A synthesis of pectenotoxin 2 (PTX-2), a cytotoxic polyether macrolide of marine origin, is proposed. Initial screening of pectenotoxin 2 has revealed high cytotoxicity against a range of cancer cell lines, with LC50's typically in the 8-50 nM range. Unfortunately, the isolation of pectenotoxin 2 from natural sources is both tedious and low-yielding, and the resulting scarcity of this compound has prevented further biological characterization. A convergent total synthesis of pectenotoxin 2 would not only provide material for such testing, but would also permit the construction of non-natural analogs. Evaluation of these analogs could allow for the identification of those PTX-2 substructures required for bioactivity, and could also lead to the development of novel cytotoxic agents. The proposed synthesis of pectenotoxin 2 is highly convergent, providing for the construction of the target compound from five separate fragments. These fragments are synthesized in short sequences of 5-14 steps, and thus should be available in large quantities. Once in hand, the fragments are coupled using a combination of novel and known methods. The novel methodology proposed for the synthesis of the furanone and bridged bicyclic ketal subunits of PTX-2 involves the acid- mediated cyclization of a silyl enol ether or a vinyl silane onto an acetal-based electrophile, and should allow for the efficient and stereoselective construction of these moieties. These cyclizations extend the work of Overman and coworkers to new systems, and should be applicable to the synthesis of other natural products as well.
