Historically, CI toxins have been constructed by patterning the retrosynthetic analysis on the presumed biogenesis , wherein an acyclic structure with maximum functionality is subjected to macrocyclization . This pioneering approach was first accomplished by Kishi et al. in the 1998 total synthesis of pinnatoxin A . In the case of the portimines, approaches thus far have followed this dogma (21-24). Thus, Brimble et al. and Harran et al. (24) aimed for a bio-inspired synthesis that mimics the polyketide synthases (PKSs), featuring bold intramolecular cyclizations of densely functionalized polyketides 3 and 4 respectively (Fig ). The former approach demonstrated that the ketalization of linear 3 was not facile, even with the well-functionalized skeleton. The latter cycloaddition-based approach resulted in undesired regioselectivity in the pivotal cyclization of 4 to 6. The difficulty encountered in these routes points to the challenge of forging key bonds in such a densely functionalized polycyclic alkaloid from an acyclic precursor. From a high level, this scenario is not unlike that encountered in the synthesis of densely functionalized, highly oxidized terpene natural products. In those cases, it has been shown that a two-phase approach to synthesis can be beneficial by building up a minimally oxidized carbon framework followed by strategic late-stage oxidations .