The ability to generate structurally complex molecules plays an important role in the discovery and development of drugs. The research presented in this thesis describes three different approaches to the synthesis of complex natural products and libraries of related compounds. Eleutherobin is a marine natural product originally isolated from an Eleutherobia species of soft-coral, demonstrating potent (low nM) in vitro activity as a microtubule-stabilizing agent. We developed the shortest synthesis of eleutherobin (20 linear steps) as well as the closely related natural product sarcodictyin B (15 linear steps). Rapid access to the eleutherobin aglycon also allowed us to produce the first library of synthetic eleutherobin carbohydrate analogues via multiple glycosylation strategies. The analogues were tested against cancer cells and highlighted the importance of eleutherobin’s β-D-arabinose sugar, plus we identified the extraordinary potency of the sarcodictyin B methyl ketal. In an effort to probe the chemical space bounded by a privileged class of marine natural products, we generated a complex library of tetrahydrofuran-containing polyketide-like macrolides. The library comprises 170 polyketide-like macrolides originating from 17 building blocks, 10 of which were synthesized using a proline-catalyzed α-chlorination aldol reaction. Northern and southern hemisphere building blocks were coupled using either an oxidation/Horner-Wadsworth-Emmons sequence or an oxidation/Steglich esterification strategy. Coupled fragments were cyclized via ring-closing metathesis to yield macrocycles 14-16 atoms in size, which we diversified using 3 eastern side chain vinyl iodides through a Nozaki-Hiyama-Kishi reaction. The utility of the library was validated by the identification of diverse bioactivity in biological assays. Finally, in a project focused on the development of new synthetic methods, we leverage non-covalent interactions to accelerate hydrogen atom abstraction using the decatungstate (DT) photocatalyst. We identified co-catalysts that accelerate the reaction rate of DT-catalyzed fluorination, with the eventual aim to promote site-selectivity and the generation of compound libraries from a single late-stage intermediate.