Total synthesis of brevetoxin A: Part 1: First generation strategy and construction of BCD ring system

Discussed herein is our first generation strategy for the total synthesis o f brevetoxin A. This approach relies upon dissection of the molecule at the nine-membered ring site (ring E), A Wittig coupling of requisite polycycli c fragments 3 and 4 followed by hydroxy dithioketal cyclization was expecte d to furnish the polycyclic framework of brevetoxin A (1). Intermediate 8 w as anticipated to be a valid synthetic precursor to phosphonium salt 3, and its synthesis was accomplished by a bis(lactonization)/thionolactone forma tion/functionalization sequence. In order to test our synthetic strategy, t he synthesis of an advanced model system (36) was attempted. Aldehyde 38 an d phosphonium salt 37 were successfully synthesized and coupled through a:W ittig reaction. Unfortunately, the planned hydroxy dithioketal cyclization to form the crucial nonacene (ring E) did not proceed as anticipated and th is synthetic approach was discontinued.