Marine ladder polyether natural products exhibit potent antitumor and antifungal activity;however, the isolation of these complex targets from natural sources has proven difficult. Current methods for the synthesis of marine ladder polyethers involve the iterative construction of each fused ring system, resulting in lengthy and inefficient approaches. More direct methods are necessary to provide researchers with significant material for medicinal studies. Therefore, the long term goal of this research project is to develop an efficient biomimetic approach to polyether synthesis by employing regioselective epoxide-opening cascades. Recent studies by the Jamison group have indicated that regioselective epoxide-openings (6-endo) are limited to systems in which there is a tetrahydropyran-directing group appended to the reacting partners (i.e., hydroxyl group and epoxide). The influence of other templating groups on these cascade events is not well understood, thus precluding the direct application of this methodology towards the synthesis of structurally-diverse natural products. The objective of this application is to expand the scope to which template diversity is tolerated in epoxide-opening cascades, and to develop tandem processes to expedite the synthesis of these targets by incorporating the formation of a template and subsequent epoxide-opening cascade into a single synthetic step. The first specific aim focuses on the synthesis and subsequent epoxide-opening cascades of model systems with varying template ring size. This study provides a correlation between template ring size and the regioselectivity of epoxide-opening events, with the goal of developing a predictive model. The focus of the second specific aim is to develop a tandem process, which combines template formation and subsequent epoxide-opening into a single synthetic step. This allows for rapid access to the core of marine ladder polyether natural products from readily accessible starting materials. Lastly, the third specific aim provides insight into the scope of this methodology, as it is applied to the F-J ring fragment of gambieric acid A. These specific aims serve to increase the efficiency of marine ladder polyether synthesis, a necessary step for the discovery of new medicinal agents. PUBLIC HEALTH RELEVANCE: Marine ladder polyether natural products are associated with harmful red tide events, and are responsible for massive fish death and subsequent human poisoning worldwide. While the negative impacts of this class of compounds are obvious, their medicinal properties are not as well understood. The inability to isolate significant quantities of material inhibits the research of marine toxins as therapeutic agents, and thus the chemical synthesis of these natural products is a necessary step to provide material for medical research.