The prostaglandins (PGs) are a class of natural products that have enjoyed unparalleled popularity among the chemical and biological community over the past century. The diverse endogenous functions of these fatty-acid-derived metabolites have provoked the pursuit of their chemical synthesis, culminating in the laboratory production of various natural and designed prostanoids, and the development of several landmark synthetic methodologies. Among the large family of PGs, a subclass known as the alkylidene-cyclopentenone prostaglandins (acyPGs) has been increasingly recognized for their prominent anticancer activities. In particular, Δ12-prostaglandin J3 (Δ12-PGJ3), a recently added member of the family, was reported to be effective in the in vitro and in vivo eradication of leukemia stem cells (LSC). This anti-LSC potency of Δ12-PGJ3 might represent a new solution in combating cancer recurrence, and therefore warrants systematic investigation into its structure–activity relationship (SAR). Thus, in Chapter 1, we described the synthesis of two key structural components of Δ12-PGJ3 — the cyclopentenone fragment (via a novel chiral lactone synthon), and the β-siloxyaldehyde fragment (via an asymmetric Keck allylation). The developed synthesis has enabled the preparation of dozens of analogs, including 15-deoxy-15-fluoro-Δ12-PGJ3 through a late-stage deoxyfluorination strategy. Biological evaluation of the synthesized compounds revealed that this “OH F” exchange at C15 was moderately beneficial for cytotoxicity improvement, presumably as a result of the increased lipophilicity and metabolic stability of the fluorinated analog. Chapter 2 describes our synthesis toward bis-tropolone cytotoxin gukulenin A. Historically, tropolone and its derivatives have been studied for their antitumor effects; and, as potent metal chelators, these aromatic structural motifs also carry great potential in material science and ligand development. However, research into tropolone-containing compounds has been hampered by their capricious chemical behavior and the inefficiency in derivatizing the aromatic backbone. In our quest toward the total synthesis of gukulenin A, we pioneered a “sequential tropolone functionalization” strategy in which the peripheral substituents were successively introduced in a regioselective manner. Our synthesis has not only furthered our knowledge in tropolone chemistry, but also provided a modular platform for the rapid generation of gukulenin analogs.