Studies in cyclic ether synthesis: Part one: Domino cyclisations to cyclic ethers -- Part two: Synthetic studies towards neopeltolide

Abstract

Tetrahydrofuran (THF) and tetrahydropyran (THP) rings are commonly found in a wide range of natural products and biologically active compounds. In total synthesis, the formation of THF/THP motifs is often the key step but existing methods often involve numerous steps and low overall efficiencies. Part one of this thesis details the development of a practical method for the synthesis of THF rings by the controlled mono-addition/cyclisation of organolithium species to C2-symmetric diepoxides (Scheme A-1). This method can also be applied to the synthesis of bis-THF rings from triepoxides and has potential applications in more complex cascade reactions. A similar cyclisation process providing THF rings from epoxyaldehydes is also described.Part two of this thesis details our efforts towards the synthesis of the marine macrolide neopeltolide. Wright and co-workers reported the isolation of neopeltolide 211 from a deep-water sponge of the family neopeltidae off the north coast of Jamaica. The structure, which was assigned by NMR and HRMS studies and reassigned by total synthesis, contains a 14-membered macrolactone, a 2,6-cis THP ring and an unsaturated oxazole side-chain. Chapter four describes the synthesis of the C2-C8 and C9-C16 fragments (Scheme A-2). Chapter five details our initial attempts in the coupling of subunits 268 and 320, as well as a revised synthetic strategy that allowed us to successfully couple C2-C9 alkyne 347 with C10-C16 aldehyde 348 and the preparation of an advanced intermediate 364 (Scheme A-3).