Novel approaches to the synthesis of ether-containing natural products

Chapter one describes a new approach to the synthesis of the antitumour macrolide (+)-acutiphycin, chiefly based on the simultaneous O-directed free radical stereoselective hydrostannation to fashion two trisubstituted olefins. The proposed route to (+)-acutiphycin required the synthesis of two main fragments, a β-silyloxyaldehyde and a functionalised acetylene. After several failed attempts to prepare the former, an alternative β-silyloxyaldehyde was prepared using Sharpless asymmetric epoxidation of a dienyl alcohol followed by a regioselective epoxide opening with Red-Al. The alkyne coupling partner was obtained via Sharpless asymmetric dihydroxylation, Pu asymmetric alkynylation and Marshall asymmetric alkynylation. Chapter two describes synthetic efforts towards the fully functionalized core of zaragozic acid A, a polyketide natural product that inhibits squalene synthase with potential for treatment of hypercholesterolemia. Our approach to the zaragozic acid core used an aldol condensation, catalytic asymmetric dihydroxylation, and mercury(II)-catalysed cyclisation reactions published by the Marson group. Initial research focused on the construction of an (E)-enynone, the precursor; an aldol condensation and Baylis-Hillman approach failed, but Wittig olefination succeeded. However, catalytic asymmetric dihydroxylation reaction on the enynone did not proceed. Instead, an approach involving Wittig olefination, catalytic dihydroxylation and mercury(II)-catalysed cyclisation afforded a highly functionalised 3-(2H)-furanone ring which underwent catalytic dihydroxylation, providing a totally functionalised precursor of the bicyclic core of zaragozic acid A in 15 steps. Assembly of the core of zaragozic acid A was attempted by several cyclisation procedures which was unsuccessful. Chapter three describes the synthesis and evaluation of tripeptide organocatalysts in asymmetric synthesis. The aim was to develop a short, flexible and resin-free synthetic route to a peptidic catalyst and to evaluate it in asymmetric Michael, Henry and Baylis-Hillman reactions. The catalyst H-Pro-Pro-Asp-NH2 was successfully prepared by solution-phase synthesis and gave satisfactory ee's with aldol and Michael additions, but was not effective in the asymmetric Baylis-Hillman and Henry reactions studied