Total synthesis of brevetoxin A: Part 2: Second generation strategy and construction of EFGH model system

Our second generation strategy for the total synthesis of brevetoxin A invo lved dissection of the molecule at the ring F oxocene. Synthetically, the F ring formation was expected to occur through Wittig coupling of requisite polycyclic fragments 2 and 3, followed by a hydroxy dithioketal cyclization , In order to test this synthetic plan, model phosphonium salt 9 and aldehy de 10 were successfully synthesized and coupled. The deprotected. product ( 46) was shown to undergo an efficient hydroxy dithioketal cyclization and t he product (47) was selectively reduced to the EFGH ring system of brevetox in A (8), The synthesis of phosphonium salt 9 utilized our cyclic ketene ac etal phosphate methodology and a [4+2] addition of singlet oxygen to genera te intermediate endoperoxide 11. The success of this model study facilitate d a synthetic plan to form and functionalize ring E nonacene and ring F oxo cene for the total synthesis of brevetoxin A.