Total synthesis of brevetoxin A: Part 4: Final stages and completion

The total synthesis of brevetoxin A is described, Our methodology of pallad ium-catalyzed couplings with cyclic ketene acetal phosphates was utilized t o functionalize nine-membered ring lactone 4 followed by a [4+2] singlet ox ygen addition to the resulting 1,3-diene (6), The product endoperoxide (7) was transformed into coupling partners 3a and 3b to be reacted with aldehyd e 2, Our first attempted union of 3a and aldehyde 2 failed, most probably d ue to steric hindrance, which led us to explore other olefination coupling reactions. Horner- Wittig type coupling was found to be successful on advan ced model systems: diphenylphosphine oxides 21 and 28 were each coupled wit h aldehyde 2. Key intermediates 3b and 2 were successfully coupled and ring F oxocene (44) was cyclized through the hydroxy dithioketal cyclization me thodology, The final manipulations were then executed to complete the first total synthesis of brevetoxin A.