique aspects of the allylic alkylation reaction is illustrated. Chapter 4 concludes by outlining the coupling strategy for eastern and western fragments and the end game studies for the completion of the synthesis of lancifodilactone G.EThOS - Electronic Theses Online ServiceGBUnited Kingdo