Azaspiracid-1, a novel marine toxin that contains 9 rings and 20 stereogenic centers, has drawn considerable attention from synthetic groups worldwide due to its structural complexity, which includes a unique trioxabisspiroketal fused to a tetrahydrofuran ring (ABCD rings), a piperidine-tetrahydrofuran spiroaminal system fused to a 2,9-dioxabicyclo[3.3.1]nonane system (FGHI rings), a connecting six-membered cyclic hemiketal bridge (E ring) and a ��,��-unsaturated terminal carboxylic acid side chain. Our efforts toward the total synthesis of azaspiracid-1 led to the completion of both C1-C26 northern and C27-C40 southern halves of azaspiracid-1. Herein, our improved and scalable synthetic studies toward the total synthesis of azaspiracid-1 is described. In particular, an improved and scalable synthesis of sulfone 3.6 with a key one-pot ketalization and methylation of ketone 3.22 to methylated hemiketal 3.24 is illustrated. A total 19 mmol of sulfone 3.6 has been prepared by this approach. An improved and scalable synthesis of aldehyde 3.7 utilizing allyl bromide 3.31 to couple with Evans auxiliary 3.33 has been developed. A total of 10 mmol of aldehyde 3.7 has been prepared by this approach. An improved synthesis toward the ABC ring fragment 3.52 with a high yield Julia coupling step is shown. Large scale improved syntheses of the linkage fragment 3.2, the aldehyde fragment 4.9 and the azide fragment 4.10 of the southern portion of (���)-azaspiracid-1 have been described. With an abundant material prepared by this scalable improved approach, we are confident that completing the total synthesis of (���)-azaspiracid-1 will occur in the near future. / Graduation date: 2013

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).