The Nakanishi hypothesis for the biogenesis of the brevetoxin natural products features a dramatic series (cascade) of epoxide-opening reactions, elegantly accounts for the structural and stereochemical features of all related “ladder” polyethers, and in principle significantly simplifies the synthesis of these extraordinarily complex molecules. In practice, however, the cascade is strongly disfavored, and the traditional approach to overcoming this inherent problem involves the use of non-natural “directing groups” that must be covalently attached to each epoxide. We will discuss several types of high-yielding cascades that avoid this approach, rendering the cascades much more efficient and general, and are also consistent with the Nakanishi hypothesis. The two salient aspects of these “directing-group-free” strategies are a single design principle (a template) and a promoter that both donates and accepts hydrogen bonds. Water (H2O) itself is the superior promoter, and it is most effective at approximately pH 7.